Breast cancer radiotherapy and the risk of lung injury: Advances and perspectives

Abstract

Breast cancer is the most prevalent malignancy among women worldwide, and radiotherapy (RT) plays a central role in reducing local recurrence and improving survival. Technological advances such as three-dimensional conformal RT (3D-CRT), intensity-modulated RT (IMRT), volumetric-modulated arc therapy (VMAT), and particle therapies have enhanced dose conformity and reduced exposure to surrounding healthy tissues, particularly the lungs. Nevertheless, radiation-induced lung injury (RILI) remains a clinically relevant concern because of the close anatomical relationship between the breast and lung. RILI is a biphasic process, comprising early radiation pneumonitis and late radiation-induced pulmonary fibrosis, with severity influenced by dose distribution and treatment modality. While 3D-CRT carries a moderate risk due to limited beam modulation, IMRT and VMAT improve target coverage but may increase low-dose exposure to larger lung volumes, potentially increasing the risks of subclinical injury and, in the long term, secondary malignancy. Adjunctive lung-sparing strategies, including deep inspiration breath-hold and image-guided techniques, further reduce pulmonary dose. Proton beam therapy, particularly pencil beam scanning, offers additional lung protection through Bragg peak-based dose deposition, minimizing exit dose and irradiation of non-target tissues. Early clinical data suggest a lower incidence of RILI with PBT, although long-term outcomes remain under investigation. Carbon ion RT remains investigational in breast cancer. This review summarizes current evidence on RILI risk across modern RT modalities. A deeper understanding of modality-specific risks is essential for guiding personalized treatment planning and implementing effective lung-sparing strategies.

Keywords

Breast cancer radiotherapy / Radiation-induced lung injury / Radiation pneumonitis / Radiation-induced lung fibrosis / Tamoxifen / Senotherapeutics

References

[1] Guglielmi G. Breast cancer is on the rise: Data reveal drastic gap in survival rates. Nature. 2025; 639(8053):16. doi: 10.1038/d41586-025-00265-2

[2] Kim J, Harper A, McCormack V, et al. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat Med. 2025; 31(4):1154-1162. doi: 10.1038/s41591-025-03502-3

[3] Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025; 75(1):10-45. doi: 10.3322/caac.21871

[4] Bennett LL. Effects of pharmacological dose of vitamin C on MDA-MB-231 cells. Biomedicines. 2025; 13(3):640. doi: 10.3390/biomedicines13030640

[5] Tang DD, Ye ZJ, Liu WW, et al. Survival feature and trend of female breast cancer: A comprehensive review of survival analysis from cancer registration data. Breast. 2025;79:103862. doi: 10.1016/j.breast.2024.103862

[6] Peeters NJMCV, Meer DJVD, Kok M, et al. Five-year conditional relative survival up to 10 years post-diagnosis among adolescent and young adult breast cancer patients by age, stage, and receptor subtype. J Natl Cancer Cent. 2025; 5(3):297-305. doi: 10.1016/j.jncc.2025.01.005

[7] Kolářová I, Melichar B, Sirák I, et al. The role of adjuvant radiotherapy in the treatment of breast cancer. Curr Oncol. 2024; 31(3):1207-1220. doi: 10.3390/curroncol31030090

[8] Polgár C, Kahán Z, Ivanov O, et al. Radiotherapy of breast cancer-professional guideline 1st central-eastern european professional consensus statement on breast cancer. Pathol Oncol Res. 2022;28:1610378. doi: 10.3389/pore.2022.1610378

[9] Qiao K, Wei Y, Tao C, Zhu J, Yuan S. Proton therapy for breast cancer: Reducing toxicity. Thorac Cancer. 2024; 15(30):2156-2165. doi: 10.1111/1759-7714.15451

[10] Gueiderikh A, Sarrade T, Kirova Y, et al. Radiation-induced lung injury after breast cancer treatment: Incidence in the CANTO-RT cohort and associated clinical and dosimetric risk factors. Front Oncol. 2023;13:1199043. doi: 10.3389/fonc.2023.1199043

[11] Giuranno L, Ient J, De Ruysscher D, Vooijs MA. Radiation-induced lung injury (RILI). Front Oncol. 2019;9:877. doi: 10.3389/fonc.2019.00877

[12] Jin H, Yoo Y, Kim Y, Kim Y, Cho J, Lee YS. Radiation-induced lung fibrosis: Preclinical animal models and therapeutic strategies. Cancers (Basel). 2020; 12(6):1561. doi: 10.3390/cancers12061561

