Breast Cancer-specific Deaths Research Articles

Breast cancer polygenic risk score and patient survival outcomes in the Pathways study.

10502 Background: Many common, low-penetrance variants have been identified for breast cancer risk through genome-wide association studies, leading to the development of polygenic scores (PGS) to aggregate the effects of individual variants for risk prediction. Much less is known about genetic determinants of breast cancer-related outcomes. We hypothesized that breast cancer patients with high breast cancer PGS are at risk of a second breast-related adverse event, such as recurrence, contralateral breast cancer, or death. Methods: The Pathways Study is a prospective cohort study of breast cancer survivors enrolled shortly after diagnosis in 2006-2013 at Kaiser Permanente Northern California, with ongoing follow-up. Genome-wide genotype data were available from 3,995 patients for calculation of 4 PGS, including PGS313, PGS4k, PGS5k, and PGS6m. Scores were categorized into tertiles to investigate their associations with 7 survival outcomes including recurrence, contralateral second primary breast cancer, other second primary cancer, and death. Hazard ratios (HR) and 95% confidence intervals (CI) were derived from multivariable Cox proportional hazards regression models. Results: The median age at diagnosis was 60 (23.6-94.8) years, and most (68%) self-identified as White. Many women had estrogen receptor (ER)+ (83.4%), stage I and II tumors (89%), with 13.3% HER2+ tumors. The majority (60%) received lumpectomy and some type of adjuvant therapy (44.3% radiotherapy, 47.0% chemotherapy, and 74.6% received hormonal therapy). By December 31, 2021, the median follow-up time was 10.5 (0.2-14.2) years, with 504 recurrences, 419 total second primary cancers, 146 contralateral second primary breast cancers, 237 non-breast second primary cancers, and 762 deaths (352 breast cancer-specific deaths) observed. In Table 1, patients with medium (T2) and high (T3) PGS313 had higher risk of recurrence, but not contralateral breast cancer or other second primary cancer. They also had higher risk of all-cause death, breast cancer-specific death, total breast cancer event, and invasive disease. The other 3 PGS were not associated with survival outcomes examined. Conclusions: Our study reveals that breast cancer patients with higher PGS313 had higher risk of recurrence, total breast cancer and invasive breast cancer events, and death. These findings highlight a potential role of breast cancer PGS for prognosis, warranting further exploration. [Table: see text]

Circulating oxysterols and prognosis among women with a breast cancer diagnosis: results from the MARIE patient cohort

BackgroundBreast cancer is the most commonly diagnosed cancer in women worldwide, and underlying mechanistic pathways associated with breast cancer-specific and non-breast cancer-related deaths are of importance. Emerging evidence suggests a role of oxysterols, derivates of cholesterol, in multiple chronic diseases including breast cancer and coronary artery diseases. However, associations between oxysterols and survival have been minimally studied in women diagnosed with breast cancer. In this large breast cancer patient cohort, we evaluated associations between a panel of circulating oxysterols and mortality and recurrence outcomes.MethodsConcentrations of 13 circulating oxysterols representing different pathways of cholesterol metabolism were quantified using liquid-chromatography mass-spectrometry. Associations between baseline levels of oxysterols and cause-specific mortality outcomes and recurrence following a breast cancer diagnosis were assessed in 2282 women from the MARIE study over a median follow-up time of 11 years. We calculated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable Cox proportional hazard models and competing risks models.ResultsWe observed no associations for circulating oxysterols and breast cancer-specific outcomes. Higher levels of six oxysterols were associated with an increased risk of cardiovascular disease death, including 24S-hydroxycholesterol (alternative bile acid pathway, HRlog2 = 1.73 (1.02, 2.93)), lanosterol (cholesterol biosynthesis pathway, HRlog2 = 1.95 (1.34, 2.83)), 7-ketocholesterol (HRlog2 = 1.26 (1.03, 1.55)), 5α,6α-epoxycholesterol (HRlog2 = 1.34 (1.02–1.77)), and 5a,6β-dihydroxycholestanol (HRlog2 = 1.34 (1.03, 1.76)). After adjusting for multiple comparisons, none of the associations were statistically significant.ConclusionWe provide first evidence on a range of circulating oxysterols and mortality following a breast cancer diagnosis, contributing to a better understanding of associations between different pathways of cholesterol metabolism and prognosis in women with a breast cancer diagnosis. The findings of this study suggest circulating oxysterols may be associated with cardiovascular mortality among women diagnosed with breast cancer. Further studies are needed to evaluate these oxysterols as potential markers of risk for cardiovascular mortality among women with a breast cancer diagnosis as well as their clinical potential.

A nomogram for predicting breast cancer specific survival in elderly patients with breast cancer: a SEER population-based analysis

BackgroundThe number of elderly patients diagnosed with breast cancer is increasing worldwide. However, treatment decisions for these patients are highly variable. Although researchers have identified the effects of surgery, radiotherapy, endocrine therapy, and chemotherapy in elderly patients with breast cancer, clinicians still struggle to make appropriate decisions for these patients.MethodsWe identified 75,525 female breast cancer patients aged ≥ 70 years in the Surveillance, Epidemiology, and End Results (SEER) database treated between January 1, 2010, and December 31, 2016. The patients were further divided into training and testing cohorts. The cumulative occurrence of breast cancer-specific deaths (BCSDs) and other cause-specific deaths (OCSD) was calculated using the cumulative incidence function. In the univariate analysis, risk factors were screened using the Fine-Gray model. In the multivariate analysis for competing risks, the sub-distribution hazard ratio with a 95% confidence interval for each independent predictor associated with BCSD was calculated for the construction of nomograms. Based on the above analyses, a competing risk nomogram was constructed to predict the probability of BCSD in the 1st, 3rd, and 5th years after treatment. During validation, the concordance index (C-index) was selected to quantify the predictive ability of the competing risk model.ResultsA total of 33,118 patients were included in this study, with 24,838 in the training group and 8,280 in the testing group. Age, race, marital status, cancer grade, tumor stage, node stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor--2 status, and treatment including surgery, radiation, and chemotherapy were used to establish a nomogram. The C-index of 0.852 (0.842-0.862) in the training cohort and 0.876 (0.868-0.892) in the testing cohort indicated satisfactory discriminative ability of the nomogram. Calibration plots showed favorable consistency between the nomogram predictions and actual observations in both the training and validation cohorts.ConclusionsOur study identified independent predictors of BCSD in elderly patients with breast cancer. A prognostic nomogram was developed and validated to aid clinical decision-making.

