NEW YORK – A significant portion of young adults with early-onset cancers may harbor germline mutations, suggesting the need for universal germline testing in this population, according to new data presented during the second virtual session of the American Association for Cancer Research's annual meeting.
The findings, presented by Zsofia Stadler of Memorial Sloan Kettering, are derived from the germline genetic testing for 88 genes that is available to cancer patients who have their tumors sequenced by the MSK-IMPACT panel and consent to additional germline analysis. Over the course of four years, researchers performed germline analysis on 1,201 patients between the ages of 18 and 39 who had been diagnosed with cancer.
Stadler and colleagues did not evaluate all 1,201 patients as one group but stratified them into "early-onset" or "young-adult" patients. The early-onset patients were defined as those diagnosed with cancers that occur far more often in patients who are older, including breast, colon, pancreas, kidney, and ovarian cancers. The young adult patients, on the other hand, had cancers typically seen in younger patients, including sarcoma, brain cancer, testicular cancer, and thyroid cancer.
For the germline analysis, researchers analyzed results from 877 patients with early-onset cancers and 324 patients with young-adult cancers. "I don't think anyone has really categorized young-adult cancer in this particular way," Stadler said in an interview. "But it's really interesting from a genetic perspective."
Indeed, Stadler and her colleagues found a significant difference in the inherited germline mutation prevalence between the two groups. Among patients with early-onset cancers, 21 percent harbored germline mutations associated with these cancers, and among patients with young-adult cancers, this figure was 13 percent. In the early-onset group, the most common mutations identified were BRCA1, BRCA2, ATM, CHEK2, and Lynch-syndrome associated genes, and in the young-adult group, the most common germline findings included TP53 and SDHA mutations, which is consistent with Li-Fraumeni syndrome.
"We have to recognize that young adults with cancer are a heterogeneous group, and that we can't generalize," Stadler said. "Because both the prevalence and the range of mutations that we see is different based on how we classify these patients."
Having found that over one-fifth of young adults with early-onset cancers had inherited cancer risk mutations, Stadler said, "I think that our data supports that, at least in the patients who are younger and have early-onset cancers, broad or agnostic germline testing should be pursued."
Part of the reason for this, Stadler emphasized, is that germline findings can have significant implications not only for these patients' long-term cancer risk surveillance and family planning, but also for their treatment plans. She offered the hypothetical example of a young woman with early-onset breast cancer found to harbor a germline BRCA mutation. This young woman, in addition to informing family members that they, too, might have inherited the same cancer risk mutation, might opt to have a bilateral mastectomy as opposed to a lumpectomy, or perhaps a prophylactic salpingo-oophorectomy to reduce her risk of developing ovarian cancer as well.
Beyond these risk-reducing measures, identifying a BRCA mutation could indicate that a patient might benefit from targeted therapies, such as a PARP inhibitor. Stadler also offered the example of patients found to have inherited Lynch syndrome-associated germline mutations. Not only would these patients benefit from annual colonoscopies and other risk-reducing measures, she said, but this information could also indicate that their tumors might respond well to immune checkpoint inhibitors.
"So, [these germline mutations] have major implications in terms of the risk of second primary cancers," Stadler said. "But they could also have oncological treatment implications."
These young adult-specific germline testing data come in the wake of research that Stadler and colleagues presented several weeks ago at the American Society of Clinical Oncology's virtual annual meeting, which also highlighted the clinical utility of germline findings in informing cancer treatment. In that analysis, researchers reported that out of 12,000 patients treated at MSK who receive germline testing, nearly 600 patients with recurrent or metastatic cancers harbored actionable germline mutations, and 44 percent of them went on to receive targeted drugs.
In recent years, the National Comprehensive Cancer Network has updated its guidelines to recommend germline testing for specific inherited gene mutations in young adult populations. For example, the NCCN recommends testing for BRCA1/2 mutations in women with breast cancer under age 45, and such testing is commonly done in clinical practice.
"But, generally, the NCCN guidelines really limit the testing to either a couple of genes or a small panel of genes," Stadler said, pointing out that germline testing guidelines aren't well established for many other young-adult cancers and that there is value to using a broader panel such as the 88-gene panel she and her colleagues use at MSK.
Even though the well-established BRCA1 and BRCA2 germline mutations were among the most common findings in this early-onset group, incidental findings could have significant treatment implications as well. For this particular study, Stadler and her colleagues have not yet broken out the proportion of detected germline mutations that were incidental or unexpected, which would not have been identified following current testing guidelines. This information will likely be included in a forthcoming paper.
However, Stadler pointed out that a prior MSK-IMPACT-based study, which assessed germline susceptibility overall, demonstrated that about half of patients had incidental findings that wouldn't have been detected otherwise.
In addition to forthcoming analyses of incidental findings, Stadler and colleagues have plans to present data from a matched tumor-normal analysis at a later date. The data on this are based on comparing sequencing data from blood and tumor samples in order to pinpoint which inherited germline mutations are really driving the tumors in these young patients. "It will add another measure of causality," Stadler said.
Additionally, in a presentation given to members of the media prior to the AACR meeting, Stadler shared that another future element of this research will be to evaluate these patients' individual family histories of cancer to further decipher their individual risks.
As a caveat to the findings presented, Stadler did point out that these data were only derived from germline testing in patients treated at MSK, and accordingly, some cancers may have been over- or underrepresented. Additionally, the researchers only tested patients with solid tumors, and young adult patients with hematologic malignancies were not factored into the study.