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

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 (a ¼ 0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1).Results: By DSP, high expression of alpha-smooth muscle actin (a-SMA), both in the leukocyte and stromal compartments, was associated with shorter DFS in univariate analysis (P ¼ 0.002 and P ¼ 0.023, respectively). High a-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 ¼ 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 ¼ 0.027).Conclusions: This work identifies a-SMA as a novel, easyto-implement biomarker of resistance to trastuzumab that may be valuable in settings where trastuzumab is combined with other therapies.

Targeting the tumor stroma for cancer therapy

“…The high expression of α-smooth muscle actin (α-SMA) is another prominent characteristic of CAFs, and its expression level has been identified as a novel biomarker of resistance to trastuzumab early-stage of HER2-positive breast cancer [ 437 ]. Specific targeting α-SMA with docetaxel-conjugate nanoparticles increased drug delivery efficiency by enhancing vascular perfusion and reduced cancer metastases [ 438 ].…”

Cancer-educated mammary adipose tissue-derived stromal/stem cells in obesity and breast cancer: spatial regulation and function

“…Specifically, the tissue sections of obese patients displayed a significantly higher αSMA level in stroma compared to the sections from lean patients. This is of specific importance, as it has been recently reported that the stromal expression of αSMA is highly associated with the resistance to trastuzumab in patients with early-stage Her2 positive breast cancer [ 95 ]. Additionally, the expression of αSMA was found to be correlated with poor prognosis in patients with ER positive breast cancer [ 96 ] and in patients with luminal breast cancer [ 97 ], likely mediated by a TMX resistance and an increased proliferation.…”

Assessment of Cognitive Function with Sleep Spindle Characteristics in Adults with Epilepsy

“…In the case of heterogeneous variances, the Welch ANOVA and Games-Howell post hoc test were used for data analysis. Considering we performed multiple ANOVA, P values were corrected using the Benjamini–Hochberg method to control the false discovery rate (FDR) at 0.10, and the adjusted P value ( P .adjust) < 0.10 was considered statistically significant [ 29 , 30 ].…”

“…Statistical significance was set at P < 0.05; statistical trends were set at P < 0.10. Since we performed a large number of regressions between cognitive function and topographical spindle characteristics, the Benjamini and Hochberg method was used to correct the P values, and P .adjust < 0.10 was considered still statistically significant after correction [ 29 , 30 ].…”