Omission of Postoperative Radiotherapy Has No Effect on Metastatic Risk in Low-Grade Breast Cancer

The use of whole breast irradiation (WBI) can be omitted in patients 65 years and older with pT1-2 tumors (≥3 cm) on local control at 10 years after breast-conserving surgery and adjuvant endocrine therapy in low risk, older patients, according to findings from the PRIME 2 trial (ISRCTN9588932) that were presented at the 2020 San Antonio Breast Cancer Symposium.1 Investigators made the recommendation for omission of postoperative radiotherapy because no evidence suggests that it increases the risk of metastatic disease or negatively affects survival.

“Our principal finding was that radiotherapy reduced the 10-year actuarial rate of local recurrence from 9.8% to 9.2%, which was a statistically significant difference [P = .000008],” lead author Ian Kunkler, MB BChir, MA, FRCR, consultant clinical oncologist, professor of clinical oncology and group leader, Department of Clinical and Translational Studies of Breast Radiotherapy, MRC Institute of Genetics & Molecular Medicine, Cancer Research UK Edinburgh Centre, in Scotland, said during the presentation.

The rationale for the trial was to initiate level 1 evidence on the effect of local control and quality of life (QoL) impact of postoperative radiotherapy after breast-conserving surgery and adjuvant endocrine therapy on low-risk older patients.

Historically, results from the PRIME 1 trial showed that radiotherapy was well-tolerated without impairing global QoL.2 The CALGB 9343 trial demonstrated that in very low-risk patients, breast-conserving surgery and tamoxifen, with or without whole breast radiotherapy, resulted in a 10-year local recurrence of 2% in the radiotherapy group and 9% in the group that did not receive radiotherapy.3

“Recently, 5-year results from the PRIME 2 trial, which had a similar design to the CALGB 9343 trial, showed that radiotherapy significantly reduced the risk of recurrence from 4.1% to 1.3%,” Kunkler said.4

Investigators recruited 1326 patients who were randomized to receive either WBI (n = 658) at 40-50 Gy in 15-25 fractions, or no WBI (n = 668). Eligible patients had histologically confirmed unilateral invasive breast cancer, tumor size ≤ 3 cm, and were previously treated with adjuvant endocrine therapy. Patients were excluded if they had grade 3 cancer plus lymphatic or vascular invasion.

The primary end point was ipsilateral breast tumor recurrence (IBTR) rates and secondary end points were regional recurrence, contralateral breast cancer, distant recurrence, disease-free survival, and overall survival (OS).

Initially, investigators wanted to recruit 1000 patients allowing for attrition over 4 years, however, this was increased to 1300 patients to detect at least a 3% difference in IBTR rates at 5 years (80% power, 5% level of significance).

Both arms were well balanced for age, tumor size grade, the presence or absence of lymphovascular involvement, and preoperative endocrine therapy.

“The majority of patients had tumors that were less than 20 millimeters,” Kunkler said. “In terms of grade, over 95% of patients had grade 1 or 2 tumors, with a minority of patients with grade 3 tumors,” he said.

Regarding secondary end points, they reported higher regional recurrence in the no radiotherapy arm (2.3%) compared with the radiotherapy arm (0.5%; P = .014). But there were no differences in distant recurrence, contralateral breast cancer, or new nonbreast cancers, said Kunkler.

OS showed no difference between the 10-year actuarial rate for the no radiotherapy arm (80.4%) versus the radiotherapy arm (81.0%). Similarly, there were no differences between metastasis-free survival between the no radiotherapy arm and radiotherapy arm (98.1% vs. 96.4%, P = .28, respectively).

The number of deaths in the no radiotherapy arm was 35 (39%) compared with 29 (37%) in the radiotherapy arm. Deaths caused by breast cancer was 8 (9%) in the no radiotherapy arm compared with 3 (4%) in the radiotherapy arm.

The investigators undertook an unplanned subgroup analysis by estrogen receptor (ER) status in the no radiotherapy arm. They compared high ER patients with low ER patients and determined that high ER patients had a 10-year failure rate of 9.2% compared with 18.8% in patients with low ER (P = .007). “We would be cautious in omitting radiotherapy from patients who are low ER status,” Kunkler said.

“Most deaths (93.4%) in this population were not caused by breast cancer,” Kunkler said. “There was a 9.8% IBTR rate at 10 years with the omission of postoperative whole breast radiotherapy in patients with tumors less than 3 cm receiving adjuvant endocrine therapy compared with 0.9% in patients who received radiotherapy,” Kunkler concluded.

_References

1. _{Kunkler IH, Williams LJ, Jack WJL, et al; PRIME 2 Trial Investigators. PRIME 2 randomized trial (Postoperative Radiotherapy in Minimum-Risk Elderly): wide local excision and adjuvant hormonal therapy +/- whole breast irradiation in women ≥65 years with early invasive breast cancer: 10 year results. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract GS2-03.}
2. _{Prescott RJ, Kunkler IH, Williams LJ, et al. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial. Health Technol Assess. 2007;11(31):1-iv. doi:10.3310/hta11310}
3. _{Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387. doi:10.1200/JCO.2012.45.2615}
4. _{Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial [published correction appears in Lancet Oncol. 2015 Mar;16(3):e105]. Lancet Oncol. 2015;16(3):266-273. doi:10.1016/S1470-2045(14)71221-5}