Survival In Premenopausal Patients Research Articles

Abstract PO2-02-03: Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country

Abstract INTRODUCTION: Oncotype DX® recurrence score (ODX RS) is a 21-gene assay warranted to determine the the prognosis in patients with hormone receptor positive, HER-2 negative early stage breast cancer. In this context, the test is also predictive of benefit of adjuvant chemotherapy.1,2,3 OBJECTIVES: We aimed to correlate the clinical and pathological factors associated with Oncotype DX® 21-Gene in patients diagnosed with early stage Breast Cancer. Additionally, description of adjuvant treatment patterns and survival outcomes were described according to the Oncotype DX® 21-Gene result. METHODS: Data from medical records from a single center in Brazil were collected retrospectively from women over 18 years diagnosed with early breast cancer between 2012 and 2022. Included patients were diagnosed with stage T1-T2 breast cancer, hormone receptor positive, HER-2 negative, with up to three positive lymph nodes. All included patients had an Oncotype DX® test performed after definitive breast surgery. The ODX RS has been categorized into two levels according to menopausal status. Correlation between breast cancer recurrence and clinicopathological characteristics was done. The software SPSS was used for statistical analyzes with the significance of 0.05. RESULTS: From 197 patients, 20 have had breast cancer recurrence (10.15%) whom 10 were premenopausal and 10 were postmenopausal. The median ODX RS in these 20 patients was 15 (ranged from 9 to 31). The most common site of recurrence was breast and regional recurrence in 18 patients (90%). Adjuvant chemotherapy was omitted in 16 patients (80%) who have had breast cancer recurrence. Among premenopausal patients whose ODX RS was >20, 33 patients (91.66%) received adjuvant chemotherapy. Among postmenopausal patients whose ODX RS was >25, 19 (86.36%) received adjuvant chemotherapy. The probability of recurrence free survival was worse in premenopausal patients > 44-years-old compared to those with < =44 years-old (p = 0.036) and also worse in histological grade 3 tumors compared to grade 1 (p=0.0048). Tumor size >14 millimeters (mm) was correlated to worse recurrence free survival in premenopausal patients (p=0.017). Low estrogen and progesterone receptor was associated with a higher ODX RS (p=0.0035 and p< 0.0001, respectively) in premenopausal patients, but not associated with recurrence free survival. Clinicopathological characteristics and recurrence free survival correlation in postmenopausal patients were not significant. CONCLUSION: This retrospective analysis suggests that factors other than the Oncotype DX® score, such as age and grade contributed to worse survival outcomes among our patients population. Of note, age older than 44 years-old, histological grade 3 and tumor size >14 mm were associated with a higher probability of recurrence in premenopausal patients, despite the Oncotype DX® score. REFERENCES: 1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med [Internet]. 2004;351(27):2817–26. Available from: http://dx.doi.org/10.1056/NEJMoa041588. 2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med [Internet]. 2018;379(2):111–21. Available from: http://dx.doi.org/10.1056/NEJMoa1804710. 3. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med [Internet]. 2021;385(25):2336–47. Available from: http://dx.doi.org/10.1056/NEJMoa2108873. Table 1 – Clinical and pathological characteristics of 197 hormone receptor positive, HER-2 negative early breast cancer patients who did the Oncotype DX® 21-Gene Recurrence Score assay. Data from medical records collected retrospectively of women diagnosed with early breast cancer between 2012 and 2022 from a single center in Brazil. Figure 1 – Probability of recurrence free survival in premenopausal patients according to age <=44 (blue line) or > 44-years-old (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Figure 2 – Probability of recurrence free survival in premenopausal patients according to histological grade. Tumor with histological grade 1 (blue line) or histological grade 3 (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Citation Format: Carolina Cavalcanti Gonçalves Ferreira, Julio Araujo, Shermann Brandão Rodrigues Moreira, Antônio Buzaid, Débora Gagliato. Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-03.

