A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial

A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial Yang Yang, Yingjian He, Zhaoqing Fan, Xue Chen, Yiqiang Liu, Chao Zhang, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1808038/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: We evaluated the use of pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer who were non-responsive to primary chemotherapy. Methods: A multi-center, open-label, randomized, controlled phase III trial was conducted. Patients with HR+/HER2−/LN+ breast cancer and non-responsive to four cycles of neoadjuvant chemotherapy (Miller and Payne grade (G) 1 to G3 or any Miller and Payne grade but with residual positive lymph nodes in surgical specimens) were randomly assigned to receive four cycles of non-cross-resistant regimen plus endocrine therapy, or endocrine therapy alone. Patients with Miller and Payne G4 or G5 and LN− status were assigned to the observation group. Distant disease-free survival was the primary endpoint. Results: Of the 433 patients enrolled between October 2010 and September 2018, 391 were non-responsive to treatment, and the final intention-to-treat analysis comprised 379 patients (chemotherapy plus endocrine therapy group, n=187; endocrine therapy-alone group, n=192). Forty patients responsive to neoadjuvant chemotherapy were assigned to the observation group. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% (95% confidence interval [CI], 88–96%) and 90% (95% CI, 86–94%) in the chemotherapy plus endocrine therapy and endocrine therapy-alone groups, respectively (hazard ratio 0.79, 95% CI 0.45‒1.37; P=0.401). There was no significant difference between any of the prespecified subgroups. Compared to these two randomized groups, the observation group showed a trend towards better distant disease-free survival (P=0.107). Conclusions: For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to endocrine therapy alone. Trial registration: The trial was registered on November 25, 2009, at ClinicalTrials.gov, and the registration number was NCT01019616. https://clinicaltrials.gov/ct2/show/NCT01019616?term=alternative+non-cross-resistant&draw=2&rank=1 breast cancer distant disease-free survival neoadjuvant chemotherapy non-cross-resistant adjuvant chemotherapy non-responsive Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Previous randomized controlled trials (RCTs) have failed to illustrate a significant difference in survival outcomes between using the same chemotherapy regimen in neoadjuvant and adjuvant settings [ 1 , 2 ]. Although no survival benefit has been found with neoadjuvant chemotherapy (NCT), these trials have demonstrated that the pathological complete response (pCR) was associated with better survival. Consequently, two strategies were established to overcome potential drug resistance; the first was adding a new drug in the NCT setting to improve the pCR rate, and the second was adding a non-cross-resistant regimen in a selected population with a high recurrence risk (i.e., non-pCR patients). Two major RCTs have explored the advantages of altering ongoing NCT after an early assessment of the initial clinical response. The GeparTrio trial adjusted the NCT regimen based on ultrasound assessment after two cycles of a combination of docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin), and cyclophosphamide (TAC therapy). All non-responsive patients were randomized to receive either four cycles of TAC or four cycles of vinorelbine plus capecitabine (NX) [ 3 ]. Patients in the study by Smith et al. [ 4 ], were administered NCT with four cycles of a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CAVP), and clinical response was evaluated by physical examination after four cycles of NCT. All responsive patients were randomized to receive four additional cycles of CAVP or docetaxel, whereas non-responsive patients received four cycles of docetaxel. Both trials failed to demonstrate a significant increase in the pCR rate after modification of treatment based on clinical response in patients who were non-responsive to NCT. Compared to clinical response, administering additional treatments with different mechanisms based on pathological response may be a reasonable therapeutic approach. Thomas et al. adapted this postoperative treatment strategy [ 5 ]. In their trial, all patients received three cycles of neoadjuvant CAVP. If the pathological response was poor, the patients were randomized to receive five cycles of CAVP or a combination of vincristine, bleomycin, methotrexate, and fluorouracil (VbMF). The patients in the VbMF group had better survival outcomes. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is known to be non-responsive to chemotherapy; however, lymph node positivity (LN+) is an indicator of chemotherapy. Therefore, it remains controversial which chemotherapy regimen is superior and how many cycles of that regimen are appropriate for HR+/HER2−/LN + patients. Non-cross-resistance regimens are commonly used in the treatment of advanced breast cancer [ 6 ]. However, no previous alternative non-cross-resistant adjuvant chemotherapy was established for HR+/HER2-/LN + patients who were non-responsive to primary chemotherapy. A retrospective analysis conducted at our center showed that, for patients with HR+/HER2 − breast cancer, switching to a non-cross-resistant regimen after NCT (containing anthracycline or taxane) could have better distant disease-free survival (DDFS) (unpublished data). Based on this result, we evaluated the strategy of using pathological response-guided non-cross-resistant adjuvant chemotherapy for patients with HR+/HER2-/LN + breast cancer who were non-responsive to primary chemotherapy. Methods This multi-center, randomized, controlled, phase III trial was conducted across eight hospitals located in Beijing, China. The trial was designed by the Peking University Cancer Hospital and supervised by the institutional review board at each study site. The study was done in accordance with the principles of the Declaration of Helsinki. All patients provided informed consent for research participation (Ethics approval number: 2009024). Eligible patients were women aged < 65 years with invasive breast cancer and positive axillary lymph nodes (diagnosed by fine needle aspiration, core needle biopsy, or sentinel lymph node biopsy). Patients with estrogen receptor-positive or progesterone receptor-positive (≥ 10% by immunohistochemistry) and HER2- (0 or 1 + by immunohistochemistry or HER2/chromosome enumeration probe ratio < 1·8 by fluorescent in situ hybridization) were required. Patients had to complete four cycles of NCT (containing anthracycline), undergo radical surgery, and be non-responsive to NCT according to pathological assessment. An experienced pathologist employed at the Peking University cancer hospital who was blinded to the groupings used the Miller and Payne (M&P) grading system to assess the pathological response of the primary tumor, as follows: grade 1: there was no change in individual tumor cells and no decrease in overall cellularity; grade 2: 90% necrosis of tumor cells; grade 5: no tumor cells were identified in sections obtained from the tumor site; however, ductal carcinoma in situ residue alone might be present. Non-responsiveness to treatment was defined as M&P grade 1–3 disease, or any stage with residual positive lymph nodes in the surgical specimen. The other seven hospitals each had their own pathologists perform pathological grading of the specimen. The main exclusion criteria were a history of other malignant tumors, metastatic breast cancer, and any clinically serious medical conditions. Randomization and treatment All intention-to-treat (ITT) patients were enrolled preoperatively, and the eligible patients were randomly assigned in a 1:1 ratio within 4 weeks postoperatively. The other ITT patients who did not meet the pathological non-responsiveness criteria were assigned to the observation group. The patients in arm A received four cycles of a non-cross-resistant regimen plus endocrine therapy (ET), while the patients in arm B patients received ET alone. The randomization sequence was created using SPSS software (version 11.0; IMB SPSS Inc., Armonk, NY, USA) and was stratified based on NCT regimens (anthracycline- or taxane-based therapy vs. concurrent anthracycline and taxane usage) and pathological response (M&P staging G1 and G2 vs. M&P staging G3) using random block sizes of four. Patients with M&P G4–5 disease and residual positive lymph nodes were assigned to the M&P G3 subgroup. For patients with limited lymph node metastasis (one or two diagnosed by sentinel lymph node biopsy) after undergoing breast-conserving surgery, we omitted axillary lymph node dissection. Patients enrolled from Beijing Cancer