Sleep duration and mortality among breast cancer survivors in the Western New York Exposures and Breast Cancer (WEB) Study.

There is increasing evidence that sleep duration may affect breast cancer survival through effects on circadian function, influencing disease progression. However, further investigation of this association is needed. In a population-based, prospective cohort study of women from the Western New York Exposures and Breast Cancer Study, we examined mortality outcomes with invasive breast cancer identified using the National Death Index. Cox proportion hazards ratios with 95% confidence intervals were used to estimate risk of all-cause (AC) and breast cancer-specific (BC) mortality associated with self-reported usual sleep duration with adjustment for age, race/ethnicity, years of education, body mass index (BMI), menopausal status, pack-years ofsmoking, tumor stage, and estrogen-receptor (ER) status. We further examined associations within strata of BMI, tumor stage, menopausal status, and ER status. A sample of 817 patients with breast cancer were followed for a median of 18.7years, during which 339 deaths were reported, including 132 breast cancer-specific deaths. Those who reported shorter or longer sleep tended to have a slightly higher BMI, to be less proportionately non-Hispanic White, to report a previous history of benign breast disease, and to have consumed more alcohol during their lifetime. We found no significant associations between sleep duration and AC or BC mortality, including within stratified analyses. Sleep duration was not associated with either AC or BC mortality including within strata of BMI, tumor stage, menopausal status, or ER status.

Abstract 5758: Regular aspirin use, breast tumor characteristics and long-term breast cancer survival

Abstract Compelling epidemiologic data, supported by experimental evidence, suggest aspirin may improve survival in breast cancer patients. However, recent clinical trials showed a lack of protective effect, though length of intervention (18 months to 4.7 years) and follow-up (20 months to 4.7 years) were limited. We sought to examine the association between post-diagnostic aspirin use (frequency, dose, and duration), timing and age of initiation on breast cancer-specific mortality. Our study included 10,493 women diagnosed with stage I, II, or III invasive breast cancer. Participants were enrolled in the large, prospective Nurses’ Health Study (NHS) and NHSII in 1980 and 1989 prior to diagnosis and followed up through June 1, 2017. We collected information on frequency, dose and duration of aspirin use. Regular aspirin use was defined as using aspirin (standard- and low-dose) ≥2 days per week, and non-regular aspirin users were those who reported use of aspirin <2 days per week. We used Cox proportional hazard models to calculate multivariable adjusted hazard ratios (HRs) for breast cancer-specific mortality. After a median follow-up of 10 years, there were 2,506 total deaths and 1,221 breast cancer-specific deaths among 10,493 stage I to III breast cancer patients over 32 years of follow-up. In multivariable models, regular use of aspirin (n=3,523; 34%) was associated with a 38% lower risk of death from breast cancer compared with non-regular users (including nonusers) (HR=0.62, 95% CI: 0.54-0.71). The association was independent of pre-diagnostic aspirin use. Associations between aspirin use and breast cancer-specific mortality were stronger with longer time since diagnosis (HRs for <5 years since diagnosis: 0.73 (95% CI: 0.59-0.90), 5-<10 years: 0.63 (95% CI: 0.49-0.80), and ≥10 years: 0.53 (95% CI: 0.41-0.69)). The relations between aspirin use and breast cancer survival were similar across categories of dose (compared to non-users, HRs for 0.5-5 tablets per week: 0.59 (95% CI: 0.51-0.68); ≥6 tablets per week: 0.60 (95% CI: 0.48-0.74)) and appeared stronger with longer duration (compared to non-users, HRs for <5 years: 0.80 (95% CI: 0.57, 1.10); ≥5 years: 0.61 (95% CI: 0.51, 0.72)). For women who initiated regular aspirin use after age 70, regular aspirin use was associated with worse survival (HR=1.74, 95% CI: 1.16-2.63); on the other hand, initiation of regular aspirin use at age ≤60 (HR=0.72, 95% CI: 0.54-0.95) or 60-≤70 (HR=0.69, 95% CI: 0.50-0.95) was associated with improved survival (p-interaction=0.02). Regular aspirin use after diagnosis of nonmetastatic breast cancer was associated with improved long-term survival over 32 years. Although the associations between post-diagnostic regular aspirin use and improved survival did not differ by BMI, smoking or tumor characteristics, women who initiated regular aspirin use >70 years of age had increased risk of death due to breast cancer. Citation Format: Cheng Peng, Michelle D. Holmes, Wendy Y. Chen, Tengteng Wang, Kristen D. Brantley, Yujing Jan Heng, Pepper J. Schedin, Bernard A. Rosner, Walter C. Willett, Meir J. Stampfer, Rulla M. Tamimi, A. Heather Eliassen. Regular aspirin use, breast tumor characteristics and long-term breast cancer survival. [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 5758.

