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Integrating radiation therapy with targeted treatments for breast cancer: From bench to bedside

  • Icro Meattini
    Correspondence
    Corresponding author at: Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Viale Morgagni, 50 - 50134 Florence, Italy.
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy

    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Lorenzo Livi
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy

    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Nicla Lorito
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy
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  • Carlotta Becherini
    Affiliations
    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Marina Bacci
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy
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  • Luca Visani
    Affiliations
    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Alessandra Fozza
    Affiliations
    Department of Radiation Oncology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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  • Liliana Belgioia
    Affiliations
    Department of Radiation Oncology, IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Department of Health Science (DISSAL), University of Genoa, Genova, Italy
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  • Mauro Loi
    Affiliations
    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Monica Mangoni
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy

    Radiation Oncology Unit – Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
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  • Matteo Lambertini
    Affiliations
    Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

    Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy
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  • Andrea Morandi
    Affiliations
    Department of Experimental and Clinical Biomedical Sciences “M. Serio”, University of Florence, Florence, Italy
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      Highlights

      • Breast cancer therapeutic landscape has significantly evolved with an array of targeted therapies.
      • Pivotal trials of new drugs did not include quality assurance in radiation therapy.
      • Preclinical models are frequently not confirmed by clinical data.
      • An overall low level of evidence on the safety data reported for populations treated with systemic therapy and concomitant radiation therapy exists.
      • There is a lack of international consensus guidelines on how to integrate targeted agents with local treatments in both the curative and advanced settings.

      Abstract

      Major advances have been made in precision medicine of breast cancer patients with a series of molecular targeted therapies now in clinical use or in late clinical development. These new therapeutic measures need to be integrated with local treatments, particularly with radiation therapy in both curative and advanced settings. Although a synergistic effect could be obtained between targeted therapies and irradiation, potential safety concerns should be carefully considered. At present, scarce evidence exists due to a lack of quality assurance on radiation therapy in pivotal trials of new drugs and missing reports on safety in case of concurrent radiation therapy, commonly administered with heterogenous doses and fractionations, especially in advanced disease. A major contribution for effectively combining radiation and targeted therapies in breast cancer could derive from clinically relevant preclinical studies.
      This review integrates preclinical and clinical evidence on how targeted agents and radiation therapy could be combined to help physicians in their daily clinical practice and to improve the clinical management of patients.

      Keywords

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      References

        • Longo D.L.
        • Burstein H.J.
        Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer.
        N Engl J Med. 2020; 383: 2557-2570
        • Swain S.M.
        • Baselga J.
        • Kim S.-B.
        • Ro J.
        • Semiglazov V.
        • Campone M.
        • et al.
        Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer.
        N Engl J Med. 2015; 372: 724-734
        • Modi S.
        • Saura C.
        • Yamashita T.
        • Park Y.H.
        • Kim S.-B.
        • Tamura K.
        • et al.
        Trastuzumab deruxtecan in previously treated HER2-positive breast cancer.
        N Engl J Med. 2020; 382: 610-621
        • Verma S.
        • Miles D.
        • Gianni L.
        • Krop I.E.
        • Welslau M.
        • Baselga J.
        • et al.
        Trastuzumab emtansine for HER2-positive advanced breast cancer.
        N Engl J Med. 2012; 367: 1783-1791
        • Foulkes W.D.
        • Smith I.E.
        • Reis-Filho J.S.
        Triple-negative breast cancer.
        N Engl J Med. 2010; 363: 1938-1948
        • Al-Shafa F.
        • Arifin A.J.
        • Rodrigues G.B.
        • Palma D.A.
        • Louie A.V.
        A review of ongoing trials of stereotactic ablative radiotherapy for oligometastatic cancers: where will the evidence lead?.
        Front Oncol. 2019; 9: 543
        • Sharma R.A.
        • Plummer R.
        • Stock J.K.
        • Greenhalgh T.A.
        • Ataman O.
        • Kelly S.
        • et al.
        Clinical development of new drug-radiotherapy combinations.
        Nat Rev Clin Oncol. 2016; 13: 627-642
        • Spring L.M.
        • Wander S.A.
        • Andre F.
        • Moy B.
        • Turner N.C.
        • Bardia A.
        Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.
        Lancet. 2020; 395: 817-827
        • Goel S.
        • DeCristo M.J.
        • McAllister S.S.
        • Zhao J.J.
        CDK4/6 inhibition in cancer: beyond cell cycle arrest.
        Trends Cell Biol. 2018; 28: 911-925
        • Pawlik T.M.
        • Keyomarsi K.
        Role of cell cycle in mediating sensitivity to radiotherapy.
        Int J Radiat Oncol Biol Phys. 2004; 59: 928-942
        • Hagen K.R.
        • Zeng X.
        • Lee M.-Y.
        • Tucker Kahn S.
        • Harrison Pitner M.K.
        • Zaky S.S.
        • et al.
        Silencing CDK4 radiosensitizes breast cancer cells by promoting apoptosis.
        Cell Div. 2013; 8https://doi.org/10.1186/1747-1028-8-10
        • Whiteway S.L.
        • Harris P.S.
        • Venkataraman S.
        • Alimova I.
        • Birks D.K.
        • Donson A.M.
        • et al.
        Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells.
        J Neurooncol. 2013; 111: 113-121
        • Johnson S.M.
        • Torrice C.D.
        • Bell J.F.
        • Monahan K.B.
