Advances in treating breast cancer “increasingly create opportunities to consider where radiation therapy might safely be omitted,” Reshma Jagsi, MD, DPhil, told participants at the 2021 Lynn Sage Breast Cancer Symposium.1 “But, I would encourage us,” she continued, “not to assume that women who don’t omit radiation therapy are making unreasonable choices. Advances in radiation therapy techniques developed over the past couple of decades may be creating situations in which patients are reasonably electing radiation, even for a relatively small disease control benefit, especially if this might allow them to forgo other toxic or burdensome treatment. That is a question that is actively being investigated.”
Dr. Jagsi called on oncologists to work “together as a field to generate and provide information about all options, so our patients themselves can make informed decisions concordant with their own values and preferences.” Dr. Jagsi is Newman Family Professor, Deputy Chair of the Department of Radiation Oncology, and Director of the Center for Bioethics and Social Sciences in Medicine University of Michigan in Ann Arbor. The symposium was sponsored by Northwestern Medicine/Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
Standard Option
“Radiation therapy omission is already a standard option for select patients,” Dr. Jagsi noted. “These patients include “women with ductal carcinoma in situ [DCIS] who have small-, low-, or intermediate-grade tumors resected with widely negative margins, as well as older women with estrogen receptor–positive, stage 1 invasive breast cancers.” Omitting radiation therapy is “under active investigation for patients with biologically favorable estrogen receptor–positive invasive cancer, with a broader age range, as well as biologically favorable estrogen receptor–positive, node-positive invasive cancer after mastectomy. And one day, it might be an option for other patients, for example those with HER2-positive invasive cancer after breast-conserving surgery.”
“Advances in treating breast cancer increasingly create opportunities to consider where radiation therapy might safely be omitted.”— Reshma Jagsi, MD, DPhil
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Evidence for recommendations for radiation therapy in DCIS “derives from randomized controlled trials” and “demonstrated a substantial 50% relative risk reduction in breast tumor recurrence with the addition of adjuvant radiotherapy,” Dr. Jagsi noted. “However, we also know that new imaging detects smaller lesions than on those historical trials, and observational studies have suggested since the 1990s that there may be identifiable subsets of patients with a sufficiently low risk of local recurrence to justify the omission of radiation treatment.”
“That inspired several more recent trials,” Dr. Jagsi added, including RTOG 9804, a prospective randomized trial comparing radiotherapy with observation following breast-conserving surgery for low- or intermediate-grade DCIS.2 At 12 years, “there was an 11.4% risk of local failure in the observation arm, but a 2.8% risk in the radiation treatment arm—a pretty substantial reduction with the administration of radiation treatment,” Dr. Jagsi noted. She also pointed out that 62% of patients in the RTOG trial received tamoxifen.
Continuing efforts to identify patients whose risk of recurrence is low enough to merit omission of radiation include the use of genomic assays. A cohort analysis3 combining traditional clinicopathologic features together with the Oncotype DX DCIS score showed “it was possible to identify a group of patients who had a 10-year risk of local recurrence of 7%,” Dr. Jagsi reported.
“For now, lumpectomy with whole-breast radiation remains the category 1 recommendation for treatment of DCIS. However, lumpectomy without radiation therapy is a category 2B option,” she added.
Higher Stakes With Invasive Disease
“For women with invasive breast cancer, the stakes are higher. However, perhaps some women are at such low risk of harboring residual locoregional disease, they might still safely avoid radiation therapy,” Dr. Jagsi stated.
“One of the only trials to date to have identified a group with sufficiently low risk after omission of radiation treatment is the CALGB 9343 trial,” Dr. Jagsi explained. Among women 70 years of age or older, with clinical nodal stage I, estrogen receptor–positive tumors treated with breast-conserving surgery, the risk of locoregional recurrence was 10% at 10 years with tamoxifen alone vs 2% with radiation plus tamoxifen.4 Although radiation did offer a statistically significant benefit, 10% is “a sufficiently low risk,” so women in their 70s or 80s “might reasonably consider omitting radiation.”
The PRIME II study had a similar design but included women 65 years of age or younger. This study yielded “5-year results that were absolutely identical to CALGB 9343, 4% vs 1% for local recurrence, and 10-year results with very similar findings, 10% vs 1%,” Dr. Jagsi reported.
Ongoing trials investigating the omission of radiation therapy among patients with invasive breast cancer who are younger than those on the CALGB 9343 and PRIME II trials include the NRG BR007 phase III trial evaluating de-escalation of breast radiation for conservative treatment of stage I, hormone receptor–positive, HER2-negative breast cancer with scores of 18 or lower on the 21-gene assay to evaluate biologic aggressiveness. “It is only through a randomized trial that we can actually understand the real impact of omission of radiation on quality of life,” Dr. Jagsi said. “The primary outcomes of the quality-of-life aspect of this trial included breast pain, which is the toxicity of radiation treatment, but also the worry about recurrence, which may actually increase in the absence of radiation treatment.”
Tumor Biology
“Tumor biology is at least as important in predicting behavior and outcomes as classic clinicopathologic features. Locoregional recurrence varies by biologic subtype, both in patients who receive radiation treatment and in those who are treated with surgery alone; it is particularly low in patients with estrogen receptor–positive disease in an era of effective long-term endocrine therapies,” Dr. Jagsi stated.