[13] Kong FM, Hayman JA, Griffith KA, et al. Final toxicity results of a radiation-dose escalation study in patients with non-small-cell lung cancer (NSCLC): Predictors for radiation pneumonitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006; 65(4):1075-1086. doi: 10.1016/j.ijrobp.2006.01.051

[14] Chen K, Liu C, Li X, et al. Risk and prognosis of secondary lung cancer after radiation therapy for thoracic malignancies. Clin Respir J. 2024; 18(5):e13760. doi: 10.1111/crj.13760

[15] Jarzebska N, Karetnikova ES, Markov AG, Kasper M, Rodionov RN, Spieth PM. Scarred lung. An update on radiation-induced pulmonary fibrosis. Front Med (Lausanne). 2020;7:585756. doi: 10.3389/fmed.2020.585756

[16] Ang L, Ghosh P, Seow WJ. Association between previous lung diseases and lung cancer risk: A systematic review and meta-analysis. Carcinogenesis. 2021; 42(12):1461-1474. doi: 10.1093/carcin/bgab082

[17] Schonfeld SJ, Curtis RE, Anderson WF, González ABD. The risk of a second primary lung cancer after a first invasive breast cancer according to estrogen receptor status. Cancer Causes Control. 2012; 23(10):1721-1728. doi: 10.1007/s10552-012-0054-3

[18] Asaithamby A, Shay JW, Minna JD. Cellular senescence and lung cancer prognosis. Transl Lung Cancer Res. 2022; 11(10):1982-1987. doi: 10.21037/tlcr-22-678

[19] Zhou L, Ruscetti M. Senescent macrophages: A new “old” player in lung cancer development. Cancer Cell. 2023; 41(7):1201-1203. doi: 10.1016/j.ccell.2023.05.008

[20] Egawa H, Furukawa K, Preston D, et al. Radiation and smoking effects on lung cancer incidence by histological types among atomic bomb survivors. Radiat Res. 2012; 178(3):191-201. doi: 10.1667/rr2819.1

[21] Vogelius IR, Bentzen SM. A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol. 2012; 51(8):975-983. doi: 10.3109/0284186X.2012.718093

[22] Dracham CB, Shankar A, Madan R. Radiation induced secondary malignancies: A review article. Radiat Oncol J. 2018; 36(2):85-94. doi: 10.3857/roj.2018.00290

[23] Corn BW, Galper S, David MB. The coming of age of breast radiotherapy. Curr Oncol. 2023; 30(5):5179-5181. doi: 10.3390/curroncol30050392

[24] González-Sanchis A, Brualla-González L, Fuster-Diana C, et al. Surface-guided radiation therapy for breast cancer: More precise positioning. Clin Transl Oncol. 2021; 23(10):2120-2126. doi: 10.1007/s12094-021-02617-6

[25] Adeneye S, Akpochafor M, Adegboyega B, et al. Evaluation of three-dimensional conformal radiotherapy and intensity modulated radiotherapy techniques for left breast post-mastectomy patients: Our experience in Nigerian sovereign investment authority-lagos university teaching hospital cancer center, South-West Nigeria. Eur J Breast Health. 2021; 17(3):247-252. doi: 10.4274/ejbh.galenos.2021.6357

[26] Racka I, Majewska K, Winiecki J. Three-dimensional conformal radiotherapy (3D-CRT) vs. volumetric modulated arc therapy (VMAT) in deep inspiration breath-hold (DIBH) technique in left-sided breast cancer patients-comparative analysis of dose distribution and estimation of projected secondary cancer risk. Strahlenther Onkol. 2023; 199(1):90-101. doi: 10.1007/s00066-022-01979-2

[27] Chang JS, Chang JH, Kim N, Kim YB, Shin KH, Kim K. Intensity modulated radiotherapy and volumetric modulated arc therapy in the treatment of breast cancer: An updated review. J Breast Cancer. 2022; 25(5):349-365. doi: 10.4048/jbc.2022.25.e37

[28] Ruan H, Okamoto M, Ohno T, Li Y, Zhou Y. Particle radiotherapy for breast cancer. Front Oncol. 2023;13:1107703. doi: 10.3389/fonc.2023.1107703

[29] Kendall R, Robinson T, Reed V, et al. Why is volumetric modulated arc therapy not considered the standard of care for locoregional radiation therapy for breast cancer patients? Adv Radiat Oncol. 2025; 10(5):101728. doi: 10.1016/j.adro.2025.101728

[30] Wang R, Shen J, Yan H, et al. Dosimetric comparison between intensity-modulated radiotherapy and volumetric-modulated arc therapy in patients of left-sided breast cancer treated with modified radical mastectomy: CONSORT. Medicine (Baltimore). 2022; 101(2):e28427. doi: 10.1097/MD.0000000000028427

