Genomic Characterization of NSCLC in African Americans: A Step Toward “Race-Aware” Precision Medicine

Lung cancer continues to be the second leading cancer diagnosis in both men and women in the United States even though it is one of the few cancers whose main cause, cigarette smoking, is known. Racial differences in incidence exist despite African Americans reporting lower levels of cigarettes smoked per day than whites.¹ Furthermore, it is the leading cause of cancer-related deaths in the United States, with 5-year survival rates hovering at approximately 20%.² Although remaining low, overall survival in advanced NSCLC has improved in the small subset of cases with actionable molecular profiles.^3–6 Most recently, immunotherapy has proven effective for advanced NSCLC without EGFR mutations or ALK translocations.⁷ Immunotherapeutic agents directed at programmed cell death-protein 1 (PD-1), programmed death-ligand 1 and CTLA4 pathways, and their combination with platinum-based chemotherapy, are now front-line therapy for advanced NSCLC, with a median overall survival ranging from 15.9 months to 30 months reported by landmark clinical trials.^7–10 The paradigm shift in the treatment of advanced NSCLC, largely driven by precision medicine approaches, has been fundamentally shaped by the foundations laid through the molecular and genetic characterization of large numbers of tumor specimens.¹¹ However, these considerable advances have been based largely on research conducted in white populations. In lung cancer, The Cancer Genome Atlas (TCGA) published a genome that included only 83 African American samples, all collected before the introduction of immunotherapy. In addition, few African Americans (<4%)¹² have been included in the targeted therapy or immunotherapy trials that drive current treatment decision making, suggesting precision medicine approaches may not be optimized for African Americans. The comprehensive evaluation of tumor genomic profiles in African Americans is needed to ensure that treatment guidelines are “race-aware.”

Arauz et al.¹³ sought to address this lack of well-characterized African American NSCLC samples through whole-exome sequencing of tumor-normal tissue pairs from participants in a study conducted by the National Cancer Institute and the University of Maryland. The 82 participants, including 47.6% with squamous cell carcinomas and 43.9% with adenocarcinomas, were accrued between 1984 and 2013, highlighting the slow pace and difficulties of enrolling a large African American population with sufficient tumor and matched normal tissue for this work. It should also be noted that only 22% of the samples came from women, and as genomic profiling is rare in African Americans, results in women are likewise limited. Most patients (59.8%) had stage I disease and another 28% had stage II disease reflecting the surgical requirement for inclusion and having enough tissue for analysis. Comparable with that reported in European Americans, tumor mutation burden was high, and the expected transition-to-transversion ratios and mutational signatures associated with cigarette smoke exposure were reported in African Americans. Whole-exome sequencing identified 178 significantly mutated genes at p less than 0.05, five of which (TP53, STK11, RB1, CDKN2A, PIK3CG) were over the false discovery threshold of p less than 0.1. STK11 mutations, in particular, were significantly higher in African Americans with both squamous cell carcinomas and adenocarcinomas than those reported in European Americans in TCGA. The authors were able to reveal that African Americans with STK11-mutated adenocarcinomas had decreased interferon signaling and these mutations often co-occurred with KRAS alterations. These findings may be especially relevant in the context of response to immunotherapy because STK11 mutations have been implicated as one of the major drivers of primary resistance to PD-1 pathway inhibitors in nonsquamous NSCLC.¹⁴ In addition to mediating resistance to PD-1 inhibitors, emerging evidence suggests that STK11 mutations promote tumor growth and increase cell motility through differential expression of genes encoding vesicle trafficking-regulating molecules.¹⁵ TCGA data, although collected from mostly white patients, reveal that patients with NSCLC with STK11 mutations have shorter disease-free survival, overall survival, and disease-specific survival compared with those with STK11 wild-type NSCLC. Neither the TCGA sample nor the samples from African Americans described were derived from patients treated with immunotherapy. Nevertheless, the higher prevalence of STK11 mutations, in addition to mutations in other tumor-suppressor genes RB1 and CDKN2A, may explain the biological differences contributing to racial disparities in NSCLC outcomes among African Americans that are not fully explained by behavioral, environmental, and economic factors.

Although the study is limited by the lack of clinical outcomes data, the findings from whole-exome sequencing of paired tumor-normal tissue of a relatively large cohort of African American patients with NSCLC provide a unique opportunity for hypothesis generation. The authors detail additional potential pathways suggested by more marginally significant findings. As so little is known about the mutation profiles in African Americans with NSCLC, this extensive characterization is welcome and provides many avenues for expanded research. What is overwhelmingly evident is the need for more comprehensive genomic profiling in African Americans being treated with the most current therapies if we are to uncover biological mechanisms underlying racial disparities in NSCLC incidence and survival. As precision medicine-driven treatment strategies and immunotherapy make their way into the therapeutic landscape of every stage of NSCLC, these data may pave the way for “race-aware” prospective studies evaluating different treatment strategies to ameliorate racial disparities in NSCLC.

In conclusion, racial disparities in lung cancer incidence and mortality continue, even as we make progress with targeted treatments and immunotherapy. Drivers of these disparities are largely unknown, but understanding the genomic profile of tumors in diverse population will continue to be necessary to understand the impact of unique racial and ethnic characteristics on incidence and survival outcomes. Arauz et al.¹³ greatly contribute to this effort. Their findings will drive the search for novel targets and biomarkers of treatment response, or a lack thereof, among African Americans. The scope of this endeavor is hampered by the limited numbers of African Americans in clinical trials and the often limited tissue available from those with advanced-stage disease. As treatment advances have taken place, particularly with standard-of-care targeted therapy and immunotherapy, resources need to be targeted toward studies that specifically sample minority populations. The molecular/genetic data will require companion detailed clinical characteristics be collected such as quantitative smoking history, diagnosis age, sex, tumor stage, treatment modalities, response to a variety of therapeutic agents, and survival outcomes. With the rapid pace at which precision oncology has been advancing, data collection efforts in underrepresented minority populations are essential if the advances in targeted treatment are to be applied effectively in these populations.