Survival In Postmenopausal Women Research Articles

PRDM1 rs2185379, unlike BRCA1, is not a prognostic marker in patients with advanced ovarian cancer.

Ovarian cancer (OC) is mostly diagnosed in advanced stages with high incidence-to-mortality rate. Nevertheless, some patients achieve long-term disease-free survival. However, the prognostic markers have not been well established. The primary objective of this study was to analyse the association of the suggested prognostic marker rs2185379 in PRDM1 with long-term survival in a large independent cohort of advanced OC patients. We genotyped 545 well-characterized advanced OC patients. All patients were tested for OC predisposition. The effect of PRDM1 rs2185379 and other monitored clinicopathological and genetic variables on survival were analysed. The univariate analysis revealed no significant effect of PRDM1 rs2185379 on survival whereas significantly worse prognosis was observed in postmenopausal patients (HR = 2.49; 95%CI 1.90-3.26; p= 4.14 × 10 - 11) with mortality linearly increasing with age (HR = 1.05 per year; 95%CI 1.04-1.07; p= 2 × 10 - 6), in patients diagnosed with non-high-grade serous OC (HR = 0.44; 95%CI 0.32-0.60; p= 1.95 × 10 - 7) and in patients carrying a gBRCA1 pathogenic variant (HR = 0.65; 95%CI 0.48-0.87; p= 4.53 × 10 - 3). The multivariate analysis interrogating the effect of PRDM1 rs2185379 with other significant prognostic factors revealed marginal association of PRDM1 rs2185379 with worse survival in postmenopausal women (HR = 1.54; 95%CI 1.01-2.38; p= 0.046). Unlike age at diagnosis, OC histology or gBRCA1 status, rs2185379 in PRDM1 is unlikely a marker of long-term survival in patients with advance OC.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor–Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination

Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease. To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. ClinicalTrials.gov Identifier: NCT01953588.

Abstract 6491: Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women

Abstract Background: Exogenous sex hormone supplements had been associated with increased lung cancer mortality in a large clinical trial. No study to date has evaluated temporal trajectories of circulating sex hormones and aromatase activity and their associations with lung cancer survival. Objective: To characterize temporal changes in prediagnostic levels of circulating sex hormones and aromatase activity and to evaluate their associations with overall survival in lung cancer patients. Methods: Included in the analysis were 385 incident lung cancer patients identified in a large prospective cohort among postmenopausal women who had never used cigarette products nor exogenous sex hormone supplements. Concentrations of sex hormones were quantitated using LC-MS/MS assays in prediagnostic plasma samples. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). A multivariable Cox model with restricted cubic spline functions was used to calculate hazard ratio (HR) for overall survival. Results: Of 385 patients with lung cancer, 308 died during a median follow-up of 18.1 years. Initial analyses in all patients showed that higher levels of circulating estrone and IAA and lower levels of androstenedione and testosterone were associated with poorer overall survival after adjusting for nonclinical covariates. In analyses restricted to those with clinical data (n=281), stronger associations were found after further adjustment for tumor stage and treatment regimens. Compared with patients at the median level of IAA, adjusted HRs (95% CI) for total mortality in those at the 30th, 70th, 90th and 95th percentiles were 0.98 (0.84-1.13), 1.05 (0.94-1.16), 1.28 (1.06-1.54), and 1.64 (1.27-2.12), respectively, with P-overall &amp;lt; 0.001. A similar positive association was observed for estrone. In contrast, inverse associations were seen for androgens. For example, compared with the median level of testosterone, HRs (95% CI) for those at the 5th, 10th, 30th, 70th percentiles were 2.10 (1.43-3.09), 1.69 (1.29-2.23), 1.45 (1.19-1.76), and 0.86 (0.78-0.94), respectively, with P-overall = 0.001. Further, we found that circulating levels of sex hormones changed during disease progression. The closer the hormone measurement to cancer diagnosis the higher the IAA and estrone levels (P-overall &amp;lt; 0.001 for both), and the temporal change plateaued 10 years before cancer diagnosis (P-nonlinearity &amp;lt; 0.001 for both). An opposite temporal pattern was found for testosterone. Moreover, the significant association between sex hormones and lung cancer survival was only observed when sex hormones were measured within 10 years before diagnosis. Conclusions: Findings from our study, for the first time, demonstrate temporal changes in circulating sex hormones and their associations with lung cancer survival in postmenopausal women. Citation Format: Yingya Zhao, Xiao-Ou Shu, Yu-Tang Gao, Mark M. Kushnir, Qiuyin Cai, Hui Cai, Qing Lan, Nathaniel Rothman, Wei Zheng, Gong Yang. Temporal changes in circulating sex hormones and aromatase activity and associations with lung cancer survival in postmenopausal women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6491.

