Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer

Abstract

ImportanceBoth tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known.ObjectiveTo examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials.Design, Setting, and ParticipantsIn this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022.Main Outcomes and MeasuresImmune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses.ResultsThe median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature–adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99).Conclusions and RelevanceResults of this study suggest that multiple B-cell–related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Nucleic acid vaccines‐based therapy for triple‐negative breast cancer: A new paradigm in tumor immunotherapy arena

“…93 progression-free survival. 95 Researchers suggest that ERBB2 type 1 T-helper cell counts in peripheral blood can be used to forecast positive clinical outcomes following trastuzumab therapy. 96 The results of this phase 1 nonrandomized clinical trial indicate that the ERBB2 ICD vaccine was linked to the induction of immunity at all dosages, with the highest levels of immunogenicity being at 100 and 500 μg.…”

“…When paired with anti‐PD‐L1 checkpoint blockade immunotherapy, E0771, and 4T1.2‐specific polyepitope neoantigen DNA vaccines were able to elicit strong immune responses and suppress tumor growth. Following trastuzumab administration, patients with breast cancer who develop ERBB2 (formerly HER2)‐specific immunity—specifically, responses that target the protein's ICD—are more likely to experience favorable clinical outcomes, such as OS and progression‐free survival 95 . Researchers suggest that ERBB2 type 1 T‐helper cell counts in peripheral blood can be used to forecast positive clinical outcomes following trastuzumab therapy 96 .…”

Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2/HER2-Positive Breast Cancer

“…We hypothesized that the biological tumor and immune heterogeneity of ERBB2/HER2 -positive EBC contribute to the inconsistent results coming from different neoadjuvant and adjuvant clinical trials. In this analysis, we examined how intrinsic subtype, immune activation status, and other gene expression signatures contribute to pCR and EFS, and the benefit of dual therapy with trastuzumab and lapatinib compared with single-agent trastuzumab, by performing individual patient-level biomarker analysis of 3 phase 3 clinical trials with similar designs: NeoALTTO, CALGB 40601, and NSABP B-41 …”

More on treatment de-escalation, biomarkers of response in human epidermal growth factor receptor 2 (HER2)-positive breast cancer: long-term outcomes and translational research findings of the PREDIX HER2 trial

“…Activation of the immune system, as measured by the expression of TILs and/or immune-related gene expression (iGES) signatures, has been intensely investigated as a potential biomarker in the neoadjuvant setting. While the expression of TILs in HER2+ BC has consistently correlated with poor prognostic features such as estrogen receptor (ER)-negativity (37)(38)(39) and high histological grade (39), it has at the same time correlated with higher pCR rates (37,38,(40)(41)(42) and, in some (38,41) but not all studies (35,39), with improved cancer outcomes. However, in some studies, TILs were shown potentially inferior to some iGES in predicting pCR in both HER2+ (37,42) and triple negative breast cancer (TNBC) (43).…”

“…While the expression of TILs in HER2+ BC has consistently correlated with poor prognostic features such as estrogen receptor (ER)-negativity (37)(38)(39) and high histological grade (39), it has at the same time correlated with higher pCR rates (37,38,(40)(41)(42) and, in some (38,41) but not all studies (35,39), with improved cancer outcomes. However, in some studies, TILs were shown potentially inferior to some iGES in predicting pCR in both HER2+ (37,42) and triple negative breast cancer (TNBC) (43). Furthermore, as with Ki-67 (44) measurements are tricky to standardize (38,(45)(46)(47); hence the special interest in digital assessments-in addition to its potential cost-saving and wider applicability in places where restricted access to specialist pathologists is the rule.…”