This was a prospective registry study from the Netherlands. Between 2011 and 2015, patients with clinical T1-2N1 breast cancer treated with neoadjuvant chemotherapy and surgery across 17 centers were enrolled. Lymph node metastasis had to be confirmed histologically, and patients with 4 or more clinically suspicious nodes were not eligible. The study guidelines assigned patients to one of three risk groups based on their nodal response to chemo. Low-risk patients were ypN0, and they received whole breast radiation after lumpectomy but no chest wall or regional nodal irradiation (RNI) regardless of axillary surgery technique. Intermediate-risk patients had 1-3 residual positive nodes, and they received breast and chest wall radiation with radiation to the low axilla (levels I and II) only if no ALND was performed. High-risk patients had 4 or more residual positive nodes, and they received radiation to all of the above plus medial axilla/supraclavicular fossa. Only 6% received internal mammary radiation, though. Of 838 patients, 35% were low risk, 44% were intermediate risk, and 21% were high risk. Overall, 64% of patients actually received radiation according to the study guidelines. Guideline concordant radiation was most frequent in the high-risk group (86%) and least in the intermediate risk group (56%). So what was the source of variation? In the low-risk group, 37% of patients received more extensive RT than recommended. In the intermediate risk group, 17% received less than recommended RT while 29% received more than recommended. In the high-risk group, 14% received less than recommended RT. At 5 years, locoregional-only recurrence was rare (2.2%) and there was no difference in recurrence among risk groups. Any locoregional recurrence occurred in ~5% when counted along with distant recurrences. When looking only at patients treated per the study guidelines, locoregional recurrence remained low at 2.3% for low risk, 1% for intermediate risk, and 1.4% for high risk. In summary, this study showed that Response-adapted adjuvant radiation for lymph node positive (1-3) breast cancer treated with neoadjuvant chemotherapy results in a ~2% risk of locoregional recurrence at 5 years across risk groups.

Reference (Pub-Med Link): de Wild, S. R., de Munck, L., Simons, et al. (2022). De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study. Lancet Oncology, 23(9), 1201–1210. https://doi.org/10.1016/S1470-2045(22)00482-X

Key Institution: Netherlands
Keywords: Breast

Both the practice of tumor bed boost and moderately hypofractionated whole breast irradiation (WBI) has been accepted in the medical community for women with invasive breast cancer thanks to large, randomized trials. For the treatment of DCIS, however, such strength and level of evidence has not existed until BIG3-07/TROG 07.01.

This study enrolled 1608 women with non-low-risk DCIS across 136 participating centers in 11 countries. Eligible patients were age >18, unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1mm of clear radiation resection margins. “Non-low risk” DCIS was defined by having at least one clinical or pathological marker for increased risk of local recurrence: younger age (<50 y), symptomatic presentation, palpable tumor, microscopic tumor size measuring 15mm+, multifocal disease, intermediate or high nuclear grade, central necrosis, comedo-histology, or a radial surgical margin of less than 10 mm.

Patients were assigned to one of four groups (1:1:1:1) of no tumor bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after the treating center prespecified conventional or hypofractionated WBI. Conventional WBI was 50 Gy in 25 fractions, and hypofractionated WBI was 42.5 Gy in 16 fractions. The boost dose was 16 Gy in 8 fractions, delivered after WBI.

Tumor bed boost after postoperative WBI significantly reduced local recurrence (92.7% -> 97.1%, HR 0.47, p<0.001) with an increase in grade 2 or higher toxicity in breast pain (10% -> 14%, p=0.003) and induration (6% -> 14%, p<0.001). The effect of tumor bed boost was consistent across all patient subgroups. Moderately hypofractionated WBI was as safe and effective (5y FFLR 94.9% vs 94.9%)  as conventional fractionation in DCIS.

This is the only randomized phase 3 trial that examines the effects of both a tumor bed boost and WBI dose fractionation in patients with non-low-risk DCIS. This supports the adoption of moderately hypofractionated WBI with tumor bed boost in non-low-risk DCIS to improve the balance of local control, toxicity, and socioeconomic burdens of treatment. The international scale of this study supports generalizability of the findings. The 16-fraction schedule used in this study may not be the clinical limit of whole breast hypofractionation in DCIS, as use of 5-fraction regimens have been adopted for invasive breast following demonstrating of non-inferiority to 15-fraction regimens in regards to tumor control and normal tissue effects.