Trends in ovarian conservation and association with survival in premenopausal patients with stage I leiomyosarcoma

<h3>Objectives:</h3> Standard therapy for women with leiomyosarcoma (LMS) entails hysterectomy with resection of gross intraabdominal disease. For women with uterine-confined disease, the role of oophorectomy remains controversial. We explored trends over time in ovarian conservation (OC) in young women with LMS and examined the association between ovarian conservation and survival. <h3>Methods:</h3> Patients under the age of 50 who were diagnosed with stage I LMS who underwent hysterectomy with and without oophorectomy between 2010 and 2016 were identified in the National Cancer Database (NCDB). Performance of oophorectomy vs ovarian conservation was determined using site-specific surgery codes. Trends in performance of OC are reported. Multivariable regression models were fit to estimate predictors of OC in the patient population. An inverse probability of treatment weighted propensity score method was used to examine the association between all-cause mortality and OC. <h3>Results:</h3> A total of 793 patients were identified. Overall, 225 patients (28%) underwent OC. The rate of OC decreased consistently from 41.2% in 2010 to 14.3% in 2016; this finding was consistent across each age group: <35, 35-39, 40-44, and 45-49 years (Figure 1). The rate of ovarian conservation was 29% among White women compared to 26% among BlackBlack women (P=0.24). Ovarian conservation was utilized in 30% of patients with private insurance and 24% of patients with Medicaid or Medicare insurance (P=0.49). Ovarian conservation was utilized in 32% of women with stage IA tumors and 27% of those with stage IB tumors (P=0.19). Women with poorly differentiated tumors were less likely to undergo OC compared to well-differentiated tumors (aRR 0.59; 95% CI 0.40-0.86). After propensity score weighting, there was no association between OC and mortality when compared to oophorectomy (HR 1.19, 95% CI 0.80 - 1.77). The 5-year survival for women who underwent OC with stage IA LMS was 86.6% (95% CI 67.6 - 94.9%) compared to 77.0% for women who underwent oophorectomy (95% CI 58.0 - 88.2%). In stage IB tumors, 5-year survival was 68.4% in the OC group (95% CI 57.4 - 77.2%) compared to 66.8% in the oophorectomy group (95% CI 59.4-73.1%). <h3>Conclusions:</h3> The practice of ovarian conservation for early stage LMS in premenopausal women across all age groups has decreased over time. There was no association between ovarian conservation all-cause mortality among women with stage I LMS. Ovarian conservation should be considered in premenopausal women with LMS that is confined to the uterus given health benefits such as prevention of osteoporosis, cardiovascular disease, and vasomotor symptoms.

Trends in ovarian conservation and association with survival in premenopausal patients with stage I leiomyosarcoma

ObjectiveTo explore trends of ovarian conservation (OCN) over time in young women with early stage leiomyosarcoma (LMS) and examine the association between OCN and survival. MethodsPatients under the age of 50 who were diagnosed with stage I LMS who underwent hysterectomy with and without oophorectomy between 2010 and 2016 were identified in the National Cancer Database (NCDB). Performance of oophorectomy vs. OCN was determined using surgery codes. Trends of OCN were reported. Multivariable regression models were fit to estimate predictors of OCN. An inverse probability of treatment weighted propensity score method was used to examine the association between all-cause mortality and OCN. ResultsOverall, 225 patients (28%) underwent OCN. Rates of OCN decreased from 41.2% (2010) to 14.3% (2016); this finding was consistent across age groups: <35, 35–39, 40–44, and 45–49 years. Race, insurance, and stage did not affect performance of OCN. Women with poorly differentiated tumors were less likely to undergo OCN compared to well-differentiated tumors (aRR 0.59; 95% CI 0.40–0.86). After propensity score weighting, there was no association between OCN and mortality (HR 1.19, 95% CI 0.80–1.77). Five-year survival for the OCN group was 67.1% (95% CI 59.8–75.2%) compared to 72.2% for the oophorectomy group (95% CI 67.2–77.5%). ConclusionsOCN for early stage LMS in premenopausal women has decreased over time. There was no association between OCN and mortality among women with stage I LMS. OCN should be considered in premenopausal women with stage I LMS given the health benefits.