Abstract P5-03-06: Effect of Sleep Traits on Subtype Specific Breast Cancer Survival: a Mendelian Randomization Analysis

Abstract Background There is increasing interest in the relationship between sleep traits and both quality of life and survival in breast cancer. Recent work has found that oestrogen receptor positive (ER+) tumour cells are more likely to spread, via the circulation, at night than in the morning, providing support for a potential role of sleep characteristics influencing metastasis and therefore survival from breast cancer. The aim of this study was to investigate causal effects of sleep traits on subtype-specific breast cancer survival. Methods Single-nucleotide polymorphisms (SNPs) identified from GWAS associated with sleep traits with were used as a genetic instruments for Chronotype (N=697,828), Insomnia (N=1,331,010), Sleep Duration (N=446,118), Napping (N=452,633), Daytime sleepiness(N=452,071) and Ease of Getting up (N=461,658). All instruments were identified in data from UK Biobank, except chronotype and insomnia, which were identified in meta-analyses of UK Biobank and 23andme. For all instruments female-specific effect estimates were used. For these SNPs, summary statistics of their association with breast cancer survival were obtained from GWAS meta-analyses of European women from the Breast Cancer Association Consortium (BCAC), (N=91,686, with 7531 breast cancer specific deaths over a median follow-up of 8.1 years). To estimate the causal effect of the sleep traits on breast cancer survival, we applied two-sample MR for both overall and subtype-specific breast cancer (Luminal A-like, Luminal B-like, Human Epidermal Growth Factor 2 (Her2) positive, Her2 negative and triple negative (TNBC)). Further stratification by tumour characteristics at diagnosis and treatment received was also used. Sensitivity analyses were used to assess the robustness of main analyses to MR assumptions. Results For every hour increase in sleep duration, we observed worsening 5-year breast cancer specific survival in patients with ER+ tumours who received endocrine therapy (HR: 2.55, 95% CI: 1.10, 5,82) and for all patients receiving aromatase inhibitors (HR: 9.57, 95% CI: 1.61, 57.10). Conversely, improved 5-year survival was observed in patients with ER- tumours who received chemotherapy (HR: 0.30, 95% CI: 0.10, 0.87) and all patients receiving taxanes (HR: 0.23, 95% CI: 0.05, 0.98). We also observed that an increase in daytime sleepiness improved 15-year survival in patients both overall (HR: 0.34, 95% CI: 0.14, 0.80) and with lymph node negative tumours at diagnosis (HR: 0.12, 95% CI: 0.02, 0.64). Detailed sensitivity analyses are ongoing. Conclusions The current study uses a causal approach to identify potential effects between sleep patterns and breast cancer survival and confirms the previously observed relationships with increased sleep duration and worse survival in ER+ breast cancer. The reasons for opposite effects seen in those with ER- and those receiving taxanes needs further mechanistic work. Although the improved survival in relation to increased daytime sleepiness appears to be in-keeping with previous findings, this may largely reflect shorter sleep duration. Further work accurately characterising sleep quality, rather than duration in those with breast cancer, examining the effects on quality of life and survival and establishing mechanisms are needed. Citation Format: Bryony Hayes, Richard Martin, Deborah Lawlor, Rebecca Richmond, Tim Robinson. Effect of Sleep Traits on Subtype Specific Breast Cancer Survival: a Mendelian Randomization Analysis [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 P5-03-06.

Association Between Residence in Historically Redlined Districts Indicative of Structural Racism and Racial and Ethnic Disparities in Breast Cancer Outcomes

Historical structural racism may be associated with racial, ethnic, and geographic disparities in breast cancer outcomes, but few studies have investigated these potential relationships. To test associations among historical mortgage lending discrimination (using 1930s Home Owners' Loan Corporation [HOLC] redlining data), race and ethnicity, tumor clinicopathologic features, and survival among women recently diagnosed with breast cancer. This cohort study used a population-based, state cancer registry to analyze breast tumor clinicopathology and breast cancer-specific death among women diagnosed from 2008 to 2017 and followed up through 2019. Participants included all primary, histologically confirmed, invasive breast cancer cases diagnosed among women aged at least 20 years and who resided in a HOLC-graded area of New Jersey. Those missing race and ethnicity data (n = 61) were excluded. Data were analyzed between June and December 2021. HOLC risk grades of A ("best"), B ("still desirable"), C ("definitely declining"), and D ("hazardous" [ie, redlined area]). Late stage at diagnosis, high tumor grade, triple-negative subtype (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression), breast cancer-specific death. Among a total of 14 964 women with breast cancer, 2689 were Latina, 3506 were non-Latina Black, 7686 were non-Latina White, and 1083 were other races and ethnicities (non-Latina Asian/Pacific Islander/Native American/Alaska Native/Hawaiian or not otherwise specified); there were 1755 breast cancer-specific deaths. Median follow-up time was 5.3 years (95% CI, 5.2-5.3 years) and estimated 5-year breast cancer-specific survival was 88.0% (95% CI, 87.4%-88.6%). Estimated associations between HOLC grade and each breast cancer outcome varied by race and ethnicity; compared with residence in HOLC redlined areas, residence in HOLC areas graded "best" was associated with lower odds of late-stage diagnosis (odds ratio [OR], 0.34 [95% CI, 0.22-0.53]), lower odds of high tumor grade (OR, 0.72 [95% CI, 0.57-0.91]), lower odds of triple-negative subtype (OR, 0.67 [95% CI, 0.47-0.95]), and lower hazard of breast cancer-specific death (hazard ratio, 0.48 [95% CI, 0.35-0.65]), but only among non-Latina White women. There was no evidence supporting associations among non-Latina Black or Latina women. Compared with redlined areas, current residence in non-redlined areas was associated with more favorable breast cancer outcomes, but only among non-Latina White women. Future studies should examine additional factors to inform how historical structural racism could be associated with beneficial cancer outcomes among privileged racial and ethnic groups.

