Although advances in radiation therapy have rendered this treatment modality more tolerable, they have not completely eliminated the burden of radiation-related toxicity. In an ideal setting, clinicians would be able to identify patients whose risk of recurrence is sufficiently low that they can safely avoid radiation therapy altogether. The field is moving in that direction, said Reshma Jagsi, MD, DPhil, Professor and Chair of Radiation Oncology at Emory University School of Medicine, Atlanta.1
“[I]f you omit radiation treatment in … older women with early-stage, estrogen receptor–positive, node-negative tumors, you can expect about a 10% risk of local/regional recurrence.”— Reshma Jagsi, MD, DPhil
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Speaking at the 2023 Miami Breast Cancer Conference, Dr. Jagsi described which patients may eventually fit into that category, pending results of clinical trials. As she noted, the omission of radiation therapy is already a standard option for select cases of ductal carcinoma in situ after breast-conserving surgery and for invasive stage I estrogen receptor–positive cancer in older women. “These patients can reasonably choose to forgo radiation therapy, though they may also decide the net benefits are meaningful enough in their own situation to pursue treatment,” she said.
The omission of radiotherapy is under active investigation in a broader age range of patients with biologically favorable estrogen receptor–positive invasive cancer, in this same subset who remain node-positive after mastectomy, and in patients with HER2-positive invasive cancer who have undergone breast-conserving surgery, Dr. Jagsi noted.
Historical Precedents for Radiation Therapy
Trials in invasive breast cancer have shown that the risk of any disease recurrence is essentially halved when radiotherapy is given after breast-conserving surgery. A meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) found a 48% reduction in the risk of any first recurrence (P < .00001) and an 18% reduction in breast cancer death (P = .00005).2 However, lumpectomy alone does not always result in locoregional recurrence, and not all women have the same absolute risk—factors that have motivated numerous trials over the years, she said.
Dr. Jagsi referenced several important older trials in node-negative early breast cancer that questioned whether tamoxifen alone might yield acceptable outcomes:
• NSABP B-21 (tumors ≤ 1 cm, after lumpectomy): At 8 years, ipsilateral recurrence was 16.5% with tamoxifen alone, 9.3% with radiotherapy, and 2.8% with both treatments.3
• Canadian trial (T1–2 tumors): At 8 years, ipsilateral recurrence was 18% with tamoxifen alone and 4% with radiotherapy plus tamoxifen. In the “favorable” cohort with T1 estrogen receptor–positive tumors, the rate was 15% vs 4%, respectively.4
• CALGB 9343 (age ≥ 70, clinical stage I, estrogen receptor–positive tumors): This trial identified a population in whom the risk of local/regional recurrence without radiotherapy was acceptable—10% at 10 years vs 2% with radiotherapy—but did not identify a population in whom radiation therapy offered no benefit.5
• PRIME II (age ≥ 65, tumors ≤ 3 cm): At 10 years, the local recurrence rate was 9.5% without radiotherapy vs 0.9% with radiotherapy; the risk associated with omitting radiotherapy was unacceptably high in patients who had estrogen receptor–low tumors (19.1% vs 12.7%, respectively).6
“None of those trials individually showed a survival benefit with radiation treatment. It took the meta-analysis of many thousands of patients to demonstrate that,” Dr. Jagsi noted. “But, importantly, CALGB 9343 was the first trial to demonstrate a risk of local/regional recurrence in the absence of radiation therapy (10% at 10 years) that was viewed by many as reasonable enough to offer the omission of radiation treatment as an option to patients…. The more recent PRIME II results were nearly identical.”
Dr. Jagsi summed up: “So, if you omit radiation treatment in these older women with early-stage, estrogen receptor–positive, node-negative tumors, you can expect about a 10% risk of local/regional recurrence. If you administer radiation therapy, you can get a 5- to 10-fold reduction in risk. What to do depends entirely on the patient’s own values and preferences. And we don’t want to omit radiation treatment in patients who have low hormonal receptor status.”
Can Tumor Biology Guide Omission of Radiotherapy?
The remaining question is whether the growing understanding of tumor biology can facilitate the omission of radiotherapy in younger patients. “We know that tumor biology is at least as important in predicting behavior and outcomes as classic clinical pathologic features and that local/regional recurrence varies by biologic subtype, both in patients receiving radiation therapy and in those treated with surgery alone. For example, rates are particularly low in patients with estrogen receptor–positive disease in this era of effective endocrine therapies,” Dr. Jagsi said.
A number of prospective single-arm cohort studies have been launched to study this question in women with biologically low-risk tumors. The LUMINA, IDEA, and PRECISION trials are targeted to a somewhat younger group, though participants are generally still postmenopausal.
“We think if we omit [radiotherapy], we will reduce things that matter to patients, such as pain. Yet we don’t know whether patients will worry more about recurrence….”— Reshma Jagsi, MD, DPhil
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At the 2022 ASCO Annual Meeting, Whelan et al presented the first results of LUMINA, which was conducted in 501 patients, median age 67 years, with luminal A tumors treated with adjuvant endocrine therapy and no radiotherapy.7 At 5 years, the local recurrence rate was 2.3%, which was considered acceptable in the trial design, and just one breast cancer death occurred. “This is compelling information,” she commented.
Additional ongoing trials investigating the omission of radiotherapy after lumpectomy include the very large UK PRIMETIME trial (age ≥ 60 years; very low–risk immunohistochemistry [IHC] 4+ score), the ANZ 1601 trial (luminal A tumors), and the phase III NRG BR007 (DEBRA) trial (age > 50 years, hormone receptor–positive, HER2-negative, 21-gene recurrence score ≤ 18).