[31] Li F, Liu H, Wu H, Liang S, Xu Y. Risk factors for radiation pneumonitis in lung cancer patients with subclinical interstitial lung disease after thoracic radiation therapy. Radiat Oncol. 2021; 16(1):70. doi: 10.1186/s13014-021-01798-2

[32] Park SH, Lim JK, Kang MK, et al. Predictive factors for severe radiation-induced lung injury in patients with lung cancer and coexisting interstitial lung disease. Radiother Oncol. 2024;192:110053. doi: 10.1016/j.radonc.2023.110053

[33] Testolin A, Ciccarelli S, Vidano G, Avitabile R, Dusi F, Alongi F. Deep inspiration breath-hold intensity modulated radiation therapy in a large clinical series of 239 left-sided breast cancer patients: A dosimetric analysis of organs at risk doses and clinical feasibility from a single center experience. Br J Radiol. 2019; 92(1101):20190150. doi: 10.1259/bjr.20190150

[34] Bergom C, Currey A, Desai N, Tai A, Strauss JB. Deep inspiration breath hold: Techniques and advantages for cardiac sparing during breast cancer irradiation. Front Oncol. 2018;8:87. doi: 10.3389/fonc.2018.00087

[35] Aznar MC, Carrasco de Fez P, Corradini S, et al. ESTRO-ACROP guideline: Recommendations on implementation of breath-hold techniques in radiotherapy. Radiother Oncol. 2023;185:109734. doi: 10.1016/j.radonc.2023.109734

[36] Kang Y, Bues M, Halyard MY, et al. Dose delivery reproducibility for PBS proton treatment of breast cancer patients with and without mask immobilization. Radiat Oncol. 2023; 18(1):157. doi: 10.1186/s13014-023-02323-3

[37] Durante M, Debus J, Loeffler JS. Physics and biomedical challenges of cancer therapy with accelerated heavy ions. Nat Rev Phys. 2021; 3(12):777-790. doi: 10.1038/s42254-021-00368-5

[38] Jette D, Chen W. Creating a spread-out Bragg peak in proton beams. Phys Med Biol. 2011; 56(11):N131-N138. doi: 10.1088/0031-9155/56/11/N01

[39] Luo W, Ali YF, Liu C, et al. Particle therapy for breast cancer: Benefits and challenges. Front Oncol. 2021;11:662826. doi: 10.3389/fonc.2021.662826

[40] Bradley JA, Dagan R, Ho MW, et al. Initial report of a prospective dosimetric and clinical feasibility trial demonstrates the potential of protons to increase the therapeutic ratio in breast cancer compared with photons. Int J Radiat Oncol Biol Phys. 2016; 95(1):411-421. doi: 10.1016/j.ijrobp.2015.09.018

[41] Smith NL, Jethwa KR, Viehman JK, et al. Post-mastectomy intensity modulated proton therapy after immediate breast reconstruction: Initial report of reconstruction outcomes and predictors of complications. Radiother Oncol. 2019; 140:76-83. doi: 10.1016/j.radonc.2019.05.022

[42] Malouff TD, Mahajan A, Krishnan S, Beltran C, Seneviratne DS, Trifiletti DM. Carbon ion therapy: A modern review of an emerging technology. Front Oncol. 2020;10:82. doi: 10.3389/fonc.2020.00082

[43] Yu B, Li KW, Fan Y, Pei X. Value of carbon-ion radiation therapy for breast cancer. Int J Part Ther. 2024;14:100629. doi: 10.1016/j.ijpt.2024.100629

[44] Karasawa K, Omatsu T, Shiba S, Irie D, Wakatsuki M, Fukuda S. A clinical study of curative partial breast irradiation for stage I breast cancer using carbon ion radiotherapy. Radiat Oncol. 2020; 15(1):265. doi: 10.1186/s13014-020-01713-1

[45] Dale RG, Jones B. The assessment of RBE effects using the concept of biologically effective dose. Int J Radiat Oncol Biol Phys. 1999; 43(3):639-645. doi: 10.1016/s0360-3016(98)00364-2

[46] Jones B. Proton radiobiology and its clinical implications. Ecancermedicalscience. 2017;11:777. doi: 10.3332/ecancer.2017.777

[47] Wedenberg M, Lind BK, Hårdemark B. A model for the relative biological effectiveness of protons: The tissue specific parameter α/β of photons is a predictor for the sensitivity to LET changes. Acta Oncol. 2013; 52(3):580-588. doi: 10.3109/0284186X.2012.705892

[48] Beach TA, Finkelstein JN, Chang PY. Epithelial responses in radiation-induced lung injury (RILI) allow chronic inflammation and fibrogenesis. Radiat Res. 2023; 199(5):439-451. doi: 10.1667/rade-22-00130.1

[49] Wennstig AK, Wadsten C, Garmo H, et al. Risk of primary lung cancer after adjuvant radiotherapy in breast cancer-a large population-based study. NPJ Breast Cancer. 2021; 7(1):71. doi: 10.1038/s41523-021-00280-2

[50] Wang Y, Zhang J, Shao C. Cytological changes in radiation-induced lung injury. Life Sci. 2024;358:123188. doi: 10.1016/j.lfs.2024.123188

[51] Kawakami W, Takamatsu S, Taka M, et al. Factors associated with radiation pneumonitis in patients receiving electron boost radiation for breast-conserving therapy: A retrospective review. Adv Radiat Oncol. 2020; 5(6):1141-1146. doi: 10.1016/j.adro.2020.08.009

[52] Lee JW, Chung MJ. Safety of hypofractionated volumetric modulated arc therapy for early breast cancer: A preliminary report. Oncol Lett. 2023; 26(2):330. doi: 10.3892/ol.2023.13916

[53] Rahi MS, Parekh J, Pednekar P, et al. Radiation-induced lung injury-current perspectives and management. Clin Pract. 2021; 11(3):410-429. doi: 10.3390/clinpract11030056

[54] Kasmann L, Deitrich A, Staab-Weijnitz C, et al. Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review. Radiat Oncol. 2020; 15(1):214. doi: 10.1186/s13014-020-01654-9

[55] Chirilă ME, Kraja F, Marta GN, et al. Organ-sparing techniques and dose-volume constrains used in breast cancer radiation therapy - results from European and Latin American surveys. Clin Transl Radiat Oncol. 2024;46:100752. doi: 10.1016/j.ctro.2024.100752

[56] Flores-Balcázar CH, Urías-Arce DM. Evaluation of tumor control and normal tissue complication probabilities in patients receiving comprehensive nodal irradiation for left-sided breast cancer. Curr Oncol. 2024; 31(6):3189-3198. doi: 10.3390/curroncol31060241

[57] Nagaraja SS, Subramanian U, Nagarajan D. Radiation-induced H3K9 methylation on E-cadherin promoter mediated by ROS/Snail axis: Role of G9a signaling during lung epithelial-mesenchymal transition. Toxicol in Vitro. 2021;70:105037. doi: 10.1016/j.tiv.2020.105037

[58] Yu Z, Xu C, Song B, et al. Tissue fibrosis induced by radiotherapy: Current understanding of the molecular mechanisms, diagnosis and therapeutic advances. J Transl Med. 2023; 21(1):708. doi: 10.1186/s12967-023-04554-0

[59] Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: Novel roles and mediators. Front Pharmacol. 2014;5:123. doi: 10.3389/fphar.2014.00123

[60] Wang X, Sun X, Mu L, Chen W. Cancer-associated fibroblasts induce epithelial-mesenchymal transition in endometrial cancer cells by regulating pituitary tumor transforming gene. Cancer Invest. 2019; 37(3):134-143. doi: 10.1080/07357907.2019.1575969

[61] Li Q, Cheng Y, Zhang Z, et al. Inhibition of ROCK ameliorates pulmonary fibrosis by suppressing M2 macrophage polarisation through phosphorylation of STAT3. Clin Transl Med. 2022; 12(10):e1036. doi: 10.1002/ctm2.1036

[62] Mukherjee A, Epperly MW, Shields D, et al. Ionizing irradiation-induced Fgr in senescent cells mediates fibrosis. Cell Death Discov. 2021; 7(1):349. doi: 10.1038/s41420-021-00741-4

[63] Chung EJ, Kwon S, Reedy JL, et al. IGF-1 receptor signaling regulates type II pneumocyte senescence and resulting macrophage polarization in lung fibrosis. Int J Radiat Oncol Biol Phys. 2021; 110(2):526-538. doi: 10.1016/j.ijrobp.2020.12.035

[64] Kim KK, Sheppard D, Chapman HA. TGF-β1 signaling and tissue fibrosis. Cold Spring Harb Perspect Biol. 2018; 10(4):a022293. doi: 10.1101/cshperspect.a022293

[65] Shi X, Young CD, Zhou H, Wang X. Transforming growth factor-β signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules. 2020; 10(12):1666. doi: 10.3390/biom10121666

[66] Fijardo M, Kwan JYY, Bissey PA, Citrin DE, Yip KW, Liu FF. The clinical manifestations and molecular pathogenesis of radiation fibrosis. EBioMedicine. 2024;103:105089. doi: 10.1016/j.ebiom.2024.105089

