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Proceedings of a Workshop WORKSHOP OVERVIEW1 Social factors such as the conditions in which people are born, grow,work, live, and age; their education and income; and many other elementscan influence their likelihood of developing cancer, the type of cancer, thecancer stage at diagnosis, the quality of care they receive, and their healthoutcomes. While the complex interactions among these factors, known as thesocial determinants of health (SDOH),2 can make it difficult to identify andquantify their biological consequences, researchers are beginning to pinpointbiological mechanisms through which social factors influence health and dis-ease and elucidate how identifying and addressing social risk factors along thecancer care continuum could improve patient outcomes. 1 This workshop was organized by an independent planning committee whose role waslimited to identification of topics and speakers. This Proceedings of a Workshop was preparedby the rapporteurs as a factual summary of the presentations and discussions that took place atthe workshop. Statements, recommendations, and opinions expressed are those of individualpresenters and participants and are not endorsed or verified by the National Academies ofSciences, Engineering, and Medicine, and they should not be construed as reflecting anygroup consensus. 2 According to WHO, social determinants of health are the nonmedical factors that influ-ence health outcomes. They are the conditions in which people are born, grow, work, live, andage and the wider set of forces and systems shaping the conditions of daily life. These forcesand systems include economic policies and systems, development agendas, social norms,social policies, and political systems. https://www.who.int/health-topics/social-determinants-of-health#tab=tab_1 (accessed July 3, 2024). 1 PREPUBLICATION COPY—Uncorrected Proofs

2 BIOLOGICAL EFFECTORS OF SDOH IN CANCER To examine the complex interactions among biological variables andSDOH, and opportunities to mitigate the negative impacts of social factorson cancer-related health outcomes, the National Cancer Policy Forum ofthe National Academies of Sciences, Engineering, and Medicine hosted aworkshop on March 20–21, 2024, that brought together participants withbackgrounds in clinical care, cancer research, health care policy, patient advo-cacy, and related areas. This Proceedings of a Workshop summarizes the issuesdiscussed and highlights observations and suggestions made. Those from indi-vidual participants are discussed throughout the proceedings, and highlightsare presented in Boxes 1 and 2. (Box 1 lists observations on the relationshipsbetween SDOH, cancer, and health care biological effectors of SDOH, andBox 2 outlines potential strategies for integrating SDOH into cancer researchand care.) Appendixes A, B, and C provide the workshop Statement of Task,agenda, and poster session participants, respectively. Speaker presentations,poster presentations, and the workshop webcast have been archived online.3 Chanita Hughes-Halbert, associate director for cancer equity and pro-fessor of public and population health sciences at the University of SouthernCalifornia, provided context for the discussions by defining cancer healthdisparities, which she said are differences in both cancer risk and outcomesthat are linked to social, economic, or environmental variables associated withdisadvantage, such as race, ethnicity, socioeconomic status (SES), gender, andlocation. She noted that as the understanding of cancer health disparitiesexpands, researchers are increasingly examining the role of these SDOH whilealso striving to create social, physical, and economic environments that enableeveryone to attain their full potential for health and well-being, includingthrough the objectives articulated in Healthy People 2030.4 Hughes-Halbert posited that a holistic, multilevel perspective can enabletransdisciplinary teams to address the complexities of the impact of SDOHon health disparities (see Figure 1) (NIMHD, 2018). She noted that research-ers are increasingly able to link social factors to health disparities, such as thehigher rate of hormone receptor-negative breast cancer among Black womencompared to White women (Linnenbringer et al., 2017). She suggested that itwill be useful for researchers to continue examining this complex web of issuesto create paradigm-shifting, transformational, multi-perspective approachesthat both identify and mitigate cancer health disparities, from basic researchto strategic implementation (Dankwa-Mullan et al., 2010). 3 See https://www.nationalacademies.org/event/41369_03-2024_biological-effectors-of-social-determinants-of-health-in-cancer-identification-and-mitigation-a-workshop (accessedJune 24, 2024). 4 See https://health.gov/healthypeople (accessed May 22, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 3 National Institute on Minority Health and Health Disparities Research Framework * blank Individual Interpersonal Community Societal Community Illness Sanitation Biological Vulnerability Caregiver–Child Interaction Biological Exposure Immunization and Mechanisms Family Microbiome Herd Immunity Pathogen Exposure Health Behaviors Family Functioning Behavioral Community Functioning Policies and Laws Coping Strategies School/Work Functioning (Over the Lifecourse) Physical/Built Household Environment Community Environment Personal Environment Societal Structure Environment School/Work Environment Community Resources Sociodemographics Social Networks Community Norms Social Norms Sociocultural Limited English Family/Peer Norms Local Structural Societal Structural Environment Cultural Identity Interpersonal Discrimination Discrimination Discrimination Response to Discrimination Insurance Coverage Health Care Patient–Clinician Relationship Availability of Services Quality of Care Health Literacy System Medical Decision-Making Safety Net Services Health Care Policies Treatment Preferences Family/ Community Population Health Outcomes Individual Health Organizational Health Health HealthNational Institute on Minority Health and Health Disparities, 2018*Health Disparity Populations: Racial and Ethnic Minority Groups (defined by OMB Directive 15), People with Lower Socioeconomic Status,FIGURE 1 Research framework for understanding how factors at the individual, inter- Underserved Rural Communities, Sexual and Gender Minority Groups, People with Disabilities Other Fundamental Characteristics: Sex and Gender, Disability, Geographic Regionpersonal, community, and societal levels influence health outcomes.NOTE: Health disparity populations: racial and ethnic minority groups (defined byOMB Directive 15),a people with lower socioeconomic status, underserved rural commu-nities, sexual and gender minority groups, people with disabilities. Other fundamentalcharacteristics: sex and gender, disability, geographic region.SOURCES: Hughes-Halbert presentation, March 20, 2024; NIMHD, 2018. aSee https://spd15revision.gov/content/spd15revision/en/2024-spd15.html (accessedJuly 17, 2024). “There is room for all of us and all disciplines to be involved in thisresearch to really increase our understanding and ability to drive policy and thedelivery of health care by understanding the contributions of racial and e­ thnicsegregation, the neighborhood environment, psychosocial stressors, psycho-logical distress, the things that we would typically include as part of ourunderstanding and work around SDOH,” Hughes-Halbert emphasized. Stanton Gerson, dean of the Case Western Reserve University Schoolof Medicine, said that residents of distressed communities suffer devastatinghealth effects because “poverty is a carcinogen,” as Samuel Broder famouslysaid in 1989 (ACS, 2011). While an individual’s living conditions can contrib-ute to cancer development, it is important to note that this depends on specificbiological factors. Gerson stressed that it is critical to uncover connections PREPUBLICATION COPY—Uncorrected Proofs

4 BIOLOGICAL EFFECTORS OF SDOH IN CANCERbetween the drivers of SDOH and the biological causes and consequences ofcancer. A range of biological mediators and pathways are associated with ­cancer,including genetics, epigenetics,5 ancestry, allostatic load, stress response,norepinephrine,6 cortisol,7 obesity, ingested and inhaled toxins, reactive oxygen,8and inherited or acquired mutations, Gerson explained, while SODH includea wide range of factors, such as poverty, racism, heat, noise, violence, disrup-tion of sleep and circadian rhythms, environmental exposures, food access, andsmoking. Hughes-Halbert noted that researchers are increasingly demonstrat-ing connections between environmental exposures and health outcomes, suchas finding microplastics in the hearts of patients with cardiovascular disease orlinking chemical exposure to multiple negative health outcomes (Marfella et al.,2024; Woodruff, 2024). HEALTH DISPARITIES AND SOCIAL DETERMINANTS OF HEALTH IN CANCER Several speakers offered context on health disparities in cancer risk, onset,screening, treatment, and response to treatment, along with an overview of therelationships among SDOH, cancer, and health care. Health Disparities in Cancer Approximately 600,000 people die from cancer in the U.S. every year,making it the second leading cause of death, after heart disease (CDC, 2022).Yet, the disease burden is not experienced equally across the population. OtisBrawley, Bloomberg Distinguished Professor of Oncology and ­Epidemiology 5 Epigenetics is the study of how age and exposure to environmental factors, such as diet,exercise, drugs, and chemicals, may change how genes are switched on and off without chang-ing the actual DNA sequence. These changes can affect a person’s risk of disease and may bepassed from parents to their children. See https://www.cancer.gov/publications/dictionaries/cancer-terms/def/epigenetics (accessed July 6, 2024). 6 Norepinephrine, or noradrenaline, is a neurotransmitter and hormone that is released inresponse to stress or low blood pressure. See https://www.cancer.gov/publications/dictionaries/cancer-terms/def/norepinephrine (accessed July 11, 2024). 7 Cortisol is a hormone that “helps your body respond to stress, regulate blood sugar,and fight infections”. See https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=cortisol_serum (accessed July 11, 2024). 8 Reactive oxygen is a free radical (an unstable molecule) that can accumulate in and causedamage to cells. See https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species (accessed July 11, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 5 BOX 1 Observations from Individual Workshop Participants on the Relationships Among SDOH, Cancer, and Health Care • Disparities in cancer screening, treatment, and outcomes are linked with social factors such as belonging to historically marginalized groups, lower socioeconomic status, and racial and economic discrimination and disadvantage, the impacts of which can go beyond the individual to span generations and communities. (Bae-Jump, Brawley, Evans, McCullough) • Where patients live and receive care influences the quality of their care. (Frencher, Gerson, Watson) • Research has linked social determinants of health (SDOH) with clinical outcomes, but an understanding of the specific pathways through which the upstream social context cre- ates downstream health outcomes remains limited, in part because a dearth of data from diverse populations has limited r­esearchers’ ability to deeply understand these complex link- ages. (­Bae-Jump, Carlos) • Biomarkers such as epigenetic changes and extracellular vesicles could provide insights into the connections between SDOH and cancer. (Carlos, Evans, Llanos, Obeng-Gyasi) • Access to biomarker testing is uneven, contributing to care disparities. (Ferris, Vidal) • Electronic health records can enable collecting and acting upon SDOH data but are generally not consistently and effectively utilized for this purpose. (Fayanju, Ferris, Hughes-Halbert) • Sufficient and sustainable funding models are important for incorporating interventions to address SDOH into clinical care and reducing health disparities. (Evans, Winn) • Even as researchers continue to elucidate the downstream biological effectors of SDOH on health outcomes and develop ways to target those mechanisms to intervene, it remains important to address the structural root causes of the inequities that lead to health disparities. (Gottlieb, Hiatt, Llanos, Mbah, McCullough, Tucker-Seeley) NOTE: This list is the rapporteurs’ synopsis of observations made by one or more individual speakers as identified. These statements have not been endorsed or verified by the National Academies of Sciences, Engineering, and Medicine. They are not intended to reflect a consensus among work- shop participants. PREPUBLICATION COPY—Uncorrected Proofs

6 BIOLOGICAL EFFECTORS OF SDOH IN CANCER BOX 2 Suggestions from Individual Workshop Participants on Integrating SDOH into Cancer Research and Care Building Trust and Collaboration • Repair bilateral trust in communities by enabling communities to lead initiatives to address health disparities and ensuring that community members benefit from the research and interventions. (Darien, McCormick, McCullough, Rogers, Winn) • Improve collaboration and communication among researchers from different disciplines and among researchers, clinicians, and com- munities. (Fayanju, Frencher, McCullough, Tucker-Seeley, Winn) • Support training and employment opportunities for community members to participate in navigation, patient advocacy, research, education, and policy. (Cogle, McDonald, Rogers, Vidal) • When asking patients about social determinants of health (SDOH) in clinical settings, explain why the information is being collected and how it will be used; then, follow up to address needs identified dur- ing this process. (Fayanju, Hughes-Halbert, McCullough, Shulman, Smith, Tucker-Seeley) • Discuss and address ethical concerns in biomarker testing to ensure trust and participation from vulnerable communities. (Cogle, McCullough) Improving Data Collection and Analysis • Improve metrics for holistically studying interconnected SDOH to accurately capture meaningful data. (Hughes-Halbert, McCullough, Shulman, Tucker-Seeley) • Develop and implement effective methods, tools, and best practices to coordinate, collect, harmonize, link, and share SDOH data for research and care, and act upon SDOH in clinical care settings. (Bradley, Fayanju, Gomez, Gottlieb, Hughes-Halbert, McCullough, Rogers, Shulman, Tucker-Seeley)at Johns Hopkins University, defined health disparities research as thestudy of why some populations—defined by their gender, race, educationlevel, area of geographic origin or residence, genetic ancestry, SES, or other­factors—­suffer unnecessarily worse health outcomes than others. The concepts of “health equity” and “health justice” relate to efforts focused on combating these health disparities, which affect disease incidence, outcome, mortality, and quality of life. PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 7• Incentivize including diverse populations in clinical trials and studies. (Evans, Mbah, McCullough, Vidal, Yates)Improving Care to Address Social Determinants of Health• Focus on early-life exposures as a critical piece of cancer preven- tion. (Brawley, Fayanju, Llanos, Rebbeck, Seewaldt, Winn)• Ensure equitable access to broadly validated biomarker tests. (­Gerson, Vidal)• Facilitate care coordination among primary care providers and ­specialists to address social needs and better support cancer prevention, screening, and treatment. (Bradley, Darien, Fayanju, Frencher)• Implement interventions that reduce disparities in care access and quality now, even as research continues to elucidate the bio- logical mechanisms linking SDOH with health outcomes. (Brawley, Shulman)Incentivizing Strategies to Improve Health Equity• Utilize existing reimbursement mechanisms for assessing and addressing SDOH and create new mechanisms. (Honig, Lofton, Tucker-Seeley)• Reduce health disparities by implementing payment models that allow clinicians to spend more time with patients. (Brawley, Ferris, Hughes-Halbert, Llanos, Rogers, Seewaldt, Winn)• Advocate for social policies that directly address socioeconomic needs, using biomarker data to highlight the severe impact of social conditions on health. (Cogle, McDonald)NOTE: This list is the rapporteurs’ synopsis of suggestions made by one or moreindividual speakers as identified. These statements have not been endorsed orverified by the National Academies of Sciences, Engineering, and Medicine. Theyare not intended to reflect a consensus among workshop participants. Health disparities researchers often aim to uncover the upstreamf­actors that contribute to differences in disease development, detection, and t­reatment. Brawley emphasized the importance of early-life factors in cancer prevalence, stating that “cancer prevention and health promotion is a pediatric issue.” He noted, for example, that most people who smoke begin in their teens, and eating habits, which can lead to obesity, are learned in childhood. PREPUBLICATION COPY—Uncorrected Proofs

