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

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

SUBMITTER: Bourgier C

PROVIDER: S-EPMC5884662 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Bourgier Céline C Castan Florence F Riou Olivier O Nguyen Tan-Dat TD Peignaux Karine K Lemanski Claire C Lagrange Jean-Léon JL Kirova Youlia Y Lartigau Eric E Belkacemi Yazid Y Rivera Sofia S Noël Georges G Clippe Sébastien S Mornex Françoise F Hennequin Christophe C Gourgou Sophie S Brengues Muriel M Fenoglietto Pascal P Ozsahin Esat Mahmut EM Azria David D

Oncotarget 20180302 21

<h4>Background</h4>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).<h4>Results</h4>HT<sup>-</sup> and RILA<sup>high</sup> were the two independent factors associated with improved breast-fibrosis free survival (BFFS). BFFS rate at 36 months was lower in patients with RILA<sup>low</sup> and HT<sup>+</sup> than in patients with RILA<sup>high</s ...[more]

PMID: 29644007

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Project description:Monocentric cohorts suggested that radiation-induced CD8 T-lymphocyte apoptosis (RILA) can predict late toxicity after curative intent radiotherapy (RT). We assessed the role of RILA as a predictor of breast fibrosis (bf +) after adjuvant breast RT in a prospective multicenter trial.A total of 502 breast-cancer patients (pts) treated by conservative surgery and adjuvant RT were recruited at ten centers. RILA was assessed before RT by flow cytometry. Impact of RILA on bf + (primary endpoint) or relapse was assessed using a competing risk method. Receiver-operator characteristic (ROC) curve analyses were also performed in intention to treat. This study is registered with ClinicalTrials.gov, number NCT00893035 and final analyses are presented here.Four hundred and fifty-six pts (90.8%) were included in the final analysis. One hundred and eight pts (23.7%) received whole breast and node irradiation. A boost dose of 10-16 Gy was delivered in 449 pts (98.5%). Adjuvant hormonotherapy was administered to 349 pts (76.5%). With a median follow-up of 38.6 months, grade ? 2 bf + was observed in 64 pts (14%). A decreased incidence of grade ? 2 bf + was observed for increasing values of RILA (p = 0.012). No grade 3 bf + was observed for patients with RILA ? 12%. The area under the ROC curve was 0.62. For cut-off values of RILA ? 20% and < 12%, sensitivity and specificity were 80% and 34%, 56% and 67%, respectively. Negative predictive value for grade ? 2 bf + was equal to 91% for RILA ? 20% and positive predictive value was equal to 22% for RILA < 12% where the overall prevalence of grade ? 2 bf + was estimated at 14%. A significant decrease in the risk of grade ? 2 bf + was found if patients had no adjuvant hormonotherapy (sHR = 0.31, p = 0.007) and presented a RILA ? 12% (sHR = 0.45, p = 0.002).RILA significantly predicts the risk of breast fibrosis. This study validates the use of RILA as a rapid screening test before RT delivery and will change definitely our daily clinical practice in radiation oncology.The French National Cancer Institute (INCa) through the "Program Hospitalier de Recherche Clinique (PHRC)".

Project description:Follistatin is a potent regulator of the inflammatory response and binds to and inhibits activin A action. Activin A is a member of the TGF? protein superfamily which has regulatory roles in the inflammatory response and in the fibrotic process. Fibrosis can occur following cell injury and cell death induced by agents such as ionizing radiation (IR). IR is used to treat cancer and marked fibrotic response is a normal tissue (non-tumour) consequence in a fraction of patients under the current dose regimes. The discovery and development of a therapeutic to abate fibrosis in these radiosensitive patients would be a major advance for cancer radiotherapy. Likewise, prediction of which patients are susceptible to fibrosis would enable individualization of treatment and provide an opportunity for pre-emptive fibrosis control and better tumour treatment outcomes. The levels of activin A and follistatin were measured in fibroblasts derived from patients who developed severe radiation-induced fibrosis following radiotherapy and compared to fibroblasts from patients who did not. Both follistatin and activin A gene expression levels were increased following IR and the follistatin gene expression level was lower in the fibroblasts from fibrosis patients compared to controls at both basal levels and after IR. The major follistatin transcript variants were found to have a similar response to IR and both were reduced in fibrosis patients. Levels of follistatin and activin A secreted in the fibroblast culture medium also increased in response to IR and the relative follistatin protein levels were significantly lower in the samples derived from fibrosis patients. The decrease in the follistatin levels can lead to an increased bioactivity of activin A and hence may provide a useful measurement to identify patients at risk of a severe fibrotic response to IR. Additionally, follistatin, by its ability to neutralise the actions of activin A may be of value as an anti-fibrotic for radiation induced fibrosis.

