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BMC Medicine
Published in: BMC Medicine 1/2019

Open Access 01-12-2019 | Breast Cancer | Minireview

Recent advances in triple negative breast cancer: the immunotherapy era

Published in: BMC Medicine | Issue 1/2019

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Abstract

Background

Several accomplishments have been achieved in triple-negative breast cancer (TNBC) research over the last year. The phase III IMpassion130 trial comparing chemotherapy plus atezolizumab versus chemotherapy plus placebo brought breast cancer into the immunotherapy era. Nevertheless, despite encouraging results being obtained in this trial, many open questions remain.

Main body

A positive overall survival outcome was achieved only in PD-L1+ TNBC patients, suggesting a need to enrich the patient population more likely to benefit from an immunotherapeutic approach. Moreover, it remains unknown whether single-agent immunotherapy might be a good option for some patients. In this context, the discovery and implementation of novel and appropriate biomarkers are required. Focusing on the early onset of TNBC, neoadjuvant trials could represent excellent in vivo platforms to test immunotherapy agents and their potential combinations, allowing the performance of translational studies for biomarker implementation and improved patient selection.

Conclusion

The aim of our review is to present recent advances in TNBC treatment and to discuss open issues in order to better define potential future directions for immunotherapy in TNBC.
Literature
1.
Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov. 2019;9(2):176–98.CrossRef
2.
Criscitiello C, Esposito A, Trapani D, Curigliano G. Prognostic and predictive value of tumor infiltrating lymphocytes in early breast cancer. Cancer Treat Rev. 2016;50:205–7.CrossRef
3.
Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–7.CrossRef
4.
Dieci MV, Mathieu MC, Guarneri V, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015;26:1698–704.CrossRef
5.
Loi S, Drubay D, Adams S, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol. 2019;37(7):559–69.CrossRef
6.
Miyashita M, Sasano H, Tamaki K, et al. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res. 2015;17:124.CrossRef
7.
Beckers RK, Selinger CI, Vilain R, et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 2016;69:25–34.CrossRef
8.
Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2:361–70.CrossRef
9.
Cimino-Mathews A, Thompson E, Taube JM, et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol. 2016;47:52–63.CrossRef
10.
Li X, Li M, Lian Z, et al. Prognostic role of programmed death ligand-1 expression in breast cancer: a systematic review and meta-analysis. Target Oncol. 2016;11:753–61.CrossRef
11.
Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.CrossRef
12.
Blank CU, Haanen JB, Ribas A, Schumacher TN. Cancer immunology. The 'cancer immunogram. Science. 2016;352:658–60.CrossRef
13.
Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56.CrossRef
14.
Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17:e542–51.CrossRef
15.
Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–3.
16.
Buttner R, Gosney JR, Skov BG, et al. Programmed death-ligand 1 immunohistochemistry testing: a review of analytical assays and clinical implementation in non-small-cell lung cancer. J Clin Oncol. 2017;35:3867–76.CrossRef
17.
Kwa MJ, Adams S. Checkpoint inhibitors in triple-negative breast cancer (TNBC): where to go from here. Cancer. 2018;124:2086–103.CrossRef
18.
Emens LA, Loi S, Rugo HS, et al. Abstract GS1-04: IMpassion130: efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab + nab-paclitaxel in patients with treatment-naïve, locally advanced or metastatic triple-negative breast cancer. Cancer Res. 2019;79:GS1–04.
19.
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213:2835–40.CrossRef
20.
Loi S, Adams S, Schmid P, et al. LBA13 relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): results from KEYNOTE-086. Ann Oncol. 2017;28(Suppl 5):mdx440.005.
21.
Loi S, Schmid P, Cortés J, et al. Relationship between tumor infiltrating lymphocytes (TILs) and response to pembrolizumab (Pembro)+chemotherapy (Chemo) as neoadjuvant treatment (NAT) for triple-negative breast cancer (TNBC): phase Ib KEYNOTE-173 trial. Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-09.
22.
Savas P, Virassamy B, Ye C, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. 2018;24:986–93.CrossRef
23.
Hendrickx W, Simeone I, Anjum S, et al. Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology. 2017;6:e1253654.CrossRef
24.
Loi S, Dushyanthen S, Beavis PA, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res. 2016;22:1499–509.CrossRef
25.
Criscitiello C, Bayar MA, Curigliano G, et al. A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer. Ann Oncol. 2018;29:162–9.CrossRef
26.
Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.CrossRef
27.
Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16:2598–608.CrossRef
28.
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunologyMutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.CrossRef
29.
Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093–104.CrossRef