        • Jiang Q.i.
        • Wang Y.
        • et al.
        Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition.
        J Clin Invest. 2010; 120: 2528-2536
        • Wei L.
        • Leibowitz B.J.
        • Wang X.
        • Epperly M.
        • Greenberger J.
        • Zhang L.
        • et al.
        Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.
        J Clin Invest. 2016; 126: 4076-4087
        • Pesch A.M.
        • Hirsh N.H.
        • Chandler B.C.
        • Michmerhuizen A.R.
        • Ritter C.L.
        • Androsiglio M.P.
        • et al.
        Short-term CDK4/6 inhibition radiosensitizes estrogen receptor-positive breast cancers.
        Clin Cancer Res. 2020; 26: 6568-6580
        • Pesch A.M.
        • Hirsh N.H.
        • Michmerhuizen A.R.
        • Jungles K.M.
        • Wilder-Romans K.
        • Chandler B.C.
        • et al.
        RB expression confers sensitivity to CDK4/6 inhibitor-mediated radiosensitization across breast cancer subtypes. JCI.
        Insight. 2022; 7https://doi.org/10.1172/jci.insight.15440210.1172/jci.insight.154402DS1
        • Petroni G.
        • Buqué A.
        • Yamazaki T.
        • Bloy N.
        • Liberto M.D.
        • Chen-Kiang S.
        • et al.
        Radiotherapy delivered before CDK4/6 inhibitors mediates superior therapeutic effects in ER(+) breast cancer.
        Clin Cancer Res. 2021; 27: 1855-1863
        • Naz S.
        • Sowers A.
        • Choudhuri R.
        • Wissler M.
        • Gamson J.
        • Mathias A.
        • et al.
        Abemaciclib, a selective CDK4/6 inhibitor, enhances the radiosensitivity of non-small cell lung cancer in vitro and in vivo.
        Clin Cancer Res. 2018; 24: 3994-4005
        • Nakamura Y.
        ATM: the p53 booster.
        Nat Med. 1998; 4: 1231-1232
        • Fernández-Aroca D.M.
        • Roche O.
        • Sabater S.
        • Pascual-Serra R.
        • Ortega-Muelas M.
        • Sánchez Pérez I.
        • et al.
        P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: Implication in cancer therapy.
        Cancer Lett. 2019; 451: 23-33
        • Huang C.-Y.
        • Hsieh F.-S.
        • Wang C.-Y.
        • Chen L.-J.
        • Chang S.-S.
        • Tsai M.-H.
        • et al.
        Palbociclib enhances radiosensitivity of hepatocellular carcinoma and cholangiocarcinoma via inhibiting ataxia telangiectasia-mutated kinase-mediated DNA damage response.
        Eur J Cancer. 2018; 102: 10-22
      1. Hashizume R, Zhang A, Mueller S, Prados MD, Lulla RR, Goldman S, et al. Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol. 2016;18:1519–28.

        • Tao Z.
        • Le Blanc J.M.
        • Wang C.
        • Zhan T.
        • Zhuang H.
        • Wang P.
        • et al.
        Coadministration of trametinib and palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo.
        Clin Cancer Res. 2016; 22: 122-133
        • Li F.
        • Xu Y.
        • Liu B.
        • Singh P.K.
        • Zhao W.
        • Jin J.
        • et al.
        YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer - rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer.
        Clin Cancer Res. 2019; 25: 2264-2277
        • Cardoso F.
        • Paluch-Shimon S.
        • Senkus E.
        • Curigliano G.
        • Aapro M.S.
        • Andre F.
        • et al.
        5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).
        Ann Oncol. 2020; 31: 1623-1649
        • Palma D.A.
        • Olson R.
        • Harrow S.
        • Gaede S.
        • Louie A.V.
        • Haasbeek C.
        • et al.
        Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial.
        J Clin Oncol. 2020; 38: 2830-2838
        • Finn R.S.
        • Martin M.
        • Rugo H.S.
        • Jones S.
        • Im S.-A.
        • Gelmon K.
        • et al.
        Palbociclib and letrozole in advanced breast cancer.
        N Engl J Med. 2016; 375: 1925-1936
        • Cristofanilli M.
        • Turner N.C.
        • Bondarenko I.
        • Ro J.
        • Im S.-A.
        • Masuda N.
        • et al.
        Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.
        Lancet Oncol. 2016; 17: 425-439
        • Hans S.
        • Cottu P.
        • Kirova Y.M.
        Preliminary results of the association of Palbociclib and radiotherapy in metastatic breast cancer patients.
        Radiother Oncol. 2018; 126: 181https://doi.org/10.1016/j.radonc.2017.09.010
        • Beddok A.
        • Xu H.P.
        • Henry A.A.
        • Porte B.
        • Fourquet A.
        • Cottu P.
        • et al.
        Concurrent use of palbociclib and radiation therapy: single-centre experience and review of the literature.
        Br J Cancer. 2020; 123: 905-908
        • Meattini I.
        • Desideri I.
        • Scotti V.
        • Simontacchi G.
        • Livi L.
        Ribociclib plus letrozole and concomitant palliative radiotherapy for metastatic breast cancer.
        Breast. 2018; 42: 1-2
        • Messer J.A.
        • Ekinci E.
        • Patel T.A.
        • Teh B.S.
        Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: a case report.
        Rep Pract Oncol Radiother. 2019; 24: 276-280
        • Kawamoto T.
