Experts Warn of Radiation Overtreatment in Older Women With Early-Stage Breast Cancer

Targeted Therapies in OncologyMarch I, 2024
Volume 13
Issue 3

Studies have found that omitting radiation therapy after breast-conserving surgery and/or omitting axillary surgery in women age 70 years or older does not affect their survival when taking endocrine therapy.

Breast Cancer Image: © Giovanni Cancemi-

Breast Cancer Image: © Giovanni Cancemi-

Although undertreatment of older women who have aggressive breast cancer has been a concern for years, a recent trend has focused on overtreatment of older women with early stage, ER-positive, HER2-negative breast cancer with radiation therapy. These treatments are unlikely to improve survival or reduce morbidity. Studies have found that omitting radiation therapy after breast-conserving surgery and/or omitting axillary surgery in women age years or older does not affect their survival when taking endocrine therapy.1,2

Overtreatment of this population, though not formally on the AGENDA for the upcoming 41st Annual Miami Breast Cancer Conference taking place March 7 to 10, 2024, in Florida, will surely be a topic of discussions among attendees and faculty during the conference.

"There have been a number of studies reported that looked at de-escalation of radiation treatment, looking at the opportunity to omit, or limit, treatment in patients with selected favorable characteristics,” cochair Reshma Jagsi, MD, DPhil, the Lawrence W. Davis Professor and chair, Department of Radiation Oncology, Emory University School of Medicine, in Atlanta, Georgia, said during an interview with Targeted Therapies in Oncology. Patrick I Borgen, MD, serves as conference chair, and Hope S. Rugo, MD, FASCO, and Debu Tripathy, MD, will serve as cochairs.

Radiotherapy Overtreatment

Dr Jagsi said the PRIME II study (ISRCTN95889329) was important regarding this topic. In the study, women who underwent breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and received no further treatment. After a median follow-up of years, patients who received radiotherapy had a recurrence rate of 1.3% (95% Ci, 0.2%-2.3%) compared with 4.1% (95% CI, 2.4%-5.7%) in patients who received no radiation therapy (P =.0002). The univariate HR for recurrence in women assigned no radiotherapy was 5.9% (95% CI, 1.9%-13.5%; P = .0007) compared with women who received radiotherapy.

“PRIME II was a randomized trial that showed that there is a benefit from radiation treatment across subgroups of patients, even highly-favorable select patients,” Jagsi said. “But in some subgroups, the risk of recurrence, even without radiation, is reasonably low enough that some women might want to choose to omit radiation,” Jagsi continued.

The investigators concluded that postoperative radiotherapy after breast-conserving strategy and adjuvant endocrine therapy resulted in significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer. They said that the 5-year rate of ipsilateral breast tumor recurrence is low enough for omission of radiotherapy to be considered for some patients.1

The Cancer and Acute Leukemia Group B (CALGB) 9343 trial (NCT00991263) randomly assigned women age 70 years and older with clinical or pathologic stage I breast cancer treated with breast-conserving surgery and endocrine therapy to receive or omit adjuvant radiotherapy. Locoregional recurrence at 10 years was among those randomly assigned to omission and 2% among those assigned to radiotherapy.2

From July 1994 to February 1999, women (n = 636) who had clinical stage I (T1NOMO according to TNM classification), ER-positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (n = 317) or tamoxifen alone (n = 319).2 After 10 years follow-up, 98% of patients receiving tamoxifen plus radiation therapy (95% CI, 96%-99%), compared with 90% of those receiving tamoxifen alone (95% CI, 62%-72%) in the tamoxifen plus radiotherapy arm vs 66% (95% CI, 61%-71%) in the tamoxifen only arm.1

The LUMINA trial (NCT01791829)3 enrolled 500 patients who were at least 55 years of age, had undergone breast-conserving surgery for T1NO, grade 1 or 2, had luminal A-subtype breast cancer, and had received adjuvant endocrine therapy.

Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25 or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast.

