Radiation-induced CD8 T-lymphocyte Apoptosis as a Predictor of Breast Fibrosis After Radiotherapy: Results of the Prospective Multicenter French Trial

Abstract

BackgroundMonocentric 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.MethodsA 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.FindingsFour 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).InterpretationRILA 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.FundingThe French National Cancer Institute (INCa) through the “Program Hospitalier de Recherche Clinique (PHRC)”.

Progressive breast fibrosis caused by extreme radiosensitivity: Oncocytogenetic diagnosis and treatment by reconstructive flap surgery

“…It is widely accepted that in most cases no single gene is responsible for radiosensitivity; therefore, research is focused on gene expression and single polymorphism patterns, but both are highly expensive. On the other hand, “Radiation‐induced CD8 T‐lymphocyte Apoptosis” method has negative predictive value and marks patient population with no radiation toxicity risk . The method uses lymphocytes as normal tissue surrogate and has been tested in large clinical cohort and at various tumour sites.…”

“…In a multicentre study including 502 breast cancer patients, 86.4% showed late side effects 3 years after radiotherapy, of which 47.8% of patients were grade 1, 13.4% grade 2, and 0.6% grade 3+ fibrosis . Others published 6%, 12.6%, and even 23% of ≥grade 2 fibrosis.…”

Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016.

“…Based on methods first developed by Crompton et al . (127), prospective studies have demonstrated a correlation between a decrease in radiation-induced apoptosis after an 8 Gy exposure in vitro and an increase in RIF (128, 129). This method has the advantage of being simple, rapid, reproducible and minimally invasive.…”

Radiogenomics and radiotherapy response modeling

“…Using this approach, it has been reported that the response of CD4 and CD8 T-lymphocytes to irradiation correlates with radiation-induced late effects following radiotherapy (Mirjolet et al , 2016; Azria et al , 2015). Most notably, an inverse correlation has been reported between radiation-induced T-lymphocyte apoptosis, particularly for CD8 cells, with the development of late effects in patients from whom the lymphocytes were derived.…”