8 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Brawley emphasized that race—a common focus of health disparitiesresearch—is not a biological trait but rather a sociopolitical categorization,which is redefined every 10 years for the U.S. census. Anthropologists and theAmerican Medical Association no longer accept biological definitions of racebecause they imply that certain traits are inherent or immutable and have beenused to harm and dehumanize people in the past.9 However, Brawley pointedout that there are nevertheless areas of intersection between race and health.For example, he noted that a person’s area of geographic origin or geneticancestry, categories that are different from but correlated with race, can influ-ence health outcomes. In addition, certain racial groups are disproportionatelyrepresented among various SDOH, such as income level (Semega et al., 2019). Methods to address health promotion and disease prevention are criti-cal, Brawley explained, because this is where the spectrum of disease controlbegins, followed by screening, diagnosis, and treatment. He posited that theemphasis on diagnosis and treatment over prevention or risk reduction in theU.S. health care system has contributed to health disparities. For example,almost half of U.S. cancer mortality is attributable to known external riskfactors, such as smoking or obesity, that are related to SDOH factors, such asrace, education, and gender (Islami et al., 2018). In addition, extrinsic envi-ronmental factors can influence genetic markers and disease behavior, blurringthe contributions of biology and health disparities to disease and making it dif-ficult to determine why, for example in the U.S., Black women are diagnosedwith triple-negative breast cancer at double the rates of White women (Dietzeet al., 2015; Millikan et al., 2008; Palmer et al., 2014). Brawley characterized providing high-quality care, including preven-tive services, to populations that rarely receive it as today’s most pressing­disease control challenge. For example, people who belong to historically dis­advantaged groups or have lower SES are more likely to receive inadequate care (Crown et. al., 2023). Brawley noted that while Black women have a consistently higher death rate from breast cancer than White women, this disparity emerged only after the implementation of screening, because some po­pulations had less access to screening and follow-up care (Lund et al., 2008; Mandelblatt et al., 2016; van Ravesteyn et al., 2011). SES is particularly associated with care access and quality in the U.S. For instance, people with lower SES are less likely to receive radiation treatment or have access to newer, higher-quality medical equipment (Mattes et al., 2021; Washington et al., 2022). Treatment disparities also stem from cultural differences, comorbidi- ties, lack of insurance or transportation, and racial or economic discrimination 9 See the American Medical Association policy H-65.953 https://policysearch.ama-assn.org/policyfinder/detail/racism%20social%20construct?uri=%2FAMADoc%2FHOD.xml-H-65.953.xml (accessed June 27, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 9(Lannin et al., 1998). Overall, Brawley stated that equitable treatment doesnot exist in the United States (NASEM, 2024). He stressed that solutions doexist, citing research estimating that making evidence-based prevention andtreatment programs accessible to all could save more than 100,000 U.S. livesevery year (Siegel et al., 2018). Defining Social Determinants of Health Reginald Tucker-Seeley, principal and owner of Health Equity Strategiesand Solutions, pointed out that in the United States, adverse SDOH are dis-proportionately distributed across race, ethnicity, SES, and other groupings.These maldistributions are shaped by interrelated social, economic, and envi-ronmental factors; affect health equity; and can be altered through informedaction (Braveman and Gottlieb, 2014; Krieger, 2001a; NASEM, 2017). The health care ecosystem is improving its understanding and conceptu-alization of SDOH and their links to poor health outcomes, social risks,10 andsocial needs,11 Tucker-Seeley explained. Addressing SDOH can reduce healthcare costs and improve efficiency, he stated, because while they may be beyondthe traditional realm of health care, they substantially influence health, healthbehaviors, and health care access and navigation. Frameworks, such as HealthyPeople 2030, that organize SDOH into separate domains can inform effortsto measure and address them. Healthy People 2030 organizes SDOH accord-ing to five domains: economic stability, education access and quality, healthcare access and quality, neighborhood and built environment, and social andcommunity context (ODPHP, 2020). Research into the associations between adverse SDOH and cancer outcomesshows that people living in areas with fewer resources have lower screeningrates, and those who live with financial insecurity and/or belong to h ­ istorically­marginalized groups experience substantial challenges in accessing health care (Islami et al., 2022). Adverse SDOH can manifest as food insecurity, lack of transportation, and social isolation. Individuals with these social needs fare worse across the cancer care continuum, from prevention to detection, diagnosis, survi- vorship, and end-of-life care (Tucker-Seeley, 2021), and research has shown that SDOH related to premature aging can have a particularly significant impact on mortality (Brady et al., 2023; Mode et al., 2016; NASEM, 2020). 10 Social risks are “specific adverse social conditions associated with poor health, such associal isolation or housing instability” (Alderwick and Gottlieb, 2019). 11 Social needs are “self-reported patient social care needs that are impacting the patient’shealth, ability to participate in research, and how the patient is navigating cancer care”(Tucker-Seeley and Shastri, 2022). PREPUBLICATION COPY—Uncorrected Proofs

10 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Tucker-Seeley noted several recent efforts to address the links betweenSDOH and patients’ social needs, health, and health care-related outcomes,such as a consensus report on Integrating Social Care into the Delivery of HealthCare: Moving Upstream to Improve the Nation’s Health (NASEM, 2019). Thereport examined opportunities to integrate services to address social needsinto health care delivery and highlighted potential actions to describe andassist with social needs, adjust clinical care to accommodate social needs,and align health care delivery with other community resources. Tucker-Seeleyalso pointed to another study that suggested methods to screen patients forsocial needs, navigate patients to appropriate services, and evaluate the impactson patient outcomes (Taira et al., 2023). Tucker-Seeley noted that programs to address social needs can be helpfulif they include strategies to ensure that efforts are consistent and sustainable.However, he cautioned that they do not typically address systemic conditionsthat lie outside the realm of health care but are nevertheless relevant to dis-ease risk (Castrucci and Auerbach, 2019). “Health care navigators and similarenhancements to health care can’t actually change the availability of resourcesin the community,” he stated. “They can’t raise the minimum wage, increasethe availability of paid sick leave, or improve the quality of our educationsystem. These are the systemic changes that are necessary to truly address theroot causes of poor health.” Financing efforts to address social needs presents another challenge.Tucker-Seeley suggested greater use of Z codes from the International S­ tatisticalClassification of Diseases and Related Health Problems (ICD-10)12 that arerelevant for capturing SDOH. He noted that while Z codes can also enhanceclinicians’ and health care systems’ quality improvement initiatives throughimproved data collection and analysis (CMS, 2023), they are underused, andpayment pathways are unclear (Maksut et al., 2021). Tucker-Seeley explained that more work is needed to implement stan-dardized, well-resourced, sustainable interventions for the communitiesthat need them most. To create fair and just opportunities for people tobe as healthy as possible and access high-quality health care, he urged afocus on reimagining and implementing multi-sectoral collaborations thatserve ­organizations, patients, and families and inviting input from patients,clinicians, payers, and social service and community-based organizations(­Tucker-Seeley and Shastri, 2022). He challenged workshop participants toconsider what tools an equitable cancer care delivery system needs so thatpatients and families come to expect—and receive—the best quality care. 12 See https://www.icd10data.com/ICD10CM/Codes/Z00-Z99 (accessed June 28, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 11 Connecting Social Determinants of Health with Cancer Risk and Outcomes Lauren McCullough, associate professor of epidemiology at the RollinsSchool of Public Health at Emory University, pointed out that the commonthroughline for all social inequities is the centuries of economic inequities thatmarginalized populations have suffered and that SDOH do not just happenbut are caused by upstream social and institutional inequities. The historical practice of mortgage and housing discrimination knownas “redlining” provides one example. The downstream consequences includeurban neighborhoods with high concentrations of poverty whose residentsexperience disparities in generational wealth, income, and education; inequi-ties in health care access; and poorer health outcomes (Swope et. al., 2022).Redlining has also contributed to residents’ increased exposure to environ-mental toxins in the air, soil, or water—which can cause molecular changesthat have been linked to cancer and are known to affect children as early as inutero (Luo et al., 2017). McCullough also highlighted how a person’s living environment cancontribute to molecular changes linked with racial, ethnic, and gender dis-parities in the incidence and prognosis of obesity-related cancers. She notedthat among women, 8 of the top 10 cancer mortality disparities are related toobesity. Obesity is especially prevalent among Black women (OMH, 2022),and they experience disparities in cancer incidence and prognosis comparedwith non-Black, non-obese people (ACS, 2022). McCullough noted that95 percent of excess cancer deaths among Black women compared to Whitewomen are attributed to three obesity-related cancers (ACS, 2022). Obesityhas other consequences that worsen health outcomes and increase cancer inci-dence, including metabolic dysfunction, insulin and glucose increases, changesin inflammation or immune function, and oxidative stress (Devericks et al.,2022; Lynch et al., 2010). McCullough added that among patients diagnosedwith breast cancer, obesity is associated with diagnosis at a later stage; moreaggressive subtypes; higher mortality rates; and poor treatment outcomes dueto suboptimal dosing, comorbidities, and lower rates of treatment adherence(Matthews and Thompson, 2016; Pierobon and Frankenfeld, 2013; Ross etal., 2019). Noting that the relationships between SDOH and health are complex,McCullough pointed to studies that show the health disparities gap betweenBlack women and White women living in better-resourced neighborhoods isactually greater than the gap between Black women and White women liv-ing in less-resourced neighborhoods, highlighting the influence of structuralracism and discrimination, which affect historically marginalized groups andcreate social isolation and stress, leading to inflammation, hormonal and epi- PREPUBLICATION COPY—Uncorrected Proofs

12 BIOLOGICAL EFFECTORS OF SDOH IN CANCERgenetic changes, and accelerated aging (Collin et al., 2019; Lord et al., 2023).She stressed that the effects of structural racism and discrimination are alsotransgenerational. “It didn’t just start with you,” McCullough said. “It was yourparents and your grandparents and their ancestors […] this can be passed fromgeneration to generation.” McCullough said that the interactions between direct and indirect effectson biology can make the consequences of SDOH difficult to quantify. How-ever, researchers have been able to pinpoint certain SDOH effects on biology,such as associations with DNA methylome13 perturbations in women withbreast cancer, development of late-stage disease, and development of cancersubtypes, with SDOH such as college graduation rates, job density,14 andcontemporary mortgage discrimination (Do et al., 2020; Gohar et al., 2022;Miller-Kleinhenz et al., 2023, 2024). To inform successful interventions, sheemphasized the importance of considering the scientific evidence and indi-vidual SDOH, such as health care access. While research into the relationshipbetween SDOH and carcinogenic processes is growing, she added that morework is necessary to improve health equity, especially research that extendsthe focus beyond neighborhoods, epigenetics, and biological aging (Saini etal., 2019). McCullough offered three suggestions for interventions to improve healthequity. First, she said that it is important for the medical community to repairtrust among marginalized communities and increase their engagement—andbiological sample size in clinical studies—by acknowledging and validatingsystemic challenges that have prevented their inclusion in the past. Second,she suggested that researchers can work to improve SDOH metrics, notingthat current metrics or indices are overlapping, do not clearly distinguishbetween SDOH elements, and may fail to capture positive elements, such associal connectedness or resilience. Finally, McCullough called for improvedcollaboration among researchers with expertise in basic science, populationscience, environmental science, and other disciplines to advance health equity. EMERGING RESEARCH ON POTENTIAL BIOMARKERS RELEVANT TO SOCIAL DETERMINANTS OF HEALTH Recent research has shed new light on the complex interaction of SDOH,cancer risks, and treatment outcomes. Several speakers described some of these 13 DNA methylation is an epigenetic process that regulates the transcription of DNAsegments. The DNA methylome is a record of DNA methylation in an organism (Pelizzolaand Ecker, 2011). 14 Job density is the number of jobs per square mile. See https://www.opportunityatlas.org/ (accessed July 11, 2023). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 13emerging findings and discussed how contextualizing cancer within a patient’sancestry, cultural background, social and economic environment, and livedexperiences can lead to better cancer prevention strategies, earlier detection,and personalized treatment decisions. They pointed to potential biomarkersthat could be used to measure the biological impacts of SDOH, along withchallenges and opportunities in incorporating these measures into care path-ways through biomarker testing. As the research community continues to identify and refine biologicalmarkers of SDOH, Lawrence Shulman, director of the Center for Global­Cancer Medicine at the University of Pennsylvania, urged participants to keep in mind the interconnected nature of factors such as poverty, geography, obesity, and smoking. “They’re not individual, unconnected factors,” he said, “Much of the research that we do is very focused on one factor or another, but we can’t lose sight of the fact that they are, in fact, all interrelated.” Examining the Interplay of Place, Space, and Ancestry Clayton Yates, the John R. Lewis Professor of Pathology, Oncology, andUrology at Johns Hopkins University, discussed the Transatlantic ProstateCancer Consortium,15 which was established to address the globally dispro-portionate burden of prostate cancer among Black men. Yates explained thatthe network of cohort participants and collection sites in Western Africa hasenabled participation in international prostate research collaborations, such asthe International Registry for Men with Advanced Prostate Cancer (Mucci etal., 2022). This registry is collecting information and blood samples to helpunderstand what care strategies offer the best outcomes for men with advancedprostate cancer. Yates and colleagues are working to identify molecular markers correlatedwith disparities in cancer outcomes. He said their research has identified atumor-suppressive signature that was more common among men of Africanancestry, who also have a lower survival rate compared to those with Europeanancestry (Minas et al., 2022). To gain more insight into the links betweenancestry and cancer outcomes, Yates said, transcriptomic data analyses wereconducted to identify which genes were expressed in samples from patients ofEuropean American, African American, or native African (Nigerian) ancestry(White et al., 2022). Yates noted that this study had the most comprehensivecharacterization of the prostate cancer exome16 among Nigerian men andfound that they had a different transcriptional profile. This discovery guided 15 See https://thecaptc.org (accessed September 6, 2024). 16 The exome is the protein-coding portion of the genome. See https://www.genome.gov/genetics-glossary/Exome (accessed July 11, 2024). PREPUBLICATION COPY—Uncorrected Proofs

