Abstract Purpose: The aim of current analyses is to report toxicity and cosmetic outcomes at 3 and up to 9 years of follow-up of post-menopausal patients randomized to receive either standard external beam whole breast radiotherapy (WBI), including hypofractionated options, versus accelerated partial breast irradiation (APBI). Methods and materials: From December 2010 to July 2015, 1006 patients were enrolled in 34 French centers (503 in each arm). Among the whole population, 28 patients who did not meet the final selection criteria or withdrew consent were excluded leading to a modified intention to treat analysis dataset of 978 patients (WBI: n=488; APBI: n=490). Median age (65y) and tumor stage pT1 (99%) rates were similar in both arms. Patients had conservative surgery with clip placement in the tumor bed. Clear margins (> 2mm) were observed in 99% of the patients. In both arms, 96-97% of the patients had negative sentinel lymph node biopsy (SLNB; median number: 4 in WBI arm and 5 in APBI), luminal BC. Ductal histology was observed 82%. Only 2% and 1% of patients had grade III and pN(i+) disease. The median time interval between surgery and radiotherapy was 57d in WBI vs 62d in APBI. WBI schedules consisted of: 50Gy in 25fr + 16Gy boost (n=212) or 40Gy in 15fr (n=156) or 42.5Gy in 16fr (n=120), while APBI arm consisted of 38.5Gy or 40Gy in 10fr. Overall, 94 patients from the APBI arm finally received standard WBI. For statistical considerations, SHARE trial, sponsored by UNICANCER (NCT01247233) is a non-inferiority randomized controlled trial comparing APBI versus WBI in terms of local control as primary objective. Secondary endpoints were severe toxicity (NCI-CTCAE v4 grade ≥ 2), and cosmetic results, evaluated by doctors and by patients, over the entire follow-up. For both outcomes, we estimated the cumulative incidences (CI) using Kalbfleish and Prentice method, considering disease relapse, secondary cancer or death as competing events. Treatment effect (APBI vs WBI) was estimated by cause-specific Hazard Ratios (cs-HR) from Cox models adjusted on stratification factors. Results: Median follow-up was 5.8y (range, 0.13-9.5). The number of deaths was 27, and the number of local relapses was 8. Among the 978 patients, 582 and 396 had finally WBI and APBI, respectively. The rates of post-operative hematoma, edema and infection were low: 8-9%, 2%, 3-2%, respectively. When considering any type of severe toxicity, we observed a significant reduction rate in APBI compared to WBI: cs-HR=0.73 (95% confidence interval: 0.61-0.88); p=0.001, and 3-year cumulative incidence (CI) of severe toxicity at 45% (41-49) in WBI vs 36% (32-40) in APBI arm. The difference was also in favor of APBI when considering breast skin toxicity alone: cs-HR=0.55 (0.44-0.70), p< 0.001 and 3-year CI at 36% (32-40) in WBI vs 21% (18-25) in APBI arm. Conversely, for breast other toxicities, WBI was found less toxic than APBI: cs-HR= 2.10 (1.51-2.91), p< 0.001, and 3-year CI at 8% (5-10) vs 15% (12-19), respectively. When considering cosmetic results according to the investigator, we observed no significant difference between the two arms: cs-HR=1.04 (0.81-1.33), p=0.26 and 3-year probability of remaining with good to excellent cosmetic results at 77% (73-81) in WBI arm and 78% (74-81) in APBI arm. Findings were similar when considering results according to the patient: cs-HR=1.07 (0.85-1.37), p=0.23, and 3-year probability at 74% (70-78) and 75% (70-79), respectively. Conclusions Historically SHARE is the first APBI trial that included hypofractionated schedules in the standard arm. We reported increased risk of severe toxicity and skin breast toxicity in standard arm as compared with APBI arm without any difference in terms of cosmetic results. Longer follow-up is needed. Citation Format: Yazid Belkacemi, Isabelle Gabelle-Flandin, Marie-Cécile Le Deley, Adeline Petit, Philippe Guilbert, Julien Geffrelot, Christian Carrie, Eleonor Rivin Del Campo, Chantal Hanzen, Claire Charra-Brunaud, Isabelle Lecouillard, Nicolas Magne, Agnès Tallet, Nicolas Leduc, Blaha Belgadi, Philippe Fourneret, Alexandre Coutte, Esther Capelo, Franck Darloy, Muriel Garcia Ramirez, Philippe Dudouet, Pierre Clavere, Jean-Philippe Suchaud, Guillaume Auzac, Thomas Lacornerie, Jérôme Lemonnier, Céline Bourgier, Eric Lartigau. Early results of the French multicenter, randomized SHARE trial comparing whole breast irradiation versus accelerated partial breast irradiation in postmenopausal women with early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-05.