Risk Of Breast Cancer-specific Mortality Research Articles

Abstract PO1-08-05: Using the CTS5 Score to Predict Late Recurrence in Male and Female Estrogen Receptor-Positive Breast Cancer Patients: a SEER database analysis of 65,729 cases

Abstract Purpose: The Clinical Treatment Score post-5 years (CTS5) score is a prognostic prediction tool to predict the risk of late distant recurrence in postmenopausal women with estrogen receptor-positive (ER+) breast cancer. Here we aimed to evaluate the prediction role of CTS5 in male breast cancer patients using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: ER+ early male and female breast cancer patients from the SEER database 2010-2013 were included. Clinicopathological features and the CTS5 score between the gender groups were compared using chi-square test. Overall survival (OS) and breast cancer-specific survival (BCSS) were estimated by Kaplan-Meier plots and compared between the groups with Log-rank test and multivariate cox proportional hazard regression models was used to determine the relationship between the CTS5 score and breast cancer survival outcomes in different gender cohorts. Results: A total of 65,729 ER+ breast cancer patients were included in the study and 611 were men. Male breast cancer was more likely to be diagnosed later in life (>50 years old, 87.1% vs 73.6%, p < 0.001), with more aggressive biological features (grade Ⅱ 51.6% vs 47.2%, p < 0.001; grade Ⅲ 37.8% vs 28.3%, p < 0.001) , and higher tumor burden (stage Ⅱ 45.8% vs 32.9%, p < 0.001, stage Ⅲ 17.5% vs 10.5%, p < 0.001) when compared to female counterparts. More male patients were CTS5 intermediate- or high-risk than female patients (high 7.9% vs 6.3%, intermediate 41.1% vs 24.6%, low 51.1% vs 69.1%, p < 0.001). Patients were divided into 0-5 year and >5 year cohorts based on whether they had a BCSS event within 5 years. In the >5 year cohort, patients with CTS5 high- or intermediate- risk had worse survival outcomes compared with low-risk cases in male and postmenopausal female patients but not in premenopausal female patients. In the 0-5 year cohort, the CTS5 score was not predictive for disease recurrence in male or postmenopausal patients. Conclusion: Male breast cancer patients were more likely to have aggressive tumors and worse survival outcomes. The CTS5 score could be applied to predict breast cancer-specific mortality risk beyond 5 years in male ER+ breast cancer patients. Citation Format: Fenhua Wang, Fang Ren, Jian Qian, Yunxia Xu, Jiayi Wu, Yu Zong, Xidong Gu. Using the CTS5 Score to Predict Late Recurrence in Male and Female Estrogen Receptor-Positive Breast Cancer Patients: a SEER database analysis of 65,729 cases [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 PO1-08-05.

Mortality Risks Over 20 Years in Men With Stage I to III Hormone Receptor–Positive Breast Cancer

In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported. To report 20-year risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I to III HR+ breast cancer and identify factors associated with late BCSM. An observational cohort study was conducted of men diagnosed with HR+ breast cancer from 1990 to 2008, using population-based data from the Surveillance, Epidemiology, and End Results program. Men diagnosed with stage I to III HR+ breast cancer were included in the analysis. Cumulative incidence function was used to estimate the outcomes of baseline clinicopathologic variables regarding cumulative risk of BCSM and non-BCSM since diagnosis. Smoothed hazard estimates over time were plotted for BCSM. Fine and Gray multivariable regression evaluated the association of preselected variables with BCSM, conditional on having survived 5 years. BCSM. A total of 2836 men with stage I to III HR+ breast cancer were included, with a median follow-up of 15.41 (IQR, 12.08-18.67) years. Median age at diagnosis was 67 (IQR, 57-76) years. The cumulative 20-year risk of BCSM was 12.4% for stage I, 26.2% for stage II, and 46.0% for stage III. Smoothed annual hazard estimates for BCSM revealed an increase in late hazard rates with each incremental node category, reaching a bimodal distribution in N3 and stage III, with each having peaks in hazard rates at 4 and 11 years. Among patients who survived 5 years from diagnosis, the adjusted BCSM risk was higher for those younger than 50 years vs older than 64 years, those with grade II or III/IV vs grade I tumors, and stage II or III vs stage I disease. The findings of this study suggest that, in men with stage I to III HR+ breast cancer, the risk of BCSM persists for at least 20 years and depends on traditional clinicopathologic factors, such as age, tumor stage, and tumor grade. Among men with higher stages of disease, the kinetics of the BCSM risk appear different from the risk that has been reported in women.

Survival benefits associated with being adherent and having longer persistence to adjuvant hormone therapy across up to five years among U.S. Medicare population with breast cancer.