Extended adjuvant aromatase inhibition after sequential endocrine therapy in postmenopausal women with breast cancer: follow-up analysis of the randomised phase 3 DATA trial

The DATA study evaluated the use of two different durations of anastrozole in patients with hormone receptor-positive breast cancer who were disease-free after 2-3 years of tamoxifen. We hereby present the follow-up analysis, which was performed after all patients reached a minimum follow-up of 10 years beyond treatment divergence. The open-label, randomised, phase 3 DATA study was performed in 79 hospitals in the Netherlands (ClinicalTrials.gov, number NCT00301457). Postmenopausal women with hormone receptor-positive breast cancer who were disease-free after 2-3 years of adjuvant tamoxifen treatment were assigned to either 3 or 6 years of anastrozole (1mg orally once a day). Randomisation (1:1) was stratified by hormone receptor status, nodal status, HER2 status, and prior tamoxifen duration. The primary outcome was adapted disease-free survival, defined as disease-free survival from 3 years after randomisation onwards. Adapted overall survival was assessed as a secondary outcome. Analyses were performed according to the intention-to-treat design. Between June 28, 2006, and August 10, 2009, 1912 patients were randomly assigned to 3 years (n=955) or 6 years (n=957) of anastrozole. Of these, 1660 patients were eligible and disease-free at 3 years after randomisation. The 10-year adapted disease-free survival was 69.2% (95% CI 55.8-72.3) in the 6-year group (n=827) and 66.0% (95% CI 62.5-69.2) in the 3-year group (n=833) (hazard ratio (HR) 0.86; 95% CI 0.72-1.01; p=0.073). The 10-year adapted overall survival was 80.9% (95% CI 77.9-83.5) in the 6-year group and 79.2% (95% CI 76.2-81.9) in the 3-year group (HR 0.93; 95% CI 0.75-1.16; p=0.53). Extended aromatase inhibition beyond 5 years of sequential endocrine therapy did not improve the adapted disease-free survival and adapted overall survival of postmenopausal women with hormone receptor-positive breast cancer. AstraZeneca.

Abstract GS3-04: GS3-04 Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial

Abstract Background: AKT pathway activation has been implicated in the development of endocrine therapy resistance in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) advanced breast cancer (ABC). In the Phase II, placebo (PBO)-controlled FAKTION trial, the addition of the pan-AKT inhibitor capivasertib to fulvestrant significantly improved progression-free survival (PFS) and overall survival in postmenopausal women with aromatase inhibitor (AI)-resistant HR+/HER2– ABC. The Phase III, randomized, double-blind, PBO-controlled CAPItello-291 trial (NCT04305496) investigated the efficacy and safety of capivasertib + fulvestrant in patients with AI-resistant HR+/HER2– ABC. Methods: Eligible pre/peri or postmenopausal women or men with HR+/HER2– ABC that had recurred or progressed on or after AI therapy with or without a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor were randomized 1:1 to receive fulvestrant (per standard dosing schedule) with either PBO or capivasertib (400 mg twice daily; 4 days on, 3 days off). Randomization was stratified by the presence of liver metastases, prior use of CDK4/6 inhibitors, and geographic location. AKT pathway alteration status (at least one qualifying PIK3CA, AKT1, or PTEN alteration) was determined using next-generation sequencing in tumor tissue. The dual primary endpoint was investigator-assessed PFS in the overall population and in patients with AKT pathway-altered tumors. Results: A total of 708 patients were randomized: 355 to capivasertib + fulvestrant and 353 to PBO + fulvestrant. Overall, 41% of patients had AKT pathway-altered tumors (48% [n=289/602] of patients with tumor sequencing results), 22% were pre/perimenopausal and 77% postmenopausal, with 1% male. Prior therapy for advanced disease included: 87% of patients with ≥1 line of prior treatment, 69% with a prior CDK4/6 inhibitor, and 18% with prior chemotherapy. Demographic and baseline characteristics were broadly balanced between the overall and altered populations and by treatment groups. At primary analysis (data cut-off Aug 15, 2022), 551 and 236 PFS events had occurred in the overall and pathway-altered populations, respectively. Overall, the median PFS was 7.2 months with capivasertib + fulvestrant and 3.6 months with PBO + fulvestrant (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.51–0.71; p&amp;lt;0.001). In patients with AKT pathway-altered tumors, median PFS was 7.3 months with capivasertib + fulvestrant and 3.1 months with PBO + fulvestrant (HR 0.50; 95% CI 0.38–0.65; p&amp;lt;0.001). The objective response rate in patients with measurable disease was 22.9% for capivasertib + fulvestrant vs 12.2% for PBO + fulvestrant overall and 28.8% vs 9.7% in the AKT pathway-altered population. The most frequent all-grade adverse events (AEs) with capivasertib + fulvestrant were diarrhea (72.4% vs 20.0% PBO + fulvestrant arm), rash (group term of rash, rash macular, rash maculo-papular, rash papular, rash pruritic; 38.0% vs 7.1%) and nausea (34.6% vs 15.4%). The most frequently reported grade ≥3 AEs were rash (group term; 12.1% vs 0.3%), diarrhea (9.3% vs 0.3%), and hyperglycemia (2.3% vs 0.3%); grade ≥3 stomatitis was 2.0% vs 0%. AEs leading to discontinuation of capivasertib/placebo were reported in 13.0% and 2.3% of patients, respectively. Conclusions: Capivasertib + fulvestrant significantly improved PFS compared to fulvestrant alone in the overall population, and in patients with AKT pathway-altered tumors, and may become a future treatment option in this setting. The safety profile of capivasertib + fulvestrant was generally manageable and consistent with prior data. Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Nicholas Turner, Mafalda Oliveira, Sacha J. Howell, Florence Dalenc, Javier Cortés, Henry Gomez, Xichun Hu, Komal Jhaveri, Sibylle Loibl, Serafin Morales Murillo, Zbigniew Nowecki, Meena Okera, Yeon H. Park, Masakazu Toi, Lyudmila Zhukova, Chris Yan, Gaia Schiavon, Andrew Foxley, Hope Rugo. GS3-04 Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-04.

