BREAST CANCER: ER+ PIK3CA mutant breast cancer show worse response to chemo and poorer survival compared with ER+ PIK3CA wild-type

Kevin Sovet

June 2, 2020

SCIENTIFIC

BREAST CANCER

ER+ PIK3CA mutant breast cancer show worse response to chemo and poorer survival compared with ER+ PIK3CA wild-type. The FDA-approved PIK3CA inhibitor alpelisib improves outcomes in this poor risk group; NICE's funding verdict is due February 2021

 

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

https://doi.org/10.1016/j.annonc.2019.11.006

 

Highlights

• Patients with HR+/Her2- mBC and PIK3CA mutation were less sensitive to chemotherapy and presented worse overall survival.
• Patients with TNBC tumors and PIK3CA mutation present a better overall survival as compared with wt.
• A subset of patients with PIK3CA-mutated TNBC could be luminal breast cancers that lost hormone receptor expression.
• Persistant levels of cell-free circulating PIK3CA mutations on plasma during chemotherapy are indicative of a poor outcome.

 

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

more info: https://www.jci.org/articles/view/132712