The application of PMRT in patients with pT3N0M0 breast cancer is controversial. Floyd et al. assessed the value of PMRT in patients with node-negative breast tumors of 5 cm or larger. They found a low 5-year LRR rate of 7.6% (95% confidence interval, 3%–16%) and 5-year DFS of 86% in the cohort and demonstrated LVI as a risk factor for worse LRFS, DFS, and OS. Taghian et al. reviewed patients with tumors larger than 5 cm who were treated in five NSABP node-negative trials, and identified locoregional failure in 7.2% of patients with tumors of more than 5 cm . In our study, the 5-year LRR rate was only 1.9% and 5-year DFS was 90.5% in the non-PMRT group, better than the findings in prior studies. Moreover, the risk of LRR at 5 years in patients treated with PMRT was even lower at 0%. The two abovementioned studies included patients between 1981 and 2002. However, in our study, seven of 28 patients (25%) treated between 2000–2008 received adjuvant chemotherapy, while 44 of 86 (81.9%) patients treated during 2009–2016 received adjuvant chemotherapy. Anthracycline-based adjuvant chemotherapy was delivered to 57.1% of patients during 2000–2008, while anthracycline- and taxane-based adjuvant chemotherapy was administered to 52.3% of patients during 2009–2016. Moreover, the application of trastuzumab in HER2-positive patients increased from 0% before 2008 to 56.8% after 2008, and hormonal therapy in ER-/PR-positive patients increased from 50% before 2008 to 93.8% after 2008. For patients who received PMRT mainly during 2009–2016, when systematic treatments were improved, it is very likely that the improvements in systematic treatment could have contributed to the lower rate of LRR and better DFS in our study. This could also partly explain why PMRT increased LRFS but without statistical significance. However, we must strengthen that for patients with risk factors, PMRT improved their LRFS and DFS and was found to be an independent prognostic factor for DFS.
Jagsi et al. analyzed the failure rate in 877 node-negative patients treated by mastectomy without PMRT. They found the chest wall was the most common site of failure, and a tumor size greater than 2 cm, a margin less than 2 mm, premenopausal status, and LVI were significant prognostic factors. We only included patients with tumors of more than 5 cm, consistent with the results of Floyd et al. and Jagsi et al. LVI was also identified as an unfavorable factor, and, with more specific information, we also identified TNBC and a family history of malignant tumors as unfavorable prognostic factors. Two of three patients who had all three risk factors (TNBC subtype, grade 3, LVI +) developed LRR in our study. Taken together, we agree with the conclusions of Jagsi et al. that node-negative patients with high-risk factors should be recommended PMRT to improve locoregional control.
The three studies mentioned above did not compare survival difference between patients with or without PMRT. We could not identify whether PMRT would benefit pT3N0M0 patients from their data analysis. In 2017, a retrospective, multi-institutional review regarding PMRT for pT3N0M0 patients was reported with a median follow-up of 6.2 years and 5.3 years in the non-PMRT and PMRT cohorts, respectively. In this study, there was an isolated local regional failure rate of 12% at 10 years without PMRT, and 5- and 10-year LRFS for the PMRT and non-PMRT cohorts were 98% and 88%, respectively (P=0.15). Consistent with their outcome, PMRT was also found to be associated with better locoregional control, but without statistical significance in our study (P=0.17). This might be because of the number of patients, and, more importantly, the number of events was relatively small in our study. However, we identified PMRT as an independent prognostic factor for DFS (P=0.042). In a study by Goulart et al. that included 100 patients with pT2=5.0 cm and pT3 >5.0 cm tumors treated by mastectomy, a low LRR rate (2.3% in the PMRT group vs 8.9% in the non-PMRT group) was demonstrated, but, similar to our results, they found no significant improvement in LRFS and BCSS with PMRT, and concluded that PMRT should be considered for patients with grade 3 histologic features and patients without hormonal therapy. In our study, there was also a trend toward worse LRFS for patients with ER negativity and grade 3 histologic features.
Studies of pT3N0M0 patients in large populations at individual or multiple institutions have been lacking because of the infrequency of this clinical scenario, and thus many databases have been explored to analyze the features of this rare cohort. A study by Johnson et al. analyzed 2525 patients treated between 2000 and 2010 from the SEER database and found a benefit for PMRT. Multivariate analysis indicated that PMRT improved OS (HR 0.63, P<0.001) and cancer-specific survival (HR 0.77, P=0.045), and concluded that PMRT should be strongly considered in T3N0M0 patients. Cassidy et al. analyzed data from National Cancer Data Base (NCDB) including 3437 patients with pT3N0M0 breast cancer who were initially treated by mastectomy between 2003 and 2011. They concluded that PMRT was found to be associated with improved OS (86.3% vs 66.4%, P<0.01), regardless of surgical margin status, tumor size, and receipt of systemic therapy. Francis et al. analyzed the survival of 4291 pT3N0M0 patients from the NCDB and found improved OS for patients with PMRT on multivariate analysis (HR 0.72, P<0.001) and in the propensity score matching cohort (P<0.001). However, both the SEER database and NCDB had no records of LRR or detailed information regarding chemotherapy and hormonal therapy, NCDB even had no information on the cause of death, which might indicate that death from causes other than breast cancer may have contributed to the improved OS, as PMRT group had more younger patients in their studies. Another analysis of pT3N0M0 patients from the SEER database including patients less than 50 years old found no differences in BCSS and OS. In our study, we did not find a significant difference in BCSS between the two groups. Altogether, all studies including ours demonstrated good survival for pT3N0M0 patients, especially in those who received PMRT.
In addition, during clinical practice, breast cancer is still commonly classified into different molecular subtypes according to immunohistochemical staining combined with the results of in situ hybridization analyses of human epidermal growth factor receptor 2 (HER2). Different subtypes represented diverse prognoses. In 2019, an analysis of the survival of 14,464 female patients with TNBC diagnosed with pT1-4N0M0 from the NCDB (2004–2014) was reported. In total, 801 patients were pT3N0M0, of which 51.6% received PMRT, application of PMRT was associated with better OS for patients with pT3 disease. Additionally, multivariate analysis reported increased age, T stage, and positive surgical margins as negative variables for OS (5-year OS 62.6% vs. 74.3%, P<0.001). However, this study had a median follow-up of only 38.2 months (interquartile range, 25.9–51.7 months) and no survival data of LRFS and chemotherapy agents used; furthermore, the prognostic factors were analyzed among all patients including pT1–2 and pT4 patients. There was no detailed information on basic characteristic distribution between pT3N0M0 TNBC patients with or without PMRT. We had more specific information, and our study found TNBC patients suffered poorer LRFS and DFS compared with non-TNBC patients or luminal subtypes. Thus, for pT3N0M0 patients with TNBC, especially among those with other risk factors, PMRT should be considered to improve outcomes.
Besides, a hypothesis has been proposed indicating that patients with breast cancer with a larger tumor volume (>5 cm) may represent a rare subgroup with benign biological behaviors. In particular, a low LRR incidence was reported in previous studies, supporting the hypothesis indirectly. With the development of breast cancer classification by genotype and immunophenotype, the diagnosis for this rare cohort with pT3N0M0 breast cancer may be better interpreted. Patients who are at high risk may be distinguished from those who are not, thus avoiding unnecessary expenditure and toxicities from various treatments.
The main strength of our study is that it represents a relatively contemporary cohort of patients treated with modern radiation techniques and current systemic therapies. We were also able to obtain relatively specific clinical and pathologic information of patients. Conversely, one limitation is that, like all retrospective studies, it has selection bias and some missing information.