“Endocrine therapy alone after breast-conserving surgery, for patients selected on biologic features, is not the standard of care right now. However, it is an exciting area of ongoing investigation,” and several prospective cohort studies are underway to identify patients with biologic features “that may help us to identify an even larger group of patients who can safely avoid radiation if they so choose,” Dr. Jagsi said.
After Mastectomy
“We are increasingly using radiation treatment in patients who undergo mastectomy as their primary breast surgery. Historically, there has been controversy centering around patients with N1 or high-risk node-negative disease. However, the growing evidence has suggested a benefit requiring serious consideration of radiation treatment, even in women with N1 disease (1–3 positive lymph nodes),” stated Dr. Jagsi.
“There is accumulating evidence that regional nodal radiation may have a benefit, particularly with respect to reducing distant failures,” she noted. The challenge is “can we use our understanding of biology to select which patients should receive treatment,” she asked. “Biology may be important, as shown in the prespecified subgroup analysis in the MA20 trial. This analysis found that patients with estrogen receptor–negative disease may benefit most from regional nodal irradiation, with a pretty striking survival benefit—81.3% vs 73.9%”
Observational analyses from other studies have suggested that the 21-gene assay results may help to tailor decisions regarding regional nodal radiation and postmastectomy radiation treatment, according to Dr. Jagsi. A large cooperative group trial, NCIC MA.39 TAILOR-RT among patients with up to three positive axillary nodes at low risk, is investigating whether “we can safely omit regional nodal radiation for some of those node-positive patients who had lumpectomy and omit radiation treatment altogether for some node-positive patients who had mastectomy.”
Reduced Toxicity
Impressive advances have reduced the burden and toxicity of modern radiation therapy, Dr. Jagsi noted. “We are now able to offer moderate hypofractionation to the whole breast for most patients who undergo lumpectomy; for select patients who undergo lumpectomy, we can also offer accelerated partial-breast irradiation. These schedules are far more convenient. Modern hypofractionation is 15 to 16 fractions to the whole breast. Sometimes, there is a four- or five-fraction boost. Not only are such schedules more convenient, but they also appear less toxic. “Whole-breast moderate hypofractionation has been demonstrated in a trial from MD Anderson and in a statewide consortium from Michigan, as having lower acute toxicity. In the START trials in the United Kingdom, this approach was found to have lower late toxicity.”
Accelerated partial-breast irradiation can be done even more quickly than that,” she added, with long-term evidence supporting 5- and 10-fraction regimens. According to Dr. Jagsi, there is also growing evidence for whole-breast ultra-hypofractionation, with five fractions total to the whole breast. “There are certainly parts of the world that have already adopted ultra-hypofractionation as the standard of care, based on the 5-year data from the FAST-Forward trial,” she noted. However, she advised caution while we await the 10-year results.
She also eagerly anticipates long-term results from other studies. “There are trials of even shorter courses of accelerated partial-breast irradiation, and hypofractionation has also been explored after mastectomy, including when the regional nodes are being treated, with trials underway in patients with breast reconstruction.” Dr. Jagsi noted.
Use of Radiation Therapy Remains High
“The use of radiation treatment remains high, even among candidates for omission. Observational studies have suggested that even after publication of trial results, most older women in the United States continue to receive radiation treatment in addition to endocrine therapy,” Dr. Jagsi said.
“Important quality-of-life analysis from the PRIME trial demonstrates that radiation-related breast symptoms resolve early,” Dr. Jagsi reported. Within 3 years after treatment, there were no significant differences in the quality of life between patients who did and did not receive radiation therapy. “In contrast, endocrine-related side effects are experienced by patients across the whole duration of treatment,” Dr. Jagsi remarked.
“Perhaps we should be asking whether some women might prefer radiation treatment alone, and might it be safe for them to avoid endocrine therapy and its associated burden and toxicity? There may be situations where a patient might prefer radiation treatment,” Dr. Jagsi said, particularly if that would mean skipping other toxic treatments.
Several trials have compared radiation therapy alone with other treatments. “The BASO II trial has suggested the actual rate of local recurrence at 10 years was 8% with radiation therapy alone and 8% with tamoxifen alone,” Dr. Jagsi reported. Recurrence rates were 2% with both treatments and 22% with neither treatment. An Ontario cohort study reported local recurrence at 1.4% with radiotherapy alone, compared with 3.4% with endocrine therapy alone, and 0.9% with both treatments.
DISCLOSURE: Dr. Jagsi has stock options as compensation for her advisory board role in Equity Quotient; has received personal fees and/or grants from the Greenwall Foundation, Doris Duke Charitable Foundation, National Institutes of Health, Komen Foundation, Genentech, and Blue Cross Blue Shield of Michigan for the Michigan Radiation Oncology Quality Consortium; and has served as an expert witness for Sherinian & Hasso, Dressman Benzinger LaVelle, and Kleinbard LLC.
REFERENCES
2. McCormick B, Winter K, Hudis C, et al: RTOG 9804: A prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol 33:709-715, 2015.
3. Rakovitch E, Nofech-Mozes S, Hanna W, et al: Multigene expression assay and benefit of radiotherapy after breast conservation in ductal carcinoma in situ. J Natl Cancer Inst 109:djw256, 2017.
4. 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 31:2382-2387, 2013.
