In the phase III PRIME II trial, designed to assess whether whole-breast irradiation could be omitted in women aged ≥ 65 years with early-stage breast cancer undergoing breast-conserving surgery and receiving adjuvant endocrine treatment, Ian H. Kunkler, MB BChir, FRCR, of Western General Hospital, Edinburgh, and colleagues found an increased risk of ipsilateral recurrence in women not receiving radiotherapy.¹ No significant differences between radiotherapy and no-radiotherapy groups were observed for regional recurrence, distant metastases, contralateral breast cancers, new breast cancers, or overall survival. The study is reported in The Lancet Oncology.

Study Details

In the trial, 1,326 women from 76 centers in the United Kingdom, Greece, Australia, and Serbia were randomly assigned between April 2003 and December 2009 to receive radiotherapy at 40 to 50 Gy in 15 to 25 fractions (n = 658) or no radiotherapy (n = 668). Patients were considered to be at low risk of recurrence on the basis of hormone receptor–positive and axillary node–negative disease, T1 to T2 disease ≤ 3 cm at the longest dimension, and clear margins. Patients could have grade 3 tumor histology or lymphovascular invasion, but not both. The primary endpoint was ipsilateral breast tumor recurrence. Follow-up in the trial continues.

The no-radiotherapy and radiotherapy groups were generally balanced for age (median, 70 and 69 years), margins (1–5 mm in 47% and 45%, > 5 mm in 34% and 36%), tumor grade (1 in 41% and 44%, 2 in 55% and 53%, 3 in 3% and 2%), tumor side (left breast for 54% and 52%), lymphovascular invasion (5% and 4%), axillary surgery (sentinel node biopsy only in 33% and 30%, sample only in 26% and 32%, both in 16% in both), preoperative endocrine treatment (9% and 8%), and estrogen receptor (ER) status (rich in 89% and 91%).

Risk of Ipsilateral Recurrence

After a median follow-up of 5 years, ipsilateral breast tumor recurrence was observed in 4.1% of patients in the no-radiotherapy group vs 1.3% in the radiotherapy group (hazard ratio [HR] = 5.19, P = .0007). On multivariate analysis including pathologic tumor size, margin status, tumor grade, age, presence of lymphovascular invasion, ER status, and use of radiotherapy, omission of radiotherapy was the only significant predictor of local recurrence (HR = 4.87, P = .0013); ER-poor status and grade 3 tumors were of borderline significance (both P = .06).

The absolute risk reduction in ipsilateral recurrence at 5 years with radiotherapy was 2.9% (95% confidence interval [CI] = 1.1%–4.8%). The number needed to treat to prevent a case of recurrence was calculated at 31.8 (95% CI = 27.4–55.0), yielding an adjusted absolute risk reduction of 3.1% (95% CI = 1.8%–3.6%).

Local recurrence occurred in 26 patients in the no-radiotherapy group, with 18 having local recurrence only, 6 both local and regional recurrences, and 2 local recurrence with distant spread. Of five women in the radiotherapy group with local recurrence, four had local recurrence only and one had local and regional recurrence. Among 23 patients in the no-radiotherapy group and 4 in the radiotherapy group with local recurrence who had such data available, mastectomy was performed in 12 vs 2 and wide local excision was performed in 11 vs 2.

In an unplanned subgroup analysis by ER score, local recurrence was observed in 20 (3%) of 593 patients in the no-radiotherapy group vs 5 (< 1%) of 601 in the radiotherapy group with ER-rich status, with 5-year ipsilateral recurrence of 3.3% vs 1.1% (P = .002). In women with ER-poor status, local recurrence was observed in 6 (9%) of 65 women in the no-radiotherapy group vs 0 of 55 in the radiotherapy group, with 5-year ipsilateral recurrence of 10.3% vs 0% (P = .026).

Additional Recurrences, Survival

For the no-radiotherapy vs radiotherapy groups, respectively, regional recurrence was observed in 1.5% vs 0.5%; distant recurrence, in 1.0% vs 0.5%; contralateral breast cancer, in 0.7% vs 1.5%; and new nonbreast cancer, in 4.3% vs 3.7%.

Five-year overall survival was 93.9% in both groups (P = .34) and 5-year breast cancer-free survival was 94.5% vs 97.6%. Among 49 patients in the no-radiotherapy group and 40 in the radiotherapy group who died, 8 and 4 died from breast cancer.

The investigators concluded:

Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local control for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. ■

Disclosure: The study was funded by the Chief Scientist Office of the Scottish Government and Breast Cancer Institute at Western General Hospital, Edinburgh. Prof. Kunkler reported no potential conflicts of interest. For full disclosures of the other study authors, visit www.thelancet.com.

Reference

1. Kunkler IH, Williams LJ, Jack WJ, et al: Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial. Lancet ­Oncol 16:266-273, 2015.

Meena S. Moran, MD, of Yale University School of Medicine, offers her perspective on the PRIME II trial discussed above.