Reference (Pub-Med Link): Chua, B. H., Link, E. K., Kunkler, I. H., et al. (2022). Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study. Lancet (London, England), 400(10350), 431–440. https://doi.org/10.1016/S0140-6736(22)01246-6

Key Institution: Multi-Center, international

Keywords: breast

Women with early-stage breast cancer and large breast size (bra band ≥ 40 in and/or ≥ D cup) have been shown to have increased risk of toxic effects related to adjuvant breast radiotherapy. In this multicenter, phase 3, single-blind randomized clinical trial of 378 patients treated with adjuvant breast radiotherapy, 182 (51.0%) were treated in the supine position and 175 (49%) were treated in the prone position. Initially, patients were treated with conventional fractionation (50 Gy in 25 fractions), though the protocol was amended at 3 years to allow hypofractionation (42.5 Gy in 16 fractions). Authors found that treatment in the prone position was statistically significantly associated with lower rates of moist desquamation (26.9%), compared with treatment in the standard supine position (39.6%). They also showed increased toxic effects associated with use of a radiotherapy boost and conventional fractionation.

(Open Access)

Reference (Pub-Med Link): Vesprini, D., Davidson, M., Bosnic, S. et al. (2022). Effect of Supine vs Prone Breast Radiotherapy on Acute Toxic Effects of the Skin  Among Women With Large Breast Size: A Randomized Clinical Trial. JAMA Oncology, 8(7), 994–1000. https://doi.org/10.1001/jamaoncol.2022.1479

Key Institution: Sunnybrook Health Sciences Centre, Toronto, Canada
Keywords: Breast

Based on the CALGB 9343 study, patients age ≥ 70 with pT1N0 ER/PR + HER2- breast cancer treated with lumpectomy and endocrine therapy have been considered candidates for omission of radiotherapy. This NCDB retrospective analysis of 11,891 patients was conducted to determine whether recurrence score (RS) test (Oncotype Dx) is predictive of who may benefit from radiation following breast conservation therapy. Patients were stratified based on their RS where: low risk=1-10, intermediate risk=11-25, high risk=26-99. The study found an overall survival benefit with the use of radiotherapy in patients with RS≥ 11, but not in patients with RS< 11. Among older women with hormone receptor positive breast cancer and high and intermediate scores, there was a survival benefit with the addition of radiation. The authors recommend assessment of RS in this older subset of patients and adjuvant radiation should be considered when RS ≥ 11. Future prospective studies should evaluate the use of RS to determine benefit of radiation.

Reference (Pub-Med Link): Chevli, N., Haque, W., Tran, K. T., et al. (2022). 21-Gene recurrence score predictive for prognostic benefit of radiotherapy in patients age ≥ 70 with T1N0 ER/PR + HER2- breast cancer treated with breast conserving surgery and endocrine therapy. Radiotherapy and Oncology, 174, 37–43. https://doi.org/10.1016/j.radonc.2022.06.013

Key Institution: USA (NCDB analysis)
Keywords: Cancer Biology, Breast

Long-term (five-year) follow-up of TARGIT-A, a prospective phase III randomized trial of 1153 patients ≥ age 45 with invasive ductal carcinoma of the breast no larger than 3.5cm status post breast-conservation surgery randomized to delayed intraoperative radiation therapy (IORT) delivered as second operative procedure via reopening of lumpectomy site vs external beam radiation therapy (EBRT). Primary outcome: Noninferiority margin of 2.5% local recurrence (LR) rate at 5 years. 581 patients were randomized to IORT, 572 to EBRT. Delayed IORT was not non-inferior to EBRT. The 5-year LR rate was 3.96% for IORT vs 1.05% for EBRT (statistically significant). At long-term follow-up at median 9 years, the following measures were not statistically significantly different between groups: LR-free survival, mastectomy-free survival, distant disease-free survival, overall survival. Conclusion: patients treated with delayed IORT after lumpectomy had a higher rate of local recurrence compared to patients treated with EBRT, though no difference in mastectomy-free survival, distant disease-free survival, or overall survival.  

(Open Access)

Reference (PubMed Link): Vaidya JS, Bulsara M, Saunders C, et al. Effect of delayed targeted intraoperative radiotherapy vs whole-breast radiotherapy on local recurrence and survival: Long-term results from the targit-a randomized clinical trial in early breast cancer. JAMA Oncol 2020;6:e200249.

Key Institution: Multi-Institution (TARGIT-A trial)
Keywords: Breast cancer, intraoperative radiotherapy, whole breast irradiation