Impact of adjuvant hormonotherapy on radiation-induced breast fibrosis according to the individual radiosensitivity: results of a multicenter prospective French trial

Céline Bourgier, Florence Castan, Olivier Riou, Tan-Dat Nguyen, Karine Peignaux, Claire Lemanski, Jean-Léon Lagrange, Youlia Kirova, Eric Lartigau, Yazid Belkacemi, Sofia Rivera, Georges Noël, Sébastien Clippe, Françoise Mornex, Christophe Hennequin, Sophie Gourgou, Muriel Brengues, Pascal Fenoglietto, Esat Mahmut Ozsahin, David Azria, Céline Bourgier, Florence Castan, Olivier Riou, Tan-Dat Nguyen, Karine Peignaux, Claire Lemanski, Jean-Léon Lagrange, Youlia Kirova, Eric Lartigau, Yazid Belkacemi, Sofia Rivera, Georges Noël, Sébastien Clippe, Françoise Mornex, Christophe Hennequin, Sophie Gourgou, Muriel Brengues, Pascal Fenoglietto, Esat Mahmut Ozsahin, David Azria

Abstract

Background: To evaluate risk of severe breast fibrosis occurrence in patients treated by breast-conserving surgery, adjuvant radiotherapy and hormonotherapy (HT) according to individual radiosensitivity (RILA assay).

Results: HT- and RILAhigh were the two independent factors associated with improved breast-fibrosis free survival (BFFS). BFFS rate at 36 months was lower in patients with RILAlow and HT+ than in patients with RILAhigh and HT- (75.8% and 100%, respectively; p = 0.004, hazard ratio 5.84 [95% confidence interval (CI) 1.8-19.1]). Conversely, BFFS at 36 months was comparable in patients with RILAhigh and HT+ and in patients with RILAlow and HT- (89.8% and 93.5%, respectively; p = 0.39, hazard ratio 1.7 [95% CI 0.51-5.65]), showing that these two parameters influenced independently the occurrence of severe breast fibrosis. BFFS rate was not affected by the HT type (tamoxifen or aromatase inhibitor) and timing (concomitant or sequential with radiotherapy).

Conclusions: HT and RILA score independently influenced BFFS rate at 36 months. Patients with RILAhigh and HT- presented an excellent BFFS at 36 months (100%).

Materials and methods: Breast Fibrosis-Free Survival (BFFS) rate was assessed relative to RILA categories and to adjuvant HT use (HT+ and HT-, respectively) in a prospective multicentre study (NCT00893035) which enrolled 502 breast cancer patients (456 evaluable patients). Breast fibrosis was recorded according to CTCAE v3.0 grading scale; RILA score was defined according to two categories (<12%: RILAlow; ≥12%: RILAhigh).

Keywords: breast cancer; hormonotherapy; individual radiosensitivity; late effects; radiotherapy.

Conflict of interest statement

CONFLICTS OF INTEREST Pascal Fenoglietto and David Azria participated in the development of NovaGray. All remaining authors declared that they have no conflict of interest.

Figures

Figure 1. Breast fibrosis-free survival (BFFS) according…
Figure 1. Breast fibrosis-free survival (BFFS) according to the RILA score (LOW and ≥12%, RILAHIGH) and hormonotherapy (with HT, HT; or without, no HT)
Figure 2. BFFS according to the RILA…
Figure 2. BFFS according to the RILA score (RILALOW or RILAHIGH) and the HT sub-categories: “TAM/no TAM”, “AI/no AI”, and “no HT”
Figure 3. BFFS according to the RILA…
Figure 3. BFFS according to the RILA score (RILALOW or RILAHIGH) and HT timing relative to radiotherapy: concomitant “co-HT”, sequential “sq-HT”, or none “no HT”