        • Shikama N.
        • Sasai K.
        Severe acute radiation-induced enterocolitis after combined palbociclib and palliative radiotherapy treatment.
        Radiother Oncol. 2019; 131: 240-241
        • Figura N.B.
        • Potluri T.K.
        • Mohammadi H.
        • Oliver D.E.
        • Arrington J.A.
        • Robinson T.J.
        • et al.
        CDK 4/6 inhibitors and stereotactic radiation in the management of hormone receptor positive breast cancer brain metastases.
        J Neurooncol. 2019; 144: 583-589
        • Ippolito E.
        • Greco C.
        • Silipigni S.
        • Dell’Aquila E.
        • Petrianni G.M.
        • Tonini G.
        • et al.
        Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity.
        Breast. 2019; 46: 70-74
        • Chowdhary M.
        • Sen N.
        • Chowdhary A.
        • Usha L.
        • Cobleigh M.A.
        • Wang D.
        • et al.
        Safety and efficacy of palbociclib and radiation therapy in patients with metastatic breast cancer: initial results of a novel combination.
        Adv Radiat Oncol. 2019; 4: 453-457
        • Nasir U.M.
        • Mozeika A.M.
        • Sayan M.
        • Jan I.
        • Kowal N.
        • Haffty B.
        • et al.
        Severe gastrointestinal mucositis following concurrent palbociclib and palliative radiation therapy.
        Anticancer Res. 2020; 40: 5291-5294
        • Dasgupta A.
        • Sahgal A.
        • Warner E.
        • Czarnota G.J.
        Safety of palbociclib concurrent with palliative pelvic radiotherapy: discussion of a case of increased toxicity and brief review of literature.
        J Med Radiat Sci. 2021; 68: 96-102
        • Guerini A.E.
        • Pedretti S.
        • Salah E.
        • Simoncini E.L.
        • Maddalo M.
        • Pegurri L.
        • et al.
        A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients.
        Sci Rep. 2020; 10https://doi.org/10.1038/s41598-020-70430-2
        • Ratosa I.
        • Orazem M.
        • Scoccimarro E.
        • Steinacher M.
        • Dominici L.
        • Aquilano M.
        • et al.
        Cyclin-dependent kinase 4/6 inhibitors combined with radiotherapy for patients with metastatic breast cancer.
        Clin Breast Cancer. 2020; 20: 495-502
        • David S.
        • Ho G.
        • Day D.
        • Harris M.
        • Tan J.
        • Goel S.
        • et al.
        Enhanced toxicity with CDK 4/6 inhibitors and palliative radiotherapy: non-consecutive case series and review of the literature.
        Transl Oncol. 2021; 14: 100939https://doi.org/10.1016/j.tranon.2020.100939
        • Howlett S.
        • Harvey-Jones E.
        • Smith D.
        • Ahmad S.
        • Goldsmith C.
        • Sawyer E.
        • et al.
        Does concurrent use of CDK4/6 inhibitors during palliative radiotherapy increase toxicity in patients with metastatic breast cancer?.
        Clin Oncol (R Coll Radiol). 2021; 33: e99https://doi.org/10.1016/j.clon.2020.10.005
        • Neven P.
        • Rugo H.S.
        • Tolaney S.M.
        • Iwata H.
        • Toi M.
        • Goetz M.P.
        • et al.
        Abemaciclib plus fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in premenopausal women: subgroup analysis from the MONARCH 2 trial.
        Breast Cancer Res. 2021; 23https://doi.org/10.1186/s13058-021-01463-2
        • Johnston S.
        • Martin M.
        • Di Leo A.
        • Im S.-A.
        • Awada A.
        • Forrester T.
        • et al.
        MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
        npj Breast Cancer. 2019; 5https://doi.org/10.1038/s41523-018-0097-z
        • Hortobagyi G.N.
        • Stemmer S.M.
        • Burris H.A.
        • Yap Y.-S.
        • Sonke G.S.
        • Hart L.
        • et al.
        overall survival with ribociclib plus letrozole in advanced breast cancer.
        N Engl J Med. 2022; 386: 942-950
        • Burris H.A.
        • Chan A.
        • Bardia A.
        • Thaddeus Beck J.
        • Sohn J.
        • Neven P.
        • et al.
        Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.
        Br J Cancer. 2021; 125: 679-686
        • Nardone V.
        • Reginelli A.
        • Vitale C.
        • Calvanese M.G.
        • Correale P.
        • Grassi R.
        • et al.
        Feasibility of stereotactic ablative reirradiation in breast cancer patient undergoing palbociclib: a case report.
        Int J Radiation Res. 2021; 19: 479-482
        • Yuan T.L.
        • Cantley L.C.
        PI3K pathway alterations in cancer: variations on a theme.
        Oncogene. 2008; 27: 5497-5510
        • Manning B.D.
        • Cantley L.C.
        AKT/PKB signaling: navigating downstream.
        Cell. 2007; 129: 1261-1274
        • Yang J.
        • Nie J.
        • Ma X.
        • Wei Y.
        • Peng Y.
        • Wei X.
        Targeting PI3K in cancer: mechanisms and advances in clinical trials.
        Mol Cancer. 2019; 18: 26
        • Zhang M.
        • Jang H.
        • Nussinov R.
        PI3K inhibitors: review and new strategies.
        Chem Sci. 2020; 11: 5855-5865
        • Wanigasooriya K.
        • Tyler R.