Abstract 3688: Survival benefit of adjuvant radiotherapy among women with high comorbidity burden and low-risk breast cancer: SEER-MHOS analysis

Abstract Background: The National Comprehensive Cancer Network Breast Cancer Guidelines Committee has suggested that adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) could be omitted among older women with low-risk breast cancer (early-stage, node-negative, and ER-positive) if they were treated with endocrine therapy. However, the effect of RT among older women with multimorbidity is not clearly understood. Objective: We examined the effect of adjuvant RT on survival outcomes among older women. We also assessed whether the association between RT and survival is modified by comorbidity burden. Methods: A total of 1105 older women (65+) diagnosed with low-risk breast cancer in 1998-2012 and who received BCS were identified from the population-based Surveillance, Epidemiology, and End-Results-Medicare Health Outcomes Survey (SEER-MHOS) data resource. A propensity score-based inverse probability of treatment weight (IPTW) was calculated with weighting applied to Cox regression models to obtain hazard ratios for the association of RT with survival outcomes. Stratified analysis was conducted to examine differential effects according to the comorbidity burden class, which was identified using the latent class analysis. Results: Over a 5-year follow-up period, a total of 117 deaths occurred (25 cancer-related and 92 noncancer-related). The IPTW-adjusted Cox proportional hazard analysis showed that RT omission did not significantly increase the risk for 5-year cancer-specific deaths (P=0.202). However, RT omission increased the risk for 5-year noncancer death by 1.84-fold (95% CI=1.35, 2.51) and all-cause death by 1.49-fold (95% CI=1.41, 1.95). The stratified analysis showed that the effect of RT omission on the risk of breast cancer-specific deaths was similar across the different comorbidity groups. For noncancer and all-cause deaths, the effect of RT omission varied by comorbidity burden. In Class 1, RT omission was not associated with an increased risk of noncancer and all-cause deaths. However, in Classes 2 and 3, RT omission is significantly associated with an increased risk of 5-year all-cause deaths in a dose-response manner: by 1.66-fold (95% CI=1.07, 2.56) in Class 2 and 1.96-fold in Class 3 (95% CI=1.13, 3.41). Similar results were observed for 10-year survival. Conclusions: RT omission does not increase the risk of cancer-specific death and appears to be a valid clinical decision for older women with low-risk breast cancer and multimorbidity. Citation Format: Eunkyung Lee, Robert B. Hines, Jianbin Zhu, Kayla Montan, Michael J. Rovito. Survival benefit of adjuvant radiotherapy among women with high comorbidity burden and low-risk breast cancer: SEER-MHOS analysis [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 3688.

The influence of treatment on hormone receptor subgroups and breast cancer-specific mortality within US integrated healthcare systems.

Estrogen receptor (ER) + /progesterone receptor (PR)- or ER-/PR + breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER + /PR-, ER-/PR + , ER + /PR + , ER-/PR-) subgroups and breast cancer-specific mortality within a general community setting in the US. A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990 and 2016 within US integrated healthcare systems (median follow-up = 7years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy). Breast cancer-specific mortality was higher for those with ER + /PR- (n = 1,233) compared with ER + /PR + tumors (n = 8,439) before (HR = 1.43; 95% CI = 1.17-1.75) and after treatment adjustment (HR = 1.58; 95% CI = 1.27-1.97). ER + /PR- breast cancer-specific mortality remained higher than ER + /PR + tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER-/PR + (n = 161) compared with ER + /PR + tumors. Our findings suggest that ER + /PR- tumors may have worse breast cancer-specific mortality than ER + /PR + tumors in a community setting.

Abstract P3-12-02: Loss of PTEN expression, PIK3CA mutations, and breast cancer survival in the Nurses’ health studies

Abstract Background: PTEN loss and/or PIK3CA mutation are hypothesized to predict more aggressive tumor behavior and worse outcomes in women with breast cancer. However, the results of previous studies with small sample size have been conflicting. Methods: We followed pre- and postmenopausal women with invasive breast cancer from the Nurses’ Health Study (diagnosed 1976-2011) and Nurses’ Health Study II (1989-2011) with data available on PTEN cytoplasmic expression (n=4316, breast cancer-specific deaths=777) and/or PIK3CA mutation (n=2930, breast cancer-specific deaths=317). PTEN protein expression was evaluated by immunohistochemistry and scored as a digitally quantified continuous measure (1-100%). Polymerase chain reaction and pyrosequencing of six hot spot mutations of PIK3CA were performed on DNA extracted from formalin-fixed paraffin-embedded tumors. Information on other covariates was self-reported at baseline and repeatedly measured with follow-up questionnaires every two to four years. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between loss of PTEN expression and/or PIK3CA mutation and breast cancer-specific mortality were estimated using Cox proportional hazards regression models. Results: In this large epidemiological study, the loss of tumor cell PTEN cytoplasmic staining expression (≤10%) occurred in 17.6% of cases, and the overall mutation of PIK3CA occurred in 10.8% of cases. After adjusting for tumor characteristics, treatment, and lifestyle factors, the loss of PTEN expression (versus expression >10%) was not associated with worse breast cancer survival among overall samples (HR =0.85; 95%CI=0.71-1.03) and among estrogen receptor (ER)-positive tumors (HR =1.11; 95%CI=0.84-1.47). However, among women with ER-negative tumors, PTEN expression loss was strongly associated with lower breast cancer mortality (HR =0.68; 95%CI=0.48-0.96). Overall mutation status of PIK3CA was not associated with breast cancer mortality (HR =1.06; 95%CI=0.78-1.45). Combining PTEN and PIK3CA status, compared with tumors without PTEN loss and without PIK3CA mutation (wild type), those with PTEN loss and/or PIK3CA mutation were not at higher risk (HR =1.05; 95%CI=0.85-1.32). However, women with PTEN loss and PIK3CA mutation jointly (n=39, breast cancer-specific deaths=15) had increased breast cancer mortality (HR =2.05; 95%CI=1.07-3.94). Conclusion: This study is the largest to date examining PTEN and PIK3CA status and breast cancer survival, in which we found that the prognostic value of PTEN status differed by ER status, and the joint status of PTEN loss of expression and PIK3CA mutation was associated with worse breast cancer survival. Citation Format: Tengteng Wang, Yujing J Heng, Gabrielle M Baker, Vanessa C Bret-Mounet, Susan E Hankinson, Michelle D Holmes, Wendy Y. Chen, Walter C. Willett, Bernard A. Rosner, Rulla M Tamimi, A. Heather Eliassen. Loss of PTEN expression, PIK3CA mutations, and breast cancer survival in the Nurses’ health studies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-02.

