A84a: Role of BRCA1 dysfunction in sporadic triple-negative breast cancer

Abstract

Background There is increasing evidence that BRCA1-related DNA-repair defects determine sensitivity to certain agents, such as platinum-based chemotherapy. There is a lot of evidence about a link between TNBC and BRCA1 deficiency. Many clinical characteristics and molecular features are shared by sporadic triple-negative breast cancer and BRCA1-associated breast cancer. The majority of BRCA1-related breast cancers are of basal-like/triple-negative phenotype. Identification of specific markers of BRCA1-dysfunction will be essential to translate an understanding of defective DNA repair into targeted treatments for this poor prognosis subtype. Materials and methods Twenty-two patients with triple-negative breast cancer (TNBC) were treated with neoadjuvant platinum-based chemotherapy followed by surgery. Pathologic treatment response was assessed in correlation with biomarkers of BRCA1-dysfunction. Pathological response was evaluated according to the Chevallier classification (Ch). All patients were screened for germ-line mutations in BRCA1 (185delAG, 5382insC, 4153delA, 4158A/G, C61G) and BRCA2 (6174delT). All samples negative for germ-line mutations in BRCA1 and BRCA2 then submitted to BRCA1-dysfunction screening. Biomarkers of BRCA1-dysfunction included: BRCA1 somatic mutations (C61G, 185delAG, 5382insC), promoter methylation of BRCA1, low BRCA1 mRNA expression, high ID4 mRNA expression, low RAD51 mRNA expression, PTEN (T4721C) mutation, p53 (Arg72Pro, Pro72Pro) mutations. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP), methylation-specific PCR were used for BRCA1-dysfunction analysis. Results Twelve patients (54.5%) achieved a pathological complete response (pCR) (Ch1+ Ch2). Ten patients (45.5%) had a residual disease (Ch3+ Ch4). BRCA1 mRNA expression was absent in 16/22 (72.7%) patients, low in 5/22 (22.7%). 11/21 (52.4%) patients with other than normal BRCA1 mRNA expression achieved a pCR. BRCA1 promoter methylation was detected in 9/22 (40.9%). 6/9 patients with BRCA1 promoter methylation achieved a pCR. RAD51 mRNA levels were low in 14/22 (63.6%), high in 1/22 (4.5%). 8/14 (57.1%) patients with other than normal RAD51 mRNA expression achieved a pCR. High ID4 mRNA levels were determined in 5/22 (22.7%). 3/5 (60%) patients with high ID4 mRNA expression achieved a pCR. p53 (Arg72Pro, Pro72Pro) mutations were identified in 12/22 (54.5%). No patient had PTEN (T4721C) mutation. No statistically significant correlation was found between the BRCA1 mRNA expression, BRCA1 promoter methylation, RAD51 mRNA expression, high ID4 mRNA levels, p53 (Arg72Pro, Pro72Pro) mutations and pCR to neoadjuvant platinum-based chemotherapy ( p > 0.05). Eleven patients had BRCA1 somatic mutations: 6/22 (27.3%) – BRCA1 5382insC, 4/22 (18.2%) – BRCA1 185delAG, 3/22 (13.6%) – BRCA1 C61G. 3/4 patients with BRCA1 185delAG mutation had BRCA1 C61G mutation. BRCA1 LOH was detected in 1/22 (4.5%) patient. All patients with BRCA1 5382insC mutation achieved a pCR ( p = 0.01). All patients with BRCA1 185delAG mutation and BRCA1 C61G mutation had residual disease (0.04 and 0.1, accordingly). Conclusion BRCA1 5382insC somatic mutation is associated with good response to neoadjuvant platinum based chemotherapy ( p = 0.01). BRCA1 185delAG and BRCA1 C61G mutations in the BRCA1 RING domain may predict resistance to neoadjuvant platinum-based chemotherapy (0.04 and 0.1, accordingly).