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Investigating the positive relationship between tumor-infiltrating lymphocytes and trastuzumab therapy “
...there is rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and how it may influence the efficacy of trastuzumab, as well as chemotherapy.
”
Keywords: adjuvant • anti-PD-1 • breast cancer • HER2 • trastuzumab • tumor-infiltrating lymphocytes
In the burgeoning field of cancer immunotherapy, breast cancer provides a unique perspective. In contrast to other tumor types, there is mounting evidence for the influence of the immune microenvironment on response to existing, standard-of-care therapies. Tumor-infiltrating lymphocytes (TILs) have emerged as a simple and robust biomarker of this relationship in triple-negative and HER2-positive breast cancer subtypes. This sets the scene for improving outcomes by modulating the immune response in combination with existing effective anti-HER2 therapies such as trastuzumab. TILs have been noted in breast cancer for many years. Their significance has only become apparent recently in line with advances in tumor immunology and the availability of cancer immunotherapies. In untreated tumors, infiltrating lymphocytes are mainly composed of activated T cells, representing the adaptive arm of the antitumor immune response [1] . A number of studies have found that infiltration by T-cell subsets correlates with prognosis on non randomized retrospective cohorts [2,3] . The most instructive data on TILs, however, comes from analyses performed on large cohorts that were involved in prospective randomized controlled trials. Several studies to date involving thousands of patients have shown that the presence of a lymphocytic infiltrate at baseline, assessed semi-quantitatively by light microscopy on hematoxylin and eosin slides, is predictive of prognosis and benefit from chemotherapy in the neoadjuvant and adjuvant
10.2217/IMT.14.60 © 2014 Future Medicine Ltd
setting [4,5] . Trastuzumab was not available when the original studies that furnished these cohorts were performed. Denkert et al. reported that increasing intratumor lymphocyte infiltration was associated with higher rates of response to neoadjuvant chemotherapy in two separate neoadjuvant studies, GeparDuo and GeparTrio [5] . Loi et al. used tumor samples from the BIG 02-98 cohort, a Phase III study of adjuvant chemotherapy in node-positive breast cancers of all subtypes, to assess the impact of TILs on disease-free and overall survival, and the interaction with chemotherapy [4] . Increasing levels of TILs predicted both diseasefree and overall survival in triple-negative breast cancer, but interestingly not in other subtypes including HER2 disease. In HER2 disease, however, TILs were associated with benefit from anthracycline chemo t herapy. This is consistent with animal studies showing that the therapeutic effect of anthracyclines is dependent on functional innate and adaptive immunity [6] . The humanized monoclonal antibody trastuzumab is standard of care as treatment for HER2-amplified breast cancer in both early and advanced stage disease. In combination with cytotoxic chemotherapy, it has been shown to improve overall survival and response rates compared with chemotherapy alone [7,8] . Although trastuzumab has a direct cytotoxic effect on HER2-amplified breast cancer cell lines in culture, animal models have suggested that functional adaptive and innate immunity is necessary for trastuzumab’s complete therapeutic effect [9,10] .
Immunotherapy (2014) 6(7), 803–805
Peter Savas Translational Breast Cancer Genomics Laboratory, Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
Sherene Loi Author for correspondence: Translational Breast Cancer Genomics Laboratory, Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Tel.: +61 3 9656 1111 Fax: +61 3 9656 1411 sherene.loi@ petermac.org
part of
ISSN 1750-743X
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Editorial Savas & Loi At present, there has been only one published investigation of the interaction between TILs and trastuzumab in the adjuvant setting utilizing patient samples from a randomized cohort; in this case, the pivotal FinHERtrial. The FinHER trial was a randomized study in 1010 patients with early breast cancer who had undergone surgery [11] . After surgery, patients received the cytotoxic chemotherapy regimens of docetaxel followed by FEC (5-fluorouracil, epirubicin and cyclophosphamide) or vinorelbine followed by FEC. In total, 232 patients with HER2-amplified tumors were then randomized to trastuzumab or no further treatment. Trastuzumab improved distant disease-free survival. TILs were subsequently determined in tumor blocks from patients participating in FinHER [12] . This analysis revealed that for each 10% increase in infiltrating lymphocytes in the peritumoral stroma, there was an 18% improvement in distant disease-free survival after treatment with trastuzumab (p = 0.025 for interaction).
