Precision medicine is all about understanding and approaching the uniqueness of each patient. We know that individuals from the same geographical population or ethnic origin share common genetic features leading to differences in the response, efficiency, and safety of drugs and therapies among different populations. Therefore, the discovery and development of personalized treatments require analysing a diverse pool of patients that is representative of the natural genetic variability. This is directly connected to ensuring the ethnic diversity of biospecimen collections used at the very early preclinical stages of drug development.
Sadly, even though genetic diversity among geographically distinct populations is a well known fact, patient cohorts used in clinical trials are mainly formed by individuals of European descent 1,2,3. While this issue is gaining momentum, it also becomes clear that the lack of ethnic diversity initiates much earlier in the research pipeline, with the majority of patient-derived cell models being mainly of uncharacterized origin or from white donors.
While the biopharma field has achieved impressive results over the past decades, drug development remains a risky, costly, and lengthy process with a significant number of molecules and treatments failing to be delivered to the market. To bypass these issues and bring healthcare to the next era, scientific and pharmaceutical communities need to identify the causes and find sustainable solutions. Working with proven, representative disease models is one of the first steps. In this article, we take a look at the geographical and ethnic disparities in cancer incidence and biomarkers expression and how they are reflected in early-stage and clinical studies. We reflect on the issues the lack of diversity generates and what actions need to be taken to overcome them.
Geographical disparities in cancer biomarker expression
Personalized medicine aims to oversee and treat disease based on each patient's genetic and molecular signature. This approach is already established as the future direction for modern medicine, showcasing the great importance of taking genetic diversity into consideration when assigning a treatment.
Conducting preclinical and clinical research needs to consider the different patterns characteristic for a given population and ensure that the pool of individuals correctly represents the populations that are expected to be using the tested drug. This mindset is fundamental in the case of cancer. A growing body of evidence reports significant differences in cancer biomarkers expression, incidence and mortality rates, and response to therapy among racially and ethnically diverse populations 4,5.
One of the most remarkable examples is lung cancer, which is associated with the highest mortality rates among malignant diseases. Mutations on the Epidermal Growth Factor Receptor (EGFR) gene are major lung cancer driver mutations, with 80% of Non-Small Cell Lung Carcinoma (NSCLC) patients having an EGFR mutation. Many successful innovative therapies targeting this mutation have been developed in the past years. And while they show promising results for many patients, cancer resistance and relapse remain persistent issues.
A recent study performed by Midha and colleagues evaluated the global map of the EGFR mutation 4. The researchers found that this lung cancer mutation has a higher incidence in women and Asian patients. However, the study also reveals a substantial lack of data regarding EGFR mutation status in lung cancer patients from Africa, the Middle East, Central Asia, Central, and South America, showcasing the crucial need for further analysis on the topic and better ethnic inclusion in clinical studies to widen the therapeutic usability of EGFR mutation status.
This is not an isolated case. While the evidence on the degree of cancer-associated geographical and ethnic disparities continue to grow, in parallel, an increasing number of studies report issues with lack of ancestral data and underrepresentation of ethnic groups in early and clinical-stage research.
The underrepresentation of patients of African descent becomes quite striking in the context of cancers with a clear pattern in this ethnic group. This is the situation with prostate and triple-negative breast cancer (TNBC), characterized with significantly high incidence in African-American men and women 6,7,8. Yet, most of the clinical research in this area is performed on patients of European ancestry 6.
The power of targeted therapies is widely appreciated by scientists, the pharma industry, and regulators. However, the above-listed biogeographical disparities are often disregarded, creating a significant shortcoming for the successful development and implementation of precision treatments and making the relevance and usability of biomarkers and target molecules identified in one ethnic group questionable when applied to another.
"Further, the lack of ethnic diversity in human genomic studies means that our ability to translate genetic research into clinical practice or public health policy may be dangerously incomplete, or worse, mistaken. For example, attempts to use estimates of genetic risk from European-based studies in non-Europeans may result in inaccurate assessment of risk and lack of interventions in under-studied populations," Sirugo et al., 2019.
The lack of ethnic data and diversity is a persistent issue
The issue of ethnic underrepresentation has been recognized already in 1990 when the NIH Office of Minority Health Research was established to focus on health disparities. A few years later, in 1993, it issued guidelines requiring government-funded biomedical research to include women and minorities 9,10. Sadly, these guidelines have been disregarded by the research and pharma communities and today clinical studies are being strongly dominated by individuals of European descent 1,2,3. Moreover, several analyses 11,12,13 show that this lack of ethnic diversity is an issue already at the translational and preclinical stages of research.
After the decoding of the human genome in the early 2000s, Genome-Wide Association Studies (GWAS) became a powerful tool for population genomics providing immense amounts of data for biomedical research. A recent study 3 evaluated the ethnic origin of individuals included in GWAS studies. It demonstrated that 78% were Europeans, with respect to 10% of Asian participants and only 2% and 1% or African and Hispanic, respectively.
Patient-derived cell cultures and tissue samples are the primary disease models used in the very early steps of drug development. Multiple studies have evaluated the availability and nature of ethnic ancestry in cancer cell line collections and patient-derived models 11,12. An analysis performed by Guerrero and collaborators 12 showed that in the NCI Patient-Derived Models Repository (PDMR) 46.1% of collected cancer cells and 62.86% of tumor tissue samples had no records on their ethnic origins. The rest of the samples with such data came primarily from donors of European ancestry and Asian, African American, and Hispanic being vastly underrepresented, with only 0.4% for the latter.
