Background: a-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CAmutated, hormone receptor-positive (HRþ)/Her2À metastatic breast cancer (mBC). Nevertheless, it is still unclear how to integrate this new drug family in the treatment landscape. Patients and methods: A total of 649 patients with mBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by nextgeneration sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n ¼ 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n ¼ 44) by next-generation sequencing and digital PCR. Results: Some 28% (104/364) of HRþ/Her2À tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HRþ/Her2À mBC was less sensitive to chemotherapy [adjusted odds ratio: 0.40; 95% confidence interval (0.22e0.71); P ¼ 0.002], and presented a worse overall survival (OS) compared with PIK3CA wild-type [adjusted hazard ratio: 1.44; 95% confidence interval (1.02e2.03); P ¼ 0.04]. PIK3CA-mutated HRþ/Her2À mBC was enriched in MAP3K1 mutations (15% versus 5%, P ¼ 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P ¼ 0.03). We further looked at the distribution of PIK3CA mutation in mTNBC according to HR expression on the primary tumor. Some 6% (9/138) of patients without HR expression on the primary and 36% (14/39) of patients with HRþ on the primary presented PIK3CA mutation (P < 0.001). The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS [continuous variable, hazard ratio: 1.03, 95% confidence interval (1.01e1.05), P ¼ 0.007]. Conclusion: PIK3CA-mutated HRþ/Her2À mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting. Trial registration: SAFIR02 trial: NCT02299999.

BackgroundOsteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells.MethodsModified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC.ResultsCYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rβ levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rβ/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities.ConclusionsTaken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5282-4) contains supplementary material, which is available to authorized users.