Neoadjuvant therapy has become the standard strategy for patients with locally advanced breast cancer. Pathologic complete response (pCR) to preoperative systemic therapy is associated with an extremely favorable disease-free and overall survival (1, 2).International guidelines recommend that a neoadjuvant approach be preferred in subtypes highly sensitive to chemotherapy, such as triple-negative and HER2+ (3–6). HR+HER2- carcinomas are generally less responsive to primary chemotherapy and may benefit less in neoadjuvant setting. Neoadjuvant endocrine therapy for this subtype is also not recommended by guidelines due to limited therapeutic efficacy. Small sample clinical trials have suggested equal rates of clinical response for endocrine therapy as for chemotherapy, though neither approach routinely achieves a rate of pCR>10% (7, 8).

Therefore, neoadjuvant concurrent endocrine therapy with chemotherapy for this particular type of tumor is worth further investigating, while whether concurrent endocrine therapy with chemotherapy in neoadjuvant setting can be of real clinical benefit has never been elaborated. Endocrine therapy needs to be sequenced after chemotherapy based on the previous understanding of adjuvant therapy. However, the prime purpose of neoadjuvant therapy is to shrink the tumor as early as possible with powerful regimens, and delaying endocrine therapy may deprive the patient of the best opportunity for treatment. The previous study suggests in patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs the time to treatment failure (TTF) for ER-positive patients (9). There are few studies of concurrent endocrine therapy with chemotherapy in neoadjuvant setting worldwide, as well as a lack of systematic reviews to objectively assess the efficacy of their concurrent treatment. This study seeks to provide more conclusive clinical evidence on this controversial topic by conducting a systematic review and meta-analysis on the data from randomized trials that investigated the role of concurrent endocrine therapy as a feasible strategy in neoadjuvant setting for patients with HR+Her2- breast cancer.

This systematic review and meta-analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines (10, 11). A protocol was developed prior to the survey launch and presented to PROSPERO. (registration number CRD42022340725).

Of the 94 entries returned during the initial database search, 89 were excluded because they failed to meet the inclusion criteria. In total, five separate randomized trials were considered eligible for this study (13–17). ( Figure 1 ) Mohammadianpanah et al. (2011) and K. Sugiu et al. (2015) trials included 24 and 5 HER2+ patients, respectively. With no neoadjuvant targeted therapy, the findings were valid and the studies were included. Two studies (M. Mohammadianpanah (2011) and G. Minckwit (2001)) enrolled some ER- patients, balanced in both studies, hence also included.

In total, 690 patients were included, of which 345 were randomized to the study group (concurrent endocrine with chemotherapy) and 345 to the control group. Two of the five studies included ER(-) patients. Tamoxifen was used for endocrine therapy in 1 study, and aromatase inhibitors (AIs) were used in the rest. All premenopausal patients were given ovarian function suppression (goserelin/leucovorin) when AIs were administered. Table 1 summarizes the main characteristics of the five included trials.

This meta-analysis of five trials investigated the role of additional concurrent endocrine therapy during chemotherapy for patients with HR+ HER2- breast cancer in neoadjuvant setting. Concurrent administration of endocrine and chemotherapy could significantly increase the clinical response rate with low toxicity.

The patients with HR+ HER2- breast cancer are less sensitive to neoadjuvant chemotherapy with a low pCR rate and lack of effective treatment. The efficacy of concurrent addition endocrine therapy to chemotherapy remains controversial. The timing of endocrine administration in neoadjuvant setting currently continues to refer to the adjuvant treatment. International guidelines still recommend sequential endocrine therapy (tamoxifen or aromatase inhibitors) after chemotherapy (3, 4). The latest edition of NCCN and ESMO guidelines both recommend sequential endocrine therapy based on the same phase 3, 3-arm RCT study (19) (tamoxifen alone, sequential tamoxifen with chemotherapy, concurrent tamoxifen with chemotherapy), in which 1477 patients were eligible for analysis after a maximum of 13 years of follow-up (median 8.94 years). The study confirmed therapy with chemotherapy plus tamoxifen combined (sequential or concurrent) was superior to tamoxifen alone for disease-free survival (DFS) (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64–0.91, p=0.002) and marginally for overall survival (OS) (HR 0.83, 0.68–1.01, p=0.057). The adjusted HRs preferred sequential over concurrent but did not achieve significance for DFS (HR 0.84, 0.70–1.01, p=0.061) or OS (HR 0.90, 0.73–1.10, p=0.30). Similarly, the GEICAM 9401 study (20) compared the clinical benefit of sequential versus concurrent tamoxifen with chemotherapy. No significant difference in DFS at 5 years was found between the two groups with 70% in concurrent and 75% in the sequential group (adjusted HR 1.11, 95% CI 0.71–1.73, P = 0.64). Both studies failed to show an advantage of sequential over concurrent tamoxifen with chemotherapy. Aromatase inhibitor (AI) has emerged as an option for endocrine therapy in recent years, and AI is significantly superior to tamoxifen in both neoadjuvant and adjuvant settings (21–26), suggesting that there may be a potential benefit of concurrent AI administration in the neoadjuvant phase.