[67] Hanania AN, Mainwaring W, Ghebre YT, Hanania N, Ludwig M. Radiation-induced lung injury: Assessment and management. Chest. 2019; 156(1):150-162. doi: 10.1016/j.chest.2019.03.033

[68] Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015; 373(4):307-316. doi: 10.1056/nejmoa1415340

[69] Poortmans PM, Collette S, Kirkove C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015; 373(4):317-327. doi: 10.1056/nejmoa1415369

[70] Gokula K, Earnest A, Wong LC. Meta-analysis of incidence of early lung toxicity in 3-dimensional conformal irradiation of breast carcinomas. Radiat Oncol. 2013;8:268. doi: 10.1186/1748-717X-8-268

[71] Us SB, Bayrak G, Ballı E, Büyükakıllı B. Histological, immunohistochemical and electron-microscopic evaluation of different radiotherapy doses effects on rat’s lung. Tissue Cell. 2025;95:102860. doi: 10.1016/j.tice.2025.102860

[72] Konkol M, Śniatała P, Milecki P. Radiation-induced lung injury - what do we know in the era of modern radiotherapy. Rep Pract Oncol Radiother. 2022; 27(3):552-565. doi: 10.5603/rpor.a2022.0046

[73] Chao PJ, Lee HF, Lan JH, et al. Propensity-score-matched evaluation of the incidence of radiation pneumonitis and secondary cancer risk for breast cancer patients treated with IMRT/VMAT. Sci Rep. 2017; 7(1):13771. doi: 10.1038/s41598-017-14145-x

[74] Ho AY, Ballangrud A, Li G, et al. Long-term pulmonary outcomes of a feasibility study of inverse-planned, multibeam intensity modulated radiation therapy in node-positive breast cancer patients receiving regional nodal irradiation. Int J Radiat Oncol Biol Phy. 2019; 103(5):1100-1108. doi: 10.1016/j.ijrobp.2018.11.045

[75] Yu NY, DeWees TA, Voss MM, et al. Cardiopulmonary toxicity following intensity-modulated proton therapy (IMPT) versus intensity-modulated radiation therapy (IMRT) for stage III non-small cell lung cancer. Clin Lung Cancer. 2022; 23(8):e526-e535. doi: 10.1016/j.cllc.2022.07.017

[76] Zou Z, Bowen SR, Thomas HMT, Sasidharan BK, Rengan R, Zeng J. Scanning beam proton therapy versus photon IMRT for stage III lung cancer: Comparison of dosimetry, toxicity, and outcomes. Adv Radiat Oncol. 2020; 5(3):434-443. doi: 10.1016/j.adro.2020.03.001

[77] Ger RB, Lentz JM, Niedzielski JS, et al. Dosimetric advantage of scanning beam proton therapy in gynecologic patients receiving adjuvant radiotherapy. Cancers (Basel). 2025; 17(12):2010. doi: 10.3390/cancers17122010

[78] Cui Y, Pan Y, Li Z, et al. Dosimetric analysis and biological evaluation between proton radiotherapy and photon radiotherapy for the long target of total esophageal squamous cell carcinoma. Front Oncol. 2022;12:954187. doi: 10.3389/fonc.2022.954187

[79] Liao Z, Lee JJ, Komaki R, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 2018; 36(18):1813-1822. doi: 10.1200/jco.2017.74.0720

[80] Mutter RW, Choi JI, Jimenez RB, et al. Proton therapy for breast cancer: A consensus statement from the particle therapy cooperative group breast cancer subcommittee. Int J Radiat Oncol Biol Phys. 2021; 111(2):337-359. doi: 10.1016/j.ijrobp.2021.05.110

[81] Yilmaz U, Koylu M, Savas R, Alanyali S. Imaging features of radiation-induced lung disease and its relationship with clinical and dosimetric factors in breast cancer patients. J Cancer Res Ther. 2023;19:S0. doi: 10.4103/jcrt.jcrt_442_21

[82] Wang W, Xu Y, Schipper M, et al. Effect of normal lung definition on lung dosimetry and lung toxicity prediction in radiation therapy treatment planning. Int J Radiat Oncol Biol Phys. 2013; 86(5):956-963. doi: 10.1016/j.ijrobp.2013.05.003

[83] Prasun P, Kharade V, Pal V, Gupta M, Das S, Pasricha R. Dosimetric comparison of hypofractionated regimen in breast cancer using two different techniques: Intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). Cureus. 2023; 15(4):e38045. doi: 10.7759/cureus.38045

