Prognostic and predictive implications of the intrinsic subtypes and gene expression signatures in early-stage HER2+ breast cancer: A pooled analysis of CALGB 40601, NeoALTTO, and NSABP B-41 trials.
Authors: Fernandez-Martinez Aranzazu , Rediti Mattia , Tang Gong , Pascual Tomas , Hoadley Katherine A. , Venet David , Rashid Naim , Spears Patricia , Islam Md N. , El-Abed Sarra , Bliss Judith , Lambertini Matteo , Huober Jens Bodo , Goerlitz David , Hu Rong , Lucas Peter C. , Swain Sandra M. , Sotiriou Christos , Perou Charles M. , Carey Lisa A. 
Published: June 2022

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Background: Several biologic features are implicated in the differences in response and survival to dual (trastuzumab and lapatinib [HL]) vs. single (trastuzumab [H]) HER2-blockade across neoadjuvant trials in early-stage HER2+ breast cancer. We evaluated the association of intrinsic subtypes and gene expression signatures with pathologic complete response (pCR) and event-free survival (EFS) in a pooled analysis of three independent phase III neoadjuvant studies with similar designs: CALGB 40601 (Alliance), NeoALTTO, and NSABP B-41. Methods: Gene expression profiling by RNA sequencing was assessed on 761 pre-treatment samples (264 from CALGB 40601, 249 from NeoALTTO, 248 from NSABP B-41). Intrinsic subtypes and 759 gene expression signatures were calculated. We studied the association of pCR and the benefit of dual (HL) vs. single (H) HER2-blockade by tumor intrinsic subtype in the pooled set. The ability of multiple gene expression signatures to predict pCR and EFS across the three studies was also tested by logistic and Cox regression analyses. Results: pCR status was associated with EFS only in HER2-Enriched (HR 0.45, 95% CI 0.29-0.71, p-value < 0.001) and Basal-like (HR 0.19, 95% CI 0.04-0.86, p-value 0.031) intrinsic subtypes, but not in Luminal and/or ER+ tumors. The EFS benefit of dual vs. single HER2-blockade was limited to HER2-Enriched tumors (HR 0.47, 95% CI 0.27-0.81, p-value 0.007). When evaluating the three clinical trials separately, we found 89/759 (11.7%) gene expression signatures in common for the prediction of pCR across the three clinical trials, including HER2-amplicon and immune activation signatures. Luminal-related signatures were associated with lower pCR rates but better EFS outcomes, especially in patients with residual disease. Stratified Cox regression models by study showed a significant and strong association of NK, B and plasma cells, as well as Ig-related signatures with a better EFS outcome, while vascular, proliferation, and metastasis signatures were associated with poor EFS. Conclusions: In early-stage HER2+ breast cancer, the relationship between pCR and EFS differs by tumor intrinsic subtype, and the benefit of dual vs. single HER2-blockade seems to be limited to HER2-Enriched subtype tumors. Immune signatures were associated with higher pCR rates and better EFS, luminal signatures were associated with lower pCR rates but good EFS outcomes, and vascular/proliferation/metastasis signatures were associated with poor EFS across the three clinical trials. Clinical trial identification: CALGB 40601: NCT00770809. (CALGB is part of the Alliance for Clinical Trials in Oncology). NeoALTTO: NCT00553358 NSABP B-41: NCT00486668