Role ofTP53mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

Abstract

BackgroundTP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.Methods450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.ResultsOf 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).ConclusionsOur study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.

Network-aware mutation clustering of cancer

“…Clusters 3 and 6, although not strongly linked to breast cancer as a whole, were significantly associated with the triple negative and HER2 positive subtypes of breast cancer (both p < 0.003 after Holm's correction for 271 tests, Figure 2c). Investigation of mutated genes in these clusters revealed TP53 mutation as a central driver for membership in these triple negative / HER2 clusters, consistent with known features of these breast cancer subtypes (Darb-Esfahani et al , 2016) . In contrast, clusters 25, 26, 27, 38, and 49, which were associated with breast cancer but not biased towards a specific subtype, were characterised by co-mutation of CDH1 , MAP3K1 , and PIK3CA , and seldom involved TP53 changes.…”

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

“…We did observe a strong significant association with TP53 mutation; however, this could be confounded by the association of TP53 mutation with other features also associated with TILs such as high grade, ER negativity, and HER2 positivity. In invasive breast cancer, higher TILs have also been observed in TP53-mutant tumors (39), including within triple-negative invasive breast cancer (40). Specific mutational signatures have also been suggested to explain the wide variation in TILs seen in luminal breast cancers, with those displaying mutational signatures 3 or 13, corresponding to homologous recombination pathway defects and the APOBEC mutational pattern, respectively, showing the highest immune infiltrates (5).…”

AR Signaling in Breast Cancer

“…There are several studies that show AR is associated with lower Ki-67 proliferative marker, lower mitotic score, lower histologic grade and lower clinical stage [23,27,63,109,110,111,112]. Interestingly, TNBC has been associated with the poor prognostic TP53 mutation in up to 80% of patients, but at least one study has shown that patients with AR-positive TNBC have a lower rate of TP53 mutations as well [109,113]. This improvement in histological and genetic features seems to translate to clinical benefit and AR-positive TNBC have both improved DFS and OS versus AR-negative [110,114,115] One retrospective study analyzing tissue microarrays from 287 patients with operable TNBC breast cancer found a statistically significant decrease in lymph node positivity in AR-positive disease.…”