Abstract PD3-08: Assessment of the tumor immune environment in inflammatory breast cancer treated with neoadjuvant dual-HER2 blockade
Authors: Pernas S , Goel S , Harrison BT , Hu J , Johnson N , Regan M , Chichester LA , Nakhlis F , Schlosnagle EJ , Winship G , Guerriero JL , Parsons H , Mittendorf EA , Overmoyer B 
Published: May 2019

Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that remains relatively understudied. We examined the efficacy of neoadjuvant dual-HER2 blockade (trastuzumab (H) and pertuzumab (P)) combined with paclitaxel (T) in HER2+ IBC, including a planned analysis to elucidate associations between the tumor immune microenvironment profile and response to therapy.

Methods: An IRB-approved, single-arm phase II trial for patients (pts) with newly diagnosed HER2+ IBC was conducted. Pts had a pre-treatment biopsy of the affected breast (D1) followed by a loading dose of HP. A second biopsy was performed 1 week (wk) later (D8), when T (80mg/m2/wk x 16 wks) was added to HP. Responding pts underwent modified radical mastectomy (MRM) where residual disease was collected. The primary objective was to determine the rate of pathologic complete response (pCR) defined as ypT0/isN0. Residual Cancer Burden (RCB) was also determined. Tumor specimens from D1, D8 and MRM were assessed for disease cellularity and scored for percentage of tumor infiltrating lymphocytes (TILs): low=0-10%, intermediate=11-59%, high&gt;60%. RNA-sequencing was performed on tumor tissue from D1 and D8 to explore the impact of short-term HP treatment on the tumor transcriptomic profile and to identify potential predictors of pCR.

Results: 23 pts with HER2+ IBC were enrolled between 8/2013-6/2017. Mean age was 48 years (range 32-74); 11 pts (48%) had estrogen and progesterone receptor (ER/PR) negative disease. Matched tumor biopsies (D1, D8) were obtained in all 23 pts; 21 underwent MRM; 1 was lost to follow-up and 1 had disease progression. In the intent to treat analysis, 10/23 (43%) pts achieved a pCR and 7 (30%) had RCB-1. Ten of the 22 evaluable pts achieved a pCR (45.5%). TILs were evaluable in 20/23 (87%) matched tumor biopsies (D1, D8). Among the D1 biopsy specimens: 19 (95%) had low levels, 2 (10%) had intermediate levels, and none had high levels. When D1 TIL levels were compared with D8 levels, 3(15%) had an increase in TILs, 16(80%) had no change in TIL levels, and 1(5%) had a decrease in the level of TILs. Both samples with intermediate levels and 2 of 3 samples with high levels of TILs on D1 and D8 were seen in ER/PR negative disease. An evaluation of biopsy specimens associated with subsequent pCR using GO enrichment analysis from the RNA-Seq data showed significant upregulation of several immune-process related gene expression signatures both at D1 and D8 (e.g. antigen processing and presentation, TCR signaling, NK cell cytotoxicity, p-value: 2.99E-48 to 1.39E-16) when compared with those associated with residual disease at the time of MRM. Across the entire cohort, D8 biopsies showed evidence of upregulated anti-tumor immunity compared to D1 biopsies (p-value: 9.57E-06 to 0.012). Notably, this change from D1 to D8 was largely restricted to tumors that achieved a pCR.

Conclusion: THP for 16 weeks was a highly effective treatment for HER2+ IBC. Immune activation as determined by gene expression signatures predicted pCR, and moreover upregulation of anti-tumor immunity after 1 wk of HP might further predict a complete pathologic response to therapy. ClinicalTrials.gov identifier: NCT01796197

Citation Format: Pernas S, Goel S, Harrison BT, Hu J, Johnson N, Regan M, Chichester LA, Nakhlis F, Schlosnagle EJ, Winship G, Guerriero JL, Parsons H, Mittendorf EA, Overmoyer B. Assessment of the tumor immune environment in inflammatory breast cancer treated with neoadjuvant dual-HER2 blockade [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-08.