Oncologic outcomes of uterine preservation for pre-menopausal patients with stage II epithelial ovarian carcinoma

ObjectiveFertility-sparing surgery is rarely offered for patients with stage II epithelial ovarian carcinoma. The aim of the present study was to evaluate the overall survival of pre-menopausal patients with stage...

Effect of bilateral salpingo-oophorectomy on the overall survival of premenopausal patients with stage I low-grade endometrial stromal sarcoma; a National Cancer Database analysis

ObjectivesInvestigate the prevalence of bilateral salpingo-oophorectomy (BSO) for women ≤50 years with early stage low-grade endometrial stromal sarcoma (LGESS) and its impact on overall survival (OS). MethodsWomen ≤50 years, diagnosed with stage I LGESS and managed with hysterectomy between 2004 and 2015 were identified from the National Cancer Database. Patient demographics were recorded and compared with the chi-square test. OS for patients diagnosed between 2004 and 2014 with at least one month of follow-up was assessed using Kaplan-Meier curves, and compared with the log-rank test. ResultsA total 743 patients with a median age of 44 years met the inclusion criteria. Use of radiatiotherapy (9%), chemotherapy (0.8%) and hormonal therapy (11%) was infrequent. BSO was performed in 541 (72.8%) patients. Patients who had ovarian preservation (OP) were younger (median age 43 vs 45 years, p < 0.001), less likely to have comorbidities (6.9% vs 12.4%, p = 0.034), or undergo LND (30.7% vs 44.4%, p = 0.001). There were no differences between the two groups in terms of substage or patient race. Five year OS rates for patients who did (n = 490) and did not (n = 191) undergo BSO were 96.2% and 97.1% and there was no difference in OS, p = 0.50. Even after controlling for presence of comorbidities performance of BSO was not associated with better survival (HR: 1.28, 95% CI: 0.51, 3.19). ConclusionsOvarian function was preserved in approximately one third of women ≤50 years with stage I LGESS with no clear detriment to overall survival. As BSO is associated with long term health effects in this patient population OP could be considered in selected women with stage I LGESS.

267P - Chemotherapy-induced amenorrhea: Prognostic impact on premenopausal Egyptian patients with breast cancer

BackgroundBreast cancer is the second most frequent cancer among women. Disease free survival (DFS) and overall survival (OS) have been improved by different adjuvant chemotherapy regimens; as a consequence, premenopausal patients developed chemotherapy-induced amenorrhea (CIA). Although chemotherapy and ovarian ablation independently improve the outcome of breast cancer, there is controversy about the effect of CIA in these patients. The aim of this study was to analyze the prognostic impact of chemotherapy- induced amenorrhea (CIA) on disease-free survival and overall survival in premenopausal patients with breast cancer following adjuvant chemotherapy. MethodsRetrospectively, we reviewed the data of 200 premenopausal breast cancer patients, who underwent adjuvant chemotherapy at the Clinical Oncology Department of Ain Shams University, Cairo, Egypt during 2014. The data of one hundred ninety-two patients were analyzed in the study. CIA was defined as the absence of menstruation for a year after the end of chemotherapy. The survival analyses were done using the Kaplan-Meier method and the log Rank Test. ResultsThe median follow-up was 4 years. Mean age was 40.8 ± 6 years. CIA occurred in 66.1% of patients. Age and tumor grade were CIA predictors in logistic regression analysis. The 4-year disease-free survival (DFS) was higher in the CIA group than that in the non-CIA group (47.39 months vs 31.80 months, respectively; P=< 0.001), and the 4- year overall survival (OS) was higher in the CIA group than that of the non-CIA group (47.85 months vs 45.296 months, respectively; P=0.030). ConclusionsChemotherapy-induced amenorrhea positively affects disease-free survival and overall survival in the Egyptian premenopausal breast cancer patients treated with adjuvant chemotherapy. It was a better prognostic marker and might be used as a surrogate marker for effective chemotherapy in those patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Molecular Subtypes and Prognostic Factors among Premenopausal and Postmenopausal Thai Women with Invasive Breast Cancer: 15 Years Follow-up Data

