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Published in: Current Breast Cancer Reports 4/2019

01-12-2019 | Breast Cancer | Immuno-oncology (S Tolaney, Section Editor)

Combining Radiation Therapy with Immune Checkpoint Blockadein Breast Cancer

Authors: Shervin Tabrizi, Susan McDuff, Alice Y. Ho

Published in: Current Breast Cancer Reports | Issue 4/2019

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Abstract

Purpose of Review

Immune checkpoint blockade (ICB) is an emerging therapy in breast cancer. Its optimal integration with radiation therapy (RT) for breast cancer remains to be established. Herein, we review the current evidence on combining ICB and RT in breast cancer and discuss the challenges, open questions, ongoing trials, and future directions for use of this treatment combination.

Recent Findings

Early trials of ICB in breast cancer show evidence of a modest response, limited due to the low baseline immunogenicity of most breast cancers. RT, as a potent stimulator of the immune system, has been used in combination with ICB with encouraging results. The optimal dose, fractionation, and timing of RT combined with ICB are active areas of investigation. Preclinical evidence suggests that moderate-dose, hypofractionated courses may be more effective at stimulating an immune response than high-dose, single-fraction courses.

Summary

Recent studies suggest that ICB can be active in breast cancer, but optimizing the response rate remains a challenge. The immunostimulatory effects of RT have the potential to overcome this obstacle, with promising data from preclinical and early clinical trials. Future investigation on the optimal dosing and fractionation of RT in combination with ICB will be critical.
Literature
2.
go back to reference •• 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. https://doi.org/10.1056/nejmoa1809615. This study was a phase III, randomized trial of nab-paclitaxel with or without atezolizumab. Progression free survival benefit was observed in the PDL1-subset of nab-paclitaxel with atezolizumab. This led to the first FDA approval for ICB in metastatic triple negative breast cancer. CrossRefPubMed •• 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. https://​doi.​org/​10.​1056/​nejmoa1809615. This study was a phase III, randomized trial of nab-paclitaxel with or without atezolizumab. Progression free survival benefit was observed in the PDL1-subset of nab-paclitaxel with atezolizumab. This led to the first FDA approval for ICB in metastatic triple negative breast cancer. CrossRefPubMed
11.
go back to reference Loi S, Sirtaine N, Piette F, Salgado R, Viale G, van Eenoo 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. https://doi.org/10.1200/jco.2011.41.0902.CrossRefPubMed Loi S, Sirtaine N, Piette F, Salgado R, Viale G, van Eenoo 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. https://​doi.​org/​10.​1200/​jco.​2011.​41.​0902.CrossRefPubMed
20.
go back to reference • Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol. 2019;20:371–82. https://doi.org/10.1016/s1470-2045(18)30812-x. This trial of trastuzumab and pembrolizumab in metastatic HER2+ breast cancer demonstrated that TIL levels greater than 5% was associated with a doubling of the response rate. CrossRefPubMed • Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol. 2019;20:371–82. https://​doi.​org/​10.​1016/​s1470-2045(18)30812-x. This trial of trastuzumab and pembrolizumab in metastatic HER2+ breast cancer demonstrated that TIL levels greater than 5% was associated with a doubling of the response rate. CrossRefPubMed
21.
go back to reference Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst. 1979;63:1229–35.PubMed Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst. 1979;63:1229–35.PubMed
32.