Abstract P3-12-03: Pre-diagnostic plasma 25-hydroxyvitamin D and mortality among women with breast cancer in the nurses’ health study cohorts

Abstract Background: Sufficient levels of vitamin D are critical for optimal health. 25-hydroxyvitamin D (25(OH)D) is an essential steroid hormone, derived from sun exposure, diet, and supplement use, that is hypothesized to influence breast cancer prognosis by inhibiting breast tumor growth. While this has been observed in laboratory-based studies, findings from observational studies are inconclusive. We examined the association between pre-diagnostic 25(OH)D concentrations and both breast cancer-specific and overall mortality to explore the potential effects of vitamin D, a modifiable exposure. Methods: We evaluated the association between pre-diagnostic plasma 25(OH)D concentrations and breast cancer-specific and total mortality among 1,300 women diagnosed with invasive, non-metastatic breast cancer enrolled in the Nurses’ Health Study 1 (NHS1) and Nurses’ Health Study 2 (NHS2) cohorts. In this analysis, women provided a blood sample from 1989-1990 and a second blood sample in 2000-2001 (NHS1) or a blood sample from 1996-1999 (NHS2). Women were diagnosed with breast cancer after blood collection up through 2016 (NHS1) and 2017 (NHS2) and censored at end of study (2016 NHS1; 2017 NHS2) or death, whichever came first. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for mortality after adjustment for tumor characteristics, type of cancer treatment, and lifestyle factors. For women with two blood samples, most recent exposure status was used in the analyses. Results: A total of 396 total deaths and 145 breast cancer-specific deaths occurred during follow-up through 2017. We observed a non-statistically significant 25% lower breast cancer-specific mortality rate among those with the highest, versus lowest, quartile of pre-diagnostic 25(OH)D levels (HRQ4vsQ1 0.75, 95%CI 0.45-1.25; p for trend=0.32), that did not vary significantly by estrogen receptor status of the tumor (p for interaction=0.61). Women in the highest vs. lowest quartile of plasma 25(OH)D experienced a 31% lower overall mortality rate (HRQ4vsQ1 0.69, 95%CI 0.51-0.93; p for trend=0.03). In cause-specific mortality analyses among non-breast cancer deaths, non-statistically significant decreases were observed for other cancer deaths and cardiovascular disease deaths. Conclusion: Pre-diagnostic plasma 25(OH)D levels were not significantly associated with lower breast cancer-specific mortality among women with breast cancer. However, significant inverse associations were observed for total mortality, which supports a potential benefit of vitamin D among these women. Citation Format: Etienne Holder. Pre-diagnostic plasma 25-hydroxyvitamin D and mortality among women with breast cancer in the nurses’ health study cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-03.

Breast Cancer in Chinese Females Aged 25 Years and Younger.

Background Breast cancer has both aggressive clinicopathological characteristics and a poor prognosis in young females. However, limited information is available for breast cancer in Chinese females aged ≤25 years. Therefore, we aimed to explore prognostic factors for invasive disease-free (iDFS) and overall survival (OS) among breast cancer patients aged ≤25 years. Methods We retrospectively analyzed data from 174 Chinese females aged ≤25 years with invasive breast cancer treated in the Cancer Hospital of the Chinese Academy of Medical Sciences from January 1, 1999, to December 31, 2018. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors. Results The median follow-up time was 75 months (ranging from 1 to 236 months). Breast cancer patients aged ≤25 years exhibited aggressive clinicopathological characteristics, including advanced tumor stage (21.8%), lymph node metastasis (47.1%), lymphovascular invasion (24.1%), estrogen receptor negativity (44.3%), progesterone receptor (PR) negativity (42.5%), and triple-negative breast cancer (25.3%). Among them, 50 cases had locoregional recurrence and metastasis, 20 had bilateral invasiveness, and 33 had breast cancer-specific deaths. Cox multivariate analysis identified that diagnosis delay, PR status, and radiotherapy were significant prognostic factors for both iDFS and OS (P < 0.05). The risk of recurrence and metastasis was five times higher in N3 than in N0 (HR: 6.778, 95% CI: 2.268–17.141, P < 0.001). Patients with lymphovascular invasion had a threefold increase in the risk of breast cancer-specific death (HR: 4.217, 95% CI: 1.956–9.090, P < 0.001). No differences were observed between mastectomy and breast-conserving surgery (BCS) plus radiotherapy for iDFS or OS (iDFS: χ2 = 0.678, P=0.410; OS: χ2 = 0.165, P=0.685). Conclusions Breast cancer in females ≤25 years old was associated with aggressive clinical features and a worse prognosis. Young females with breast lumps should receive timely diagnosis and treatment. Young breast cancer patients with lymphovascular invasion, PR-negative status, and lymph node metastasis have an increased risk of experiencing recurrence and metastasis and should hence be closely monitored. Age at diagnosis should not be the sole deciding factor for surgical treatment methods.