To assess associations between adherence to and persistence with adjuvant hormone therapy and mortality among older women with breast cancer. The surveillance, epidemiology, and end results data linked with U.S. Medicare claims was used. This study included older women diagnosed with stage I-III hormone receptor-positive breast cancer from 2009 through 2017. Adherence was defined as having proportion of days covered (PDC) ≥ 0.80. Persistence was defined as having no discontinuation, i.e., no break of ≥ 180 continuous days. Length of persistence was calculated as time from therapy initiation to discontinuation. Cox models with time-dependent covariates were used to assess associations between adherence and persistence with mortality. This study included 25,796 women. Adherence rates were 78.1 percent, 75.2 percent, 72.4 percent, 70.0 percent, and 61.5 percent from year1 to year5 after hormone therapy initiation. Persistence rates were 87.5 percent, 81.7 percent, 77.1 percent, 72.9 percent, and 68.9 percent through cumulative intervals of 1year up to 5years. Adherence was associated with all-cause mortality but not associated with breast cancer-specific mortality. Persistent women had lower risk of all-cause mortality and breast cancer-specific mortality. Each additional year of persistence had additional contributions to survival benefits (11% decreased risk of all-cause mortality and 37% decreased risk of breast cancer-specific mortality). This study confirms the detrimental effect of nonadherence to adjuvant hormone therapy across up to 5years on all-cause survival in older U.S. women. It also reveals the survival benefits associated with having longer persistence across up to 5years.

Associations of low-carbohydrate diets with breast cancer survival.

The objective of this study was to evaluate the role of low-carbohydrate diets after breast cancer diagnosis in relation to breast cancer-specific and all-cause mortality. For 9621 women with stage I-III breast cancer from two ongoing cohort studies, the Nurses' Health Study and Nurses' Health Study II, overall low-carbohydrate, animal-rich low-carbohydrate, and plant-rich low-carbohydrate diet scores were calculated by using food frequency questionnaires collected after breast cancer diagnosis. Participants were followed up for a median 12.4years after breast cancer diagnosis. We documented 1269 deaths due to breast cancer and 3850 all-cause deaths. With the use of Cox proportional hazards regression and after controlling for potential confounding variables, we observed a significantly lower risk of overall mortality among women with breast cancer who had greater adherence to overall low-carbohydrate diets (hazard ratio for quintile 5 vs. quintile 1 [HRQ5vsQ1 ],0.82; 95% CI,0.74-0.91; ptrend =.0001) and plant-rich low-carbohydrate diets (HRQ5vsQ1 ,0.73; 95% CI,0.66-0.82; ptrend < .0001) after breast cancer diagnosis but not animal-rich low-carbohydrate diets (HRQ5vsQ1 ,0.93; 95% CI,0.84-1.04; ptrend =.23). However, greater adherence to overall, animal-rich, or plant-rich low-carbohydrate diets was not significantly associated with a lower risk of breast cancer-specific mortality. This study showed that greater adherence to low-carbohydrate diets, especially plant-rich low-carbohydrate diets, was associated with better overall survival but not breast cancer-specific survival among women with stage I-III breast cancer.

Association between marital status and all-cause mortality of patients with metastatic breast cancer: a population-based study

This study aimed to investigate the association between marital status and the prognosis of patients with metastatic breast cancer (MBC). Data of patients with MBC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were classified into married and unmarried groups. Kaplan–Meier analysis with the log-rank test was conducted to compare breast cancer-specific survival (BCSS) and overall survival (OS) between the groups. Univariable and multivariable Cox proportional models were used to determine whether marital status was independently associated with OS, and the Fine–Gray subdistribution hazard method was performed to determine whether marital status was independently associated with BCSS. In total, 16,513 patients with MBC were identified, including 8949 married (54.19%) and 7564 unmarried (45.81%) patients. The married patients were significantly younger [median age (interquartile range), 59.0 (50.0–68.0) vs. 63.0 (53.0–75.0); p < 0.001] and received more aggressive treatments, such as chemotherapy (p < 0.001) and surgery (p < 0.001), than the unmarried patients. Moreover, married patients had higher 5-year BCSS (42.64% vs. 33.17%, p < 0.0001) and OS (32.22% vs. 21.44%, p < 0.0001) rates. Multivariable analysis revealed that marital status was an independent prognostic factor, and married status was associated with a significant reduction in the risk of breast cancer-specific (sub-hazard ratio, 0.845; 95% confidence interval, 0.804–0.888; p < 0.001) and all-cause (hazard ratio, 0.810; 95% confidence interval, 0.777–0.844; p < 0.001) mortality. Unmarried patients had a 15.5% increased risk of breast cancer-specific mortality and a 19.0% increased risk of overall mortality compared with married patients with MBC. BCSS and OS were superior in married populations compared with unmarried populations in most subgroups. Marital status was an independent prognostic indicator for survival in patients with MBC and was associated with significant survival benefits.

Estimating mortality in women with triple-negative breast cancer: The ‘ESTIMATE triple-negative’ tool

