Are Immune Signatures a Worthwhile Tool for Decision Making in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer?
Authors: John A. Foekens, John W.M. Martens, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2015)

The advent of trastuzumab in the adjuvant setting has greatly improved the outcome for patients with HER2-amplified early breast cancer. However, there is clearly room for improvement. Many patients are overtreated with trastuzumab because of our failure to properly identify those cured already by local treatments and/or by perioperative systemic treatment alone; conversely, a subgroup is confronted with relapses despite trastuzumab-based adjuvant treatment. Obviously, better prognostic and predictive factors are urgently needed. With regard to predictive factors to discriminate human epidermal growth factor receptor 2 (HER2) –positive patients who are likely to benefit from trastuzumab-based regimens from those who do not, the focus of research so far has been predominantly on tumor cell– related factors. For instance, patients with tumors in which the phosphatidylinositol 3-kinase pathway has been activated through either PIK3CA mutation or loss of PTEN seem to benefit less from trastuzumab-based approaches; however, because of a lack of validation or evidence of clinical utility, these findings are not yet ready to be introduced into clinical practice. Apart from these tumor-related genetic markers, there is accumulating evidence that immune response mechanisms also affect outcome in patients with breast cancer, both in those who do receive treatment in the (neo)adjuvant setting and in those who do not. The article accompanying this editorial substantially contributes to the existing knowledge in this field. Perez et al developed a genomic signature that predicts benefit from trastuzumab in HER2-positive breast cancer using samples from patients who participated in the North Central Cancer Treatment Group N9831 phase III trial. In this trial, 3,005 patients with early-stage HER2-positive operable breast cancer were randomly assigned to adjuvant doxorubicin plus cyclophosphamide, which was followed by paclitaxel alone (arm A), paclitaxel with sequential trastuzumab (arm B), or paclitaxel with concurrent trastuzumab (arm C). A total of 1,282 formalin-fixed, paraffin-embedded tumor tissues from 2,840 eligible patients then underwent whole-transcriptome analysis with DASL (cDNAmediated annealing, selection, extension, and ligation) technology. A system biology approach showed that certain biologic processes linked to immune functions, such as Tand B-cell responses, chemokine signaling, and inflammation, were predictive for relapse-free survival (RFS) in the composite group of trastuzumab-treated patients. The authors subsequently built a predictive signature consisting of 14 genes related to immune function and herewith grouped the tumors in arm A and arms B and C into immune response–enriched (IRE) and nonimmune response–enriched (NIRE) tumors. Immune gene enrichment status was not significantly associated with RFS in patients who received chemotherapy alone. However, in contrast, patients with IRE tumors treated with concurrent or sequential adjuvant trastuzumab had an increased RFS compared with patients with IRE tumors treated with chemotherapy alone (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.35; P .001), whereas in patients with NIRE tumors, RFS was not different between patients treated with trastuzumab versus those who received chemotherapy alone (HR, 0.89; 95% CI, 0.62 to 1.28; P .53). Although we do not yet know what this immune signature exactly represents, or whether the 14 immune function genes are exclusively expressed in intratumoral lymphocytes, stromal lymphocytes, or tumor cells or present in various compartments, 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. Trastuzumab is a humanized antibody that consists of human immunoglobulin G with a conserved Fc portion and two antigen-specific sites that bind to the extracellular domain of HER2 to prevent activation of its intracellular tyrosine kinase function. When bound to HER2 on tumor cells, trastuzumab can potentially recruit tumor infiltrating lymphocytes (TILs) that express the Fc receptor, thereby manipulating the innate host immune response to the breast tumor through antibody-dependent cellular cytotoxicity (ADCC). Indeed, an increase in Fc receptor–expressing natural killer cells has been observed in HER2-positive tumors after preoperative trastuzumab therapy. This ADCC at the tumor site induced by activation of innate immunity and T cells subsequently triggers a CD8-dependent adaptive antitumor immunity, which seems to be necessary for effective tumor clearance. Thus, it is plausible to assume that in tumors with a large number of tumor-associated immune cells already present, trastuzumab will be able to rapidly recruit these cells to induce ADCC. With respect to an association between outcome with chemotherapy and the immune system, the situation is less clear. Using JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 7 MARCH 1 2015