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Background and Purpose: Recent phase 3 clinical trials have evaluated the addition of bevacizumab (B) to standard chemotherapy in the treatment of patients with non-metastatic breast cancer. But few data are available about the tolerance of B with locoregional radiation therapy (RT). The objective was to evaluate the 5 years late toxicities of the concurrent B and RT in non-metastatic breast cancer. Material and methods: This is a multicenter prospective study including non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT (BEATRICE, BETH, BEVERLY 1, BERVERLY 2) versus RT alone. All patients received neo-adjuvant or adjuvant chemotherapy and normo-fractionated breast or chest wall RT, with or without regional lymph nodes RT. B was administrated as an equivalent of 5 mg/kg every week for 1 year. The safety profile (using the Common Terminology Criteria for Adverse Events version 3.0) was evaluated at 1, 3 and 5 years after the completion of radiotherapy. Results: From October 2007 to January 2012, 151 patients totally included. Median follow-up was 60 months (36-84) and 5 years late toxicities were available for 104 patients (46 with B and RT, 58 with RT alone). Median age was 51 (22-81). 61% of patients received regional lymph nodes RT. The majority of tumor was triple negative (65.6%), tumor size Conclusion: Concurrent B and locoregional RT provides acceptable 5-years toxicities in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed. Citation Format: Clément-Zhao A, Tanguy M-L, Cottu P, De La Lande B, Bontemps P, Lemanski C, Baumann P, Levy C, Peignaux K, Reynaud-Bougnoux A, Gobillion A, Kirova Y. TOxicities of Locoregional Radiotherapy Associated with Bevacizumab in patients with non-metastatic breast cancer (TOLERAB): Final long-term evaluation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-06.

Purpose/Objectives The purpose of this study was to determine early and late toxicities among patients with non-metastatic breast cancer (BC) receiving concurrent bevacizumab (BV) and radiation therapy (RT). Materials/Methods Multicentre, prospective study, of the toxicity of adjuvant concomitant association of BV and RT in patients with non-metastatic BC enrolled in Phase 3 BEATRICE, BEVERLY and BETH trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during RT, 12 months and 36 months after its completion. Results Sixty-four patients were included from october 2007 to august 2010. They all received adjuvant RT and BV concomitant treatment, plus neo-adjuvant BV for 24 patients. RT was adjuvant and normo-fractionated. Twelve months toxicity was available for 60 patients and 36 months toxicity was available for 43 patients. Median follow-up was 46 months (18-77). Median age was 51 years old (23-68). Among 63 evaluated patients during RT, acute radiation dermatitis was observed in 48 (76%) patients : Grade 1 for 27 (43%), grade 2 for 17 (27%), grade 3 for 4 patients (6%). Grade 2 acute oesophagitis was observed in 1 patient. At 3 years, few toxicities were observed : 6 patients (14%) had grade 1 pain, 4 (9%) had grade 1 fibrosis, one (2%) had grade 1 telangiectasis, one (2%) had grade 1 paresis, 3 (7%) had grade 1 lymphoedema and one grade 3 lymphoedema. No grade 4 toxicity was observed. At 12 months, only one evaluated patient had a LVEF Conclusions Concurrent bevacizumab with locoregional RT is associated with acceptable early and late 3-years toxicities in patients with BC. Determination of late toxicity at 60 months is currently underway. Citation Format: Dautruche A, Belin L, Cottu P, Bontemps P, Lemanski C, De La Lande B, Baumann P, Missohou F, Levy C, Peignaux K, Reynaud-Bougnoux A, Denis F, Gobillion A, Ady Vago N, Fourquet A, Kirova Y. Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-17.