The pCR rate has been recognized as an indicator of efficacy after neoadjuvant therapy. The US Food and Drug Administration and European Medicines Agency support the use of pCR in early-stage neoadjuvant breast cancer randomized trials as a surrogate for long-term patient clinical outcomes, in the accelerated approval process of new drugs (26, 27). Almost all of the studies included in this meta-analysis investigated pCR rates as the primary endpoint, and the results indicated that concurrent therapy did not significantly improve pCR rates compared with chemotherapy alone. However, the value of pCR rates in predicting prognosis is controversial. The pCR rate to preoperative systemic therapy was previously believed to be associated with an extremely favorable disease-free and overall, but the correlation between pathological response and long-term outcome was highest for triple negative breast cancer (TNBC), slightly less for HER2-positive disease, and least for ER-positive disease (1, 2). Recent meta-analysis (28) confirmed that the weak relationship between pCR and long-term clinical outcomes was evident across all subgroups studied, and pCR should not be recommended as a surrogate for prognosis. Therefore, pCR may not be an appropriate primary endpoint to assess efficacy in neoadjuvant trials of HR+ HER2- breast cancer.

In this study, we assessed the clinical response as the secondary endpoint, and found that the concurrent therapy was more likely to achieve CR than chemotherapy alone, although a statistical difference was not yet reached; however, the concurrent therapy could achieve significantly high ORR than chemotherapy alone. This suggests that concurrent therapy can lead to higher clinical response rates than chemotherapy alone, furthermore, may result in improving BC rates for patients ineligible for breast-conserving surgery at baseline. Unfortunately, only two of the five studies with small samples explored the BC rates for patients ineligible for breast-conserving surgery at baseline, and further studies with large samples may still be needed. A high Ki67 level may serve as a predictor of good clinical response. Meanwhile, one study (14) showed that patients with a higher Ki67 level at baseline were more likely to benefit from disease-free progression survival (PFS rate) with concurrent therapy than with chemotherapy alone (2-year PFS rate 91.5% vs 76.5%, P=0.058), whereas patients with a lower Ki67 level did not (P=0.317). However, whether higher clinical response rates can lead to longer survival benefits was not mentioned in all studies and further investigation is needed.

The previous belief that tamoxifen could increase the incidence of thrombotic events and cardiovascular disease (18, 29) was similarly confirmed in the only study in which tamoxifen was used (15). Concurrent tamoxifen appears to be more prone to occur these adverse events than chemotherapy alone (3/4 vs. 1/4; 4/5 vs. 1/5), and hematologic toxicity was more pronounced in the concurrent tamoxifen group. While concurrent AI as endocrine therapy did not show serious endocrine-related adverse effects (≥ grade 3), and its symptoms such as hot flashes and bone pain were mild or moderate and well-tolerated for patients. Therefore, concurrent tamoxifen seems to increase the incidence of adverse events, while concurrent AI therapy is safe and low-toxicity.

Some limitations of the current study should be acknowledged. Sample sizes were uneven, with some studies having small sample sizes which appear to be inadequate by today’s standard to make definitive conclusions. K.Sugiu et al. (2015) trial had a low sample size (n=28) and an imbalanced group allocation (only 1 T3 and 2 T4 tumors were included in the chem-endo group and none in the chemo-group). Some individual study was dated and did not use ovarian function suppression in premenopausal patients, which may have affected the efficacy of endocrine therapy. Also, since this study was not based on individual patient-level data, it was impossible to obtain treatment data for patients with different menopausal statuses, to perform subgroup analysis, and to analyze whether menopausal status affected the efficacy of concurrent endocrine therapy.

In conclusion, our systematic review and meta-analysis provides evidence for the efficacy and safety of concurrent endocrine therapy for patients of HR+HER2- breast cancer in neoadjuvant setting. The pCR rate should not be the primary end point for this subtype of breast cancer. Given the findings of our study, concurrent endocrine therapy should be considered as an available option to improve clinical response, or even maybe increase breast conservation rate. Concurrent AI therapy is safe and well-tolerated, without a significant increase in adverse effects. Further studies are still needed to investigate whether long-term survival benefits can be achieved from concurrent endocrine therapy in neoadjuvant setting.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

PW: Data curation, Writing – original draft. WL: Conceptualization, Formal analysis, Investigation, Supervision, Writing – review & editing.