After 5-year follow-up, recurrence was reported in 2.3% of the patients (95% CI, 1.2%-4.1%), which met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1%-3.2%), and recurrence of any type was observed in 2.7% (90% CI, 1.6%-4.1%).3

Researchers concluded that among women who were at least 55 years old and treated with breast-conserving surgery and endocrine therapy alone, local recurrence at 5-year follow-up was low with the
omission of radiotherapy.3

Jagsi and colleagues investigated whether younger postmenopausal patients could be successfully treated without radiation in the IDEA trial (NCT02400190).4 Postmenopausal patients aged 50 to 69 years
with margins 2 mm or greater after breast-conserving surgery whose tumors were ER+, progesterone receptor positive, and EGFR2 negative with Oncotype DX 21-gene recurrence score 18 or less were
prospectively enrolled in a single-arm trial of radiotherapy omission. The primary end point was the rate of locoregional recurrence 5 years after breast-conserving surgery.4

Two hundred patients were enrolled, and among those with clinical follow-up of at least 56 months (n =186), overall and breast cancer–specific survival rates at 5 years were both 100%. The 5-year freedom from recurrence rate was 99% (95% CI, 96%-100%).4

Overall, Jagsi noted that the emphasis placed on avoiding toxicity and burden of radiation treatment, though meaningful, is not equitably distributed across patient groups, so further follow-up is needed.

“That’s why we have to be careful when presenting these results to patients, to make sure they understand both the risks and the benefits of radiation treatment,” Jagsi said.

Mitigating Disparities

At the conference, Jagsi will be presenting “Understanding and Mitigating Disparities: A Radiation Oncologist’s Perspective” on March 8, addressing many system-level factors that lead to unacceptable mortality disparities. She expects to touch on many factors that are deeply embedded in society and that radiation oncologists may not have direct control over.

“I’m going to present a series of studies that we have conducted that have demonstrated that not only are there unacceptable disparities in mortality, and in financial toxicity, but also in pain experiences and acute toxicities while receiving radiation treatment,” Jagsi said.

Jagsi pointed out that there are even disparities among providers’ recognition of those toxicities, which in part might explain the uncontrolled toxicities that are more frequent among patients of color. For
example, Jagsi noted that some African American patients are receiving care in centers that don’t provide access to breath hold devices. These devices help reduce the amount of radiation that reaches the heart. They also help ensure that patients’ breath holds are consistent during each treatment.

“If your hospital doesn’t purchase the equipment you need, that’s problematic. If you’re serving an underserved community, you probably under-resource certain settings of care,” Jagsi said.

Factors that practicing radiation oncologists do have control over involve the type of radiation delivered. For example, radiation oncologists can opt for shorter courses of hypofractionated radiation, especially in older patients. “It gives us a little window into something that is entirely within the control of a treating radiation oncologist,” Jagsi said. “Hopefully, the presentation will inspire conversation about how each of us has a role to play in mitigating these unacceptable disparities and inequities that exist.”

Radiation Oncology Track

Jagsi is particularly excited this year because the conference will feature the very first fully focused radiation oncology track.

“I’m looking forward to reconnecting with a number of peers in radiation oncology and with experts in our complementary disciplines of medical oncology, surgical oncology, radiology, and pathology,” Jagsi said. “There have been some interesting advances in radiation oncology management over the past year alone that will benefit us as a community. We’ll learn how to best present those advances to our patients so that they can make decisions that feel right for them.”

1. 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. Lancet Oncol. 2015;16(3):266-273. doi:10.1016/S1470-2045(14)71221-5
2. 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
3. Whelan TJ, Smith S, Parpia S, et al. Omitting radiotherapy after breast-conserving surgery in luminal A breast cancer. N Engl J Med. 2023;389(7):612-619. doi:10.1056/NEJMoa2302344
4. Jagsi R, Griffith KA, Harris EE, et al. Omission of radiotherapy after breast-conserving surgery for women with breast cancer with low clinical and genomic risk: 5-year outcomes of IDEA. J Clin Oncol. 2024;42(4):390-398. doi:10.1200/JCO.23.02270
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