Greater Diversity of Cancer Models May Help Combat “Imprecision” in Personalized Care

A greater understanding of genomic characteristics of racial and ethnic minority populations with cancer are necessary to further advance therapy development and lead to successful treatment for all patients.

“It has been up to the scientific community to investigate the role of biology and biological differences and how cancers manifest and progress in individuals across different racial and ethnicity groups,” John D. Carpten, PhD, professor and chair of translational genomics and director of the Institute of Translational Genomics at Keck School of Medicine of the University of Southern California in Los Angeles, said during a virtual presentation about the AACR Cancer Disparities Progress Report 2020 hosted by the American Association for Cancer Research (AACR).¹ “In order to make continued progress, one gap we face is the limited diversity in our cohorts of patients in biomedical research.”

Personalized approaches, or precision medicine, have driven oncology care away from the one-size-fits-all treatment model of patient care. Genomics of both patients and their tumors are the foremost factors influencing the advancement of novel targeted agents across tumor types, so much so that the clinical development process of these therapeutics may come with a higher chance of success when compared against nonbiomarker-targeting agents. In one analysis of aggregated data, overall success of oncology clinical trials occurred at a rate of 10.7% versus 1.6% in therapeutic groups with and without treatment biomarkers, respectively. In the phase-3-to-approval category, those corresponding rates were 63.6% and 33.6%.²

These data may emphasize both strengths and weaknesses of the precision-medicine approach since patients of diverse backgrounds are typically subject to different standards of care based on considerations unrelated to disease biology, such as socioeconomic factors and lifestyle (FIGURE).¹

Real-world data suggest that racial and ethnic minority groups in general are not screened for therapy biomarkers at the same rate as White patients. In one report involving Medicare claims for molecular testing in patients diagnosed with stage IV lung adenocarcinoma, patients who were Black were least likely to undergo any testing (14.1%) when compared with those who were White (26.2%; odds ratio, 0.53; 95% CI, 0.40-0.72).³

A foremost resource in the understanding of cancer genomics, The Cancer Genome Atlas was created to accelerate the understanding of different diseases by cataloguing genetic mutations associated with patients’ tumors. However, a retrospective study of the database in 2015 revealed that White patients were overrepresented in the 5729 samples analyzed (77%). As such, there were enough data for all tumor types to detect a 10% mutational frequency in White patients. By contrast, among people of color, only Black patients with breast cancer had enough samples to detect the same mutational frequency, with all other tumor types in ethnic and minority groups being poorly understood.⁴

“There are observed differences in the clinical characteristics of certain cancers when we look at tumors derived from racial and ethnic minority patients,” Carpten said. “One area of specific need is the development of a more diverse set of cancer model systems. We need these models to help us gain broader and more comprehensive understanding of cancer and to validate findings in ways that do not force us to generalize results based on information gained from cohorts with little or no diversity.”

Research Initiatives

To examine issues related to patient care that affect the receipt of personalized medicinal approaches, the National Institute on Minority Health and Health Disparities (NIMHD) and the National Cancer Institute (NCI) have invested in Transdisciplinary Collaborative Centers (TCC) whose goal is understanding the combined effects of patients’ genetics, environment, and lifestyle factors in health care outcomes.¹

Centers currently funded as of September 2020 are the Center of Excellence in Precision Medicine and Population Health of Vanderbilt University, Stanford Precision Health for Ethnic and Racial Equity Transdisciplinary Collaborative Center, Medical University of South Carolina Transdisciplinary Collaborative Center in Precision Medicine and Minority Men’s Health, Yale Transdisciplinary Collaborative Center for Health Disparities Research Focused on Precision Medicine, and African American Cardiovascular pharmacogenetic CONsorTium of Northwestern University.⁵

Each center establishes its own focus by a transdisciplinary framework, with priority research areas emphasizing data integration; pharmaceuticals outcomes and pharmacogenomic discoveries, such as genomic information, in disparity populations; and implementation research.⁵

“Precision medicine research endeavors must go beyond biologic and clinical markers and include social determinants of health, such as the economic, social, and political conditions that influence health status,” NIMHD Director Eliseo J. P.rez-Stable, MD, said in a statement following the launch of the program.⁶ “Ultimately, the TCCs will generate new knowledge about precision medicine that resonates from the community level to the national population level.”