        • Barros-Silva J.D.
        • Sinha Y.
        • Ismail T.
        • Beggs A.D.
        Radiosensitising cancer using phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT) or mammalian target of rapamycin (mTOR) inhibitors.
        Cancers (Basel). 2020; 12: 1278https://doi.org/10.3390/cancers12051278
        • Chuang F.-C.
        • Wang C.-C.
        • Chen J.-H.
        • Hwang T.-Z.
        • Yeh S.-A.
        • Su Y.-C.
        • et al.
        PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy.
        PLoS ONE. 2021; 16: e0245715https://doi.org/10.1371/journal.pone.0245715
        • Park J.H.
        • Jung K.H.
        • Kim S.J.
        • Fang Z.
        • Yan H.H.
        • Son M.K.
        • et al.
        Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer.
        Oncotarget. 2017; 8: 112893-112906
        • Chang L.
        • Graham P.H.
        • Hao J.
        • Ni J.
        • Bucci J.
        • Cozzi P.J.
        • et al.
        PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.
        Cell Death Dis. 2014; 5
        • Zhu W.
        • Fu W.
        • Hu L.
        NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, prominently enhances radiosensitivity of prostate cancer cell line PC-3.
        Cancer Biother Radiopharm. 2013; 28: 665-673
        • Prevo R.
        • Deutsch E.
        • Sampson O.
        • Diplexcito J.
        • Cengel K.
        • Harper J.
        • et al.
        Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity.
        Cancer Res. 2008; 68: 5915-5923
        • Chen Y.-H.
        • Wei M.-F.
        • Wang C.-W.
        • Lee H.-W.
        • Pan S.-L.
        • Gao M.
        • et al.
        Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer.
        Cancer Lett. 2015; 357: 582-590
        • Chang W.I.
        • Han M.G.
        • Kang M.H.
        • Park J.M.
        • Kim E.E.
        • Bae J.
        • et al.
        PI3Kalphadelta inhibitor combined with radiation enhances the antitumor immune effect of anti-PD1 in a syngeneic murine triple-negative breast cancer model.
        Int J Radiat Oncol Biol Phys. 2021; 110: 845-858
        • McGowan D.R.
        • Skwarski M.
        • Bradley K.M.
        • Campo L.
        • Fenwick J.D.
        • Gleeson F.V.
        • et al.
        Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: a phase I study in patients with advanced non-small cell lung carcinoma.
        Eur J Cancer. 2019; 113: 87-95
        • Lai Y.
        • Yu X.
        • Lin X.
        • He S.
        Inhibition of mTOR sensitizes breast cancer stem cells to radiation-induced repression of self-renewal through the regulation of MnSOD and Akt.
        Int J Mol Med. 2016; 37: 369-377
        • Mauceri H.J.
        • Sutton H.G.
        • Darga T.E.
        • Kocherginsky M.
        • Kochanski J.
        • Weichselbaum R.R.
        • et al.
        Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer.
        Oncol Rep. 2012; 27: 1625-1629
        • Chen Y.
        • Li W.-W.
        • Peng P.
        • Zhao W.-H.
        • Tian Y.-J.
        • Huang Y.u.
        • et al.
        mTORC1 inhibitor RAD001 (everolimus) enhances non-small cell lung cancer cell radiosensitivity in vitro via suppressing epithelial-mesenchymal transition.
        Acta Pharmacol Sin. 2019; 40: 1085-1094
        • Nam H.Y.
        • Han M.W.
        • Chang H.W.
        • Lee Y.S.
        • Lee M.
        • Lee H.J.
        • et al.
        Radioresistant cancer cells can be conditioned to enter senescence by mTOR inhibition.
        Cancer Res. 2013; 73: 4267-4277
        • Chang L.
        • Huang Z.
        • Li S.
        • Yao Z.
        • Bao H.
        • Wang Z.
        • et al.
        A low dose of AZD8055 enhances radiosensitivity of nasopharyngeal carcinoma cells by activating autophagy and apoptosis.
        Am J Cancer Res. 2019; 9: 1922-1937
        • Hayman T.J.
        • Kramp T.
        • Kahn J.
        • Jamal M.
        • Camphausen K.
        • Tofilon P.J.
        Competitive but not allosteric mTOR kinase inhibition enhances tumor cell radiosensitivity.
        Transl Oncol. 2013; 6: 355-362
        • Liu Z.-G.
        • Tang J.
        • Chen Z.
        • Zhang H.
        • Wang H.
        • Yang J.
        • et al.
        The novel mTORC1/2 dual inhibitor INK128 enhances radiosensitivity of breast cancer cell line MCF-7.
        Int J Oncol. 2016; 49: 1039-1045
        • Hayman T.J.
        • Wahba A.
        • Rath B.H.
        • Bae H.
        • Kramp T.
        • Shankavaram U.T.
        • et al.
        The ATP-competitive mTOR inhibitor INK128 enhances in vitro and in vivo radiosensitivity of pancreatic carcinoma cells.
        Clin Cancer Res. 2014; 20: 110-119
        • Kahn J.
        • Hayman T.J.
        • Jamal M.
        • Rath B.H.
        • Kramp T.
        • Camphausen K.
        • et al.
        The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells.
        Neuro Oncol. 2014; 16: 29-37
        • Luo J.
        • Pi G.
        • Xiao H.
        • Ye Y.
        • Li Q.
        • Zhao L.
        • et al.