Hospital started with four cycles of CEF3w (cyclophosphamide 600 mg/m 2 on day 1; epirubicin 90–100 mg/m 2 on day 1; 5-fluorouracil 600 mg/m 2 on day 1, every 3 weeks), and after being assigned to the chemotherapy group, they received four cycles of Tq1w (paclitaxel 80 mg/m 2 on days 1, 8, and 15, every 3 weeks) or TPq1w (paclitaxel 80 mg/m 2 on days 1, 8, and 15 and carboplatin AUC 6 on day 1, every 3 weeks). Patients from the other hospitals started with four cycles of TAC (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 , every 3 weeks) or TE (docetaxel 75 mg/m 2 and epirubicin 75 mg/m 2 , every 3 weeks) and received four cycles of adjuvant chemotherapy with NX (vinorelbine 25 mg/m 2 on days 1 and 8 plus capecitabine 1,000 mg/m 2 orally twice/day on days 1–14, every 3 weeks) or NP (vinorelbine 25 mg/m 2 on days 1 and 8 and carboplatin AUC 6 on day 1, every 3 weeks) when assigned to the chemotherapy group. Patients in both arms received tamoxifen or aromatase inhibitors for 5 years, and underwent whole breast irradiation after breast-conserving surgery, or chest wall and supraclavicular region irradiation after mastectomy, before 2014. After the results of the SOFT and TEXT trials were published (2014), the doctors decided on the use of gonadotropin-releasing hormone agonists for premenopausal patients with breast cancer. The adjuvant treatment regimen for patients in the observation group was also determined by doctors, with four cycles of non-cross-resistant chemotherapy plus ET or ET alone being prescribed. All enrolled patients were followed up postoperatively every 3 months over the first 2 years, every six months over the next 3–5 years, and once a year for 5 years after that. Endpoint assessment The primary endpoint was DDFS, defined as the interval between the date of surgery and occurrence of the first distant event or breast cancer-specific death, whichever occurred first. The secondary endpoints were invasive disease-free survival (iDFS) and overall survival (OS). Liver metastases, loco-regional metastases, contra-lateral breast cancer, and second primary cancer were diagnosed based on pathology, while brain, bone, and lung metastases were diagnosed based on radiology. Statistical analysis A sample of 350 patients (ET-alone group: n = 175; non-cross-resistant chemotherapy plus ET group: n = 175) was planned due to a requirement of 74 distant disease events to provide 80% power to detect a hazard ratio (HR) of 0.75 with a two-sided significance level of 5% in the primary analysis. According to the retrospective data available at our center, we assumed that the DDFS at 5 years was 88% in the non-cross-resistant adjuvant chemotherapy group and 73% in the ET-alone group. Because the median follow-up time at the time of writing was 72.4 months, the DDFS event rates were substantially lower than originally expected, and since an additional delay of 5–8 years was considered to be unacceptably long, we deduced that “time-driven” rather than “event-driven” analyses would be more appropriate. All cases were analyzed on an ITT basis, including patients in the observation group (Fig. 1 ). Time-to-event endpoints were calculated using the Kaplan‒Meier method and compared between patient groups using the log-rank test. HRs and 95% confidence intervals (95% CIs) were estimated using a Cox proportional hazards regression model. A two-sided P -value < 0.05 was considered statistically significant. Results From October 2010 to September 2018, 433 patients were enrolled in the present trial. From this group, 195 patients were randomly assigned to receive four cycles of non-cross-resistant chemotherapy plus ET, while 196 patients were assigned to receive ET alone across the eight participating hospitals located in Beijing. Forty-two of these patients with M&P G4–5 disease but no pathological lymph nodes. Fourteen patients were excluded from the final analysis, seven patients were lost to follow-up, and the others did not meet the eligibility criteria (i.e., four patients had triple-negative breast cancer, and three had HER2 + breast cancer). Therefore, the final ITT analysis comprised 379 patients (Chemotherapy plus ET group: n = 187; ET-alone group: n = 192) in the two randomized groups and 40 patients in the observation group. Table 1 presents the baseline characteristics of the patient sample. All patients had stage IIB, IIIA, or IIIB breast cancer. In the two randomized groups, 89.1% of patients received four cycles of the CEF regimen as NCT, while the others received four cycles of concurrent regimens (TAC or TE) as NCT. The pathological evaluation in 40.9% of patients was M&P G1 and G2, 53% were M&P 3, and 6.1% were M&P 4 or 5. Moreover, positive lymph nodes were found in 67.7% of patients after NCT. The baseline characteristics of the two groups were balanced. The observation group included 9.5% of cases; patients in this group had a higher Ki67 rate and were more responsive to NCT according to clinical response; all patients were M&P G4 or G5 according to pathological evaluation, and only one patient had a positive lymph node after NCT (Table 1 ). Table 1 Basic characteristics ET followed by CT N = 187 ET alone N = 192 Observation group N = 40 Age, years Median (range) 48 (27‒72) 47 (24‒73) 47.8 (33‒71) Menopausal status Yes 49 52 9 No 138 140 31 Tumor size 1 38 36 9 2 135 139 30 3 14 17 1 Histological type IDC 177 183 36 ILC 8 8 4 Mucinous tumor 2 1 0 Ki67 ≤ 14% 50 59 3 ≥ 15% 137 133 37 Lymph node diagnostic method CNB or FNA 122 125 24 SLNB 65 67 16 NCT regimen CEF 169 175 36 TAC or TE 18 17 4 Clinical response uCR 0 0 5 uPR 87 90 27 uSD 100 102 8 Surgery Mastectomy 136 138 24 Conserving surgery 51 54 16 M&P staging 1 or 2 80 77 0 3 96 105 0 4 or 5 11 10 40 No. of lymph nodes involved after NCT ypN0 51 49 39 ypN1 81 79 1 ypN2 49 54 0 Unknown 6 10 0 CPS + EG score 1 or 2 with ypN0 54 53 39 3 or 2 with ypN+ 149 157 1 Unknown 6 10 0 ET regimen TAM 36 34 8 AI 138 140 31 AI + OFS 13 18 1 Abbreviations: ET, endocrine therapy; CT, chemotherapy; M&P staging, Miller and Payne staging; IDC, invasive ductal cancer; ILC, invasive lobular cancer; CNB, core needle biopsy; FNA, fine needle aspiration; SLNB, sentinel lymph node biopsy; uCR, ultrasound complete response; uPR, ultrasound partial response; uSD, ultrasound stable disease; NCT, neoadjuvant chemotherapy; CPS + EG, clinical, pathological stage, estrogen receptor grading; TAM, tamoxifen; AI, aromatase inhibitor; OFS, ovarian function suppression. [Insert Table 1 ] Only 50 patients developed distant disease after a median follow-up of 72.4 months. DDFS events occurred in 22 patients in the chemotherapy plus ET group (11.7%) and in 28 patients in the ET-alone group (14.6%). These events are summarized in Table 2. The 5-year DDFS was 92% (95% CI, 88–96%) in the chemotherapy plus ET group and 90% (95% CI, 86–94%) in the ET-alone group (HR 0.79, 95% CI 0.45‒1.37) ( P = 0.401) (Fig. 2 ). No significant improvement in DDFS was found in the chemotherapy plus ET groups in the prespecified NCT regimen and M&P staging subgroups (Fig. 3 ). Table 2. Site of first distance disease-free survival events Site of first DDFS event ET followed by CT N = 22 ET alone N = 28 Observation N = 1 Overall N = 51 Bone 4 12 0 16 Lung 2 3 0 5 Liver 0 4 0 4 Pleura 3 1 0 4 Brain 1 0 0 1 multiple distant metastases 11 5 1 17 death without event 1 3 0 4 Abbreviations: DDFS, distant disease-free survival; ET, endocrine therapy; CT, chemotherapy. In a further exploratory analysis, we stratified the patients into ypN0 or ypN+ subgroups. These subgroups were further divided into patients with a clinicopathologic stage plus ER status and nuclear grading ( CPS+EG) score of 1 or 2 for the ypN0 group and a CPS+EG score of 3 or 2 for the ypN+ group. Non-cross-resistant chemotherapy did not improve the survival in these subgroups. In the ypN+ subgroup, compared to the ET-alone group, we found a 7% absolute benefit for 5-year DDFS in the non-cross-resistant chemotherapy plus ET group (90.2% vs. 83.2%, HR 0.73, 95% CI: 0.4‒1.33; P = 0.196) (Figure 4). In the observation group, only one DDFS event was observed. Patients in the observation group had a trend towards better DDFS compared to the two randomized groups ( P = 0.107) (Figure 2). However, this trend was not observed for OS. The secondary endpoints were OS and iDFS. Overall, 22 deaths were reported (11 in the non-cross-resistant chemotherapy plus ET group and 11 in the ET-alone group). Both OS (HR 1.04; 95% CI, 0.45‒2.40) and iDFS (HR 0.77; 95% CI, 0.45‒1.32) differed significantly between the two groups (Figure 3). Discussion We previously retrospectively analyzed patients with HR+/HER2- breast cancer who were diagnosed before 2007 and had received two to four cycles of NCT (containing anthracycline or taxane). After a median follow-up of 44 months, we