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

BackgroundGiven the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.MethodsWe performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).ResultsEvidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.ConclusionsWe found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Abstract LB081: Systemic inflammation is associated with increased risk of mortality after invasive breast cancer among Hispanic women from New Mexico

Abstract Introduction: Soluble tumor necrosis factor receptor-II (sTNF-R2), a circulating pro-inflammatory biomarker, has been found to associated with obesity and increased risk of breast cancer. No studies to date have examined the association between sTNF-R2 and risk of mortality among Hispanic breast cancer survivors, an at-risk population due to their high prevalence of obesity and poor prognosis. The current study examined the long-term effects of sTNF-R2 on risk of mortality among Hispanic and non-Hispanic white (NHW) breast cancer survivors from the New Mexico Health Eating Activity and Lifestyle Study. Methods: A total of 397 invasive breast cancer survivors (96 Hispanic, 301 NHW) contributed data for the present study. Women with breast cancer diagnosed between July 1996 and March 1999 were ascertained through the National Cancer Institute's Surveillance Epidemiology and End Results registry in New Mexico. Baseline demographic characteristics, anthropometric measures, and blood samples were collected approximately 5 months post diagnosis by trained interviewers. Plasma levels of sTNF-R2 were assayed and measures were log-transformed to conform to normality. The main predictor of low (referent) vs high sTNF-R2 levels was based on the median value. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the associations between sTNF-R2 and all-cause mortality were calculated using Cox proportional hazards regression models overall and by ethnicity. Models were adjusted for age at diagnosis, education, breast cancer stage, treatment, and body mass index (BMI). Results: A total of 133 deaths (53 breast cancer-specific deaths) were observed after a median follow-up time of 13 years. While Hispanic women had higher baseline BMI (mean= 27.21, standard deviation (SD)= 5.83) compared to NHW women (mean= 25.68, SD= 5.36) (p&amp;lt; 0.001), significant differences by ethnicity for sTNF-R2 levels were not observed. In models adjusted for ethnicity and other covariates, the association between high vs low levels of plasma sTNF-R2 and risk of mortality was not statistically significant among all women (HR, 1.36; 95% CI 0.90-2.03). However, in models stratified by ethnicity, Hispanic women had increased risk of mortality of almost 3-fold (HR, 2.83; 95% CI 1.21-6.63), while the association among NHW women was attenuated and was not statistically significant (HR, 0.99; 95% CI 0.61-1.61). The statistical interaction between sTNF-R2 and ethnicity with risk of mortality was not statistically significant (p= 0.10). Conclusion: Our study results suggest Hispanic breast cancer survivors with high levels of systemic inflammation measured by sTNF-R2 are at increased risk of mortality. These results could inform targeted intervention studies to decrease inflammation and reduce risk of mortality among this at-risk population. Citation Format: Avonne E. Connor, Stephanie D. Boone, Kathy B. Baumgartner, Richard N. Baumgartner. Systemic inflammation is associated with increased risk of mortality after invasive breast cancer among Hispanic women from New Mexico [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 LB081.

Association of statin use with clinical outcomes in patients with triple-negative breast cancer.

523 Background: Statins have been shown to target pathways related to breast cancer carcinogenesis, specifically in more aggressive breast cancer subtypes such as triple negative breast cancer (TNBC). Given the limited toxicity profile, low cost, and ease of use of statins, an association between statin therapy and improved breast cancer outcomes, particularly in aggressive breast cancers with more limited treatment options, could have important public health implications. Here we examine the association of statin therapy with breast cancer outcomes in women with stage I-III breast cancer, specifically TNBC. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER)-Medicare and Texas Cancer Registry (TCR)-Medicare data. We included women age 66 years or older with histologically confirmed stage I-III breast cancer diagnosed from 2008-2015. We used multivariable Cox proportional hazards regression models to examine the association of statin use with overall survival (OS) and breast cancer specific survival (BCSS) adjusting for age, race, education, state buy-in, residence area, stage, subtype, endocrine therapy, radiation, chemotherapy, surgery, baseline statin use, comorbidity, and baseline hypertension. For BCSS, we accounted for the competing risk of death using the Fine and Grey method. We required all individuals to survive until 12 months post-diagnosis, which we defined as the start of the follow-up period, to account for immortal time bias. Results: We identified 45,063 patients with stage I-III breast cancer meeting inclusion criteria, out of which 22,518 (50.0%) received a statin within one year following diagnosis (statin-users). The 5-year cumulative estimates of breast cancer specific deaths were 5.9% and 6.9% for statin-users and non-users (P &lt;.001), respectively. In the overall cohort, adjusted models showed a statistically significant association between statin use and improved BCSS (subdistribution hazard ratio [SHR], 0.82; 95% CI, 0.70 to 0.97; P =.021), but no association with OS (hazard ratio [HR], 0.96; 95% CI, 0.90 to 1.03; P =.23). The association was strongest in patients with TNBC for BCSS (SHR, 0.60; 95% CI, 0.42 to 0.86; P =.006) and OS (HR, 0.76; 95% CI, 0.61 to 0.95; P =.018). Stratification by stage showed that the effect of statin therapy in TNBC was limited to patients with localized disease. Our results were consistent using propensity score matched models and when limiting our analysis to statin therapy initiated following breast cancer diagnosis. Conclusions: Among women with non-metastatic breast cancer, we found that statin use was associated with an OS and BCSS benefit among women with TNBC. Our data suggest that statins may have a role as an adjuvant therapy in select patients with breast cancer and supports further investigation, particularly among patients with TNBC, for whom effective treatment options are more limited.