Abstract P2-02-01: Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials

Abstract Introduction: Based on trials performed over a 25-year period, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a small but significant benefit of adjuvant bisphosphonates (BP) in reducing bone recurrence with a subsequent modest improvement in breast cancer-specific survival in post-menopausal women. Multiple studies show that contemporary event rates in early-stage breast cancer are much lower than those observed over a decade ago. This observation likely reflects the impact of modern adjuvant systemic therapy such as anthracycline and taxane chemotherapy and aromatase inhibitors. Therefore, re-evaluating the benefit of adjuvant bisphosphonate in the modern era is warranted. Methods: We reviewed reports of randomized trials of adjuvant BP that accrued patients exclusively beyond 2000 and extracted 5-year disease free survival (DFS) and overall survival (OS) in BP and control group arm along with hazard ratios (HR) when reported. The mean 5-year DFS and OS weighted by study sample size was calculated for each group. HR for DFS and OS were pooled in a meta-analysis using generic inverse variance and random effects modelling. Trial level absolute differences in DFS and OS between BP and control arms were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was then performed to explore association between disease and treatment related factors and absolute differences in benefit from BP. Quantitative significance was explored using methods described by Burnand et al. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY) and Review manager v5.4. Results: Twelve trials comprising 24109 patients were included in the analysis. Weighted mean DFS and OS in patients receiving BP were 85.8% and 91.7% respectively. For control group patients, these estimates respectively were 83.4% and 91.0%. For DFS, pooled HR across trials was 0.89 (0.81-0.97) with a 2.9% weighted mean difference favoring BP over control. Among patients receiving anthracycline and taxane based chemotherapy (n=3007), relative benefits were smaller; (HR DFS 0.94, 0.85-1.05). There was no significant OS benefit with BP (HR 0.92, 0.82-1.03) and this finding was observed irrespective of type of chemotherapy. The impact of BP on OS was smaller in both relative and absolute terms in studies with recruitment occurring more recently. Meta-regression results are shown in Table. There was lesser benefit in higher risk patients (node+, larger tumor size, ER-, grade 3 or those receiving chemotherapy). Overall, 1.13% patients experienced osteonecrosis related to BP therapy. Conclusions: Compared to EBCTCG data, relative and absolute benefit from BP is similar or modestly lower among more recent trials. Benefit from adjuvant BP appears smaller in patients treated with more contemporary adjuvant systemic therapy especially anthracycline and taxane containing chemotherapy. It is uncertain if the impact of BP on OS (rather than breast-cancer specific survival) is of a clinically meaningful magnitude. Despite de-escalated dosing compared to metastatic disease, osteonecrosis was observed in &amp;gt;1% of patients. It is possible that the benefits of BP are driven by patients with clinically low-risk disease rather than those with at high-risk. The balance between benefits and risks of adjuvant BP should be considered in individual patients. Table 1: Metaregression Results Citation Format: Abhenil Mittal, Faris Tamimi, Consolacion Molto Valiente, Massimo Di Iorio, Eitan Amir. Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-01.