observed significantly better DDFS in patients who received non-cross-resistant chemotherapy plus ET after surgery, compared to those who received ET alone (124 vs. 75 months, P = 0.049) (unpublished data). To evaluate the strategy of using pathological response-guided non-cross-resistant adjuvant chemotherapy for HR+/HER2-/LN+ breast cancer patients who were non-responsive to NCT, we started this trial in 2010. There had been no previous phase III randomized controlled trial that attempted to demonstrate a post-neoadjuvant treatment strategy in patients with HR+/HER2-/LN+ status. After a median follow-up of 72.4 months, the 5-year DDFS rate in our trial was 92% (95% CI, 88–96) in the non-cross-resistant adjuvant chemotherapy plus ET group and 90% (95% CI, 86–94) in the ET-alone group (HR 0.79, 95% CI 0.45‒1.37; P = 0.401). Similar to previous studies, our trial failed to demonstrate a survival benefit for additional non-cross-resistant adjuvant chemotherapy in non-responsive patients with HR+/HER2-/LN+ breast cancer. The absolute benefit of the 5-year DDFS was 2% in our trial in the additional chemotherapy group, compared to 3% in the HR+ subgroup in the CREATE-X trial. There are several explanations for our findings. First, additional non-cross-resistant chemotherapy might be also non-responsive for HR+/HER2-/LN+ patients; therefore, enhanced chemotherapy did not improve survival. Second, 73% of all patients were post-menopausal, and 31% of pre-menopausal patients had used drugs which suppress ovarian function; these features might affect the effectiveness of chemotherapy. Third, the chemotherapy regimens in sub-sites were different from that in our center; each sub-site used its own pathologist to evaluate the pathological response. These confounding factors might have affected the results of our study. In the survival analysis of the prespecified subsite group (TAC/TE group), there was an intersection of the survival curves between the non-cross-resistant chemotherapy group and endocrine alone group. Only one multi-center, open-label, randomized, controlled, phase III trial (POTENT) had shown survival improvement when using additional chemotherapy in patients with HR+/HER2-/LN+ breast cancer. This trial included 392 (20%) patients who received NCT, and adjuvant S1 significantly improved the 5-year iDFS (HR 0.66) in this subgroup [6]. Therefore, the role of postoperative chemotherapy in HR+/HER2-/LN+ patients remains controversial. An association between pCR, recurrence-free survival and OS in patients with breast cancer was found in a previous pooled analysis [7]. Partial drug resistance in tumors could be indicated by the presence of residual disease (non-pCR) after NCT. The administration of non-cross-resistant adjuvant treatment based on pathological response could potentially overcome drug resistance. The CREATE-X trial administered non-cross-resistant adjuvant treatment to non-pCR patients with HER2- breast cancer, while the KATHERINE trial used this treatment in non-pCR patients with HER2+ breast cancer. The role of post-neoadjuvant treatment was highlighted in triple-negative and HER2+ breast cancer [8,9]. However, this strategy of using non-cross-resistant chemotherapy in non-pCR patients was not validated in the HR+ subgroup in the CREATE-X trial, and the absolute benefit in terms of DFS and OS was only 3% and 3.4%, respectively, in the capecitabine group [8]. The CTNeoBC pooled analysis showed that the pCR rate was only 9.6% in HR+/HER2- patients, which was much lower than in patients with HER2+ and triple-negative breast cancer [7]. Therefore, we did not use non-pCR as an indicator to administer additional post-neoadjuvant treatment in this study. We defined M&P G1 to G3, or any grade of M&P staging with pathological lymph nodes, in surgical specimens as cancer non-responsive to NCT. Besides our non-responsive criterion for patients with HR+/HER2- breast cancer, Mittendorf et al. developed the CPS+EG staging system in 2008 and validated this staging system in two independent cohorts in 2011, 1 year after the initiation of our trial [10,11]. Patients with CPS+EG score ≥3 or 2 and pathological lymph nodes had worse DFS. In our study, 81% of patients were CPS+EG score ≥3 or 2 and had pathological lymph nodes. Therefore, we believed that using different non-responsive criteria would not affect our results. In the exploratory analysis of our trial, we found a 7% absolute DDFS benefit in patients with pathological lymph nodes (69.3%) in the chemotherapy plus ET group ( P = 0.196). Further studies are needed to demonstrate this benefit in patients with pathological lymph nodes. In the present study, 9.2% of patients were responsive to NCT (observation group). When comparing the two randomized groups and the observation group, patients in the observation group showed a trend towards better DDFS ( P = 0.107) (Figure 2). After a median follow-up of 72.4 months, only one of the 40 patients in the observation group had a DDFS event. Thus, four cycles of NCT plus ET might be considered sufficient for these patients. Besides chemotherapy, cyclin-dependent kinase inhibitors have been administered to patients with high-risk HR+/HER2- early breast cancer in some trials. The Monarch E and PALLAS trials showed different results when administering additional adjuvant CDK4/6 inhibitors for 2 years in the aforementioned patient groups [12,13]. Abemaciclib combined with ET achieved better iDFS compared to ET alone in the Monarch E trial, while palbociclib plus ET did not achieve better iDFS compared to ET alone in the PALLAS trial. PENELOPE-B was the first trial to administer palbociclib for 1 year after NCT and surgery, and patients with CPS+EG scores of more than 2, or a score 2 along with pathological lymph nodes in that trial were randomized to the ET or ET plus palbociclib groups. After a median follow-up of 43 months, 1-year additional palbociclib administration did not achieve better iDFS in the PENELOPE-B trial. The main limitation of the trial was the unexpectedly low rate of distant recurrences. According to the data from our center before 2007, we assumed that the 5-year DDFS rate would be 88% in the non-cross-resistant adjuvant chemotherapy plus ET group and 73% in the ET alone group. However, in this trial, the 5-year DDFS rate was 92% in the chemotherapy group and 90% in the ET group. We only found trends towards better DDFS in patients with pathological lymph nodes, and further studies should be performed on patients with pathological node-positive breast cancer. Conclusion In conclusion, this is the first prospective phase III randomized trial to validate the benefit of switching to a non-cross-resistant regimen after NCT for non-responsive patients with HR+/HER2-/LN+ breast cancer. However, additional non-cross-resistant adjuvant chemotherapy did not improve survival in non-responsive HR+/HER2-/LN+ patients. A trend towards better DDFS was observed in patients who were responsive to NCT; thus, four cycles of NCT (containing anthracycline) might be considered sufficient for these patients. Abbreviations CAVP: cyclophosphamide, doxorubicin, vincristine, and prednisone CI: confidence interval DDFS: distant disease-free survival ET: endocrine therapy HER2-: human epidermal growth factor receptor 2-negative HR: hazard ratio HR+: hormone receptor-positive iDFS: invasive disease-free survival ITT: intention-to-treat LN+: lymph node positive LN-, lymph node negative M&P: Miller and Payne NCT: neoadjuvant chemotherapy OS: overall survival pCR: pathological complete response RCTs: randomized controlled trials VbMF: vincristine, bleomycin, methotrexate, and fluorouracil Declarations Ethics approval and consent to participate The study was performed in accordance with the principles of the Declaration of Helsinki, and was approved by the ethics committee of Peking University Cancer Hospital. All patients provided informed consent for research participation (Ethics approval number: 2009024). Consent for publication Not applicable. Availability of data and materials The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the Beijing Municipal Science & Technology Commission (Grant number: D09050703570904). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation. Authors’ contributions TO (corresponding author) contributed to the conception of the study. YY performed the data analyses and wrote the manuscript. YH contributed significantly to trial design, analysis and manuscript preparation. ZF performed the trial, helped perform the analysis with constructive discussions. XC helped perform the trial and hand writing. YL performed the pathological assessment. CZ helped perform the trial. HJ helped perform the trial. XW helped perform the trial. XW. helped perform the trial. FX helped perform the trial. SW helped perform the trial. BL helped perform the trial. HK helped perform the trial. TW helped perform the trial. ZJ helped perform the trial. PY helped perform the trial. BX helped perform the trial. LX helped perform the trial. YL helped perform the trial. JL helped perform the trial. YX helped perform the trial. TW helped perform the trial. Acknowledgments Not applicable. References Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;1927–39. Wang-Lopez Q, Mouret-Reynier MA, Savoye AM, Abrial C, Kwiatkowski F, Garbar C, et al. Is it important to adapt neoadjuvant chemotherapy to the visible clinical response? 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Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22:74–84. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72. Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147–59. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617–28. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12:320–7. Mittendorf EA, Jeruss JS, Tucker SL, Kolli A, Newman LA, Gonzalez-Angulo AM, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:1956–62. Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38:3987–98. Mayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2021;22:212–22. Additional Declarations No competing interests reported. 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yingjian","middleName":"","lastName":"He","suffix":""},{"id":117742344,"identity":"2e820117-373e-47a4-8a7b-14795cab5767","order_by":2,"name":"Zhaoqing Fan","email":"","orcid":"","institution":"Peking University Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhaoqing","middleName":"","lastName":"Fan","suffix":""},{"id":117742345,"identity":"2685e40a-7923-4fd8-b1fc-89ba09d5df6c","order_by":3,"name":"Xue Chen","email":"","orcid":"","institution":"Peking University Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Chen","suffix":""},{"id":117742346,"identity":"2beaac2a-3f2e-40c0-9c6b-48803afbde1f","order_by":4,"name":"Yiqiang Liu","email":"","orcid":"","institution":"Peking University Cancer Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yiqiang","middleName":"","lastName":"Liu","suffix":""},{"id":117742347,"identity":"f6263224-68c0-4ce0-94cf-dda91c968a71","order_by":5,"name":"Chao Zhang","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Zhang","suffix":""},{"id":117742348,"identity":"d311fe77-cff3-4147-a7a9-8cee24f77306","order_by":6,"name":"Hongchuan Jiang","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongchuan","middleName":"","lastName":"Jiang","suffix":""},{"id":117742349,"identity":"3b8b840f-de95-4584-bf14-2301165b836a","order_by":7,"name":"Xin Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Wang","suffix":""},{"id":117742350,"identity":"1b8926fa-de23-403a-9200-c142f0c4f956","order_by":8,"name":"Xiang Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Wang","suffix":""},{"id":117742352,"identity":"59a5d468-aef4-48cc-bbeb-3c3f9e02c88f","order_by":9,"name":"Fei Xie","email":"","orcid":"","institution":"Peking University People's Hospital, Breast Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Xie","suffix":""},{"id":117742354,"identity":"b412c743-aa1e-48de-b735-456251ac7a7d","order_by":10,"name":"Shu Wang","email":"","orcid":"","institution":"Peking University People's Hospital, Breast Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shu","middleName":"","lastName":"Wang","suffix":""},{"id":117742355,"identity":"524cd6f1-7cab-4e8a-a4df-f570a1a578ab","order_by":11,"name":"Bin Luo","email":"","orcid":"","institution":"Beijing Tsinghua Changgung Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Luo","suffix":""},{"id":117742356,"identity":"dde35959-82b3-4f4c-aa57-9abffe5a50d0","order_by":12,"name":"Hua Kang","email":"","orcid":"","institution":"XuanWu Hospital Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Kang","suffix":""},{"id":117742357,"identity":"77d402b8-9d06-4100-97a8-1cde666bc486","order_by":13,"name":"Tao Wang","email":"","orcid":"","institution":"307 Hospital of PLA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Wang","suffix":""},{"id":117742358,"identity":"f26cb3e6-99ff-458b-afb0-456222f4693b","order_by":14,"name":"Zefei Jiang","email":"","orcid":"","institution":"307 Hospital of PLA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zefei","middleName":"","lastName":"Jiang","suffix":""},{"id":117742359,"identity":"a7a869f2-3257-46f3-837b-05a6017ab011","order_by":15,"name":"Peng Yuan","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Yuan","suffix":""},{"id":117742360,"identity":"80e06b9d-b2ed-4540-9459-f3710932de7b","order_by":16,"name":"Binhe Xu","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Binhe","middleName":"","lastName":"Xu","suffix":""},{"id":117742361,"identity":"f2d332ba-9845-4d1e-8ad3-e823fa0fc74e","order_by":17,"name":"Ling Xu","email":"","orcid":"","institution":"Peking University First Hospital, Breast Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Xu","suffix":""},{"id":117742363,"identity":"62b8f3a2-baee-4641-bb7c-1ccd36fad6b4","order_by":18,"name":"Yinhua Liu","email":"","orcid":"","institution":"Peking University First Hospital, Breast Cancer Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yinhua","middleName":"","lastName":"Liu","suffix":""},{"id":117742364,"identity":"3f91e59f-b56f-4d74-9a48-de46a054bcaa","order_by":19,"name":"Jinfeng Li","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jinfeng","middleName":"","lastName":"Li","suffix":""},{"id":117742366,"identity":"49fb09f5-9846-468e-b50d-d128274deb8a","order_by":20,"name":"Yuntao Xie","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuntao","middleName":"","lastName":"Xie","suffix":""},{"id":117742368,"identity":"12b16d29-5b71-4f60-827a-b56dbecec2e8","order_by":21,"name":"Tianfeng Wang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tianfeng","middleName":"","lastName":"Wang","suffix":""},{"id":117742370,"identity":"45945c37-cc7c-4647-8ad3-b2b6f734d379","order_by":22,"name":"Tao Ouyang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYPCCA1C6woaHn72BaC3MQHwmTUay5wB+tahaGNsO2xjccMCvll8ix/Bzwa87cub86w9++MB2nofhBgPjh485uLVIzsgxlp7Z98zYcsZjZskZPLd5GGc3MEvO3IZbi8GNHANp3p7DiRtuHGaQ5pG4zcMsc4CNmRe/FuPfUC3Mv3kMzvGwSSQQ1GImzfMDqOV8M5s0T8IBHh5CWiR7npVZ8zYcNja4wWxmOeNAMo8Ez8FmvH7hZ0/efJvnz2E5g/MHH9/4+M/O3v5488EPH/FoYWDgMABGB5CWSICJMDbgUw8E7A8YGP6A7DtAQOEoGAWjYBSMWAAAyjZWjW1EYHgAAAAASUVORK5CYII=","orcid":"","institution":"Peking University Cancer Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Ouyang","suffix":""}],"badges":[],"createdAt":"2022-06-29 13:29:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1808038/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1808038/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":23328224,"identity":"039d569e-90a5-474b-8208-55474f5bf973","added_by":"auto","created_at":"2022-07-01 14:53:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45410,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram\u003c/p\u003e\u003cp\u003eM\u0026amp;P, Miller and Payne; LN, lymph node negative\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1808038/v1/bc898d76c722a6ad7dcd1448.png"},{"id":23327862,"identity":"780f0253-255d-4a33-b7e0-9b40fc2f65a6","added_by":"auto","created_at":"2022-07-01 14:48:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29259,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan‒Meier estimates for DDFS. DDFS, distant disease-free survival; CT, chemotherapy; ET, endocrine survival; HR, hazard ratio.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1808038/v1/3d588fae8b0f223b7051353a.png"},{"id":23328223,"identity":"e1106ffb-dc1c-4149-a602-f5cdcec7d42f","added_by":"auto","created_at":"2022-07-01 14:53:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":51846,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan‒Meier estimates for OS (a) and Kaplan‒Meier estimates for iDFS (b). OS, overall survival; iDFS, invasive disease-free survival; CT, chemotherapy; ET, endocrine survival; HR, hazard ratio\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-1808038/v1/b264181d5931f8de95996ee4.png"},{"id":23327863,"identity":"166d18a8-f9a8-4f80-aa5a-edd813cadbf7","added_by":"auto","created_at":"2022-07-01 14:48:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51293,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of univariable Cox regression for DDFS in subgroups. DDFS, distant disease-free survival; CT, chemotherapy; ET, endocrine survival; HR, hazard ratio; M\u0026amp;P, Miller and Payne; CPS-EG, clinical, pathological stage, estrogen receptor, grading; NCT, neoadjuvant chemotherapy; CEF, cyclophosphamide, epirubicin, 5-fluorouracil; TAC, docetaxel, doxorubicin, cyclophosphamide; TEC, docetaxel, epirubicin; ypN0, yield pathological lymph node negative; ypN+, yield pathological lymph node positive.