14 BIOLOGICAL EFFECTORS OF SDOH IN CANCERmore in-depth analyses comparing prostate cancer signatures among AfricanAmerican, Nigerian, and European men. At a cell-population level, they noteddifferences in immune cell populations between African American and Euro-pean American men with prostate cancer. Additionally, Yates said they foundthat the tumors from African American men were enriched for interferon-expressing cells, making them more difficult to treat (Elhussin et al., 2023).Yates said additional analyses were conducted to identify potential gene targetsresponsible for the observed inflammatory signature, which provided a linkbetween the expression of different genes and the resulting tumor-level differ-ences in immune response in patients of different ancestries. Yates said thatthese research approaches identified potential biomarkers that might not havebeen obvious without a large African cohort and could inform future clinicaltherapies, including personalized treatment approaches for native African andAfrican American men with prostate cancer. Noting that White populations living in rural areas are three times morelikely than any group living in urban areas to have poor outcomes from lungcancer, Robert A. Winn, director and Lipman Chair in Oncology at VirginiaCommonwealth University Massey Comprehensive Cancer Center, pointedout that disparities between rural and urban populations illustrate anotheraspect of how place and space influence health. Genomic Pathways Connecting Exposures with Health Outcomes Articulating an overarching goal for “the right patient to receive the righttest and the right treatment at the right time for the right price,” Ruth Carlos,professor of radiology at the University of Michigan, said that accomplishingthis vision may require viewing SDOH in a more nuanced way that incorpo-rates a holistic “society to cells to outcomes” approach. Exogenous and endogenous stressors induce physiological reactions thataffect cell function and disease development, she explained. The physiologyof scarcity—whether of time, food, or other resources—also induces biologi-cal and psychological effects and can have a negative impact on downstreamdisparities and health, she explained. Research has linked SDOH with clinical outcomes, Carlos stated, butthe pathways through which the upstream social context creates downstreamhealth outcomes are still largely unknown (Carlos et al., 2022). Potentialmechanisms include genomic and epigenomic changes, peri-tumor17 envi-ronmental effects, and inflammation from stress responses. Evidence sup-porting these mechanisms includes a study that modeled how inequity in 17 The peri-tumor is the “microenvironment at the interface between healthy and malig-nant tissue” (Zhang et. al., 2023). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 15FIGURE 2 Schematic illustrating the potential for SDOH to pass through generationsvia epigenetic modifications, affecting disease risk across the lifespan.NOTE: mRNA = messenger RNA; FASD = fetal alcohol spectrum disordersSOURCES: Carlos presentation, March 20, 2024; Mancilla et al., 2020.the social environment promotes epigenetic changes that can last from earlychildhood into successive generations, pointing to the potential for the heri-tability of social trauma (see Figure 2) (Mancilla et al., 2020); a study thatlinked paternal SDOH and epigenetic changes with obesity rates of offspring(Milliken-Smith and Potter, 2021); and a study that found an association ofnoise and air pollution with epigenetic changes linked to cancer developmentand regulation (Eze et al., 2020). Although it may be impossible to undo an environmental exposure,Carlos noted that some SDOH and the conserved transcriptional responsesto adversity (CTRA)18 they induce are reversible. For example, the negativeeffects of social isolation, which is correlated with worse health outcomes,could be ameliorated through social, pharmacological, or behavioral interven-tions (Antoni and Dhabhar, 2019; Cacioppo et al., 2015; Knight et al., 2019).In addition, some CTRA are associated with improved well-being, presentingan opportunity to look beyond social risks and focus on social resilience, which 18 Conserved transcriptional responses to adversity is a sustained change in immune cellgene expression profiles in response to environmental conditions (Cole, 2019). PREPUBLICATION COPY—Uncorrected Proofs

16 BIOLOGICAL EFFECTORS OF SDOH IN CANCERCarlos said has been an understudied part of the social context (Boyle et al.,2019; Fredrickson et al., 2015). She pointed out that it is also possible thatCTRA-related gene expression could improve people’s ability to manage socialstress through enhanced wariness or hypervigilance, she said (Cole, 2014). Carlos noted the potential ethical dilemmas inherent in interventionsthat target the genetic effectors of SDOH to solve problems that have beencollectively imposed on a specific group of people. However, she emphasizedthat social genetics, when appropriately aligned with policy and regulationsthat do not further burden populations, can offer a pathway to advancehealth equity. Characterizing Cancer Subtypes and Social Determinants of Health with Population-Based Research Victoria Bae-Jump, professor of gynecologic oncology at the Universityof North Carolina at Chapel Hill, discussed how population-based researchapproaches can help uncover the relationships between SDOH and patterns incancer subtypes. Her research focuses on endometrial cancer, the fourth mostcommon cancer among U.S. women (Siegel et al., 2024). Both the frequencyand mortality rate of endometrial cancer are rising (Siegel et al., 2024; Ward etal., 2019), trends that researchers have linked with increasing rates of obesity,diabetes, and insulin resistance—known risk factors for this cancer type—aswell as with an unexplained rise in more aggressive subtypes (Chia et al., 2007;Siegel et al., 2024). Roy Jensen, director of the University of Kansas Cancer Center, agreedwith Bae-Jump on the strong evidence for an association between endometrialcancer and obesity but noted that most of the biological research on cancerand obesity focuses on the tumor microenvironment and its adjacent adiposecells, which raises questions about the mechanism for this association becauseno adipose cells are near the endometrium. Bae-Jump stated that although thespecific mechanisms are still being investigated, researchers hypothesize thatobesity may create circulating signals that alter systemic factors in the uterusand lead to endometrial cancer. Bae-Jump described significant racial disparities for endometrial cancer;Black and Hispanic women have higher mortality rates, increasing incidencerates, and lower 5-year survival rates than White women (Cote et al., 2015;Siegel et al., 2022). While the exact drivers of these racial disparities areunclear, Bae-Jump posited that they are likely influenced by multiple ­factors(see Figure 3), from historical structural and institutional inequities to SDOH,and known and unknown social and biological factors that culminate in­inequities in cancer screening, detection, diagnosis, treatment, survivorship, and mortality (Warnecke et al., 2008). PREPUBLICATION COPY—Uncorrected Proofs

FIGURE 3 Interacting factors that can contribute to inequities across the cancer care continuum. NOTE: GWAS = genome-wide association studies. SOURCES: Bae-Jump presentation, March 20, 2024; The “Cell to Society” model created by the UNC Lineberger Cancer Center, adapted fromPREPUBLICATION COPY—Uncorrected Proofs Warnecke et al., 2008. 17

18 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Historically, researchers focused on two broad subtypes of endometrialcancer. Type 1 was more common and treatable, and Type 2 was less commonoverall but more common in Black women, more aggressive, and associatedwith lower survival rates (Fowler and Mutch, 2008). With further genomiccharacterization of tumors through The Cancer Genome Atlas (TCGA) pro-gram, researchers identified four distinct molecular subtypes, each with differ-ent treatment pathways and survival rates but all with poorer health outcomesfor Black women (who were not well represented in TCGA, Bae-Jump noted)(Dubil et al., 2018; Kandoth et al., 2013). Determining which molecular subtype of endometrial cancer a patienthas is critical to assigning the appropriate therapy. Recent research has shownthat Black patients develop more aggressive subtypes and have worse progres-sion and outcomes with all subtypes (Weigelt et. al., 2023). The reason forthese differences remains unclear. A significant challenge in endometrial cancerdisparities research, Bae-Jump noted, is the lack of prospective population-based epidemiological studies that link endometrial cancer subtype with race,obesity, related comorbidities, SDOH, care access, and treatment offerings.Other challenges include a dearth of endometrial cancer samples from Blackwomen to conduct large-scale molecular profiling studies and a limited under-standing of how obesity and its related comorbidities affect endometrial cancerprogression and treatment in Black women, she said. Bae-Jump highlighted ways that the Carolina Endometrial Cancer Study(CECS) could help to answer some of these questions. CECS is a population-based prospective study of nearly 2,000 patients with endometrial cancer withthe goal of uncovering how epidemiological factors, SDOH and upstreamdrivers, and tumor biology contribute to racial health disparities. “As we know,these factors have been looked at in their individual silos but really haven’tbeen brought together in one study,” Bae-Jump said, noting that the resultscould inform social, behavioral, and biological interventions. Extracellular Vesicles and Epigenetic Aging Michele Evans, deputy scientific director of the National Instituteon Aging, discussed insights from investigations of the biologic pathwaysthrough which SDOH create health disparities. These investigations arebased on data from Healthy Aging in Neighborhoods of Diversity across theLifespan (HANDLS), an interdisciplinary, community-based, longitudinalepidemiologic study of race, SES, and age-associated health disparities amongnearly 4,000 Black and White adults across Baltimore (Evans et al., 2010).19 19 See https://handls.nih.gov (accessed June 20, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 19 Describing SDOH as agents that change molecular and biological pathways, Evans explained that they create biomarkers such as inflammatory proteins, extra­cellular vesicles (EVs),20 DNA methylation, and circulating cell-free­mitochondrial DNA,21 which are associated with accelerated aging and health disparities. She described the measurement of these biomarkers as “liquid biopsies” that could potentially be used to aid early detection and inform treatment selection and prognosis. She noted that researchers are studying how SDOH influence these biomarkers (Mirza et al., 2023). Studying EVs could also elucidate some of the molecular changes that may lead to cancer development. EVs mediate intracellular communica- tion and contain various forms of RNA, DNA, protein, and lipids (Noren Hooten and Evans, 2020). Mitochondrial DNA could be an important bio- marker of health disparities, Evans noted, as it is released by cells under stresses associated with SDOH, cancer, and other chronic inflammatory diseases (Lazo et al., 2021). Her team’s research into EVs, inflammatory proteins, and poverty revealed that people in worse health, specifically men living below the poverty line, had higher levels of mitochondrial DNA and inflammatory proteins in their EVs (Byappanahalli et al., 2023). Surprisingly, the researchers did not find expected associations with race, which Evans said suggests that ancestry and genomic variation may be more important factors in health and biomarker differences than race (Byappanahalli et al., 2024; Morning, 2017; Wallace, 2012, 2013). Another important factor in health and biomarker differences is epi- genetic age acceleration, which is similar to weathering22 and can be studied via DNA methylation (Brown, 2015). A study of 19 biomarkers of organ system integrity in the HANDLS cohort found that White people living below the poverty level and Black people at all income levels showed acceler- ated e­ pigenetic aging (Shen et al., 2023). This result, Evans said, “hammers home the effects of race-related stressors that lead to poor health and negative health outcomes.” 20 Extracellular vesicles are small, membranous fluid-filled sacs that help move substancesinto and out of cells and are involved in many pathological physiological processes (van Nielet al., 2018). 21 Circulating cell-free mitochondrial DNA are small segments of mitochondrial DNAthat are released by stressed or damaged cells (Lazo et al., 2021). Mitochondrial DNA is thegenetic material of the mitochondria, which produce energy for the cell. See https://www.genome.gov/genetics-glossary/Mitochondrial-DNA (accessed June 30, 2024). 22 The weathering hypothesis states that “the health of African American women may beginto deteriorate in early adulthood as a physical consequence of cumulative socioeconomicdisadvantage” (Geronimus, 1992). PREPUBLICATION COPY—Uncorrected Proofs

20 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Stress and Allostatic Load Several speakers highlighted opportunities to measure and understand therelationship between social stressors and cancer by focusing on allostatic load,which reflects the cumulative effects of chronic stress on the body. Samilia Obeng-Gyasi, associate professor of surgery at The Ohio StateUniversity, investigates the mechanistic pathways that link socio-­environmentalfactors, such as low SES or high rates of social isolation, with breast cancerinitiation, progression, and metastasis (Abdel-Rahman et al., 2019; Bower etal., 2018; Ramsey et al., 2016). She discussed how the conceptual frameworksof ecosocial theory and weathering describe how these factors are internalized. Ecosocial theory proposes that the world one lives in can become physi-cally internalized. Its components include embodiment (how one’s body inter-nalizes socio-environmental factors), embodiment pathways (internal biologi-cal or environmental mechanisms), and the interplay between structural andintermediary health determinants (such as governmental policy, the socialconstruct of race or gender, living and working conditions, and the health caresystem) and disease exposure, susceptibility, and resistance (Krieger, 2001b,2012). Building on Evans’ discussion, Obeng-Gyasi defined weathering as theidea that adverse health outcomes and early health deterioration, for Blackwomen in particular, stem from chronic exposure to racism, sexism, andclassism (Geronimus, 1992). For example, African immigrant women havesubstantially better birth outcomes than U.S.-born women who are racial-ized as Black, despite being of similar genetic background (Agbemenu et al.,2019). Obeng-Gyasi explained that weathering becomes embodied throughstress pathways, which are biological responses to stressful socio-environmental­factors, such as social isolation or financial insecurity, and have multiple over- lapping physiological and molecular impacts (Antoni and Dhabhar, 2019; Cole, 2013; Thames et al., 2019). Allostatic load reflects the physiological and immune dysregulation that occurs with exposure to repeated stress events, failure to adapt to repeated stressors, failure to end a stress response, and inadequate release of stress hormones (IOM, 2001). Obeng-Gyasi described how allostatic load can be measured through biomarkers of primary mediators, such as cortisol or ­epinephrine, or their secondary and tertiary outcomes, such as high blood pressure or diabetes (see Figure 4) (Duong et al., 2017; Seeman et al., 1997). High allostatic load can lead to permanent biological changes, is associ- ated with poor health outcomes (Mathew et al., 2021; Rodriquez et al., 2019; Wiley et al., 2016), and appears to affect every part of the cancer continuum, from initiation to progression, treatment tolerability, metastasis, and ­mortality, Obeng-Gyasi said. Studies have shown that women with breast cancer and high allostatic loads—whether related to residential segregation, limited eco- PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 21FIGURE 4 Allostatic load measured by biomarkers of mediators involved in severalmajor processes that are influenced by stress.SOURCE: Obeng-Gyasi presentation, March 20, 2024; Wiley et al., 2016.nomic opportunities or services, or lower SES—had more comorbidities, ahigher incidence of triple-negative breast cancer, and worse all-cause mortal-ity rate; they were also more likely to be Black, enrolled in Medicaid, and­unmarried (Chen et al., 2024a, 2024b; Obeng-Gyasi et al., 2023). Adana Llanos, associate professor of epidemiology at Columbia Univer- sity, described how research is increasingly connecting higher levels of allostatic load with increased risk of more aggressive tumors and a lower quality of life (Guan et al., 2023; Wang et al., 2024; Xing et al., 2020a, 2020b). Her research team has demonstrated that living in areas of neighborhood divestment or redlining is associated with being underinsured and an increased risk of late- stage diagnosis, higher-grade tumors, greater incidence of triple-negative breast cancer, and lower breast cancer survival rates (Chen et al., 2024a; Plascak et PREPUBLICATION COPY—Uncorrected Proofs

