1. Froelich, Warren

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Young adults with early cancers frequently associated with older patients have a higher percentage of inherited or germline mutations than previously thought, according to a study presented during the American Association for Cancer Research (AACR) Virtual Annual Meeting II, held between June 22-24.

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Although representing only about 4 percent of all cancers, young adults aged 18-39 with cancer face unique challenges and, according to the study, should be encouraged to seek genetic testing to understand potential reproductive implications, counseling about risk-reducing surgeries, and screening for second primary cancers.


"Moreover, young adults need this genetic information to identify at-risk family members, including potentially young siblings or even children who should pursue genetic testing and, if positive, appropriate cancer screening for preventive measures," said Zsofia K. Stadler, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK), who presented the study's findings during a press briefing.


Study Details

Previous research suggested that if a person has a genetic mutation, his or her first-degree relatives-sisters, brothers, sons, and daughters-have a 50 percent risk of having the same mutation.


For this study, Stadler and colleagues conducted germline analyses on 1,201 young adults aged 18-39 who were diagnosed with cancer between 2015 and 2019 at Memorial Sloan Kettering. The researchers analyzed blood-based DNA sequencing data from these patients using the germline protocol of MSK-IMPACT to study up to 88 genes associated with cancer risk.


The team split their study group into two categories based on SEER (Surveillance, Epidemiology, and End Results) data, a program of the National Cancer Institute that collects incidence and survival information in population-based cancer registries across the United States.


The first category consisted of 324 patients with "young adult" cancers, malignancies typically seen in young or pediatric patients, including sarcoma, brain, testicular, and thyroid. The second category included 877 patients with "early-onset" cancers found more often in adult patients, including breast, prostate, colon, lung, pancreas, kidney, and ovaries.


Their analysis showed a significant difference in the inherited germline mutations prevalence between the two groups. Among the early-onset patients, some 21 percent harbored germline mutations associated with cancer, while just 13 percent were found in young adult patients.


"I think what our study demonstrates is that young adult cancer patients really represent a heterogeneous group," Stadler said. "The distinct set of germline variants appear to suggest that patients with early-onset cancers harbor mutations similar to those also found in older individuals with cancer, but at a higher prevalence."


Among the early-onset patients, the most frequent mutations were BRCA1 and BRCA2, accounting for 4.9 percent of the mutations, as well as ATM, CHEK2, and genes linked to Lynch syndrome, including MLH1, MSF2, MSH6, PMS2, and EPCAM. For those with young adult cancers, the most common mutations were TP53, consistent with Li-Fraumeni syndrome, often associated with childhood cancers; and SDHA and SDHB, found in sarcoma patients.


"Here, the surprising finding is that the germline prevalence of these mutations is significantly higher than we had previously thought," said Elaine Mardis, PhD, Co-Executive Director of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, who co-chaired the press briefing.


Mardis added the study also carried treatment implications that might range from access to immune checkpoint blockade therapy to accelerated imaging in some cases and even liquid biopsies at specific intervals to understand whether a recurrent cancer is in play.


"I think this (germline testing) is a very changing area, but certainly one that does predict accelerated screening as well as differences in treatment based on specific diagnoses," she said.


When asked during the press briefing, Stadler said the increased prevalence of CHEK2 mutations in early-onset patients did not point to earlier screening for breast cancer than is now recommended for the general population in women with known CHEK2 mutations.


"As we know, the general guidelines are that women with CHEK2 mutations should undergo enhanced cancer surveillance starting by age 40, but earlier if there is a family history of breast cancer," Stadler said. "Our next step is to actually evaluate the family cancer history of each of these patients to see if we can decipher further what their risks are."


In a press release, Stadler added the researchers also are now analyzing sequencing data from tumor-derived DNA in these patients, in addition to studying the germline mutations from blood-derived DNA. This can help determine if a specific tumor a patient was diagnosed with is driven by the identified mutation, she said.


Limitations to the study include that it was a single-institution study from a tertiary cancer center, therefore over-representing or under-representing some cancer types, when compared to young adults in the general population. Also, the analysis was limited to solid tumors and did not include hematologic malignancies.


Warren Froelich is a contributing writer.