Outcome and mutational landscape of patients with PIK3CA-mutated metastatic breast cancer (mBC)

Date 03 May 2019
Event ESMO Breast Cancer 2019
Session Best abstracts session
Topics Tumour Immunology
Personalised/Precision Medicine
Immunotherapy
Breast Cancer
Translational Research
Presenter Fernanda Mosele
Citation Annals of Oncology (2019) 30 (suppl_3): iii47-iii64. 10.1093/annonc/mdz100
Authors F.F. Mosele1, A. Lusque2, A. Tran Dien3, N. Droin4, C. Le Tourneau5, L. Lacroix6, I. Bieche7, C. Massard8, F. Bertucci9, F. André10
  • 1Department Of Medical Oncology, Gustave Roussy - Cancer Campus, 94800 - Villejuif/FR
  • 2Biostatistics, Institut Claudius Regaud, IUCT-O, Toulouse/FR
  • 3Bioinformatics Platform, Gustave Roussy, Villejuif/FR
  • 4Genomic Core Facility Ums Ammica, Gustave Roussy, Villejuif/FR
  • 5Department Of Drug Development And Innovation, Institut Curie, Paris & Saint-Cloud, France and INSERM U900, Saint-Cloud, France, Paris/FR
  • 6Department Of Medical Biology And Pathology & Genomic Platform-molecular Biopathology Unit (bmo) And Biological Resource Center, Ammica, Inserm Us23/cnrs Ums3655, Gustave Roussy Cancer Campus, Villejuif; Inserm, Gustave Roussy Cancer Campus, Umr981, Gustave Roussy, Villejuif/FR
  • 7Department Of Genetics, Institut Curie, Paris Sciences Et Lettres Research University, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France, Institut Curie, Paris/FR
  • 8Drug Development Unit (ditep), Gustave Roussy - Cancer Campus, Villejuif, France, Villejuif/FR
  • 9Crcm, Predictive Oncology Team, Aix-marseille Univ, Cnrs, Inserm, Institut Paoli-Calmettes, Marseille/FR
  • 10Department Of Medical Oncology, Université Paris Sud, Inserm, Umr981, Gustave Roussy Cancer Campus, Villejuif/FR

Abstract

Background

In a recent study, α-selective PI3K inhibitor improved outcome in PIK3CA mutated HR+/Her2- mBC. Thus, to optimally position PI3K inhibitors, we have investigated the natural history of PIK3CA mutated BC.

Methods

649 patients with mBC from SAFIR02 trial (NCT02299999), with available mutational profile and clinical data were selected for outcome analysis. PIK3CA mutations were prospectively determined by NGS on metastatic sample. In addition, we looked at mutations enriched in PIK3CA mutant mBC (n = 629, whole exome sequencing).

Results

22% of patients (n = 143) harbor PIK3CA mutation in tumor sample. 29% (n = 104) of HR+/Her2- and 10% (n = 27) of TNBC tumors presented PIK3CA mutation (p < 0.001). HR+/Her2- PIK3CA mutated patients were less sensitive to chemotherapy (Odds ratio multivariate: 0.40; 95% CI [0.22-0.71]; p = 0.002). The median overall survival (OS) for patients with PIK3CA mutated HR+/Her2- mBC was 19.6 months vs. 23.5 for PIK3CA wt (p = 0.048) (HR multivariate: 1.44; 95% CI [1.02-2.03]; p = 0.039). PIK3CA mutated HR+/Her2- mBC were enriched in MAP3K1 mutation (17% vs. 5%, p = 0.0002), whereas PIK3CA wt tumors were enriched in GATA3 (25% vs. 14%, p = 0.022) or AKT1 mutations (11% vs. 3%, p = 0.008). In patients with HR+/Her2-/PIK3CA mutant mBC, the 24 months OS for MAP3K1 mutated patients was 14.7% vs. 45.5% for wt (p = 0.0059) (HR multivariate: 1.84; 95% CI [1.07-3.15]; p = 0.02). In TNBC, the median OS in patients with PIK3CA mutated tumors was 24.2 months vs. 14 for PIK3CA wt (p = 0.028). We further looked at the distribution of PIK3CA mutation in mTNBC, according to HR expression on 1ry tumor. 6% of patients with TNBC both on primary and metastasis presented a PIK3CA mutation (9/138), whereas 39% of patients with TNBC on metastasis and HR+ on 1ry tumor had PIK3CA mutation (14/36).

Conclusions

Patients with PIK3CA mutated HR+/Her2- mBC are less sensitive to chemotherapy and present a poor outcome. In this population, MAP3K1 mutations are more frequent and are associated with shorter survival. Patients with PIK3CA mutated TNBC have better survival. This could be explained by an enrichment of PIK3CA mutations in luminal BC who lost HR in the metastatic setting.

Editorial acknowledgement

Bojana Stefanovska.

Clinical trial identification

NCT02299999.

Legal entity responsible for the study

Unicancer/Gustave Roussy.

Funding

ARC, Breast Cancer res Foundation and French NCI.

Disclosure

C. Massard: Consultant/advisory fees: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. F. André: Research grants and compensation to institution: Novartis, AZ, Daiichi, Roche, Lilly, Pfizer. All other authors have declared no conflicts of interest.