22 BIOLOGICAL EFFECTORS OF SDOH IN CANCERal., 2022). As a possible explanation, Llanos said that the weathering manyBlack women experience from chronic psychological stress results in highallostatic loads, measurable even in childhood and adolescence (Geronimus,1992; Rainisch and Upchurch, 2013). Llanos noted that this could contributeto the higher breast cancer incidence among Black women compared withWhite women (Geronimus et al., 2006; Parente et al., 2013). Because bothBlack women and Black men are likely to have higher allostatic loads, Llanosurged a focus on developing early-life interventions that could help to reducechronic stress before the cumulative impacts begin to build. Researchers are investigating the feasibility of developing a standardized,validated method for calculating allostatic load scores to better understandcancer epidemiology and inequities, Llanos said. Studying the combinedimpact of allostatic load and neighborhood context on breast cancer couldalso shed light on biological mechanisms caused by persistent inequities, sheexplained, suggesting that incorporating SDOH could provide insights atmultiple levels, from biology and disease etiology23 to improve public health(Kehm et al., 2022; McDade and Harris, 2022; Warnecke et al., 2008).“Given these multidimensional, multilevel factors, we need multilevel, multi-dimensional approaches,” Llanos stated. Richard Schilsky, professor emeritus at the University of Chicago, cau-tioned that allostatic load is multidimensional and reflects many differentprocesses and that its use as a biomarker for clinical practice should becontingent on appropriate validation and context. Obeng-Gyasi suggestedthat it could be incorporated into the clinical setting, noting that recentresearch into the feasibility of biological interventions to improve healthoutcomes by reducing a patient’s allostatic load has presented promising earlyresults (OSUCCC, 2022). However, she cautioned that it is important to beaware that some treatment modalities, such as surgery or chemotherapy, canincrease allostatic load. Shulman added that for those who already experiencemultiple stresses, a cancer diagnosis often leads to further stress. Gerson stated that Black people are more likely to live with multipleoverlapping social stressors and that separating ethnicity, race, or ancestry fromthese socioeconomic disease drivers is often challenging for researchers. Headded that it is also a challenge to explain these drivers to the public. High-lighting how the embodiment of historical trauma—the biological effects ofstress and weathering—becomes measurable through allostatic load, ScarlettLin Gomez, professor of epidemiology and biostatistics at the University ofCalifornia, San Francisco, underscored the importance of studies examiningdifferent social epigenetic pathways (Carlos et al., 2022). 23 Etiology is the “cause or causes of a disease.” See https://medlineplus.gov/ency/article/002356.htm (accessed June 30, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 23 Suzanne Conzen, chief of the division of hematology and oncology atthe University of Texas Southwestern Medical Center, discussed emerginglaboratory research on the relationship between social stressors and breastcancer outcomes. Conzen noted that in vitro research demonstrated thatglucocorticoid receptor tumor signaling activation can promote cancer cellsurvival and other pro-oncogenic functions (Moran et al., 2000). Additionally,a meta-analysis found that high glucocorticoid receptor expression in tumorsamples from patients with early-stage breast cancer was correlated with worseoutcomes for women with estrogen receptor-negative breast cancer (Pan et al.,2011). Conzen and colleagues conducted research to see if the physiologicaleffects of social stressors in rodents play a role in cancer biology (Antoni etal., 2006; McClintock et al., 2005; Volden and Conzen, 2013) (see Figure 5). The first model Conzen discussed involved assessing social stressors ingenetically identical female mice with susceptibility to triple-negative breastcancer. Mice were maintained in either group housing or social isolation fromweaning through 15 weeks of age (i.e. through puberty and young adulthood)and examined them for behavioral differences and endocrine responses whenrestrained (emulating a burrow collapse, a common stressful situation in thewild). Socially isolated mice had higher glucocorticoid levels in response togentle restraint, consistent with a maladaptive stress response (Williams et al.,2009). Chronic isolation was also associated with increased triple-negative Social Circumstances Social Environment Psychological StatesNeuroendocrine Changes Malignant Cell Survival Changes in Gene/Protein & Tumor Growth ExpressionFIGURE 5 Center for Interdisciplinary Health Disparities Research multilevel modelfor studying health disparities in breast cancer and its application for understanding thebiology and mechanisms behind tumor growth due to social circumstances in rodents.SOURCES: Conzen presentation, March 20, 2024; adapted from Gehlert et al., 2010. PREPUBLICATION COPY—Uncorrected Proofs

24 BIOLOGICAL EFFECTORS OF SDOH IN CANCERbreast cancer tumor burden in this transgenic mouse model (Williams etal., 2009). The second model Conzen discussed was designed to assess the develop-ment of spontaneous tumors in female rats experiencing social isolation versusgrouped housing, again initiated from weaning through puberty and youngadulthood. Social isolation was associated with earlier-onset and more aggres-sive breast cancer compared to rats who were in group housing from birth(Hermes et al., 2009). The researchers also found that social isolation throughpuberty and early adulthood correlated with impaired mammary gland devel-opment (Johnson et al., 2018) and a higher mammary stem cell population,corresponding to higher corticosterone (a glucocorticoid) reactivity (Johnsonet al., 2018; Johnson, M., forthcoming). Conzen concluded that this research demonstrates that chronic socialisolation versus social support can be modeled in animals to study the impacton cancer in a laboratory setting. The physiologic stress response to social iso-lation includes increased stress hormone production, accompanied by behav-ioral vigilance. Following chronic stress exposure (i.e. social isolation duringpuberty and young adulthood) in genetically predisposed mice and rats, breasttumors in these laboratory animal models appear earlier and are more aggres-sive. Additionally, Conzen said that the effects of chronic stress in late puberty/early adulthood need to be studied further to assess the impact of mammarygland development on breast cancer risk. She noted that ongoing researchwill assess if the biological effects of social isolation (as a model of early lifestressors) can be mitigated by reintroducing group housing during puberty andyoung adulthood in female rats. Equity Implications of Biomarker Testing Defining biomarkers as measurement variables associated with diseaseoutcomes, Gregory Vidal, medical oncologist at West Cancer Center, discussedhow biomarker testing (or a lack of it) can influence cancer care and outcomes,with implications for health equity and health disparities. Certain biomarkerscan be targeted with drugs, and many tumor types and mutations are beingstudied to facilitate the development of new targeted therapies (Hanjie Mo,2021; Vogelstein et al., 2013). The cost of next-generation sequencing (NGS)of a patient’s DNA to find biomarkers has gone down dramatically,24 Vidalnoted, and in many situations, NGS and hereditary germline testing arecovered by the Centers for Medicare & Medicaid Services (CMS). This hasmade it more accessible and affordable for some patients to be tested and more 24 See https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Costs-Data (accessed May 22, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 25likely for them to participate in clinical trials that require certain biomarkers(Sheinson et al., 2021a). Biomarkers can only reduce health disparities if they are implementedequitably, noted Vidal. If certain groups receive less biomarker testing, thenit follows that they may be less likely to participate in clinical trials or receiveoptimal treatment. Not all insurance companies cover biomarker testing,and not all health care organizations can afford to offer it. Despite an overallincrease in biomarker testing, one study found that Black patients were beingtested at lower rates than White patients for many cancers, which also affectedtheir representation in clinical trials for new therapies (Bruno et al., 2022).Studies have also revealed testing disparities for those who lived in the South,enrolled in Medicaid, or older (Sheinson et al., 2021b). Investigating these testing inequities further, Vidal and colleagues foundthat at the practice level, White patients with lung cancer received more timelytesting than Black or Latinx patients (Vidal et al., 2023). Many clinicians whosee mainly Black or Latinx patients were also less likely to offer testing (Vidalet al., 2024). The same racial disparities are seen in germline testing (Kurian etal., 2023). In response to these findings, Vidal’s clinic mandated that all patientsundergoing first-line treatment for metastatic cancer receive NGS. They foundthat testing and clinical trial participation rates increased because this newpolicy reduced confusion over who met screening criteria and eliminated theimpacts of any clinician bias. The clinic also established a tumor board to­recommend clinical trials and treatment decisions to clinicians (VanderWalde et al., 2020). Vidal said that both steps reduced racial disparities, and the clinic now has a much higher percentage of patients who are Black, older, or female enrolled in clinical trials. Based on these results, Vidal suggested that other institutions create systemic NGS and germline testing plans to take the decision out of the hands of clinicians and reduce the impact of bias (Subbiah and Kurzrock, 2016, 2023) and that continuing medical education focused on NGS could help clinicians become more educated about its usefulness. Gerson added that policies mandating full coverage for biomarker testing could also help to address inequities. Karriem Watson, chief engagement officer at the National Institutes of Health (NIH) All of Us Research Program,25 highlighted the importance of access to care in influencing many aspects of a person’s cancer trajectory. Where patients live, where they receive their health care, and where clinical trials are undertaken all affect the care they receive. Watson noted that patients who receive care in community clinics are frequently excluded from clinical trials and suggested diversifying where they are conducted. For example, they 25 See https://allofus.nih.gov (accessed July 11, 2024). PREPUBLICATION COPY—Uncorrected Proofs

26 BIOLOGICAL EFFECTORS OF SDOH IN CANCERcould be expanded to include federally qualified health centers, which carefor many underrepresented groups—who have the greatest burden of healthdisparities. Watson added that, to support equity, it is important for clinicalresearch staff to reflect patient diversity, especially for those with the greatestburden of health disparities. Andrea Ferris, president and chief executive officer of the LUNGevityFoundation, described how some of these issues are playing out in lungcancer. Lung cancer has been at the forefront of precision medicine, asresearchers have pinpointed various disease drivers and developed targetedtherapies and care pathways. However, despite the availability of tests todetect the known drivers, Ferris said that precision medicine care pathwaysare not being implemented effectively or equitably. Many patients are simplynot receiving the tests that could inform targeted treatment decisions. Thismay be due to a number of factors, including reimbursement policy, over-whelmed clinicians, and lack of effective strategies for incorporating thesetests into clinical workflows. Ferris expressed doubt that new knowledgegenerated through research will have a real impact on patients without betterimplementation strategies. Building on these points in the context of research aimed at identifyingbiomarkers relevant to SDOH, Christopher Cogle, professor of medicine atthe University of Florida and chief medical officer for Florida Medicaid, cau-tioned that laboratory tests are useful only if they inform interventions. Giventhe amount of evidence already available, he asked, “Why do we need a geneexpression [test] to tell us that we need to focus on social needs?” Cogle notedthat biomarker testing should not be used to validate socioeconomic issues,rather they should be used as tools to inform policy to address socioeconomicneeds. He cautioned that it is essential to ensure investments in biomarkertesting do not divert attention and resources from necessary social reforms.Cogle posited that while currently SDOH biomarkers are not meaningfullyinforming care, they may do so in the future. Cogle agreed with other ­speakerswho noted that frequent surveys could be burdensome for patients, but heexpressed skepticism that replacing in-person conversations about social needswith blood tests or cheek swabs—which may be seen as easier for many­clinicians—would actually benefit patients. He suggested that an area with more promise may be public health surveillance. For example, he suggested that strategies such as testing sewage or air pollution levels could be leveraged to guide precision social health initiatives that are informed by biomedical evidence and targeted to areas with the greatest need. PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 27 OPPORTUNITIES FOR HEALTH CARE SYSTEMS TO ADDRESS SOCIAL RISK FACTORS Many SDOH and health-related social needs extend beyond the areasthat have traditionally been within the purview of health care systems. Severalparticipants discussed the relevance of SDOH to care delivery, gaps in cur-rent practice that can lead to inadequate attention to social risk factors, andopportunities and considerations to better integrate SDOH into the cancercare continuum. Recognizing the Influence of Upstream Factors on Health Throughout the workshop, many participants highlighted the impor-tance of upstream factors affecting a person’s health and the care they receive.Even as researchers elucidate the downstream biological mechanisms that con-nect SDOH with health outcomes—and potentially find ways to target thosemechanisms to intervene—a number of speakers cautioned that it remainsimportant to address the root causes of the inequities that lead to health dispari-ties. Laura Gottlieb, professor of family community medicine at the ­Universityof ­California, San Francisco, pointed out that even if scientists invented a pillthat blocks the biological effects of racism, including the allostatic loads thatworsen cancer outcomes, it would not address the social needs patients andcommunities face. “This is an ethical dilemma that I think really challenges theentire research endeavor in this space or around biomedical research. […] All ofus have to be grappling with it constantly, and as we do the downstream work,we also have to be doing the upstream work,” Gottlieb said. Tucker-Seeley pointedly asked, “How much of the causal pathway dowe need to explicate before we all believe that systemic racism is the driverthat has sorted specific groups into these adverse circumstances, which havedetrimental effects on their health?” He added that if racism is a key driver, itmay be necessary to explore multilevel, multifactorial interventions—in healthcare and policy—that address historical harms, dismantle systemic racism, andimprove SDOH. Shulman reiterated that many of the factors that appear to be linkedwith health disparities (e.g., divested neighborhoods, challenges with healthcare access, epigenetic changes, and stress responses) are interrelated and stemfrom economic disparities. Llanos, Robert Hiatt, associate director of popula-tion sciences at the University of California, San Francisco, and Olive Mbah,senior health equity scientist at Flatiron Health, added that much of theresearch examines individual interventions—behavioral, dietary, therapeutic,and so on—that improve outcomes or prevent cancer development but sug-gested that focusing more on structural drivers at the population level could PREPUBLICATION COPY—Uncorrected Proofs

