Abstract
BackgroundA fraction of sporadic breast cancers has low BRCA1 expression. BRCA1 mutation carriers are more likely to achieve a pathological complete response with DNA-damage-based chemotherapy compared to non-mutation carriers. Furthermore, sporadic ovarian cancer patients with low levels of BRCA1 mRNA have longer survival following platinum-based chemotherapy than patients with high levels of BRCA1 mRNA.Methodology/Principal FindingsTumor biopsies were obtained from 86 breast cancer patients who were candidates for neoadjuvant chemotherapy, treated with four cycles of neoadjuvant fluorouracil, epirubicin and cyclophosphamide. Estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 and vimentin were examined by tissue microarray. HER2 were also assessed by chromogenic in situ hybridization, and BRCA1 mRNA was analyzed in a subset of 41 patients for whom sufficient tumor tissue was available by real-time quantitative PCR. Median time to progression was 42 months and overall survival was 55 months. In the multivariate analysis for time to progression and overall survival for 41 patients in whom BRCA1 could be assessed, low levels of BRCA1 mRNA, positive PR and negative lymph node involvement predicted a significantly lower risk of relapse, low levels of BRCA1 mRNA and positive PR were the only variables associated with significantly longer survival.Conclusions/SignificanceWe provide evidence for a major role for BRCA1 mRNA expression as a marker of time to progression and overall survival in sporadic breast cancers treated with anthracycline-based chemotherapy. These findings can be useful for customizing chemotherapy.
Highlights
Breast cancer is the most common cancer in women worldwide, comprising 23% of all cancers, with more than 1 million new cases per year[1]
In a retrospective series of 86 breast cancer patients treated with neoadjuvant fluorouracil, epirubicin and cyclophosphamide (FEC), we evaluated response, time to progression (TTP) and overall survival (OS) according to the simplified classification of breast cancer subtypes based on estrogen receptor (ER), progesterone receptor (PR) and HER2
Patients were treated with a schedule of only four cycles of anthracyclines before surgery, which was standard practice at the time of the study, before taxanes were introduced in the primary treatment setting; this could explain the relatively low rate of pathological complete responses (1.2%) and conservative surgery (8%)
Summary
Breast cancer is the most common cancer in women worldwide, comprising 23% of all cancers, with more than 1 million new cases per year[1]. Microarray analysis has identified breast cancer subtypes with distinct gene expression profiles [4,5] These subtypes have been correlated with clinical outcome, and the impact of subtype on response to neoadjuvant chemotherapy has been evaluated in different series [6]. Low levels of BRCA1 mRNA were associated with longer survival in a retrospective cohort of lung cancer patients following cisplatin gemcitabine [18] and in two retrospective cohorts of ovarian cancer patients treated with platinum-based chemotherapy [19]. All these studies suggest that BRCA1 mutations and reduced expression levels of BRCA1 mRNA could predict a benefit from DNA-damage-based chemotherapy.
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