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Alpha-smooth muscle actin expression in the stroma predicts resistance to trastuzumab in patients with early-stage HER2-positive breast cancer

Ioannis A Vathiotis, Myrto K Moutafi, Prajan Divakar, Thazin Nwe Aung, Tao Qing, Aileen Fernandez, Vesal Yaghoobi, Sarra El-Abed, Yingbo Wang, Sébastien Guillaume, Paolo Nuciforo, Jens Huober, Serena Di Cosimo, Sung-Bae Kim, Nadia Harbeck, Henry Gomez, Saba Shafi, Konstantinos N Syrigos, George Fountzilas, Christos Sotiriou, Lajos Pusztai, Sarah Warren & David L Rimm

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 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.
   
citation Vathiotis I A, Moutafi M K, Divakar P, Aung T N, Qing T, Fernandez A, Yaghoobi V, El-Abed S, Wang Y, Guillaume S, Nuciforo P, Huober J, Di Cosimo S, Kim S B, Harbeck N, Gomez H, Shafi S, Syrigos K N, Fountzilas G, Sotiriou C, Pusztai L, Warren S, Rimm D L. Alpha-smooth muscle actin expression in the stroma predicts resistance to trastuzumab in patients with early-stage HER2-positive breast cancer. Clin Cancer Res 2021;.
   
type journal paper/review (English)
date of publishing 31-08-2021
journal title Clin Cancer Res
ISSN electronic 1557-3265
PubMed 34465600
DOI 10.1158/1078-0432.CCR-21-2103