Abstract P6-06-22: Outcome of patients with intrinsic hypersensitivity to ionizing radiation and included in the COHORT phase II randomized trial evaluating concurrent or sequential letrozole with adjuvant breast radiotherapy
Authors: Azria D , Lemanski C , Gourgou-Bourgade S , Romieu G , Gutowski M , Jacot W , Fenoglietto P , Ozsahin M , Bourgier C 
Published: August 2014

Abstract
Purpose/objectives : At a short median follow-up of 26 months, we showed that letrozole could be safely delivered concomitantly with adjuvant radiotherapy after breast-conserving surgery for early breast cancer (Azria et al., Lancet Oncol, 2010). We present here the final clinical results according to the radiation-induced lymphocyte apoptosis (RILA) assay identifying hypersensitive patients to ionizing radiation.
Materials/methods : The present study is registered with ClinicalTrials.gov, number NCT0020208273. One hundred fifty patients postmenopausal women with early-stage breast cancer were randomly assigned to either concurrent radiotherapy-letrozole (RL, n = 75, arm A) or sequential RL (n = 75, arm B). Randomization was open label with a minimization technique, stratified by investigational centers (Montpellier, Lille, Lausanne), chemotherapy (yes vs. no), radiation boost (yes vs. no) and value of RILA (≤16% vs. &gt;16%).
Letrozole was administered at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-irradiation in arm A, and 3 weeks post-radiotherapy in arm B).
The primary endpoint was the occurrence of acute and late radiation-induced grade 2 or worse toxic effects of skin and lung (functional pulmonary test and lung CT-scan). Analyses were by intention to treat. The long term follow-up after 2 years was only performed in Montpellier for 121 patients (80.6% of the patients) by evaluation of skin toxicity (clinical examination every 6 months), lung fibrosis (CT-scan yearly), and cosmetic and quality of life outcomes.
Results : All patients were analyzed apart from one in the concurrent group who withdrew consent before any treatment. With a median follow-up of 74 months (range, 48-85), five patients (one and four in arms A and B, respectively presented a grade ≥2 radiation-induced subcutaneous fibrosis (RISF). Four events appeared within the first two years and one patient presented a late breast fibrosis five years after adjuvant radiotherapy. Globally, median RILA value was 12.9% (1.5-42). All the 5 patients (100%) had a RILA value ≤16% irrespective of the sequence with letrozole. Median RILA value was significantly lower (6.9%) in these patients compared to patients with grade ≤1 RISF (13%, p = 0.019). The other factors that strongly influenced RISF were younger age (52 vs. 62), the presence of boost, the large breast volume, and the dose received by the lung within the field. No grade ≥2 lung toxicity was observed by CT-scan and no modification from baseline was noted by the lung diffusion capacity test. Grade 1 lung fibrosis (n = 43) was more frequent in smokers and in patients receiving higher dose within the breast. Cosmetic results (photographies) and quality of life were considered good to excellent and will be presented in details at the congress. Three recurrences or new cancers were observed but all patients are still alive.
Conclusions : Letrozole can safely be delivered concomitantly with adjuvant breast radiotherapy. Late subcutaneous fibrosis is a rare event but strongly influenced by intrinsic radiosensitivity evaluated by RILA. Grade 2 lung fibrosis is no longer described after breast radiotherapy with modern technique.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-22.