Another initiative from the National Institutes of Health is the All of Us Research Program, which is building a diverse database by collecting information from 1 million patients who will be asked to share their electronic health records, donate biospecimens for analysis, respond to surveys, and have standardized physical measurements taken. The goals of this program are similar to those of the TCCs, as it aims to examine health disparities and disease biomarkers together rather than as separate entities.^1,7

According the AACR report, All of Us uses community engagement to help with data gathering and has furnished funds to providers who identify best practices for recruiting and enrolling medically underserved patients in the program. As of the middle of 2019, the program had enrolled 175,000 participants with more than half of patients identifying as non-White.¹

What’s Needed?

What these research programs and initiatives have in common is the goal for deeper understanding of disease characteristics of previously underrepresented groups by gathering real-world data for informing treatment decisions and future drug development. In their report, AACR said data sharing is one way in which the oncology community can accelerate the rate by which these proposals are achieved.

By relying on the collection of “big data,” investigators can start finding answers to looming questions related to health disparities and uncover other areas of need that may not have been evident previously. For example, information gathered from the AACR Project Genie database indicate that significant differences exist in the frequency of genetic alteration in Black and White patients. The AACR report depicts higher frequency of mutations in USH2A, DNAH9, PKD1L2, and TP53 in patients who are Black, but more copy-number alterations in PAG1 AMP, PTPN6 AMP, and CD36 AMP in patients who are White.¹

As such, the organization emphasized that both clinicians and stakeholders from outside the medical field need to make concerted efforts toward gaining better understanding of diverse patient biology. Professional medical organizations, such as AACR, have led the charge in creating programs and initiatives with the end goal of greater inclusion.

“The AACR is establishing a task force that will focus on racial inequalities in cancer research… which will include thought leaders from across the country representing academia, government, industry, and cancer survivors and patient advocates,” AACR president Antonio Ribas, MD, PhD, who is also director of the Tumor Immunology Program at the University of California Los Angeles Jonsson Comprehensive Cancer Center, announced during the meeting. “The major goal of the task force will be to establish various ways to make positive change [and to] provide leadership on the pursuit of initiatives in and addressing longstanding racial injustices in the biomedical field and in cancer health care.”

Including more diverse populations in biomedical research and better development of cancer models that include racial and ethnic minority populations will be necessary to achieve better outcomes for all patients with cancer.

_References

_{1. Sengupta R, Honey K. AACR Cancer Disparities Progress Report 2020: achieving the bold vision of health equity for racial and ethnic minorities and other underserved populations. Cancer Epidemiol Biomarkers Prev. Published online September 16, 2020. doi:10.1158/1055-9965.EPI-20-0269}

_{2. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019;20(2):273-286. doi:10.1093/biostatistics/kxx069}

_{3. Kehl KL, Lathan CS, Johnson BE, Schrag D. Race, poverty, and initial implementation of precision medicine for lung cancer. J Natl Cancer Inst. 2019;111(4):431-434. doi:10.1093/jnci/djy202}

_{4. Spratt DE, Chan T, Waldron L, et al. Racial/ethnic disparities in genomic sequencing. JAMA Oncol. 2016;2(8):1070-1074. doi:10.1001/jamaoncol.2016.1854}

_{5. Transdisciplinary Collaborative Centers for Health Disparities Research focused on precision medicine. National Institutes of Health. Accessed September 22, 2020. https://bit.ly/33NUfMM}

_{6. NIH funds precision medicine research with a focus on health disparities. News release. National Institute on Minority Health and Health Disparities. July 28, 2016. Accessed September 22, 2020. https://bit.ly/3hUkzK7}

_{7. The future of health begins with you. National Institutes of Health. Accessed September 22, 2020. https://allofus.nih.gov/}