In this retrospective study, we evaluated the survival outcomes of individuals diagnosed with T2N1M0 HR + /HER2- breast cancer who underwent either NACT or ACT. Our findings indicated that non-pCR patients who received NACT exhibited inferior OS and BCSS than those who received ACT.

Previous studies have attempted to explore the effectiveness of NACT compared with ACT for early-stage breast cancer. The landmark NSABP B‐18, NSABP B‐27, and EORTC 10902 clinical trials initially revealed that the use of preoperative chemotherapy yielded similar results in terms of progression-free survival and OS compared with conventional postoperative chemotherapy [25,26,27]. A meta-analysis conducted by the Early Breast Cancer Trialists’ Collaborative Group compared the long-term outcomes of patients with early breast cancer treated with NACT versus ACT. The results demonstrated that no significant difference between NACT and ACT was observed in survival and overall disease progression [28]. Notably, none of the aforementioned studies considered the molecular subtypes of breast cancer or assessed the impact of response to NACT on prognosis.

Herein, we specifically focused on HR + /HER2- patients with T2N1M0 stage tumors to assess the survival outcomes of NACT compared with ACT. Our analysis revealed that ACT was superior to NACT in improving survival outcomes. Findings from stratified analyses across diverse subgroups, including menopausal status, marital status, race, tumor grade, and axillary surgical approach, demonstrated consistency. This could be attributed to the delay in timely surgery. Emerging investigations have revealed that HR + /HER2- tumors exhibit lower sensitivity to NACT compared with other biologic subtypes [29, 30]. Hence, the initial application of NACT is not as effective in tumor eradication as surgery, potentially leading to adverse impacts on survival outcomes [31, 32]. In addition, another factor contributing to reduced OS and BCSS may be the higher likelihood of patients with severe disease receiving NACT. Studies have consistently indicated that patients undergoing NACT present with larger tumors compared with those receiving ACT [10, 19]. Although we attempted to control for factors that could impact survival outcomes in the multivariate model, we did not exclude some unaccounted factors that may potentially influence the selection between NACT and ACT.

pCR demonstrates sensitivity to agents received in the neoadjuvant setting. It has been acknowledged that patients who failed to achieve pCR experienced deleterious long-term outcomes across all breast cancer subtypes [33, 34]. In line with previous research, our study demonstrated that non-pCR after NACT independently predicted an unfavorable prognosis. Patients failing to achieve pCR exhibited the lowest OS and BCSS. Additionally, the pCR rate for the entire cohort was 17.0% (398 out of 2341 patients who received NACT), leaving as much as 83.0% (1943 out of 2341 patients who received NACT) without achieving pCR. Consequently, the high rate of residual disease could be responsible for the compromised survival outcomes among T2N1M0 stage HR + /HER2- breast cancer patients who adopted NACT. The results from the logistic regression model indicated that patients with low tumor grade were more inclined to achieve non-pCR. As a consequence, they should not be routinely recommended for NACT.

Understanding the pathologic response to NACT also provides an opportunity for adjuvant therapy and helps identify high-risk patients for inclusion in novel clinical trials. Patients with residual invasive carcinoma after completing NACT may benefit from subsequent intensive adjuvant therapy. Findings from the CREATE-X and KATERINE clinical trials demonstrated that post-surgical capecitabine and T-DM1, respectively, can improve prognosis in early-stage triple-negative and HER2-positive breast cancer patients when the disease persists after NACT [35, 36]. Furthermore, the MonarchE study revealed that incorporating Aemaciclib into adjuvant endocrine therapy significantly enhanced invasive disease-free survival in patients with HR + /HER2-, node-positive, high-risk early breast cancer, while maintaining an acceptable safety profile. Therefore, adjuvant Aemaciclib may be necessary for patients with T2N1M0 stage HR + /HER2- tumors who did not achieve pCR after NACT. This could represent the potential benefit of NACT for T2 stage operable HR + /HER2- patients.

To our knowledge, this is the first population-based retrospective study examining the prognosis of T2N1M0 stage HR + /HER2- breast cancer patients undergoing NACT or ACT. Leveraging a substantial sample size and extended follow-up duration, our findings carried considerable credibility. Furthermore, we employed PSM to mitigate the impact of confounding variables. Our findings provide valuable insights for guiding the chemotherapy in T2N1M0 stage HR + /HER2- patients. However, the applicability of our findings to populations outside the United States needs to be considered given the variations in demographic traits and healthcare systems. Further multi-center clinical studies are warranted. There are also some limitations in our study. Firstly, despite the ambiguous classification of menstrual status based on RxPONDER clinical trial definitions, the SEER database lacks crucial details essential for HR + breast cancer survival, including reproductive history, family history of breast cancer, endocrine therapy, and specific chemotherapeutic regimens. Additionally, HR + /HER2- breast cancer is predisposed to recurrence, underscoring the importance of studying recurrence risk. Nonetheless, the data lacks information on recurrences and 21-gene recurrence scores (RS) that could predict the magnitude of chemotherapy benefit in early-stage HR + /HER2- breast cancer. Importantly, a high RS can forecast greater chemotherapy benefits, while patients with a low RS receive less benefit without compromising survival [24, 37, 38]. Thus, the absence of this indicator will not influence our primary outcomes. Finally, it is noteworthy that SEER only recorded information about neoadjuvant therapy effects on the primary tumor, while information on the nodal aspect was unavailable. This limitation might affect the assessment of chemotherapy effectiveness and could not be adjusted in the analysis.