Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer

Abstract

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.

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

“…PIK3CA is one of the most frequent mutated genes in TNBC (∼10%), being enriched in basal-like and LAR subtypes 24,25,[28][29][30][31][32][33][34]36,63 . Notably, metastatic TNBCs carrying PIK3CA mutations seem to have better overall survival (OS) than wild-type counterparts.…”

“…Notably, metastatic TNBCs carrying PIK3CA mutations seem to have better overall survival (OS) than wild-type counterparts. However, such observation could be partially explained by an enrichment in PIK3CA mutations in luminal BCs that loss ER expression in the metastatic setting 63 . Furthermore, loss-of-function of PTEN and INPP4B have been described in up to one-third of the TNBCs, especially in BLBC where heterozygous loss of PTEN has been identified in >45% of cases 28 .…”

Systems pharmacology in combination with proteomics reveals underlying mechanisms of Xihuang pill against triple-negative breast cancer

“…Among the hub targets, AR is a clinically evidenced promising therapeutic target in TNBC [57][58][59][60], which can directly interact with 22 bio-active compounds. Another clinically trialed therapeutic target, PIK3CA, is the most frequent mutant gene in estrogen receptor (ER)-positive and HER2-negative advanced BC patients [61,62], which was found to link with seven compounds. Furthermore, KEGG pathway enrichment analysis of the hub targets revealed that multiple signaling pathways related to cancer were enriched.…”

Integrative Bioinformatics Study Reveals Tangeretin Targets and Molecular Mechanisms Against Metastatic Breast Cancer

“…Mutation in PIK3CA is present in most solid tumors (42) and is found in 12-15% of patients with breast cancers (43). A recent study has shown that mutation in PIK3CA corresponds to a poor prognosis in patients with hormone receptorpositive metastatic breast cancer but a good prognosis in patients with triple-negative breast cancer (44).…”