        Torin2 enhances the radiosensitivity of MCF7 breast cancer cells by downregulating the mTOR signaling pathway and ATM phosphorylation.
        Mol Med Rep. 2018; 17: 366-373
        • Azria D.
        • Magné N.
        • Zouhair A.
        • Castadot P.
        • Culine S.
        • Ychou M.
        • et al.
        Radiation recall: a well recognized but neglected phenomenon.
        Cancer Treat Rev. 2005; 31: 555-570
        • Bourgier C.
        • Massard C.
        • Moldovan C.
        • Soria J.-C.
        • Deutsch E.
        Total recall of radiotherapy with mTOR inhibitors: a novel and potentially frequent side-effect?.
        Ann Oncol. 2011; 22: 485-486
        • Detti B.
        • Francolini G.
        • Becherini C.
        • Olmetto E.
        • Giacomelli I.
        • Scartoni D.
        • et al.
        Complete response in metastatic renal cell carcinoma after radiotherapy and everolimus: a clinical case and review of the literature.
        J Chemother. 2016; 28: 432-434
        • Ioannidis G.
        • Gkogkou P.
        • Charalampous P.
        • Diamandi M.
        • Ioannou R.
        Radiation-recall dermatitis with the everolimus/exemestane combination ten years after adjuvant whole-breast radiotherapy.
        Radiother Oncol. 2014; 112: 449-450
        • Visy A.
        • Bachelot T.
        • Racadot S.
        Radiation recall syndrome in a patient with breast cancer, after introduction of everolimus.
        Cancer Radiother. 2019; 23: 423-425
        • Wang H.
        • Zhang C.
        • Zhang J.
        • Kong L.
        • Zhu H.
        • Yu J.
        The prognosis analysis of different metastasis pattern in patients with different breast cancer subtypes: a SEER based study.
        Oncotarget. 2017; 8: 26368-26379
      2. Bailey TA, Luan H, Clubb RJ, Naramura M, Band V, Raja SM, et al. Mechanisms of Trastuzumab resistance in ErbB2-driven breast cancer and newer opportunities to overcome therapy resistance. J Carcinog. 2011;10:28.

        • Chen Y.
        • Wang R.
        • Huang S.
        • Henson E.S.
        • Bi J.
        • Gibson S.B.
        Erb-b2 receptor tyrosine kinase 2 (ERBB2) promotes ATG12-dependent autophagy contributing to treatment resistance of breast cancer cells.
        Cancers (Basel). 2021; 13: 1038https://doi.org/10.3390/cancers13051038
        • Wang J.
        • Xu B.
        Targeted therapeutic options and future perspectives for HER2-positive breast cancer.
        Signal Transduct Target Ther. 2019; 4: 34
        • Kim Y.G.
        • Yoon Y.N.
        • Choi H.S.
        • Kim J.-H.
        • Seol H.
        • Lee J.K.
        • et al.
        Breast cancer stem cells in HER2-negative breast cancer cells contribute to HER2-mediated radioresistance and molecular subtype conversion: clinical implications for serum HER2 in recurrent HER2-negative breast cancer.
        Oncotarget. 2018; 9: 5811-5822
        • Duru N.
        • Candas D.
        • Jiang G.
        • Li J.J.
        Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society.
        J Cancer Res Clin Oncol. 2014; 140: 1-14
        • Hou J.
        • Zhou Z.
        • Chen X.
        • Zhao R.
        • Yang Z.
        • Wei N.a.
        • et al.
        HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo.
        Oncotarget. 2016; 7: 45186-45198
        • Mignot F.
        • Ajgal Z.
        • Xu H.
        • Geraud A.
        • Chen J.Y.
        • Mégnin-Chanet F.
        • et al.
        Concurrent administration of anti-HER2 therapy and radiotherapy: systematic review.
        Radiother Oncol. 2017; 124: 190-199
        • Pietras R.J.
        • Poen J.C.
        • Gallardo D.
        • Wongvipat P.N.
        • Lee H.J.
        • Slamon D.J.
        Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene.
        Cancer Res. 1999; 59: 1347-1355
        • Liang K.
        • Lu Y.
        • Jin W.
        • Ang K.K.
        • Milas L.
        • Fan Z.
        Sensitization of breast cancer cells to radiation by trastuzumab.
        Mol Cancer Ther. 2003; 2: 1113-1120
        • Yu T.
        • Cho B.J.
        • Choi E.J.
        • Park J.M.
        • Kim D.H.
        • Kim I.A.
        Radiosensitizing effect of lapatinib in human epidermal growth factor receptor 2-positive breast cancer cells.
        Oncotarget. 2016; 7: 79089-79100
        • Mu Y.
        • Sun D.
        Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and HER-2, enhances radiosensitivity in mouse bladder tumor line-2 (MBT-2) cells in vitro and in vivo.
        Med Sci Monit. 2018; 24: 5811-5819
        • Mignot F.
        • Kirova Y.
        • Verrelle P.
        • Teulade-Fichou M.-P.
        • Megnin-Chanet F.
        In vitro effects of Trastuzumab Emtansine (T-DM1) and concurrent irradiation on HER2-positive breast cancer cells.
        Cancer Radiother. 2021; 25: 126-134
        • Costantini D.L.
        • Bateman K.
        • McLarty K.
        • Vallis K.A.
        • Reilly R.M.
