Abstract P1-18-20: Breast cancer with HER2 FISH test result in group 2: Should HER2 test be repeated?
Authors: Chen Hui , Wang Minhua , Sun Hongxia , Gu Jun , Tang Zhenya , Tang Guilin , Sfamenos Steven , Robinson Melissa , Sahin Aysegul 
Published: March 2020

Abstract
Introduction: Interpretation of HER2 result in breast cancer patients with monosomy of CEP17 has been controversial due to the loss of CEP17 signals and the subsequent relatively increased HER2/CEP17 ratio. HER2 FISH group 2 (HER2&lt; 4 and HER2/CEP17 ratio ≥ 2) was historically considered HER2 positive (HER2+) irrespective of the negative HER2 overexpression and anti-HER2 therapy response. The updated 2018 ASCO/CAP guidelines incorporated immunohistochemistry (IHC) results to facilitate HER2 reporting. However both IHC and FISH can be subjective to analytical variables, which can lead to challenge in interpretation cases in this group. This study aimed to assess if repeat IHC and FISH tests could assist final HER2 interpretation for group 2 cases.
Methods: We retrospectively reviewed HER2 FISH cases performed at our institution from 2012 to 2017 and identified 23 of 3554 (0.6%) breast cancer cases with at least one time HER2 FISH result fell into group 2 category. A chart review for clinicopathological characteristics and biomarker status was performed in all 23 cases. The HER2 IHC and FISH tests were repeated for cases with available alternative tumor samples. Final HER2 interpretation was modified by following 2018 ASCO/CAP guidelines.
Results: Patients’ age ranged from 26-67. These tumors were predominantly ductal (n = 17, 74%), high grade (n = 13, 57%), ER positive (n = 17, 74%), and equivocal HER2 (2+) by IHC (n = 15, 60%). These HER2 FISH group 2 cases were from 18 primary tumors and 5 metastatic/recurrent tumors. All 23 cases (100%) were considered HER2 amplified according to 2013 ASCO/CAP guidelines, only 2/23 (9%) can be interpreted as HER2+ in conjunction with their corresponding IHC result according to 2018 ASCO/CAP guidelines. The corresponding primary tumors for the 5 metastatic/recurrent group 2 tumors were 2 HER2+ and 3 HER2-. Repeat HER2 tests were performed in 15 of 18 group 2 primary tumors; the concordance rates between initial and repeat tests were 27% (4/15) for the HER2 FISH group category and 73% (11/15) for the final HER2 results. Three (20%) cases changed from HER2- (group 2 and IHC 2+) to HER2+ (group 1 [HER2/CEP17 ratio ≥ 2 and HER2 ≥ 4] and IHC 2+); one case changed from HER2+ (group 2 and IHC 3+) to HER2- (group 5 [HER2/CEP17 ratio &lt; 2 and HER2&lt; 4] and IHC 1+); and 11 cases remained as HER2- on repeat (4 for group 2 with IHC 1-2+ and 7 for group 5 with IHC 0-2+). Eight of these 15 patients received neoadjuvant chemo and Herceptin therapy, 3 (38%) achieved a complete pathologic response and 5 (62%) did not respond (Table 1). The 3 responders had ductal tumors and at least 40% of Ki67 in contrast the other 5 non-responders with either lobular histology or Ki67 &lt; 40% (p &lt; 0.05).
Conclusion: Breast cancer with a group 2 HER2 FISH result represents heterogeneous populations of tumor cells being originated de novo or preferentially selected secondary to chemotherapy, and leading to challenges in HER2 interpretation. Repeat HER2 IHC and FISH test on alternative samples either different tumor block of the same biopsy or tumor from excision may assist in final classification to guide treatment decision.
Table 1. Repeat HER test in breast cancer patients with initial HER2 FISH test in group 2CaseInitial test on biopsy (IHC/FISH)Repeat test on biopsy (IHC/FISH)Repeat test on excision (IHC/FISH)Final HER2 resultHistologyGradeERKi-67Response to NAC+H12+/Group 22+/Group 1N/APosDuctal3Low Pos40%pCR22+/Group 22+/Group 1N/APosDuctal3Neg90%pCR32+/Group 22+/Group 1N/APosLobular3Pos5%RCB-II43+/Group 2N/A1+/Group 5PosDuctal3Pos15%RCB II51+/Group 20/Group 5N/ANegDuctal3Pos73%pCR62+/Group 2N/A2+/Group 5NegLobular3Pos10%RCB II72+/Group 2N/A1+/Group 2NegDuctal2Pos38%RCB II81+/Group 2N/A2+/Group 2NegDuctal/Lobular3PosNPRCB IINAC+H: Neoadjuvant chemo and HerceptinpCR: complete pathologic responseRCB: residual tumor burden
Citation Format: Hui Chen, Minhua Wang, Hongxia Sun, Jun Gu, Zhenya Tang, Guilin Tang, Steven Sfamenos, Melissa Robinson, Aysegul Sahin. Breast cancer with HER2 FISH test result in group 2: Should HER2 test be repeated? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-20.