Germline Testing Offers Valuable Insights in the Treatment of Early-Onset and Advanced Cancers

TON - October 2020, Vol 13, No 5

Results from 2 studies highlight the increasingly important role of germline testing in the management of patients with cancer. These findings were presented by Zsofia K. Stadler, MD, Medical Oncologist, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York City.

Germline Analysis Valuable in Selecting Therapies for Patients with Advanced Cancer

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 Dr Stadler during the presentation.

“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,” she concluded.

Surprisingly High Prevalence of Germline Mutations in Young Adults with Early-Onset Cancer

Patients with “early-onset cancer”—that is, cancers that typically do not occur in younger adults (aged 18-39)—had a significantly higher rate of germline mutations than patients with the “young adult cancers” that are typically seen in this age-group (21% vs 13%, respectively; P = .002), according to results of a new study. The results were presented by Dr Stadler at the 2020 AACR virtual annual meeting and were highlighted at a meeting press cast.

In this study, early-onset cancers were defined as cancers that are not typically seen in younger patients; young adult cancers were defined as those likely to occur at younger ages.

Early-onset cancers—such as breast, colon, pancreatic, kidney, prostate, and ovarian—are rarely seen in young adults. Cancers that are often seen in young adults include brain, testicular, and sarcoma.

“Although they only represent about 4% of all cancers, young adults with cancer, defined as those diagnosed with cancer between the ages of 18 and 39, face unique challenges,” stated Dr Stadler.

“Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is important, as it can result in a substantial change in clinical management, such as increased cancer surveillance aimed at early detection, and risk-reducing surgery to prevent new cancers, and may even have reproductive implications for young families,” she added.

“These results suggest that there is a role for genetic testing in young adults with early-onset cancer irrespective of tumor type,” Dr Stadler emphasized.

The study included 1201 young adults diagnosed with cancer between 2015 and 2019 at Memorial Sloan Kettering Cancer Center. The presence of germline mutations was assessed using the MSK-IMPACT next-generation sequencing assay that includes a panel of 88 genes known to be associated with susceptibility to cancer. The investigators analyzed DNA from blood samples of these patients for this study.

The SEER (Surveillance, Epidemiology, and End Results) registry data were used to identify 977 patients with early-onset cancers, as defined in this study.

The analysis showed that the most common early-onset cancers among these patients were colorectal (20%), breast (39%), kidney (6%), pancreatic (6%), and ovarian (6%). In addition, young adult cancers were diagnosed in 324 patients; of these, the most common were sarcoma (36%), brain (23%), testicular (17%), and thyroid cancers (9%).

Among the early-onset breast, kidney, or pancreatic cancers, the most common germline mutations were BRCA1 or BRCA2 (4.9%), ATM (1.6%), CHEK2 (1.7%), and in genes associated with Lynch syndrome (2.2%). Germline TP53 mutations (2.2%) and SDHA/B (1.9%) were the most common in patients with young adult cancers.

“The findings are surprising. The prevalence of these germline mutations is significantly higher [in young adults] than previously thought: 21% of early-onset patients and 13% of patients with young adult cancer had germline pathogenic mutations, which has implications for genetic testing, surveillance, and counseling,” stated AACR Past President Elaine R. Mardis, PhD, FAACR, Co-Executive Director, Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, speaking at a premeeting press cast.

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