Abstract 2978: Clinical evaluation of lapatinib induced BCL-2 adaptive responses
Authors: Jason J. Zoeller, Sara A. Hurvitz, Michael F. Press, Laura M. Selfors, Judy Dering, Dennis J. Slamon, Joan S. Brugge
Journal: Cancer Research (2019)

Abstract Our pre-clinical data identified BCL-2 upregulation as a critical component and biomarker of the adaptive response to blockade of PI3K/mTOR in vitro and inhibition of HER2 via lapatinib in vivo. We therefore evaluated whether a similar BCL-2 upregulation could be identified in patient clinical samples. Gene expression profiles of patient biopsies collected before and after lapatinib treatment from the TRIO-TORI-B-07 clinical trial were evaluated. Eighteen cases with matched samples were available for analysis. BCL-2 transcriptional upregulation was detected in both HER2+ER- (7 out of 11) as well as HER2+ER+ (5 out of 7) patient tumor samples. To address whether RNA expression correlated with BCL-2 protein expression, pre- and post-treatment FFPE tumors were evaluated for BCL-2 via IHC. We evaluated BCL-2 by intensity and proportion scores to calculate an H-score on a case-by-case basis. Twenty-three cases with matched samples were evaluated by blinded pathological assessment. Despite BCL-2 mRNA upregulation within lapatinib-treated HER2+ER- tumors, only 2 out of 12 cases displayed a minor increase in BCL-2 protein levels following treatment. BCL-2 protein levels were undetectable in most of the lapatinib-treated HER2+ER- tumors. 11 matched cases were HER2+ER+ (baseline ER H-score &amp;gt; 0). All of these cases were BCL-2-postive before treatment. Post-treatment, BCL-2 upregulation was evident in 9 out of 11 HER2+ER+ cases (p = 0.0107). Evaluation of ER status by SP1 IHC in these specimens indicated parallel upregulation of ER in a subset of the HER2+ER+ tumors (p = NS). ER was upregulated in 6 out of the 9 cases where BCL-2 was upregulated in response to lapatinib. To determine whether treatment altered other prosurvival proteins, we performed BCL-XL IHC on the HER2+ER+ cases. BCL-XL was upregulated in 4 out of the 9 cases where BCL-2 was upregulated in response to lapatinib (p = NS). To determine whether BCL-2 upregulation correlated with HER2 inhibition, we performed Ki67 IHC on the HER2+ER+ samples. We observed an overall reduction in Ki67+ tumor cells post-lapatinib (p = 0.0273). Ki67 was reduced in 7 out of the 9 cases where BCL-2 was upregulated in response to lapatinib. Together, these results indicate that BCL-2 mRNA is upregulated following HER2 inhibition via lapatinib; however, protein levels post-treatment are undetectable in most HER2+ER- tumors. Within HER2+ER+ tumors, BCL-2 upregulation correlated with ER upregulation, consistent with evidence that BCL-2 is a direct target of ER transcriptional regulation; however, BCL-2 upregulation was also observed in tumors without ER upregulation, suggesting ER-independent regulation of BCL-2. These findings support evaluation of BCL-2 inhibitors to enhance the therapeutic efficacy of HER2 receptor tyrosine kinase inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Jason J. Zoeller, Sara A. Hurvitz, Michael F. Press, Laura M. Selfors, Judy Dering, Dennis J. Slamon, Joan S. Brugge. Clinical evaluation of lapatinib induced BCL-2 adaptive responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2978.