Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study

Abstract

Background: Trastuzumab and pertuzumab have been shown to work by inhibiting the intracellular signaling linked to HER2 receptor activation, and cytotoxic immune mechanisms, including Fc-dependent immune cell activation. ER+ and ER−/HER2+ breast cancers (BC) are considered molecularly distinct entities (Bianchini G, ASCO 2011; Iwamoto T, ESMO 2012). Regardless of the ER status, immune gene signatures are prognostic and predictive of chemotherapy response (Iwamoto T, ESMO 2012). The gene expression profiles of pre-treatment tumor samples from patients of the NeoSphere trial of neoadjuvant pertuzumab+trastuzumab ± docetaxel (T) (Gianni L, Lancet Oncol 2012) were characterized. We assessed the association of pre-selected adaptive immune functions and key immune regulatory genes with the likelihood of achieving a pathological complete response (pCR) in NeoSphere. Methods: Baseline core biopsies were collected from 387/417 patients. Gene expression profiles (Affymetrix U133 Plus 2.0) were obtained for 367 samples (88% of all patients) that were evenly distributed among arms A (TH, n=90), B (THP, n=95), C (HP, n=98), and D (TP, n=84). ER status was defined by IHC. The primary endpoint was pCR in breast. We assessed metagenes (average expression of the associated genes) corresponding to: immunoglobulins (IgG), CD8A, MHC type I and type II (MHC1, MHC2), interferon inducible genes (I-IG) and STAT1-related genes. We also assessed the individual genes PD1, PD-L1, PD-L2, CTLA4, IFNG. Results: ER+ and ER− tumors had differential mRNA expression for: CD8A, IgG, PD-L2, PD1, IFNG (overexpressed in ER−), and I-IG (overexpressed in ER+). Positive correlations were observed between most of these biomarkers. Only PD1 was inversely correlated with STAT1, interferon and MHC2. In logistic univariate regression analyses some biomarkers showed moderate association with pCR or residual disease without consistent patterns between treatment arms. However, a multivariate logistic regression model constructed for all the selected biomarkers revealed that high expression of PD-L1 was consistently associated with lower pCR rate in all chemotherapy containing arms (A, B and D). A similar trend was present also in Arm C, the arm with antibody treatment alone. In all arms, high expression of IFNG and/or STAT1 were associated with higher pCR rate. In multivariate analysis PD-L1, PD1 and STAT1 were associated with pCR irrespective of the ER status in combined arms A, C and D. In arm B, both CTLA4 and PD-L1 were independently associated with lower pCR in ER− tumors. Conclusions: The association between pCR and selected immune biomarkers in patients treated with pertuzumab, trastuzumab, or both, with or without chemotherapy, supports our understanding of the key role of the immune system in contributing to HER2-targeted antibody therapy on top of signaling inhibition. High PD-L1 expression emerged for its consistent association with lower pCR. These results provide a rationale for combining HER2-targeted treatments with immune-modulating agents and may allow the prediction of treatment benefit. Validation of these results with different assays is ongoing. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-7.

Genomic Analysis Reveals That Immune Function Genes Are Strongly Linked to Clinical Outcome in the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

“…11 -14 It has been reported that there is an association between tumor-infiltrating lymphocytes and patient outcome in the Fluorouracil, Epirubicin 10,15,16 Our observations represent, to the best of our knowledge, the first demonstration of a cohort of immune function genes that seem to predict benefit from adjuvant trastuzumab in patients with HER2-positive breast tumors.…”

“…The FinHER trial reported that lymphocyte infiltration was associated with increased disease-free survival in 209 patients randomly assigned to receive adjuvant trastuzumab or no trastuzumab for 9 weeks after chemotherapy. 10 Likewise, a preliminary report from the NeoSphere trial 16 reported that metagene signatures involving immune function genes were predictive of complete pathologic response to neoadjuvant anti-HER2 therapy. Thus, it appears that the data from these preliminary analyses are entirely consistent with and support our conclusion that there is an association between immune function and benefit from trastuzumab in the adjuvant setting and suggest that a similar association may prevail in the neoadjuvant setting.…”

“…An obvious strategy involves attenuation of immune-suppressive signaling pathways (eg, by targeting entities such as the PD1/CD279 receptor and/or its ligand PDL1/CD274). 16 An alternative strategy involves enrolling patients with nonenriched tumors onto clinical trials to test the effects of modification of the immunoglobulin backbone of anti-HER2 antibodies to enhance immunoreactivity. 31 These 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.…”

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

“…The genes were chosen from literature review on the basis of their being identified as (i) possible prognostic factors in residual disease at protein (4,(6)(7)(8)(9)(10) or mRNA level (11), (ii) as significantly up-or downregulated, but of unknown prognostic value in residual disease (12)(13)(14)(15)(16)(17)(18)(19)(20), (iii) as predictive of chemotherapy resistance (6,11,16,19,(21)(22)(23)(24)(25)(26)(27)(28)(29), and/or (iv) identified as possible prognostic factors over several previous datasets (26,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). In addition to the previously established prognostic factors ESR1 and ERBB2, the genes were also chosen to represent different pathways and biological processes of known implication in tumor progression or response to therapy, such as stemcellness (ALDH1A1, CD44, and STAT3), proliferation (TOP2A, MKI67, and AURKA), apoptosis (BCL2, BCL2L1, and PAWR), immunologic response (CD3D, CXCL13, and STAT1), epithelial-to-mesenchymal transition (EMT; SNAI1, SNAI2, SOX9, and TWIST), stromal activation (DECORIN, ...…”

Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

“…Comparable results with anti HER 2 therapy were found in Neo-Sphere study which examined neoadjuvant trastuzumab, pertuzumab, or both, with or without chemotherapy. A high expression of immune checkpoint, like PD1 or PDL1, which role is to suppress the activation of T cells, was associated with lower pCR rate after chemotherapy in combination with biological anti HER 2 therapy like trastuzumab and pertuzumab (39).…”