        Trastuzumab-resistant breast cancer cells remain sensitive to the auger electron-emitting radiotherapeutic agent 111In-NLS-trastuzumab and are radiosensitized by methotrexate.
        J Nucl Med. 2008; 49: 1498-1505
        • Cameron D.
        • Piccart-Gebhart M.J.
        • Gelber R.D.
        • Procter M.
        • Goldhirsch A.
        • de Azambuja E.
        • et al.
        11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.
        Lancet. 2017; 389: 1195-1205
        • Meattini I.
        • Cecchini S.
        • Muntoni C.
        • Scotti V.
        • De Luca Cardillo C.
        • Mangoni M.
        • et al.
        Cutaneous and cardiac toxicity of concurrent trastuzumab and adjuvant breast radiotherapy: a single institution series.
        Med Oncol. 2014; 31https://doi.org/10.1007/s12032-014-0891-x
        • Cao L.u.
        • Cai G.
        • Chang C.
        • Yang Z.-Z.
        • Feng Y.
        • Yu X.-L.
        • et al.
        Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab.
        Oncotarget. 2016; 7: 1042-1054
        • Shaffer R.
        • Tyldesley S.
        • Rolles M.
        • Chia S.
        • Mohamed I.
        Acute cardiotoxicity with concurrent trastuzumab and radiotherapy including internal mammary chain nodes: a retrospective single-institution study.
        Radiother Oncol. 2009; 90: 122-126
        • Nack E.
        • Koffer P.P.
        • Blumberg C.S.
        • Leonard K.L.
        • Huber K.E.
        • Fenton M.A.
        • et al.
        New cardiac abnormalities after radiotherapy in breast cancer patients treated with trastuzumab.
        Clin Breast Cancer. 2020; 20: 246-252
        • Belkacémi Y.
        • Gligorov J.
        • Ozsahin M.
        • Marsiglia H.
        • De Lafontan B.
        • Laharie-Mineur H.
        • et al.
        Concurrent trastuzumab with adjuvant radiotherapy in HER2-positive breast cancer patients: acute toxicity analyses from the French multicentric study.
        Ann Oncol. 2008; 19: 1110-1116
        • Jacob J.
        • Belin L.
        • Pierga J.-Y.
        • Gobillion A.
        • Vincent-Salomon A.
        • Dendale R.
        • et al.
        Concurrent administration of trastuzumab with locoregional breast radiotherapy: long-term results of a prospective study.
        Breast Cancer Res Treat. 2014; 148: 345-353
        • Ajgal Z.
        • de Percin S.
        • Diéras V.
        • Pierga J.Y.
        • Campana F.
        • Fourquet A.
        • et al.
        Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: assessment of early toxicity.
        Cancer Radiother. 2017; 21: 114-118
        • von Minckwitz G.
        • Procter M.
        • de Azambuja E.
        • Zardavas D.
        • Benyunes M.
        • Viale G.
        • et al.
        Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer.
        N Engl J Med. 2017; 377: 122-131
        • Geyer C.E.
        • Forster J.
        • Lindquist D.
        • Chan S.
        • Romieu C.G.
        • Pienkowski T.
        • et al.
        Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
        N Engl J Med. 2006; 355: 2733-2743
        • Piccart-Gebhart M.
        • Holmes E.
        • Baselga J.
        • de Azambuja E.
        • Dueck A.C.
        • Viale G.
        • et al.
        Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial.
        J Clin Oncol. 2016; 34: 1034-1042
        • Kimple R.J.
        • Horton J.K.
        • Livasy C.A.
        • Shields J.M.
        • Lawrence J.A.
        • Chiu W.M.
        • et al.
        Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.
        Oncologist. 2012; 17: 1496-1503
        • Khan M.
        • Zhao Z.
        • Arooj S.
        • Zheng T.
        • Liao G.
        Lapatinib plus local radiation therapy for brain metastases from HER-2 positive breast cancer patients and role of trastuzumab: a systematic review and meta-analysis.
        Front Oncol. 2020; 10576926
        • von Minckwitz G.
        • Huang C.-S.
        • Mano M.S.
        • Loibl S.
        • Mamounas E.P.
        • Untch M.
        • et al.
        Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
        N Engl J Med. 2019; 380: 617-628
        • Krop I.E.
        • Kim S.-B.
        • González-Martín A.
        • LoRusso P.M.
        • Ferrero J.-M.
        • Smitt M.
        • et al.
        Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial.
        Lancet Oncol. 2014; 15: 689-699
        • Cortés J.
        • Kim S.-B.
        • Chung W.-P.
        • Im S.-A.
        • Park Y.H.
        • Hegg R.
        • et al.
        Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer.
        N Engl J Med. 2022; 386: 1143-1154
        • Mamounas E.P.
        • Untch M.
        • Mano M.S.
        • Huang C.-S.
        • Geyer Jr C.E.
        • von Minckwitz G.
        • et al.
        Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.
        Ann Oncol. 2021; 32: 1005-1014
        • Zolcsak Z.
        • Loirat D.
        • Fourquet A.
        • Kirova Y.M.
        Adjuvant trastuzumab emtansine (T-DM1) and concurrent radiotherapy for residual invasive HER2-positive breast cancer: single-center preliminary results.
        Am J Clin Oncol. 2020; 43: 895-901
        • Mills M.N.
        • Walker C.
        • Thawani C.
        • Naz A.
        • Figura N.B.
        • Kushchayev S.
        • et al.
        Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases.