PurposeTriple-negative breast cancer (TNBC) is associated with a high risk of breast cancer-specific mortality (BCSM). Estimating the risk of BCSM and non-BCSM in TNBC would aid clinical decision-making. We developed the tool ‘ESTIMATE-TN’, to assess BCSM, non-BCSM, and all-cause mortality in non-metastatic TNBC. MethodsUsing Surveillance, Epidemiology, and End Results (SEER), we created an interactive tool that provides a nonparametric estimate of the cumulative risk of BCSM and non-BCSM between years 0 and 7 from diagnosis, accounting for baseline clinical and pathologic variables, using Gray’s subdistribution method. ResultsWe included 37,293 women with TNBC diagnosed during 2010–2017. Most patients were White (71.9%) and aged 50–69 years (51.3%). Most tumour characteristics were high-grade (78.6%), T2 (42.4%), and N0 (69.5%). ESTIMATE-TN allows to input patient and tumour characteristics, and the preferred timeframe. For example, patients aged 50–59 years with a new diagnosis of T2, N1, high-grade TNBC have a risk of BCSM at 7 years of 30.8% (95% confidence interval [CI]: 26.3–35.4%) and a risk of non-BCSM over the same period of 2.8% (95% CI: 1.3–4.3%). After 3 years from initial diagnosis, the residual cumulative risks of BCSM and non-BCSM at 7 years are 17.4% (95% CI: 12.6–22.2%) and 1.1% (95% CI: 0–2.5%), respectively. ConclusionsESTIMATE-TN is an interactive tool for TNBC that can be used to integrate population-based risks of BCSM and non-BCSM based on patient and tumour characteristics, facilitating our understanding of competing risks of death, which can aid clinical decision-making.

Red Blood Cell Polyunsaturated Fatty Acid Composition and Mortality Following Breast Cancer: Results From the Women's Healthy Eating and Living (WHEL) Study

Purpose: To examine the associations between red blood cell (RBC) composition of polyunsaturated fatty acids (PUFAs) and mortality among women with breast cancer. Methods: This nested case-control study included 1,104 women from the Women's Healthy Eating and Living Study, a randomized controlled trial of a plant-based dietary change on breast cancer survival. Cases were women who died from any cause (n = 290) from 1995 to 2006. Controls were women who were alive at the end of follow-up matched to cases on age at diagnosis, years since randomization, intervention group, and stage (n = 814). RBC fatty acid composition was measured in blood samples collected at baseline using gas chromatography and included the proportions of four n-3 and seven n-6 PUFAS. We examined each PUFA individually as well as factor analysis-derived factors in association with all-cause and breast cancer-specific mortality using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In fully-adjusted models, all-cause mortality ORs were elevated among women with PUFAs &amp;gt;median (versus ≤ median) for alpha-linolenic acid (ALA, C18:3n3; OR = 1.56; 95% CI = 1.14–2.14) and for linolenic acid (LnA, C18:2n6, OR = 1.54; 95% CI = 1.15–2.07), and breast cancer-specific mortality ORs were elevated for LnA (OR = 1.72, 95% CI = 1.24–2.38) and gamma-linolenic acid (GLA, C18:3n6; OR = 1.40; 95% CI = 0.97–2.00). Factor 1 [arachidonic acid, C20:4n6; adrenic acid, C22:4n6; and docosapentaenoic acid, C22:5n6] scores &amp;gt;median (versus ≤median) were associated with lower odds of all-cause (OR = 0.72; 95% CI = 0.53–0.98) and breast cancer-specific (OR = 0.67; 95% CI = 0.47–0.94) mortality, and Factor 4 [ALA and GLA] scores &amp;gt;median (versus ≤median) were associated with increased odds of breast cancer-specific mortality (OR = 1.42; 95% CI = 1.01–2.01). Additionally, 1-SD increase in Factor 4 scores were associated with ORs of 1.22 (95% CI = 1.04–1.42) for all-cause mortality and 1.24 (95% CI = 1.05–1.47) for breast cancer-specific mortality. Conclusions: RBC PUFA composition profiles are associated with all-cause and breast cancer-specific mortality risk among women with breast cancer.

Increased breast cancer mortality due to treatment delay and needle biopsy type: a retrospective analysis of SEER-medicare

BackgroundSubstantial evidence indicates that delay of first treatment after diagnosis is associated with poorer survival outcomes in breast cancer. Accordingly, the Commission on Cancer introduced a quality measure for receipt of therapeutic surgery within 60 days of diagnostic biopsy for stage I–III breast cancer patients in the non-neoadjuvant setting. It is unknown, however, what may contribute to mortality associated with treatment delay. Therefore, we investigated whether biopsy type moderates the effect of the mortality risk posed by treatment delay.MethodsRetrospective analysis of 31,306 women with stage I–III breast cancer diagnosed between 2003 and 2013 selected from the SEER-Medicare database was performed to determine whether needle biopsy type [core needle biopsy (CNB) or vacuum-assisted biopsy (VAB)] impacts time to treatment (TTT)-associated survival outcomes. Multivariable Fine-Gray competing risk survival models, adjusted for inverse propensity score weights, were used to determine the association between biopsy type, TTT, and breast cancer-specific mortality (BCSM).ResultsTTT ≥ 60 days was associated with 45% higher risk of BCSM (sHR = 1.45, 95% CI 1.24–1.69) compared to those with TTT < 60 days in stage I–III cases. Independent of TTT, CNB was associated with 28% higher risk of BCSM compared to VAB in stage II–III cases (sHR = 1.28, 95% CI 1.11–1.36), translating to a 2.7% and 4.0% absolute difference in BCSM at 5 and 10 years, respectively. However, in stage I cases, the BCSM risk was not associated with type of biopsy.ConclusionsOur results suggest that treatment delay ≥ 60 days is independently associated with poorer survival outcomes in breast cancer patients. In stage II–III, CNB is associated with higher BCSM than VAB. However, type of biopsy does not underlie TTT-associated breast cancer mortality risk.

