Pathologic complete response after preoperative anti-HER2 therapy correlates with alterations in PTEN, FOXO, phosphorylated Stat5, and autophagy protein signaling

• Published in: BMC research notes Vol. 6; no. 1; p. 507
• Main Authors: Holmes, Frankie Ann, Espina, Virginia, Liotta, Lance A, Nagarwala, Yasir M, Danso, Michael, McIntyre, Kristi J, Osborne, Cynthia R C, Anderson, Thomas, Krekow, Lea, Blum, Joanne L, Pippen, John, Florance, Allison, Mahoney, Janine, O’Shaughnessy, Joyce A
• Format: Journal Article
• Language: English
• Published: London BioMed Central 05.12.2013; BioMed Central Ltd
• Subjects: Adult; Aged; Analysis; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Biomarkers; Biomarkers, Pharmacological; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; Chemotherapy; Confidence intervals; Deoxyribonucleic acid; DNA; Drug Administration Schedule; Epidermal growth factor; Female; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Lapatinib; Life Sciences; Medical research; Medicine, Experimental; Medicine/Public Health; Middle Aged; Neoadjuvant Therapy - methods; Oncology; Paclitaxel - administration & dosage; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proteins; Proteomics; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Quinazolines - administration & dosage; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Research Article; Response rates; Signal Transduction - drug effects; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Statistical analysis; Surgery; Trastuzumab; Tumors; Invasive breast cancer; Protein signaling; Lapatinib; Autophagy; Trastuzumab
• ISSN: 1756-0500; 1756-0500
• DOI: 10.1186/1756-0500-6-507

Background To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy. Methods This open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m 2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes. Results Of 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n = 78]). pCRs by arm are: trastuzumab (n = 26), 54% [n = 14]; lapatinib (n = 29), 45% [n = 13]; trastuzumab plus lapatinib (n = 23), 74% [n = 17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR. Conclusion In this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible. Trial registration ClinicalTrials.gov: NCT00524303