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Breast cancer Bohuslav Melichar Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic Malignant tumor Tumor cell proliferation Host response Hanahan D, Weinberg RA. Cell 2011, 144, 646 Objective response in early studies with interleukin-2based therapy of National Biotherapy Study Group primary number of patients number of patients with objective response % objective response melanoma 188 33 18 lung 51 8 16 breast 34 5 15 renal 167 13 8 colon 1 76 1 other 122 12 10 Dillman et al. Cancer 1993, 71, 2358 - 2370 Frequency of somatic mutations in different tumors Lawrence MS et al. Nature 2013, 499, 214 Tumor biomarkers Hayes DF et al. J Natl Cancer Inst 1996, 88, 1456-1466. Prognostic significance of TIL in ovarian cancer Tomsova, Melichar et al. Gyn Oncol 2008, 108, 415 – 420. Prognostic significance of TIL in endometrial cancer Čermáková P, Melichar B, Tomšová M et al. Anticancer Res 2014, 34, 5555-62. Functional activity of TIL Baxevanis CN et al. Cancer 1994, 74, 1275-1282. Lymphocytic infiltration as prognostic parameter in breast cancer Aaltomaa S et al. Eur J Cancer 1992, 28A, 859-864. Pathologic complete response as a model to study the efficacy of systemic treatment in breast cancer Melichar B et al. Med Oncol 2012, 29, 2577 Liedtke C. et al. J Clin Oncol, 26, 2008, 1275 Prowell & Pazdur NEJM 2012, 366:2438-2441. Intraepithelial and stromal TIL in breast cancer Hornychová, Melichar, Ryška et al. Cancer Invest 2008, 26, 1024 - 1031 TIL as predictive biomarker of pathological complete response in breast cancer Hornychová, Melichar, Ryška et al. Cancer Invest 2008, 26, 1024 - 1031 Immunogenic cell death Kepp O et al. Cancer Metastasis Rev 2011, 30, 61-69 TIL as predictor of pCR Denkert C et al. J Clin Oncol 2010, 28, 105-113. Association of TIL populations with pCR Oda N et al. Breast Cancer Res Treat 2012 Predictive role of CD8+ TIL in patients treated with neodjuvant chemotherapy Seo AN et al. Br J Cancer 2013, 109, 2705-13. Association between TIL, regimen and pCR Denkert C et al. J Clin Oncol 2015, 33, 983-991. Meta-analysis of predictive significance of TIL Mao Y et al. Plos One 2014 Meta-analysis of predictive significance of TIL Mao Y et al. Plos One 2014 Retrospective analysis of prognostic significance of TIL in triple negative breast cancer patients treated with adjuvant chemotherapy Adams S et al. J Clin Oncol 2014, 32, 2959-66. Prognostic significance of TIL in triple negative breast cancer - DFS Adams S et al. J Clin Oncol 2014, 32, 2959-66. Prognostic significance of TIL in triple negative breast cancer – DRFI and OS Adams S et al. J Clin Oncol 2014, 32, 2959-66. Prognostic significance of TIL in triple negative breast cancer – multivariate analysis Adams S et al. J Clin Oncol 2014, 32, 2959-66. Interaction between CD3 TIL and effect of anthracycline-based chemotherapy West NR et al. Breast Cancer Res 2011, 13, R126 Association of outcome of trastuzumab therapy and TIL in FinHER Loi S et al. Ann Oncol 2014, 25, 1544-1550. PD-1 positive TIL and breast cancer prognosis Muenst S et al. Breast Cancer Res Treat 2013, 139, 667-676 Advantages of TILs as biomarkers in breast cancer • A powerful predictive and prognostic biomarker in adjuvant and neoadjuvant settings • No sophisticated technology required • Low cost • Potential use in the era of resurge of interest in immunotherapy Limitations of TILs as biomarkers in breast cancer • Across studies, different TIL populations, different methods and different antibodies have been used • No standardization • Need for the expertise and time-consuming • Research use only Standardization of TIL determination • • • • • • • H&E or IHC? Which surface biomarker -CD3?CD4?CD8?FOXP3? Which antibody? Method of tissue processing? Method of counting? Stromal vs. intraepithelial lymphocytes Which type of sample (core cut biopsy? resection specimen?) • Which cutoff? Recommendations Salgado R et al. Ann Oncol 2015, 26, 259-271 Salgado R et al. Ann Oncol 2015, 26, 259-271 Neopterin (2-amino-4-oxo-6-(D-erythro-1, 2, 3 – trihydroxypropyl) – pteridine) • • 1967 Sakurai and Goto isolation from human urine 1979 Wachter and collaborators observed increased neopterin concentrations in patients with malignant tumors and viral infections • 1984 release of neopterin regulated by interferon-γ • 1993 antioxidant activity of reduced neopterin described Prognostic significance of increased urinary neopterin concentrations Kalábová H et al. Eur J Gynaecol Oncol 2011, 32, 525-528. Immunotherapy Clinical trials with monoclonal antibody targeting immune check point inhibitors Cimino-Mathews A et al. Oncology (Williston Park) 2015, 29, 375-385 Clinical trials with vaccines Cimino-Mathews A et al. Oncology (Williston Park) 2015, 29, 375-385 Mechanism of action of trastuzumab Hudis CA N Engl J Med 2007, 357, 39-51 Activity of trastuzumab and immunoglobulin receptor polymorphism Musolino A et al. J Clin Oncol 26, 2008, 1789 – 1796. Conclusions • With the notable exception of anti-HER-2 antibodies, immunotherapy currently plays limited role in breast cancer • TIL counts represent a powerful prognostic and predictive biomarker in patients with breast cancer • More research should be devoted to the immune mechanisms and potential of immunotherapy for this most common malignancy in women Thank you for your attention Olomouc, Czech Republic
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