Abstract P6-01-37: Tumor microenvironment subtype influence the response of neoadjuvant chemotherapy in breast cancer
Authors: Kim ji-Yeon , Park Kyunghee , Park woong-Yang , Lee Jeong Eon , Kim Seok Won , Nam Seok Jin , Lee Se Kyung , Park Yeon Hee 
Published: March 2023

Abstract
Introduction Recent transcriptome analysis developed a holistic tumor microenvironment (TME) classification platform based on immune and fibrotic markers. This TME classification had four categories, immune enriched, fibrotic (IE/F); immune enriched, non-fibrotic (IE); Fibrotic (F); and Immune Desert (D). And these four TME subtypes are a predictive biomarker to immunotherapy in multiple cancer and four subtypes have been changed during treatment. Previously our study suggested baseline immune features and dynamic immune response on-treatment were predictive of treatment outcome in BC with neoadjuvant chemotherapy (NAC). In this study, we evaluated the impact of TME classification and dynamic change of TME classification on treatment outcome in BC with NAC. Methods Early and locally advanced BCs which would be planned to receive standard NAC (four cycles of anthracycline plus cyclophosphamide and four cycles of docetaxel or docetaxel plus trastuzumab for human epidermal growth factor receptor 2[HER2+] disease or six cycles of docetaxel, carboplatin, trastuzumab and pertuzumab for HER2+ disease) followed by curative surgery. We prospectively collected tumor tissue and matched blood three times for each patients: at BC diagnosis (T1), three weeks after the first cycle of NAC (T2), and curative surgery (T3). RNASeq was performed to classify TME subtype. In terms of clinical variables, clinical stage and IHC subtype at diagnosis, pathologic complete response (pCR), distant recurrence free survival (DRFS) and overall survival (OS) were used. Generalized logistic regression was used for predicting RCB class and pCR with clinical and genomic characteristics at T1. Kaplan-Meier analysis were performed to analysis DRFS and OS. Results In total, 210 patients who were treated with scheduled NAC were enrolled. Finally, RNASeq in 240 BC tissues (T1:119, T2:91 and T3:30) were conducted from 142 patients. In 119 BCs which was performed RNASeq at T1, hormone receptor(HR)+, HER2- BC was 32 (26.9%), 29 of HR+HER2+ BC (24.4%), 18 of HR-HER2+ BC (15.1%) and 44 of triple negative BC (TNBC) (37.0%). In TME classification, immune desert (D) was most frequently observed (45.3%), followed by IE (35.3%), F (10.1%) and IE/F (9.2%). The association between BC subtype and TME subtype suggested that HR+HER2- BC was frequently categorized into D (22 of 32, 68.8%) whereas TNBC was into IE (24 of 44, 54.5%) (p&lt; 0.001). TME subtype has been dynamically changed during NAC. At T2, IE subtype was most frequently observed (27.5%) followed by D (25.3%), IE/F (24.2%) and F (23.1%). The inclination of TME change were different according to NAC response. In BC achieved pCR, IE/F subtype had increased (4 at T1 and 10 at T2) and decrease of D subtype (15 at T1 and 3 at T2). In BC with non-pCR, IE/F subtype had slightly increased at T2 (7 at T1 and 12 at T2) but there was no IE/F subtype at T3 point. Contrarily, D subtype had decreased at T2 but increased at T3 (39 at T1, 20 at T2 and 24 at T3). The impact of TME subtype was different according to pCR status. In BC with pCR, F subtype had poor prognosis in DRFS and OS compared to other subtype ([5year DRFS rate for F vs. others: 66.7% vs. 93.2%, p=0.028], [5year OS rate for F vs. others: 70.7% vs. 100%, p&lt; 0.001]). In BC without pCR, there was no different DRFS and OS according to TME subtypes. Conclusion Our data suggested that TME subtype has been changed during NAC and the subtype switching was affected by the NAC response. Moreover, TME subtype may have prognostic role in DRFS and OS according to pCR status.
Citation Format: ji-Yeon Kim, Kyunghee Park, woong-Yang Park, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Se Kyung Lee, Yeon Hee Park. Tumor microenvironment subtype influence the response of neoadjuvant chemotherapy in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-37.