Impact of body mass index on the prognosis of Japanese women with operable hormone receptor-positive breast cancer: A single institutional retrospective study.

e12547 Background: Higher body mass index (BMI) has been associated with an increased risk of developing hormone receptor (HR)-positive breast cancer (BC) in postmenopausal women, but its relationship with prognosis in patients with HR-positive BC remains unclear. In particular, there is limited data on BMI and prognosis in Asian patients with BC, whose BMI distribution differs from that of Westerners. Methods: We retrospectively reviewed data from Japanese women who underwent curative surgery for clinical stage I-III HR-positive BC in our institution between January 2007 and December 2017. The patients were classified into five groups based on BMI: underweight (UW), BMI &lt; 18.5 kg/m2; normal weight (NW), 18.5 to 24.9 kg/m2; obese 1 degree (OB1), 25.0 to 29.9 kg/m2; obese 2 degree (OB2), 30.0 to 34.9 kg/m2; obese 3 degree (OB3), ≥ 35 kg/m2. We compared the clinicopathological features between patients with OB1-3 and those with UW and NW. The prognostic analysis of breast cancer-specific survival (BCSS) and overall survival (OS) was performed using the log-rank test and Cox proportional hazards model between the two groups. Subgroup analysis of BCSS and OS was performed in premenopausal and postmenopausal patients. Results: Overall, 6,421 patients were included in the study. The median follow-up duration was 5.9 years (range, 0.2-12.9). The number of patients with UW, NW, OB1, OB2, or OB3 was 599 (9%), 4477 (70%), 1085 (17%), 224 (3%), and 36 (1%), respectively. Of these, 3380 (53%) were premenopausal and 2968 (46%) were postmenopausal. Patients with OB1-3 had a significantly higher stage of BC, a higher number of lymph node metastases, and were associated with higher Ki67 index and nuclear grade compared to those with UW and NW. A total of 521 all-cause and 307 breast cancer-specific deaths as well as 824 recurrences were observed. Both BCSS and OS in patients with OB1-3 were significantly worse than those in the UW and NW patients (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.14-2.42; HR, 1.64; 95%CI, 1.25-2.18, respectively) by univariate analysis. In addition, the Kaplan-Meier curve for each BMI group showed that the prognosis of BCSS and OS was gradually worse in the order of NW, OB1, OB2, and OB3. Subgroup analysis revealed that BCSS and OS were significantly worse in patients with OB1-3 than in those with UW and NW for premenopausal patients (HR, 2.37; 95%CI, 1.40-4.02; HR, 1.91; 95%CI, 1.17-3.11, respectively), but not for postmenopausal patients (HR, 1.26; 95%CI, 0.74-2.16; HR, 1.29; 95%CI, 0.92-1.82, respectively). Multivariate analysis showed that tumor stage and nuclear grade were independent prognostic factors, but OB1-3 was not. Conclusions: Obesity was associated with a worse prognosis as it correlated with advanced stage and high nuclear grade in Japanese patients with HR-positive BC, especially in premenopausal patients.

Increased risk of breast cancer-specific mortality among cancer survivors who developed breast cancer as a second malignancy

BackgroundCancer survivors who develop breast cancer as a second malignancy (BCa-2) are common. Yet, little is known about the prognosis of BCa-2 compared to first primary breast cancer (BCa-1).MethodsUsing the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study including 883,881 patients with BCa-1 and 36,313 patients with BCa-2 during 1990–2015. Compared with patients with BCa-1, we calculated hazard ratios (HRs) of breast cancer-specific mortality among patients with BCa-2, using multivariable Cox regression.ResultsDuring the follow-up (median 5.5 years), 114,964 and 3829 breast cancer-specific deaths were identified among BCa-1 and BCa-2 patients, respectively. Patients with BCa-2 had more favorable tumor characteristics and received less intensive treatment e.g., surgery and chemo−/radio-therapy, compared to patients with BCa-1. When adjusting for demographic factors, patients with BCa-2 were at similar risk of breast cancer-specific mortality (HR 1.00, 95% CI 0.97–1.03) compared to patients with BCa-1. However, when additionally controlling for tumor characteristics and treatment modes, BCa-2 patients were at an increased risk of breast cancer-specific mortality (HR 1.11, 95% CI 1.08–1.15). The risk elevation was particularly greater when the first malignancy was lung, bladder, ovarian or blood malignancy (HRs 1.16–1.85), or when the first malignancy was treated with chemotherapy and radiotherapy (HR 1.44, 95% CI 1.28–1.63).ConclusionsOverall, patients with BCa-2 have worse breast cancer-specific survival, compared with their BCa-1 counterparts, although the risk elevation is mild. High-risk subgroups based on first malignancy’s characteristics may be considered for active clinical management.

Post-diagnostic coffee and tea consumption and breast cancer survival.

We examined the role of post-diagnostic coffee and tea consumption in relation to breast cancer-specific and all-cause mortality among women with breast cancer in prospective cohort studies. We identified 8900 women with stage I-III breast cancer from 1980 through 2010 in the Nurses' Health Study (NHS) and from 1991 through 2011 in the NHSII. Post-diagnostic coffee and tea consumption was assessed by a validated food frequency questionnaire every 4 years after diagnosis. During up to 30 years of follow-up, we documented 1054 breast cancer-specific deaths and 2501 total deaths. Higher post-diagnostic coffee consumption was associated witha lower breast cancer-specific mortality: compared with non-drinkers, >3 cups/day ofcoffee was associated with a 25% lower risk (hazard ratio (HR) = 0.75, 95% confidence interval(CI) = 0.59-0.96; Ptrend = 0.002). We also observeda lower all-cause mortality with coffee consumption: compared withnon-drinkers,>2 to 3 cups/day was associated with a 24% lower risk (HR = 0.76, 95% CI = 0.66-0.87) and >3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.63-0.87, Ptrend < 0.0001). Post-diagnostic tea consumption was associated witha lower all-cause mortality: compared with non-drinkers, >3 cups/day was associated with a 26% lower risk (HR = 0.74, 95% CI = 0.58-0.95; Ptrend = 0.04). Among breast cancer survivors, higher post-diagnostic coffee consumption was associated with better breast cancer and overall survival. Higher post-diagnostic tea consumption may be related to better overall survival.