Background and Purpose:This study focused on molecular subtypes and prognostic factors for survival of pre- and post-menopausal breast cancer patients.Methods:A retrospective cohort study was performed on 523 patients with invasive carcinoma of the breast treated at Ubon Ratchathani Cancer Hospital, Thailand from 2002 to 2016. Patient characteristics were collected based on a systematic chart audit from medical records. Prognostic factors were performed by observe survival analysis. A Cox regression model was used to calculate hazard ratios of death, taking into account the age and menopause status, molecular subtype, stage of disease, histological grade, lymphatic and vascular invasion, resection margin, hormone receptor expression, and treatment modality.Results:The median time from the diagnosis of invasive breast cancer to the last follow-up or death was 10.2 [95% CI = 9.28-11.95] years in premenopausal women, and 7.4 [95% CI = 6.48-8.44] years in postmenopausal cases. The overall survival estimates at 5 and 10 years for younger woman of 71.2% and 51.8% respectively, appeared slightly better than the 68.3% and 40.9% for postmenopausal women [HRadj = 1.27, 95% CI =0.99-1.63]. In the multivariate analysis, 3 prognostic indicators significantly predicted a worse overall survival in premenopausal patients, triple negative subtype [HRadj = 6.03, 95% CI = 1.94-18.74], HER2-enriched status [HRadj = 4.11, 95% CI = 1.59-10.65] and stage III [HRadj = 2.73, 95% CI = 1.10-6.79]. Statistically significant increased risk of death in postmenopausal patients was noted for only chemotherapy after mastectomy [HRadj = 8.76, 95% CI = 2.88-26.61], and for a Luminal B status [HRadj = 3.55, 95% CI = 1.47-8.53].Conclusion:Postmenopausal women with invasive breast cancer experience a significantly shorter survival than do their premenopausal counterparts. The predictors of worse overall survival were molecular subtype, stage of disease and type of treatment administered.

Relationship between young age at diagnosis and disease free survival in premenopausal patients according to breast cancer subtypes.

e12557Background: Previous studies have shown that young women are at high risk of recurrence and death. We aim to explore the roles of the clinic-pathological characteristics and treatment in dise...

158PD - Adjuvant anti-HER2 therapy, treatment-induced amenorrhea (TIA) and survival in premenopausal patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Analysis from the ALTTO trial (BIG 2-06)

158PD - Adjuvant anti-HER2 therapy, treatment-induced amenorrhea (TIA) and survival in premenopausal patients (pts) with HER2-positive (HER2+) early breast cancer (EBC): Analysis from the ALTTO trial (BIG 2-06)

Nomogram Model of LNR Predicts Survival in Premenopausal Patients with Node-positive Luminal Breast Cancer.

The aim of this study was to assess the prognostic value of lymph node ratio (LNR) in premenopausal patients with luminal breast carcinoma. A total of 885 female patients who presented with axillary lymph node-positive luminal breast cancer between 2000 and 2009 were investigated. Using X-tile, we classified patients into low-, intermediate- and high-risk groups based on LNR. The Kaplan-Meier method was used to determine cumulative survival curves. Cox proportional hazards analyses were used to identify the factors that contributed to disease-free (DFS) and overall (OS) survival. The median age of patients was 42 years (range=21-58 years). A training set of 295 patients and a validation set of 590 patients were used to determine the optimal LNR cut-off points (0.20 and 0.63). DFS was 87.7%, 77.4% and 53.9% (p<0.001) and OS was 91.5%, 76.7% and 50.9% (p<0.0001) for the low- (≤0.20), intermediate- (0.21-0.63) and high-risk (>0.63) groups, respectively. The 10-year DFS and OS rates were significantly longer in the low-risk group than in the high-risk group. Nomogram analysis demonstrated that LNR contributed more compared to nodal stage in predicting both DFS and OS. We conclude that LNR strongly predicts prognosis in premenopausal patients with lymph node-positive luminal breast cancer.

