Breast Cancer Genetics Vary Dramatically by Ancestry

According to Nature, researchers analyzed 40,425 breast tumors to identify associations between genetic ancestry and tumor mutations, representing the largest study of its kind. The cohort included predominantly European ancestry (77%), followed by African (13.8%), East Asian (3.3%), Indigenous American (1.9%), and South Asian (1.1%) groups. The study identified 91 significant associations between tumor somatic mutations and ancestry across 58 genes, with African ancestry showing higher frequencies of copy number alterations in genes like MYC and FGFR1, while European ancestry was associated with lower frequencies of TP53 mutations but higher PIK3CA mutations. Notably, Indigenous American ancestry showed dramatically elevated BRCA1 mutations with an odds ratio of 6.9, and East Asian ancestry was strongly associated with EGFR mutations that also appear in other cancers. These findings highlight how ancestry influences cancer biology beyond just social determinants of health.

The Precision Medicine Revolution Hits a Crossroads

This research fundamentally challenges the one-size-fits-all approach to cancer treatment that has dominated oncology for decades. The discovery that copy number variations and specific mutations vary so dramatically across ancestral groups means that targeted therapies may need to be tailored not just to cancer type, but to patient ancestry. For instance, the finding that African ancestry patients have fewer mutations in the PI3K-AKT pathway—including PIK3CA mutations that are commonly targeted by drugs like alpelisib—suggests these treatments might be less effective for this population. Conversely, the elevated EGFR mutations in East Asian patients could mean they benefit more from EGFR inhibitors even in breast cancer, expanding beyond the established lung cancer applications.

Biology Versus Access: Untangling Health Disparities

For years, the higher mortality rates from breast cancer among Black women have been primarily attributed to socioeconomic factors, later diagnosis, and healthcare access barriers. This study reveals there’s a biological component that cannot be ignored. The higher prevalence of TP53 mutations and copy number alterations in African ancestry patients correlates with more aggressive, ER-negative breast cancer subtypes. This doesn’t diminish the importance of addressing systemic healthcare inequities, but it does mean we need dual approaches: improving access while also developing ancestry-informed treatment protocols. The research methodology itself, using sophisticated principal component analysis for ancestry determination, represents a significant advancement over self-reported race in clinical studies.

The Urgent Need for Diverse Clinical Trials

These findings expose a critical weakness in how cancer drugs are developed and approved. Most clinical trials remain overwhelmingly white—often 80-90% European ancestry—meaning we’re essentially testing treatments on a biological subset of the population. When drugs like PIK3CA inhibitors show promise in predominantly white trials, we might be missing that they’re less effective for other groups. The pharmaceutical industry needs to completely rethink trial design and recruitment strategies. More concerning, we may have already approved drugs that work well for one ancestry group while providing minimal benefit to others, wasting precious treatment time and resources for patients who deserve better outcomes.

Rethinking Diagnostic Standards and Screening

The standard immunohistochemistry and genetic testing panels used in breast cancer diagnosis were developed primarily using European populations. This research suggests we might need ancestry-adjusted testing protocols. For example, the dramatically elevated BRCA1 and RAD51C mutations in Indigenous American populations indicate that genetic counseling and testing criteria should be different for these communities. Similarly, the unique mutation patterns mean that the prognostic value of certain genetic markers might vary by ancestry. A mutation that predicts poor outcomes in one group might not carry the same significance in another, potentially leading to overtreatment or undertreatment based on flawed assumptions.

Important Caveats and Research Limitations

While groundbreaking, this study has important limitations that temper immediate clinical application. The sample sizes for some ancestral groups—particularly Indigenous American and South Asian—remain relatively small, meaning some associations might be overestimated or others missed entirely. The study also focuses on somatic tumor mutations rather than germline genetics, leaving open questions about whether these differences reflect inherited predisposition or tumor evolution pathways. Additionally, the research used genetic ancestry determination rather than self-identified race, which provides more precision but doesn’t capture the complex interplay of genetics, environment, and culture that influences health outcomes.

Toward Truly Personalized Cancer Care

The path forward requires massive investment in diverse biobanks and research cohorts that reflect global genetic diversity. We need similar studies in other cancer types to determine if these ancestry patterns are breast-cancer-specific or represent broader trends. The pharmaceutical industry should prioritize developing ancestry-specific clinical trials and potentially even ancestry-informed drug development pipelines. Most importantly, healthcare systems need to prepare for the ethical and practical challenges of implementing ancestry-informed treatment protocols without reinforcing harmful racial stereotypes or creating new forms of discrimination. This research doesn’t suggest rigid biological determinism by race, but rather highlights the genetic diversity within our species that medicine has largely ignored until now.