The role ofTP53pathogenic variants in early-onset HER2-positive breast cancer

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germlineTP53variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting thatHER2amplification or over-expression in a young woman may be a useful criterion to test for germline variants in theTP53gene. We assessed the prevalence of germlineTP53variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern ofHER2amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germlineTP53variants as compared with those of noncarriers. Among 149 women tested, three presented a deleteriousTP53germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenicTP53variant. Additionally, allTP53deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels ofHER2amplification were found in breast carcinomas ofTP53pathogenic variant carriers than in those of noncarriers. Deleterious germlineTP53variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higherHER2amplification ratios. AllTP53pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update theTP53testing criteria.

Automated summary

Breast cancer is a frequent event in Li-Fraumeni syndrome associated with germline TP53 variants, particularly in HER2-positive cases. This study evaluated the prevalence of TP53 germline variants in young women with HER2-positive breast cancer and found a small proportion of cases with deleterious TP53 variants, which showed higher levels of HER2 amplification compared to non-carriers. All TP53 pathogenic variant carriers in this study had their first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further research is needed to determine the utility of HER2 status in early-onset breast cancer patients for updating TP53 testing criteria.