\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-1808038/v1/34425ab99ba9aff14aedf1c2.png"},{"id":23990686,"identity":"77115ad2-faed-4a42-8b8c-b81e5d740add","added_by":"auto","created_at":"2022-07-18 15:44:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":756238,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1808038/v1/755e0b13-8ad2-4084-b66b-a4ad01c6c518.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial","fulltext":[{"header":"Background","content":"\u003cp\u003ePrevious randomized controlled trials (RCTs) have failed to illustrate a significant difference in survival outcomes between using the same chemotherapy regimen in neoadjuvant and adjuvant settings [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although no survival benefit has been found with neoadjuvant chemotherapy (NCT), these trials have demonstrated that the pathological complete response (pCR) was associated with better survival. Consequently, two strategies were established to overcome potential drug resistance; the first was adding a new drug in the NCT setting to improve the pCR rate, and the second was adding a non-cross-resistant regimen in a selected population with a high recurrence risk (i.e., non-pCR patients).\u003c/p\u003e \u003cp\u003eTwo major RCTs have explored the advantages of altering ongoing NCT after an early assessment of the initial clinical response. The GeparTrio trial adjusted the NCT regimen based on ultrasound assessment after two cycles of a combination of docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin), and cyclophosphamide (TAC therapy). All non-responsive patients were randomized to receive either four cycles of TAC or four cycles of vinorelbine plus capecitabine (NX) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Patients in the study by Smith et al. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], were administered NCT with four cycles of a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CAVP), and clinical response was evaluated by physical examination after four cycles of NCT. All responsive patients were randomized to receive four additional cycles of CAVP or docetaxel, whereas non-responsive patients received four cycles of docetaxel. Both trials failed to demonstrate a significant increase in the pCR rate after modification of treatment based on clinical response in patients who were non-responsive to NCT.\u003c/p\u003e \u003cp\u003eCompared to clinical response, administering additional treatments with different mechanisms based on pathological response may be a reasonable therapeutic approach. Thomas et al. adapted this postoperative treatment strategy [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In their trial, all patients received three cycles of neoadjuvant CAVP. If the pathological response was poor, the patients were randomized to receive five cycles of CAVP or a combination of vincristine, bleomycin, methotrexate, and fluorouracil (VbMF). The patients in the VbMF group had better survival outcomes. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is known to be non-responsive to chemotherapy; however, lymph node positivity (LN+) is an indicator of chemotherapy. Therefore, it remains controversial which chemotherapy regimen is superior and how many cycles of that regimen are appropriate for HR+/HER2\u0026minus;/LN\u0026thinsp;+\u0026thinsp;patients. Non-cross-resistance regimens are commonly used in the treatment of advanced breast cancer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, no previous alternative non-cross-resistant adjuvant chemotherapy was established for HR+/HER2-/LN\u0026thinsp;+\u0026thinsp;patients who were non-responsive to primary chemotherapy.\u003c/p\u003e \u003cp\u003eA retrospective analysis conducted at our center showed that, for patients with HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;breast cancer, switching to a non-cross-resistant regimen after NCT (containing anthracycline or taxane) could have better distant disease-free survival (DDFS) (unpublished data). Based on this result, we evaluated the strategy of using pathological response-guided non-cross-resistant adjuvant chemotherapy for patients with HR+/HER2-/LN\u0026thinsp;+\u0026thinsp;breast cancer who were non-responsive to primary chemotherapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis multi-center, randomized, controlled, phase III trial was conducted across eight hospitals located in Beijing, China. The trial was designed by the Peking University Cancer Hospital and supervised by the institutional review board at each study site. The study was done in accordance with the principles of the Declaration of Helsinki. All patients provided informed consent for research participation (Ethics approval number: 2009024).\u003c/p\u003e \u003cp\u003eEligible patients were women aged\u0026thinsp;\u0026lt;\u0026thinsp;65 years with invasive breast cancer and positive axillary lymph nodes (diagnosed by fine needle aspiration, core needle biopsy, or sentinel lymph node biopsy). Patients with estrogen receptor-positive or progesterone receptor-positive (\u0026ge;\u0026thinsp;10% by immunohistochemistry) and HER2- (0 or 1\u0026thinsp;+\u0026thinsp;by immunohistochemistry or HER2/chromosome enumeration probe ratio\u0026thinsp;\u0026lt;\u0026thinsp;1\u0026middot;8 by fluorescent in situ hybridization) were required. Patients had to complete four cycles of NCT (containing anthracycline), undergo radical surgery, and be non-responsive to NCT according to pathological assessment. An experienced pathologist employed at the Peking University cancer hospital who was blinded to the groupings used the Miller and Payne (M\u0026amp;P) grading system to assess the pathological response of the primary tumor, as follows: grade 1: there was no change in individual tumor cells and no decrease in overall cellularity; grade 2: \u0026lt;30% necrosis of tumor cells; grade 3: 30\u0026ndash;90% necrosis of tumor cells; grade 4: \u0026gt;90% necrosis of tumor cells; grade 5: no tumor cells were identified in sections obtained from the tumor site; however, ductal carcinoma in situ residue alone might be present. Non-responsiveness to treatment was defined as M\u0026amp;P grade 1\u0026ndash;3 disease, or any stage with residual positive lymph nodes in the surgical specimen. The other seven hospitals each had their own pathologists perform pathological grading of the specimen.\u003c/p\u003e \u003cp\u003eThe main exclusion criteria were a history of other malignant tumors, metastatic breast cancer, and any clinically serious medical conditions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eRandomization and treatment\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAll intention-to-treat (ITT) patients were enrolled preoperatively, and the eligible patients were randomly assigned in a 1:1 ratio within 4 weeks postoperatively. The other ITT patients who did not meet the pathological non-responsiveness criteria were assigned to the observation group. The patients in arm A received four cycles of a non-cross-resistant regimen plus endocrine therapy (ET), while the patients in arm B patients received ET alone. The randomization sequence was created using SPSS software (version 11.0; IMB SPSS Inc., Armonk, NY, USA) and was stratified based on NCT regimens (anthracycline- or taxane-based therapy vs. concurrent anthracycline and taxane usage) and pathological response (M\u0026amp;P staging G1 and G2 vs. M\u0026amp;P staging G3) using random block sizes of four. Patients with M\u0026amp;P G4\u0026ndash;5 disease and residual positive lymph nodes were assigned to the M\u0026amp;P G3 subgroup. For patients with limited lymph node metastasis (one or two diagnosed by sentinel lymph node biopsy) after undergoing breast-conserving surgery, we omitted axillary lymph node dissection.