ASSOCIATION OF PSYCHOSOCIAL FACTORS WITH MORTALITY IN OLDER FEMALE SURVIVORS OF CANCER

Abstract Understanding factors associated with survival after a cancer diagnosis among older adults is critical as the population ages and cancer survivorship increases. The purpose of this study was to: (1) identify clusters of postmenopausal cancer survivor characteristics by demographic and lifestyle factors; 2) describe the characteristics of each cluster; and 3) evaluate the association of cluster assignment with survival. Participants from the Women’s Health Initiative (WHI) who reported either a prevalent cancer diagnosis at baseline (n=14294) or were diagnosed with a first primary incident cancer within the first 10 years of WHI (n=12934) were included. Latent class analysis was used to identify survivor clusters using psychosocial variables. Clusters were characterized using descriptive statistics. We tested for differences in cluster characteristics using ANOVA and Chi-square tests as appropriate. Cox proportional hazards regression was used to evaluate the association between cluster and mortality. Prevalent (n=7) and incident (n=9) cancer survivors clusters were identified. Among both (prevalent and incident) sets of clusters, age at WHI baseline, age at menopause, race, ethnicity, income, education, body mass index, diet quality, smoking, alcohol consumption and exercise all differed by cluster (p&amp;lt;.0001 for all). The most racially and ethnically diverse cluster had higher mortality rates compared to the largest most homogenous cluster; hazard ratio (95%CI) 1.30 (1.15, 1.48) and 1.33 (1.16, 1.53), respectively. Understanding how clusters of risk factors influence cancer survival in postmenopausal women will inform future interventions to improve outcomes and reduce health disparities for cancer survivors.

The crosstalk within the breast tumor microenvironment in type II diabetes: Implications for cancer disparities.

Obesity-driven (type 2) diabetes (T2D), the most common metabolic disorder, both increases the incidence of all molecular subtypes of breast cancer and decreases survival in postmenopausal women. Despite this clear link, T2D and the associated dysfunction of diverse tissues is often not considered during the standard of care practices in oncology and, moreover, is treated as exclusion criteria for many emerging clinical trials. These guidelines have caused the biological mechanisms that associate T2D and breast cancer to be understudied. Recently, it has been illustrated that the breast tumor microenvironment (TME) composition and architecture, specifically the surrounding cellular and extracellular structures, dictate tumor progression and are directly relevant for clinical outcomes. In addition to the epithelial cancer cell fraction, the breast TME is predominantly made up of cancer-associated fibroblasts, adipocytes, and is often infiltrated by immune cells. During T2D, signal transduction among these cell types is aberrant, resulting in a dysfunctional breast TME that communicates with nearby cancer cells to promote oncogenic processes, cancer stem-like cell formation, pro-metastatic behavior and increase the risk of recurrence. As these cells are non-malignant, despite their signaling abnormalities, data concerning their function is never captured in DNA mutational databases, thus we have limited insight into mechanism from publicly available datasets. We suggest that abnormal adipocyte and immune cell exhaustion within the breast TME in patients with obesity and metabolic disease may elicit greater transcriptional plasticity and cellular heterogeneity within the expanding population of malignant epithelial cells, compared to the breast TME of a non-obese, metabolically normal patient. These challenges are particularly relevant to cancer disparities settings where the fraction of patients seen within the breast medical oncology practice also present with co-morbid obesity and metabolic disease. Within this review, we characterize the changes to the breast TME during T2D and raise urgent molecular, cellular and translational questions that warrant further study, considering the growing prevalence of T2D worldwide.

Changes in Dietary Intake of Methionine, Folate/Folic Acid and Vitamin B12 and Survival in Postmenopausal Women with Breast Cancer: A Prospective Cohort Study.