30.
Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.CrossRef
31.
Thomas A, Routh ED, Pullikuth A, et al. Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. Oncoimmunology. 2018;7:e1490854.CrossRef
32.
Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180.CrossRef
33.
34.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.CrossRef
35.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.CrossRef
36.
Obeid E, Ellerbrock A, Handorf E et al. Distribution of microsatellite instability, tumor mutational load, and PD-L1 status in molecularly profiled invasive breast cancer. Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-03.
37.
Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.CrossRef
38.
Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33.CrossRef
39.
40.
Nolan E, Savas P, Policheni AN, et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med. 2017;9(393).
41.
Mouw KW, Goldberg MS, Konstantinopoulos PA, D'Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017;7:675–93.CrossRef
42.
Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/Keynote-162: niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. J Clin Oncol. 2018;36:1011.CrossRef
43.
Aigner J, Marmé F, Smetanay K, et al. Nab-paclitaxel monotherapy as a treatment of patients with metastatic breast cancer in routine clinical practice. Anticancer Res. 2013;33:3407–13.PubMed
44.
Kroemer G, Senovilla L, Galluzzi L, et al. Natural and therapy-induced immunosurveillance in breast cancer. Nat Med. 2015;21:1128–38.CrossRef
45.
Pol J, Vacchelli E, Aranda F, et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology. 2015;4:e1008866.CrossRef
46.
Heinhuis KM, Ros W, Kok M, et al. Enhancing anti-tumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol. 2019;30(2):219–35.CrossRef
47.
Galluzzi L, Buque A, Kepp O, et al. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111.CrossRef
48.
Demaria S, Volm MD, Shapiro RL, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7:3025–30.PubMed
49.
Kodumudi KN, Woan K, Gilvary DL, et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010;16:4583–94.CrossRef
50.
Roselli M, Cereda V, di Bari MG, et al. Effects of conventional therapeutic interventions on the number and function of regulatory T cells. Oncoimmunology. 2013;2:e27025.CrossRef
51.
Li JY, Duan XF, Wang LP, et al. Selective depletion of regulatory T cell subsets by docetaxel treatment in patients with nonsmall cell lung cancer. J Immunol Res. 2014;2014:286170.PubMedPubMedCentral
52.
Ghiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641–8.CrossRef
53.
Kwa M, Li X, Novik Y, et al. Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer. Breast Cancer Res Treat. 2018;168:57–67.CrossRef
54.
Homma Y, Taniguchi K, Nakazawa M, et al. Changes in the immune cell population and cell proliferation in peripheral blood after gemcitabine-based chemotherapy for pancreatic cancer. Clin Transl Oncol. 2014;16:330–5.CrossRef
55.
Vincent J, Mignot G, Chalmin F, et al. 5-fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 2010;70:3052–61.CrossRef
56.
Jackaman C, Majewski D, Fox SA, et al. Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo. Cancer Immunol Immunother. 2012;61:2343–56.CrossRef
57.
Nio Y, Hirahara N, Minari Y, et al. Induction of tumor-specific antitumor immunity after chemotherapy with cisplatin in mice bearing MOPC-104E plasmacytoma by modulation of MHC expression on tumor surface. Anticancer Res. 2000;20:3293–9.PubMed
58.
Huang X, Cui S, Shu Y. Cisplatin selectively downregulated the frequency and immunoinhibitory function of myeloid-derived suppressor cells in a murine B16 melanoma model. Immunol Res. 2016;64:160–70.CrossRef
59.
Tolaney S, Kalinsky K, Kaklamani V, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Cancer Res. 2018;78(abstr):PD6–PD13.
60.
Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol. 2016;34:2460–7.CrossRef
61.
Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort a of the phase 2 KEYNOTE-086 study. Ann Oncol. 2019;30(3):397–404.CrossRef
62.
Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat. 2018;167:671–86.CrossRef
63.
Emens LA, Cruz C, Eder JP, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 2019;5(1):74–82.CrossRef
64.
Emens LA, Loi S, Rugo HS, et al. Abstract GS1-04: IMpassion130: efficacy in immune biomarker subgroups from phase III study of atezolizumab + nab-paclitaxel in patients with treatment-naïve, locally advanced or metastatic TNBC. Cancer Res 2019;79(4 Suppl):Abstract nr GS1–04.
65.
Gil Del Alcazar CR, Huh SJ, Ekram MB, et al. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discov. 2017;7:1098–115.CrossRef
66.
Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.CrossRef
67.
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35.CrossRef
68.
Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–50.CrossRef
69.
Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–59.
Metadata
Title
Recent advances in triple negative breast cancer: the immunotherapy era
Publication date
01-12-2019
Published in
BMC Medicine / Issue 1/2019
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1326-5

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