These studies clearly show a persistent issue in the way preclinical disease models and clinical trial cohorts are designed and how they fail to reflect the diversity of the patients. When it comes to cancer treatment, we know that "one size fits all" does not work, and we should not expect it to work either during the drug discovery and development process. Further work is needed to understand and improve how biomarkers identified in one ethnic group can be applied in another and evaluate whether the ethnic and genetic underrepresentation could be the key to non-responsiveness or severe side effects detected in some patients.
"To ensure that medical discoveries, new treatments, and interventions are applicable to all populations for whom they are intended, appropriately representative clinical trial diversity is a moral, scientific, and medical imperative," Clark et al., 2022.
What actions are needed?
The team of Clark and colleagues 10 studied the barriers for minorities in the US to participate in clinical trials, among which they identified mistrust and lack of awareness. This is in line with another analysis from Europe showing that while biobanking and donating tissue for research is widely accepted and practiced in the Nordic countries, this is not the case in the south and east parts of the continent 14.
In the current scenario, the least represented populations are most likely to be the ones where new treatments have lower efficiency, undetected side effects, and biomarkers are not representative. These are all factors potentially fueling further mistrust towards the pharma and medical systems creating a "chicken or the egg" conundrum in which it is not clear whether it is the minorities underrepresentation generating the mistrust or the mistrust is one of the reasons contributing to the issue of ethnic underrepresentation.
To overcome this obstacle, the importance of geographical diversity needs to be understood and implemented at all levels and from the very early stages of biomarker and drug development. Scientists need to consider the ethnic origin of their disease models and consider the geographical disparities in the expression profiles of their target molecules. Biobankers need to collect as much information on the origin and background of donors. Medical doctors should be motivated to participate in clinical and preclinical projects and work towards including patients from diverse ethnic backgrounds. And most of all, patients should be educated, included, and protected. These changes are an objective for each field of biomedical research and the path toward preventing financial and time losses but most of all for ensuring that future patients can benefit from safe and efficient drugs.
How is Audubon tackling this issue?
Audubon supports cutting-edge translational research by providing researchers with access to the crucial biospecimens they need for their projects. With such a responsible position for improving and saving the lives of the next generation of patients, we try to be as vigilant as possible about the challenges and issues related to our field of work and expertise.
We recognize the issues with ethnic underrepresentation in pre- and clinical studies, and therefore put substantial efforts into emphasizing the collection of ethnic status from donors. We aim to deliver highly diversified biospecimen collections to our partners by constantly expanding our clinics' network geographically.
Defining the population's genetic signature is another promising strategy. This is the idea behind our Mars ShotTM Research project, which aims to support better characterization of cancer mutation profiles of the populations in the countries where we have the largest clinical networks.
And nevertheless, we work towards raising awareness about this issue among research partners and clinicians. Our work strongly depends on our partnerships with clinicians who are the connection between patients and the scientific process. It is essential that medical professionals understand the need to engage in such projects. This is one of our top priorities at Audubon, and the key to unleashing the fullest potential personalized medicine has to offer.
- Call for scientific community to increase diversity and inclusivity in medical research. EurekAlert! (n.d.). Retrieved February 2, 2022, from https://www.eurekalert.org/news-releases/634130
- Financial Times. (2019, January 18). How to stop a lack of diversity undermining clinical trial data. Financial Times. Retrieved February 2, 2022, from https://www.ft.com/content/afd0ac7e-fd3a-11e8-b03f-bc62050f3c4e
- Sirugo, G., Williams, S. M. & Tishkoff, S. A. The Missing Diversity in Human Genetic Studies. Cell 177, 26–31 (2019).
- Midha, A. et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 9, 2892, (2015).
- Jia, F. et al. Discordance of Somatic Mutations Between Asian and Caucasian Patient Populations with Gastric Cancer. Mol. Diagn. Ther. 21, 179–185 (2017).
- Matossian, M. D. et al. Patient-Derived Xenografts as an Innovative Surrogate Tumor Model for the Investigation of Health Disparities in Triple Negative Breast Cancer. Womens Health Rep. 1, 383–392 (2020).
- Rencsok, E. M. et al. Diversity of Enrollment in Prostate Cancer Clinical Trials: Current Status and Future Directions. Cancer Epidemiol. Biomarkers Prev. 29, 1374–1380 (2020).
- Lewis, D. D. & Cropp, C. D. The Impact of African Ancestry on Prostate Cancer Disparities in the Era of Precision Medicine. Genes 11, 1471 (2020).
- Popejoy, A. B. Diversity In Precision Medicine And Pharmacogenetics: Methodological And Conceptual Considerations For Broadening Participation. Pharmacogenomics Pers. Med. Volume 12, 257–271 (2019).
- Clark, L. et al. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers. Curr Probl Cardio 44, 148 (2022).
- Kessler, M. D., Bateman, N. W., Conrads, T. P., Maxwell, G. L., Dunning Hotopp, J. C., & O’Connor, T. D. (2019). Ancestral characterization of 1018 cancer cell lines highlights disparities and reveals gene expression and mutational differences. Cancer, 125(12), 2076–2088. https://doi.org/10.1002/cncr.32020
- Guerrero, S. et al. Analysis of Racial/Ethnic Representation in Select Basic and Applied Cancer Research Studies. Sci. Rep. 8, 13978 (2018).
- Jing, L., Su, L. & Ring, B. Z. Ethnic Background and Genetic Variation in the Evaluation of Cancer Risk: A Systematic Review. PLoS ONE 9, e97522 (2014).
- Domaradzki & Pawlikowski. Public Attitudes toward Biobanking of Human Biological Material for Research Purposes: A Literature Review. Int. J. Environ. Res. Public. Health 16, 2209 (2019).