Omission of radiation ‘is an option’ for some older women with early breast cancer
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Omission of whole-breast irradiation did not appear to have a negative impact on survival or risk for distant metastases among older women with early-stage hormone receptor-positive breast cancer, according to phase 3 study results.
The findings, published in The New England Journal of Medicine, indicate these patients can safely avoid whole-breast irradiation, according to researchers.
Rationale, methodology
“With the exclusion of many patients aged older than 70 years from trials evaluating the role of postoperative whole-breast irradiation after breast conservation surgery and adjuvant endocrine therapy, we felt that we should examine whether irradiation could be omitted in older patients at low risk for local recurrence,” Ian H. Kunkler, MB, BChir, professor and consultant in clinical oncology at Edinburgh Cancer Center at University of Edinburgh, told Healio. “This was the motivation of the University of Edinburgh research team for establishing the PRIME II trial and for creating a more robust evidence base for treating these patients.”
Incidence of breast cancer among older patients has increased, he added, with more than 50% of patients with a new diagnosis aged 65 years or older.
“The research question is therefore relevant to an increasing number of patients,” Kunkler said. “We were keen that older patients should neither be overtreated nor undertreated. Practice varies.”
The randomized, phase 3 PRIME II trial included 1,326 women (median age, 70 years) with hormone receptor-positive, node-negative, T1 or T2 primary breast cancer who underwent breast-conserving surgery with clear excision margins and adjuvant endocrine therapy across 76 centers in the U.K., Greece, Australia and Serbia.
Researchers randomly assigned patients to 40 Gy to 50 Gy whole-breast irradiation (n = 658) or no irradiation (n = 668).
Local breast cancer recurrence served as the primary endpoint. Secondary endpoints included regional recurrence, breast cancer-specific survival, distant recurrence and OS.
Median follow-up was 9.1 years.
Findings
Results showed a 10-year cumulative incidence of local breast cancer recurrence of 9.5% (95% CI, 6.8-12.3) among women assigned to the no-irradiation group compared with 0.9% (95% CI, 0.1-1.7) among those who underwent whole-breast irradiation (HR = 10.4; 95% CI, 4.1-26.1).
However, researchers did not observe a higher 10-year incidence of distant recurrence as first event among the no-irradiation group (1.6%; 95% CI, 0.4-2.8) vs. the whole-breast irradiation group (3%; 95% CI, 1.4-4.5).
Results also showed comparable 10-year OS rates among women who received no irradiation (80.8%; 95% CI, 77.2-84.3) and those who received irradiation (80.7%; 95% CI, 76.9-84.3).
Moreover, researchers found no differences in regional recurrence and breast cancer-specific survival between the two groups.
Implications
“The results of the PRIME II trial provide robust, long-term evidence that omission of postoperative whole-breast irradiation is an option for women aged 65 years and older with T1 to T2 early breast cancer up to 3 cm in diameter who are hormone receptor-positive, axillary node-negative with grade 1 or grade 2 [disease], and received at least 5 years of adjuvant endocrine therapy,” Kunkler told Healio. “This data should inform shared decision-making between clinicians and patients.”
Results of PRIME II should be incorporated into clinical guidelines, Kunkler added.
“In the future, the selection of patients at low risk for recurrence for postoperative radiotherapy after breast-conserving therapy and adjuvant endocrine therapy may be further enhanced by biomarkers, such as molecular signatures of breast cancer radiosensitivity, and validated in patient cohorts similar to PRIME II,” he said.
Doubts about whether radiotherapy can be safely omitted for women aged 65 years or older with ER-positive, early-stage breast cancer can now be put to rest, Alice Y. Ho, MD, radiation oncologist at Duke University School of Medicine, and Jennifer R. Bellon, MD, radiation oncologist at Dana-Farber Cancer Institute, wrote in an accompanying editorial.
“These results do not undermine the value of radiotherapy in enhancing local control, which is a compelling endpoint in and of itself, particularly now that radiotherapy can be delivered in less burdensome ways,” the editorial authors wrote. “Individualizing the treatment so that it is concordant with the patient’s goals and values is critical. Taken together, these data will help patients navigate these complex choices so that they can make well-informed and prudent decisions for the management of their breast cancer.”
References:
Ho AY, et al. N Engl Med. 2023;doi:10.1056/NEJMe2216133.
Kunkler I, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2207586.
For more information:
Ian H. Kunkler, MB, BChir, can be reached at iankunkler@yahoo.com.
Perspective
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Chirag Shah, MD
Since the inception of breast-conserving therapy, the role of adjuvant radiation therapy has been questioned. In the past, studies consistently demonstrated a significant benefit in local control with the addition of radiation therapy, with a meta-analysis also demonstrating an improvement in breast cancer mortality. However, subsequent trials evaluating the omission of radiation therapy have sought to evaluate lower-risk cohorts of patients undergoing breast-conserving surgery, including those aged 65 to 70 years or older with smaller tumors (2 cm to 3 cm or less) that were estrogen positive.
The updated results from the PRIME II trial confirm the findings seen in CALGB 9343. Among low-risk patients aged 65 to 70 years or older following breast-conserving surgery and receiving endocrine therapy, the addition of radiation therapy reduced local recurrence (approximately 10% without radiation therapy vs. 1% to 2% with radiation therapy at 10 years), with no impact on survival.
One implication is that these data can be used as part of shared decision-making with patients when considering the role of radiation therapy. Patients can be counseled on these outcomes, with some patients choosing to still receive radiation therapy and others choosing to forgo it.
Another implication is the need to rethink treatment de-intensification. Classically, radiation therapy was chosen to be removed when de-intensifying treatment given the length of radiation therapy and adverse effects associated with older radiation techniques. In PRIME II, the radiation course was 3 to 5 weeks of daily treatment. However, modern advances in radiation allow for treatment to be completed in just 5 days, with very low rates of toxicities compared with endocrine therapy for 5 years, which has a different toxicity profile, as well. As such, the question of whether radiation alone is the preferred modern de-intensification approach is being evaluated in the ongoing EUROPA trial, with modeling studies suggesting both approaches may be appropriate for low-risk patients.
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