Abstract 4237: Social isolation induces gut dysbiosis, mitochondrial metabolic dysfunction, and infiltration of tumor immunosuppressive cells: Do they explain enhanced mammary tumorigenesis

Abstract Social isolation (SI), are associated with increased mortality from many diseases, including breast cancer. Up to 41% of breast cancer patients are estimated to feel socially isolated when assessed between 6 months and 2 years following their cancer diagnosis. Since socially isolated breast cancer survivors are at a 64% higher risk of breast cancer-specific mortality than socially integrated survivors, the biological mechanisms which mediate the effects of SI need to be identified to prevent increased mortality. In a preclinical model, we found that SI caused recurrence of mammary cancers which had been treated with hormone therapy and thus led cancer cells to emerge from dormancy. We further found that mammary glands of SI rats exhibited upregulation of IL6/JAK/STAT3 signaling pathway and impaired oxidative phosphorylation (OXPHOS), compared with group housed (GH) rats. We investigated if these changes could be mediated through the gut-brain-axis. Stress can affect the gut microbiota, and the gut microbiota is critical for regulating the host immunity. In four separate experiments, the effect of SI on the gut microbiota composition was assessed in C57BL/6 mice that were either group housed or housed singly in SI for 4 weeks. In each study replicate, several differences in the gut microbiota composition were seen, but these differences were mostly unique to each experiment. Beta-diversity was increased in three of the four experiments in SI mice. Nevertheless, at the genus level, SI suppressed the abundance of Akkermansia in all four replicates and increased Acetatifactor in three of the four replicates. These two bacterial changes are expected to disrupt OXPHOS, perhaps by resulting a suppression in short-chain fatty acid production. Further, low Akkermansia and high Acetatifactor are expected to increase inflammation. Thus, it is possible that the changes in the composition of the gut microbiota of SI animals explain an increase in IL6 signaling and a suppression in OXPHOS in their mammary gland. We also have studied immune cells in the spleen in SI and GH mice. SI increased the frequency of pro-inflammatory CD4+RORy+ cells, and the immunosuppressive Treg cells (CD4+Foxp3+) and myeloid derived suppressor cells (PMN-MDSCs). SI also increased PD1 expression in Foxp3+ cells. In an on-going study, we found that fecal microbiota transplant (FMT) from SI mice increased E0771 mammary tumor growth in antibiotic treated GH recipient mice, compared with mice receiving FMT from GH mice. Whether the FMT also altered IL6 and OXPHOS signaling in the mammary glands and tumors of recipient mice is currently being investigated. Our findings suggest that social isolation may increase breast cancer through inducing gut dysbiosis. Citation Format: Fabia de Oliveira Andrade, Maddie McDermott, Lu Jin, Vivek Verma, Karla Andrade de Oliveira, Christopher Staley, Leena Hilakivi-Clarke. Social isolation induces gut dysbiosis, mitochondrial metabolic dysfunction, and infiltration of tumor immunosuppressive cells: Do they explain enhanced mammary tumorigenesis. [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 4237.

Abstract PD6-08: PD6-08 Mortality risks over 20 years in men with stage I-III hormone receptor-positive breast cancer

Abstract Background: In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years (y) from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported. The aims of this study were to evaluate long-term risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I-III HR+ breast cancer. In addition, we aimed to identify factors associated with late deaths from breast cancer in men. Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) program, we identified men diagnosed with stage I-III HR+ breast cancer between 1990-2008. We used cumulative incidence function to estimate the effect of baseline clinical and pathologic variables including age at diagnosis, stage, tumor size (T), nodal status (N), and tumor grade, on cumulative risks of BCSM and non-BCSM over time. We estimated annual rate of events per 100 person-years. We plotted smoothed hazard estimates over time for BCSM by stage and nodal status. Fine and Gray multivariable regression was used to evaluate the association of pre-selected variables with BCSM, conditional on having survived 5 y. Results: We included 2,836 patients (pts) with a median follow-up of 15.41 y. Median age at diagnosis was 67 y (IQR 57-76 y). Stage distribution was: 34.5% stage I, 46% stage II, and 19.5% stage III. The table shows risks of BCSM and non-BCSM and annual event rates by stage, N status, and grade. The cumulative risk of BCSM in y 0-20 was 12.4% for stage I, 26.2% for stage II and 46.0% for stage III. In contrast, the cumulative risk of non-BCSM over the same period ranged from 42.8% in stage III to 52.4% in stage I. Of all BCSM events, the proportion that occurred 0-&amp;lt; 5y, 5-&amp;lt; 10y and ≥10y was: For stage I 22.55%, 50% and 27.45%; For stage II 37.58%, 38.93% and 23.49%, For stage III 49.15%, 31.62% and 19.23%; respectively (p&amp;lt; 0.001). Among pts with stage II breast cancer, we observed a peak in the risk of BCSM at 6 y with a hazard rate of 3%, followed by a minimal decline in risk thereafter. However, among pts with stage III (n=554), and those with N3 (n=160), we observed a risk of BCSM that peaked first at 4-5 y (hazard rates: 6.3% and 9.9% for stage III and N3, respectively) followed by a small decline and then peaked again at 11-12 y (hazard rates: 7.5% and 12.7% for stage III and N3, respectively). In adjusted Fine and Gray regression conditional on having survived 5 y, risks of BCSM were higher for pts aged &amp;lt; 50 y vs &amp;gt;64 y (Hazard ratio [HzR] 1.59; 95% CI, [1.17 – 2.16]), grade III/IV vs grade I (HzR 1.85; 95% CI, [1.22 – 2.79]), and stage III vs stage I (HzR 3.93; 95% CI, [2.93 – 5.26]). Conclusions: In HR+ male breast cancer, risks of BCSM persist for at least 20 y after diagnosis and depend on traditional clinicopathologic factors such as age, tumor stage and tumor grade. Among the relatively small group of men with higher stages of disease, we observed a prolonged risk of BCSM with an early and late peak, which is different from the risk that is reported in women (Leone JP, BCRT 2021). Whether the observed trends in hazards over time reflect biologic differences in tumor characteristics, tumor dormancy, and/or host factors between male and female breast cancer cannot be elucidated from these data. Better adjuvant therapies are warranted to reduce early and late BCSM risks. Risks of BCSM, non-BCSM and annual event rates in men with stage I-III hormone receptor-positive breast cancer Citation Format: Julieta Leone, Michael J. Hassett, Rachel Freedman, Sara Tolaney, Noah Graham, Nabihah Tayob, Carlos T. Vallejo, Eric Winer, Nancy U. Lin, Jose P. Leone. PD6-08 Mortality risks over 20 years in men with stage I-III hormone receptor-positive breast cancer. [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 PD6-08.