\u003c/p\u003e \u003cp\u003ePatients enrolled from Beijing Cancer Hospital started with four cycles of CEF3w (cyclophosphamide 600 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1; epirubicin 90\u0026ndash;100 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1; 5-fluorouracil 600 mg/m\u003csup\u003e2\u003c/sup\u003e on day 1, every 3 weeks), and after being assigned to the chemotherapy group, they received four cycles of Tq1w (paclitaxel 80 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 8, and 15, every 3 weeks) or TPq1w (paclitaxel 80 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1, 8, and 15 and carboplatin AUC 6 on day 1, every 3 weeks). Patients from the other hospitals started with four cycles of TAC (docetaxel 75 mg/m\u003csup\u003e2\u003c/sup\u003e, doxorubicin 50 mg/m\u003csup\u003e2\u003c/sup\u003e, and cyclophosphamide 500 mg/m\u003csup\u003e2\u003c/sup\u003e, every 3 weeks) or TE (docetaxel 75 mg/m\u003csup\u003e2\u003c/sup\u003e and epirubicin 75 mg/m\u003csup\u003e2\u003c/sup\u003e, every 3 weeks) and received four cycles of adjuvant chemotherapy with NX (vinorelbine 25 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1 and 8 plus capecitabine 1,000 mg/m\u003csup\u003e2\u003c/sup\u003e orally twice/day on days 1\u0026ndash;14, every 3 weeks) or NP (vinorelbine 25 mg/m\u003csup\u003e2\u003c/sup\u003e on days 1 and 8 and carboplatin AUC 6 on day 1, every 3 weeks) when assigned to the chemotherapy group. Patients in both arms received tamoxifen or aromatase inhibitors for 5 years, and underwent whole breast irradiation after breast-conserving surgery, or chest wall and supraclavicular region irradiation after mastectomy, before 2014. After the results of the SOFT and TEXT trials were published (2014), the doctors decided on the use of gonadotropin-releasing hormone agonists for premenopausal patients with breast cancer. The adjuvant treatment regimen for patients in the observation group was also determined by doctors, with four cycles of non-cross-resistant chemotherapy plus ET or ET alone being prescribed. All enrolled patients were followed up postoperatively every 3 months over the first 2 years, every six months over the next 3\u0026ndash;5 years, and once a year for 5 years after that.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEndpoint assessment\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe primary endpoint was DDFS, defined as the interval between the date of surgery and occurrence of the first distant event or breast cancer-specific death, whichever occurred first. The secondary endpoints were invasive disease-free survival (iDFS) and overall survival (OS). Liver metastases, loco-regional metastases, contra-lateral breast cancer, and second primary cancer were diagnosed based on pathology, while brain, bone, and lung metastases were diagnosed based on radiology.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eA sample of 350 patients (ET-alone group: n\u0026thinsp;=\u0026thinsp;175; non-cross-resistant chemotherapy plus ET group: n\u0026thinsp;=\u0026thinsp;175) was planned due to a requirement of 74 distant disease events to provide 80% power to detect a hazard ratio (HR) of 0.75 with a two-sided significance level of 5% in the primary analysis. According to the retrospective data available at our center, we assumed that the DDFS at 5 years was 88% in the non-cross-resistant adjuvant chemotherapy group and 73% in the ET-alone group. Because the median follow-up time at the time of writing was 72.4 months, the DDFS event rates were substantially lower than originally expected, and since an additional delay of 5\u0026ndash;8 years was considered to be unacceptably long, we deduced that \u0026ldquo;time-driven\u0026rdquo; rather than \u0026ldquo;event-driven\u0026rdquo; analyses would be more appropriate.\u003c/p\u003e \u003cp\u003eAll cases were analyzed on an ITT basis, including patients in the observation group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Time-to-event endpoints were calculated using the Kaplan‒Meier method and compared between patient groups using the log-rank test. HRs and 95% confidence intervals (95% CIs) were estimated using a Cox proportional hazards regression model. A two-sided \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom October 2010 to September 2018, 433 patients were enrolled in the present trial. From this group, 195 patients were randomly assigned to receive four cycles of non-cross-resistant chemotherapy plus ET, while 196 patients were assigned to receive ET alone across the eight participating hospitals located in Beijing. Forty-two of these patients with M\u0026amp;P G4\u0026ndash;5 disease but no pathological lymph nodes. Fourteen patients were excluded from the final analysis, seven patients were lost to follow-up, and the others did not meet the eligibility criteria (i.e., four patients had triple-negative breast cancer, and three had HER2\u0026thinsp;+\u0026thinsp;breast cancer). Therefore, the final ITT analysis comprised 379 patients (Chemotherapy plus ET group: n\u0026thinsp;=\u0026thinsp;187; ET-alone group: n\u0026thinsp;=\u0026thinsp;192) in the two randomized groups and 40 patients in the observation group.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the baseline characteristics of the patient sample. All patients had stage IIB, IIIA, or IIIB breast cancer. In the two randomized groups, 89.1% of patients received four cycles of the CEF regimen as NCT, while the others received four cycles of concurrent regimens (TAC or TE) as NCT. The pathological evaluation in 40.9% of patients was M\u0026amp;P G1 and G2, 53% were M\u0026amp;P 3, and 6.1% were M\u0026amp;P 4 or 5. Moreover, positive lymph nodes were found in 67.7% of patients after NCT. The baseline characteristics of the two groups were balanced. The observation group included 9.5% of cases; patients in this group had a higher Ki67 rate and were more responsive to NCT according to clinical response; all patients were M\u0026amp;P G4 or G5 according to pathological evaluation, and only one patient had a positive lymph node after NCT (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBasic characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eET followed by CT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;187\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eET alone\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;192\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eObservation group\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (27‒72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (24‒73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.8 (33‒71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenopausal status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIDC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eILC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucinous tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;14%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eLymph node diagnostic method\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCNB or FNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSLNB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNCT regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAC or TE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003euCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003euPR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003euSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMastectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConserving surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM\u0026amp;P staging\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 or 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 or 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eNo. of lymph nodes involved after NCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eypN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPS\u0026thinsp;+\u0026thinsp;EG score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 or 2 with ypN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 or 2 with ypN+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eET regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTAM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAI\u0026thinsp;+\u0026thinsp;OFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ET, endocrine therapy; CT, chemotherapy; M\u0026amp;P staging, Miller and Payne staging; IDC, invasive ductal cancer; ILC, invasive lobular cancer; CNB, core needle biopsy; FNA, fine needle aspiration; SLNB, sentinel lymph node biopsy; uCR, ultrasound complete response; uPR, ultrasound partial response; uSD, ultrasound stable disease; NCT, neoadjuvant chemotherapy; CPS\u0026thinsp;+\u0026thinsp;EG, clinical, pathological stage, estrogen receptor grading; TAM, tamoxifen; AI, aromatase inhibitor; OFS, ovarian function suppression.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e[Insert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOnly 50 patients developed distant disease after a median follow-up of 72.4 months. DDFS events occurred in 22 patients in the chemotherapy plus ET group (11.7%) and in 28 patients in the ET-alone group (14.6%). These events are summarized in Table\u0026nbsp;2. The 5-year DDFS was 92% (95% CI, 88\u0026ndash;96%) in the chemotherapy plus ET group and 90% (95% CI, 86\u0026ndash;94%) in the ET-alone group (HR 0.79, 95% CI 0.45‒1.37) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.401) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No significant improvement in DDFS was found in the chemotherapy plus ET groups in the prespecified NCT regimen and M\u0026amp;P staging subgroups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eTable\u0026nbsp;2.