Project description:PurposeVariability exists in the adjuvant treatment for endometrial cancer (EC) based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multigene expression index that estimates tumor radiosensitivity. We evaluate RSI as a genomic predictor for pelvic failure (PF) in EC patients treated with adjuvant radiation therapy (RT).Methods and materialsUsing our institutional tissue biorepository, we identified EC patients treated between January 1999 and April 2011 with primarily endometrioid histology (n = 176; 86%) who received various adjuvant therapies. The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined using the previously identified cutpoint where RSI ≥ 0.375 denotes radioresistance (RR) and RSI < 0.375 describes radiosensitivity.ResultsA total of 204 patients were identified, of which 83 (41%) were treated with adjuvant RT. Median follow-up was 38.5 months. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n = 181; 88%). In patients treated with radiation, RR tumors were more likely to experience PF (3-year pelvic control 84% vs 100%; P = .02) with worse PF-free survival (PFFS) (3-year PFFS 65% vs 89%; P = .04). Furthermore, in the patients who did not receive RT, there was no difference in PF (P = .87) or PFFS (P = .57) between the RR/radiosensitive tumors. On multivariable analysis, factors that continued to predict for PF included the RR phenotype (hazard ratio [HR], 12.2; P = .003), lymph node involvement (HR, 4.4; P = .02), and serosal or adnexal involvement (HR, 5.3; P = .01).ConclusionsOn multivariable analysis, RSI was found to be a significant predictor of PF in patients treated with adjuvant RT. We propose using RSI to predict which patients are at higher risk for failing in the pelvis and may be candidates for treatment escalation in the adjuvant setting.

Project description:IntroductionThe organization of health care for breast cancer (BC) constitutes a public health challenge to ensure quality of care, while also controlling expenditure. Few studies have assessed the global care pathway of early BC patients, including a description of direct medical costs and their determinants. The aims of this multicenter prospective study were to describe care pathways of BC patients in a geographic territory and to calculate the global direct costs of early stage BC during the first year following diagnosis.MethodsOPTISOINS01 was a multicenter, prospective, observational study including early BC patients from diagnosis to one-year follow-up. Direct medical costs (in-hospital and out-of-hospital costs, supportive care costs) and direct non-medical costs (transportation and sick leave costs) were calculated by using a cost-of-illness analysis based on a bottom-up approach. Resources consumed were recorded in situ for each patient, using a prospective direct observation method.ResultsData from 604 patients were analyzed. Median direct medical costs of 1 year of management after diagnosis in operable BC patients were €12,250. Factors independently associated with higher direct medical costs were: diagnosis on the basis of clinical signs, invasive cancer, lymph node involvement and conventional hospitalization for surgery. Median sick leave costs were €8,841 per patient and per year. Chemotherapy was an independent determinant of sick leave costs (€3,687/patient/year without chemotherapy versus €10,706 with chemotherapy). Forty percent (n = 242) of patients declared additional personal expenditure of €614/patient/year. No drivers of these costs were identified.ConclusionInitial stage of disease and the treatments administered were the main drivers of direct medical costs. Direct non-medical costs essentially consisted of sick leave costs, accounting for one-half of direct medical costs for working patients. Out-of-pocket expenditure had a limited impact on the household.

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

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

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