Related Experiment Video
Updated: Dec 28, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer
F Mosele1, B Stefanovska2, A Lusque3
1Department of Medical Oncology, Gustave Roussy, Villejuif, France.
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.
Insights
PIK3CA mutations in metastatic breast cancer (mBC) are linked to chemotherapy resistance and worse outcomes in HR+/Her2- patients. However, PIK3CA-mutated triple-negative breast cancer (TNBC) shows improved overall survival.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Selective phosphatidylinositol 3-kinase (PI3K) inhibitors show promise for PIK3CA-mutated, hormone receptor-positive (HR+)/Her2- metastatic breast cancer (mBC).
- Optimal integration of PI3K inhibitors into mBC treatment remains unclear.
Purpose of the Study:
- To analyze the impact of PIK3CA mutations on treatment outcomes in mBC.
- To investigate the mutational landscape and prognostic value of PIK3CA mutations in mBC.
Main Methods:
- Analysis of 649 mBC patients from the SAFIR02 trial (NCT02299999) with available mutational profiles.
- Prospectively determined PIK3CA mutations using next-generation sequencing and whole-exome sequencing.
- Assessed prognostic value of PIK3CA mutations in plasma via next-generation sequencing and digital PCR.
Main Results:
- PIK3CA mutations found in 28% of HR+/Her2- mBC and 10% of triple-negative breast cancer (TNBC).
- PIK3CA-mutated HR+/Her2- mBC exhibited chemotherapy resistance (aOR=0.40) and worse overall survival (OS) (aHR=1.44).
- PIK3CA-mutated TNBC showed improved median OS (24 vs. 14 months). Residual plasma PIK3CA mutations post-chemotherapy correlated with poor OS (aHR=1.03).
Conclusions:
- PIK3CA-mutated HR+/Her2- mBC patients face poor outcomes and chemotherapy resistance.
- PIK3CA-mutated TNBC patients demonstrate improved OS, potentially due to enrichment in luminal BC with lost HR expression.
- PIK3CA mutation status is a significant prognostic factor in mBC.
