This study is a first large series from Pakistan evaluating the efficacy of PMRT in 1–3 positive node group who had Modified Radical Mastectomy with adequate axillary clearance. Our study supports the hypotheses that benefit of radiotherapy is quite distinct in group with 1–3 positive nodes who received radiation post mastectomy than in non PMRT group.
The patients were subjected to radiotherapy based on prognostic factors (age, high histologic grade, presence of LVI, extracapsular extension of tumour deposit, molecular subtype and/or ER/PR negative status) at the discretion of multidisciplinary tumour board meeting. The results showed that radiotherapy has improved the loco regional control and distant recurrences in PMRT vs Non PMRT. At median follow up of 78 months the disease-free survival rate and overall survival rate was significantly superior for PMRT patients (p < 0.000).
Our study identified that Loco regional recurrence (LRR) is an important predictor of DFS. Interestingly we found that only 4 (1.4%) patients developed loco regional recurrences in radiotherapy versus 74(15.9%) in the no radiotherapy group and the distant recurrence was seen in 34 cases of non PMRT group. Our results support other retrospective studies that the lack of PMRT is a strong predictor of a shorter DFS which they correlated with distant metastasis and greater lymph node involvement in triple negative subtype and/or high nuclear grade.9–11
We reviewed Regional and international data to identify factors associated with improved DFS and OS. Cosar et al showed that LRR was significantly higher in non PMRT vs PMRT (17% vs 3%) with noteworthy improvement in DFS (p 0.034), similar findings were reported from China reported LRR rate 1.1% and 90.1% in PMRT vs Non PMRT respectively at median follow up of 65 months. Both of these study results did not show any improvement in the overall survival the reason could be a small sample size and short follow up period.3,9 Recently, results from the Breast International Group 02–98 trial also showed no significant improvement in OS in two cohorts with or without RT which they postulated that use of modern systemic chemotherapy obviates the value of PMRT in improving OS. Nevertheless, majority of our patients received anthracycline and taxane based chemotherapy and where needed trastuzumab was given in both the cohorts.12 Overgaard et al have performed subgroup analysis of the DBCG 82 b&c randomized trials to evaluate the loco-regional recurrence rate and survival in relation to number of 1–3 positive nodes, they limited the analysis to 1152 node positive patients with 8 or more nodes removed. They reported improved overall 15-year survival rate in this subgroup 39% and 29% (p = 0.015) with or without radiation which is consistent with our results.12 Meta-analysis on role of PMRT in 1–3 nodes regardless of use systemic therapy identified that the majority of retrospective studies used had shorter follow up time (53–150 months), they indicated that longer follow-up time may allow the significant benefit of reducing LRR and distant recurrence to translate to an increased benefit in OS which is a fair explanation as in our study the follow up time was significantly longer as reported in meta-analysis also (24 months − 336 months).11
The logical question is whether radiotherapy is equally effective in situations where there is small tumour size with comparatively smaller disease burden i.e. 1–3 positive nodes? Another pertinent question cam be asked, is it logical to determine XRT need based on the number of positive nodes only? Overgaard and his group have reached the conclusion in their sub group analysis that taking the decision to irradiate only on the basis of number of lymph nodes is a crude method to define the potential need to recommend radiation, more strong recommendation can be made on the basis of lymphovascular invasion, extra nodal extension of tumour, molecular subtype, young age and high grade in intermediate risk category i.e. 1–3 nodes positive.12
Multivariate analysis of our cohorts has proved that low burden disease i.e. one node positive in the presence of other poor prognostic factors did not show any significant benefit in improving LRR or OS. This is consistent with results from several other retrospective reviews and trials. However, 2–3 node positive disease with molecular subtype and/or ER/PR negative, presence of LVI, high nuclear grade, extra capsular extension of tumour deposit reached statistics significance in improving LRR, DFS, DMFS and OS.
