De-escalating postoperative radiation therapy after primary systemic therapy in cT1-2N1 breast cancer: lesson from the RAPCHEM/BOOG 2010-03 trial

Primary systemic therapy (PST) in operable breast cancer is recommended by international guidelines for most of node-positive disease likely to obtain a pathological complete nodal response, for clinical T stage (cT) ≥2 or clinical N stage (cN) ≥1 human epidermal growth factor receptor 2 (HER2) positive or triple-negative disease or for patients who need a downstaging of the primary lesion to undergo breast conserving surgery (1). Indication to PST is also increasing for small node-negative tumours.

Guidelines and indications concerning postoperative locoregional radiation therapy (RT) are mainly based on trials evaluating patients treated with upfront surgery. Therefore, clinical evidence about locoregional treatment after PST are less robust and clear. Such indications are based on several retrospective and pooled analysis studies (2) and recommend postoperative locoregional RT in clinical stage III irrespective of response to PST, while no added benefit is demonstrated in cT1–2 N0 disease (1,3). It is debated whether locoregional RT is beneficial for patients with intermediate-risk disease, namely cT1–2 N1 breast cancer, where the risk of recurrence depends also on the response to PST and tumour biology-related factors (4,5).

A burning question is if and how to tailor locoregional RT depending on axillary response to PST (6). Postoperative RT de-escalation strategies in this setting were so far evaluated on evidence from retrospective series, post-hoc analyses, and pooled retrospective series, showing conflicting results (7). On the other hand, several centres started to tailor postoperative RT based on pathological response to PST in their routine practice (8).

de Wild et al. (9), recently published the 5-year follow-up results from the RAPCHEM (BOOG 2010-03) registry, a prospective multicentre Dutch study on RT de-escalation after PST for cT1–2 N1 breast cancer patients. The study included 848 patients from 17 centres in The Netherlands treated with at least three cycles of PST followed by surgery of the breast and axilla. Axillary status had to be cytologically or histologically confirmed before PST. The patients were treated with postoperative RT following a pre-specified consensus-based study guideline endorsed by the Dutch Breast Cancer Research Group. The study protocol was then amended in 2013 after the publication of the outcomes of the ACOSOG Z0011 trial (10) to include patients who did not receive axillary lymph node dissection (ALND). Following the guideline, patients were assigned to one of the three predefined locoregional recurrence (LRR) risk groups: low (i.e., ypN0), intermediate (i.e., ypN1, one to three positive nodes in surgical specimen after PST), or high risk (i.e., ypN2–3, four or more positive nodes in surgical specimen after PST). Other risk factors were used to assign patients who did not receive ALND, and were identified as follow: tumour grade 3, lymph vascular invasion, and tumour size ≥3 cm.

The low-risk group was then addressed to whole breast irradiation in case of breast conserving surgery. The intermediate-risk group was treated with breast or chest wall irradiation after breast-conserving or radical surgery, respectively, with the addition of I–II axillary regions irradiation in case of ALND omission. Finally, the high-risk group received a regional nodal irradiation (RNI; including III–IV axillary regions). RT to the internal mammary nodes was optional. Authors designed the trial with the hypothesis that 5-year LRR rate would be less than 4%, with a 95% confidence internal (95% CI) upper limit inferior to 7.8, requiring 237 patients per risk arm for an 80% statistical power and one-sided α of 5%.

Only the 5-year results are presented in the recent publication since the long-term endpoints were not yet reached. In a previous paper, authors pointed out that the adherence to the study guideline was relatively low, being followed for the 64% of patients (11). The final analysis included 291 patients in the low-risk group, 370 patients in the intermediate-risk group and 177 patients in the high-risk group, with a median age of 49 years. The overall population included 64% of hormone-receptor (HR)-positive HER2 negative patients, 13% of triple-positive patients, 7% of HR-negative HER2 positive patients, and 15% of triple-negative patients. About 80% of patients in the high-risk group were HR-positive and HER2 negative, while roughly half of the patients with triple positive, triple negative or HER2 enriched subtypes were allocated in the low-risk group, showing higher response rates to PST. Neoadjuvant chemotherapy mainly consisted of regimens based on anthracyclines and taxanes (76%), ALND was performed in most patients (>80%), and RT was mostly delivered with moderately hypofractionated schedules (87%). In the 54% of patients, a tumour bed boost (16 Gy in 8 fractions) was also delivered, while internal mammary chain was irradiated only in the 6% of patients.