“Several key questions remain regarding
the immunobiology of HER2-positive breast cancer as it relates to tumorinfiltrating lymphocytes, and the immune microenvironment more broadly.
”
Pathological complete response following neoadjuvant chemotherapy is strongly associated with disease-free survival. Studies are ongoing on the predictive effects of lymphocyte infiltration on pathological complete response in HER2-positive tumors. TILs were associated with a higher rate of complete pathological response in the GeparQuattro study, which compared response rates with trastuzumab and nontrastuzumab chemotherapy regimens. The pathological complete response rate in 156 patients with greater than 50% stromal TILs was significantly higher than in the whole HER2-positive cohort (47.4 vs 31.7%) [12] . Stromal TILs were also evaluated in the more recent GeparSixto trial, which compared paclitaxel and pegylated doxorubicin with or without carboplatin in the neoadjuvant setting for triple-negative and HER2-positive breast cancers. Trastuzumab and the oral HER2/EGFR tyrosine kinase inhibitor lapatinib were administered to all HER2-positive patients. Socalled lymphocyte-predominant breast cancers, where greater than 60% of the cells in a histological section were lymphocytes, showed higher complete pathological response rates with chemotherapy. Response rates were particularly high with the addition of carboplatin, reaching 77.8%, compared with 20–30% in nonlymphocytepredominant breast cancers [13] . A natural corollary of the association between TILs and trastuzumab benefit is that promoting the antitumor immune response will enhance trastuzumab’s effect.
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This may further improve clinical outcomes for patients with existing high level TILs, and may also extend these benefits to patients that lack TILs. The use of immune checkpoint regulators is one possible avenue for combining immunotherapeutics with trastuzumab. Monoclonal antibodies targeting, CTLA4, PD-1 and PD-L1 have generated promising results in melanoma, lung and renal cell carcinoma [14–16] . Their putative mechanism of action is to relieve tumor-mediated immune suppression affecting T cells in the tumor microenvironment. These compounds have not demonstrated efficacy as monotherapy in small numbers of breast cancer patients, but preclinical data suggest they may have a role in combination with chemotherapy or targeted therapies such as trastuzumab. In a mouse model of HER2-amplified breast cancer, treatment with anti-HER2 monoclonal antibody was synergistic with administration of antiPD-1 antibody [10] . This study also showed synergy between trastuzumab and anti-CD137 antibodies. In another study, anti-HER2 therapy was synergistic with anti-CTLA4 antibodies [17] . On this basis, a clinical trial of combined therapy with trastuzumab and anti-PD-1 antibody in HER2-positive metastatic breast cancer has been initiated. Several key questions remain regarding the immunobiology of HER2-positive breast cancer as it relates to TILs, and the immune microenvironment more broadly. The reason for differing levels of TILs in HER2-positive tumors is currently obscure. It is possible that the presence of TILs in viable tumor indicates an exhausted immune response and intratumoral immunosuppression that may be relieved by trastuzumab. The presence of TILs may also define an immuno-edited breast cancer phenotype, where immunogenic subclones have been eliminated, and the remaining tumor is relatively less immunogenic. Furthermore, the relationship between known genomic alterations in breast cancer, host immune factors and TILs is still to be explored, as is the significance of these relationships in metastatic disease. In summary, there is rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and how it may influence the efficacy of trastuzumab, as well as chemotherapy. TILs are emerging as a robust and reproducible predictive biomarker of trastuzumab benefit in both the adjuvant and neoadjuvant settings for HER2-positive breast cancer. To our knowledge, TILs represent the only predictive biomarker of trastuzumab benefit aside from HER2 amplification itself, and provide an opportunity for defining subgroups in need of more effective treatments in early breast cancer. In advanced disease, trastuzumab and related therapeutics, pertuzumab and TDM-1 have proven successful, but concerns about the inevitable development of resistance to these
future science group
Investigating the positive relationship between tumor-infiltrating lymphocytes & trastuzumab therapy
therapies may be overcome by rational combination with immunotherapies. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial inter-
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est in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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