Reactive stroma and trastuzumab resistance in HER2‐positive early breast cancer. Issue 1 (22nd January 2020)

• Record Type: Journal Article
• Authors: Sonnenblick, Amir; Salmon‐Divon, Mali; Salgado, Roberto; Dvash, Efrat; Pondé, Noam; Zahavi, Tamar; Salmon, Asher; Loibl, Sibylle; Denkert, Carsten; Joensuu, Heikki; Ameye, Lieveke; Van den Eynden, Gert; Kellokumpu‐Lehtinen, Pirkko‐Liisa; Azaria, Amos; Loi, Sherene; Michiels, Stefan; Richard, François; Sotiriou, Christos
• Is Part Of: International journal of cancer. Volume 147:Issue 1(2020)
• Page Start: 266
• Page End: 276
• Publication Date: 2020-01-22
• Subjects: HER2 -- breast cancer -- reactive stroma -- CAF -- TILs; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32859
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : We investigated the value of reactive stroma as a predictor for trastuzumab resistance in patients with early HER2‐positive breast cancer receiving adjuvant therapy. The pathological reactive stroma and the mRNA gene signatures that reflect reactive stroma in 209 HER2‐positive breast cancer samples from the FinHer adjuvant trial were evaluated. Levels of stromal gene signatures were determined as a continuous parameter, and pathological reactive stromal findings were defined as stromal predominant breast cancer (SPBC; ≥50% stromal) and correlated with distant disease‐free survival. Gene signatures associated with reactive stroma in HER2‐positive early breast cancer ( N = 209) were significantly associated with trastuzumab resistance in estrogen receptor (ER)‐negative tumors (hazard ratio [HR] = 1.27 p interaction = 0.014 [DCN], HR = 1.58, p interaction = 0.027 [PLAU], HR = 1.71, p interaction = 0.019 [HER2STROMA, novel HER2 stromal signature]), but not in ER‐positive tumors (HR = 0.73 p interaction = 0.47 [DCN], HR = 0.71, p interaction = 0.73 [PLAU], HR = 0.84; p interaction = 0.36 [HER2STROMA]). Pathological evaluation of HER2‐positive/ER‐negative tumors suggested an association between SPBC and trastuzumab resistance. Reactive stroma did not correlate with tumor‐infiltrating lymphocytes (TILs), and the expected benefit from trastuzumab in patients with high levels of TILs was pronounced only in tumors with low stromal reactivity (SPBC <50%). In conclusion, reactive stroma in HER2‐positive/ER‐negative early breast cancer tumors may predict resistance to adjuvant trastuzumab therapy. Abstract : What's new Tumor cells can interact with the surrounding microenvironment, to alter gene expression, suppress immune function, and enhance their own growth. While trastuzumab has dramatically improved clinical outcomes for patients with HER2‐positive breast cancer, not all tumors respond to treatment. In this study, the authors found that one mechanism of trastuzumab resistance may be due to altered gene expression representing "reactive" stromal cells surrounding the tumor, even when high levels of tumor‐infiltrating lymphocytes (TILs) are present. These "reactive" genetic signatures may provide valuable biomarkers for predicting treatment response.