[84] Hanczyk E, Piecuch D, Kopcial S, Jonska-Gmyrek J. Factors affecting the effectiveness of DIBH (Deep inspiratory breath hold) in patients with left breast cancer: A Narrative review. Appl Sci. 2024; 14(16):7287. doi: 10.3390/app14167287

[85] Kong W, Huiskes M, Habraken SJM, et al. Reducing the lateral dose penumbra in IMPT by incorporating transmission pencil beams. Radiother Oncol. 2024;198:110388. doi: 10.1016/j.radonc.2024.110388

[86] Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys. 2010; 76(3 Suppl):S70-S76. doi: 10.1016/j.ijrobp.2009.06.091

[87] Liu Y, Wang W, Shiue K, et al. Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer. Radiother Oncol. 2021; 156:231-238. doi: 10.1016/j.radonc.2020.10.015

[88] Park SH, Kim JC.Regional nodal irradiation inpT1-2 N1 breast cancer patients treated with breast-conserving surgery and whole breast irradiation. Radiat Oncol J. 2020; 38(1):44-51. doi: 10.3857/roj.2019.00647

[89] Taylor C, Correa C, Duane FK, et al. Estimating the risks of breast cancer radiotherapy: Evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol. 2017; 35(15):1641-1649. doi: 10.1200/jco.2016.72.0722

[90] Mangesius J, Minasch D, Fink K, et al. Systematic risk analysis of radiation pneumonitis in breast cancer: Role of cotreatment with chemo-, endocrine, and targeted therapy. Strahlenther Onkol. 2023; 199(1):67-77. doi: 10.1007/s00066-022-02032-y

[91] Ford MB, Sigurdson AJ, Petrulis ES, et al. Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer. 2003; 98(7):1457-1464. doi: 10.1002/cncr.11669

[92] Prochazka M, Hall P, Gagliardi G, et al. Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: Case-only design. J Clin Oncol. 2005; 23(30):7467-7474. doi: 10.1200/jco.2005.01.7335

[93] Kaufman EL, Jacobson JS, Hershman DL, Desai M, Neugut AI. Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer. J Clin Oncol. 2008; 26(3):392-398. doi: 10.1200/jco.2007.13.3033

[94] Ding NH, Li JJ, Sun LQ. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets. 2013; 14(11):1347-1356. doi: 10.2174/13894501113149990198

[95] Gurtner K, Kryzmien Z, Koi L, et al. Radioresistance of KRAS/TP53-mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo. Int J Cancer. 2020; 147(2):472-477. doi: 10.1002/ijc.32598

[96] Abo-Madyan Y, Aziz MH, Aly MM, et al. Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer. Radiother Oncol. 2014; 110(3):471-476. doi: 10.1016/j.radonc.2013.12.002

[97] Pithadia KJ, Advani PG, Citrin DE, et al. Comparing risk for second primary cancers after intensity-modulated vs 3-dimensional conformal radiation therapy for prostate cancer, 2002-2015. JAMA Oncol. 2023; 9(8):1119-1123. doi: 10.1001/jamaoncol.2023.1638

[98] Cartechini G, Fracchiolla F, Menegotti L, et al. Proton pencil beam scanning reduces secondary cancer risk in breast cancer patients with internal mammary chain involvement compared to photon radiotherapy. Radiat Oncol. 2020; 15(1):228. doi: 10.1186/s13014-020-01671-8

[99] Paganetti H, Depauw N, Johnson A, Forman RB, Lau J, Jimenez R. The risk for developing a secondary cancer after breast radiation therapy: Comparison of photon and proton techniques. Radiother Oncol. 2020; 149:212-218. doi: 10.1016/j.radonc.2020.05.035

[100] Kadakia KC, Henry NL. Adjuvant endocrine therapy in premenopausal women with breast cancer. Clin Adv Hematol Oncol. 2015; 13(10):663-672.

[101] Uslu Y, Kocatepe V, Sezgin DS, Uras C. Adherence to adjuvant tamoxifen and associated factors in breast cancer survivors. Support Care Cancer. 2023; 31(5):285. doi: 10.1007/s00520-023-07742-2

[102] Azria D, Gourgou S, Sozzi WJ, et al. Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer. 2004; 91(7):1251-1260. doi: 10.1038/sj.bjc.6602146

[103] Harris EE, Christensen VJ, Hwang WT, Fox K, Solin LJ. Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment. J Clin Oncol. 2005; 23(1):11-16. doi: 10.1200/jco.2005.09.056

[104] McGee SF, Clemons M, Pond G, et al. A randomized trial comparing concurrent versus sequential radiation and endocrine therapy in early-stage, hormone-responsive breast cancer. Curr Oncol. 2024; 31(8):4531-4545. doi: 10.3390/curroncol31080338

