The 10-year outcomes of the PRIME II study provide robust evidence indicating that radiotherapy can be safely omitted in women 65 years of age or older who have grade 1 or 2, hormone receptor (HR)-positive early breast cancer treated by breast-conserving surgery, provided that they receive 5 years of adjuvant endocrine therapy. Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival (OS). The findings are published by Prof. Ian H. Kunkler of the Institute of Genetics and Cancer, University of Edinburgh in Edinburgh, UK and colleagues on 16 February 2023 in The New England Journal of Medicine.
The authors wrote in the background that a prevalence of breast cancer is rising among older adults. Underrepresentation of older patients with breast cancer in clinical studies has led to under- and overtreatment. A meta-analysis performed by the Early Breast Cancer Trialists’ Cooperative Group showed that radiotherapy after breast-conserving surgery confers only a modest survival benefit, although it reduces the overall cumulative incidence of recurrence among patients with lymph node-negative disease. Omission of radiotherapy after breast-conserving surgery in low-risk, older patients with smaller HR–positive tumours remains controversial, with only limited long-term level 1 evidence available to guide treatment decisions.
The 5-year results of the PRIME II study showed that among women 65 years of age or older who had HR-positive T1 or T2 primary tumours (≤3 cm in the largest dimension) and no lymph-node involvement and who were treated with breast-conserving surgery and adjuvant endocrine therapy, radiotherapy was associated with a lower percentage of patients having local breast cancer recurrence (4.1% without radiotherapy vs. 1.3% with radiotherapy). Despite guidelines supporting the omission of radiotherapy in women 70 years of age or older with T1 or small selected T2 oestrogen-receptor (ER)–positive tumours treated with breast-conserving surgery and adjuvant endocrine therapy, the use of radiotherapy in the United States (US) in this clinical context remains common.
The PRIME II is a phase III randomised study of the omission of radiotherapy; the study population was treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast radiotherapy (40 to 50 Gy) or no radiotherapy. The primary endpoint was local breast cancer recurrence. Regional recurrence, breast cancer–specific survival, distant recurrence as the first event, and OS were also assessed.
A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast radiotherapy and 668 without radiotherapy. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI] 6.8 to 12.3) in the group without radiotherapy and 0.9% (95% CI 0.1 to 1.7) in the radiotherapy group (hazard ratio 10.4; 95% CI 4.1 to 26.1; p < 0.001).
Although local recurrence was more common in the group without radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the group without radiotherapy than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. OS at 10 years was almost identical in the two groups, at 80.8% (95% CI 77.2 to 84.3) without radiotherapy and 80.7% (95% CI 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer–specific survival also did not differ substantially between the two groups.
The low cumulative incidence of local recurrence at 10 years after breast-conserving surgery and radiotherapy is consistent with the results of the earlier CALGB 9343 study, which involved patients 70 years of age or older who had T1, node-negative, HR-positive tumours treated with breast-conserving surgery and tamoxifen. The PRIME II observations in a higher-risk population show a similar between-group difference in the incidence of local recurrence.
The 9.5% cumulative incidence of local recurrence at 10 years among the patients who did not receive radiotherapy in PRIME II lies within range from the EUSOMA guidelines, which cited a maximum rate of locoregional recurrence of 10% at 10 years. EUSOMA guidelines recommend that patients older than 70 years of age receiving adjuvant endocrine therapy for low-risk tumours may be treated without radiotherapy, similar to the recommendations of the NICE and the NCCN guidelines, which allow omission of radiotherapy in women 65 years of age or older or 70 years of age or older with stage I, ER-positive breast cancer after breast-conserving surgery.
In an accompanied editorial article, Drs. Alice Y. Ho of the Duke University School of Medicine in Durham, NC, US and Jennifer R. Bellon of the Dana–Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School in Boston, MA, US wrote that PRIME II data offer a response to the long-standing problem of overtreatment in older women with low-risk breast cancer. The ability to omit radiotherapy is one of many options in a lengthy list that also includes the use of abbreviated radiotherapy regimens and smaller target volumes. Omitting radiotherapy can allow the patients to avoid side effects such as breast pain, dermatitis, and the risk of heart and lung complications. Pragmatically, radiotherapy can strain time and finances. Therefore, robust data solidifying the option to omit radiotherapy in selected patients are welcome.
The results do not undermine the value of radiotherapy in enhancing local control, which is a compelling endpoint, particularly now that radiotherapy can be delivered in less burdensome ways. Individualising the treatment so that it is concordant with the patient’s goals and values is critical. According to the editorialists, taken together, these data will help patients navigate these complex choices, so that they can make well-informed decisions.
The study was funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh.
- Kunkler IH, Williams LJ, Jack WJL, et al. Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer. N Engl J Med 2023;388:585-594.
- Ho AY, Bellon JR. Overcoming Resistance — Omission of Radiotherapy for Low-Risk Breast Cancer. N Engl J Med 2023;388:652-653.