The trade-off of post-mastectomy radiotherapy usage for the breast cancer patients aged 70 years or older: a study based on SEER database

To critically assess the impact of PMRT in elderly patients, we conducted a large retrospective population-based study in older women from the SEER database and further analyzed various subgroups seeking to investigate the impact of adjuvant radiotherapy in various subgroups of elderly breast cancer patients.

The rather limited category I evidence has demonstrated the impact of PMRT usage in older women, and there is no randomized controlled trial evaluating PMRT in this population. A comparative study about the SEER database from 1992 to 1999 explored the impact of PMRT on elderly breast cancer. Results have shown that PMRT was not associated with improved survival in the whole cohort (adjusted HR 1.03; P = 0.49), only favor the patients in the high-risk group (T3/T4 and/or N2/N3) [13]. In our study, after adjusting confounding factors by the propensity score matching, PMRT substantially prolongs the breast cancer-specific and overall survival of elderly patients, especially with unfavorable disease features as T3-T4 and/ or N2-N3 stage. It demonstrated that PMRT still improves the outcomes of most elderly patients.

To date, adjuvant radiotherapy for patients with less than four positive lymph nodes has not yet become a consensus. Previous studies, such as the British Columbia randomized trials, the Danish Breast Cancer Cooperative Group (DBCG) protocols 82b and 82c trials, showed the significant improvement of adjuvant radiotherapy on survival [14]. A large meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) demonstrated that PMRT could reduce locoregional recurrence, overall recurrence, and breast cancer mortality for women with axillary dissection and 1–3 positive lymph nodes, even when stratified by age [17]. In contrast, at the retrospective analysis of the SEER database (1992–1999), for low-risk (T1/T2 N0) and intermediate-risk (T1/T2 N1) breast cancer, PMRT did not improve survival. While for high-risk (T3/T4 and/or N2/N3) patients, PMRT was associated with a significant improvement in survival (p = 0.02) [13]. However, the EBCTCG analysis evaluated trials that recruited patients from 1964 to 1986, and the retrospective analysis of the SEER database involved patients from 1992 to 1999. This period’s systemic therapy and RT treatment differed significantly from the new therapies used in the modern treatment era. Also, the analysis in EBCTCG did not focus on patients with less than 5 cm size tumors. Therefore, reevaluating survival outcomes in elderly patients impacted by PMRT is warranted, particularly for those with T1-2N1.

Our study found that there was no significant correlation between PMRT and survival for patients with T1-2N1 tumors, both on BCSS and OS. This finding was consistent with the further analysis of patients with T1-2N1 tumors stratified by different grades, different numbers of positive LNs, different HR statuses, and different subtypes. In accordance with our findings, Patel et al. investigated the role of PMRT in the treatment of patients with T1-T2, N1mic disease, and their results showed that PMRT does not affect the survival of breast cancer patients with N1mic disease, even though elderly patients only accounted for a small portion of the population (with 16% of patients being 65 years or older) [18]. Contrasting our study, a previous study published by Zhou et al. found that PMRT could improve OS for patients aged 75 + years old with a tumor size of ≤ 5 cm and 1–3 positive lymph nodes [19]. Whereas it is a pity that the population in that study consisted of earlier diagnosed patients (between 1998 and 2005), and the missing data of chemotherapy therapy also could affect the reliability of this study’s results. In addition, another recent clinical trial reported by Cao et al. showed that PMRT could not improve the survival outcome for all elderly patients with 1–3 positive lymph nodes. Only an improvement in survival by PMRT was detected in patients with tumors > 5 cm, [20]. which is supportive of our results. Combined with these results, our findings further confirm the feasibility of separating patients with 5 cm less or above tumor in the discussion of PMRT usage range.