Previous experimental studies showed that limiting methionine in the diet of animals or in cell culture media suppresses mammary cancer cell proliferation or metastasis. However, no previous study has investigated the associations of changes in methionine intake with survival among breast cancer survivors. We aimed to examine the association between changes in dietary intake of methionine, folate/folic acid, and vitamin B12 from before to after diagnosis of breast cancer, and mortality among breast cancer survivors. We included 1553 postmenopausal women from the Women's Health Initiative who were diagnosed with invasive breast cancer and completed a food frequency questionnaire both before and after breast cancer diagnosis. Multivariable Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence (CIs) of all-cause and breast cancer mortality associated with changes in methionine intake and changes in folate/folic acid and vitamin B12 intake. Relative to pre-diagnosis, 28% of women decreased methionine intake by ≥20%, 30% of women increased methionine intake by ≥20%, and 42% of women had a relatively stable methionine intake (±19.9%) following breast cancer diagnosis. During a mean 16.1 years of follow up, there were 772 deaths in total, including 195 deaths from breast cancer. Compared to women with relatively stable methionine intake, women with decreased methionine intake had lower risks of all-cause (HR 0.78, 95% CI 0.62-0.97) and breast cancer mortality (HR 0.58, 95% CI 0.37-0.91) in fully adjusted models. In contrast, increased methionine intake or changes in folate/folic acid or vitamin B12 intake were not associated with all-cause or breast cancer mortality. Among breast cancer survivors, decreased methionine intake after breast cancer diagnosis was associated with lower risk of all-cause and breast cancer mortality.

Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer.

Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations. Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.

Hormone replacement therapy is associated with reduced hepatocellular carcinoma risk and improved survival in postmenopausal women with hepatitis B: A nationwide long-term population-based cohort study.

Postmenopausal women with hepatitis B virus (HBV) infection are more likely to have accelerated liver fibrosis, eventually advancing to liver cirrhosis or hepatocellular carcinoma (HCC). The association between sex hormones and HBV-related HCC risk is unclear. We investigated whether hormone replacement therapy (HRT) is beneficial to postmenopausal women with HBV infection. This retrospective study selected the data of 44,465patients with HBV infection between January 2000 and December 2018 from Taiwan’s National Health Insurance Research Database. After excluding patients with preexisting liver diseases, liver cirrhosis, or liver malignancies, we grouped the remaining 10,474 patients by whether they had undergone HRT for at least 3 months (n = 5,638) and whether they had not received HRT (n = 4,836). After propensity score matching, we assigned 3080 patients to an HRT cohort and matched them (1:1) with those in a non-HRT cohort. The incidence of HCC (P < 0.022) and all-cause mortality rate (P < 0.001) were lower in the HRT cohort than in the non-HRT cohort. The liver cirrhosis risk was not significantly higher in the HRT cohort (P = 0.355). HRT is associated with reduced HCC risk and improved survival outcomes but is unrelated to liver cirrhosis development in postmenopausal women.

Sentinel Lymph Node Biopsy Alone is Adequate for Chemotherapy Decisions in Postmenopausal Early-Stage Hormone-Receptor-Positive, HER2-Negative Breast Cancer with One to Three Positive Sentinel Lymph Nodes.

The RxPONDER trial randomized patients with cT1-3N0 hormone receptor-positive, HER2-negative (HR+HER2-) breast cancer and one to three positive nodes and Recurrence Score (RS) < 26 to endocrine therapy (ET) or chemoendocrine therapy (CET) with equivalent survival in postmenopausal women. In current practice, cN0 patients with one or two positive sentinel lymph nodes (SLN) do not undergo axillary lymph node dissection (ALND), raising concerns about applying these data in patients who may have additional nodal disease. We identified institutional [Dana-Farber Brigham Cancer Center (DF/BCC), 2016-2020] and national [National Cancer Database (NCDB), 2012-2017] cohorts of women aged 50-75 years with cT1-3N0 HR+HER2- breast cancer and RS < 26 treated with upfront surgery with one to three positive SLN. Axillary nodal burden and outcomes were assessed on the basis of the number of positive nodes and CET use. A total of 197 and 13,499 HR+HER2- eligible patients with one to three positive SLN and RS < 26 were identified in the DF/BCC and NCDB databases, respectively, and 12.7% of DF/BCC and 32.4% of NCDB patients had ALND. Of these, only 12.0 and 4.9% had more than three total positive nodes, respectively. Rates of CET were 6.6% in DF/BCC and 20.9% in NCDB patients. In the NCDB, similar adjusted 4-year overall survival was seen between patients treated with CET or ET for any number of positive nodes (98.1-99.9%, all p > 0.05). Postmenopausal women with cT1-3N0 HR+HER2- breast cancer and RS < 26 with one to three positive SLN are unlikely to have more than three total positive nodes. CET decisions should continue to be based on SLN biopsy as ALND is unlikely to change treatment recommendations or outcomes.

How to choose the bone modifying treatment for early stage and locally advanced breast cancer?

