Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers

Abstract

Breast carcinomas caused by inheritance of cancer-predisposing germ-line mutations have specific bioclinical features. This study aimed to analyze the efficacy of conventional cytotoxic treatment in BRCA1 and CHEK2 mutation carriers and non-carriers. The study included 415 Russian breast cancer patients aged 50 years or younger, who were subjected to various standard schemes of neoadjuvant therapy. The choice of therapy was done without the knowledge of the mutations status, because DNA testing was performed retrospectively using the archival tissue samples. 19 BRCA1 (4.6%) and 8 CHEK2 (1.9%) heterozygous genotypes were identified. BRCA1 mutation carriers achieved pathological complete response more frequently than non-carriers [6/19 (31.6%) vs. 46/388 (11.9%), p = 0.024]; this effect was limited to women treated by anthracycline-based therapy without taxanes [5/9 (55.6%) vs. 28/247 (11.3%), p = 0.002] and was not observed in any of 7 BRCA1 carriers receiving taxane-containing regimens. CHEK2 heterozygotes did not experience pathological complete response and showed lower frequency of objective clinical responses as compared to mutation non-carriers [4/8 (50%) vs. 333/388 (85.5%), p = 0.020]; the efficacy of neoadjuvant therapy was particularly poor in CHEK2 carriers receiving anthracyclines without taxanes. This study provides evidence for distinct sensitivity of BRCA1 and CHEK2 mutation-driven breast carcinomas to standard chemotherapeutic schemes.

Atl

“…Anthracyclines may deserve particular consideration, given that anthracycline-based regimens demonstrate good activity in patients both with and without BRCA1 germ-line mutations. 28,29 Some reasonable intensification of preoperative chemotherapeutic schemes may be discussed, including a novel composition of drug triplets or some increase of treatment doses. It is of interest that, among historical series of breast cancer patients, who underwent highdose chemotherapy, a long-term benefit was observed mainly in BRCA1/2 mutation carriers.…”

Cytotoxic and targeted therapy for hereditary cancers

“…Recently Byrski et al [15] reported an update on their experience of using cisplatin in the neoadjuvant BC setting: pCR was documented in 65/107 (61%) patients. Cisplatin appears to be clearly superior when compared to other schemes of preoperative therapy in BRCA1 mutation carriers [16, 17]. Furthermore, remarkable performance of cisplatin in chemonaive BRCA1-related BC was confirmed in several independent reports [18–20].…”

“…BRCA1 is required for the execution of taxane-induced apoptosis, and at least some data indicate that taxane-containing regimens show limited efficacy towards BRCA1-associated breast cancers [16, 17, 60]. It is essential to acknowledge that some breast cancer studies do not support this concept [61].…”

“…Anthracyclines appear to exert substantial activity against BRCA1/2-driven tumors [6, 16, 17], with the novel formulations of these drugs producing remarkable responses in a subset of patients [49, 66–68]. There are limited data on the use of alkylating cytotoxic drugs in BRCA1/2-mutated cancers [7].…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…Furthermore, immunohistochemical and RNA expression studies revealed several distinct subtypes of BC, and at least some of these subtypes are strongly tailored to particular germ-line mutations. For example, up to 80% of breast tumors arising in BRCA1 heterozygous carriers have receptor triple-negative and/or basal-like phenotype, which is relatively uncommon in unselected BC patients [154,155]. Some researchers pay specific attention to the heterogeneity of common cancer types, and attempt to collect patients with similar disease characteristics.…”