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Background: Breast-conserving surgery (BCS) followed by postoperative radiation therapy (RT) to the residual breast represents the current standard of care for most women affected by early breast cancer. However, standard postoperative regimens are characterized by postsurgical waiting time and potential acute and late locoregional adverse events. Several studies suggested that breast cancer cells can be more sensitive to high doses administered in short intervals. Preoperative robotic stereotactic radiotherapy (SBRT) followed by BCS may yield potential advantages in selected patients. An exploratory phase II study (ROCK trial – NCT03520894) was conducted in our institution. Materials: Women with histologically proven unifocal invasive hormonal receptors positive, HER2 negative breast cancer, sized less than 25 mm, with negative clinical nodal status, aged 50+ and eligible for BCS were enrolled. Fiducial markers were introduced in peri/ intralesional position. Magnetic resonance imaging (MRI) was used in addition to standard CT-based planning. Patients received 21 Gy in single fraction with CyberKnife® followed by BCS two weeks after preoperative SBRT. The primary endpoint was the acute skin toxic effect rate. Secondary objectives were the pathological response rate and the late adverse events rate. Echocardiography and spirometry were performed before preoperative SBRT and yearly thereafter. Translational research was conducted to identify correlations between radiogenomic, immunological and biochemical biomarkers with treatment-related response and toxicity. Results: From August 2018 to September 2021, a total of 70 patients were screened on mammography; 29 of them were eligible following inclusion criteria. Seven were excluded due to multiple foci disease at basal MRI, and 22 patients were successfully treated. All required dosimetric parameters and normal tissue constraints were met in all cases. Median age at diagnosis was 68 years (range 50-86) and median tumor size was 13 mm (range 7.5-25). All treated patients received surgery within 14 days from preoperative SBRT without any delay or complication. No patients experienced acute skin toxicity of grade (G) 2 or higher; only one patient had a G1 erythema one month after BCS. Two patients reported a pathological complete response, according to Chevallier’s classification. At a median follow up of 18 months, no patients experienced locoregional recurrence or distant metastases. No clinically meaningful changes were observed regarding left-ventricular ejection fraction and spirometric parameters. Conclusion: Results from the ROCK trial showed that single fraction preoperative robotic SBRT is a feasible technique in selected breast cancer patients with a good safety profile and encouraging activity. This new approach warrants further investigations. [ABSTRACT FROM AUTHOR]

• CDK4/6 inhibitors represent the standard-of-care for metastatic HR+/HER2 breast cancer. • Available data on CDK4/6 inhibitors and concomitant RT are conflicting. • We showed that concurrent RT did not increase treatments severe toxicity. • A consensus guideline to help physician's routine practice is strongly needed. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3–78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction. [ABSTRACT FROM AUTHOR]