Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).Patients and methods: Advanced NSCLC patients with c-MET 6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET 6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET 6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET 6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET 6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.

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To date, there is no available targeted therapy for patients who are diagnosed with triple-negative breast cancers (TNBC). The aim of this study was to identify a new specific target for specific treatments. Frozen primary tumors were collected from 83 adjuvant therapynaive TNBC patients. These samples were used for global proteome profiling by iTRAQ-OFFGEL-LC-MS/MS approach in two series: a training cohort (n ‫؍‬ 42) and a test set (n ‫؍‬ 41). Patients who remains free of local or distant metastasis for a minimum of 5 years after surgery were classified in the no-relapse group; the others were in the relapse group. OPLS and Kaplan-Meier analyses were performed to select candidate markers, which were validated by immunohistochemistry. Three proteins were identified in the training set and validated in the test set by Kaplan-Meier method and immunohistochemistry (IHC): TrpRS as a good prognostic markers and DP and TSP1 as bad prognostic markers. We propose the establishment of an IHC test to calculate the score of TrpRS, DP, and TSP1 in TNBC tumors to evaluate the degree of aggressiveness of the tumors. Finally, we propose that DP and TSP1 could provide therapeutic targets for specific treatments. Molecular & Cellular

Human olfactomedin‐4 (OLFM4) is a secreted protein involved in a variety of cellular functions including proliferation, differentiation, apoptosis, and cell adhesion. OLFM4 expression has been studied in several tumor types including gastric, colorectal, lung, and endometrioid cancers where it has been suggested to be an independent favorable or unfavorable prognostic marker. For breast cancer, the clinical significance of OLFM4 is still unclear. In the present study, SWATH‐MS is used as a tool for the robust identification and quantification of breast tissue proteins. SWATH‐MS data show that OLFM4 expression is higher in DCIS than in invasive breast cancer. In‐depth analysis of the breast tumor proteome show that OLFM4 is a favorable pronostic marker. Serum OLFM4 levels in peripheral blood are also analyzed by ELISA in 825 cases, including 94 cases of healthy individuals, 61 cases of non‐invasive breast tumor (DCIS) and 670 cases of breast cancer (BC). It is found that serum OLFM4 levels are significantly higher in the DCIS cohort and in the breast cancer cohort compared with the healthy controls. This result suggests that circulating OLFM4 could be an interesting biomarker of early breast cancer. Data are available via ProteomeXchange with identifier PXD014194.

Background: Prognostic factors for pure mucinous carcinomas of the breast are controversial; data on DNA ploidy and S-phase fraction (SPF) are lacking. We examined the relation of these parameters with histological features and patient survival.Methods: DNA flow cytometry was performed on 69 fresh or frozen pure mucinous carcinomas samples. Results were interpreted according to patient survival.Results: Tumor size exceeded 2 cm in 40.5% of cases. Lymph nodes were involved in 11.5% of cases and never when tumor size was less than 2 cm. Aneuploidy was only observed in one-quarter of the tumors. Very few tumors had a high-SPF or a high histological grade (7.2% of all cases). These two parameters were of prognostic value respectively for disease-free (P = 0.035) and overall survival (0.050). Patients with tumors >2 cm had shorter overall survival than patients with tumors ≤2 cm (P 5 0.028). Disease-free and overall survivals were not influenced by nodal status and hormone receptors (HRs) status. Patients with aneuploid tumors had shorter disease-free survival than patients with diploid tumors (P 5 0.031). The combination of tumor size and DNA ploidy was strongly predictive of survival (P < 10 23 ): six patients with large aneuploid tumors had a poor outcome (1-year overall survival 16.7%).Conclusion: We identified a subset of patients with a poor prognosis, namely those with large aneuploid tumors. This study confirms the good prognosis of pure mucinous carcinomas, particularly when tumor is less than 2 cm (corresponding to cases without lymph nodes involvement), thus challenging the need for axillary nodal examination. q

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