go back to reference •• Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. https://doi.org/10.1038/ncomms15618. This preclinical study demonstrated that release of cytosolic DNA following RT promotes an immune response. It also showed that relative to hypofractionated doses of RT, large, single fraction doses are associated with increased expression of the Trex1 endonuclease, which is associated with decreased cytosolic DNA and diminished immune response. This study established important preclinical rationale for RT fraction size and dose regimen when administered with ICB. CrossRefPubMedPubMedCentral •• Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017;8:15618. https://​doi.​org/​10.​1038/​ncomms15618. This preclinical study demonstrated that release of cytosolic DNA following RT promotes an immune response. It also showed that relative to hypofractionated doses of RT, large, single fraction doses are associated with increased expression of the Trex1 endonuclease, which is associated with decreased cytosolic DNA and diminished immune response. This study established important preclinical rationale for RT fraction size and dose regimen when administered with ICB. CrossRefPubMedPubMedCentral
33.
go back to reference Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 2002;62:1462–70.PubMed Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 2002;62:1462–70.PubMed
59.
go back to reference Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–34.PubMed Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–34.PubMed
64.
go back to reference Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Investig. 2013;31:140–4. https://doi.org/10.3109/07357907.2012.762780.CrossRef Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Investig. 2013;31:140–4. https://​doi.​org/​10.​3109/​07357907.​2012.​762780.CrossRef
74.
go back to reference • Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–8. https://doi.org/10.1200/jco.2017.76.2229. This phase II trial included multiple tumor types treated with SBRT in combination with pembrolizumab for solid tumors. Only 8% of patients in this trial had breast cancer. CrossRefPubMedPubMedCentral • Luke JJ, Lemons JM, Karrison TG, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–8. https://​doi.​org/​10.​1200/​jco.​2017.​76.​2229. This phase II trial included multiple tumor types treated with SBRT in combination with pembrolizumab for solid tumors. Only 8% of patients in this trial had breast cancer. CrossRefPubMedPubMedCentral
80.
go back to reference McArthur H, Beal K, Halpenny D, et al. Abstract 4705: CTLA4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases (BCBM). In: Immunology. Philadelphia: American Association for Cancer Research; 2017. p. 4705.CrossRef McArthur H, Beal K, Halpenny D, et al. Abstract 4705: CTLA4 blockade with HER2-directed therapy (H) yields clinical benefit in women undergoing radiation therapy (RT) for HER2-positive (HER2+) breast cancer brain metastases (BCBM). In: Immunology. Philadelphia: American Association for Cancer Research; 2017. p. 4705.CrossRef
93.
go back to reference Cardoso F, Bardia A, Andre F, et al. Abstract OT3-04-03: KEYNOTE-756: a randomized, double-blind, phase III study of pembrolizumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk early-stage ER + /HER2 − breast cancer. In: Ongoing Clin. Trials. Philadelphia: American Association for Cancer Research; 2019. p. OT3-04-03-OT3-04–03. Cardoso F, Bardia A, Andre F, et al. Abstract OT3-04-03: KEYNOTE-756: a randomized, double-blind, phase III study of pembrolizumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk early-stage ER + /HER2 breast cancer. In: Ongoing Clin. Trials. Philadelphia: American Association for Cancer Research; 2019. p. OT3-04-03-OT3-04–03.
94.
go back to reference Pusztai L, Barlow W, Ganz P, et al. Abstract OT1-02-04: SWOG S1418/NRG -BR006: a randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with > 1 cm residual invasive cancer or positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy. In: Ongoing Clin. Trials. Philadelphia: American Association for Cancer Research; 2018. p. OT1–02-04-OT1–02–04. Pusztai L, Barlow W, Ganz P, et al. Abstract OT1-02-04: SWOG S1418/NRG -BR006: a randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with > 1 cm residual invasive cancer or positive lymph nodes (>pN1mic) after neoadjuvant chemotherapy. In: Ongoing Clin. Trials. Philadelphia: American Association for Cancer Research; 2018. p. OT1–02-04-OT1–02–04.
Metadata
Title
Combining Radiation Therapy with Immune Checkpoint Blockadein Breast Cancer
Authors
Shervin Tabrizi
Susan McDuff
Alice Y. Ho
Publication date
01-12-2019
Publisher
Springer US
Published in
Current Breast Cancer Reports / Issue 4/2019
Print ISSN: 1943-4588
Electronic ISSN: 1943-4596
DOI
https://doi.org/10.1007/s12609-019-00327-1

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