28 BIOLOGICAL EFFECTORS OF SDOH IN CANCERyield greater impacts. Llanos suggested that changes to health care reimburse-ment structures could help to reduce care inequities, and Hiatt pointed tothe importance of focusing on alleviating the impacts of persistent poverty.Although many SDOH connected with poverty, such as education, power,privilege, and social connections, cannot be changed quickly, Hiatt positedthat income may be uniquely modifiable, noting that his group is studyingthe impact of policies such as earned income tax credits and basic guaranteedincome on cancer rates and outcomes. Stanley Frencher, medical director of surgical outcomes and quality atMartin Luther King, Jr. Community Hospital, added that there may beancillary benefits from addressing patients’ social needs, even with little datato suggest it can impact cancer incidence or outcomes. “Even if we haven’tproven today that those things impact their cancer biology or even their canceroutcomes, I would argue they’re just the right thing to do,” he emphasized. The Role of Trust and Communication Several participants underscored the role of trust and communication inaddressing SDOH and health disparities in research and health care. BeverlyRogers, chief executive officer of From Momma’s House, spoke about herexperience as a breast cancer survivor and patient advocate. She described howher interactions with the health care system, as both a patient and a caregiver,have often left her feeling confused and frustrated. Citing patient–cliniciancommunication as a key challenge, Rogers recalled often feeling that her clini-cians were not communicating in a way that she was likely to understand. Forexample, it is well known that stress has a negative impact on health, but thatinformation alone is not actionable. “Everybody tells you; your doctor tellsyou, your cardiologist tells you, your endocrinologist tells you, stress causesdiabetes, stress causes heart problems, stress causes arthritis. I got all of those.So, what are you going to do for me?” Rogers asked. Noting that health caresystems are challenging to navigate for many people, but especially olderadults, she stressed the need to improve communication and coordinationamong the full spectrum of clinicians that patients see. The importance of plain language and making information relevant topeople’s lives also extends to researchers. Rogers suggested that researcherscould go beyond describing best practices or hosting public listening sessionsto engage with communities more meaningfully. She said building trust isessential and suggested that community members will be more willing toanswer questions, about their neighborhood environment, for example, if theysee a clear value in doing so and the results will apply to their lives and healthconcerns. Rogers emphasized that researchers and clinicians have a responsibil-ity to use their training to improve people’s lives. PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 29 Tucker-Seeley pointed out that some of the health care delivery chal-lenges that Rogers alluded to are solvable. Clinicians are not incentivized toview patients as humans struggling to navigate the complex, unfamiliar healthcare landscape, which contributes to health and health care disparities. “Ms.Rogers highlighted that she’s not just the arm that you’re using to take bloodfrom. She’s not just this body part that’s being treated for this condition. She’sa whole person,” he stated. To build better relationships and receive better care, Rogers pointed outthat patients would benefit from more time with clinicians. Hughes-Halbertagreed that a lack of time creates missed opportunities to understand nuancesin patients’ lives. Brawley noted that administrative realities prevent cliniciansfrom spending more than 20 minutes with each patient and suggested thatit could be valuable for people from all facets of the health care system, fromclinicians to administrators to payers to CMS, to recognize and understandhow their workflow may be contributing to health disparities. In both health care and research, Winn said that organizations know itis important to build trust in communities, but he suggested that many havefailed to examine their own lack of trustworthiness. Gaining trust takes time,and it is important to consistently show up and speak the right language, hesaid. Gwen Darien, executive vice president of the National Patient AdvocateFoundation and a cancer survivor, agreed that access and trust are cruciallyimportant in the clinician–patient relationship. “We have to trust patients,patients’ voices, patients’ experiences, and what they think that they need, andnot make any assumptions,” she said. Noting that she regularly hears stories of bias, neglect, mistrust, and­inequitable care from Black patients with cancer, Darien suggested that stan- dardizing screening and testing processes, in addition to engaging meaningfully with patients to understand their perspectives, could help to increase access and equity. “This bias and this inequity are just persistent and intractable,” she said. “Making this [screening] the standard of practice for everybody—it would go such a long way towards addressing a number of inequities.” Integrating Social Determinants of Health into the Care Continuum Several participants spoke about opportunities for health care systems tosystematically assess and attend to patients’ social needs, a goal that Gomezsaid can also benefit from community-based research and partnerships.­Gottlieb described the 5A Framework, which outlines opportunities for health care systems to acknowledge patients’ SDOH and intervene when relevant (NASEM, 2019). Conceptually, Gottlieb said it is important to recognize that SDOH are part of a broader spectrum of factors that shape individual and com- PREPUBLICATION COPY—Uncorrected Proofs

30 BIOLOGICAL EFFECTORS OF SDOH IN CANCERmunity health, neither good nor bad in and of themselves, and distinct frompopulation health (Alderwick and Gottlieb, 2019). In addition to individualcomponents, SDOH encompass upstream structural drivers, such as institu-tional policies, and their downstream effects on social risks, assets, and needs(Castrucci and Auerbach, 2019). The 5A Framework organizes the different activities that fall under socialcare into five distinct categories. Each serves as an umbrella for many relatedcomponents that affect health care access and delivery. Gottlieb detailed thethree that focus on patients and health care delivery: awareness and identifi-cation of social risk factors, assistance to intervene on social risk factors andadjustments to accommodate care for social risks. The other two categories,alignment of existing resources and advocacy to develop new resources, aremore community focused. Awareness relates to activities or strategies that health care systems employto collect social information about their patients. These can be patient ques-tionnaires, insurer-based health risk assessments, or analysis of consumerdata. Clinicians also employ screening tools, but Gottlieb noted that availabletools lack consistency and suggested that it may be helpful to undertake morevalidity testing and consensus building to determine the most promising tools(SIREN, 2019). Gottlieb noted that technology could help facilitate socialrisk screening; for example, many electronic health records (EHRs) includesocial risk dashboards. However, she said that these approaches are underusedfor SDOH applications and lack the data standardization needed to facilitatemeaningful interventions. Assistance refers to activities health care systems undertake to improvepatients’ social context and thus their health and well-being, such as connect-ing patients with food resources or rent support. To guide and understandthe impacts of such efforts, Gottlieb said that it is important to ask whetherawareness of social factors contributes to assistance and then whether assis-tance, in whatever form it may take, leads to actual health improvements. Forexample, cancer care assistance has emphasized patient navigation but withlittle research on whether the interventions improve racial health equity out-comes (Korn et al., 2023). In addition, service referrals may not be effectiveif the services are not actually accessible. “Even if we provide assistance, noteveryone gets their need met, in part because […] the effectiveness of refer-rals depends on the availability of services and decreasing the administrativeburden of enrollment and sustaining enrollment,” Gottlieb said, noting theavailable resources to help researchers better understand these challenges.26,27 26 See https://www.pcori.org/research-results/2020/scoping-review-and-evidence-map-social-needs-interventions-improve-health-outcomes (accessed May 22, 2024). 27 See https://sirenetwork.ucsf.edu/tools/evidence-library (accessed May 22, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 31 Adjustment strategies attempt to use social risk data to inform clinical caredecisions. Gottlieb said that these strategies include offering less expensivemedicine; reducing the complexity of treatment regimens; providing inter-preting services; or offering mobile, evening, or weekend care (Korn et al.,2023). Clinicians often make these adjustments, but implementation has notbeen systematic or large scale, Gottlieb said, noting that one challenge is thatclinicians often do not have access to a patient’s social risk data. Carlos addedthat downstream effects of SDOH, such as allostatic load, could be used asbiomarkers that prompt health care systems to intervene with early-stage sup-portive potential actions to improve outcomes, such as treatment adherencesupport. The final two framework categories, alignment and advocacy, canstrengthen the social resources landscape at the community level. To advancethese efforts, Gottlieb said that it would be helpful if health care systems col-laborated with community advocates to improve social conditions by offeringemployment, investing resources, and supporting local services and activities. DATA ISSUES AND GAPS RELEVANT TO SOCIAL DETERMINANTS OF HEALTH Appropriately and accurately measuring SDOH is important if scientistsand clinicians are to incorporate greater awareness and utility of these fac-tors into cancer research and care. Reflecting on the workshop presentationsand discussions, Shulman posited that a shared goal is to identify effectivemethods for collecting information about SDOH that are relevant to patientexperiences and outcomes. Creating a standardized, unified approach acrossmultiple, diverse care sites is a key challenge, Shulman said, and Gomez addedthat this challenge also extends into the research realm, where harmonizingSDOH measurement tools and factors is important for comparing resultsacross studies. Cathy Bradley, dean of the Colorado School of Public Health,suggested that policies can help to support research into best practices toeffectively collect, harmonize, link, and share data from all population groups. Examples of Social Determinants of Health Screening Tools for Research and Clinical Support Several speakers described examples of how health systems and researchgroups have sought to collect and use SDOH information to reduce disparitiesacross the cancer care continuum. Oluwadamilola Fayanju, chief of the division of breast surgery at theUniversity of Pennsylvania Perelman School of Medicine, said that addressing PREPUBLICATION COPY—Uncorrected Proofs

32 BIOLOGICAL EFFECTORS OF SDOH IN CANCERthe unmet social needs of patients with cancer is the best way to reduce cancertreatment disparities, but there are a number of challenges to collecting the datanecessary to understand these social needs. Using the National ComprehensiveCancer Network’s Distress Thermometer and Problem List,28 Fayanju surveyed1,000 women with breast cancer and found that those whose distress increasedover time were more likely to be unmarried or covered through M ­ edicaid; inaddition, Black respondents reported lower baseline distress scores, promptingfewer referrals for social services, but experienced less improvement in theirdistress over time (Fayanju et al., 2019), a disconnect that Fayanju suggestedindicates a potential flaw in applying the distress assessment methods acrossracial or ethnic groups. Fayanju and her team also found that Black patientsexperienced longer times to their first postdiagnosis evaluation, more practicalstressors, and delayed time to treatment, all of which are associated with worsesurvival rates (Fayanju et al., 2021; Richards et. al., 1999). Noting that oncologists are gatekeepers during key points of a patient’scancer care journey, Fayanju underscored the importance of timing in terms ofidentifying and responding to social needs. “If we’re only collecting informa-tion about SDOH [or] unmet social needs at the time of first consult, we arealready too late,” she said. “By the time someone arrives for her [treatment]visit, a die has been cast. And therefore, we have an opportunity, if not anobligation, to start collecting that data sooner.” How SDOH information is collected is also very important, Fayanjustated. Electronic approaches have advantages and disadvantages, and it couldbe that people with the greatest needs are the least able to use patient portalsor other technologies. In addition, Fayanju noted that EHRs typically captureonly limited data on social needs, because it was never entered, collection wasrushed or inconsistent, or status changes are unrecorded. Fayanju is leading a clinical trial to assess strategies for collecting andaddressing information on patients’ SDOH and social needs (ACC, 2024),with a goal of determining whether collecting this information as soon aspossible after a breast cancer diagnosis could help alleviate modifiable SDOHand thereby improve care equity, effectiveness, and efficiency and reduce out-come disparities. The study will also assess time to intervention and enablea systematized, standardized comparison of three self-administered screeningtools alongside the “usual care” of unstructured clinical collection. If the trial issuccessful for patients with breast cancer, Fayanju suggested that the approachcould be expanded to other cancers and diseases. Fayanju said that the greatest challenges have been the technical com-plexities of integrating the distress survey data into patient EHRs, leadership 28 See https://www.nccn.org/global/what-we-do/distress-thermometer-tool-translations(accessed July 22, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 33changes, and the lengthy review and approval processes from the many organi-zations involved. She also added that sufficient research funding will be criticalto further elucidating best practices in this area and that successful researchand interventions around SDOH will require strong and enduring partner-ships among researchers, clinicians, institutions, and patients. Cardinale Smith, chief quality officer for oncology for the Mount SinaiHealth System, discussed how her institution implemented an EHR-integratedapproach to assessing and addressing psychosocial distress. The psychological,social, spiritual, and financial burdens of cancer contribute to significantpsychosocial distress among patients with cancer and cancer survivors (Liuet al., 2023), Smith said. The American College of Surgeons Commission onCancer now mandates distress screening among its accredited institutions,29and despite important progress toward reducing patients’ psychosocial distress,significant challenges remain. To address these challenges, Mount Sinai staff created the Quality ofLife and Support Survey, a customized electronic screening tool embedded inEHRs that asks patients about financial strain; mental and spiritual health;and access to transportation, food, and social support (Jones et. al., 2024).The evidence-based questions underwent interdisciplinary review before beingfurther refined by a community advisory board. Patients can access the surveyin English or Spanish through a patient portal, and their responses are madeavailable to their clinicians. The survey is typically given before or during a patient’s second visit. AnEHR mechanism to confirm communication helps to create a “closed loop” toensure adequate response to the information patients provide, such as by prompt-ing notifications to a social worker, chaplain, or child life coordinator. Smithexplained that transportation has emerged as a common issue, and the system hasalso been instrumental in connecting patients with social workers, mental healthspecialists, or chaplains to address both practical and emotional needs. Smith identified several lessons learned since the survey went live in2022. First, she said that it is ideal to administer the surveys well in advanceof appointments and via the patient portal rather than during in-person clinicvisits. Noting that patients do not always feel comfortable discussing unmetneeds, especially if they are not eventually addressed, Smith added that it ishelpful for clinicians to clearly explain why the survey matters, what actionsare being taken in response, and what patients can expect. Mount Sinai plansto update the survey to add more languages, expand its use to additionalcancer center sites and patient groups, and create more mechanisms to ensurepatients are connected to people and resources they need. 29 See https://www.facs.org/media/t5spw4jo/2016-coc-standards-manual_interactive-pdf.pdf (accessed June 18, 2024). PREPUBLICATION COPY—Uncorrected Proofs