\u003c/b\u003e Site of first distance disease-free survival events\u003c/p\u003e\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003eSite of first DDFS event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003eET followed by CT\u003c/p\u003e\n \u003cp\u003eN = 22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003eET alone\u003c/p\u003e\n \u003cp\u003eN = 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003eObservation\u003c/p\u003e\n \u003cp\u003eN = 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003cp\u003eN = 51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003eBone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003ePleura\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003eBrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003emultiple distant metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"24.242424242424242%\"\u003e\n \u003cp\u003edeath without event\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.181818181818183%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.171717171717173%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.2020202020202%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DDFS, distant disease-free survival; ET, endocrine therapy; CT, chemotherapy.\u003c/p\u003e\n\u003cp\u003eIn a further exploratory analysis, we stratified the patients into ypN0 or ypN+ subgroups. These subgroups were further divided into patients with a \u003cspan lang=\"\"\u003eclinicopathologic stage plus ER status and nuclear grading (\u003c/span\u003eCPS+EG) score of 1 or 2 for the ypN0 group and a CPS+EG score of 3 or 2 for the ypN+ group. Non-cross-resistant chemotherapy did not improve the survival in these subgroups. In the ypN+ subgroup, compared to the ET-alone group, we found a 7% absolute benefit for 5-year DDFS in the non-cross-resistant chemotherapy plus ET group (90.2% vs. 83.2%, HR 0.73, 95% CI: 0.4‒1.33; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.196) (Figure 4). In the observation group, only one DDFS event was observed. Patients in the observation group had a trend towards better DDFS compared to the two randomized groups (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.107) (Figure 2). However, this trend was not observed for OS.\u003c/p\u003e\n\u003cp\u003eThe secondary endpoints were OS and iDFS. Overall, 22 deaths were reported (11 in the non-cross-resistant chemotherapy plus ET group and 11 in the ET-alone group). Both OS (HR 1.04; 95% CI, 0.45‒2.40) and iDFS (HR 0.77; 95% CI, 0.45‒1.32) differed significantly between the two groups (Figure 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe previously retrospectively analyzed patients with HR+/HER2- breast cancer who were diagnosed before 2007 and had received two to four cycles of NCT (containing anthracycline or taxane). After a median follow-up of 44 months, we observed significantly better DDFS in patients who received non-cross-resistant chemotherapy plus ET after surgery, compared to those who received ET alone (124 vs. 75 months, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.049) (unpublished data). To evaluate the strategy of using pathological response-guided non-cross-resistant adjuvant chemotherapy for HR+/HER2-/LN+ breast cancer patients who were non-responsive to NCT, we started this trial in 2010. There had been no previous phase III randomized controlled trial that attempted to demonstrate a\u0026nbsp;post-neoadjuvant treatment strategy in patients with HR+/HER2-/LN+ status. After a median follow-up of 72.4 months, the 5-year DDFS rate in our trial was 92% (95% CI, 88\u0026ndash;96) in the non-cross-resistant adjuvant chemotherapy plus ET group and 90% (95% CI, 86\u0026ndash;94) in the ET-alone group (HR 0.79, 95% CI 0.45‒1.37; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.401).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSimilar to previous studies, our trial failed to demonstrate a survival benefit for additional non-cross-resistant adjuvant chemotherapy in non-responsive patients with HR+/HER2-/LN+ breast cancer. The absolute benefit of the 5-year DDFS was 2% in our trial in the additional chemotherapy group, compared to 3% in the HR+ subgroup in the CREATE-X trial. There are several explanations for our findings. First, additional non-cross-resistant chemotherapy might be also non-responsive for HR+/HER2-/LN+ patients; therefore, enhanced chemotherapy did not improve survival. Second, 73% of all patients were post-menopausal, and 31% of pre-menopausal patients had used drugs which suppress ovarian function; these features might affect the effectiveness of chemotherapy. Third, the chemotherapy regimens in sub-sites were different from that in our center; each sub-site used its own pathologist to evaluate the pathological response. These confounding factors might have affected the results of our study. In the survival analysis of the prespecified subsite group (TAC/TE group), there was an intersection of the survival curves between the non-cross-resistant chemotherapy group and endocrine alone group. Only one multi-center, open-label, randomized, controlled, phase III trial (POTENT) had shown survival improvement when using additional chemotherapy in patients with HR+/HER2-/LN+ breast cancer. This trial included 392 (20%) patients who received NCT, and adjuvant S1 significantly improved the 5-year iDFS (HR 0.66) in this subgroup [6]. Therefore, the role of postoperative chemotherapy in HR+/HER2-/LN+ patients remains controversial.\u003c/p\u003e\n\u003cp\u003eAn association between pCR, recurrence-free survival and OS in patients with breast cancer was found in a previous pooled analysis [7]. Partial drug resistance in tumors could be indicated by the presence of residual disease (non-pCR) after NCT. The administration of non-cross-resistant adjuvant treatment based on pathological response could potentially overcome drug resistance. The CREATE-X trial administered non-cross-resistant adjuvant treatment to non-pCR patients with HER2- breast cancer, while the KATHERINE trial used this treatment in non-pCR patients with HER2+ breast cancer. The role of post-neoadjuvant treatment was highlighted in triple-negative and HER2+ breast cancer [8,9]. However, this strategy of using non-cross-resistant chemotherapy in non-pCR patients was not validated in the HR+ subgroup in the CREATE-X trial, and the absolute benefit in terms of DFS and OS was only 3% and 3.4%, respectively, in the capecitabine\u0026nbsp;group [8]. The CTNeoBC pooled analysis showed that the pCR rate was only 9.6% in HR+/HER2- patients, which was much lower than in patients with HER2+ and triple-negative breast cancer [7]. Therefore, we did not use non-pCR as an indicator to administer additional post-neoadjuvant treatment in this study. We defined M\u0026amp;P G1 to G3, or any grade of M\u0026amp;P staging with pathological lymph nodes, in surgical specimens as cancer non-responsive to NCT. Besides our non-responsive criterion for patients with HR+/HER2- breast cancer, Mittendorf et al. developed the CPS+EG staging system in 2008 and validated this staging system in two independent cohorts in 2011, 1 year after the initiation of our trial [10,11]. Patients with CPS+EG score\u0026nbsp;\u0026ge;3 or 2 and pathological lymph nodes had worse DFS. In our study, 81% of patients were CPS+EG score\u0026nbsp;\u0026ge;3 or 2 and had pathological lymph nodes. Therefore, we believed that using different non-responsive criteria would not affect our results.\u003c/p\u003e\n\u003cp\u003eIn the exploratory analysis of our trial, we found a 7% absolute DDFS benefit in patients with pathological lymph nodes (69.3%) in the chemotherapy plus ET group (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.196). Further studies are needed to demonstrate this benefit in patients with pathological lymph nodes.\u003c/p\u003e\n\u003cp\u003eIn the present study, 9.2% of patients were responsive to NCT (observation group). When comparing the two randomized groups and the observation group, patients in the observation group showed a trend towards better DDFS (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.107) (Figure 2). After a median follow-up of 72.4 months, only one of the 40 patients in the observation group had a DDFS event. Thus, four cycles of NCT plus ET might be considered sufficient for these patients.\u003c/p\u003e\n\u003cp\u003eBesides chemotherapy, cyclin-dependent kinase inhibitors have been administered to patients with high-risk HR+/HER2- early breast cancer in some trials. The Monarch E and PALLAS trials showed different results when administering additional adjuvant CDK4/6 inhibitors for 2 years in the aforementioned patient groups [12,13]. Abemaciclib combined with ET achieved better iDFS compared to ET alone in the Monarch E trial, while palbociclib plus ET did not achieve better iDFS compared to ET alone in the PALLAS trial. PENELOPE-B was the first trial to administer palbociclib for 1 year after NCT and surgery, and patients with CPS+EG scores of more than 2, or a score 2 along with pathological lymph nodes in that trial were randomized to the ET or ET plus palbociclib groups. After a median follow-up of 43 months, 1-year additional palbociclib administration did not achieve better iDFS in the PENELOPE-B trial.