Genomics Add Insight Into Worse Colorectal Cancer Outcomes in Black Patients

ORLANDO -- Black patients with colorectal cancer (CRC) had fewer targetable genetic mutations and genomically were less likely to qualify for immunotherapy, possible factors in their worse outcomes, a large retrospective study showed.

The analysis showed that patients of African ancestry had a median overall survival (OS) almost 2 years shorter than that of patients with European ancestry. Genomic profiling showed that 13.5% of patients with African ancestry versus 20.4% of the European ancestry group met FDA criteria for immunotherapy, such as microsatellite instability (MSI) or high tumor mutation burden (TMB). Among patients with microsatellite stable (MSS) or low TMB, twice as many with European ancestry had targetable mutations compared with the patients with African ancestry.

The African ancestry group also had worse survival regardless of the alteration status (mutated or wild type) of the tumor suppressor gene APC (adenomatous polyposis coli), often called the "first hit" in development of colon cancer, reported computational biologist Henry Walch, MS, of Memorial Sloan Kettering Cancer Center in New York City, at the American Association for Cancer Research annual meeting.

"This is a complex problem involving many unseen factors, and the genomic landscape is a piece of the larger puzzle," said Walch. "We're working on getting comprehensive treatment information, environmental exposure information, lifestyle and socioeconomic factors that are known to play an important role here.

"Our future work will include incorporating these components into our models with the ultimate goal of identifying opportunities to intervene and improve outcomes for this underserved health population," he added.

With fewer actionable mutations, patients with African ancestry might have fewer treatment options, especially with the types of drugs that have improved outcomes in many patients with colon cancer, said Walch. He declined to say whether the genomic differences may apply to other types of cancer, noting that he specializes in CRC.

"I think [the study] highlights the need to find alternative treatment strategies and highlights the need to find new targets for these patients, because they don't have the molecular profiles that would qualify them for more powerful treatments that they might receive otherwise," said Walch.

The findings quite likely apply to other types of cancer where racial/ethnic outcome disparities have been observed, said Umut Sarpel, MD, of Mount Sinai Health System in New York City.

"We already know that there are race-based differences in the patterns of tumor types found in other cancers -- for example, triple-negative breast cancer," she told MedPage Today via email. "It is such a complex matter, because while we know that race is a social construct, this study provides clear evidence that racial ancestry does correlate with certain tumor types. These findings underscore the call to include racially diverse patients in clinical trials."

The treatment implications are consistent with an ongoing therapeutic transformation and transitioning away from a one-size-fits-all approach.

"We are moving toward treating a tumor based on its genetic signature, instead of a one-size-fits-all approach -- which, more accurately means one size fits non-pregnant, non-incarcerated, non-HIV, [etc] white people, who make up the majority of clinical trials," Sarpel added. "The authors state that patients with African ancestry had fewer clinically actionable alterations, but a slightly different take on that is that patients with African ancestry had fewer alterations in the cancer genes that have been studied."

Black patients with CRC have a higher incidence of the disease, as well as worse outcomes, including survival. The explanation is multifaceted, likely reflecting socioeconomic inequalities and differences in risk factors and access to care, Walch noted. The contributions of germline and somatic genetic alterations to the outcome differences remain unclear.

To delve into potential genetic contributions to the outcome disparity, the investigators reviewed data for 4,441 patients with CRC treated at Memorial Sloan Kettering since 2014. As part of patient management, tumor specimens from all patients were analyzed by the cancer center's next-generation sequencing assay.

The cohort comprised 3,265 patients of European ancestry, 245 of African ancestry, 263 of Asian ancestry, 89 of South Asian origin, 15 North American natives, and 564 with ancestry admix.

Analysis of clinical outcomes showed that Black patients with CRC had a median OS of 45.7 months versus 67.1 months for the European ancestry subgroup (P<0.0001). Genomic analysis showed that significantly fewer Black patients met criteria (such as MSI or high TMB) for treatment with targeted therapies or immunotherapy (P=0.008).

Among patients with MSS and low TMB tumors, 5.6% of Black patients versus 11.2% of whites had clinically actionable genetic alterations (P=0.01). Most of the difference was driven by a lack of BRAF mutations in Black patients (1.8% vs 5.0%, P=0.04), said Walch. APC alterations (versus wild type) were associated with significantly better OS among the European (64.6 vs 45.6 months, P<0.0001), Asian (63.1 vs 35.0, P=0.0015), and South Asian (NR vs 39.4 months, P<0.001) subgroups. In contrast, Black patients with or without APC alterations had similar median OS (45.0 vs 45.9, P=0.91).

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