After a median follow-up of 5.8 years, the primary endpoint of the study was met, with a 5-year LRR of 2.2% (95% CI: 1.4–3.4%) for the whole group and no statistical difference in terms of LRR among the different risk groups. In a post-hoc analysis conducted on patients for which the study guideline was followed, the primary study endpoint was also met, with a LRR of 2.3% for the low-risk group, 1% for the intermediate-risk group, and 1.4% for the high-risk group. The 5-year relapse-free survival rate was 86.4% and the 5-year overall survival rate was 92.2%. Both outcomes significantly differed among risk groups. At the multivariate analysis, triple negative disease and grade 3 tumours negatively correlated with relapse-free survival, while a complete response to PST showed an independent favourable correlation.

Before the RAPCHEM study, retrospective available data on RT after PST provided conflicting results. In a series of 134 clinical stage II–III patients who achieved pathological complete nodal response after PST, chest wall irradiation did not demonstrate a benefit in terms of LRR or survival (12); while in another series investigating the same target population, the benefit from irradiation in terms of LRR seemed to be dependent on the breast cancer subtype (13). In a meta-analysis of retrospective heterogeneous studies of patients with pathological complete response after PST, locoregional RT demonstrated significant benefit in clinical node positive patients achieving a pathological nodal complete response in terms of LRR but failed to demonstrate a significant benefit in terms of disease-free and overall survival (14). These results were in line with the National Cancer Database analysis published by Rusthoven et al. (15), analysing 15,315 cT1–3 N1 breast cancer patients treated with PST and surgery to breast and axilla. In this large series, postmastectomy RT was significantly associated with a survival improvement regardless of the axillary pathological response, while RNI did not demonstrate an additional benefit in terms of survival in patients treated with breast conserving surgery irrespectively of axillary pathological response.

The RAPCHEM registry is the first study providing prospective data on de-escalation of postoperative RT according to response to PST in cT1–2 N1 breast cancer patients. The strategy proposed by the authors did not translate in worse outcomes according to the study results. However, being low-represented, no definitive conclusions can be drawn for the no-ALND population, also considering that these patients are less intensively staged and therefore it is more difficult to properly assign them to the correct risk group according to the RAPCHEM guideline principles. Several randomized ongoing trials will help to prospectively assess the value of ALND and RNI in the clinical node positive population after PST (6). The relatively high rate of deviation from the study guideline, which consisted especially in treatment intensification in the low- and intermediate-risk groups, not only lowers the reliability of the results, but also reflects the need for clinicians to safely consider RT de-escalation in the context of interventional randomized trials.

The crucial aspect is how to properly select patients who might benefit from de-escalation strategies. A pathological response-based approach, as proposed in the RAPCHEM study, seems to be easy to apply (when ALND is performed) and supported by the differences obtained in terms of relapse-free and overall survival among the different risk groups. On the other hand, it may lead to paradoxically classify those patients affected by more aggressive breast cancer subtypes, which are more sensitive to PST, into low-risk groups with higher benefit expected from locoregional RT de-escalation. At the same time, biological features, such as triple negative disease or tumour grade 3 disease, were correlated with worse outcomes at the multivariate analysis. For these reasons, whether considering the pathological response rather than the histological risk features to guide a de-escalation strategy is still an open question. An intriguing future approach might be represented by the integration of clinical and histological characteristics with circulating tumour DNA (ctDNA) (16).

In conclusion, according to the results of the RAPCHEM study, pathological response to PST seems to be a reliable tool for considering RT de-escalation, especially in patients obtaining a pathological complete response. However, in our opinion available data are not sufficiently univocal to automatically translate RAPCHEM strategy into clinical practice. In addition, the possibility to de-escalate surgery for selected patients adds uncertainty for a pathological response-based approach and other factors, such as ctDNA and genomic testing, may have an impact on the estimation risk of relapse and could be therefore considered for optimisation strategies in the next future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1051/coif). IM disclosed occasional fees for advisory board supported by Novartis, Eli Lilly, Pfizer, Seagen, Gilead, and Accuray. The other authors have no conflicts of interests to disclose.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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