Previous studies have noted the strong relationship between the host immune response and neoadjuvant trastuzumab therapy of HER2-positive BC patients [4, 5]. Researchers often use a single immune-related gene or overall immune infiltration as a predictive biomarker for neoadjuvant trastuzumab therapy. Although these results have important implications, they may not systematically indicate an effector immune response in patients. In this study, we found that genes associated with response to neoadjuvant trastuzumab therapy were highly enriched in pathways closely related to antitumor immune activities. Interestingly, most of these pathways including cytotoxic CD8 + T cells, Th1, Tfh and NK signatures, were important in the production of IFN-γ. Hence, based on the above conclusion, we designed an IES to evaluate the immune effective phenotype. In two independent cohorts, high-IES patients showed a higher pCR rate for preoperative trastuzumab therapy than the low-IES cohort.
Several anti-HER2 agents have currently been used in the neoadjuvant setting, including trastuzumab, pertuzumab and lapatinib[25, 26]. The combination of dual anti-HER2 blockade, such as trastuzumab plus lapatinib and trastuzumab plus pertuzumab, has shown increased effectiveness over single blockade in clinical studies (NeoALTTO trial, NCT00553358; CHER-LOB trial, NCT00429299; NeoSphere trial, NCT00545688). However, trastuzumab alone remains the standard of care in combination with systemic chemotherapy (paclitaxel-based), given the possibility of increased toxicity. A recent review showed a range of pCR rate between 29% and 52% for neoadjuvant trastuzumab therapy. Due to the different chemotherapy regimens, as well as the inclusion/exclusion criteria, it is difficult to compare pCR levels between different studies. What is interesting about our data is the pCR rate from the GSE66305 cohort in the high-IES group (88 samples from CHER-LOB trial) reached 50%, but the overall pCR rate in chemo + trastuzumab arm was only 25% in CHER-LOB trial. In the GSE66305 cohort, patients from the high-IES group in chemo + trastuzumab arm also showed a higher pCR rate (64%) than the average level previously reported. No similar results were observed in arms with other treatment measures, implying that IES may serve as a predictive biomarker specific to neoadjuvant trastuzumab therapy. In addition, based on TCGA cohort analysis we found an enrichment in the low-IES community for activation of the FGFR1-PI3K-mTOR signaling axis. FGFR1, as a member of trans-membrane receptor tyrosine kinase (RTKs), has been reported to be associated with resistance to anti-HER2 therapies[20, 30]. These findings suggest that in combination with trastuzumab, patients in the low-IES group can derive more benefit from FGFR inhibitor therapies. However, FGFR inhibitors have not yet reached clinical routine practice in BC and therefore these results should be interpreted with caution.
In addition, high rates of lymphocyte infiltration have been linked with a more favorable prognosis in patients with triple-negative and HER2-positive breast cancer. This is an indication that the immune effective phenotype may also be associated with a better prognosis. We applied multivariate Cox regression analysis in TCGA cohort and METABRIC cohort to discern this property. Further, we demonstrated the significance of the IES in predicting survival in HER2-positive breast cancer. Besides, the PFI benefit was much more pronounced, indicating that patients with low-IES are prone to progression and recurrence.