[105] Etori S, Nakano R, Kamada H, et al. Tamoxifen-induced lung injury. Intern Med. 2017; 56(21):2903-2906. doi: 10.2169/internalmedicine.8649-16

[106] Zhao T, Sun Z, Lai X, et al. Tamoxifen exerts anti-peritoneal fibrosis effects by inhibiting H19-activated VEGFA transcription. J Transl Med. 2023; 21(1):614. doi: 10.1186/s12967-023-04470-3

[107] Koc M, Polat P, Suma S. Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother Oncol. 2002; 64(2):171-175. doi: 10.1016/s0167-8140(02)00136-6

[108] Kuo SH, Tseng LM, Chen ST, et al. Radiotherapy versus low-dose tamoxifen following breast-conserving surgery for low-risk and estrogen receptor-positive breast ductal carcinoma in situ: An international open-label randomized non-inferiority trial (TBCC-ARO DCIS Trial). BMC Cancer. 2023; 23(1):865. doi: 10.1186/s12885-023-11291-6

[109] Wong LY, Kapula N, He H, et al. Risk of developing subsequent primary lung cancer after receiving radiation for breast cancer. JTCVS Open. 2023; 16:919-928. doi: 10.1016/j.xjon.2023.10.031

[110] Burns TF, Stabile LP. Targeting the estrogen pathway for the treatment and prevention of lung cancer. Lung Cancer Manag. 2014; 3(1):43-52. doi: 10.2217/lmt.13.67

[111] Debbi K, Grellier N, Loganadane G, et al. Interaction between radiation therapy and targeted therapies in HER2-positive breast cancer: Literature review, levels of evidence for safety and recommendations for optimal treatment sequence. Cancers. 2023; 15(8):2278. doi: 10.3390/cancers15082278

[112] Lin MX, Zang D, Liu CG, Han X, Chen J. Immune checkpoint inhibitor-related pneumonitis: Research advances in prediction and management. Front Immunol. 2024;15:1266850. doi: 10.3389/fimmu.2024.1266850

[113] Weller A, Dunlop A, Oxer A, et al. Spect perfusion imaging versus CT for predicting radiation injury to normal lung in lung cancer patients. Br J Radiol. 2019; 92(1101):20190184. doi: 10.1259/bjr.20190184

[114] Zhang X, Zhang Z, Huang M, et al. Pathological mechanisms of radiation-induced lung injury and novel nano-drug delivery therapeutic strategies. Int J Nanomedicine. 2025; 20:12431-12465. doi: 10.2147/IJN.S551477

[115] Qi YJ, Su GH, You C, et al. Radiomics in breast cancer: Current advances and future directions. Cell Rep Med. 2024; 5(9):101719. doi: 10.1016/j.xcrm.2024.101719

[116] Nardone V, Reginelli A, Rubini D, et al. Delta radiomics: An updated systematic review. Radiol Med. 2024; 129(8):1197-1214. doi: 10.1007/s11547-024-01853-4

[117] Ma M, Chu Z, Quan H, et al. Natural products for anti-fibrotic therapy in idiopathic pulmonary fibrosis: Marine and terrestrial insights. Front Pharmacol. 2025;16:1524654. doi: 10.3389/fphar.2025.1524654

[118] Suman S, Jain S, Chandna S. Recent patents in the field of radioprotector development: Opportunities and challenges. Recent Pat Biotechnol. 2013; 7(3):219-227. doi: 10.2174/18722083113076660012

[119] Antonadou D, Throuvalas N, Petridis A, et al. Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2023; 57(2):402-408. doi: 10.1016/s0360-3016(03)00590-x

[120] Rabbani ZN, Batinic-Haberle I, Anscher MS, et al. Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury. Int J Radiat Oncol Biol Phys. 2007; 67(2):573-580. doi: 10.1016/j.ijrobp.2006.09.053

[121] Kadivar F, Haddadi G, Mosleh-Shirazi MA, Khajeh F, Tavasoli A. Protection effect of cerium oxide nanoparticles against radiation-induced acute lung injuries in rats. Rep Pract Oncol Radiother. 2020; 25(2):206-211. doi: 10.1016/j.rpor.2019.12.023

[122] Singh VK, Serebrenik AA, Fatanmi OO, et al. The radioprotectant, BIO 300, protects the lungs from total-body irradiation injury in C57L/J mice. Radiat Res. 2023; 199(3):294-300. doi: 10.1667/rade-22-00142.1

[123] Lin Y, Xu Z, Zhou B, Ma K, Jiang M. Pentoxifylline inhibits pulmonary fibrosis by regulating cellular senescence in mice. Front Pharmacol. 2022;13:848263. doi: 10.3389/fphar.2022.848263

