Early-Onset Cancers Confer a High Risk of Harboring Germline Mutations

Zsofia K. Stadler, MD

Patients 18 to 39 years of age with early-onset cancer had a significantly high risk of harboring germline mutations, suggesting that this population should undergo germline genetic testing, irrespective of tumor type, according to results of a study that were presented during a press program ahead of the AACR Virtual Annual Meeting II.^1,2

The results showed that 21% of patients with early-onset cancer (n = 877) had a germline mutation versus 13% of patients with young-adult cancer (n = 324; P = .002). The enrichment of high-and moderate-penetrance pathologic variants was 15% versus 10%, respectively (P = .01).

Among early-onset cancers, the most common mutations were BRCA1/2 (4.9%), Lynch syndrome–associated genes (2.2%), ATM (1.6%), and CHEK2 (1.7%), with pancreatic, breast, and kidney cancer harboring the highest rates of germline pathologic variants. Among young-adult cancers, the most common mutations were SDHA/B (1.9%) and TP53 (2.2%), the latter of which is consistent with Li-Fraumeni syndrome, which is known to be associated with childhood cancers, such as sarcoma.

“This study highlights that genetic susceptibility among young cancer patients is heterogeneous,” lead study author, Zsofia K. Stadler, MD, of Memorial Sloan Kettering (MSK) Cancer Center, stated in a press release. “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 patients with young-adult cancers, the mutations were more similar to those we encounter in our pediatric cancer patients.”

Young adults with cancer, defined as those diagnosed between the ages of 18 to 39, represent only 4% of all cancers. However, with germline testing, providers can glean the risk of second primary cancers, the need for long-term surveillance aimed at early detection, risk-reducing surgery to prevent new cancers, and understand potential reproductive implications.

“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,” Stadler said during the presentation.

Moreover, germline testing results can help identify at-risk family members, including young siblings or children who should pursue genetic testing, and if positive, appropriate cancer screening or prevention measures.

To that end, investigators sought to quantify the prevalence of germline mutations in young patients with solid tumors. In the study, a total of 1201 blood samples were collected from patients who had been diagnosed with cancer at MSK between 2015 and 2019 and analyzed with the next-generation sequencing panel, MSK-IMPACT, which has the ability to sequence up to 88 genes that are known to be associated with cancer susceptibility.

Using The Surveillance, Epidemiology, and End Results data, investigators further divided patients into those with early-onset cancer, defined as cancer wherein age 39 was more than 1 standard deviation below the mean age of diagnosis for that cancer type and those with young-adult cancer, defined as cancer wherein age 39 was less than 1 standard deviation below the mean age at cancer diagnosis.

Additional results showed that the most common early-onset cancers (n = 877) included

colorectal (n = 179; 20%), breast (n = 342; 39%), kidney (n = 53; 6%), pancreatic (n = 50; 6%), and ovarian cancer (n = 50; 6%), whereas the most common young-adult cancers (n = 324) included sarcoma (n = 116; 36%), brain (n = 75; 23%), testicular (n = 57; 17%), and thyroid cancer (n = 30; 9%).

The mutation prevalence of sarcoma in young-adult patients with cancer was 18.1%, which was similar to the prevalence in patients with early-onset cancer.

Despite the increased prevalence of CHEK2 mutations in early-onset cancers, Stadler stated that these data do not support breast cancer screening earlier than is recommended for the general population in women with known CHEK2 mutations. Though, investigations are ongoing to determine whether these patients have a family history of breast cancer, in which case, screening before the age of 40 would be warranted.

In terms of insurance coverage for genetic testing in early-onset and young-adult cancers, Stadler explained that all patients with pancreatic cancer are now covered for germline genetic testing and expects that as the field broadens clinical guidelines for genetic testing, so too will coverage for the early-onset and young-adult patient populations.

References

1. Young adults with cancer may harbor germline mutations [news release]: Philadelphia, Pennsylvania. AACR. Published June 22, 2020. Accessed June 22, 2020.

2. Stadler Z, Maio A, Padunan A, et al. Germline mutations prevalence in young adults with cancer. Presented at: the 2020 AACR Virtual Annual Meeting II; June 22-24, 2020. Abstract 1122/4. bit.ly/2BlsMHS.