The role of postoperative radiotherapy after primary tumor resection in patients with de novo stage IV breast cancer

This study was undertaken to investigate the role of postoperative radiotherapy (PORT) including post‐breast conserving radiotherapy (PBCRT) and post‐mastectomy radiotherapy (PMRT) in stage IV breast cancer patients who underwent planned primary tumor resection (PTR).


INTRODUCTION
Breast cancer is the most common malignancy in women in the United States 1 and the second most common malignancy in the Republic of Korea. 2 Approximately 5-8% of patients with breast cancer are initially diagnosed with distant metastases 3 . Due to the heterogeneous demographic and tumor characteristics of stage IV breast cancer patients, their survival varies from months to years. 4,5 The standard of care for stage IV breast cancer is a systemic treatment, as the disease itself is regarded as incurable, with primary tumor resection (PTR) usually performed for palliative purposes only. 6 Advances in systemic agents since the mid-1990s have prolonged survival in patients with metastatic breast cancer, 7 suggesting that early PTR may be beneficial. Several retrospective studies have reported that PTR has a positive impact on local control and overall survival (OS). [8][9][10] Although three prospective randomized controlled trials (RCTs) in India, Turkey, and Austria, compared PTR with systemic therapy alone, [11][12][13] conflicting results were observed, suggesting that the benefits of PTR remain unclear. Recent data from the ECOG-ACRIN research group also failed to demonstrate the benefit of early PTR, and the data maturation is awaited. 14 In real-world practice, however, PTR has been performed on 35-80% of patients with stage IV breast cancer. 8,9 Thus, the incidence of postoperative radiotherapy (PORT), including post-mastectomy radiotherapy (PMRT) and post-breast conserving RT (PBCRT), has also increased. 15 Despite these increases, relatively little is known about the efficacy of PORT in patients with stage IV breast cancer. A study in Turkey reported that 38% of patients who underwent PTR received PMRT, with no difference in OS between patients who did and did not receive PMRT. 12 A retrospective study of patients with advanced T-/N-stage tumors found that PMRT improved local control and OS, but the differences were not significant. 9 By contrast, another retrospective study reported that PORT was a significant predictor of OS and progression-free survival (PFS). 10 The present study evaluated the impact of PORT on clinical outcomes in patients with stage IV breast cancer who underwent PTR.
Also, subgroup analyses of several prognostic factors were performed to identify populations that would benefit most from locoregional treatment.

Patients
Patients who presented with de novo stage IV breast cancer and who Metastatic burden was assorted into three categories: single, oligo, and disseminated metastases, as described. 16 Patients who satisfied all of the following criteria were considered as having oligometastases: (a) ≤2 organs involved other than the breast and its regional lymph nodes (LNs), (b) ≤5 metastases per organ (≤10 in patients with tiny, unclear lesions in the lungs and/or bones), and (c) lesion size ≤5 cm.
To compensate for the differences between patients who did and did not receive PORT, additional analyses excluding the patients with disseminated metastases were conducted. Also, we subdivided this cohort according to molecular subtypes and evaluated the effect of PORT separately. The study protocol was approved by the local institutional review board, which waived requirements for informed consent.

Treatments and follow-up
Overall treatments were decided by multidisciplinary teams, which included a surgeon, a medical oncologist, a radiation oncologist, and a radiologist.

Statistical analysis
The primary outcome of the present study was 5 year OS, and secondary endpoints were 5-year locoregional recurrence-free survival (LRRFS) and distant PFS (DPFS). Locoregional recurrence (LRR) was defined as a failure in the breast/chest wall or regional nodal areas.

Patient characteristics
The characteristics of the total of 112 patients who were included are listed in Table 1. PMRT was administered to 33.9% of the patients (n = 38) and PBCRT was performed in 21.4% of the cohort (n = 24).  in patients who did not receive postoperative chemotherapy and 7 months (range, 3-9 months) in patients who did receive postoperative chemotherapy.

