Mutter Discusses Partial Breast Irradiation in Low-Risk Breast Cancer

Robert W. Mutter, MD

Due to the multitude of available therapeutic options for patients with low-risk breast cancer, clinicians must consider each patient’s unique clinical profile and treatment goals when selecting the appropriate treatment course, according to a presentation given by Robert W. Mutter, MD, during The Radiation Oncology Summit: ACRO 2024.¹

“A range of surgical, systemic, and radiation options are available for [patients with] low-risk breast cancer,” Mutter, the chair of research in the Department of Radiation Oncology, as well as an associate professor of radiation oncology and an associate professor of pharmacology at the Mayo Clinic in Rochester, Minnesota, said during the presentation. “The optimal approach must account for each individual's unique combination of clinical risk, comorbidities, life expectancy, and personal evaluation of risks and benefits. I am not saying that endocrine therapy is always bad, [but] patients need to be aware of all of the options.”

Long-Term Disease Control and Safety Outcomes of Seminal PBI Trials

Mutter began his presentation by reviewing key data from randomized clinical trials of partial breast irradiation (PBI). The studies encompassed techniques including interstitial brachytherapy, intracavity brachytherapy, intra-operative radiotherapy, and external beam radiation.

Mutter highlighted topline findings from 7 studies of various radiation therapy strategies in early breast cancer: the ELIOT trial (NCT01849133); the phase 3 TARGIT-A (NCT00983684), GEC-ESTRO (NCT00402519), and APBI-IMRT-Florence (NCT02104895) trials; the NSABP B-39/RTOG 0413 (NCT00103181) and RAPID (NCT00282035) trials; and the phase 3 IMPORT LOW trial (ISRCTN12852634). The respective studies examined intraoperative irradiation cancer; risk-adapted targeted intraoperative radiotherapy vs whole-breast radiotherapy; accelerated PBI via sole interstitial multicatheter brachytherapy vs whole-breast irradiation; accelerated PBI vs whole-breast irradiation; accelerated PBI after breast-conserving surgery; external beam accelerated PBI vs whole breast irradiation after breast conserving surgery; and partial-breast radiotherapy after breast conservation surgery.^2-8

The median follow-up times for data from ELIOT (n = 1305), TARGIT-A (n = 3451), GEC-ESTRO (n = 1184), FLORENCE (n = 520), NSABP B-39/RTOG 0413 (n = 4216), RAPID (n = 2135), and IMPORT LOW (n = 2016), were 12.4 years (IQR, 9.7-14.7), 2.4 years (IQR, 12-52), 10.36 years (IQR, 9.12-11.28), 10.7 years, 10.2 years (IQR, 7.5-11.5), 8.6 years (IQR, 7.3-9.9), and 72.2 months (IQR, 61.7-83.2), respectively. The local recurrence rates for whole breast irradiation vs PBI in the respective studies were 1.1% (95% CI, 0.5%-2.2%) vs 8.1% (95% CI, 6.1%-10.3%; 10-year rates; P < .0001); 1.3% (95% CI, 0.7%-2.5%) vs 3.3% (95% CI, 2.1%-5.1%; 5-year rates; P = .042); 1.58% (95% CI, 0.37%-2.8%) vs 3.51% (95% CI, 1.99%-5.03%; 10-year rates; P = .074); 2.5% vs 3.7% (10-year rates; HR, 1.56; 95% CI, 0.55-4.37; P = .40); 4.6% (95% CI, 3.7%-5.7%) vs 3.9% (95% CI, 3.1%-5.0%; 10-year rates); 2.8% (95% CI, 1.8%-3.9%) vs 3.0% (95% CI, 1.9%-4.0%; 8-year rates; HR, 1.27; 90% CI, 0.84-1.91); and 1.1% (95% CI, 0.5%-2.3%) vs 0.5% (95% CI, 0.2%-1.4%; 5-year rates).

“[What] is most important to think about when interpreting these trials is the differences in irradiated breast volume with these various techniques,” Mutter noted.

Mutter went on to outline general guiding principles to help clinicians determine which patients should receive PBI as standard-of-care treatment over whole-breast irradiation. He pointed out that although whole-breast irradiation was superior to PBI in most of the studies, the long-term local recurrence rates were comparable between the 2 therapies in the IMPORT LOW, RAPID, and NSABP B-39/RTOG 0413 studies. Notably, in an exploratory analysis of the B-39/RTOG 0413 trial, investigators noted that patients who received PBI via 3-dimensional conformal radiation therapy experienced a 10-year local recurrence rate of 3.7% compared with 3.8% among those who received whole breast irradiation (HR, 1.04; 95% CI, 0.73-1.49).⁶