[124] Jha SK, De Rubis G, Devkota SR, et al. Cellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions. Ageing Res Rev. 2024;97:102315. doi: 10.1016/j.arr.2024.102315

[125] Kumar K, Angdisen J, Ma J, Datta K, Fornace AJ, Suman S. Simulated galactic cosmic radiation exposure-induced mammary tumorigenesis in ApcMin/+ mice coincides with activation of ERα-ERRα-SPP1 signaling axis. Cancers (Basel). 2024; 16(23):3954. doi: 10.3390/cancers16233954

[126] Feng T, Xie F, Lee LMY, et al. Cellular senescence in cancer: From mechanism paradoxes to precision therapeutics. Mol Cancer. 2025; 24(1):213. doi: 10.1186/s12943-025-02419-2

[127] K lepacki H, Kowalczuk K, Łepkowska N, Hermanowicz JM. Molecular regulation of SASP in Cellular senescence: Therapeutic implications and translational challenges. Cells. 2025; 14(13):942. doi: 10.3390/cells14130942

[128] Kumar K, Moon BH, Kumar S, et al. Senolytic agent ABT-263 mitigates low- and high-LET radiation-induced gastrointestinal cancer development in Apc1638]N/+ mice. Aging (Albany NY). 2025; 17(1):97-115. doi: 10.18632/aging.206183

[129] Kumar K, Kumar S, Datta K, Fornace AJ, Suman S. High-LET-radiation-induced persistent DNA damage response signaling and gastrointestinal cancer development. Curr Oncol. 2023; 30(6):5497-5514. doi: 10.3390/curroncol30060416

[130] Chen C, Chen J, Zhang Y, Zhang Q, Shi H. Senescence-associated secretory phenotype in lung cancer: Remodeling the tumor microenvironment for metastasis and immune suppression. Front Oncol. 2025;15:1605085. doi: 10.3389/fonc.2025.1605085

[131] Suman S. Integrative analysis of radiation-induced senescence-associated secretory phenotype factors in kidney cancer progression. Genes (Basel). 2025; 16(1):85. doi: 10.3390/genes16010085

[132] Pan J, Li D, Xu Y, et al. Inhibition of Bcl-2/xl With ABT-263 selectively kills senescent type II pneumocytes and reverses persistent pulmonary fibrosis induced by ionizing radiation in mice. Int J Radiat Oncol Biol Phys. 2017; 99(2):353-361. doi: 10.1016/j.ijrobp.2017.02.216

[133] Suman S, Fornace AJ. Countermeasure development against space radiation-induced gastrointestinal carcinogenesis: Current and future perspectives. Life Sci Space Res (Amst). 2022; 35:53-59. doi: 10.1016/j.lssr.2022.09.005

[134] Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019; 40:554-563. doi: 10.1016/j.ebiom.2018.12.052

[135] Rosell J, Nordenskjöld B, Bengtsson NO, et al. Long-term effects on the incidence of second primary cancers in a randomized trial of two and five years of adjuvant tamoxifen. Acta Oncol. 2017; 56(4):614-617. doi: 10.1080/0284186X.2016.1273547

[136] Liang B, Tian Y, Chen X, et al. Prediction of radiation pneumonitis with dose distribution: A convolutional neural network (CNN) based model. Front Oncol. 2020;9:1500. doi: 10.3389/fonc.2019.01500

[137] Hatamabadi Farahani E, Sadeghi H, Seif F, Marzabadi MA, Rezaee R. Analyzing secondary cancer risk: A machine learning approach. Asian Pac J Cancer Prev. 2025; 26(1):239-248. doi: 10.31557/apjcp.2025.26.1.239

[138] Felici A, Peduzzi G, Pellungrini R, Campa D. Artificial intelligence to predict cancer risk, are we there yet? A comprehensive review across cancer types. Eur J Cancer. 2025;222:115440. doi: 10.1016/j.ejca.2025.115440

[139] Kim JS, Kim HJ. FLASH radiotherapy: Bridging revolutionary mechanisms and clinical frontiers in cancer treatment - a narrative review. Ewha Med J. 2024; 47(4):e54. doi: 10.12771/emj.2024.e54

[140] Guo Y, Hao S, Huang Q, et al. Unraveling the dual nature of FLASH radiotherapy: From normal tissue sparing to tumor control. Cancer Lett. 2025;630:217895. doi: 10.1016/j.canlet.2025.217895

[141] Webster M, Podgorsak A, Li F, et al. New approaches in radiotherapy. Cancers (Basel). 2025; 17(12):1980. doi: 10.3390/cancers17121980