Purpose/Objectives Few data are available regarding the safety of the concurrent combination of bevacizumab with adjuvant radiotherapy (RT) in breast cancer, especially in terms of late toxicity. The aim of this study was to determine early and late loco-regional toxicities among patients with non-metastatic breast cancer treated with this combination. Materials/Methods In our prospective and descriptive study, we analyzed loco-regional toxicities of adjuvant RT in patients with non-metastatic breast cancer receiving either concurrent bevacizumab or not in the randomized trial BEATRICE. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events (v3.0). Evaluation was done during RT and 12 months after the end of RT. All patients provided written informed consent before enrollment. Statistical analysis was performed to analyze toxicity between the two groups. Results From September 2007 to July 2009, we included 84 patients from the randomized trial BEATRICE which evaluate the efficacy and safety of the addition of bevacizumab to standard adjuvant therapy in patients with triple negative breast cancer; 39 women received an adjuvant RT with concurrent bevacizumab and 45 women received an adjuvant RT alone. Evaluation at 12 months was available for all the patients. All patients had a triple negative non-metastatic breast cancer and had an adjuvant chemotherapy then RT. Among patients receiving concurrent bevacizumab with RT, a total of 35 patients (90%) achieved a whole breast irradiation (median dose: 50 Gy) with a boost in the surgical bed (median dose: 16 Gy) and 4 patients (10%) had a post mastectomy RT (median dose 50 Gy); lymph node RT was performed in 19 patients (49%) with internal mammary chain RT in 12 patients (31%). Mean time of bevacizumab treatment was 11.7 months [2.1-12.6] and mean total dose of bevacizumab was 15000 mg [3330-28080]. Among patients receiving RT alone, 38 patients (84%) achieved a whole breast irradiation (median dose: 50 Gy) with a boost in the surgical bed (median dose: 16 Gy) and 7 patients (16%) had a post mastectomy RT (median dose 50 Gy); lymph node RT was performed in 21 patients (47%) with internal mammary chain RT in 14 patients (31%). Radiation treatment parameters were not significantly different between the two groups. Incidence of acute grade 3 dermatitis was 10% in patients receiving bevacizumab associated with RT and 6% in patients receiving RT alone without significant difference. One year after the end of RT, the most common late toxicities in the group receiving bevacizumab and RT were grade 1-2 pain (18%), grade 1-2 fibrosis (8%), grade 1-2 arm lymphedema (8%) and grade 1-2 telangiectasia (6%).There was no significant difference in pain, radiation fibrosis, telangiectasia, arm lymphedema and dyspnea between the two groups. No patient experienced grade 3-4 toxicity in the two groups. Conclusions Our results indicate that concurrent bevacizumab with loco-regional RT provide acceptable early and late toxicities after one year in patients with non-metastatic breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-11.

Background and purpose: Postoperative whole breast external radiotherapy remains the current standard of care for patients with early operable breast cancer. In the elderly, the low crude numbers of recurrence and the frequency of comorbidities urged teams to investigate the feasibility and the results of intraoperative radiotherapy (IORT) delivered in one fraction during the surgical procedure. Material and methods: 94 patients (> 65 years old) accepted to be included in this phase II trial according to clinical and histopathology criteria and signed the informed consent. Among them, 42 presented all the inclusion criteria, namely pT0-1 pN0, non lobular invasive unifocal carcinoma, margin ≥ 2 mm (assessed during the surgical procedure) and estrogen receptors positivity. All patients were operated upon in a dedicated IORT facility (linear accelerator) located centrally among six operated rooms. After tumor removal, the surgical bed was approximated by sutures to bring the tissue within the radiation target volume. The tumor beds were completely encompassed by 4 to 6 cm circular fields using flattened applicators at a 110 cm distance. One fraction of 21 Gy was prescribed and specified at the 90% isodose using electron with energies ranging from 6 to 10 MeV. In vivo dosimetry was performed for all patients using real-time in vivo semiconductor detectors (PTW) fixed by the surgeon within the surgical bed. A 5 year adjuvant hormonotherapy was prescribed according to the recommendations. Primary end-point was the quality index [QI] - ratio between the prescribed dose and the in vivo measured dose-. Secondary endpoints corresponded to quality of life, local recurrences, cosmetic results, specific and overall survival. Results: Median follow-up is now 54 months [range 12–62]. Median age was 72 years [66-80] and median tumor diameter was 10 mm [3-19 mm]. 36 tumors were grade 1 or 2 and 100 % of the tumors expresses estrogen receptors. All patients received the total prescribed dose. No external postoperative radiotherapy was delivered. Intraoperative dosimetry demonstrated a good accordance between the delivered and the prescribed doses for 97% of the 37 evaluable patients. No acute grade 2 or greater toxicities were observed. Scores for quality of life were collected for all patients and showed no modification between pre and posttreatment evaluations. Late cosmetic result was good to excellent. All patients are still alive and the 4 year-disease-free-survival is currently 97%. Two patients recurred: (i) one infracentimetric superficial recurrence in the border of the surgical bed and close to the skin (at 18 months) (ii) a second primary tumor in another quadrant (at 6 months). These two patients underwent salvage mastectomy and are free of disease at the time of analysis. Conclusion: For a very selected population, these results confirm that partial breast IORT with electrons may be considered as an interesting alternative to the standard 6-weeks radiotherapy, offering therefore a safe one-step procedure treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-13-12.