Effects of PORT in patients without disseminated metastases
To reduce the discrepancies between the patients who did and did not receive PORT, patients with disseminated metastases were excluded.  Table 3.
In a total of 94 patients without disseminated metastases, PBCRT was a significant factor in the univariate analysis compared to No PORT (Figure 2A), however, it lost its significance in multivariate analysis. There was a trend of better LRRFS in PBCRT and PMRT arms ( Figure 2B), however, they failed to show significance in univariate and multivariate analyses. PORT also had no impact on DPFS ( Figure 2C).   (Table 3).

DISCUSSION
The present study showed that PORT following PTR yielded favorable outcomes in patients with de novo stage IV breast cancer. Median OS was 55 months, in agreement with the results of previous studies, which reported median OS ranging from 19.2 to 56.1 months (Table 4). 8,[11][12][13]18 This was likely due to the strict inclusion criteria of the present study, in those patients who progressed after neoadjuvant chemotherapy or within 2 months after PTR were excluded. A previous RCT in India also excluded patients who showed progressive or stable disease after neoadjuvant chemotherapy because these patients were deemed unfit for PTR. 11 The present study, therefore, focused on the patients who could benefit most from planned PTR, with or without PORT.
Several RCTs and retrospective trials have assessed the effects of PTR in patients with stage IV breast cancer (Table 4). A recent systematic review and meta-analysis, which included a total of 67 986 patients, found that PTR may benefit selected patients with limited disease burden. 19 In the present study, luminal type A or B was significantly predictive of a good prognosis in the overall patient population.
These results were in good agreement with those of previous studies, which reported that the expression of ER or PR was independently associated with OS (HR, 0.37-0.79). 8,11,20 Moreover, a subgroup analysis of the MF07-01 study found that PTR had significant survival benefit in patients with luminal types A and B and HER2-negative tumors. 12 Although PBCRT was also a significant predictor of OS in the entire population, there may have been a possible bias due to differences between patients who did and did not receive PORT. Because the percentage of patients with disseminated metastases was significantly higher in patients who did not receive PORT, we attempted to minimize this bias by excluding patients with disseminated metastases. Although  The present study also evaluated the effect of a planned intervention to metastatic lesions performed within 3 months after PTR or postoperative chemotherapy. Although not significantly predictive of survival, these interventions may benefit patients. For example, a phase II trial evaluating the effects of radical radiotherapy to all metastatic sites (≤5 lesions) showed promising results, with 1 and 2 year PFS rates of 75% and 53%, respectively; and 2-year local control and OS rates of 97% and 95%, respectively. 22 The results of an ongoing phase II/III trial (NRG-BR002) assessing the role of stereotactic body radiotherapy or surgical ablation in patients with oligometastatic breast cancer are pending. 23 The present study had several limitations, including its retrospective design making it susceptible to possible selection bias and its inclusion of patients treated over 14 years. In addition, the number of patients was small, such that not all factors were well balanced between groups of patients who did and did not receive PORT. Furthermore, this study did not assess toxicity on quality of life. Despite these limitations, the present study is the second largest retrospective study, with the longest median follow-up time, to evaluate the effects of PORT in a homogenous population of stage IV breast cancer patients diagnosed and treated in a single tertiary medical center.
Patients with de novo stage IV breast cancer who received planned PTR showed favorable survival outcomes compared with historical cohorts, suggesting that PTR may benefit these patients, especially those with luminal A or B type tumors. Administration of PBCRT was significantly predictive of longer LRRFS, suggesting that PORT may benefit these patients. Large randomized control trials focusing on patients with good prognoses are needed.

CONFLICT OF INTEREST
No potential conflict of interest was reported by the authors.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
Approval to conduct this study (version 1.1 on 18 April 2019) was granted by the Institutional Review Board of Seoul Asan Medical Center (S2018-1826-0001), and the present retrospective study was conducted in accordance with the Helsinki Declaration.

FUNDING INFORMATION
This work was supported by the National Research Foundation (NRF) grant funded by the Korean government (NRF-2018R1D1A1B07049970).