Alpha-smooth Muscle Actin Expression in the Stroma Predicts Resistance to Trastuzumab in Patients with Early-stage HER2-positive Breast Cancer

Vathiotis, Ioannis A.; Moutafi, Myrto K.; Divakar, Prajan; Aung, Thazin Nwe; Qing, Tao; Fernandez, Aileen; Yaghoobi, Vesal; El-Abed, Sarra; Wang, Yingbo; Guillaume, Sebastien; Nuciforo, Paolo; Huober, Jens; Di Cosimo, Serena; Kim, Sung-Bae; Harbeck, Nadia; Gomez, Henry; Shafi, Saba; Syrigos, Konstantinos N.; Fountzilas, George; Sotiriou, Christos; Pusztai, Lajos; Warren, Sarah and Rimm, David L. (2021): Alpha-smooth Muscle Actin Expression in the Stroma Predicts Resistance to Trastuzumab in Patients with Early-stage HER2-positive Breast Cancer. In: Clinical Cancer Research, Vol. 27, No. 22: pp. 6156-6163

Abstract

Purpose: The companion diagnostic test for trastuzumab has not changed much in the last 25 years. We used high-plex digital spatial profiling to identify biomarkers besides HER2 that can help predict response to trastuzumab in HER2-positive breast cancer. Experimental design: Fifty-eight protein targets were measured in three different molecularly defined compartments by the NanoString GeoMx Digital Spatial Profiler (DSP) in a tissue microarray containing 151 patients with breast cancer that received adjuvant trastuzumab as part of the Hellenic Cooperative Oncology Group 10/05 clinical trial. Promising candidate biomarkers were orthogonally validated with quantitative immunofluorescence (QIF). RNA-sequencing data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Study (NeoALTTO) were accessed to provide independent cohort validation. Disease-free survival (DFS) was the main outcome assessed. Statistical analyses were performed using a two-sided test (alpha = 0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1). Results: By DSP, high expression of alpha-smooth muscle actin (alpha-SMA), both in the leukocyte and stromal compartments, was associated with shorter DFS in univariate analysis (P = 0.002 and P = 0.023, respectively). High alpha-SMA expression in the stroma was validated by QIF after controlling for estrogen receptor and progesterone receptor status [HR, 3.12;95% confidence interval (CI), 1.12-8.68;P = 0.029] showing recurrence on trastuzumab in the same cohort. In the NeoALTTO cohort, elevated levels of ACTA2 were predictive for shorter DFS in the multivariate analysis (HR, 3.21;95% CI, 1.14-9.05;P = 0.027). Conclusions: This work identifies a-SMA as a novel, easy-to-implement biomarker of resistance to trastuzumab that may be valuable in settings where trastuzumab is combined with other therapies.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1078-0432
• Language: English