Genetic Markers Associated With Pathologic Complete Response to Neoadjuvant Therapy Identified in HER2-Positive Breast Cancer
In an analysis reported in JAMA Oncology, Fumagalli et al identified genetic markers associated with pathologic complete response among women with early-stage HER2-positive breast cancer receiving neoadjuvant therapy in the phase III NeoALTTO trial.
Study Details
In the NeoALTTO trial, 455 patients were randomized to receive trastuzumab (Herceptin), lapatinib (Tykerb), or both for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks and then 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The current substudy examined the association of pretreatment gene-expression levels measured by RNA sequencing with pathologic complete response and event-free survival among 254 patients with available sequencing data. Of them, 35.0% were in the lapatinib group, 31.1% were in the trastuzumab group, and 33.9% were in the combination group.
Associations With Pathologic Complete Response
In univariate analysis, ERBB2/HER2 expression was the most significant predictor of pathologic complete response, followed by HER2-enriched subtype; ESR1; treatment arm; estrogen receptor immunohistochemical analysis scores; Genomic Grade Index; and immune, proliferation, and AKT/mTOR gene signatures. In analysis adjusting for clinicopathologic variables and treatment groups, ERBB2/HER2 (odds ratio [OR] = 3.1, P < .001), HER2-enriched subtype (OR = 3.2, P < .001), ESR1 (OR = 0.53, P = .008), and Genomic Grade Index (OR = 1.5, P = .01) remained significant factors. Immune gene signatures were associated with a higher likelihood of pathologic complete response only in the combination treatment group (OR = 2.1, interaction test P = .01); stroma gene signatures were significantly associated with a higher likelihood of pathologic complete response in the single-agent groups and a lower likelihood of pathologic complete response in the combination group (OR = 0.46, P = .009).
Analysis of association of markers with event-free survival was underpowered, and none was associated with event-free survival after correction for multiple testing.
The investigators concluded: “High levels of ERBB2/HER2 and low levels of ESR1 were associated with [pathologic complete response] in all treatment arms. In the combination arm, high expression of immune and stroma [gene signatures] were significantly associated with higher and lower [pathologic complete response] rates, respectively, and should be further explored as candidate predictive markers.”
The study was sponsored by GlaxoSmithKline.
Christos Sotiriou, MD, PhD, of Institut Jules Bordet, Université Libre de Bruxelles, is the corresponding author of the JAMA Oncology article.
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