• Mothaffar F Rimawi, Carmine De Angelis, Alejandro Contreras, Fresia Pareja, Felipe C Geyer, Kathleen A Burke, Sabrina Herrera, Tao Wang, Ingrid A Mayer, Andres Forero, Rita Nanda, Matthew P Goetz, Jenny C Chang, Ian E Krop, Antonio C Wolff, Anne C Pavlick, FuquaSuzanne A WSAWDan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA., Carolina Gutierrez, Susan G Hilsenbeck, Marilyn M Li, Britta Weigelt, Jorge S Reis-Filho, Kent OsborneCCDan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA., and Rachel Schiff.
• Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA. rimawi@bcm.edu.
• Breast Cancer Res. Treat. 2018 Feb 1; 167 (3): 731-740.

PurposeAberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.Patients And MethodsBaseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).ResultsOf 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).ConclusionPI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.

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