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Background: Breast conserving surgery (BCS) is typically followed by adjuvant radiotherapy (RT) based on several landmark trials demonstrating improvements in disease control and survival. Since completion of these historical trials, the advent of molecular subtyping has revealed that breast cancer is not a single disease entity, but rather a class of cancers with differential risk profiles. We evaluated whether RT could be safely omitted following BCS for patients with the most favorable subtype as defined by the Prosigna PAM50 assay. Methods: We conducted a multicenter prospective single-arm cohort study with IRB approval and an FDA investigational device exemption (IDE). Eligible patients were women 50 to 75 years of age (inclusive) who had undergone BCS revealing tumors ≤2cm in size, that were estrogen or progesterone receptor positive (HR+), HER2 negative, grade 1-2, node negative (N0), with negative excision margins (no ink on tumor). Intent to take endocrine therapy was required. Upon registration, tumors were submitted for central Prosigna testing and those with Risk of Recurrence (ROR) score ≤40 were deemed eligible for the investigational omission of RT. The primary endpoint was the 5-year locoregional recurrence rate (LRR). Anticipating a total of 345 RT-omitting patients to enroll over 3.5 years, the study was designed with 90% power to exclude a 5-year LRR of 5% using a one-sample exponential test with one-sided type I error of 0.025. Results: From 2016 to 2020, 671 patients were registered from 13 centers, inclusive of affiliated regional network sites. Of these, 382 patients had a ROR Score ≤40 and opted to forego RT, comprising the main intention-to-treat (ITT) study population. Median age was 65 years (range 50 to 75), and median tumor size was 0.9 cm (range 0.1 to 2.0 cm). At a median follow-up of 26.9 months, 12 events were observed: 4 patients had ipsilateral in-breast recurrences, 7 had contralateral breast cancers, and 1 developed an unrelated melanoma. There were no regional-nodal or distant recurrences. The 2-year cumulative rate of LRR was 0.3% (95% CI: 0 – 1.0%). Of the 4 ipsilateral breast recurrences, 2 were in the same quadrant as the original primary tumor. Conclusion: In this preliminary report of the PRECISION trial, patients 50-75 years of age undergoing BCS and endocrine therapy for pT1N0 HR+ HER2-negative breast cancer with ROR score ≤40 had exceedingly low rates of LRR in the absence of adjuvant RT at a median follow-up of 26.9 months. Additional follow-up is required to determine whether these favorable results are durable. Citation Format: Lior Z. Braunstein, Julia Wong, Deborah A. Dillon, Yu-Hui Chen, Paul Catalano, Oren Cahlon, Mahmoud B. El-Tamer, Rachel Jimenez, Atif Khan, Carmen Perez, Rinaa Punglia, Ron Shiloh, Laura Warren, David Wazer, Jean Wright, Elizabeth Buckley, Tari King, Simon Powell, Eric Winer, Jennifer Bellon. Preliminary report of the PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk 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 OT1-12-02.

Background: Radiation therapy (RT) following breast conserving surgery (BCS) is known to improve locoregional and distant control in women with invasive breast cancer; however, RT does pose significant cost and potential risk, including concern for cardiopulmonary toxicity and secondary malignancy. Randomized trials show that the omission of RT among older women with otherwise favorable-risk breast cancer does not affect overall survival (OS) at 10 years, and modestly increases the risk of local recurrence (LR). Nevertheless, there is little prospective support for RT omission in younger women. Moreover, risk stratification in the randomized prospective studies to date relies on limited methods with potentially low fidelity at distinguishing luminal subtypes. Enhanced molecular profiling techniques could better discern tumor biology and, in turn, more precisely assess risk. PAM-50 is an expression profile of 50 genes used to classify breast cancer intrinsic subtype with consequent prognostic implications. The goal of this study is to identify low-risk breast cancer patients with luminal A subtype who may feasibly omit RT from their therapeutic regimen. Methods: This is a phase II prospective cohort study (NCT02653755) designed to assess the safety of treatment de-escalation (omission of RT) in women with favorable-risk invasive breast cancer following BCS. Eligibility criteria include female patients with invasive breast cancer, age 50-75, with tumors less than or equal to 2cm, negative surgical margins, ER+ or PR+ and HER2- disease, grade 1 or 2, no lymph node involvement, and no plans for chemotherapy or biologic therapy, who are eligible for and willing to receive endocrine therapy. Tumor samples from eligible patients will undergo PAM-50 transcriptional profiling using the Nanostring Prosigna assay. A low Risk of Recurrence (ROR) score, corresponding to the luminal A subtype, will permit patients to forego radiotherapy should they so choose. The primary endpoint is 5-year risk of local or regional recurrence of invasive or in situ breast carcinoma within the ipsilateral breast or regional lymph nodes. Study enrollment began in May 2016. Citation Format: Mira A. Patel, Deborah A. Dillon, Giulia Digiovanni, Yu-Hui Chen, Paul Catalano, Carmen Perez, David Wazer, Jean Wright, Rachel Jimenez, Eric Winer, Julia Wong, Jennifer Bellon, Lior Z. Braunstein. PRECISION (Profiling early breast cancer for radiotherapy omission): A phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT271.