Abstract Introduction: Breast cancer continues to be the most frequent malignancy in women worldwide. Considerable advances in oncology over the years have led to decreased mortality in early stage (EBC) and locally advanced (ABC) breast cancer, but this has raised concerns about possible long-term effects of anticancer treatment nonetheless. Purpose: The present paper aims to describe the efficacy and safety of osteoclast inhibitors, both as antiresorptive agents, reducing osteoporosis and fracture risk, and as adjuvant anticancer agents, potentially improving disease-related outcomes in patients with early stage and locally advanced breast cancer. Materials and methods: In this article, literature sources were selected and evaluated using the PRISMA 2020 guideline. Conclusions: Bisphosphonates are recommended for early stage and advanced breast cancer patients, either premenopausal or postmenopausal, with osteoporosis. Denosumab may also be used for postmenopausal women. Bisphosphonates also showed a statistically significant benefit for overall survival in postmenopausal women only. However, denosumab is not presently used for indications other than prevention or treatment of osteoporosis.

How we treat HR-positive, HER2-negative early breast cancer.

The present goal of therapy for early HR+/HER2- breast cancer (BC) is to optimize disease-free survival (DFS) and overall survival (OS) rates with the currently available therapies while avoiding any relevant long-term sequalae. Local therapies have evolved towardless aggressive techniques (i.e. breast-preserving surgery, sentinel lymph node biopsy andintraoperative radiotherapy), which significantly reduce the long-term sequalae observed with more radical treatments. Endocrine therapy (ET) is still the cornerstone of adjuvant treatment because it significantly reduces BC relapse and mortality. Adjuvant chemotherapy is today recommended only for a particular subset of patients with a high risk of recurrence with ET alone, identified through genomic assays, age and/or disease stage. Bisphosphonates reduce the risk of bone metastasis and produce a slight although statistically significant improvement in survival in postmenopausal women. The CDK 4/6 inhibitor abemaciclib has been recently approved by the USFDA for patients at high risk of relapse.

Association of bilateral salpingo-oophorectomy with all cause and cause specific mortality: population based cohort study

ObjectivesTo determine if bilateral salpingo-oophorectomy, compared with ovarian conservation, is associated with all cause or cause specific death in women undergoing hysterectomy for non-malignant disease, and to determine how this...

Fatty liver disease and changes in dense breasts in pre- and postmenopausal women: the Kangbuk Samsung Health Study.

While increased breast density is a risk factor for breast cancer, the effect of fatty liver disease on breast density is unknown. We investigated whether fatty liver is a risk factor for changes in breast density over ~ 4years of follow-up in pre- and postmenopausal women. This study included 74,781 middle-aged Korean women with mammographically determined dense breasts at baseline. Changes in dense breasts were identified by more screening mammograms during follow-up. Hepatic steatosis (HS) was measured using ultrasonography. Flexible parametric proportional hazards models were used to determine the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs), and a Weibull accelerated failure time model (AFT) was used to determine the time ratios (TRs) and 95% CIs. During a median follow-up of 4.1years, 4022 women experienced resolution of the dense breasts. The association between HS and dense breast resolution differed by the menopause status (P for interaction < 0.001). After adjusting for body mass index and other covariates, the aHRs (95% CI) for dense breast resolution comparing HS to non-HS were 0.81 (0.70-0.93) in postmenopausal women, while the association was converse in premenopausal women with the corresponding HRs of 1.30 (1.18-1.43). As an alternative approach, the multivariable-adjusted TR (95% CI) for dense breast survival comparing HS to non-HS were 0.81 (0.75-0.87) and 1.19 (1.06-1.33) in premenopausal and postmenopausal women, respectively. The association between HS and changes in dense breasts differed with the menopause status. HS increased persistent dense breast survival in postmenopausal women but decreased it in premenopausal women.

Abstract 741: Characterization of high-grade serous ovarian carcinoma by measuring functional signal transduction pathway activity