According to Mutter, generous PBI is preferred over whole-breast irradiation in patients with low-risk (T1, G1-2, ER+) tumors such as those in IMPORT LOW, and a biologically effective dose of 40 Gy in 15 fractions appears adequate for these patients, with the absolute benefit of boost dosing likely being minimal under the assumption that endocrine therapy has been administered. He also noted that outcomes from B-39/RTOG 0413 may indicate that patients with higher-risk disease features may achieve noninferior disease control with generous PBI, although additional investigation into this assertation is still needed; notable patient characteristics in this study included a median age of 54 years, ER and/or PR negativity rate of 19%, 10% of patients having pN1 disease, and 24% of patients having ductal carcinoma in situ.^1,6,7

“26 Gy x 5 [fractions] is my preferred evidence-based approach for PBI,” Mutter said in reference to the optimal dose fractionation for low- and higher-risk PBI candidates. “We know from the [phase 3] FAST-Forward whole-breast irradiation trial [ISRCTN19906132] that IMPORT LOW is equivalent in terms of disease control as well as toxicity to 40 gy x 15. We [also] know that excellent outcomes can be achieved with that biological dose of 40 gy x 15 from IMPORT LOW. So, we can extrapolate between those 2 and just give 26 Gy x 5 fractions if you don't want to bring patients in for 3 weeks.”

Radiation and Endocrine Monotherapy

Later in his presentation, Mutter discussed the role of endocrine therapy as it relates to radiation therapy in patients with low-risk breast cancer. He highlighted findings from a meta-analysis that examined the 20-year risks of breast cancer recurrence after stopping endocrine therapy at 5 years. Study authors noted that following 5 years of adjuvant endocrine therapy, the risk of recurrence continued to occur steadily throughout the study period. Recurrence risk was strongly correlated with TN status, with a rate ratio of 0.85 (95% CI, 0.75-0.96; P = .01) for T1a/bN0 vs T1cNo; the risk was also correlated with tumor grade, with a rate ratio of 0.67 (95% CI, 0.54-0.82; P < .001) for low vs high grade.⁹

Mutter then discussed an analysis of the phase 3 PRIME II (ISRCTN95889329) and the CALGB 9343 study, in which authors Ho and Bellon contended that radiotherapy could potentially be omitted for some patients with low-risk breast cancer. In both studies, patients received adjuvant endocrine therapy without radiotherapy. However, Mutter noted that radiation and endocrine therapy are highly synergistic in luminal breast cancer and that the absolute benefit of radiation therapy increases with longer follow-up. In PRIME II, the 10-year local recurrence rates were 0.9% vs 9.8% for patients who received radiation therapy (n = 658) vs those who did not (n = 668); the 10-year regional recurrence rates were 0.5% vs 2.3%, respectively.¹⁰

Mutter also highlighted several ongoing clinical trials that are investigating radiotherapy omission in T1/N0 breast cancer with low-risk biomarkers, including the phase 2 PRECISION study (NCT02653755), the IDEA trial (NCT02400190), and the observational LUMINA trial (NCT01791829).¹

“[Patients] with longer life expectancies may reasonably prefer combined-modality therapy given the improved disease control, breast conservation, and reduced morbidity from management of recurrent disease in the context of real-world endocrine therapy adherence. [Additionally], investigations into optimizing radiation with better-tolerated endocrine therapy may yield the maximum therapeutic ratio,” Mutter said in conclusion.

References

1. Mutter RW. Partial breast irradiation and early stage breast cancer: known knowns, known unknowns and unknown unknowns. Presented at: 2024 ACRO Annual Meeting; March 13-16, 2024; Orlando, FL.
2. Orecchia R, Veronesi U, Maisonneuve P, et al. Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial. Lancet Oncol. 2021;22(5):597-608. doi:10.1016/S1470-2045(21)00080-2
3. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603-613. doi:10.1016/S0140-6736(13)61950-9
4. Strnad V, Polgár C, Ott OJ, et al. Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial. Lancet Oncol. 2023;24(3):262-272. doi:10.1016/S1470-2045(23)00018-9
5. Meattini I, Marrazzo L, Saieva C, et al. Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term results of the randomized phase III APBI-IMRT-Florence trial. J Clin Oncol. 2020;38(35):4175-4183. doi:10.1200/JCO.20.00650
6. Vicini FA, Cecchini RS, White JR, et al. Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial. Lancet. 2019;394(10215):2155-2164. doi:10.1016/S0140-6736(19)32514-0
7. Whelan TJ, Julian JA, Berrang TS, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial. Lancet. 2019;394(10215):2165-2172. doi:10.1016/S0140-6736(19)32515-2
8. Coles CE, Griffin CL, Kirby AM, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet. 2017;390(10099):1048-1060. doi:10.1016/S0140-6736(17)31145-5
9. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377(19):1836-1846. doi:10.1056/NEJMoa1701830
10. Ho AY, Bellon JR. Overcoming resistance - omission of radiotherapy for low-risk breast cancer. N Engl J Med. 2023;388(7):652-653. doi:10.1056/NEJMe2216133