        BMC Cancer. 2021; 21https://doi.org/10.1186/s12885-021-07971-w
        • Stumpf P.K.
        • Cittelly D.M.
        • Robin T.P.
        • Carlson J.A.
        • Stuhr K.A.
        • Contreras-Zarate M.J.
        • et al.
        Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of aquaporin-4.
        Clin Cancer Res. 2019; 25: 3946-3953
        • Werner E.M.
        • Eggert M.C.
        • Bohnet S.
        • Rades D.
        Prevalence and characteristics of pneumonitis following irradiation of breast cancer.
        Anticancer Res. 2019; 39: 6355-6358
        • Omarini C.
        • Thanopoulou E.
        • Johnston S.R.D.
        Pneumonitis and pulmonary fibrosis associated with breast cancer treatments.
        Breast Cancer Res Treat. 2014; 146: 245-258
        • Zhao W.
        • Hu H.
        • Mo Q.
        • Guan Y.
        • Li Y.
        • Du Y.
        • et al.
        Function and mechanism of combined PARP-1 and BRCA genes in regulating the radiosensitivity of breast cancer cells.
        Int J Clin Exp Pathol. 2019; 12: 3915-3920
        • Sonnenblick A.
        • de Azambuja E.
        • Azim H.A.
        • Piccart M.
        An update on PARP inhibitors–moving to the adjuvant setting.
        Nat Rev Clin Oncol. 2015; 12: 27-41
        • Donawho C.K.
        • Luo Y.
        • Luo Y.
        • Penning T.D.
        • Bauch J.L.
        • Bouska J.J.
        • et al.
        ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models.
        Clin Cancer Res. 2007; 13: 2728-2737
        • Kummar S.
        • Kinders R.
        • Gutierrez M.E.
        • Rubinstein L.
        • Parchment R.E.
        • Phillips L.R.
        • et al.
        Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies.
        J Clin Oncol. 2009; 27: 2705-2711
        • Powell C.
        • Mikropoulos C.
        • Kaye S.B.
        • Nutting C.M.
        • Bhide S.A.
        • Newbold K.
        • et al.
        Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers.
        Cancer Treat Rev. 2010; 36: 566-575
        • Scott C.L.
        • Swisher E.M.
        • Kaufmann S.H.
        Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.
        J Clin Oncol. 2015; 33: 1397-1406
        • Efimova E.V.
        • Mauceri H.J.
        • Golden D.W.
        • Labay E.
        • Bindokas V.P.
        • Darga T.E.
        • et al.
        Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors.
        Cancer Res. 2010; 70: 6277-6282
        • Veuger S.J.
        • Hunter J.E.
        • Durkacz B.W.
        Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance.
        Oncogene. 2009; 28: 832-842
        • Sizemore S.T.
        • Mohammad R.
        • Sizemore G.M.
        • Nowsheen S.
        • Yu H.
        • Ostrowski M.C.
        • et al.
        Synthetic lethality of PARP Inhibition and Ionizing Radiation is p53-dependent.
        Mol Cancer Res. 2018; 16: 1092-1102
        • Robson M.
        • Im S.-A.
        • Senkus E.
        • Xu B.
        • Domchek S.M.
        • Masuda N.
        • et al.
        Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
        N Engl J Med. 2017; 377: 523-533
        • Litton J.K.
        • Rugo H.S.
        • Ettl J.
        • Hurvitz S.A.
        • Gonçalves A.
        • Lee K.-H.
        • et al.
        Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.
        N Engl J Med. 2018; 379: 753-763
        • Tutt A.N.J.
        • Garber J.E.
        • Kaufman B.
        • Viale G.
        • Fumagalli D.
        • Rastogi P.
        • et al.
        Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer.
        N Engl J Med. 2021; 384: 2394-2405
        • Jagsi R.
        • Griffith K.A.
        • Bellon J.R.
        • Woodward W.A.
        • Horton J.K.
        • Ho A.
        • et al.
        Concurrent veliparib with chest wall and nodal radiotherapy in patients with inflammatory or locoregionally recurrent breast cancer: the TBCRC 024 phase I multicenter study.
        J Clin Oncol. 2018; 36: 1317-1322
        • Mehta M.P.
        • Wang D.
        • Wang F.
        • Kleinberg L.
        • Brade A.
        • Robins H.I.
        • et al.
        Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study.
        J Neurooncol. 2015; 122: 409-417
        • de Haan R.
        • van Werkhoven E.
        • van den Heuvel M.M.
        • Peulen H.M.U.
        • Sonke G.S.
        • Elkhuizen P.
        • et al.
        Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib.
        BMC Cancer. 2019; 19https://doi.org/10.1186/s12885-019-6121-3
        • Loap P.
        • Loirat D.
        • Berger F.
        • Cao K.
        • Ricci F.
        • Jochem A.
        • et al.
        Combination of Olaparib with radiotherapy for triple-negative breast cancers: One-year toxicity report of the RADIOPARP Phase I trial.
        Int J Cancer. 2021; 149: 1828-1832
        • Loi M.
        • Desideri I.
        • Greto D.
        • Mangoni M.
        • Sottili M.
        • Meattini I.
        • et al.
        Radiotherapy in the age of cancer immunology: current concepts and future developments.
        Crit Rev Oncol Hematol. 2017; 112: 1-10
        • Trowell O.A.
        The sensitivity of lymphocytes to ionising radiation.
        J Pathol Bacteriol. 1952; 64: 687-704
        • Reits E.A.