34 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Wayne Lawrence, research fellow in the Division of Cancer Epidemiology& Genetics at the National Cancer Institute (NCI), said that he is encour-aged by what he described as a change in focus among epidemiologists fromidentifying health risks to considering potential actions that could not onlyimprove survivorship but also resolve health disparities. To continue forwardprogress, NCI has launched the Connect for Cancer Prevention Study,30 alarge prospective cohort to study cancer causes and prevention. The study’sStructural and Social Determinants of Health Working Group is chargedwith describing measures that can capture both the cohort’s SDOH and theupstream structures that influence them, such as laws, policies, and culturalbeliefs. Participants fill out questionnaires developed by researchers with exper-tise in cancer inequities, SDOH, and structural racism that are based on inputfrom a participant advisory board about the difficulties, miscommunication,and mistrust people experience when navigating the health care system andtheir racial consciousness in the health care setting and beyond, Lawrence said. Leveraging Real-World Data Mbah discussed opportunities to leverage real-world data (RWD) to gen-erate insights on SDOH, highlighting how analyzing EHR data, examiningdifferential biomarkers, and investigating underlying social drivers of disease,care access, and treatment outcomes can help reveal the complex relationshipbetween SDOH and cancer biomarkers and enable interventions that addresscancer inequities. Mbah explained that RWD is routinely collected from a variety of sources,such as wearable devices, insurance claims, clinical visits, and EHRs (FDA,2024; Liu and Panagiotakos, 2022). She pointed out that data relevant toSDOH can be examined at the individual, care, or societal levels and describedhow integrating SDOH data with RWD from EHRs can help researchersstudy health equity. EHRs contain detailed clinical data not found in othersources, such as genomic biomarkers or mutations, and integrating these datacan illuminate how SDOH contribute to racial and ethnic differences inpredictive or prognostic biomarkers, including how that impacts treatmentand outcomes. From a research perspective, Mbah noted that an importantadvantage is that accessing EHR data for a large study cohort is much easierand less expensive than conducting in-person longitudinal studies. Flatiron, which is dedicated to generating real-world evidence from RWDanalysis, has access to the EHR data of more than 3 million patients withcancer,31 and its researchers have published numerous studies linking area-level 30 See https://www.cancer.gov/connect-prevention-study (accessed June 18, 2024). 31 See https://flatiron.com/real-world-evidence (accessed June 30, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 35SDOH with RWD on a range of outcomes to advance cancer health equityin areas such as clinical trials participation, treatment initiation, and survivalrates (Guadamuz et al., 2023a, 2023b, 2023c, 2023d). Flatiron researchershave found associations among societal advantage or deprivation, aggressivetumor characteristics, and negative breast cancer outcomes (Krieger et al.,2016; Pittell et al., 2023). To build on this work, Mbah said that Flatiron is working on integratinga standardized SDOH screening into its EHR system to help cancer practicescollect health-related social needs data at the point of care, an effort that shesaid supports CMS’ Enhancing Oncology Model (EOM)32 to improve healthequity. She added that Flatiron is also assessing interactions among SDOHand clinical and genomic factors, such as biomarkers, treatment regiment, andoutcomes. Considerations for Using Electronic Health Records Ferris suggested that enabling EHRs to collect more SDOH data in amore structured way could help advance research and the development ofeffective interventions to address SDOH. Fayanju emphasized the importanceof EHR transparency and interoperability, noting that clinicians across spe-cialties and health systems would have more information about their patients’social needs—and know their patients better—if the data were easily viewablein an EHR. Gerson noted the opportunity to comprehensively assess the abil-ity to record and reflect critical and intersecting SDOH and biomarkers withinEHRs and make datasets available for studying these interactions as well asinformation sources for treatment decisions. Hughes-Halbert posited that allostatic load is a factor that is particularlypromising in terms of being potentially actionable clinically and via publichealth initiatives but said that inconsistencies in EHR data pose a challengefor using this metric effectively. She suggested that it may be useful to createa policy for structured, systematic EHR data collection to measure allostaticloads. Obeng-Gyasi agreed that more standardized and structured EHR datawould be helpful, noting that implementing new methods for calculatingallostatic load can be successful if they have clear, action-oriented workflowswith assigned roles. However, she cautioned that calculating allostatic load isdifficult because it is dynamic and relies on frequent clinical visits, adding thatmore clarity around its clinical utility is needed. Darien emphasized the importance of eliminating persistent biases inEHRs and algorithms, which is particularly critical if the goal is to develop 32 See https://www.cms.gov/priorities/innovation/innovation-models/enhancing-oncol-ogy-model (accessed July 11, 2024). PREPUBLICATION COPY—Uncorrected Proofs

36 BIOLOGICAL EFFECTORS OF SDOH IN CANCERstrategies to better meet the social needs of diverse patients. In addition tofunding, she said that multidisciplinary partnerships and collaborations thatinclude the perspectives of patients and community-based organizations willbe important in addressing these persistent biases. Considerations for Using Questionnaires Many participants discussed some common challenges associated withusing questionnaires to assess SDOH. Rogers noted a need for improvementin the questionnaires she has encountered as a patient and family caregiver andstressed the importance of considering the challenges encountered by thosewith disabilities, limited literacy, or limited health knowledge when filling outscreening tools or surveys. She also observed that creating a whole picture ofone person’s SDOH across their lifespan and generational history is a large andtime-consuming, but incredibly important, task. Carlos noted that in-depthcollection of social risks and resilience factors is especially difficult, which iswhy a patient’s race is still used in prediction models as a proxy for SDOH.She suggested that it may be helpful to re-evaluate those methods to facilitatebetter collection of ancestry information along with SDOH and help clini-cians see beyond a patient’s race. Susan Schneider, past president of the Oncology Nursing Society, com-mented that it is also important to consider how and by whom screeningforms are filled out. Based on waiting-room observations, Schneider said shehas seen patients and their families take a variety of approaches to completingquestionnaires, and that information could be important to interventions butis generally not being captured. Fayanju agreed and noted that her team islaunching a qualitative research study of how forms are filled out in the wait-ing room to determine best methods for ensuring completion. Cogle added that family support, and especially consent and consensus,is very important. For certain procedures, such as bone marrow transplants,many families appoint a spokesperson who communicates with clinicians andthen reports back to the other family members. He suggested that this practicecould also inform approaches to social needs assessments. The Importance of Trust in Data Collection and Use Several participants underscored how trust (or the lack of it) plays intothe effectiveness of different approaches to SDOH data collection and use.Tucker-Seeley pointed out that SDOH-oriented questions in health care set-tings often focus on food, housing, and transportation (Moen et al., 2020).For patients who do not understand why they are being asked about thosethings or do not have a trusted relationship with the clinician or institution, PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 37these questions can seem intrusive and suspicious. McCullough noted thateven if patients share their food or housing insecurities, in many cases, littleif anything is done to address them (Yan et al., 2022). Hughes-Halbert addedthat social risk screening is neither standardized nor typically acted upon andsuggested that improved harmonization, consistency, and accountability couldhelp health systems to effectively act upon needs, not merely identify them. Darien emphasized the need for clinicians and health care systems tobuild trusted relationships with patients and understand the context of theirdaily lives. Jasmine McDonald, associate professor of epidemiology at theColumbia University Irving Medical Center and a self-identified Black female,shared that as a patient, she feels that lack of trust and often tells physiciansthat she too holds a doctorate to ensure the physician does not make falseassumptions about her. First visits are especially anxiety inducing for patients,which offers an opportunity for clinicians to create a positive experience.Darien agreed, noting that asking questions is preferable to making assump-tions, which are based on conscious and unconscious biases. While questionsmay feel intrusive, asking the right ones can be instrumental in directing careto where it will have the most impact. Cogle suggested that ensuring patientsconsistently see the same clinicians would build trust. “How can you buildtrust if you’re seeing a different person?” he asked. Fayanju added that it is important, even for routine data collection, toexplain to patients why they are being asked questions that may seem intrusiveand clarify that all patients are being surveyed, not just one specific group.These clarifications can help people feel more comfortable revealing personalinformation, she said. Done correctly, Darien said, SDOH screening can buildtrust and trustworthiness. “People are afraid if they give some of this dataout or talk about challenges, that they will be given lesser treatment,” Dariennoted (Tucker-Seeley et al., 2024), “So, reframing this to actually build trustand build conversation is a really important goal.” POTENTIAL AREAS OF FOCUS FOR FUTURE RESEARCH Even as new insights and interventions emerge, much remains to learnabout the social factors involved in cancer development and outcomes. Severalparticipants pointed to opportunities to further elucidate how place, space,and ancestry interact to influence cancer risk and outcomes, as well as thestructural root causes behind SDOH and possible interventions that couldreduce health disparities. They discussed how different approaches to researchpractice and funding could help to make cancer research more relevant andapplicable for diverse populations, particularly those who have been histori-cally disadvantaged. Highlighting opportunities to advance community-drivenresearch questions and approaches, many speakers also described strategies PREPUBLICATION COPY—Uncorrected Proofs

38 BIOLOGICAL EFFECTORS OF SDOH IN CANCERto build evidence for multidimensional approaches targeting the individual,health system, environment, and policy levels. Broadening Research Aims Shulman observed that scientific grant programs may inadvertentlyencourage researchers to focus on overly narrow, measurable questions that,in their attempt to separate out one SDOH, such as smoking, fail to elucidatehow SDOH are interrelated and part of a much larger picture. McCulloughagreed that this poses a problem and suggested a need for improved collabora-tion among researchers, who she said are often more apt to work within theirindividual silos than together on large-scale projects that look beyond indi-vidual SDOH. For example, social scientists, computational biologists, andexperts in artificial intelligence may be able to help researchers move beyondtheir niche specialties and create comprehensive care models that better reflectthe patient experience and can be incorporated into pooled, coordinated,multidisciplinary efforts to improve it. “With coordinated efforts to be able tolook at the breadth of social determinants and social factors, having data thatcan be pooled and merged, I think we make more than incremental steps,”McCullough said. Tucker-Seeley noted the lack of an obvious infrastructure or overarchingentity to support efforts that can truly move the needle. He said that commu-nity members are likely aware that researchers’ community visits or individualgrant-funded projects are not going to be sufficient to truly solve these com-plex problems and suggested that funders emphasize new metrics that focuson real problems being solved. Diversifying Clinical Studies and Trials Many workshop participants considered how the diversity of patients whoare included in research studies influences insights into SDOH and cancer andhow this knowledge can be applied. A key issue Mbah noted is the lack oflarge and diverse datasets that cover tumor histology and subtypes, biomarkers,SDOH, treatment access, and treatment outcomes. Such datasets could assessthe association of aggressive tumor subtypes with SDOH, treatment access,and outcomes, she said. Evans emphasized that including diverse populations in clinical trials isimportant for eliminating disparities and improving cancer treatments andaccess to care (Oyer et al., 2022). Vidal added that diagnostics companiesare developing risk stratification tools but fail to rigorously validate themfor multiple populations based upon patient characteristics, such as race andother social factors. For example, he said that researchers have found that the PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 39available risk stratification tools for breast cancer are inadequate for use withBlack patients; one metric applied across all patients incorrectly labels Blackpatients as lower risk, resulting in worse outcomes (Fayanju et al., 2023).Evans suggested that policies could be developed to require that studies of­cancer ­screening tools include diverse populations and prevention compo- nents, adding that NCI and NIH could also use funding structures to incen- tivize diversity in studies. Since drug developers are very responsive to the rules of the U.S. Food and Drug Administration (FDA), Evans and Vidal also suggested that FDA could mandate diverse representation in clinical trials as a condition for drug approvals. While many people have encouraged diversifying clinical trials, Yates posited that this would only help improve efficacy in diverse populations if the drugs are developed for and tested on diverse biology in the first place. He noted that drug developers are increasingly aware of this mismatch, and rec- ognition of a market for precision medicine therapies that target underserved populations is emerging. Timothy Rebbeck, associate director for cancer equity and engagement at the Dana-Farber Cancer Institute and Harvard University, said that more diverse clinical trial data can help support clinical decisions that reduce dis- parities and improve care. However, he cautioned that such data should not be used to create race-based treatment pathways. Genomic differences exist among subgroups, but further research is needed to distinguish these differ- ences from social drivers. Watson added that the All of Us study has data on a large and diverse population and takes a team science approach to that is supported by a multidisciplinary slate of researchers and social scientists asking complex, intersectional questions. Collaborating Across Disciplines and Communities Winn noted that precision medicine is supposed to create individual-ized, whole-person care, but these approaches have been based on a patient’s­genetics and do not account for SDOH. This exclusion creates an artifi- cial conflict between “hard” and “soft sciences,” he said, and suggested that ­better alignment among researchers could facilitate more productive, multi­ disciplinary conversations about translational research and population health. Winn and other participants highlighted how researchers could focus on learning to communicate better with various communities. Hughes-Halbert shared that her work on transdisciplinary, collaborative teams taught her that harmonizing terms and concepts can help scientists move forward. Tucker-Seeley suggested that community members could also be included in this harmoniza- tion process to ensure their perspective is heard and noted that researchers would benefit from a better understanding of the U.S. health care policy process. PREPUBLICATION COPY—Uncorrected Proofs