In NRG BR007, postlumpectomy patients will receive endocrine therapy and be randomly assigned to radiation therapy or observation. Of note, a detailed examination of quality of life is part of the design. “We make assumptions about the experience of modern radiotherapy. We think if we omit it, we will reduce things that matter to patients, such as pain. Yet we don’t know whether patients will worry more about recurrence, and we don’t know the impact of these decisions on cosmetic outcomes and other things that matter to patients, so these outcomes will be evaluated rigorously in that randomized trial,” Dr. Jagsi said.
Radiotherapy After Mastectomy: Controversies
“What about radiotherapy after mastectomy? Quite a bit of controversy has centered around patients with N1 high-risk, node-negative disease. Growing evidence suggests there is a benefit with radiotherapy, requiring serious consideration of radiation treatment, even in women with N1 disease,” she said. She cited the EBCTCG meta-analysis8 and the landmark EORTC 22922 trial,9 along with extrapolation from the NCIC MA20 trial.10
Here again, biology may be informative. A prespecified subgroup analysis of MA20 showed the most substantial benefit was in patients with estrogen receptor–negative disease, with an improvement in overall survival. In addition, observational analysis of NSABP B28, SWOG 8814, and SWOG S1007 has also suggested the 21-gene recurrence score may help to tailor decisions regarding postmastectomy radiotherapy and regional nodal irradiation.
The large NCIC MA.39 TAILOR-RT trial is examining this question now. Women with N1 disease postlumpectomy or postmastectomy and biomarker-assessed low risk by the 21-gene assay are prescribed 5 years of endocrine therapy and randomly assigned to regional radiotherapy or no regional radiotherapy. The regional radiotherapy group will receive whole-breast irradiation plus regional nodal irradiation after breast-conserving surgery or radiation to the chest wall plus regional nodes after mastectomy. The no-regional-radiotherapy group will receive whole-beast irradiation after breast-conserving surgery and no radiotherapy after mastectomy. A recent amendment allows T3N0 tumors and micrometastases.
Radiotherapy for HER2-Positive Disease
“An exciting area being explored is HER2-positive disease,” Dr. Jagsi commented. “We now know that among patients with favorable-risk, HER2-positive tumors (< 3 cm, node-negative), we can perhaps de-escalate systemic therapy,” based on the 1.2% locoregional recurrence rate seen in the APT trial of women with small tumors treated with trastuzumab/paclitaxel and radiotherapy.11 This is a population of patients in whom de-escalation of radiotherapy might also be appropriate. NRG BR008 will evaluate the omission of radiotherapy in this important subgroup.
Don’t Make Assumptions
“In the end, whether a woman chooses to forgo a modest disease control benefit really depends on how burdensome and toxic modern radiotherapy is,” Dr. Jagsi said. If recent advances (such as hypofractionation) have minimized the toxicity and burden of radiation therapy, there could be situations in which radiation treatment is preferred over certain other standard treatments, she pointed out.
In fact, radiotherapy use remains frequent even among candidates for omission—such as women meeting the -CALGB 9343 criteria. “I would encourage us not to dismiss the possibility that some women may be intentionally choosing radiation treatment—and not not being offered omission,” she said, noting that radiation-related breast symptoms resolve much earlier than endocrine-related side effects, which can persist for the entire treatment duration. “It’s quite possible that some older women may be choosing radiation treatment alone and omitting the endocrine therapy, yet we have strikingly little information on what the outcomes are if one chooses this.”
Radiation therapy alone and the omission of endocrine therapy is an approach now being studied in ongoing trials outside of the United States and is being considered by trialist groups in the United States and Canada. “I think this is the next step,” she said.
“In conclusion, our goal is not to omit radiation. Our goal is to reduce the toxicity and burden of treatment. Advances and other disciplines are increasingly creating opportunities for us to consider where radiation therapy may safely be omitted, but we should not assume that when women do not omit radiation that they are making unreasonable choices…. We have to generate and provide information on all options, so patients themselves can make informed decisions concordant with their own values and preferences.”
DISCLOSURE: Dr. Jagsi has conducted investigator-initiated trials with Genentech; she was a legal expert witness for Sherinian and Hasso, Dressman Benzinger LaVelle, and Kleinbard LLC and has received grant and research support from NIH and numerous nonprofit organizations.
REFERENCES
1. Jagsi R: Selecting patients for omission of radiotherapy. 2023 Miami Breast Cancer Conference. Morning Plenary Session. Presented March 3, 2023.
2. Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011.
3. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002.
4. Fyles AW, McCready DR, Manchul LA, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963-970, 2004.
5. Hughes KS, Schnaper LA, Berry D, et al: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 351:971-977, 2004.
6. Kunkler IH, Williams LJ, Jack W, et al: PRIME II randomised trial (postoperative radiotherapy in minimum-risk elderly): Wide local excision and adjuvant hormonal therapy whole breast irradiation in women ≥ 65 years with early invasive cancer: 10-year results. 2020 San Antonio Breast Cancer Symposium. Abstract GS2-03. Presented December 9, 2020.
7. Whelan TJ, Smith S, Nielsen TO, et al: LUMINA: A prospective trial omitting radiotherapy following breast conserving surgery in T1N0 luminal A breast cancer. 2022 ASCO Annual Meeting. Abstract LBA501. Presented June 7, 2022.
8. McGale P, Taylor C, Correa C, et al: Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet 383:2127-2135, 2014.
9. Poortmans PM, Collette S, Kirkove C, et al: Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med 373:317-327, 2015.
10. Whelan TJ, Olivotto IA, Parulekar WR, et al: Regional nodal irradiation in early-stage breast cancer. N Engl J Med 373:307-316, 2015.
11. Tolaney SM, Guo H, Pernas S, et al: Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol 37:1868-1875, 2019.