The effect of folate-related SNPs on clinicopathological features, response to neoadjuvant treatment and survival in pre- and postmenopausal breast cancer patients

This study aimed to investigate the relationship of ten single nucleotide polymorphisms (SNPs) in the MTHFR, MTR, MTRR, DHFR, MTHFD1, TS, RFC1 and DNMT3b genes with cancer survival, therapeutic response to neoadjuvant chemotherapy and clinicopathological characteristics in 300 pre- and postmenopausal breast cancer patients of a Russian Western Siberian population. We found that the MTHFR 677CT genotype as well as combination of MTHFR 677CT and 677TT genotype was related to tumor size and estrogen-positive status in postmenopausal group. The RFC1 80А allele was associated with an increased risk of lymph node metastases among postmenopausal women. The MTHFR 677TT genotype was significantly correlated with a better progression-free survival in premenopausal patients. In contrast, a worse outcome was observed in this group patient with MTHFD1 1958AA genotype. In the multivariate analysis, the MTHFD1 1958AA genotype was identified as an independent prognostic factor for premenopausal breast cancer survival. Our findings provide evidence for associations of breast cancer survival with folate-related SNPs in a population of Western Siberian region of Russia and the MTHFD1 (1958G>A) may have additional prognostic value especially among premenopausal patients.

Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer

We investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer. Medical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed. The median patient age was 41 years (range, 21-54) and the median follow-up duration was 6.2 years (range, 0.7-10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2-2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4-3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0-4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2-2.7, P = 0.004) remained significant factors for DFS on multivariate analysis. A considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.

P2-12-24: Resumption or Persistence of Menstruation after Cytotoxic Chemotherapy Is a Poor Prognostic Factor for Disease Free Survival in Premenopausal Patients with Early Breast Cancer.

Abstract Background : We investigated the relationship between resumption or persistence of menstruation after chemotherapy and disease free survival (DFS) in premenopausal patients with early breast cancer. Patients and methods : A total of 843 patients diagnosed with a stage I to III breast cancer between March 2001 and December 2006 were included in this study. All patients received cytotoxic chemotherapy after surgery; 411 (48.8%) with anthracycline based, 416 (49.3%) with anthracycline and taxane containing, and 16 (1.9%) with other regimens. We reviewed the medical records with a long term follow-up. Results : The median age of patients was 41 years (range, 21–54 years) and the median follow-up duration was 6.2 years (range, 0.7−10.4 years). Of all, 632 (75%) patients were hormone receptor (HR) positive who received tamoxifen therapy upon completion of chemotherapy. The chemotherapy induced amenorrhea (CIA) rate was 78.1% (n=658) and 52.4% (n= 442) experienced the resumption of period during the long term follow-up. One hundred two (12.1%) patients had persistent menstruation without CIA. The disease free survival (DFS) was significantly affected by the younger age (≤ 35 years) (HR=1.58, [95% CI, 1.10−2.70], P=0.014), advanced stage (stage 3) (HR=4.45, [95% CI, 3.17−6.25], P&amp;lt;0.001), HR negativity (HR=2.21, [95% CI, 1.57−3.12], P&amp;lt;0.001), HER2 positivity (HR=1.56, [95% CI, 1.04−2.34], P=0.032), and the resumption or persistent period (HR=2.03, [95% CI, 1.42−2.91], P&amp;lt;0.001). HR negativity (HR=2.03, [95% CI, 1.43−2.90], P&amp;lt;0.001), advanced stage (HR=4.40, [95% CI, 3.12−6.21], P&amp;lt;0.001), and the resumed or persistent period (HR=1.85, [95% CI, 1.24−2.77], P=0.002) were remained significant factors for DFS on multivariate analysis. Conclusions : A considerable proportion of premenopausal patients treated by chemotherapy experienced resuming period after CIA. The resumption or persistence of menstruation was a poor prognostic factor for disease free survival in premenopausal patients with early breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-24.

