Details

Autor(en) / Beteiligte

• 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
• Rimm, David L

Titel

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

Ist Teil von

• Clinical cancer research, 2021-11, Vol.27 (22), p.6156-6163

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. 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 (α = 0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1). 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 ( = 0.002 and = 0.023, respectively). High α-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; = 0.029] 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; = 0.027). 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.