New research highlights the importance of germline analysis in the identification of germline alterations for cancer treatment. According to a large analysis presented at the ASCO 2020 virtual annual meeting, nearly 9% of patients with advanced cancer harbor a targetable germline variant. Therefore, germline analysis is crucial for selecting the best FDA-approved therapies as well as for clinical trial participation with germline-targeted therapeutics.
“Our study represents the first comprehensive assessment of the clinical utility of germline alterations for therapeutic actionability in a population of patients with advanced cancer,” said Zsofia K. Stadler, MD, Medical Oncologist, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City, who presented the results. “Of those tested, 7.1% harbored a germline variant with targeted therapeutic actionability, and 8.6% of patients had a targetable germline variant using less stringent criteria,” Dr Stadler added.
Unlike somatic mutations that have implication for treatment only, the identification of cancer susceptibility syndromes through germline alterations is also important for cancer surveillance, risk reduction, and cascade genetic testing for at-risk family members. However, the clinical impact of germline findings on targeted cancer treatment is less well-known.
For this pan-cancer analysis, Dr Stadler and colleagues used MSK-IMPACT, a targeted tumor-sequencing test of more than 400 oncologic genes, to analyze tumor and normal blood samples from nearly 12,000 patients between 2015 and 2019. The researchers reviewed the medical record of patients with likely pathogenic germline alterations in genes with known therapeutic targets to identify germline-targeted treatment in a clinical or a research setting.
The germline variants were then classified into tiers based on evidence for therapeutic actionability. Tier 1 alterations had sufficient evidence of clinical benefit to gain regulatory approval for therapies, whereas Tier 2 alterations had similar quality and level of evidence, but without regulatory approval.
Among the nearly 12,000 patients tested, breast, prostate, colorectal, and pancreas cancers comprised nearly 50% of the cohort. The prevalence of germline mutations was 17%, with 11% of the patients harboring pathogenic alterations in high- or moderate-penetrance cancer predisposition genes. This variant prevalence is consistent with previous analyses of patients undergoing germline analysis, said Dr Stadler.
When limited to genes with actionable targeted therapies in Tiers 1 and 2, 7.1% of the patients harbored a targetable germline alteration. Of these, 50% were BRCA alterations and 20% were Lynch-related mutations. Tier 2 genes, including PALB2, ATM, and RAD51C or RAD51D genes, represented nearly 25% of the targetable genes.
When less stringent criteria were applied by adding Tier 3 genes and genes associated with homologous recombination repair DNA, 8.6% of patients had a targetable mutation.
Of the 849 patients who had germline variants with actionable therapeutics, 593 had recurrent or metastatic disease, and 44% of these patients received therapy targeting the alteration.
When analyzed by specific genes or groups of genes, 50% of BRCA1 or BRCA2 carriers and 58% of patients with Lynch syndrome received targeted treatment. Within the Tier 2 genes, 40% of PALB2, 19% of ATM, and 37% of RAD51C or RAD51D patients received a poly (ADP-ribose) polymerase (PARP) inhibitor.
Of the 176 individuals harboring BRCA mutations, 56% had advanced breast or ovarian cancer, for which an FDA-approved PARP inhibitor is available. However, because this study ended before the FDA approval of a PARP inhibitor for advanced cancer, said Dr Stadler, more than 40% of the patients only received a PARP inhibitor in the setting of a clinical trial.
“With the emergence of novel targeted treatments with new FDA indications, the therapeutic actionability of germline variants is likely to increase over time,” Dr Stadler concluded.