Abstract P4-07-08: IMPACT ON OVERALL SURVIVAL ACCORDING TO BREAST CANCER IMMUNOPHENOTYPES: REAL-WORLD DATA IN METASTATIC BREAST CANCER IN ECUADOR

Abstract Background: Breast cancer immunohistochemistry subtype classification by hormone receptor has become the standard practice for therapeutic decision making. The subtype is one of the crucial factors affecting breast cancer prognostic. Despite the progress in understanding of complex mechanisms in progression of breast cancer, the treatment is a global challenge health around the world, the 5-year survival rate is 26%. Currently in develop countries, in the metastatic stage, a gain in survival in the HR+/HER2+ subtype has been evidenced, likely attributable to major advances in HER2-targeted treatment (1). However, although in developed countries there is access to targeted therapy, in the Ecuadorian health system, difficulties complicate patients access to health care and treatment. Methods: We conducted a retrospective study about survival data in breast cancer metastatic according immunohistochemistry subtype. We analyzed all primary invasive breast cancer cases in the period from 2016 to 2020 in an oncology institute of Ecuador, the final study sample consisted for 83 patients. The overall survival was calculated by the Kaplan-Meier method and compared by the long-rank test. Multivariable adjusted hazard ratios (HR) were estimated by Cox regression models. Results: There were 31 patients (37.1%) with a HR(+)/HER2(-) breast cancer subtype, 15 patients HR(+)/HER2(+), 5 patients HER2 (+),18 patients HR(-)/HER2(-) and 14 patients without breast cancer subtype identified. Most patients were treated with different chemotherapy protocols; additional, in the group of women with HR(+)/HER2(+) subtype and HER2 (+) subtype only 15.87% were treated with HER2-targeted treatment, the vast majority in the last year. The best survival pattern was observed among women with HR(+)/HER2(-) breast cancer subtype with 35 months (IC 95% = 14,9 – 55), followed by HR(+)/HER2(+) with 27 months (IC 95% = 13,21 – 40,79), HER2 with 24 months (IC 95% = 4.4 – 32), and 14 months (IC 95% = 0 – 29.7) for HR(-)/HER2(-), however the difference wasn’t significant (p = 0.08). Hazard ratio of HR(+)/HER2(-) breast cancer subtype for breast cancer specific mortality risk was 1.61 (IC 95% = 0.64 – 4.19 p = 0.29). Conclusions: Hormone receptor subtype wasn’t s a significant independent prognostic factor in female metastatic breast cancer patients in a single center of Ecuador. However, there is a trend that subtype HR(+)/HER2(-) breast cancer subtype, has a better survival than the rest of the subtypes. These results differ from those of the rest of the world, probably access to target medicine and difficulties in access to health care system are the cause. Thus, better strategies for early access to adequate chemotherapy protocols should be developed Citation Format: Evelyn Valencia-Espinoza, Emiliano Pulla-Cadmilema, Lissette P. Velez Avila, Lissette Yagual Bohorquez, Maria del Mar Sanchez Salazar, Patricia Tamayo Aguilar, Jimmy Martin-Delgado, Glenda Ramos Martinez, Katherine Garcia Matamoros, Roberto Escala Cornejo, Felipe Campoverde Merchan, Ruth Engracia Vivanco, Mayra Santacruz Maridueña, Isabel Delgado Guerrero, Veronica Torres Floril, Diego Garcia Gamboa, Elina A. Rodriguez-Melendez. IMPACT ON OVERALL SURVIVAL ACCORDING TO BREAST CANCER IMMUNOPHENOTYPES: REAL-WORLD DATA IN METASTATIC BREAST CANCER IN ECUADOR [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 P4-07-08.