Abstract Introduction: The majority of advanced stage high-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, recurs within the first 24 months despite complete remission after initial treatment. Yet there are remarkable differences in disease-free (DFS) and overall survival (OS). We hypothesize that differences in signal transduction pathway (STP) activity may relate to survival and may also improve targeted therapy selection. We investigate the STP activity in relation to survival in patients diagnosed with advanced stage HGSC, as well as identify STPs that may be targeted in alternative treatment strategies. Methods: We included 85 HGSC patients (DFS &amp;lt;12 months, n=52 and DFS &amp;gt;24 months, n=33) who achieved complete remission after treatment with debulking surgery and chemotherapy. Total mRNA was extracted, and RT-qPCR was performed to determine expression levels of pathway-specific target genes in primary HGSC samples taken prior to start of chemotherapy. OncoSignal pathway assays were used to quantitatively measure functional STP activity of the androgen and estrogen receptor (ER), PI3K, Hedgehog, TGF-β and Wnt pathways. Survival analysis in relation to STP activity was performed by means of Cox regression analysis and differences between groups were analyzed with Mann-Whitney U tests. Results: Differences in PI3K, Hedgehog and TGF-β pathway activity were observed across the HGSC cohort, suggesting unique tumor activation patterns. Median STP activity was not discernably different between the short and long DFS groups. Significantly higher ER pathway activity was found in premenopausal women (n=16) compared to postmenopausal women (n=67) (p=0.002). Cox regression analysis in postmenopausal women (n=67) showed that ER pathway activity was positively associated with DFS (HR=0.943, p=0.033) and OS (HR=0.930, p=0.041) in univariate analysis. None of the pathways were significantly related to DFS or OS in premenopausal women (n=16). Conclusion: We observed a positive association between ER pathway activity and survival in postmenopausal women but not in premenopausal women. Also, differences in activation levels of the other STPs were observed in individual patients. STP analysis may be used to aid targeted therapy selection, such as anti-hormonal therapy, in HGSC patients. Citation Format: Phyllis van der Ploeg, Laura van Lieshout, Yvonne Wesseling-Rozendaal, Anja van de Stolpe, Diederick Keizer, Steven Bosch, Marjolein Lentjes-Beer, Caroline Vos, Joanne de Hullu, Ruud Bekkers, Jurgen Piek. Characterization of high-grade serous ovarian carcinoma by measuring functional signal transduction pathway activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 741.

PCN4 Overall Survival in Post-Menopausal Women with HR+/HER2- Advanced Breast Cancer Receiving a CDK 4 and 6 Inhibitor + Fulvestrant after Progressing on/after Prior Endocrine Therapy: A Fractional Polynomial Network Meta-Analysis

Three trials evaluating CDK4&6i+fulvestrant have recently reported overall survival (OS) data among women with HR+/HER2− advanced breast cancer. The objective of this research was to compare the OS of post-menopausal (including, but not limited to, natural, surgical or ovarian suppression) women treated with CDK4&6i+fulvestrant who progressed on or immediately after (<12 months) adjuvant endocrine therapy (ET) or while receiving their first ET for advanced disease. A SLR identified RCTs based on pre-defined eligibility criteria. Data from the intention-to-treat (ITT) populations and subgroups were extracted. There was a suggestion of a departure from the proportional hazards (PH) assumption. Therefore, a time-to-event NMA based on Fractional Polynomials (FP) proposed by Jansen (2011) was conducted in a Bayesian framework allowing non-PH. A range of first and second order FP were considered. For each FP, random effect (RE) and fixed effects (FE) were examined. The best fitting model was selected using the deviance information criteria (DIC). Afterwards, the relative treatment effects were assessed, and the survival curves displayed. A FE model with P1 = -0.5 & P2 = 0 was the best fitting model for this network. The mean difference (95% Credible Interval [CrI]) in expected survival at month 80 for palbociclib+fulvestrant vs abemaciclib+fulvestrant was -11.44 (-21.86 to 2.85) months and for ribociclib+fulvestrant vs abemaciclib+fulvestrant was 2.16 (-6.70 to 10.65) months. The overlapping 95% CrI indicate no differences between the CDK4&6i. The results showed no differences in OS between the CDK4&6i+fulvestrant based on the restricted network. The FP NMA allowed us to address uncertainties associated with violation of PH assumption. Interpretation is limited by important uncertainties around the estimates of relative treatment effects, suggesting heterogeneity among trial populations generated by differences in key prognostic factors.

The preoperative systemic inflammation response index (SIRI) independently predicts survival in postmenopausal women with breast cancer

