Background:Phosphatidylinositol 3-kinase (PI3K) pathway activation has been suggested to negatively influence response to anti-HER2 therapy in breast cancer patients. The present study focused on mutations of the PIK3CA gene, encoding one of the two PI3K subunits.Methods:PIK3CA mutations were assessed by direct sequencing in 80 HER2-positive patients treated with 1 year of trastuzumab. All patients preoperatively received four cycles of anthracycline-based chemotherapy, followed by four cycles of docetaxel and 1 year of trastuzumab, starting either before surgery with the first cycle of docetaxel and continuing after surgery (neoadjuvant trastuzumab arm, n=43), or only after surgery (adjuvant trastuzumab arm, n=37).Results:PIK3CA mutations were found in 17 tumours (21.3%). Better disease-free survival (DFS) was observed in patients with PIK3CA wild-type compared with mutated tumours (P=0.0063). By combining PIK3CA status and treatment arms, four separate prognostic groups with significantly different DFS (P=0.0013) were identified.Conclusion:These results confirm that the outcome of HER2-positive patients treated with trastuzumab is significantly worse in patients with PIK3CA-mutated compared with wild-type tumours.

Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.

Background Circulating tumor cell (CTC) count is a major prognostic factor in metastatic breast cancer (MBC) and has been reported to be associated with thrombosis in short-term studies on MBC patients. Objective To assess whether CTC detection (CellSearch ) before first-line chemotherapy impacts the risk of thrombosis throughout the course of MBC. Patients/Methods Among patients included before first-line chemotherapy for MBC in the prospective IC2006-04 CTC detection study (NCT00898014), the electronic medical files of those patients treated at Institut Curie (Paris, France) were searched in silico and manually checked for incident venous or arterial thrombotic events (TE) in the course of MBC. Univariate and multivariate analyses were performed using Cox and Fine-Gray models, adjusted for age and Khorana score. Results/Conclusions With a median follow-up of 64 months (25-81 months), among the 142 patients included, 34 (24%) experienced a TE (incidence rate, 8 TE/100 patient-years). The TE incidence rate was 13 TE/100 patient-years for the 80 patients with ≥ 1 CTC/7.5 mL of blood before initiating first-line chemotherapy, vs. only 4 TE/100 patient-years for the 62 CTC-negative patients. Fine-Gray multivariate analysis (with death as competing event) included age, Khorana score and baseline lactate dehydrogenase and CTC levels: detectable CTC was the only factor significantly associated with an increased risk of TE (sub-distribution hazard ratio [SHR] for patients with [1-4] CTC = 3.1, 95% CI [1.1; 8.6], SHR for patients with ≥ 5 CTC = 1.4, 95% CI [0.5; 4.6]). This study shows that CTC detection before starting first-line chemotherapy is an independent risk factor for TE in MBC patients.