\u003c/p\u003e\n\u003cp\u003eThe main limitation of the trial was the unexpectedly low rate of distant recurrences. According to the data from our center before 2007, we assumed that the 5-year DDFS rate would be 88% in the non-cross-resistant adjuvant chemotherapy plus ET group and 73% in the ET alone group. However, in this trial, the 5-year DDFS rate was 92% in the chemotherapy group and 90% in the ET group. We only found trends towards better DDFS in patients with pathological lymph nodes, and further studies should be performed on patients with pathological node-positive breast cancer.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this is the first prospective phase III randomized trial to validate the benefit of switching to a non-cross-resistant regimen after NCT for non-responsive patients with HR+/HER2-/LN+ breast cancer. However, additional non-cross-resistant adjuvant chemotherapy did not improve survival in non-responsive HR+/HER2-/LN+ patients. A trend towards better DDFS was observed in patients who were responsive to NCT; thus, four cycles of NCT (containing anthracycline) might be considered sufficient for these patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCAVP: cyclophosphamide, doxorubicin, vincristine, and prednisone\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003eDDFS: distant disease-free survival\u003c/p\u003e\n\u003cp\u003eET: endocrine therapy\u003c/p\u003e\n\u003cp\u003eHER2-: human epidermal growth factor receptor 2-negative\u003c/p\u003e\n\u003cp\u003eHR: hazard ratio\u003c/p\u003e\n\u003cp\u003eHR+: hormone receptor-positive\u003c/p\u003e\n\u003cp\u003eiDFS: invasive disease-free survival\u003c/p\u003e\n\u003cp\u003eITT: intention-to-treat\u003c/p\u003e\n\u003cp\u003eLN+: lymph node positive\u003c/p\u003e\n\u003cp\u003eLN-,\u0026nbsp;lymph node negative\u003c/p\u003e\n\u003cp\u003eM\u0026amp;P: Miller and Payne\u003c/p\u003e\n\u003cp\u003eNCT: neoadjuvant chemotherapy\u003c/p\u003e\n\u003cp\u003eOS: overall survival\u003c/p\u003e\n\u003cp\u003epCR: pathological complete response\u003c/p\u003e\n\u003cp\u003eRCTs: randomized controlled trials\u003c/p\u003e\n\u003cp\u003eVbMF: vincristine, bleomycin, methotrexate, and fluorouracil\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the principles of the Declaration of Helsinki, and was approved by the ethics committee of Peking University Cancer Hospital. All patients provided informed consent for research participation (Ethics approval number: 2009024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eBeijing Municipal Science \u0026amp; Technology Commission (Grant number: D09050703570904). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTO (corresponding author) contributed to the conception of the study. YY performed the data analyses and wrote the manuscript. YH contributed significantly to trial design, analysis and manuscript preparation. ZF performed the trial, helped perform the analysis with constructive discussions. XC helped perform the trial and hand writing. YL performed the pathological assessment. CZ helped perform the trial. HJ helped perform the trial. XW helped perform the trial. XW. helped perform the trial. FX helped perform the trial. SW helped perform the trial. BL helped perform the trial. HK helped perform the trial. TW helped perform the trial. ZJ helped perform the trial. PY helped perform the trial. BX helped perform the trial. LX helped perform the trial. YL helped perform the trial. JL helped perform the trial. YX helped perform the trial. TW helped perform the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEarly Breast Cancer Trialists' Collaborative Group (EBCTCG). Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018;1927\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang-Lopez Q, Mouret-Reynier MA, Savoye AM, Abrial C, Kwiatkowski F, Garbar C, et al. Is it important to adapt neoadjuvant chemotherapy to the visible clinical response? An open randomized phase II study comparing response-guided and standard treatments in HER2-negative operable breast cancer. Oncologist. 2015;20:243\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013;31:3623\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, et al. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol. 2002;20:1456\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThomas E, Holmes FA, Smith TL, Buzdar AU, Frye DK, Fraschini G, et al. The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol. 2004;22:2294\u0026ndash;302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToi M, Imoto S, Ishida T, Ito Y, Iwata H, Masuda N, et al. Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22:74\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOgston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12:320\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMittendorf EA, Jeruss JS, Tucker SL, Kolli A, Newman LA, Gonzalez-Angulo AM, et al. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011;29:1956\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020;38:3987\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayer EL, Dueck AC, Martin M, Rubovszky G, Burstein HJ, Bellet-Ezquerra M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2021;22:212\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, distant disease-free survival, neoadjuvant chemotherapy, non-cross-resistant adjuvant chemotherapy, non-responsive","lastPublishedDoi":"10.21203/rs.3.rs-1808038/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1808038/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: We evaluated the use of pathological response-guided non-cross-resistant adjuvant chemotherapy in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-positive (LN+) breast cancer who were non-responsive to primary chemotherapy.\nMethods: A multi-center, open-label, randomized, controlled phase III trial was conducted. Patients with HR+/HER2−/LN+ breast cancer and non-responsive to four cycles of neoadjuvant chemotherapy (Miller and Payne grade (G) 1 to G3 or any Miller and Payne grade but with residual positive lymph nodes in surgical specimens) were randomly assigned to receive four cycles of non-cross-resistant regimen plus endocrine therapy, or endocrine therapy alone. Patients with Miller and Payne G4 or G5 and LN− status were assigned to the observation group. Distant disease-free survival was the primary endpoint.\nResults: Of the 433 patients enrolled between October 2010 and September 2018, 391 were non-responsive to treatment, and the final intention-to-treat analysis comprised 379 patients (chemotherapy plus endocrine therapy group, n=187; endocrine therapy-alone group, n=192). Forty patients responsive to neoadjuvant chemotherapy were assigned to the observation group. After a median follow-up period of 72.4 months, the 5-year distant disease-free survival was 92% (95% confidence interval [CI], 88–96%) and 90% (95% CI, 86–94%) in the chemotherapy plus endocrine therapy and endocrine therapy-alone groups, respectively (hazard ratio 0.79, 95% CI 0.45‒1.37; P=0.401). There was no significant difference between any of the prespecified subgroups. Compared to these two randomized groups, the observation group showed a trend towards better distant disease-free survival (P=0.107).\nConclusions: For patients non-responsive to neoadjuvant chemotherapy, adjuvant non-cross-resistant chemotherapy did not significantly improve distant disease-free survival compared to endocrine therapy alone. Trial registration: The trial was registered on November 25, 2009, at ClinicalTrials.gov, and the registration number was NCT01019616. https://clinicaltrials.gov/ct2/show/NCT01019616?term=alternative+non-cross-resistant\u0026draw=2\u0026rank=1","manuscriptTitle":"A phase III study of HR-positive/HER2-negative and lymph node-positive breast cancer non- responsive to primary chemotherapy: a randomized clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-07-01 14:48:12","doi":"10.21203/rs.3.rs-1808038/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bc171059-9fba-426a-9842-d35c9584103d","owner":[],"postedDate":"July 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-07-18T15:44:21+00:00","versionOfRecord":[],"versionCreatedAt":"2022-07-01 14:48:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1808038","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1808038","identity":"rs-1808038","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}