PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer.

Abstract

PURPOSE:

We investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer.

PATIENTS AND METHODS:

Baseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping.

RESULTS:

PIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P = .012).

CONCLUSION:

Activating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.

• Authors: Ian J Majewski, Paolo Nuciforo, Lorenza Mittempergher, Astrid J Bosma, Holger Eidtmann, Eileen Holmes, Christos Sotiriou, Debora Fumagalli, Jose Jimenez, Claudia Aura, Ludmila Prudkin, Maria Carmen Díaz-Delgado, Lorena de la Peña, Sherene Loi, Catherine Ellis, Nikolaus Schultz, Evandro de Azambuja, Nadia Harbeck, Martine Piccart-Gebhart, René Bernards, José Baselga
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 12 Pg. 1334-9 (Apr 20 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 25559818 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

• Antibodies, Monoclonal, Humanized
• Quinazolines
• Lapatinib
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Chemotherapy, Adjuvant
• Class I Phosphatidylinositol 3-Kinases
• Female
• Humans
• Lapatinib
• Middle Aged
• Molecular Targeted Therapy
• Mutation
• Neoadjuvant Therapy
• Neoplasm Staging
• Phosphatidylinositol 3-Kinases (genetics)
• Quinazolines (administration & dosage)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Trastuzumab