40 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Conzen and Victoria Seewaldt, the Ruth Ziegler Professor and Chairof the Department of Population Sciences at City of Hope, suggested thatenvironmental health researchers could partner with social scientists tountangle the complex stressors different communities face. For example,rural communities may experience very different types of challenges thanurban communities, and pollution exposures, access to healthy foods, accessto resources, and access to health care may interact to create unique chal-lenges (CDC, 2024; Losada-Rojas et al., 2021). Gerson suggested that poli-cies could help to improve the feedback loop between researchers, individualpatients, and at-risk communities to uncover knowledge gaps and identifywhat interventions people and communities want. He also suggested inte-grating the study of SDOH on cancer outcomes with targeting social needsto improve SDOH and therefore cancer outcomes. McCullough posited that community members are more likely to sup-port research if they are compensated as collaborators, similar to industrypartnerships, and can see that the research is likely to produce tangible healthimpacts. “Research for the sake of research to end up in high-impact journalsdoes not improve population health,” she noted. McCullough also emphasizedthe importance of studying the interconnectedness of not just SDOH and dis-eases but overall systems, such as the criminal justice system or environmentaldiscrimination. “All of these things are connected,” she stated. Advancing Meaningful Community Engagement Several participants highlighted how community-engaged research meth-ods can improve understanding of SDOH and discussed some of the nuancesinvolved in effectively working with communities. McCullough said that itis important for communities to be included and engaged through the entireresearch process, pointing to focus groups she holds for Black women withcancer as one example. Rogers advised researchers to avoid entering communi-ties by declaring they are “here to help.” Unless they can offer the specific helpthe community is asking for, she said, the visit usually will not bring value oryield helpful data. Brawley added that many communities are seeking actionrather than more research. Nicole Stout, assistant research professor of cancer prevention and con-trol, health policy, management, and leadership at West Virginia University,emphasized how important it is for researchers to understand the cultural­context in which they work and how it influences the stressors people experi- ence. For example, rural communities often emphasize resilience and self- efficacy, and Yates shared that in his experience, rural residents were sometimes suspicious of outside intervention, at least until they had the opportunity to vet it themselves and perceive that it met their needs, not the needs identified PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 41by the researchers. Winn and Stout added that rural communities are quitediverse in terms of age, race, and SDOH. Pointing to HANDLS as an example of a study in which researcherswere successful in gaining participants’ trust, Evans said that researchers firstdetailed their plan to key members of the neighborhood, including tenants’associations, health ministries, state assemblymen, and city council members,who then formed a community advisory board. Next, they hosted a commu-nity event and invited residents to tour the mobile data collection unit andsuggest improvements, which the researchers made, and started pilot visits toneighborhoods and local festivals, meeting more people along the way andsharing what they were learning as the study progressed. Several participants emphasized the important role of language in facili-tating effective communication and community partnerships. Rebbeck saidthat use of jargon is often a challenge when researchers speak with com-munities and attempt to collaborate with researchers in other disciplines.He suggested that a shared vocabulary that is refined, clear, and scientificallyrigorous would help these relationships. Darien said that plain language andjargon-free communication can help but cautioned against overly simplifyingor “dumbing down” medical language. She also pointed out that trust is amultidimensional relationship. Despite a lot of focus on why patients can trusttheir clinicians, she said that there has been less attention to the importanceof clinicians’ trust in their patients (Grob et al., 2019). OPPORTUNITIES TO INVEST IN IMPLEMENTATION Throughout the workshop, many participants underscored the urgency ofusing existing knowledge to address health inequities and disparities and broadlyimplementing available solutions. Several speakers shared examples of programsand initiatives that seek to incorporate SDOH interventions into cancer preven-tion and clinical workflows. Building on these examples, many participants alsodiscussed opportunities and challenges in translating evidence generated throughresearch into practical solutions, intervening to prevent cancer and reduce dis-parities earlier in life, and creating patient- and community-driven interventionsthat effectively reach underserved communities. Some speakers also discussedways to overcome technical, cultural, and institutional implementation chal-lenges and build a community health workforce that is equipped to implementand sustain best practices to support equitable health systems. Acting on Existing Knowledge Highlighting a point raised throughout the workshop, Shulman stated thatit is important to continue research into the biological effectors of SDOH, but PREPUBLICATION COPY—Uncorrected Proofs

42 BIOLOGICAL EFFECTORS OF SDOH IN CANCERin the meantime, it is equally important to use existing knowledge to interveneand try to reduce health disparities. For example, if transportation is knownto be a major factor that prevents patients from receiving the care that theyneed, he suggested that health care systems implement solutions to addressthat problem even while researchers continue to study other factors that alsomight impact care delivery or quality. Brawley added that while many work-shop participants had emphasized the importance of conducting more researchto better understand health disparities, especially racial disparities, and otherdifferences among populations, they also underscored the importance of clos-ing gaps in the implementation of effective interventions. For example, he saidthat new therapies are always welcome, but many patients cannot access orafford existing treatments, so the additional benefit of new therapies will belimited unless access and implementation challenges are addressed. Assuming it is possible to effectively collect SDOH data, Bradley askedparticipants to suggest policy approaches that would put these data to usefor addressing patients’ social needs. Shulman replied that it is important todetermine patients’ social needs, intervene to address them, and measure theresults to ensure they received optimal care. Schilsky noted that while manyclinical trials ask quality-of-life questions, very little of that data ends up ondrug labels, but he suggested that making that information available couldbe meaningful to patients and clinicians. Rebbeck suggested creating a “go,no-go” guiding statement, akin to the FDA approval process, that indicateswhen data are sufficient to implement an intervention to address SDOH atthe individual or public health level. McDonald said that policies to facilitate communication and collabo-ration with community health workers will be especially important, andexpressed her belief that broader SDOH screening can improve patient–­clinician trust and reduce clinicians’ conscious and unconscious biases. Shesaid that key challenges in assessing SDOH include the lack of standardizedmeasures, uniformity in the frequency of delivering measures, choosing whichSDOH measures to implement in the clinic, and the evaluation of the SDOHinterventions implemented. Moreover, many SDOH scales have not beenvalidated in different populations, suggesting that they may not be transfer-able to all groups. McDonald described the Persistent Poverty Initiative,33 coordinated by theNCI, which funds five centers to address cancer prevalence in areas of persistentpoverty by building up local social capital through multigenerational initia-tives that target both individuals and systems. Her institution, in collaborationwith other New York-based institutions that are a part of the Social Capital 33 See https://cancercontrol.cancer.gov/hdhe/research-emphasis/underserved-areas/persistent-poverty (accessed August 7, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 43grant,34 seeks to focus on these issues through multiple cores. These includethe Career Enhancement Core,35 which aims to equip the next generation ofclinical research coordinators with the ability to identify and mitigate SDOH;and the Research and Methods Core,36 which creates standards for data collec-tion, analysis, and harmonization across different studies and regions to enableassessment of associations and downstream impacts. Highlighting prostate cancer as an example, Rebbeck discussed how clini-cians can improve cancer care by acting on available evidence about the role ofSDOH. As discussed throughout the workshop, Rebbeck said that disparitiesexist at all phases of the cancer continuum and are driven by complex, over-lapping, and individual biological and social factors, such as genetics, SDOH,systemic racism, risk factors, health behaviors, and care quality. He positedthat individually tailored interventions would help improve patient outcomes. Rebbeck noted the significant disparities in prostate cancer incidence andmortality rates among people in different racial and ethnic groups (Siegel et al.,2024; Sung et al., 2021). Known risk factors for prostate cancer include age,family history, race and ethnicity, height, and obesity, most of which are notmodifiable (Kensler and Rebbeck, 2020). Germline-inherited genetics couldcontribute to some disparities, Rebbeck noted, as prostate cancer is highly heri-table (Conti et al., 2021); however, the relative impact of other factors, includ-ing SDOH, tumor size, or treatment pathway, does not appear to fully explainthe higher mortality rates for non-Hispanic Black men (Ellis et al., 2018). Cancer stage at the time of diagnosis is highly predictive for mortality.While prostate cancer screening can identify earlier-stage cases, Black menare screened at lower rates than other races (Bryant et al., 2022), suggestingthat broader use of prostate cancer screening in this population could reducedisparities in mortality rates. Rebbeck added that standardizing care interven-tions can also reduce racial disparities, stating that when all the variables arecontrolled, as in a clinical trial, the disparities disappear (Dess et al., 2019).“We see this many times,” he said. “If we can completely control not for theselection of who gets in the trial but for what kind of care people get, we donot see disparities in the outcomes.” Rebbeck suggested that it may be helpful to study how the moleculardifferences of the many prostate cancer subtypes differ by race (Kensler et al.,2022) and added that clinicians can also determine which patients’ geneticprofiles increase their prostate cancer risk. 34 See https://reporter.nih.gov/project-details/10661344 (accessed August 5, 2024). 35 See https://www.socacenternyc.org/careerenhancementcore (accessed September 6,2024). 36 See https://www.socacenternyc.org/reasearchandmethodscore (accessed September 6,2024). PREPUBLICATION COPY—Uncorrected Proofs

44 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Seewaldt highlighted how applying existing knowledge about prevent-ing metabolic disorders could help to address some of the drivers behinda range of health conditions. Noting that the age-adjusted mortality rateamong U.S. women has risen over time (Kindig and Cheng, 2013), she saidthat factors such as lack of exercise and healthy food as well as increasedincidence of Type 2 diabetes have played a particularly important role inwomen’s health in recent decades. As other speakers noted, Seewaldt under-scored that many overlapping neighborhood SDOH contribute to poorhealth and lower life expectancies, from lack of access to healthy food tofewer trees, greater carcinogenic exposures, and increased air and noise pollu-tion (Churchwell et al., 2020; Hoffman et al., 2020; Kind and ­Buckingham,2018; Nardone et al., 2020; Sistrunk et al., 2022;). As discussed, manyof these overlapping SDOH can be traced back to historic mortgage dis-crimination and similar institutionally, structurally, and culturally racistpolicies that created segregated neighborhoods whose current residents haveincreased disease risk and burden and worse health outcomes (Hoffman etal., 2020; Nardone et al., 2020). “We’re looking at a very complex picture—ahistory of structural racism, discrimination, and ultimately, it’s not leadingto one thing, not just breast cancer or prostate cancer, but it really leads tomany diseases,” she said. Seewaldt said that the diet of many Americans contains too many calo-ries and too few nutritious elements, which, combined with a lack of otherresources that encourage healthy living, is contributing to an increase in theincidence of insulin resistance, obesity, heart disease, hypertension, Type 2diabetes, and cancer (USDA, 2020). Insulin resistance is a particularly seri-ous health issue, as it stimulates hunger, turns carbohydrates into fat, andinhibits fat breakdown, creating conditions ripe for prediabetes (NIDDK,2018). While research has consistently shown that Type 2 diabetes can be pre-vented through modest changes in diet and exercise and the drug m ­ etformin(Knowler et al., 2009), Seewaldt lamented that this knowledge has not led tosignificant reductions in diabetes rates. “We have the means to reverse pre­diabetes and prevent it from turning into diabetes. We have clinical trials, wehave all the guidelines, and we are not implementing [them],” she said. Seewaldt noted that no single variable, such as obesity or body mass index,can be used to predict breast cancer risk (Bandera et al., 2015; Chiu et al.,2011). Through her research into epigenetic changes in women with i­nsulinresistance (but not diabetes), Seewaldt showed that the signaling pathways ofcertain genes linked to both insulin resistance and breast cancer accelerate cellaging that can increase cancer susceptibility (Shalabi et al., 2021; Vidal et al.,2024). To help reverse insulin resistance and prevent Type 2 diabetes throughearly interventions, she suggested further research and updates to public healthguidelines. Conzen highlighted the value of upstream prevention strategies, PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 45including low carbohydrate/high fiber nutrition education before insulin resis-tance begins (Foley, 2021). Advancing Prevention and Early-Life Interventions Several participants emphasized the role of early-life exposures in contrib-uting to cancer risk and highlighted potential opportunities to reduce that riskthrough early-life interventions. Winn suggested that policies to intervene atthe elementary school age could cover physical education, nutrition, mentalhealth, and overall wellness behaviors. Brawley also suggested integratingprevention and risk reduction programs in childhood education and target-ing social settings rather than hospitals and clinics. Rebbeck agreed, notingthat racial disparities exist well before diagnosis (Rebbeck and Haas, 2014).Seewaldt suggested increasing emphasis on physical education in schools andhighlighted the importance of policies to reduce air pollution and other envi-ronmental exposures. Fayanju added that interventions are likely to be more effective whenthey are introduced as early in life as possible. Evans suggested that cancerprevention specialists and other health workers could find ways to collaboratewith labor unions to develop practical interventions, such as including healthinitiatives in their bargaining agreements or insisting on having a nurse on sitein every school. She also noted that collaborating with teachers could offeranother avenue to impact student health. Focusing on Underserved Communities Frencher urged attendees to focus on implementing SDOH-orientedinterventions in communities facing the greatest health disparities. Becausefactors such as insurance status can impact a person’s access to care, includingaccess to clinical trials, he stressed that health disparities do not come down tobiology or SDOH but rather biology and SDOH, “and we have to do a betterjob of trying to combine those things.” To deliver high-quality care in underserved communities, Frencher sug-gested focusing on increasing awareness of bias and finding opportunities toalign goals and resources. He also suggested expanding the discussion beyondacademics and nonprofit community clinics to include industry, entrepre-neurs, and others, stressing that “if we don’t create business models thatultimately can deliver better care to our patients and communities of colorin underserved areas, it’s not going to happen.” Ray Michael Bridgewater,president and chief executive officer of Assembly of Petworth, added that itis important to understand challenges vulnerable communities face, such aslow literacy, really listen to them, and let them take the lead. “You’ll get more PREPUBLICATION COPY—Uncorrected Proofs