Background Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast (WB) in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. The phase III randomized trial “BONBIS” is elaborated to evaluate the impact of a 16-Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days. Methods: A total of 1950 patients DCIS breast cancer patients are planned to be enrolled in this trial. Patients will receive the following treatment: (A) WB radiotherapy of 50 Gy in 25 fractions vs. (B) WB radiotherapy of 50 Gy in 25 fractions plus a localized 16-Gy boost in 8 fractions. The primary endpoint is local-relapse free survival (LRFS). This trial is designed to detect an expected rate in control arm of 7% and 4 % in experimental arm. With 90% power and a=0.05, 137 events are necessary to achieve the main goal. An interim analysis is planned after 50% of observed event. Stratifications are made based on recognized prognostic factors: age, hormonal treatment, differentiation, circumstance of diagnosis, surgical margin, centre. Secondary endpoints are relapse free survival, overall survival, acute and late toxicities, cosmetic results, and quality of life. Translational researches are also planned to identify intrinsic radiosensitivity of normal tissues (radiation-induced apoptosis assay, genome-wide association study) but also predictive models of tumor recurrences. Inclusions have started in November 2008 and are not so far than the planned estimation. This trial is granted by the French National Cancer Institute (PHRC 2008) and supported by the French National Society of Radiation Oncology (SFRO). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-06-01.

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. >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.

Purpose: Letrozole (LET) has recently been shown to be superior to tamoxifen for postmenopausal patients (pts). In addition, LET radiosensitizes breast cancer cells in vitro. We conducted a phase II randomized study to evaluate concurrent and sequential radiotherapy (RT)-LET in the adjuvant setting. We present here clinical results with a minimum follow-up of 24 months.Patients and Methods: Postmenopausal pts with early-stage breast cancer were randomized after conservative surgery to either: A) concurrent RT-LET (LET started 3 weeks before the first day of RT) or B) sequential RT-LET (LET started 3 weeks after the end of RT). Whole breast RT was delivered to a total dose of 50 Gy. A 10-16 Gy boost was allowed according to age and pathological prognostic factors. Pts were stratified by center, adjuvant chemotherapy, boost, and radiation-induced CD8 apoptosis (RILA). RILA was performed before RT as previously published (Ozsahin et al. Clin Cancer Res, 2005). An independent monitoring committee reviewed individual safety data. Skin toxicities were evaluated by two different clinicians at each medical visit (CTCAE v3.0). Lung CT-scan and functional pulmonary tests were performed regularly. DNA samples were screened for SNPs in candidate genes as recently published (Azria et al., Clin Cancer Res, 2008).Results: A total of 150 pts were randomized between 01/05 and 02/07. Median follow-up is 26 months (range, 3-40 months). No statistical differences were identified between the two arms in terms of mean age; initial TNM; median surgical bed volume; post surgical breast volume. Chemotherapy and RT boost were delivered in 19% and 38% of pts, respectively. Nodes received 50 Gy in 23% of patients without differences between both arms. During RT and within the first 6 weeks after RT, 10 patients (6.7%) presented grade 3 acute skin dermatitis during RT but no differences were observed between both arms (4 and 6 patients in arm A and B, respectively). At 26 month of follow-up, grade 2 and more radiation-induced subcutaneous fibrosis (RISCF) was present in 4 patients (3%) without any difference between arm A (n = 2) and B (n = 2), p=0.93. In both arms, all patients that presented a RICSF had a RILA lower than 16%. Sensitivity and specificity were 100% and 39%, respectively.No acute lung toxicities were observed and quality of life was good to excellent for all patients.SNPs analyses are still on-going (Pr Rosenstein, NY).Conclusion: Acute and early late grade ≥ 2 dermatitis were similar in both arms. The only factor that influenced RISCF was a low radiation-induced lymphocyte apoptosis yield. We confirmed prospectively the capacity of RILA for identifying hypersensitive patients to radiation. Indeed, patients with RILA superior to 16% did not present late effects to radiation and confirmed the first prospective trial we published in 2005 (Ozsahin et al., Clin Cancer Res). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 956.

