Abstract P3-06-28: Alterations in HER2 status and outcome following neoadjuvant chemotherapy in HER2-positive breast cancer (BC)
Authors: Ng Dianna , Krings Gregor , Yau Christina , White Kristie , Hou Jie , Chua Anthony , Grenert James P , Chen Yunn-Yi 
Published: May 2015

Abstract
Background: Emerging data suggest that chemotherapy and anti-HER2 agents can change HER2 status in HER2+ BC and that this may have prognostic implications. The findings suggest a role for post-treatment (tx) retesting of HER2 status in surgical specimens. However, few studies have specifically examined this phenomenon, and direct comparisons of post-tx HER2 testing modalities are lacking. Furthermore, the biologic basis for HER2 alterations remains poorly understood. The aims of this study were to systematically evaluate the effects of neoadjuvant chemotherapy (NAT) including anti-HER2 agents on HER2 protein expression (P-EXP) and gene amplification (G-AMP), and to examine the potential prognostic impact of HER2 alterations on outcomes in HER2+ BC.
Design: We retrospectively identified 129 patients with HER2+ BC who received NAT at our institution. HR (ER and PR) and HER2 P-EXP were evaluated by immunohistochemistry (IHC) and HER2 G-AMP by fluorescence in situ hybridization (FISH) in pre- and post-tx samples. Pathologic tumor responses were categorized as no residual disease (RD; no invasive or in situ cancer), residual ductal carcinoma in situ (DCIS) only, and residual invasive carcinoma. Pathologic complete response (pCR) was defined as DCIS only or no RD. Association between groups was determined by Fisher exact test. For survival analysis, Kaplan Meier curves were constructed and significance in curve separation was assessed by log rank test.
Results: Mean follow-up was 52.6 months (range 6-162). Eighty-four (65%) cases had residual invasive cancer, 21 (16%) residual DCIS only and 24 (19%) no RD. Post-tx HER2 status was available in 70 cases with residual invasive cancer, and 27 (39%) of these showed reduced HER2 P-EXP (staining intensity 0, 1+, 2+) by IHC. Twenty-one (78%) of 27 cases with reduced HER2 P-EXP retained HER2 G-AMP (IHC-/FISH+), and 6 (22%) were negative for both HER2 P-EXP and G-AMP (IHC-/FISH-). The subset of IHC-/FISH- patients showed 100% 5-year recurrence free survival (RFS), whereas IHC-/FISH+ and IHC+ (intensity 3+) cases demonstrated similarly decreased 5-year RFS of 67% and 71%, respectively. There was a trend towards reduced HER2 expression in HR+ versus HR- cases (46% vs 26%, p=0.19). HR-HER2+ tumors were more likely to achieve pCR than HR+HER2+ cases (48% vs 26%; p=0.014, OR=0.375). In the HR- subset, RFS was significantly better in patients with no RD compared to those with residual invasive cancer (p=0.047); this relationship was not observed in the HR+ group (p=0.693).
Conclusion: A significant fraction of pre-tx HER2+ BC demonstrate reduced HER2 P-EXP following NAT. In a subset of these, post-tx decreased HER2 P-EXP is associated with retained HER2 G-AMP, suggestive of HER2 protein downregulation. In another subset, decreased HER2 P-EXP with associated lack of HER2 G-AMP indicates selection for HER2 non-amplified clones in HER2 heterogeneous tumors. Array comparative genomic hybridization studies are in progress to further elucidate these mechanisms. Lastly, our results suggest that post-tx evaluation of HER2 status by FISH in addition to IHC may have prognostic and/or predictive value in HER2+ BC. Further studies in larger prospective study populations are needed to confirm our findings.
Citation Format: Dianna Ng, Gregor Krings, Christina Yau, Kristie White, Jie Hou, Anthony Chua, James P Grenert, Yunn-Yi Chen. Alterations in HER2 status and outcome following neoadjuvant chemotherapy in HER2-positive breast cancer (BC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-28.