Dynamic changes in CD44v-positive cells after preoperative anti-HER2 therapy and its correlation with pathologic complete response in HER2-positive breast cancer

Teruo Yamauchi, Jose Rodrigo Espinosa Fernandez, Chiyo Imamura, Hideko Yamauchi, Hiromitsu Jinno, Maiko Takahashi, Yuukou Kitagawa, Seigo Nakamura, Bora Lim, Savitri Krishnamurthy, James M. Reuben, Diane Liu, Debasish Tripathy, Helen Chen, Naoko Takebe, Hideyuki Saya, Naoto T. Ueno

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Abstract

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.

Original languageEnglish
Pages (from-to)6872-6882
Number of pages11
JournalOncotarget
Volume9
Issue number6
DOIs
Publication statusPublished - 2018 Jan 1

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Keywords

  • Biomarker
  • Breast cancer
  • CD44v
  • HER2
  • Predictive

ASJC Scopus subject areas

  • Oncology

Cite this

Yamauchi, T., Fernandez, J. R. E., Imamura, C., Yamauchi, H., Jinno, H., Takahashi, M., Kitagawa, Y., Nakamura, S., Lim, B., Krishnamurthy, S., Reuben, J. M., Liu, D., Tripathy, D., Chen, H., Takebe, N., Saya, H., & Ueno, N. T. (2018). Dynamic changes in CD44v-positive cells after preoperative anti-HER2 therapy and its correlation with pathologic complete response in HER2-positive breast cancer. Oncotarget, 9(6), 6872-6882. https://doi.org/10.18632/oncotarget.23914