Associations between antidiabetic medication use and breast cancer survival outcomes among medicare beneficiaries

Abstract Objective This study examined the associations between mortality (all-cause and breast cancer-specific) and different antidiabetic medication use before breast cancer diagnosis. Methods This study used a longitudinal, retrospective cohort design. Linked Surveillance, Epidemiology and End Results (SEER)-Medicare databases from 2007 to 2013 were used to identify female beneficiaries who had continuous Medicare enrollment, a new breast cancer diagnosis between 2008 and 2013, and exposure to the antidiabetic medication. Different classes of antidiabetic medications from one year before their breast cancer diagnosis were considered as users while all other non-users were excluded. Both all-cause mortality and breast cancer-specific mortality were treated as outcomes. Cox proportional hazards models for all-cause mortality and sub-distribution hazards models for breast cancer-specific mortality were employed to estimate both unadjusted and adjusted hazard ratios and 95% confidence intervals (CI) for risks of survival outcomes, controlling for severity of diabetes and other covariates. Key findings A total of 1715 women with breast cancer used antidiabetic medications one year before their breast cancer diagnosis. Compared to metformin, women using insulin, sulfonylurea and combination treatments before their breast cancer diagnosis had a higher risk for all-cause mortality (adjusted Hazard Ratio, aHR: 1.64, 95% CI 1.29, 2.07; aHR: 1.35, 95% CI 1.04, 1.75 and aHR: 1.44, 95% CI 1.14, 1.83, respectively). Women with advanced-stage breast cancer and higher levels of diabetes severity were more likely to get all-cause mortality (all P &amp;lt; 0.05). Women with combination treatments had a statistically higher risk of breast cancer-specific mortality (aHR: 1.52, 95% CI 1.05, 2.19) than metformin users. Conclusions Among women with breast cancer, mortality risk is associated with pre-diagnosis exposure to different types of antidiabetic medications.

The effect of the Flemish breast cancer screening program on breast cancer-specific mortality: A case-referent study

BackgroundBreast cancer screening programs were introduced in many countries worldwide following randomized controlled trials in the 1980s showing a reduction in breast cancer-specific mortality. However, their effectiveness remains debated and estimates vary. A breast cancer screening program was introduced in 2001 in Flanders, Belgium where high levels of opportunistic screening practices are observed. The effectiveness of this program was estimated by measuring its effect on breast cancer-specific mortality. MethodsWe performed a case-referent study to investigate the effect of participation in the Flemish population-based mammography screening program (PMSP) on breast cancer-specific mortality from 2005 to 2017. A multiple logistic regression model assessed the association between breast cancer-specific death and screening program participation status in the four years prior to (pseudo)diagnosis (yes/no), with adjustment for potential confounders (individual socio-economic position and calendar year of diagnosis) and stratified for age. In addition, we performed different sensitivity analyses. ResultsWe identified 1571 cases and randomly selected 6284 referents. After adjustment, women who participated in PMSP had a 51 % lower risk of breast cancer-specific mortality compared to those who did not (adjusted odds ratio [aOR] =0.49, 95 % CI: 0.44–0.55). Sensitivity analyses did not markedly change the estimated associations. Correction for self-selection bias reduced the effect size, but the estimate remained significant. ConclusionOur results indicate that in a context of high opportunistic screening rates, participation in breast cancer screening program substantially reduces breast cancer-specific mortality. For policy, these results should be balanced against the potential harms of screening, including overdiagnosis and overtreatment.

Metabolic abnormalities and survival among patients with non-metastatic breast cancer

BackgroundResearch on the impact of metabolic abnormalities on breast cancer prognosis is limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In this population-based cohort, time-updated laboratory values were adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides) and breast cancer survival.Methods13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL-C, LDL-C, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, diabetes, dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, tamoxifen, and aromatase inhibitors).ResultsMean (SD) age at diagnosis was 62.3 (11.8) years. Over a median follow-up of 8.6 years, 2,876 patients died; 1,080 of breast cancer. Patients with low HDL-C (≤ 45 vs. > 45 mg/dL) had higher breast cancer-specific mortality (HR, 1.77; 95% CI, 1.53-2.05), as did those with elevated fasting glucose (> 99 vs. 60-99 mg/dL) (HR, 1.19; 95% CI, 1.03-1.37). Elevated levels of triglycerides and LDL-C were not associated with breast cancer-specific mortality.ConclusionsHigh fasting glucose and low HDL-C evaluated over time after cancer diagnosis were associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Future studies should address whether pharmacologic or lifestyle treatment of glucose and lipids after breast cancer diagnosis can optimize survival outcomes.

Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses' Health Studies.

The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. We followed women with invasive breast cancer from the Nurses' Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%-100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. We found loss of PTEN expression (≤10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71-1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79-1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48-0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67-1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86-1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83-3.26). In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms.

