A study comparing sequential biopsies suggests that repeating whole-genome sequencing is not necessary in most cases. Researchers found that 99% of actionable mutations detected by the initial round of sequencing were present in later biopsies, although repeating the test could be beneficial for patients receiving certain therapies.

Repeating whole-genome sequencing (WGS) is not necessary for most patients undergoing treatment for metastatic cancer, a recent study shows (Nat Med 2021 Aug 9 [Epub ahead of print]). Researchers found that 99% of actionable mutations identified in initial biopsies of metastases were present in subsequent samples. However, additional WGS may be beneficial for some patients.

More and more people with cancer are having their tumors analyzed with WGS to match their genomic alterations with a targeted therapy. But to what extent does treatment increase heterogeneity in driver mutations over time? Does repeating WGS provide enough additional information to change treatment plans? These are the questions that a team led by Joris van de Haar, MD, PhD, and Emile Voest, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, investigated.

The researchers performed WGS on biopsy samples from 231 patients in the Netherlands who were receiving treatment for 24 different metastatic cancers, including breast, prostate, colorectal, lung, and skin. All patients had at least two biopsy samples available; the median time between biopsies was 6.4 months.

The tumors accumulated 1,574 to 781,855 mutations between biopsies, but these alterations almost never changed the recommended therapy. Overall, 23% of tumors carried actionable mutations that indicated standard-of-care treatments, and these same mutations were present in 99% of the follow-up biopsies. Additionally, 72% of patients initially harbored mutations in their metastases that made them eligible for clinical trials, and 94% of the patients retained these mutations; only 9% gained biomarkers that would make them newly eligible for trials. Given that these alterations are essential for cancer cell survival, “it makes sense that tumors don't lose these variants and that the mutations were already present” at the first biopsy, van de Haar says.

According to Voest, the results indicate that almost all patients with metastatic cancer require comprehensive genomic profiling of their tumors only once—if not with WGS, then with large panels that assess at least 500 genes. Some scientists worry about performing WGS prematurely and missing key mutations that arise later in the disease, but the study allays that concern and supports performing WGS as early as possible, Voest says.

However, additional WGS may be advisable for patients undergoing treatment with small-molecule inhibitors or hormone blockers, both of which can induce mutations that may necessitate changes in therapy. The team found that targeted genes mutated in 21% of patients receiving small-molecule inhibitors and 22% of patients receiving hormone inhibitors. Researchers now need to determine whether these patients would benefit more from another WGS analysis or from testing with specific gene panels.

Repeating WGS could be particularly beneficial for patients with lung cancer who are undergoing treatment with small-molecule inhibitors. In the study, all three patients for whom a second round of WGS suggested a different treatment had non–small cell lung cancer and were receiving these drugs.

Kornelia Polyak, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who wasn't connected to the study, is not surprised that the researchers did not detect changes in actionable mutations in most cases. Such mutations are not very common, the study compared only metastatic lesions that are already highly heterogeneous, and the gap between biopsies was short, she says. Moreover, she adds, few patients were responding to therapy, and thus there was little selection that would drive tumor evolution. Polyak agrees that repeating WGS “would not be worth doing at a population level.”

Another independent expert, Sameek Roychowdhury, MD, PhD, of The Ohio State University Comprehensive Cancer Center in Columbus, calls the study “very helpful” for clarifying the value of repeating WGS. He agreed, however, that second biopsies are still valuable for tracking evolution of cancers with alterations in genes such as ALK, EGFR, ESR1, and BRCA1/2 that are treated with targeted therapies. –Mitch Leslie

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©2021 American Association for Cancer Research.
2021
American Association for Cancer Research.