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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.

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The regulation of CD4 T-cell numbers during an immune response should take account of the amount of antigen (Ag), the initial frequency of Ag-specific T cells, the mix of naive versus experienced cells, and (ideally) the diversity of the repertoire. Here we describe a novel mechanism of T-cell regulation that potentially deals with all of these parameters. We IntroductionBecause the frequency of T cells specific for any antigen (Ag) is low, T-cell proliferation is an important part of primary immune responses. However, proliferation must stop at some point to allow Ag-specific T cells to become effectors (and to accommodate a limited body size). In a typical primary immune response, CD4 T cells proliferate extensively and generate effector cells before a contraction phase sets in. The extent of proliferation depends upon the initial frequency of the Ag-specific T cells and is therefore much greater for naive T cells than for the more numerous memory T cells. [1][2][3] Because memory and naive cells reach the same plateau, even though memory cells respond faster, there must be mechanisms that regulate T-cell proliferation early during an immune response. 4,5 It has been suggested that T-cell proliferation is related to the disappearance of Ag or antigen-presenting cells (APCs), [6][7][8] to exhaustion of the APCs, 9 to suppression by regulatory T cells, 10 or to competition among responding T cells. [11][12][13][14] However, disappearance or exhaustion of APCs should generate higher final plateaus for the fasterresponding memory T cells; and pure competition for waning Ag would rapidly lead to preferential expansion of high-avidity T-cell clones, and thus to a narrowing of the repertoire. This is not observed for CD4 T-cell responses, where the avidity range remains quite wide. 15 While studying regulation of a localized CD4 immune response, we found yet another mechanism. Responding CD4 T cells capture and present their cognate MHC/Ag complexes in a manner that is strongly inhibitory for activated/memory CD4 T cells but not for naive T cells. This inhibition regulates the intensity of the immune response in relation to the amount of presented Ag while keeping the repertoire diverse, as new naive T cells can still enter the immune response. Methods MiceMarilyn TCR-transgenic Rag2 Ϫ/Ϫ mice are specific for the Dby-H-Y male antigen presented by A b . 16 For Marilyn T cells expressing diphtheria toxin receptor (DTR), we crossed Marilyn Rag2 Ϫ/Ϫ CD45.1 mice to Lat-DTR knockin mice (harboring, in the 3Ј untranslated region of the Lat gene, 17 a human diphtheria toxin receptor (DTR) cassette, driven by an internal ribosomal entry site [A.K. and B.M., manuscript in preparation]) to finally obtain Marilyn-Lat-DTR.Rag2 Ϫ/Ϫ .CD45.1/2 mice. B6-OT-II 18 and B6 mice were from CRL (Charles River Laboratories, L'Arbresle, France). Live animal experiments were done according to French Veterinary Department guidelines. Cell preparationEffector and memory T cells were generated in vivo as described, 19 by transferring 10 6 Marily...