Estimating long-term mortality in women with hormone receptor-positive breast cancer: The ‘ESTIMATE’ tool

PurposeThe risk of breast cancer-specific mortality (BCSM) persists for at least 20 years from diagnosis. Estimating the risk of BCSM over this extended period along with competing risks of death would aid clinical decision-making. We aimed to develop an interactive tool called ‘ESTIMATE’, to explore the Surveillance, Epidemiology, and End Results (SEER) registry to quantify residual risks of BCSM, non-BCSM and all-cause mortality in non-metastatic, hormone receptor (HR)-positive breast cancer patient subgroups at any given time after diagnosis, up to 20 years. MethodsUsing SEER data, we included 264,237 women with invasive, non-metastatic, HR-positive breast cancer diagnosed from 1990 to 2006. We developed a tool that provides a nonparametric estimate of the residual cumulative risk of BCSM and non-BCSM by year 20 after any specified time from initial diagnosis, among patients defined by baseline clinical and pathologic variables, using Gray’s subdistribution method. ResultsESTIMATE allows the user to input patient and tumour characteristics and the preferred timeframe. For example, patients in the age group of 40–49 diagnosed with T1cN1, grade II breast cancer who survived 7 years, have a 14% (95% confidence interval [CI]: 11.9%–16.1%) residual cumulative risk of BCSM in the next 13 years, and a 6.4% (95% CI: 4.7%–8.1%) residual cumulative risk of non-BCSM over the same period. ConclusionsESTIMATE provides population-based risks of BCSM, non-BCSM and all-cause mortality through 20 years after diagnosis of HR-positive breast cancer, based on patient and tumour characteristics. ESTIMATE can inform discussions about prognosis, a balance between competing risks and aid clinical decision-making.

The prognostic role of surgery and a nomogram to predict the survival of stage IV breast cancer patients.

BackgroundSince numerous retrospective studies and prospective trials have shown divergent results, whether the surgical excision of the primary tumor results in survival benefits for de novo stage IV breast cancer patients is inconclusive. Consequently, we need a prediction model of prognosis, judge the efficiency of breast surgery, and identify the advanced breast cancer patients who would benefit from surgery.MethodsWe analyzed the data of 2,747 metastatic breast cancer patients (the surgery group) and 4,508 patients (the non-surgery group) from the Surveillance, Epidemiology, and End Results (SEER) database during 2010–2015. Propensity score matching (PSM) was used to attain a balance between the covariates of both groups. We then assessed the potential risk factors for the breast cancer-specific survival (BCSS) of patients in the non-surgery group by Cox regression and constructed a nomogram to predict BCSS. All the patients were classified into different risk groups based on the median risk score obtained from the nomogram. The hazard ratios of BCSS and overall survival (OS) of patients in the two groups were calculated.ResultsAfter PSM, 2,288 patients severally in the two groups (the surgery group and the non-surgery group) were enrolled in the study. A nomogram incorporating 13 potential risk factors (i.e., age, race, cohabitation status, income, tumor grade, histotype, tumor size, lymph node status, molecular subtype, metastasis to brain, liver, lung, and chemotherapy) was constructed using the data of patients in the non-surgery group. The C statistics for the internal (patients in the non-surgery group) and external (patients in the surgery group) validation of the nomogram were 0.70 [95% confidence interval (CI), 0.69–0.71] and 0.73 (95% CI, 0.72–0.74), respectively. In the low-risk group, patients in the surgery group had lower risks of breast cancer-specific mortality (BCSM) (hazard ratio =0.53; 95% CI, 0.47–0.59; P for interaction =0.014) and overall mortality (OM) (hazard ratio =0.52; 95% CI, 0.46–0.58; P for interaction =0.002) than those in the non-surgery group.ConclusionsBreast surgery might improve the survival of metastatic breast cancer patients in the low-risk group. The established nomogram could provide a reference for clinicians in enabling personalized treatment among advanced breast cancer patients.

Abstract 12: Social isolation promotes mammary cancer recurrence, increases IL6/JAK/STAT3 signaling and causes mitochondrial dysfunction in tamoxifen treated rats, and a traditional herbal mixture reverses all these changes

