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MIAMI BEACH -- Advances in breast cancer management have created opportunities to omit radiotherapy (RT) in selected situations, but women who choose RT should not be considered unreasonable, a radiation oncologist said here.

Modern RT has greatly reduced, but not eliminated, toxicity and treatment burden. Omission is already a standard option for select cases of ductal carcinoma in situ after breast conservation and for older women with stage I hormone receptor (HR)-positive disease.

However, decision-making should occur with a realistic appraisal of just how burdensome and toxic modern RT really is, said Reshma Jagsi, MD, of Emory University and Winship Cancer Institute in Atlanta, during the Miami Breast Cancer Conference.

"Our goal is not to omit radiation therapy but to reduce the toxicity and burden of treatment," she said. "Advances in other disciplines are increasingly creating opportunities for us to consider where radiation therapy might be safely omitted. But we should not assume that when women don't omit radiation they're making unreasonable choices."

If toxicity and burden have been minimized, RT might actually be preferred in some situations over certain other standard treatments, "but we still have to generate the information that's necessary [to make informed decisions]."

Historical Data

Historical have shown that RT reduces the risk of any breast cancer recurrence by almost 50%, and the risk of breast cancer death by 15-20%. However, not all patients have locoregional recurrence after lumpectomy alone and not all patients have the same absolute risk of recurrence. That recognition has motivated numerous clinical trials to identify and better define low-risk patients, said Jagsi.

Investigators in randomized 1,009 women with small invasive breast cancers treated with lumpectomy to adjuvant tamoxifen, adjuvant RT, or both. The 8-year incidence of ipsilateral recurrence was 16.5% with tamoxifen alone, 9.3% with RT alone, and 2.8% with both.

A compared tamoxifen plus observation or RT after breast-conserving surgery (BCS) in women 50 or older with stage I-II node-negative disease. At 8 years, rates of ipsilateral recurrence were 18% with observation and 4% with RT.

also compared BCS plus adjuvant tamoxifen with or without RT in women 70 or older with clinical stage I, HR-positive breast cancer. The 5-year rate of locoregional recurrence was 5% with tamoxifen alone versus 1% with the addition of RT, and continued to favor the RT arm (P<0.001). Distant metastasis, breast cancer-specific mortality, and all-cause mortality did not differ significantly.

Yet , known as PRIME II, evaluated lumpectomy followed by endocrine therapy with or without RT in women 65 or older with tumors ≤3 cm and 1-mm surgical margins. At 5 years, the incidence of local recurrence was 4.1% without RT and 1.3% with it. The authors concluded that the risk of recurrence was "probably low enough for omission of radiotherapy to be considered for some patients."

By 10 years, rates of recurrence were 0.9% with RT and 9.5% without it, a statistically significant difference but a "modest" absolute difference. Noting the lack of significant difference in other clinical endpoints, the study investigators that "postoperative radiotherapy in this patient group who are receiving adjuvant hormonal therapy does not impact on overall survival in the context of modern approaches to local and systemic adjuvant therapy, with most patients in both arms dying of causes unrelated to breast cancer or its treatment."

A stratified analysis by estrogen receptor (ER) expression did provide some insight into the potential risk of omitting RT, said Jagsi. Patients with low ER expression and randomized to no RT had a 10-year local recurrence rate of 19%.

Biology Considerations

The findings relative to HR receptor status reflect the current interest in using improved understanding of tumor biology to identify younger patients who might safely omit RT.

"Tumor biology is at least as important in predicting behavior and outcomes as clinicopathologic features," said Jagsi. "Locoregional recurrence varies by biologic subtype in patients receiving RT and in those treated with surgery alone and is particularly low in patients with ER-positive disease in an era of effective long-term endocrine therapies."

Investigators in the LUMINA trial asked whether patients with the luminal A subtype of breast cancer, defined by HR expression and Ki67 proliferation rate, represented a low-risk group that might avoid RT. The prospective non-randomized trial assigned 501 patients age 55 and up (median age 67) to adjuvant endocrine therapy and no RT. At 5 years, the local recurrence rate was 2.3% and the overall survival rate was 97.2%, which met prespecified statistical criteria for success.

"Compelling information, but I will point out the median age of 67," said Jagsi.

With respect to the need for RT after mastectomy, most of the controversy has centered on patients with N1 or high-risk node-negative disease, she continued. An accumulation of evidence suggests an RT benefit that requires serious consideration, even in patients with N1 disease.

Biology may help resolve some of the controversy. A subgroup analysis of the from Canada showed that patients with ER-negative breast cancer gained the most from regional nodal irradiation, with almost an 8% absolute difference in overall survival at 10 years.

Limited evidence has accumulated regarding omission of RT in HER-positive breast cancer. The single-arm APT trial evaluated adjuvant paclitaxel and trastuzumab (Herceptin), followed by trastuzumab maintenance in patients with low-risk HER2-positive breast cancer (≤3 cm, node-negative). RT was required after BCS but field and dose were not specified. The results showed a locoregional recurrence rate of 1.2%.

Jagsi cautioned against trying to extrapolate the results to women who omit RT in the absence of prospective data. The results do suggest an "intriguing opportunity to explore whether there's another population of patients in whom de-escalation of radiation treatment might be appropriate."

Numerous studies are evaluating different strategies for reducing or omitting RT in low-risk breast cancer. Studies to date have collected limited data on "what really matters to patients," and multiple planned and ongoing studies are incorporating patient-reported outcome assessments.

"Radiation therapy has become a lot less burdensome from when I trained 20 years ago and everyone got six weeks of treatment," said Jagsi. "We've also learned how to do radiation therapy more safely."

Growing evidence suggests hypofractionation holds great potential for RT de-escalation while still delivering effective doses with less toxicity, she added.

Data on omission of RT in low-risk breast cancer populations is "remarkably consistent," said Nisha Ohri, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick.

"Particularly in women ages 65 to 70 and older with small, hormone receptor-positive tumors receiving endocrine therapy, there is strong data demonstrating that radiotherapy can be omitted without compromising survival outcomes," Ohri told MedPage Today via email. "Other studies are investigating the omission of radiotherapy based on tumor biology. However, it is worth noting that radiotherapy will still significantly reduce a woman's risk of in-breast tumor recurrence."

"There is also a question of compliance with extended endocrine therapy," she added. "While it is perfectly reasonable for older, low-risk patients to omit radiotherapy, consultation with a radiation oncologist for discussion of the risks/benefits of treatment is warranted to facilitate informed decision-making."

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