Dynamic changes in CD44v-positive cells after preoperative anti-HER2 therapy and its correlation with pathologic complete response in HER2-positive breast cancer
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Teruo Yamauchi1, Jose Rodrigo Espinosa Fernandez2, Chiyo K. Imamura3, Hideko Yamauchi4, Hiromitsu Jinno5, Maiko Takahashi6, Yuko Kitagawa6, Seigo Nakamura7, Bora Lim2, Savitri Krishnamurthy8, James M. Reuben9, Diane Liu10, Debasish Tripathy2, Helen Chen11, Naoko Takebe11, Hideyuki Saya12 and Naoto T. Ueno2
1Division of Medical Oncology, St. Luke’s International Hospital, Tokyo, Japan
2Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan
4Department of Breast Surgery, St. Luke’s International Hospital, Tokyo, Japan
5Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
6Department of Surgery, Keio University School of Medicine, Tokyo, Japan
7Department of Breast Surgical Oncology, Showa University School of Medicine, Tokyo, Japan
8Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
9Department of Hematopathology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
10Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
11Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA
12Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
Teruo Yamauchi, email: [email protected]
Naoto T. Ueno, email: [email protected]
Keywords: CD44v; predictive; biomarker; HER2; breast cancer
Received: October 26, 2017 Accepted: December 26, 2017 Published: January 04, 2018
Chemotherapy has been reported to increase the proportion of cancer stem cells (CSCs) and to promote epithelial-mesenchymal transition (EMT) phenotype changes. Anti-HER2 therapy may provide a strategy for eliminating CSC and EMT, which contribute to therapeutic resistance. No study has determined the changes in the quantity or characteristics of CSCs or circulating tumor cells (CTCs) with EMT phenotype during preoperative anti-HER2 therapy, and whether these changes correlate to response to dual anti-HER2 therapy. In a prospective clinical trial to evaluate pharmacodynamic biomarkers, 18 patients with operable primary HER2-positive breast cancer received dual anti-Her2 preoperative therapy with trastuzumab and lapatinib with paclitaxel. Proportions of tumor cells with CSC characteristics and EMT markers in CTC’s were estimated at baseline, after 6 and 18 weeks of preoperative therapy to determine the quantitative cutoff value to predict pathologic complete response (pCR). Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v at baseline and none were positive on the 6-week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p=0.0128). Other biomarkers were not statistically significant predictors of pCR. Enrichment of CD44v-positive tumor cells after dual anti-HER2 therapy alone may predict poor response to dual anti-HER2 therapy plus chemotherapy.
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