Publikation
Alpha-smooth muscle actin expression in the stroma predicts resistance to trastuzumab in patients with early-stage HER2-positive breast cancer
Wissenschaftlicher Artikel/Review - 31.08.2021
Vathiotis Ioannis A, Kim Sung-Bae, Harbeck Nadia, Gomez Henry, Shafi Saba, Syrigos Konstantinos N, Fountzilas George, Sotiriou Christos, Pusztai Lajos, Warren Sarah, Di Cosimo Serena, Huober Jens, Nuciforo Paolo, Moutafi Myrto K, Divakar Prajan, Aung Thazin Nwe, Qing Tao, Fernandez Aileen, Yaghoobi Vesal, El-Abed Sarra, Wang Yingbo, Guillaume Sébastien, Rimm David L
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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 breast cancer patients that received adjuvant trastuzumab as part of the HeCOG 10/05 clinical trial. Promising candidate biomarkers were orthogonally validated with quantitative immunofluorescence (QIF). RNA sequencing data from the NeoALTTO study 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 (α=0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1).
RESULTS
By DSP, high expression of alpha-smooth muscle actin (α-SMA), both in the leukocyte and stromal compartments, was associated with shorter DFS in univariate analysis ( = .002 and = .023, respectively). High α-SMA expression in the stroma was validated by QIF after controlling for ER and PR status (HR, 3.12; 95% CI, 1.12-8.68; = .029) showing recurrence on trastuzumab in the same cohort. In the NeoALTTO cohort, elevated levels of were predictive for shorter DFS in the multivariate analysis (HR, 3.21; 95% CI, 1.14-9.05; = .027).
CONCLUSIONS
This work identifies α-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.