        • Hodge J.W.
        • Herberts C.A.
        • Groothuis T.A.
        • Chakraborty M.
        • Wansley E.K.
        • et al.
        Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy.
        J Exp Med. 2006; 203: 1259-1271
        • Kroemer G.
        • Galluzzi L.
        • Kepp O.
        • Zitvogel L.
        Immunogenic cell death in cancer therapy.
        Annu Rev Immunol. 2013; 31: 51-72
        • Xing D.
        • Siva S.
        • Hanna G.G.
        The abscopal effect of stereotactic radiotherapy and immunotherapy: fool's gold or El Dorado?.
        Clin Oncol (R Coll Radiol). 2019; 31: 432-443
        • Mondini M.
        • Nizard M.
        • Tran T.
        • Mauge L.
        • Loi M.
        • Clémenson C.
        • et al.
        Synergy of radiotherapy and a cancer vaccine for the treatment of HPV-associated head and neck cancer.
        Mol Cancer Ther. 2015; 14: 1336-1345
        • Vanpouille-Box C.
        • Alard A.
        • Aryankalayil M.J.
        • Sarfraz Y.
        • Diamond J.M.
        • Schneider R.J.
        • et al.
        DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity.
        Nat Commun. 2017; 8https://doi.org/10.1038/ncomms15618
        • Mirjolet C.
        • Charon-Barra C.
        • Ladoire S.
        • Arbez-Gindre F.
        • Bertaut A.
        • Ghiringhelli F.
        • et al.
        Tumor lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer: the LYMPHOREC study.
        Oncoimmunology. 2018; 7: e1396402https://doi.org/10.1080/2162402X.2017.1396402
        • Park S.S.
        • Dong H.
        • Liu X.
        • Harrington S.M.
        • Krco C.J.
        • Grams M.P.
        • et al.
        PD-1 restrains radiotherapy-induced abscopal effect.
        Cancer Immunol Res. 2015; 3: 610-619
        • Dovedi S.J.
        • Illidge T.M.
        The antitumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade.
        Oncoimmunology. 2015; 4: e1016709https://doi.org/10.1080/2162402X.2015.1016709
        • Dewan M.Z.
        • Galloway A.E.
        • Kawashima N.
        • Dewyngaert J.K.
        • Babb J.S.
        • Formenti S.C.
        • et al.
        Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
        Clin Cancer Res. 2009; 15: 5379-5388
        • Anscher M.S.
        • Arora S.
        • Weinstock C.
        • Amatya A.
        • Bandaru P.
        • Tang C.
        • et al.
        Association of radiation therapy with risk of adverse events in patients receiving immunotherapy: a pooled analysis of trials in the US Food and drug administration database.
        JAMA Oncol. 2022; 8: 232https://doi.org/10.1001/jamaoncol.2021.6439
        • Voorwerk L.
        • Slagter M.
        • Horlings H.M.
        • Sikorska K.
        • van de Vijver K.K.
        • de Maaker M.
        • et al.
        Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.
        Nat Med. 2019; 25: 920-928
        • McBride S.
        • Sherman E.
        • Tsai C.J.
        • Baxi S.
        • Aghalar J.
        • Eng J.
        • et al.
        Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.
        J Clin Oncol. 2021; 39: 30-37
        • Theelen W.
        • Peulen H.M.U.
        • Lalezari F.
        • van der Noort V.
        • de Vries J.F.
        • Aerts J.
        • et al.
        Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
        JAMA Oncol. 2019; 5: 1276https://doi.org/10.1001/jamaoncol.2019.1478
        • Formenti S.C.
        • Lee P.
        • Adams S.
        • Goldberg J.D.
        • Li X.
        • Xie M.W.
        • et al.
        Focal irradiation and systemic TGFbeta blockade in metastatic breast cancer.
        Clin Cancer Res. 2018; 24: 2493-2504
        • Jiang D.M.
        • Fyles A.
        • Nguyen L.T.
        • Neel B.G.
        • Sacher A.
        • Rottapel R.
        • et al.
        Phase I study of local radiation and tremelimumab in patients with inoperable locally recurrent or metastatic breast cancer.
        Oncotarget. 2019; 10: 2947-2958
        • Schmid P.
        • Cortes J.
        • Pusztai L.
        • McArthur H.
        • Kümmel S.
        • Bergh J.
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 810-821
        • Schmid P.
        • Adams S.
        • Rugo H.S.
        • Schneeweiss A.
        • Barrios C.H.
        • Iwata H.
        • et al.
        Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
        N Engl J Med. 2018; 379: 2108-2121
        • Barroso-Sousa R.
        • Krop I.E.
        • Trippa L.
        • Tan-Wasielewski Z.
        • Li T.
        • Osmani W.
        • et al.
        A phase II study of pembrolizumab in combination with palliative radiotherapy for hormone receptor-positive metastatic breast cancer.
        Clin Breast Cancer. 2020; 20: 238-245
        • Ho A.Y.
        • Barker C.A.
        • Arnold B.B.
        • Powell S.N.
        • Hu Z.I.
        • Gucalp A.
        • et al.
        A phase 2 clinical trialassessing theefficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer.
        Cancer. 2020; 126: 850-860
        • Demaria S.
        • Romano E.
        • Brackstone M.
        • Formenti S.C.
        Immune induction strategies to enhance responses to PD-1 blockade: lessons from the TONIC trial.
        J Immunother Cancer. 2019; 7: 318