Abstract P1-02-03: Tumor-infiltrating lymphocytes but not HER2 copy number or ratio show prognostic value in trastuzumab-treated HER2-positive breast cancer
Authors: Robertson Stephanie , Rönnlund Caroline , Fredriksson Irma , Foukakis Theodoros , Hartman Johan 
Published: March 2022

Abstract
Background: Around 15% of all breast cancers are HER2+, a subtype that prior to HER2-targeted therapy was associated with a poor prognosis. With advances in treatment the survival has dramatically improved, and previous studies suggest that the level of HER2 copies are predictive of the effect of anti-HER2 therapies. However, some patients progress despite HER2-targeted therapy and routine HER2 testing is hampered by inaccuracy to discriminate patients with therapy-resistant disease. Furthermore, tumor-infiltrating lymphocytes (TILs) in the tumor stroma shows prognostic value not only in triple negative but also in HER2+ breast cancer. However, the clinical utility in the adjuvant setting for HER2+ disease needs further validation. The aim of this study was to investigate the prognostic significance of HER2/CEP17 ratio, HER2 copy numbers and TILs among early breast cancer patients treated with HER2-targeted therapy. Materials and methods: A retrospective study cohort comprising a total of 584 patients with HER2+ early breast cancer, all treated with the monoclonal antibody trastuzumab targeting HER2 during 2006-2014 in the Stockholm Region, Sweden, was identified and HER2 re-testing (silver in situ hybridization and immunohistochemistry (IHC)) was performed on 474 whole tissue sections prior to neoadjuvant (18.1%) or adjuvant therapy. Stromal TILs were manually assessed on all hematoxylin-eosin stained slides. Registry-based information on patient- and tumor characteristics including treatment were completed from medical records with a median follow-up of 8.0 years. Results: Among the 474 analyzed tumors, 11.4% were HER2 IHC score 2+ and 86.7% were 3+. In addition, 61.6% were ER+ and the median TIL score was 15%. The median HER2 copy number was 9.8 signals/cell and only 12.9% had &lt;6.0 average HER2 signals/cell and 2.5% had a HER2/CEP17 ratio &lt;2.0. Survival analysis showed no significant association between HER2 IHC score (recurrence: p=0.58; breast cancer specific death: p=0.69), HER2 signals (p=0.77; p=0.73), HER2/CEP17 ratio (p=0.73; p=0.85), ER status (p=0.55; p=0.11), PR status (p=0.97; p=0.46), Ki67 (p=0.14; p=0.77) or tumor grade (p=0.71; p=0.16) with risk of recurrence or breast cancer specific death. The hazard ratio (HR) for recurrence did not significantly differ by HER2 signals/cell (HR 1.12, CI 0.53-2.37, p=0.77) or ER status (HR 1.18, CI 0.68-2.05, p=0.55). Tumors with low TILs were independently associated with recurrence (cutoff &lt;40%: HR 4.5, CI 1.4-14.9, p=0.012) and breast cancer specific survival (cutoff &lt;30%: HR 3.5, CI 1.2-10.1, p=0.02). Among the 56 recurrences (11.8%), 37.5% had ER- primary tumors and 82.4% of the 34 HER2-analyzed recurrent tumors remained HER2+. Conclusions: This study demonstrates that routine clinicopathological data, including HER2 status, is insufficient to predict breast cancer recurrence among patients treated with HER2-targeted therapy. Neither HER2 levels, HER2/CEP17 ratio or ER status correlated to risk of recurrence. Importantly, TILs showed robust prognostic potential in trastuzumab-treated patients. Our results emphasize the need for detailed molecular analyses to understand the biology behind resistance to HER2-targeted therapy and to further tailor therapy for HER2+ breast cancer patients.
Citation Format: Stephanie Robertson, Caroline Rönnlund, Irma Fredriksson, Theodoros Foukakis, Johan Hartman. Tumor-infiltrating lymphocytes but not HER2 copy number or ratio show prognostic value in trastuzumab-treated HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-03.