In our study, PMRT did not improve BCSS and OS for patients with 1, 2, or 3 positive lymph nodes. Luo et al [21] also discussed this topic, but there are some differences in their findings compared to ours. In their retrospective analysis of the SEER database, they specifically assessed the impact of radiotherapy on different numbers of positive lymph nodes and found that only patients with tumor diameters of 2–5 cm, 3 positive lymph nodes, and no chemotherapy received survival benefits from PMRT. The limitation is that this study did not achieve a good balance in terms of age and tumor stage between the radiotherapy group and the non-radiotherapy group, which may have led to the differences in findings compared to our study, considering that these factors are significantly associated with survival outcomes. Furthermore, Chen et al [22] analyzed breast cancer patients aged 75 and older with T3 and lymph node-negative disease, finding that those who received adjuvant radiotherapy showed a trend of improvement in both BCSS and OS. After adjusting for multiple factors in their analysis, these improvements were not statistically significant. As the study population in their article was from before 2009 and did not use more precise methods such as propensity score matching to balance the differences between groups, our study findings provide a better confirmation of this observation.

Although molecular subtype has not been recommended to guide the usage of PMRT, this issue has still been discussed in several studies. Few studies analyzed the different roles of PMRT for older patients on the basis of HER2/neu status and molecular subtypes. The DBCCG 82b and 82c trials analyzed the response to PMRT on different subtypes for patients with PMRT. It showed significant overall survival improvement after receiving PMRT was found in the HR+/HER-2- subtype patients, while not found in the HR-/HER-2 + and triple-negative subtype [23]. Another study for patients with T1-2N1 tumors found that HER2 positive patients (including Luminal B and HER2 enriched subtype) did not improve survival, with only a marginal advantage of overall survival observed for the HR+/ HER-2 + group [24]. Our study displayed the benefit from PRMT for HR+/HER-2- and HR-/HER-2- subtype on both BCSS and OS. Interestingly, elderly patients with HER-2 + tumors did not significantly BCSS benefit from PMRT, with only a marginal survival advantage was shown for the HR+/ HER-2 + subtype in patients with T1-2N1 tumor. Indeed, some literature reported that overexpressed HER-2 with receipt of RT have an increased recurrence risk than HER-2 negative subtype [25]. These results may be due to individual radioresistance associated with multiple molecular mechanisms in the HER-2 positive subtype [26].

A key clinical challenge is to determine specific elderly patients who are more likely to avoid PMRT. Based on the results of the univariable and multivariable analysis in the non-PMRT cohort, we confirmed its independent prognostic factors (age, race, marital status, histology grade, T stage, N stage, ER status, PR status, and given chemotherapy). Then we developed a prognostic nomogram to predict 1-, 3-, and 5-years OS in the non-PMRT cohort. C-index and calibration curves demonstrated its accuracy and discrimination. X-tile helped us to stratify the entire cohort into different risk groups by the optimal cut-off values. Results found that PMRT did not improve overall survival in the low-risk group, while a substantial survival difference is shown in the moderate- and high-risk groups. To the best of our knowledge, this is the first study to build up a nomogram predicting the effect of PMRT in elderly breast cancer patients based on large sample size.

This study has several limitations: (1) The data of neoadjuvant chemotheray, endocrine therapy and targeted therapy was over permission in the SEER database. Also, it does not contain data about the locoregional recurrence rate, which was a predictor widely used to reflect the local tumor control by radiotherapy; (2) A notable limitation of our study is the lack of data on comorbidities within the SEER database, which may impact the interpretation of our results. The absence of comorbidity data may lead to an underestimation or overestimation of the true effect of post-mastectomy radiotherapy on survival in our population, as comorbidities can influence patients’ overall health and prognosis; (3) The retrospective nature of this study may lead to selection bias, although PSM has been introduced to minimize baseline differences between the two groups; thus, we need further prospective trials to validate our findings. One prospective randomized trial, the SUPREMO trial, will be reported in 2023, which randomized patients with T1-2N1, T3N0, or T2N0 to be treated with or without postmastectomy radiotherapy [27].

In conclusion, our study demonstrates that post-mastectomy radiotherapy has a definite role in improving survival for females with elderly breast cancer. After a comprehensive assessment of the side effects and the quality of life, the omission of PMRT could be considered in patients with T1-2N1 breast cancer.