Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials

Abstract

Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).

Conflict of interest statement

There are no relevant conflicts of interest for Ms. Li, Mr. Serie, Ms. Tenner, Mr. Gavin, Ms. Van Dooren, Ms. Holmes, and Drs. Norton, Partridge, Carey, Hilbers, Holmes, Di Cosimo, Dueck, Sotirios, Knutson, and Thompson. Dr. Chumsri receives institutional research funding from Merck & Co. and Pfizer. Mr. Mashadi-Hossein, Drs. Brauer, Warren, and Danaher worked at NanoString Technologies, Inc. Dr. Werner worked at Novartis. Dr. Colon-Otero receives funding support for investigator-initiated trial from Novartis. Dr. Huober receives funding support from Novartis, honoraria, consulting advisory relationship, and travel expenses from Novartis and Roche. Dr. Perez worked at Genentech. Dr. Moreno-Aspitia receives institutional research funding from Genentech, GSK, Sermonix, and Daiichi.

© 2022. The Author(s).

Figures

Fig. 1. Kaplan–Meier curves of RFS in the NCCTG N9831 comparing between patients with CD45 high vs. low.

A Chemotherapy-only arm (AC–T). B Sequential (AC–T–H) or concurrent trastuzumab arm (AC–TH).

Fig. 2. Forest plot of RFS with immune-subset signatures in the NCCTG N9831 with chemotherapy-only arm (AC–T) in blue and sequential (AC–T–H) or concurrent trastuzumab arm (AC–TH) in red.

The HR on the forest plots was from multivariate models adjusting for age, nodal status, ER/PR status, tumor size, and tumor grade. The size of the box in the forest plots represents the precision (standard error) of the estimates.

Fig. 3. Kaplan–Meier curves of RFS in the NCCTG N9831 comparing between AIS-high vs. -low patients.

A Chemotherapy-only arm (AC–T). B Sequential (AC–T–H) or concurrent trastuzumab arm (AC–TH).

Fig. 4. Kaplan–Meier curves of AIS-low patients in the NeoALTTO.

Patients in arm A were treated with lapatinib alone, arm B with trastuzumab alone, and arm C with the combination of trastuzumab and lapatinib.