46 BIOLOGICAL EFFECTORS OF SDOH IN CANCERcooperation, you’ll get more trust if you let the community drive the car,” heexplained. Alma McCormick, executive director of Messengers for Health37 and amember of the Crow Nation, shared how she put these approaches into prac-tice in her community-based research to address cervical cancer among Crowwomen. The Crow community faces daunting socioeconomic circumstances,and most members lack access to quality health care. McCormick said thatprior to her work, Crow women were not being screened for cervical cancer.In 2001, she helped create community-led cancer awareness and preventionmeasures that built upon Crow cultural strengths, values, and resources, suchas spirituality, health, and community resilience. McCormick explained that being a member of the community herselfwas critical to her ability to overcome community mistrust. She noted thather research partners also built trust with residents by demonstrating integrity,showing sincere compassion and concern, and engaging the community bymaking long drives to visit with them, listening to community voices, andallowing the community to take the lead. By focusing on the individual,woman-to-woman level, she said, the team was able to create an environmentwhere women felt comfortable speaking openly about cancer. She added thatit also helped that the project directly benefited Crow women and includedservices to address other pressing social issues, such as substance use disorders. Medical mobile units are one strategy that some researchers and healthsystems have used to reach underserved communities. Shulman said that hisinstitution uses mobile care units for screening, prevention, and risk reductionbut only once they have established trust within the communities they serve.He said that mobile units are most effective if they are prepared to support thenext steps. “If you find somebody who’s got an abnormal mammogram andshe doesn’t have insurance, and she doesn’t have a primary care doctor, and shedoesn’t have any connection with the health system, you need to be preparedto close those gaps and take care of that person without delay, without com-promising her treatment and her outcome,” he said. Many participants also discussed what resources are available to help com-munity advocates and health workers. McDonald said that her institution, incollaboration with City University of New York, created a community scienceinstitute38 that trains community members to join institutional review boards,understand research details and clinical trial protocols, and become commu-nity advocates. She and Rogers suggested that it would be helpful if pathwayscould be created to connect such training programs with actual jobs. Cogle 37See https://www.messengersforhealth.org/about-us (accessed June 20, 2024). 38See https://news.columbia.edu/events/community-science-institute# (accessed June 20,2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 47suggested that Medicaid provider enrollment policies can create opportunitiesto pay community health workers to offer peer support to patients, as is donein Florida and some other states. Yates commented that during his time atTuskegee University, he hired community residents as patient navigators andcommunity health educators and treated them as professional peers. However,in that case, their pay came from NIH grants, not the institution itself. “Ithink the model does work, but we have to find the funds,” he said. Supporting Equitable Care Delivery To accomplish the goals discussed throughout the workshop, Winn andothers said that sufficient, sustained funding models will be critical. Evanssuggested that policies could require that all patients with cancer be givenstate-of-the-art treatment, and Randall Oyer, executive medical director ofcancer services at Penn Medicine Lancaster General Hospital, suggested thiscould be aided by a policy to eliminate “cancer deserts,” large areas withoutaccess to NCI-designated cancer centers. Evans also suggested that health careworkers engage with policy proposals, such as House Resolution 40, a billto study reparations proposals.39 Winn added that policies to address drugshortages could also help, because historically disadvantaged communities aresignificantly affected. Batsheva Honig, health insurance specialist at CMS, described howemerging policies and reimbursement models, such as CMS’ EOM,40 canhelp to reduce health care disparities and advance health equity. EOM isa 5-year voluntary payment model for clinicians that aims to incentivizedelivery of high-quality, person-centered, equitable care to Medicare fee-for-service beneficiaries who receive qualifying chemotherapy. In addition totraditional fee-for-service payments, Honig explained, EOM participants areeligible for two financial incentives to improve care quality and reduce costs:a Monthly Enhanced Oncology Services payment, which reimburses servicessuch as patient navigation, social needs screening, and care planning, and aperformance-based payment, which considers the total cost of a patient’s careand the quality of care after starting chemotherapy. Honig said that CMS is continually testing and optimizing new waysto embed health equity into care, such as collecting beneficiary-level socio­demographic data, covering social needs screening, supporting patient naviga- 39 See https://www.congress.gov/bill/117th-congress/house-bill/40 (accessed July 1, 2024). 40 For information on EOM and Monthly Enhanced Oncology Services, see https://www.cms.gov/priorities/innovation/innovation-models/enhancing-oncology-model(accessed June 20, 2024). PREPUBLICATION COPY—Uncorrected Proofs

48 BIOLOGICAL EFFECTORS OF SDOH IN CANCERtion, and developing health equity plans.41 EOM mandates that participantsconduct social needs screening in transportation, food insecurity, and housinginstability; additional optional screenings include social isolation, emotionaldistress, interpersonal safety, and financial toxicity. The idea is that by betterunderstanding each beneficiary’s needs, individually tailored care plans canbe developed that include referrals to community resources. “The key here isestablishing and developing community linkages and partnerships as a way toaddress whole-person care needs,” Honig said. EOM participants also collect electronic patient-reported outcomes(ePROs),42 without clinician amendment or interpretation, on topics such assymptoms, physical functioning, behavioral health, and social needs, Honignoted, adding that ePROs help clinicians focus on patient needs and improvepatient communication, care management, satisfaction, and cancer outcomes. Honig noted that the addition of new codes to the 2024 Physician FeeSchedule,43 including for SDOH risk assessment and community health inte-gration, can improve health equity and outcomes. Under EOM, participantsscreen every beneficiary for health-related social needs monthly; the SDOHrisk assessment, however, is included in the total cost-of-care model, not as aseparate payment. The aims of the risk assessment requirement are to facilitatethe process of connecting patients with resources to address their needs, help-ing to build patient trust; identify and address gaps in services; avoid serviceduplications; and establish community service partnerships. Staci Lofton, senior director for health equity at Families USA,44 dis-cussed these and other policies from her perspective as a consumer advocate.Families USA advocates for all people to have equitable access to high-qualityhealth care to enable their best possible health, particularly those who havebeen historically marginalized. Lofton shared the story of a woman whorecently passed away from misdiagnosed cervical cancer, an outcome that sheargued was preventable. While clinicians want to help their patients, Loftonsaid that they are trapped inside a system that rewards clinicians who see alarge volume of patients and provide many services, regardless of whether theseservices address patients’ health needs or reduce persistent health disparities. To shift the incentives, Families USA advocates for a transition to avalue-based payment system that would enable clinicians to conduct opti- 41 See https://www.cms.gov/files/document/mln9201074-health-equity-services-2024-physician-fee-schedule-final-rule.pdf-0 (accessed June 20, 2024). 42 See https://www.cms.gov/priorities/innovation/media/document/eom-epros-fs?domain=lnks.gd (accessed June 20, 2024). 43 See https://www.cms.gov/medicare/payment/fee-schedules/physician (accessed July 1,2024). 44 See https://familiesusa.org/about (accessed June 20, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 49mal social needs assessments, connect patients with community resources,and support person-centered holistic care that minimizes preventable deaths.Lofton expressed enthusiasm for CMS’ EOM and the 2024 update to theMedicare Physician Fee Schedule. She said that the new codes for communityhealth integration are particularly helpful because they enable patients toaccess services and resources in their own communities. She added that thesechanges can also create a demand for more community health workers, andshe suggested focusing funding and policies on building a community healthworkforce that can leverage individuals’ shared backgrounds to build trustedpatient–clinician relationships and thereby increase screening rates and otheractions that improve public health. Lofton also called attention to the Consolidated Appropriations Act of2023,45 which provides funding mechanisms to build up community healthworkforce capacity, and the proposed Community Health Worker AccessAct,46 which would improve access to community health services for Medicareand Medicaid enrollees to address preventable diseases, reduce cost inefficien-cies, and improve health outcomes. Finally, Lofton noted that the process ofcollecting and assessing patient-reported data could be made easier if it werecovered by a separate payment and clinicians were able to share that data withrelevant caregivers, other clinicians, and health care institutions to create acoordinated and integrated care process. Many speakers discussed strategies to leverage funding sources for imple-menting interventions to reduce disparities. Fayanju suggested that diversifiedpartnerships can reduce funding uncertainties and added that the overall goalis not to collect data but to generate the evidence needed to convince healthcare systems of the importance of hiring and training staff to do the workthat will improve health disparities and then building the infrastructure tosupport that work. To achieve sustainable funding for initiatives that addresshealth disparities, Cogle suggested it will be important to understand newstate laws such as HB 885 in Florida,47 which mandates insurance coverageof all biomarker tests for any health condition based not on medical necessitybut clinical utility. “This [change from medical necessity to clinical utility] isa huge game changer,” he said. 45 See https://www.congress.gov/bill/117th-congress/house-bill/2617 (accessed June 20,2024). 46 See https://www.congress.gov/bill/118th-congress/senate-bill/3892/text (accessedJune 20, 2024). 47 See https://www.flsenate.gov/Session/Bill/2024/885 (accessed August 7, 2024). PREPUBLICATION COPY—Uncorrected Proofs

50 BIOLOGICAL EFFECTORS OF SDOH IN CANCER Integrating Interventions for Social Determinants of Health into Clinical Workflows Several participants suggested that important next steps are to increaseinvestments in transdisciplinary research to translate laboratory-generatedevidence on SDOH and cancer into concrete practices and then integratethose practices into clinical workflows. Gerson and Hughes-Halbert notedthat policies to address care coordination, which is already fragmented, will beimportant as new screenings and interventions are added to care pathways andemphasized that all policies to address SDOH will be most effective if they aredriven by patient and community input and engagement. Several speakers highlighted opportunities to better equip primary careproviders (PCPs) to assess and address SDOH and better support cancer pre-vention, screening, and treatment. Fayanju noted that the separation betweenprimary and specialty care has led to situations where specialists are seeingpatients whose health problems could have been addressed by PCPs, but shealso acknowledged many PCPs are overburdened and struggle to screen andaddress social needs (Drake et al., 2021; Tikkanen et al., 2020). Bradley sug-gested that payment reforms to reimburse clinicians for patient-reported datacollection and social needs interventions could also help by providing incen-tives for addressing social needs and connecting patients to resources throughreferrals. Frencher added that community PCPs may need more support toconduct complex and expensive genomic tests, perhaps through telemedicine-based mentoring, programs like Project Extension for Community HealthcareOutcomes,48 or overall enhanced collaboration among community healthworkers, specialists, and researchers. Many participants also pointed out that adequately gathering andresponding to SDOH information takes time. Winn, Ferris, and Seewaldtsuggested that policies that allow clinicians to be reimbursed for taking thetime to get to know their patients’ social needs could encourage them to spendmore time with patients, develop lasting relationships, and offer holistic,whole-person care. Darien highlighted the importance of building up the health care work-force in shortage areas so that patients can access care and build trusted rela-tionships with clinicians. Bradley agreed that workforce development policiesare important to create health care teams that can address social needs, andTucker-Seeley suggested that health care systems build on current workflows,as opposed to adding new ones, to facilitate buy-in from busy clinicians. Healso observed that having health care leaders and administrators experienced 48 See https://www.ahrq.gov/patient-safety/settings/multiple/project-echo/index.html(accessed June 20, 2024). PREPUBLICATION COPY—Uncorrected Proofs

PROCEEDINGS OF A WORKSHOP 51in social care delivery would help create effective pathways for implementation(Taira et al., 2023). Moving from Ideas to Implementation to Advance Health Equity Reflecting on the workshop discussions, Hughes-Halbert and Gersonstressed the importance of fostering clear and respectful communication andconnections among clinicians, patients, communities, and researchers. “I thinkthe main goal for this workshop was to really listen—to listen to each other, tolisten to our communities, to listen to what the data are telling us, and to driveour path forward,” Hughes-Halbert said. To build upon the insights raised atthe workshop, many participants also underscored the importance of action.Gerson emphasized that moving from ideas to implementation will requirepolicy changes, funding, and collaboration. As Rogers put it, “Everybody istalking about disparities and equity, but who is going to take the ball and say,‘I got this’? Let’s get some folks together and do what we need to do.” REFERENCESAbdel-Rahman, O., Y. Xu, S. Kong, J. Dort, M. L. Quan, S. Karim, A. Bouchard-Fortier, H. Cho, and W. Y. Cheung. 2019. Impact of baseline cardiovascular comorbidity on outcomes in women with breast cancer: A real-world, population-based study. Clinical Breast Cancer 19(2):e297–e305.ACC (Abramson Cancer Center at Penn Medicine). 2024. Early point-of-service social and behavioral determinants of health (SDOH) screening and enhanced navigation on care delivery for patients with breast cancer (BREAST_SDOH). Bethesda, MD: National Library of Medicine. https://www.clinicaltrials.gov/study/NCT06019988?term=fayanju&rank=1ACS (American Cancer Society). 2011. Cancer Facts and Figures 2011. https://www.cancer. org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2011. html (accessed July 11, 2024).ACS. 2022. Cancer Facts & Figures for African American/Black People 2022–2024. https:// www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer- facts-and-figures-for-african-americans/2022-2024-cff-aa.pdf (accessed May 22, 2024).Agbemenu, K., S. Auerbach, N. S. Murshid, J. Shelton, and N. Amutah-Onukagha. 2019. Reproductive health outcomes in African refugee women: A comparative study. Journal of Women’s Health 28(6):785–793.Alderwick, H., and L. M. Gottlieb. 2019. Meanings and misunderstandings: A social determinants of health lexicon for health care systems. The Milbank Quarterly 97(2):407–419.Antoni, M. H., and F. S. Dhabhar. 2019. The impact of psychosocial stress and stress management on immune responses in patients with cancer. Cancer 125(9):1417–1431.Antoni, M. H., S. K. Lutgendorf, S. W. Cole, F. S. Dhabhar, S. E. Sephton, P. G. McDonald, M. Stefanek, and A. K. Sood. 2006. The influence of bio-behavioural factors on tumour biology: Pathways and mechanisms. Nature Reviews Cancer 6(3):240–248. PREPUBLICATION COPY—Uncorrected Proofs

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