Susceptibility Gene Mutations Rare in Young HER2-Amplified Breast Cancer Patients

Patients diagnosed with HER2-amplified breast cancer at a younger age have a low risk of being a high-risk gene carrier, according to a new study examining susceptibility genes among this patient population.

“HER2-amplified breast cancers account for around 20% of breast cancers,” said study lead author Diana M. Eccles, MD, of Southampton General Hospital in the United Kingdom, in an email. “This type of breast cancer is atypical amongst people who carry a faulty BRCA1 or BRCA2 gene.” Mutations of TP53, in contrast, are more commonly HER2-amplified.

The researchers aimed to determine the prevalence of various breast cancer susceptibility genes specifically in younger patients-diagnosed at age 40 or younger-with HER2-amplified disease. They included a total of 591 patients; results were published online ahead of print in Annals of Oncology.

Among that full cohort, 20% could have been selected for BRCA mutation testing based on current guidelines. Out of 396 patients tested for BRCA1/2 testing, only 2% had a BRCA2 mutation and 2% had a BRCA1 mutation. Of a total of 304 patients tested for TP53 mutations, 3% were found to harbor one.

When a testing threshold based on family history or development of a secondary primary tumor was used, though, the pathogenic BRCA mutation rate reached 11%. Raised thresholds for TP53 testing yielded a 12% rate of mutation. “This study shows that a young person who has a HER2-amplified breast cancer and a family history of breast cancer is more likely to carry a TP53 gene fault than either a BRCA1 or a BRCA2 gene fault,” Eccles said.

Deleterious mutations in 14 less common susceptibility genes including ATM, BLM, BRIP1, and others were found in 4.9% of 263 patients tested.

“Testing a broad panel of genes has limited value in the clinic as faults in these genes are unlikely to explain in large part why someone developed breast cancer young,” Eccles said, adding that they may add a partial explanation. They also are unlikely to reliably aid in predicting risks to other family members. “We just simply have insufficient information at present because of their rarity,” she said.