Randomized Trial Comparing Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF) Regimen with Rotational CMFEV Regimen (E=Epirubicin, V=Vincristine) as Adjuvant Chemotherapy in Moderate Risk Operable Breast Carcinoma

Objectives: The CMFEV (cyclophosphamide, methotrexate, 5-fluorouracil, epirubicin, vincristine) regimen is an innovative schedule, designed by our Group, aimed at administering five partially or totally no cross-resistant cytotoxic agents in breast carcinoma. It was randomly compared to CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as primary treatment in operable disease and demonstrated a short-term significant increase in clinical complete response rate and a long-term significant locoregional relapse-free survival in premenopausal patients. So, it seemed worth comparing this regimen with CMF as adjuvant chemotherapy in moderate risk operable breast carcinoma. Methods: Four hundred and eighty-nine patients with stage I or II moderate risk breast carcinoma were randomized to receive CMF or CMFEV regimen for 6 cycles after surgery. Main end points were overall survival (OS), invasive disease-free survival (IDFS) and recurrence-free interval (RFI), as estimated by Kaplan-Meier analyses and log-rank tests. Results: At a median observation time of 7.3 years (range 5.4 months-10.3 years), no significant differences in OS and IDFS were observed between the two arms. Deaths from breast carcinoma were more frequent with CMF (58.5%) than with CMFEV regimen (41.7%) as well as recurrences from breast carcinoma (58.8% with CMF and 41.2% with CMFEV). These differences were not statistically significant. Conclusion: CMFEV appears more effective than CMF in preventing recurrences from primary disease in patients with moderate risk stage I-II breast carcinoma. The lack of statistical significance of the observed differences was probably due to the limited number of patients enrolled which rendered the study underpowdered.

Longer Therapy, Iatrogenic Amenorrhea, and Survival in Early Breast Cancer

The effectiveness and superiority of sequential versus concurrent administration are unknown for regimens used in patients with operable, node-positive, early-stage breast cancer. There is evidence that the adjunctive use of ovarian ablation or suppression independent of chemotherapy may be associated with improved survival in premenopausal patients with hormone-receptor-positive breast cancer. The added benefit of ovarian suppression to chemotherapy outcomes in early-stage node-positive breast cancer is unclear. This randomized, multicenter, phase 3 trial compared the effect of sequential and concurrent regimens on overall survival and disease-free survival in patients with operable, node-positive, early-stage breast cancer. A total of 5351 patients were randomized to receive 1 of the following 3 regimens: (1) 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel (the sequential-ACT regimen); (2) 4 cycles of doxorubicin plus docetaxel (the concurrent doxorubicin-docetaxel regimen); or (3) 4 cycles of doxorubicin plus cyclophosphamide plus docetaxel (the concurrent-ACT regimen). The primary aims of this trial were to determine whether the concurrent ACT regimen was more effective than the sequential ACT regimen and whether the doxorubicin-docetaxel regimen was as effective as the concurrent-ACT regimen. Secondary aims were to investigate the effect of amenorrhea on outcome end points of disease-free and overall survival. The patients were followed for up to 8 years. Treatment with sequential ACT was associated with a significant improvement in overall survival (8-year overall survival, 83%) compared with doxorubicin-docetaxel (overall survival, 79%); the hazard ratio (HR) was 0.83; P = 0.03. There was a nonsignificant improvement for concurrent ACT (overall survival, 79%; HR, 0.86; P = 0.09). With respect to disease-free survival, patients treated with sequential ACT (8-year disease-free survival, 74%) showed a significant reduction in the likelihood of disease recurrence, a second malignant condition, or death compared with either doxorubicin-docetaxel (disease-free survival, 69%; HR, 0.80; P = 0.001) or concurrent ACT (disease-free survival, 69%; HR, 0.83; P = 0.01). No difference was noted between the doxorubicin-docetaxel group and the concurrent-ACT group for either overall survival (HR, 0.96; P = 0.67) or disease-free survival (HR, 0.96; P = 0.58). There was improved overall and disease-free survival among women who had treatment-induced amenorrhea for 6 months or more, independent of the treatment and estrogen-receptor status. These findings show that the sequential administration of ACT is a superior treatment option for women with operable node-positive breast cancer to improve disease-free survival compared with doxorubicin-docetaxel or concurrent ACT, and to improve overall survival compared with doxorubicin-docetaxel. These data provide support for the added benefit of ovarian suppression induced by chemotherapy to improve survival, regardless of the regimen.