Abstract Social isolation is associated with increased risk and mortality from many diseases, such as breast cancer. Socially isolated breast cancer survivors have a 43% higher risk of recurrence and a 64% higher risk of breast cancer-specific mortality than socially integrated survivors. Since Covid-19 has dramatically increased the incidence of social isolation, it is important to determine if social isolation affects the response to endocrine therapy and/or recurrence after the therapy is completed. Since previous studies indicate that social isolation increases circulating inflammatory cytokines, we investigated if an anti-inflammatory herbal mixture Jaeumkanghwa-tang (JGT) prevents the adverse effects of social isolation on breast cancer mortality. Estrogen receptor positive mammary tumors were initiated with 7,12-dimethylbenz[a]anthracene. When a rat developed a palpable mammary tumor, it was either socially isolated (SI) by housing it singly or a rat was allowed to remain group-housed (GH). Tamoxifen (340ppm via diet) or tamoxifen + JGT (500ppm via drinking water) started when the first mammary tumor reached a size of 11 mm in diameter. Tamoxifen administration ended when a complete response to this therapy had lasted for 9 weeks (corresponds to 5 years in women). During tamoxifen therapy, social isolation non-significantly reduced the rate of complete responses to 21%, from 31% in GH group (p&amp;gt;0.05). After the therapy was completed, SI significantly increased local mammary tumor recurrence (p&amp;lt;0.001; 45% GH vs 75% SI). RNAseq analysis was performed in the mammary glands. Gene set enrichment analysis (GSEA) of transcriptome showed that the increased recurrence risk in socially isolated rats was associated with an enrichment of IL6/JAK/STAT3 signaling: this result was confirmed in the tumors. In addition, oxidative phosphorylation (OXPHOS) pathway was suppressed: the suppressed genes included those involved in mitochondrial pyruvate transport and conversion of pyruvate to acetyl CoA as well as genes in the TCA cycle and mediating electron transport in mitochondrial complexes I-IV. Social isolation also increased the expression of inflammatory receptor for advanced glycation end-products (RAGE) (p≤0.05). Consumption of an anti-inflammatory JGT inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling and prevented the increased risk of mammary cancer recurrence in socially isolated animals. The percentage of recurrences in the SI rats dropped from 75% without JGT to 22% with JGT (p&amp;lt;0.001). Breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and correct disrupted OXPHOS and mitochondrial dysfunction. Citation Format: Fabia de Oliveira Andrade, Lu Jin, Robert Clarke, Imani Wood, MaryAnn Dutton, Chezaray Anjorin, Grace Rubin, Audrey Gao, Surojeet Sengupta, Kevin FitzGerald, Leena Hilakivi-Clarke. Social isolation promotes mammary cancer recurrence, increases IL6/JAK/STAT3 signaling and causes mitochondrial dysfunction in tamoxifen treated rats, and a traditional herbal mixture reverses all these changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 12.

Association of metabolic risk factors with breast cancer survival in a population-based cohort.

12089 Background: Metabolic abnormalities may impact breast cancer prognosis, but research has been limited by small samples and assessment of laboratory values at a single time point, often prior to cancer diagnosis and treatment. In a population based cohort, we utilized time-updated laboratory values and adjusted for cancer treatment to assess the association between metabolic risk factors (glucose, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides) and breast cancer survival. Methods: 13,434 women diagnosed with stage I-III breast cancer from 2005-15 at Kaiser Permanente were included. All outpatient fasting glucose, HDL, LDL, and triglyceride values from diagnosis through 2019 or death were extracted from electronic medical records. Lab values were updated a median of 5 times between 1-7 years post-diagnosis. Risk of breast cancer-specific mortality was evaluated with Cox proportional hazards models adjusted for metabolic labs, demographics, body mass index, and diabetes, and then for dyslipidemia and anti-hypertensive medications, tumor characteristics (stage, ER and HER2 receptor status) and cancer treatment (use of chemotherapy, and tamoxifen v. aromatase inhibitors). Results: Mean (SD) age at diagnosis was 62.3 (11.8) years. Over median follow-up of 9 years, 2,876 patients died (1,080 of breast cancer). Patients with low HDL (≤45 vs. &gt;45 mg/dL) had higher breast cancer-specific mortality (HR, 1.87; 95% CI, 1.62-2.16); high levels of glucose, triglycerides, and LDL were not associated. The increased risk associated with low HDL persisted after adjusting for tumor characteristics, cancer treatment, and medications. Conclusions: Low HDL evaluated over time after cancer diagnosis is associated with higher breast cancer mortality independent of cancer treatments and changes in other metabolic risk factors. Cholesterol may play a role in breast cancer due to its role in cell membrane structure, signaling pathways, and steroid hormone synthesis. Future studies should address whether pharmacologic or lifestyle treatment of lipids after breast cancer diagnosis can optimize survival outcomes.[Table: see text]

Impact of time to initiation of postoperative radiotherapy after neoadjuvant chemotherapy on the prognosis of breast cancer: A retrospective cohort study in China

The optimal time to the initiation of postoperative radiotherapy (TTR) in breast cancer patients after neoadjuvant chemotherapy (NAC) and surgery is unclear. We explored the association between TTR and outcomes among breast cancer females to determine the optimal timing for radiotherapy. We included 1022 women with breast cancer who underwent NAC and surgery between 1997 and 2019. Patients were categorized into three groups based on the TTR: <8 weeks, 8 to 16 weeks and >16 weeks. We used Cox proportional hazards models and analyzed the hazard ratios (HRs) for breast cancer-specific mortality (BCSM) and all-cause mortality (ACM). The median TTR for the cohort was 97 days. Compared to patients with TTRs of 8 to 16 weeks, those with TTRs <8 weeks or >16 weeks had an increased risk of BCSM (HR, 2.59; 95% confidence interval [CI], 1.26-5.36 and HR, 2.01; 95% CI, 1.24-3.28, respectively) and ACM (HR, 2.32; 95% CI, 1.17-4.56 and HR, 1.92; 95% CI, 1.24-2.98, respectively) after adjusting for the confounders. Furthermore, at TTR of >16 weeks, each additional week of TTR was associated with a 3% increase in BCSM risk and 2% increase in ACM risk. Our findings suggest that patients who have undergone NAC and surgery show lower BCSM and ACM risks at TTR of 8 to 16 weeks compared to <8 weeks or >16 weeks.