Background:The impact of postmastectomy radiotherapy (PMRT) on survival has been controversial for decade in intermediate-risk patients.We present here our monocentric long-term carcinologic and quality of life results in the subset of patients classified at intermediate risk and treated with PMRT.Material and Methods: From 1990 to 2000, 1622 patients received adjuvant radiotherapy after mastectomy. Among them, 421 were defined at intermediate risk of local recurrence i.e. (i) one to 3 positive nodes (ii) negative node but younger than 35 years old and/or pT3-T4 and/or grade 3 and/or invasive multifocality and/or lymphovascular invasion. PMRT consisted in a 50 Gy-electron therapy to the chest wall with node irradiation if indicated. Adjuvant chemotherapy and/or hormonotherapy were administered according to our local guideline. Patients were visited every 6 months for at least 10 years. Quality of life questionnaires (EORTC QLQC30/BR23) were filled in at the last medical visit.Results: Median age was 57 years (range, 27-80). One-hundred thirty five patients (32%) and 286 (68%) were premenopausal and menopausal, respectively. Seventy-five percent of the patients presented a ductal invasive carcinoma and 55% one to three positive axillary nodes. The median number of nodes was 13 (range, 3-27). 77% of the patients presented an axillary dissection with more than 10 nodes. 32% of the nodes were associated with capsular effraction. In the node negative subgroups, grade 3, lymphovascular invasion, multifocality, pT3-4, and age < 35 were found in 57%, 19%, 33%, and 4%, respectively. Extensive DCIS was found in 227 patients (54%). Hormonal receptors (ER and/or PR) were positive in 321 patients (76%) and therefore treated with postoperative tamoxifen for 5 years. Adjuvant chemotherapy was delivered in 126 patients and mainly included anthracyclin. HER2 status was not available at that time in our center. Chest wall RT was delivered in all patients to a median total dose of 50 Gy (range, 43-62). Sus-clavicular and internal mammary chain were irradiated in 294 and 346 patients, respectively. With a 10-y median follow-up, 12 (2.8%) and 74 (17.6%) patients presented locoregional and metastatic recurrences, respectively. Locoregional-free survival (LRFS) was 98.3% and 97.1% at 5 and 10 years, respectively. None of the 12 patients presented metastasis before local recurrence. Multifactorial analysis showed a significant impact of LRFS on metastatic-free survival (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4112.

Abstract #6153 Background Breast cancer (BC) is the most frequent second malignancy in women treated for Hodgkin's disease (HD), but there are few specific data on these tumors. This study assesses histopathological features, locoregional and systemic treatments as well as prognostic factors of these secondary BC. Material and methods: 127 women treated for HD in 9 centers subsequently developed 143 BC. Median age at HD diagnosis was 25 years. HD stages were I, II, III and IV in 28%, 49%, 16% and 7%. Radiotherapy (RT) alone was used in 44 cases and chemotherapy (CT) + RT in 83 cases. Twelve patients relapsed and had a new treatment by RT (3), CT (5) or both (4). Results: First BC occurred after 18-year median interval (20 years: 40%). TNM classification (126/143) showed 23 mammographically detected T0 (18%), 54 T1 (43%, 40 T2 (32%) and 9 T3T4 (7%). 129 tumors were infiltrating carcinoma (IC) and 14 (10%) DCIS. Twenty-four (17%) tumors were multifocal. Five patients had metastasis at diagnosis; 135 tumors were operated (121 IC and 14 DCIS): 57 (42%) by conservative surgery (40 with RT) and 78 (58%) by mastectomy (5 with RT). Axillary dissection (AD) and SNB were performed in 74% and 23% of the cases. Median tumor size for IC was 19 mm. Axillary nodal involvement (ANI) was found in 28% of IC (pN1-3 : 22%; pN>3 : 6%). ER and PgR were positive in 57% and 49%. 43 (39%) tumors were SBR III (high grade). Chemotherapy (CT) and hormonotherapy (HT) were performed in 47% and 42% of IC. With a 5-year median FU, 17 patients (12%) developed local recurrences (LR) and 35 (30%) had metastases. Significant metastasis predictive factors were ANI and SBR III; 12 (10%) women developed a third cancer. 5 and 10-year overall survival (OS) rates were 69% and 53%, and disease-specific survival (DSS) rates 72% and 62%. 5-year DSS rates were 79% for T0T1 versus 44% for pT2T3T4 (p=0.0068) and 81% for pN0 versus 65% for pN+ (p=0.0012). Conclusion Young women (especially 15-25 years) treated for HD should be carefully monitored by mammography, ultrasound and maybe MRI in order to detect early occurrence of BC. The prognosis of small lesions (pTis/pT1) is excellent and conservative treatment often feasible. This study is still ongoing, with 200 planned cases. Optimal adjuvant treatment options will be discussed and compared with a former series including 133 cases (Radiotherapy and Oncology, 2001, 59: 247-255). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6153.