476 PFS by patient subgroup for standard chemotherapies in combination with bevacizumab (BV) in the first-line treatment of HER2-negative locally recurrent (LR) or metastatic breast cancer (mBC): results from RIBBON-1

Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437–0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

High Progesterone Receptor Expression Correlates to the Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer Patients

Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70); P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84); P = 0.010] survival. Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER.

Chemotherapy-induced amenorrhea: influence on disease-free survival and overall survival in receptor-positive premenopausal early breast cancer patients

The aim of this study was to evaluate the influence of early chemotherapy-induced amenorrhea (CIA) on disease-free survival and overall survival in premenopausal patients with receptor-positive early breast cancer treated with adjuvant chemotherapy without any hormonotherapy. Retrospectively, we reviewed data from 130 premenopausal patients with localized hormone-sensitive breast cancer. These patients were treated between 1985 and 1995 at the same institution. They all underwent a loco-regional treatment and adjuvant chemotherapy. Early CIA was defined as an amenorrhea arising during the first year following the beginning of chemotherapy. Predictors of early CIA were examined. The survival analyses were done using the Kaplan-Meier method and Cox analysis. Median follow-up was 9 years. Mean age was 42.9 +/- 5 years. Ninety-two per cent of patients had histologically-proven positive axillary nodes. Adjuvant chemotherapy contained no anthracycline in 63%. Early CIA occurred during or after adjuvant chemotherapy in 57% of the patients. It was definitive in 91%. In our study, age was the only CIA predictor in univariate analysis. Women who experienced early CIA tend to have a longer disease-free survival, but the difference was not significant. This trend was lost in multivariate analysis, most probably due to the small sample size. The overall survival was not different. Although not statistically significant, our results on a very selected population of patients suggest that a chemotherapy-induced amenorrhea might have its own therapeutic effect besides the cytotoxic action of chemotherapy.

Quality of life scores predict outcome in metastatic but not in early breast cancer

SUMMARY We compared the prognostic value of quality of life (QL) scores in the adjuvant setting and after relapse in two randomized trials of the International Breast Cancer Study Group (IBCSG). More than 2000 premenopausal and postmenopausal patients with node-positive breast cancer participating in randomized trials comparing adjuvant therapies completed QL assessments for physical wellbeing (PWB), mood, appetite and coping at study entry, at months 3 and 18 if they remained relapse-free, and at 1 month and at 6 months after relapse. Cox regression models were used to test the relationship between QL scores and disease-free survival (DFS) in the adjuvant setting, or overall survival in the case of post-relapse QL measurement. All models were stratified by language/country group and included other factors related to QL and/or outcome. DFS was not significantly predicted by QL scores at baseline or month 18, or by changes in QL score between baseline and months 3 or 18. In contrast, after relapse, QL scores were predictive for subsequent overall survival. One month after relapse, better mood (P = 0.04) was associated with longer survival in premenopausal patients, and better appetite (P = 0.005) in postmenopausal patients. Six months after relapse, PWB (P = 0.03) and appetite (P = 0.03) were predictive for survival in premenopausal, and PWB (P Any prognostic significance of QL scores in the adjuvant setting is minimal or obscured by chemotherapy effects, but there is strong prognostic significance after disease relapse. The contrast suggests that patient perception of the severity of underlying illness may determine reported QL scores.