Immune Gene Signature Predicts Trastuzumab Response In HER2-Postive Breast Cancer

Human epidermal growth factor receptor 2-positive breast cancer patients with tumours expressing a 14-immune gene signature may benefit more from adjuvant trastuzumab therapy compared with those lacking the signature

medwireNews: Elevated expression of a subset of immune function genes is significantly associated with relapse-free survival (RFS) in trastuzumab -treated breast cancer patients who are positive for human epidermal growth factor receptor 2 (HER2), research suggests.

“The potential clinical significance of our results, within the context of identification of patients who are likely to benefit (increased RFS) from adjuvant trastuzumab, is considerable”, Edith Perez, from Mayo Clinic in Jacksonville, Florida, USA, and team write in the Journal of Clinical Oncology.

Editorialists John Foekens, John Martens and Stefan Sleijfer, from Erasmus University Medical Center in Rotterdam, the Netherlands, agree with the authors, highlighting that avoiding trastuzumab in patients unlikely to gain from treatment could reduce toxicity and save costs.

But they caution that the study findings need to be “independently confirmed” before they can make a bench-to-bedside transfer.

The researchers performed whole-transcriptome analysis on 1282 tumour samples from the North Central Cancer Treatment Group N9831 phase III trial in which women with early-stage, HER2-positive breast cancer either received chemotherapy alone or in combination with sequential or concurrent trastuzumab. The trastuzumab-treated patients were grouped together in this study.

Using a systems biology approach, the team identified biological processes (such as chemokine signalling) that predicted RFS in response to adjuvant trastuzumab therapy, and generated a signature consisting of 14 immune-related genes. This signature was subsequently used to categorise participants as having immune response-enriched or nonimmune response-enriched tumours, where the former expressed at least nine of the 14 immune function genes at or above the 0.40 quantile for the cohort.

In multivariate analysis, women with immune response-enriched tumours who received adjuvant trastuzumab had a significantly longer RFS than their counterparts who were treated with chemotherapy alone, at a hazard ratio of 0.36.

By contrast, when participants with nonimmune response-enriched malignancies were considered, RFS did not vary significantly between women given adjuvant trastuzumab and those who received chemotherapy alone.

The editorial authors point out that although questions remain regarding what the immune signature exactly represents and the expression pattern of the constituent genes, “these results support previous preclinical and clinical studies suggesting that in addition to inhibiting HER2 signaling, the immune system is crucial for the combination of trastuzumab and chemotherapy to be effective.”

Edith Perez et al say that “alternative approaches to harness the immune system gene expression profiles to predict and potentially enhance benefit from adjuvant trastuzumab could have considerable significance for those patients with HER2-positive breast cancer who are likely to develop tumor relapse after adjuvant anti-HER2 therapy.”


Perez EA, Thompson EA, Ballman KV,et al.Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcome in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial. J Clin Oncol 2015; Published online before print 20 January. doi:10.1200/JCO.2014.57.6298

Foekens JA, Martens JWM, Sleijfer S.Are Immune Signatures a Worthwhile Tool for Decision Making in Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer? J Clin Oncol 2015; Published online before print 20 January. doi:10.1200/JCO.2014.59.5058

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