Abstract PS10-39: Risk factors for all-cause death and breast cancer-specific death in patients with HER2-positive and lymph node negative breast cancer : A retrospective analysis based on SEER database (2010 to 2017)

Abstract Purpose: Trastuzumab combined with pertuzumab (HP) is currently the standard treatment for HER2-positive (HER2+) and lymph node-positive (LN+) breast cancer, but it is not clear which subgroup of patients with HER2+ and LN- breast cancer are suitable for HP dual-targeted therapy. By collecting the clinicopathological and prognostic information of HER2+ and LN- breast cancer patients in the SEER database from 2010 to 2017, we explored the risk factors of recurrence in these populations, aiming to identify subgroup who may need HP dual-targeted therapy among HER2+ and LN- breast cancer patients. Methods: From the SEER database, the clinicopathological and prognostic information of pathologically confirmed HER2+ and LN- breast cancer from 2010 to 2017 were extracted, and the risk factors of breast cancer-specific survival and overall survival were analyzed by multivariate Cox risk proportional model and competitive risk model.Results: After data cleaning, a total of 5163 patients were included in the current analysis. The median survival time was 49 months (IQR: 34 to 70 months). A total of 209 patients had breast cancer-specific deaths, and 325 patients died due to all causes. Multivariate Cox analysis showed that compared with patients of 20-34 years old, the 70-74 age group (HR=2.683, 95%CI=[1.221,5.895], P=0.014), 75-79 age group (HR=5.303, 95% CI=[2.437,11.543], P&amp;lt;0.001), 80-84 age group (HR=7.971, 95%CI=[3.655,17.386], P&amp;lt;0.001) and 85+ age group (HR=13.591, 95%CI =[6.327,29.192], P&amp;lt;0.001) had significantly higher risk of all-cause death, respectively; compared with T1 patients, the T2 patients (HR=1.784, 95%CI=[1.481,2.148], P&amp;lt;0.001), Patients with T3 (HR=2.413, 95%CI=[1.649,3.532], P&amp;lt;0.001), patients with T4 (HR=2.943, 95%CI=[1.968,4.401], P&amp;lt;0.001) are at significantly higher risk of total cause of death, respectively. Compared with patients of 20-34 years old, the 85+ age group (HR=2.923, 95%CI=[1.299,6.583], P=0.010) had significantly higher risk of breast cancer-specific death; compared with T1 patients, the T2 patients (HR=2.316, 95%CI=[1.709,3.139], P&amp;lt;0.001), T3 patients (HR=2.421, 95%CI=[1.298,4.514], P=0.005), and T4 patients (HR=8.906, 95%CI=[5.394,14.713], P&amp;lt;0.001) are at significantly higher risk of breast cancer-specific death, respectively; compared with patients with histological Grade I, the risk of breast cancer-specific death is significantly increased in patients with Grade III (HR=2.424, 95%CI=[1.021,5.751], P=0.045); compared with PR-positive patients, the risk of breast cancer specific death was significantly increased for PR-negative patients (HR=1.665, 95%CI=[1.141 , 2.431], P=0.008).Conclusion: Tumor size, histological grade, and hormone receptor status are independent prognostic factors for breast cancer-specific death in patients with HER2+ and LN- breast cancer. In clinical practice, patients can be recommended for single-targeted (H) or double-targeted (HP) therapy according to the individualized factor. Citation Format: Ju Wang, Yi Zhang, Jun Jiang, Xiaowei Qi. Risk factors for all-cause death and breast cancer-specific death in patients with HER2-positive and lymph node negative breast cancer : A retrospective analysis based on SEER database (2010 to 2017) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-39.

Clinical significance of HER2 status in T1bN0 breast cancer: a nationwide study from the Korean Breast Cancer Society.

The prognosis of patients with node-negative T1b tumors according to human epidermal growth factor receptor 2 (HER2) status is not known. This group of patients has not been studied in the available randomized trials. The objective of this study was to evaluate the survival of patients in a monoethnic group diagnosed with T1b lymph node-negative breast cancer depending on HER2 status. We analyzed 3110 patients with T1bN0M0 breast cancer whose data were deposited into the Korean Breast Cancer Society Registry database between 2000 and 2009. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared according to HER2 status. Among all patients, 494 (15.9%) had HER2-positive breast cancer. At a mean follow-up of 93months, 108 deaths and 86 breast cancer-specific deaths were noted among all patients. There was no significant difference in OS between the HER2-negative and HER2-positive groups (p = 0.103). The same result was observed for BCSS. However, in the subgroup of estrogen receptor (ER)-positive women, HER2-negative patients had a better BCSS prognosis than HER2-positive patients (p = 0.025). Multivariate analysis also indicated a significant difference in BCSS in the ER-positive subgroup (HR 2.60; 95% CI 1.15-5.87; p = 0.021). This study analyzed a large nationwide and monoethnic cohort and found a significant difference only in BCSS in the ER-positive subgroup according to HER2 status. Anti-HER2 therapy may be considered in HER2-positive and ER-positive patients with small, node-negative breast cancer.