Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline 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 pathogenic TP53 variant. Additionally, all TP53 deleterious 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 of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic 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 the TP53 testing criteria.
Keywords: HER2-positive breast cancer; Li-fraumeni syndrome; Next-generation sequencing; TP53 germline variants.