African Ancestry Is Associated With Fewer Actionable Alterations in CRC

Henry Walch, MS

Patients with African ancestry with colorectal cancer (CRC) have fewer actionable gene mutations than those with European ancestry, leading to fewer targeted treatment options in this population, according to findings from a study that were presented at the 2023 AACR Annual Meeting.^1,2

Of a cohort of patients with CRC treated at Memorial Sloan Kettering Cancer Center in New York, New York, patients with African ancestry had a median overall survival (OS) of 45.7 months compared with 67.1 months in those with European ancestry (P < .0001). Patients with African ancestry also had worse outcomes compared with those of East Asian (P = .0169) and South Asian (P = .0077) ancestry.

“African American patients are known to have worse clinical outcomes from colorectal cancer than patients from other racial backgrounds,” lead study author Henry Walch, MS, of Memorial Sloan Kettering Cancer Center, stated in a press release. “However, the extent to which differences in germline or somatic genomic alterations influence outcomes remains unknown.”

According to the American Cancer Society, between 2015 and 2019, the incidence of CRC in Black patients in the US was higher than that in White patients, at 41.7 cases for every 100,000 Black people vs 35.7 cases for every 100,000 White people. Additionally, the CRC mortality rates from 2016 to 2020 demonstrate a disparity between Black and White patients with CRC, at 17.6 instances of mortality for every 100,000 Black people vs 13.1 instances for every 100,000 White people.²

Black patients are also more likely than White patients to be diagnosed with metastatic CRC. Between 2015 and 2019, 25% vs 21% of all CRC diagnoses were metastatic in Black and White patients, respectively. In addition, across all CRC stages, between 2012 and 2018, the 5-year survival rate was 60% in Black patients vs 65% in White patients.

This study aimed to determine the differences in the presence of actionable mutations between patient groups of different ancestries.¹ It included 4441 patients who received treatment for CRC at Memorial Sloan Kettering Cancer Center between 2014 and 2022 and were sequenced with the next-generation tumor-normal sequencing assay MSK-IMPACT, which can detect mutations in up to 505 genes. Based on their sequencing data, patients with a predominant ancestry fraction of at least 80% were stratified into European (n = 3265), African (n = 245), East Asian (n = 263), or South Asian (n = 89) subgroups. Fifteen patients with predominantly North American ancestry and 564 patients with admixed ancestry were excluded because of the small sample size and cohort heterogeneity, respectively.

This study used the 5-level precision oncology knowledgebase OncoKB to determine the levels of therapeutic actionability of all genomic alterations found in the study cohort. Biomarkers in level 1 are recognized by the FDA as predictive of response to FDA-approved drugs in the corresponding indications. Biomarkers in level 2 are recommended by guidelines, such as the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, and are predictive of response to FDA-approved drugs in the corresponding indications. Biomarkers in level 3A contain compelling clinical evidence to support their capabilities of predicting response to drugs in the corresponding indications. Biomarkers in level 3B are standard care or investigational biomarkers that predict response to a drug that is FDA approved or investigational in another indication. Biomarkers in level 4 contain compelling biological evidence that supports their predictive capabilities of response to a drug.

Compared with patients with European ancestry who had microsatellite stable disease and low tumor mutational burden (TMB), those with African ancestry had fewer actionable alterations, including BRAF V600E alterations, for which encorafenib (Braftovi) plus cetuximab (Erbitux) is available; ERBB2 amplifications, for which trastuzumab (Herceptin) plus pertuzumab (Perjeta) is available and lapatinib (Tykerb) plus trastuzumab, as well as fam-trastuzumab deruxtecan-nxki (Enhertu), are being investigated; and KRAS G12C alterations, for which adagrasib (Krazati) plus cetuximab is available. The rates of clinically actionable alterations were 5.6% and 11.2% in patients with African vs European ancestry. This disparity in actionable alterations was predominantly driven by the lower incidence of actionable BRAF mutations in patients with African ancestry (P < .05).

Regarding immunotherapy qualifications, patients with African or East Asian ancestry had fewer microsatellite instability– and TMB-high tumors vs patients with European ancestry and were therefore less likely to qualify for immunotherapy. In total, 13.5% of patients with African ancestry qualified for immunotherapy vs 20.4% of those with European ancestry (P < .05).

APC is the most frequently altered gene in CRC. The presence of APC alterations is associated with worse patient outcomes vs the presence of APC wild type (P < .001). In this study, patients with African ancestry had similar outcomes regardless of their APC status (wild-type, n = 41; altered, n = 173; P = .91). In contrast, the presence of APC alterations in patients in the European (wild-type, n = 663; altered, n = 2064), East Asian (wild-type, n = 65; altered, n = 169), and South Asian (wild-type, n = 25; altered, n = 53) subgroups was associated with improved OS compared with the presence of wild-type APC, with respective P values of less than .0001, and equal to .0015 and .012. Furthermore, a multivariate outcome analysis incorporating known CRC driver genes, primary tumor location, disease stage at diagnosis, sex, and age showed a significant association between APC status and outcomes in patients with European ancestry (HR, 0.64; 95% CI, 0.52-0.79; P < .001), but not for those with African ancestry (HR, 0.74; 95% CI, 0.31-1.7; P = .495).

“Our findings provide novel insights into the genomic basis of racial disparities in colorectal cancer andhighlight the need of ancestry stratification for the analysis of associations between molecular profiles and clinical outcomes,” Walch explained in the press release.

The investigators noted that this study was limited by the absence of comprehensive treatment information, lifestyle factors, environmental exposures, and socioeconomic factors that, in addition to the genomic landscape, likely play a role in patient outcomes. Future studies will evaluate these aspects to further understand the reasons behind poor CRC outcomes that disproportionately affect patients with African ancestry.

“Our ultimate goal is toidentify opportunities to intervene and improve outcomes in this underserved population,” Walch concluded in the press release.

Disclosures: Dr Walch reports no disclosures.

References

1. Walch HS, Luthra A, Arora KS, et al. Clinical genomic profiling identifies lower frequency of therapeutically actionablealterations and lower prognostic value of APC inactivation in colorectal cancer patients of African ancestry. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023. Orlando, FL. Abstract 1908.
2. Colorectal cancer patients with African ancestry had fewer clinically actionable alterations than White patients. Press release. AACR. April 17, 2023. Accessed April 17, 2023. https://aacr.ent.box.com/s/7z0rqhxgralzm2kdvyfissqiy4v53vqr
3. American Cancer Society. Colorectal Cancer Facts & Figures 2023-2025. Accessed April 17, 2023. https://www.cancer.org/research/cancer-facts-statistics/colorectal-cancer-facts-figures.html