Several theories have been proposed to justify the potential benefit of radiotherapy (RT) in TNBC. Accepting the fact that ER/PR – or triple negative are a poor prognostic group with highly proliferative, poorly differentiated, high grade disease aggressive nature. It is frequently associated with a BRCA-1 mutated pathologic subtype; its presence can reduce the capacity of DNA repair which enhanced the radio sensitivity of TNBC cells.14 Moran hypothesized that different biological subtypes within TNBC have different radio sensitivities that could be the reason that despite lack of level 1 evidence these cohort do better with radiation.15 Another potential mechanism could be that radiation promotes cancer cell autophagy which is recognized as having the potential to contribute to cell killing in response to a variety of chemotherapeutic agents as well as ionizing radiation.16 However conflicting reports has been published from separate studies on impact of PMRT in different molecular subtypes of breast cancer in reducing LRR and improving survival. Contrary to our finding a retrospective analysis of 16521 from SEER data showed PMRT significantly prolonged survival in Luminal A patients, their results were consistent with findings from Danish Breast Cancer Cooperative group.17, 18 Congruent to our results retrospective analysis of 1369 patients from China reported PMRT reduced LRR rate in TNBC, but showed no effect on OS irrespective of subtypes. Wang et al reported that that the combination of chemotherapy and radiotherapy could significantly increase five-year recurrence-free survival and overall survival in TNBC women after mastectomy in stage I-II.10, 19 St. Galen Consensus Conference 2019 on early breast cancer treatment standards strongly recommended post-mastectomy radiotherapy in N + 1–3 with adverse features such as TNBC (yes 85% vs no 8%).5
Several retrospective analyses reported association between LRR and survival with LVI, high grade disease or ECE of tumour in 1–3 node positive group.3, 9, 19 We observed in our results that grade III disease, presence of LVI and extra capsular extension is associated with improved prognosis and lesser recurrences.
A retrospective analysis from Cleveland clinic has shown that LRR rate was 50.4% in non-radiation group with both Grade III disease and ECE over 5 years, similarly Katz et al reported that high grade disease with ECE > 2 mm experienced high rate of LRR without RT.20,21 Evidence has suggested that LVI is an adverse prognostic factor for relapse and survival particularly in triple negative breast cancer.22,23 Based on their analysis Ahn et al concluded that adjuvant RT minimized the negative prognostic effect of LVI on DFS p = 0.068 [with RT] vs. p = 0.011 [without RT]. 24 Cosar at al associated LVI with improved OS.3
Another compelling fact the study revealed is that the Her 2 neu enriched tumours also demonstrated marked difference in LRFS between two groups however half of the studied patients did not receive Trastuzumab hence we could not ascertain with confidence that Her 2 neu molecular subtype may benefit from radiotherapy in 1–3 node positive group the same observation has been shared by Zhen et al.3 Due to the fact that patients who received trastuzumab have a very low rate of LRR as compare to other molecular subtypes with that in mind it is inexplicit whether targeted treatment may modify the study result.26
There are certain limitations to this study. First, inherent selection bias exists as this is a retrospective chart review therefore there might be some missing data and information that was included besides small sample size. Second, multivariate model was used to control confounders however there is a possibility of unmeasured confounders during data collection.
Patient were assigned to radiotherapy based on decision of multidisciplinary tumour board, the decision was taken based on available evidence from meta-analysis and well-designed controlled trials.
The only solution to uniformly address this grey zone is RCT hence clinicians are desperately waiting for result of 02–04 MRC EORTC SUPREMO trial which recruited > 1600 patients prospectively between April 2007 and May 2013. This trial aim to determine the effect on overall survival of chest wall irradiation after mastectomy and axillary surgery in women with operable breast cancer at ‘intermediate-risk’ of loco regional recurrence and who also received modern systemic therapy.25 However, the results of this trial are expected in 2023 at the earliest, hoping much of the controversy will be resolved with their data!