BACKGROUND α-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CA-mutated, hormone receptor-positive (HR+)/Her2- 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 next-generation sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n = 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n = 44) by next-generation sequencing and digital PCR. RESULTS Some 28% (104/364) of HR+/Her2- tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HR+/Her2- mBC was less sensitive to chemotherapy [adjusted odds ratio: 0.40; 95% confidence interval (0.22-0.71); P = 0.002], and presented a worse overall survival (OS) compared with PIK3CA wild-type [adjusted hazard ratio: 1.44; 95% confidence interval (1.02-2.03); P = 0.04]. PIK3CA-mutated HR+/Her2- mBC was enriched in MAP3K1 mutations (15% versus 5%, P = 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P = 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 HR+ 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 (1.01-1.05), P = 0.007]. CONCLUSION PIK3CA-mutated HR+/Her2- 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.

中文翻译：

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PIK3CA突变型转移性乳腺癌患者的结局和分子情况。

背景技术α-选择性磷脂酰肌醇3激酶（PI3K）抑制剂可改善PIK3CA突变的激素受体阳性（HR +）/ Her2转移性乳腺癌（mBC）患者的结局。然而，目前尚不清楚如何在治疗领域整合该新药家族。患者和方法从SAFIR02试验（NCT02299999）中总共选择了649例mBC患者，并选择可用的突变谱进行结果分析。PIK3CA突变通过转移样品的下一代测序来确定。通过全外显子组测序评估了PIK3CA突变的mBC的突变态势（n = 617）。最后，通过下一代测序和数字PCR对血浆样品（n = 44）中化疗期间PIK3CA突变的预后价值进行了评估。结果HR + / Her2-肿瘤中约28％（104/364）和三阴性乳腺癌（TNBC）中约10％（27/255）表现出PIK3CA突变（P <0.001）。PIK3CA突变的HR + / Her2- mBC对化疗的敏感性较低[调整后的优势比：0.40；95％置信区间（0.22-0.71）; P = 0.002]，与PIK3CA野生型相比，总生存率（OS）较差[调整后的危险比：1.44；95％置信区间（1.02-2.03）; P = 0.04]。PIK3CA突变的HR + / Her2- mBC富含MAP3K1突变（15％对5％，P = 0.0005）。在转移性TNBC（mTNBC）中，PIK3CA突变患者的中位OS为24个月，而野生型PIK3CA为14个月（P = 0.03）。我们根据原发性肿瘤上的HR表达进一步研究了mTNBC中PIK3CA突变的分布。原发性无HR表达的患者中约有6％（9/138），原发性HR +的患者中约有36％（14/39）有PIK3CA突变（P <0.001）。一到三个化疗周期后血浆中残留的PIK3CA突变水平与OS差有关[连续变量，危险比：1.03，95％置信区间（1.01-1.05），P = 0.007]。结论PIK3CA突变的HR + / Her2-mBC患者表现出较差的结果和对化疗的耐药性。PIK3CA突变的TNBC患者表现出更好的OS。这可以通过在管腔BC中丰富PIK3CA突变来解释，该PIK3CA突变在转移性环境中丧失了HR表达。试用注册SAFIR02试用版：NCT02299999。一到三个化疗周期后血浆中残留的PIK3CA突变水平与OS差有关[连续变量，危险比：1.03，95％置信区间（1.01-1.05），P = 0.007]。结论PIK3CA突变的HR + / Her2-mBC患者表现出较差的结果和对化疗的耐药性。PIK3CA突变的TNBC患者表现出更好的OS。这可以通过在管腔BC中丰富PIK3CA突变来解释，该PIK3CA突变在转移性环境中丧失了HR表达。试用注册SAFIR02试用版：NCT02299999。一到三个化疗周期后血浆中残留的PIK3CA突变水平与OS差有关[连续变量，危险比：1.03，95％置信区间（1.01-1.05），P = 0.007]。结论PIK3CA突变的HR + / Her2-mBC患者表现出较差的结果和对化疗的耐药性。PIK3CA突变的TNBC患者表现出更好的OS。这可以通过管腔BC中PIK3CA突变的富集来解释，该PIK3CA突变在转移性环境中丧失了HR表达。试用注册SAFIR02试用版：NCT02299999。这可以通过在管腔BC中丰富PIK3CA突变来解释，该PIK3CA突变在转移性环境中丧失了HR表达。试用注册SAFIR02试用版：NCT02299999。这可以通过在管腔BC中丰富PIK3CA突变来解释，该PIK3CA突变在转移性环境中丧失了HR表达。试用注册SAFIR02试用版：NCT02299999。