The recently developed preoperative systemic inflammation response index (SIRI) was reported as a useful biomarker that could predict survival in certain types of malignant tumors. However, the prognostic value of preoperative SIRI in postmenopausal breast cancer remains unclear. This study aimed to explore the relationship between SIRI and survival in postmenopausal patients with breast cancer. A total of 390 postmenopausal patients with breast cancer who underwent a mastectomy at Sun Yat-sen University Cancer Center were retrospectively studied. SIRI was based on peripheral neutrophil, monocyte, and lymphocyte counts, calculated as: neutrophil count × monocyte count/lymphocyte count. The best cut-off value for SIRI was determined using receiver operating characteristic curve analysis. Patients were divided into 2 groups:Low SIRI < 0.54 and high SIRI > 0.54. High SIRI was significantly related to progesterone receptor status. Kaplan-Meier survival analysis showed that T stage, N stage, clinical stage, carcinoembryonic antigen, estrogen receptor, progesterone receptor, endocrinotherapy, and SIRI were significantly correlated with overall survival (OS). Multivariate analysis showed that SIRI could also independently predict OS. Preoperative SIRI may be a reliable predictor of OS in postmenopausal patients with operable breast cancer to provide personalized prognostication and to assist in the formulation of a clinical treatment strategy.

Abstract P5-07-03: Metabolic syndrome impacts survival in postmenopausal women with triple negative breast cancer: Results from the women’s health initiative

Abstract INTRODUCTION: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer associated with poor clinical outcome. Patients diagnosed with TNBC may experience many treatment-associated changes, including weight gain, reduced physical activity levels, and worsening metabolic profiles. We sought to identify the association between baseline metabolic syndrome (MetS) components with survival outcomes in WHI participants diagnosed with TNBC. METHODS: The WHI comprises 161,308 post-menopausal women aged 50-79 who were enrolled from 1993-1998 and were at low risk of 3-year mortality at study screening. After excluding women with a history of cancer and those randomized to the dietary modification treatment arm, we identified 615 participants diagnosed with non-metastatic TNBC while on study. MetS status at baseline was assessed at study entry (prior to subsequent breast cancer diagnosis) using the following risk factors: 1) high waist circumference (≥88 cm), 2) high blood pressure (&amp;gt;135 mg Hg systolic and/or &amp;gt; 85 diastolic, or anti-hypertension medication use), 3) history of high cholesterol, and 4) history of diabetes. Groups were stratified into: 1) no MetS components (none), 2) 1-2 MetS components, and 3) 3-4 MetS components. All breast cancers were verified by medical record review. Survival status was augmented by serial National Death Index queries. Outcomes of interest included breast cancer specific survival, as well as all-cause survival after breast cancer, with survival time calculated from date of TNBC diagnosis to date of death or off-study. Baseline demographic, clinicopathologic, and treatment differences were assessed across MetS groups using chi-squared analyses. Kaplan-Meier curves were plotted across MetS groups and survival rates were compared using the log-rank statistic. RESULTS: Of 615 participants diagnosed with TNBC, the distribution of MetS was as follows: 29% had no MetS components (n=178), 53% had 1-2 components (n=323), and 7% had 3-4 components (n=43). The median time from enrollment to TNBC diagnosis was 8.6 years (median), with those in the highest MetS group having a significantly shorter time to diagnosis than those without any MetS (7.0 years vs. 9.8 years, respectively, p&amp;lt;0.001). In addition, those in the highest MetS group were more often black (28% 3-4 vs. 4% none, p&amp;lt;0.001), had incomes &amp;lt;$50,000/year (83% 3-4 vs. 49% none, p&amp;lt;0.001), and had lower rates of menopausal hormone therapy use at baseline (p=0.02). There were no differences in tumor characteristics or treatment modalities across baseline MetS groups. After 8.3 years (median) follow-up since TNBC, breast cancer survival rates at 10 years were lower in participants with 3-4 MetS (63%) compared to those with 1-2 (79%) or none (84%) (p=0.09). All-cause survival rates at 10 years after breast cancer diagnosis were also lower in participants with 3-4 MetS (45%) compared to those with 1-2 (65%) or none (71%) (p=0.008). CONCLUSION: Although TNBC is associated with poor clinical outcome, differences in all-cause mortality in women with TNBC remain significantly influenced by MetS. TNBC patients with 3-4 MetS components have 10-year all-cause survival rates over 35% lower than TNBC survivors with no MetS components. This finding highlights the importance of women’s overall health status and medical condition, even after the diagnosis of an aggressive breast cancer. Table 1. Breast cancer and all-cause survival rates by MetS group.MetSNBreast Cancer Survival (%)All-Cause Survival (%)3-year5-year10-yearp-value3-year5-year10-yearp-value01789087840.098782710.0081-23238983798777653-443877363836445 Citation Format: Yuan Yuan, Rebecca Nelson, Kathy Pan, Jessica Yan, Susan E Yost, Rami Nassir, Rowan Chlebowski. Metabolic syndrome impacts survival in postmenopausal women with triple negative breast cancer: Results from the women’s health initiative [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-03.