References

    1. Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378:1707–16. .
    1. Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, Bliss J, Boccardo F, Coates A, Coombes RC, Cuzick J, Dubsky P, Gnant M, Kaufmann M, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386:1341–52. .
    1. Al-Ghazal SK, Fallowfield L, Blamey RW. Does cosmetic outcome from treatment of primary breast cancer influence psychosocial morbidity? Eur J Surg Oncol. 1999;25:571–3. .
    1. Darby SC, Ewertz M, Hall P. Ischemic heart disease after breast cancer radiotherapy. N Engl J Med. 2013;368:2527. .
    1. Azria D, Betz M, Bourgier C, Jeanneret Sozzi W, Ozsahin M. Identifying patients at risk for late radiation-induced toxicity. Crit Rev Oncol Hematol. 2012;84:e35–41. .
    1. Bourgier C, Lacombe J, Solassol J, Mange A, Pelegrin A, Ozsahin M, Azria D. Late side-effects after curative intent radiotherapy: Identification of hypersensitive patients for personalized strategy. Crit Rev Oncol Hematol. 2015;93:312–9. .
    1. Schmidberger H, Hermann RM, Hess CF, Emons G. Interactions between radiation and endocrine therapy in breast cancer. Endocr Relat Cancer. 2003;10:375–88.
    1. Toillon RA, Magne N, Laios I, Lacroix M, Duvillier H, Lagneaux L, Devriendt D, Van Houtte P, Leclercq G. Interaction between estrogen receptor alpha, ionizing radiation and (anti-) estrogens in breast cancer cells. Breast Cancer Res Treat. 2005;93:207–15. .
    1. Azria D, Larbouret C, Cunat S, Ozsahin M, Gourgou S, Martineau P, Evans DB, Romieu G, Pujol P, Pelegrin A. Letrozole sensitizes breast cancer cells to ionizing radiation. Breast Cancer Res. 2005;7:R156–63.
    1. Osborne CK, Boldt DH, Clark GM, Trent JM. Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res. 1983;43:3583–5.
    1. Anscher MS, Murase T, Prescott DM, Marks LB, Reisenbichler H, Bentel GC, Spencer D, Sherouse G, Jirtle RL. Changes in plasma TGF beta levels during pulmonary radiotherapy as a predictor of the risk of developing radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1994;30:671–6.
    1. Colletta AA, Wakefield LM, Howell FV, van Roozendaal KE, Danielpour D, Ebbs SR, Sporn MB, Baum M. Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts. Br J Cancer. 1990;62:405–9.
    1. Bentzen SM, Skoczylas JZ, Overgaard M, Overgaard J. Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst. 1996;88:918–22.
    1. Bese NS, Umay C, Yildirim S, Ilvan S, Dirican A, Salar S, Altug T, Ober A. The effects of tamoxifen on radiation-induced pulmonary fibrosis in Wistar albino rats: results of an experimental study. Breast. 2006;15:456–60. .
    1. Kim D, Lee AS, Jung YJ, Yang KH, Lee S, Park SK, Kim W, Kang KP. Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor alpha-mediated transforming growth factor-beta1/Smad signaling pathway. Nephrol Dial Transplant. 2014;29:2043–53. .
    1. Carthy JM, Sundqvist A, Heldin A, van Dam H, Kletsas D, Heldin CH, Moustakas A. Tamoxifen Inhibits TGF-beta-Mediated Activation of Myofibroblasts by Blocking Non-Smad Signaling Through ERK1/2. J Cell Physiol. 2015;230:3084–92. .
    1. Azria D, Riou O, Castan F, Nguyen TD, Peignaux K, Lemanski C, Lagrange JL, Kirova Y, Lartigau E, Belkacemi Y, Bourgier C, Rivera S, Noel G, et al. Radiation-induced CD8 T-lymphocyte Apoptosis as a Predictor of Breast Fibrosis After Radiotherapy: Results of the Prospective Multicenter French Trial. EBioMedicine. 2015;2:1965–73. .
    1. Azria D, Gourgou S, Sozzi WJ, Zouhair A, Mirimanoff RO, Kramar A, Lemanski C, Dubois JB, Romieu G, Pelegrin A, Ozsahin M. Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients. Br J Cancer. 2004;91:1251–60.
    1. Cecchini MJ, Yu E, Potvin K, D’Souza D, Lock M. Concurrent or Sequential Hormonal and Radiation Therapy in Breast Cancer: A Literature Review. Cureus. 2015;7:e364. .
    1. Ahn PH, Vu HT, Lannin D, Obedian E, DiGiovanna MP, Burtness B, Haffty BG. Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates. J Clin Oncol. 2005;23:17–23.
    1. 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;23:11–6.
    1. Pierce LJ, Hutchins LF, Green SR, Lew DL, Gralow JR, Livingston RB, Osborne CK, Albain KS. Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer. J Clin Oncol. 2005;23:24–9.
    1. Valakh V, Trombetta MG, Werts ED, Labban G, Khalid MK, Kaminsky A, Parda D. Influence of concurrent anastrozole on acute and late side effects of whole breast radiotherapy. Am J Clin Oncol. 2011;34:245–8. .
    1. Ishitobi M, Shiba M, Nakayama T, Motomura K, Koyama H, Nishiyama K, Tamaki Y. Treatment sequence of aromatase inhibitors and radiotherapy and long-term outcomes of breast cancer patients. Anticancer Res. 2014;34:4311–4.
    1. Azria D, Belkacemi Y, Romieu G, Gourgou S, Gutowski M, Zaman K, Moscardo CL, Lemanski C, Coelho M, Rosenstein B, Fenoglietto P, Crompton NE, Ozsahin M. Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial. Lancet Oncol. 2010;11:258–65. .
    1. Bourgier C, Kerns S, Gourgou S, Lemanski C, Gutowski M, Fenoglietto P, Romieu G, Crompton N, Lacombe J, Pelegrin A, Ozsahin M, Rosenstein B, Azria D. Concurrent or sequential letrozole with adjuvant breast radiotherapy: final results of the CO-HO-RT phase II randomized trialdagger. Ann Oncol. 2016;27:474–80. .
    1. Yavas G, Yavas C, Acar H, Toy H, Yuce D, Ata O. Comparison of the effects of aromatase inhibitors and tamoxifen on radiation-induced lung toxicity: results of an experimental study. Support Care Cancer. 2013;21:811–7. .
    1. Tell R, Edgren MR, Sverrisdottir A, Castro J, Fornander T, Hansson LO, Skog S, Lewensohn R. Radiation-induced cell cycle response in lymphocytes is not related to clinical side-effects in breast cancer patients. Anticancer Res. 2003;23:3077–83.
    1. Ryu SH, Chung YH, Lee JK, Kim JA, Shin JW, Jang MK, Park NH, Lee HC, Lee YS, Suh DJ. Antifibrogenic effects of tamoxifen in a rat model of periportal hepatic fibrosis. Liver Int. 2009;29:308–14. .
    1. Ozsahin M, Crompton NE, Gourgou S, Kramar A, Li L, Shi Y, Sozzi WJ, Zouhair A, Mirimanoff RO, Azria D. CD4 and CD8 T-lymphocyte apoptosis can predict radiation-induced late toxicity: a prospective study in 399 patients. Clin Cancer Res. 2005;11:7426–33.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe