Cancer-free Women Research Articles

The abundance of the long intergenic non-coding RNA 01087 differentiates between luminal and triple-negative breast cancers and predicts patient outcome

The molecular complexity of human breast cancer (BC) renders the clinical management of the disease challenging. Long non-coding RNAs (lncRNAs) are promising biomarkers for BC patient stratification, early detection, and disease monitoring. Here, we identified the involvement of the long intergenic non-coding RNA 01087 (LINC01087) in breast oncogenesis. LINC01087 appeared significantly downregulated in triple-negative BCs (TNBCs) and upregulated in the luminal BC subtypes in comparison to mammary samples from cancer-free women and matched normal cancer pairs. Interestingly, deregulation of LINC01087 allowed to accurately distinguish between luminal and TNBC specimens, independently of the clinicopathological parameters, and of the histological and TP53 or BRCA1/2 mutational status. Moreover, increased expression of LINC01087 predicted a better prognosis in luminal BCs, while TNBC tumors that harbored lower levels of LINC01087 were associated with reduced relapse-free survival. Furthermore, bioinformatics analyses were performed on TNBC and luminal BC samples and suggested that the putative tumor suppressor activity of LINC01087 may rely on interferences with pathways involved in cell survival, proliferation, adhesion, invasion, inflammation and drug sensitivity. Altogether, these data suggest that the assessment of LINC01087 deregulation could represent a novel, specific and promising biomarker not only for the diagnosis and prognosis of luminal BC subtypes and TNBCs, but also as a predictive biomarker of pharmacological interventions.

Incidence of hypothyroidism after treatment for breast cancer\u2014a Danish matched cohort study

BackgroundBreast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment.MethodsUsing nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996–2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities.ResultsWe included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7–1.9) and 1.6% (95%CI = 1.5–1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25–4.67) and 3.81 (95%CI = 3.73–3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11–1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50–2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14–1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45–2.01 and HR = 1.36, 95%CI = 1.17–1.58, respectively].ConclusionsBCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy.

Dietary and Lifestyle Oxidative Balance Scores and Incident Colorectal Cancer Risk among Older Women; the Iowa Women’s Health Study

Background Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology, but in epidemiologic studies, associations of most individual exposures with CRC have been weak or inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial. Methods Using food frequency and lifestyle questionnaire data from the prospective Iowa Women’s Health Study (1986-2012), we investigated associations of 11-component dietary and 4-component lifestyle oxidative balance scores (OBS) with incident CRC using multivariable Cox proportional hazards regression. Results Of the 33,736 cancer-free women aged 55-69 years at baseline, 1,632 developed CRC during follow-up. Among participants in the highest relative to the lowest dietary and lifestyle OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures), the adjusted hazard ratios (HRs) and their 95% confidence intervals (CI) were, respectively, 0.77 (0.63, 0.94) (Ptrend =0.02) and 0.61 (0.52, 0.71) (Ptrend <0.0001). Among those in the highest relative to the lowest joint lifestyle/dietary OBS quintile, the HR was 0.45 (95% CI 0.26, 0.77). Conclusions Our findings suggest that a predominance of antioxidant over pro-oxidant dietary and lifestyle exposures—separately and especially jointly—may be inversely associated with CRC risk among older women.

Association of a Diagnosis of Ductal Carcinoma In Situ With Death From Breast Cancer

It is not clear to what extent a diagnosis of ductal carcinoma in situ (DCIS) impacts a woman's lifetime risk of dying of breast cancer. Under ideal circumstances, treatment will eliminate the risk of invasive ipsilateral recurrence and prevent subsequent mortality from breast cancer. The risk of dying of breast cancer after a diagnosis of DCIS had not been compared with that of women without cancer in the general population. To determine the risk of death from breast cancer in a large cohort of patients treated for DCIS and to compare the risk with that of women in the general population. This cohort study included data for women who had first primary DCIS diagnosed between 1995 and 2014 from the Surveillance, Epidemiology and End Results (SEER) registries database. Women with DCIS underwent surgical treatment, and approximately half also received radiotherapy. These women were followed from the date of DCIS diagnosis until death from breast cancer or date of last follow-up. Women in the general population without breast cancer were analyzed as controls. Follow-up information was available up to December 2016. The data were analyzed in March 2020. Patients with DCIS who underwent surgical treatment. Breast cancer death was the main outcome. Standardized mortality ratios were estimated by comparing deaths from breast cancer among women diagnosed with DCIS with expected deaths from breast cancer among women in the general population who did not have cancer. Expected probability of death from breast cancer in the general population was calculated by an incidence-based mortality approach using standardized SEER-based incidence and case-fatality rates. Probability of breast cancer death was estimated based on the assumption that a cancer-free control was cancer free on the date the woman with DCIS was diagnosed and was studied until the end of follow-up. A total of 144 524 women diagnosed with first primary DCIS were included (mean [SD] age at diagnosis, 57.4 [11.0] years). There were 1540 deaths from breast cancer in the cohort. Based on SEER-based incidence and case-fatality rates, 458 breast cancer deaths were expected in an equivalent number of cancer-free women from the general population with equal follow-up. The standardized mortality ratio for death from breast cancer among women with DCIS was 3.36 (95% CI, 3.20-3.53). The elevated risk of death persisted more than 15 years after diagnosis. In the population studied, the risk of dying of breast cancer was increased 3-fold after a diagnosis of DCIS. This suggests that our current treatment focus on preventing invasive recurrence is insufficient to eliminate all deaths from breast cancer after DCIS.

Abstract 5795: Long-term diabetes risk among ovarian cancer survivors in a population-based cohort study

Abstract Objective. In the United States, ovarian cancer is the eleventh most common female cancer and the fifth most common cause of cancer death among women. Although incidence and death rates have been declining over the last 10 years, the 5-year survival rate is 47.6%. Diabetes was the seventh leading cause of death in the United States and is associated with an increased mortality rate among cancer patients. While previous studies have examined the association between diabetes and the risk of ovarian cancer, there are very few studies investigating the risk of diabetes after an ovarian cancer diagnosis. We previously reported increased risks of type I and II diabetes among endometrial cancer survivors, but there is no previous study, to our knowledge, that examined the risk of diabetes among ovarian cancer survivors. The aim of this study was to investigate long-term diabetes risk among ovarian cancer survivors compared with a general population of women. Methods. Ovarian cancer patients diagnosed from 1996 to 2012 in the Utah Cancer Registry were matched to up to 5 cancer-free women on birth state and birth year using the Utah Population Database. Diabetes diagnoses were identified with ICD-9 codes from statewide ambulatory surgery records, statewide inpatient databases and electronic medical records. We estimated hazard ratios with Cox Proportional Hazards models to: (1) investigate risk for diabetes after cancer diagnosis among ovarian cancer survivors compared with the general population, and (2) examine risk factors for type II diabetes among ovarian cancer survivors. Results. A total 1,520 ovarian cancer patients and 5,709 women from the general population were included in the final cohort. A slightly higher proportion of ovarian cancer patients were obese at baseline (16.3%) than the general population cohort (14.9%). Ovarian cancer survivors had a higher risk of type II diabetes in the first year after cancer diagnosis (HR=3.09, 95%CI=2.09, 4.56) and overall (HR=1.52, 95%CI=1.23, 1.88) compared with the general population. However, associations between ovarian cancer and type II diabetes were not observed in the later follow up periods. High BMI was a significant risk factor for type II diabetes among ovarian cancer survivors, with a dose-response relation (overweight; HR=1.81, 95%CI=1.21, 2.71, obese; HR=2.48, 95%CI=1.61, 3.83, P-trend &amp;lt;0.001). Clinical factors such as cancer treatment, stage, and histology did not contribute to an increased risk of type II diabetes among ovarian cancer patients. Other factors such as race and baseline comorbidities were also not associated with type II diabetes risk among ovarian cancer patients. Conclusion. Ovarian cancer survivors had an increased risk of type II diabetes compared with women in the general population. Risk was elevated only within the first year of cancer diagnosis, thus surveillance bias cannot be ruled out. Our findings suggest that the increased risk of type II diabetes does not persist beyond the first year after cancer diagnosis. Citation Format: Seungmin Kim, Kerry Rowe, John Snyder, Alison Fraser, Ken Smith, Vikrant G. Deshmukh, Michael Newman, Kimberley Herget, Chun-Pin Chang, Dominik Ose, Mary C. Playdon, David Gaffney, Mia Hashibe. Long-term diabetes risk among ovarian cancer survivors in a population-based cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5795.

Abstract 5797: Genitourinary disease risks among ovarian cancer survivors in a population-based cohort study

Abstract Background. While genitourinary complications during treatment for ovarian cancer are well known, long-term adverse outcomes in the growing population of ovarian cancer survivors have yet to be characterized. The aim of our study is to describe the incidence of genitourinary diseases among ovarian cancer survivors after ovarian cancer diagnosis, compared to the general female population. Methods. We identified a cohort of 1,270 ovarian cancer survivors diagnosed between 1996 and 2012 in the Utah Cancer Registry, and up to five cancer-free women were matched to ovarian cancer survivors on birth year and state from the Utah Population Database (N=5,286). Genitourinary disease diagnoses were identified with ICD-9 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for genitourinary outcomes at 1 to &amp;lt;5 years after cancer diagnosis and 5+ years after cancer diagnosis with adjustment for potential confounders (e.g., race, baseline body mass index (BMI), and baseline Charlson Comorbidity Index (CCI)). Results. Urinary system disorders were diagnosed more frequently in ovarian cancer survivors compared to women without cancer (34.6% vs 19.3%, p-value &amp;lt;0.001) in years 1-5 of follow up (HR: 2.53, 95% CI: 2.12-3.01). More than 5 years after cancer diagnosis, ovarian cancer survivors had a higher risk of hydronephrosis compared to the general population (HR: 9.10, 95% CI: 4.29-19.33). Genital organ disorders were also more common among ovarian cancer survivors (22.0%) compared to women in the general population (16.3%; HR: 1.89, 95% CI: 1.57-2.27). The risk of pelvic peritoneal adhesions was highest 1-5 years after cancer diagnosis (HR: 16.59, 95% CI: 7.00-39.34) and persisted 5+ years after cancer diagnosis (HR: 8.88, 95% CI: 1.88-41.91). A higher risk of urinary system disorders among ovarian cancer patients was associated with advanced cancer stage (HRadvanced vs. localized: 3.11, 95% CI: 2.18-4.45), older age at cancer diagnosis (HR80+ vs. 18-49: 2.85, 95% CI: 1.62-5.01), and higher baseline CCI score (HR2+ vs. 0: 2.71, 95% CI: 1.84-3.99). The associations remained when we restricted analyses to ovarian cancer survivors with high-grade serous ovarian cancer. Conclusions. In this population-based cohort study, ovarian cancer survivors experienced increased risks of various genitourinary diseases for many years after cancer diagnosis. Understanding the multimorbidity trajectory for ovarian cancer survivors after cancer treatment is needed to ultimately improve clinical care after cancer diagnosis. The present results point to the importance of monitoring for genitourinary diseases among ovarian cancer survivors. Citation Format: Chun-Pin Chang, Yuji Chen, Brenna Blackburn, Sarah Abdelaziz, Kerry Rowe, John Snyder, Mark Dodson, Vikrant Deshmukh, Michael Newman, Joseph B. Stanford, Christina A. Porucznik, Jennifer Ose, Alison Fraser, Ken Smith, Jennifer Doherty, David Gaffney, Mia Hashibe. Genitourinary disease risks among ovarian cancer survivors in a population-based cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5797.

Abstract 2357: Lipid-lowering drug use, duration of use, and age at first use is associated with a lower risk of colorectal cancer mortality in men and women in the Atherosclerosis Risk in Communities (ARIC) Study

Abstract Background: While lipid-lowering drugs, particularly statins, are associated with a modestly reduced risk of developing colorectal cancer (CRC), the association of lipid-lowering drug use, duration of use, and age at first use with CRC mortality in men and women without the diagnosis at baseline, has not been well studied. Further, whether associations are similar across race is unknown. Thus, we aimed to characterize the association between lipid-lowering drug use and CRC mortality in men and women and by race. We classified lipid-lowering drug use in a time-dependent manner as current use, duration of use, and age at first use. Methods: We conducted a prospective cohort study of 14,428 cancer-free men and women attending visit 2 (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) Study. Death from CRC was ascertained from the underlying cause on death certificates. Follow-up began at visit 2 and ended at date of death or 12/31/2015, whichever came first. There were 384 incident CRC cases and 144 deaths in 290,249 person-years. Cox regression was used to estimate relative hazards (HR) and 95% confidence intervals (CI) for CRC incidence and death adjusting for age, sex, education, race and field center, BMI, smoking status and pack years, alcohol use, red and processed meat consumption, aspirin use, and family history of any cancer and family history of CRC overall and by gender and race. Current lipid-lowering medication use, duration of use (&amp;lt;15 years, ≥15 years), and age at first use (&amp;lt;50, 50-59, 60-69, and ≥70 years of age) were modeled as time-dependent variables. Results: Mean age was 57 years and mean BMI was 28.1 kg/m2; 54.9% were women and 27.9% were Black. By visit 4 (1996-98), after an average of 6 years of follow-up, 22% of participants were using lipid-lowering drugs. Compared to never users, current use was associated with 53% lower risk of CRC death (HR 0.47; 95%CI 0.32-0.71). Inverse associations were present in both men (HR 0.59; 95%CI 0.35-0.99) and women (HR 0.37; 95%CI 0.20-0.69) and in Black (HR 0.44; 95%CI 0.19-1.00) and White (HR 0.49; 95%CI 0.31-0.77) participants. Inverse associations were consistent across different patterns of duration of use and was inverse irrespective of age at first use. Current use was also associated with a lower risk of CRC incidence (HR: 0.72; 95%CI 0.57-0.92). Conclusions: Current use of lipid-lowering drugs was associated with a statistically significant lower risk of dying from CRC in participants without cancer at baseline, including men and women and in Black and white participants, irrespective of the duration (15 year intervals) or age at first use. Support: NHLBI contracts, NCI grants, NPCR Citation Format: Michael T. Marrone, John R. Barber, Alison M. Mondul, Anna E. Prizment, David Couper, Corinne E. Joshu, Elizabeth A. Platz. Lipid-lowering drug use, duration of use, and age at first use is associated with a lower risk of colorectal cancer mortality in men and women in the Atherosclerosis Risk in Communities (ARIC) Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2357.

Abstract 4645: Lifestyle and dietary oxidative balance scores and risk for incident colorectal cancer among older women: The Iowa Women's Health Study

Abstract Background: Basic science literature strongly supports a role of oxidative stress in colorectal cancer (CRC) etiology; however, in epidemiologic studies, associations of individual lifestyle and dietary anti- and pro-oxidant exposures with CRC have been largely inconsistent. However, recent epidemiologic evidence suggests that the collective effects of these exposures on oxidative balance and CRC risk may be substantial. Methods: From lifestyle and food frequency questionnaire data from the prospective Iowa Women's Health Study (1986 - 2012), we calculated equal-weight, 4-component lifestyle and 11-component dietary oxidative balance scores (OBS), and investigated their separate and joint associations with incident CRC using multivariable Cox proportional hazards regression. Results: Of the 34,135 cancer-free women aged 55 to 69 at baseline, 1,635 developed CRC during follow-up. Among participants in the highest lifestyle and dietary OBS quintiles (higher anti-oxidant relative to pro-oxidant exposures) relative to the lowest, the multivariable-adjusted hazard ratios (HRs) were, respectively, 0.63 (95% confidence interval (CI), 0.54-0.73; Ptrend &amp;lt; 0.0001) and 0.77 (95% CI, 0.64-0.94; Ptrend = 0.01. The lowest risk was among those in the highest relative to the lowest joint lifestyle/dietary OBS quintile (HR = 0.47; 95% CI, 0.29-0.76). Conclusions: Our findings suggest that a predominance of antioxidant over pro-oxidant lifestyle and dietary exposures–especially lifestyle separately and jointly with dietary exposures–may be inversely associated with CRC risk among older women. Citation Format: Ziling Mao, Anna E. Prizment, DeAnn Lazovich, David C. Gibbs, Roberd M. Bostick. Lifestyle and dietary oxidative balance scores and risk for incident colorectal cancer among older women: The Iowa Women's Health Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4645.

Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster

The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.

All-Cause and Cardiovascular Disease Mortality Among Breast Cancer Survivors in CLUE II, a Long-Standing Community-Based Cohort.

There is growing evidence that breast cancer survivors have higher cardiovascular disease (CVD) mortality relative to the general population. Information on temporal patterns for all-cause and CVD mortality among breast cancer survivors relative to cancer-free women is limited. All-cause and CVD-related mortality were compared in 628 women with breast cancer and 3140 age-matched cancer-free women within CLUE II, a prospective cohort. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression for all-cause mortality, and Fine and Gray models for CVD-related mortality to account for competing risks. Over 25 years of follow-up, 916 deaths occurred (249 CVD related). Breast cancer survivors had an overall higher risk of dying compared with cancer-free women (HR = 1.79, 95% CI = 1.53 to 2.09) irrespective of time since diagnosis, tumor stage, estrogen receptor status, and older age at diagnosis (≥70 years). Risk of death was greatest among older survivors at more than 15 years after diagnosis (HR = 2.69, 95% CI = 1.59 to 4.55). CVD (69.1% ischemic heart disease) was the leading cause of death among cancer-free women and the second among survivors. Survivors had an increase in CVD-related deaths compared with cancer-free women beginning at 8 years after diagnosis (HR = 1.65, 95% CI = 1.00 to 2.73), with the highest risk among older survivors (HR = 2.24, 95% CI = 1.29 to 3.88) and after estrogen receptor-positive disease (HR = 1.85, 95% CI = 1.06 to 3.20). Breast cancer survivors continue to have an elevated mortality compared with the general population for many years after diagnosis. Preventing cardiac deaths, particularly among older breast cancer patients, could lead to reductions in mortality.

Smoking cessation prolongs survival in female cancer survivors - the Danish nurse cohort.

To explore smoking cessation between cancer survivors and cancer-free women, and the potential survival benefits from smoking cessation in cancer surviving women. We pooled 46,334 responses from the Danish Nurse Cohort. The cohort consists of female nurses, who were invited for surveys in 1993, 1999 and 2009. Participants were linked to nationwide registries on hospitalization, cause of death and migration through 2016. Odds for smoking cessation by cancer diagnosis were computed in propensity score matched logistic regression models, while survival by postdiagnosis smoking cessation was estimated in cox proportional hazards models. Eligible for analysis were 7841 women (mean age=56.7 years, SD±7.2), who were smokers at baseline and survived to the next follow-up survey. Of these, 545 women were diagnosed with cancer and matched by propensity score (1:2) with 1090 cancer-free women. Odds for smoking cessation were significantly higher in cancer-diagnosed women compared to their cancer-free peers (OR=1.31, 95% CI: 1.06-1.61). Moreover, mortality risk was significantly lower among cancer survivors who stopped smoking (HR=0.64, 95% CI: 0.46-0.91), compared to persistent smokers. The results suggest considerable survival benefits from smoking cessation in cancer surviving female nurses, and that the time surrounding cancer diagnosis may serve as a teachable moment for smoking cessation. However, due to substantial methodological limitations embedded in the study, careful interpretation of the presented results is warranted. Future studies are needed to demonstrate the effects of diagnosis on smoking cessation as well as the effects of smoking cessation on survival in female cancer populations.

Machine learning-based lifetime breast cancer risk reclassification compared with the BOADICEA model: impact on screening recommendations

BackgroundThe clinical utility of machine-learning (ML) algorithms for breast cancer risk prediction and screening practices is unknown. We compared classification of lifetime breast cancer risk based on ML and the BOADICEA model. We explored the differences in risk classification and their clinical impact on screening practices.MethodsWe used three different ML algorithms and the BOADICEA model to estimate lifetime breast cancer risk in a sample of 112,587 individuals from 2481 families from the Oncogenetic Unit, Geneva University Hospitals. Performance of algorithms was evaluated using the area under the receiver operating characteristic (AU-ROC) curve. Risk reclassification was compared for 36,146 breast cancer-free women of ages 20–80. The impact on recommendations for mammography surveillance was based on the Swiss Surveillance Protocol.ResultsThe predictive accuracy of ML-based algorithms (0.843 ≤ AU-ROC ≤ 0.889) was superior to BOADICEA (AU-ROC = 0.639) and reclassified 35.3% of women in different risk categories. The largest reclassification (20.8%) was observed in women characterised as ‘near population’ risk by BOADICEA. Reclassification had the largest impact on screening practices of women younger than 50.ConclusionML-based reclassification of lifetime breast cancer risk occurred in approximately one in three women. Reclassification is important for younger women because it impacts clinical decision- making for the initiation of screening.

A 15-year follow-up study on long-term adherence to health behaviour recommendations in women diagnosed with breast cancer.

Whilst a cancer diagnosis may prompt health behaviour change, there is limited evidence regarding whether such changes are maintained in the long-term. We aimed to investigate the impact of cancer diagnosis on health behaviour changes over the long-term survivorship period among breast cancer survivors (BCSs). The sample comprised 153 BCSs and 4778 cancer-free women, aged 49-55years in 2001 (our baseline), from the 1946-1951 birth cohort of the Australian Longitudinal Study on Women's Health. Health behaviours (physical activity, smoking, alcohol, diet and Body Mass Index), recommended by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), were assessed in five survivorship periods: ≤ 3years, 3 to ≤6years, 6to ≤9years, 9 to ≤12years, and 12 to 15years since diagnosis. A validated semi-quantitative Food Frequency Questionnaire was used for dietary assessment. Pre-diagnosis (baseline) health behaviours of BCSs and cancer-free women were compared (using Generalized Linear Models (GLM)). Multilevel (mixed effect) models were used for longitudinal data in BCSs. There was no significant difference in health behaviours between BCSs (prior to diagnosis) and cancer-free women. Following diagnosis, BCSs were significantly more physically active (≥ 600 MET min/week; 50.8% to 63.3%; p = 0.02) and consumed more fruit (≥ 2 serves/day; 57.4% to 66.4%; p = 0.01) in the recent survivorship period, but were less likely to be classified in the healthy weight range (p < 0.01). The proportion of non-drinkers and non-smokers slightly increased over the survivorship period. Whole-vegetable intake did not significantly change; however, the intake of non-starchy vegetables significantly increased from pre-diagnosis (LS mean = 89.1g/day) to post-diagnosis, 6 to ≤9years (LS mean = 137.1g/day), and 9 to ≤12years (LS mean = 120.8g/day). There were no significant changes in the total intake of fibre, carotenoids, calcium, fat, saturated fat, vitamin C, or vitamin E observed, except for increased total energy intake (p = 0.012). Before diagnosis, BCSs had similar adherence to health behaviours compared to cancer-free women. Initial positive changes to health behaviours were observed post BC diagnosis, except healthy body weight, but maintenance of such changes over the long-term was poor. BCSs may benefit from additional advice and support to make healthy lifestyle choices throughout survivorship.

Abstract D096: Disparities in toxic heavy metal burden and breast cancer risk: Findings from the Metropolitan Chicago Breast Cancer Registry

Abstract BACKGROUND: Evidence regarding associations of ambient toxic heavy metals (THMs) and breast cancer (BC) incidence is mixed. Observed inconsistencies may be a consequence of utilizing ambient THM levels collected close to time of BC diagnosis, and not incorporating an appropriate latent period. In addition, most studies have not examined associations of ambient THMs and BC incidence stratified by estrogen receptor (ER) and menopausal status, and have examined relatively homogenous populations of non-Hispanic White (nHW) women. We examined time-to-event associations of ambient THM concentrations and BC subtypes among women enrolled in the racially/ethnically diverse Metropolitan Chicago Breast Cancer Registry (MCBCR) cohort. METHODS: Using the Environmental Protection Agency’s 2005 National Air Toxics Assessment (NATA), we examined census tract-level ambient concentrations for 11 THMs (antimony, arsenic, beryllium, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, and selenium). For women enrolled in MCBCR between 2003-2007, residential addresses were geocoded and matched to census-tract estimates of the ambient THM concentrations. Women were followed to time of BC diagnosis or December 31, 2014. Cox proportional hazards (PH) regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI), adjusted for age and race. RESULTS: Over a mean follow up time of 10 years, there were 6,579 incident BC cases (with a mean time to diagnosis of 3 years) and 205,095 cancer-free women in the cohort. Over a quarter of our study population was African American (AA), and nearly 10% were Hispanic. Compared to nHW women, AA women were more likely to reside in census tracts with higher quartile ambient concentrations of beryllium, cadmium, chromium, cobalt, lead, manganese, and mercury (p&amp;lt;0.001 for all). Similarly, Hispanic women were more likely to reside in census tracts characterized by higher quartile oncentrations of beryllium, cadmium, chromium, lead, manganese, mercury, and nickel (p&amp;lt;0.001 for all). In age and race adjusted models, compared to women residing in census tracts with the lowest quartile of ambient concentrations, increased BC incidence was observed for women residing in census tracts with the highest quartile of ambient concentrations of antimony (HR=1.08, 95% CI 1.00-1.17), beryllium (HR=1.09, 95% CI 1.01-1.18), cadmium (HR=1.07, 95% CI 1.00-1.17), lead (HR=1.18, 95% CI 1.09, 1.28), and nickel (HR=1.24, 95% CI 1.15-1.33). In models stratified by ER status and menopausal status, associations with beryllium, lead, and nickel were stronger for ER positive post-menopausal BC. Associations with antimony and cadmium were stronger for ER-negative BC risk. DISCUSSION: We found that African American and Hispanic women were disproportionately exposed to higher levels of ambient THMs, which in turn were associated with specific subtypes of BC. Future studies will focus on determinants of these observed environmental disparities in the MCBCR cohort. Citation Format: Alpana Kaushiva, Jacob Kresovich, Serap Erdal, Garth Rauscher. Disparities in toxic heavy metal burden and breast cancer risk: Findings from the Metropolitan Chicago Breast Cancer Registry [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D096.

Associations of aspirin and other anti-inflammatory medications with mammographic breast density and breast cancer risk

We investigated the associations of aspirin and other non-steroid anti-inflammatory drugs with mammographic breast density (MBD) and their interactions in relation to breast cancer risk. This study included 3,675 cancer-free women within the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) cohorts. Percent breast density (PD), absolute dense area (DA), and non-dense area (NDA) were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square root-transformed. Information on medication use was collected in 1980 (NHS) and 1989 (NHSII) and updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users from all bi-annual questionnaires preceding the mammogram date. We used generalized linear regression to quantify associations of medications with MBD. Two-way interactions were examined in logistic regression models. In multivariate analysis, none of the anti-inflammatory medications were associated with PD, DA, and NDA. We found no interactions of any of the medications with PD with respect to breast cancer risk (all p-interactions > 0.05). However, some of the aspirin variables appeared to have positive associations with breast cancer risk limited only to women with PD 10-24% (past aspirin OR 1.56, 95% CI 1.03-2.35; current aspirin with < 5years of use OR 1.82, 95% CI 1.01-3.28; current aspirin with ≥ 5years of use OR 1.89, 95% CI 1.26-2.82). Aspirin and NSAIDs are not associated with breast density measures. We found no interactions of aspirin with MBD in relation to breast cancer risk.

Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.

6072 Background: Effective screening tests for ovarian cancer (OC) are lacking; most cases present at advanced stage and portend poor prognosis. DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. In DNA extracted from tissues, we first discovered, then validated discriminant methylated DNA marker (MDM) candidates for OC and subsequently tested independent plasma from women with and without OC. Methods: For discovery, DNA from 67 frozen tissues (18 high grade serous (HGS), 18 endometrioid, 15 clear cell (CC), 6 mucinous OCs; 10 benign fallopian tube epithelium (FT); and 19 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with OC. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent FFPE tissues from OCs (36 HGS, 22 endometrioid, 21 CC, and 14 mucinous) and 29 FT. Top performing MDMs in tissue were tested using long-probe quantitative amplified signal assays in independent pre-treatment plasma samples from women newly-diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. Results: After RRBS discovery and biological validation, 33 MDMs showed marked methylation fold changes (10 to &gt; 1000) across all OC histologies vs FT. The top 11 MDMs ( GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, DSCR6, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (76 (84%) HGS) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95%CI 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86 - 0.96)). Among HGS, the panel correctly identified 83%, including 5/6 stage I/II, and the majority of other subtypes (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded outstanding candidate MDMs for OC that performed with promisingly high sensitivity and specificity in plasma. Larger plasma-based OC MDM testing studies, with larger numbers of non-HGS histologies are warranted. [Table: see text]

Prediagnostic serum selenium levels in relation to breast cancer survival and tumor characteristics.

Women with lower levels of serum selenium (Se) may have a worse survival in breast cancer than women with higher levels, despite no difference in incidence of the disease. Our study was conducted to test whether Se is associated with the aggressiveness of breast tumors. Both the risk of having a tumor characteristic associated with worse prognosis, as well as the overall and breast cancer-specific mortality, were studied. We identified breast cancer cases and controls within the Malmö Diet and Cancer Study, a population-based cohort with 17 035 women recruited between 1991 and 1996. Inclusion criteria were incident breast cancer. Exclusion criteria were carcinoma in situ and bilateral breast cancer. Controls were selected among breast cancer-free women both from matching (n = 694) as well as randomization (n = 492). After exclusion, 1066 cases remained and were compared to controls regarding their prediagnostic serum Se levels and subsequent risk of having a certain tumor characteristic or intrinsic subtype. We also followed breast cancer patients regarding overall and breast cancer-specific mortality, comparing different Se quartiles. No association between serum Se quartile and any tumor characteristic or intrinsic subtype was found. Lower overall mortality was found among women in the highest Se quartile compared to the lowest using an adjusted Cox proportional hazards model, hazard ratio 0.63 (95% confidence interval: 0.44-0.89). Similar results were seen for breast cancer-specific mortality, 0.60 (0.37-0.98). The results of our study support that Se is associated with a lower mortality in breast cancer, not related to established prognostic factors.

Cardiovascular Outcomes in Relation to Antihypertensive Medication Use in Women with and Without Cancer: Results from the Women's Health Initiative.

Recent clinical trials have evaluated angiotensin-converting enzyme (ACE) inhibitors (ACEis), angiotensin receptor blockers (ARBs), and beta blockers (BBs) in relation to cardiotoxicity in patients with cancer, typically defined by ejection fraction declines. However, these trials have not examined long-term, hard clinical endpoints. Within a prospective study, we examined the risk of heart failure (HF) and coronary heart disease (CHD) events in relation to use of commonly used antihypertensive medications, including ACEis/ARBs, BBs, calcium channel blockers (CCB), and diuretics, comparing women with and without cancer. In a cohort of 56,997 Women's Health Initiative study participants free of cardiovascular disease who received antihypertensive treatment, we used multivariable-adjusted Cox regression models to calculate the hazard ratios (HRs) of developing CHD, HF, and a composite outcome of cardiac events (combining CHD and HF) in relation to use of ACEis/ARBs, CCBs, or diuretics versus BBs, separately in women with and without cancer. Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer-free women (HR = 0.99 [0.88-1.12]), among cancer survivors ACEi/ARB users were at a 2.24-fold risk of total cardiac events (1.18-4.24); p-interaction = .06). When investigated in relation to CHD only, an increased risk was similarly observed in ACEi/ARB versus BB use for cancer survivors (HR = 1.87 [0.88-3.95]) but not in cancer-free women (HR = 0.91 [0.79-1.06]; p-interaction = .04). A similar pattern was also seen in relation to HF but did not reach statistical significance (p-interaction = .23). These results from this observational study suggest differing risks of cardiac events in relation to antihypertensive medications depending on history of cancer. Although these results require replication before becoming actionable in a clinical setting, they suggest the need for more rigorous examination of the effect of antihypertensive choice on long-term cardiac outcomes in cancer survivors. Although additional research is needed to replicate these findings, these data from a large, nationally representative sample of postmenopausal women indicate that beta blockers are favorable to angiotensin-converting enzyme inhibitors in reducing the risk of cardiac events among cancer survivors. This differs from the patterns observed in a noncancer cohort, which largely mirrors what is found in the randomized clinical trials in the general population.

Detection of aberrant methylation of HOXA9 and HIC1 through multiplex MethyLight assay in serum DNA for the early detection of epithelial ovarian cancer.

Accumulated evidence revealed that aberrant CpG island hypermethylation plays an important role in carcinogenesis which can serve as a promising target for molecular detection in body fluids. Despite a myriad of attempts to diagnose ovarian cancer (OC) at an early stage, this clinical aim remains a major challenge. To date, no single biomarker is able to accurately detect early OC in either tissue or body fluid. Aberrant DNA methylation patterns in circulating DNA provide highly specific cancer signals. In our study, we establish a novel panel of methylation-specific genes for the development of a TaqMan based qPCR assay to quantify methylation levels. We analyzed promoter methylation of homeobox A9 (HOXA9) and hypermethylated in cancer 1 (HIC1) quantitatively in 120 tissue samples and in 70 matched serum cell-free DNA (CFDNA) of cancerous and noncancerous samples by MethyLight assay. HOXA9 and HIC1 methylation occurred in 82.3 and 80.0% of OC tissue samples in singleplex assay, thereby confirming that methylation was highly cancer-specific. When either or both gene promoter showed methylation, the sensitivity was 88.2% with a specificity of 88.6% in tissue samples. The combined sensitivity for this novel marker panel in serum CFDNA was 88.9% (area under the curve [AUC] = 0.95). In contrast, no hypermethylation was observed in serum from matched cancer-free control women. Our results confirm the elevated performance of novel epigenetic marker panel (HOXA9 and HIC1) when analyzed in tissue and matched serum samples. Our findings reveal the potential of this biomarker panel as a suitable diagnostic serum biomarker for early screening of OC.

Biophysicochemical motifs in T cell receptor sequences as a potential biomarker for high-grade serous ovarian carcinoma.

We previously showed, in a pilot study with publicly available data, that T cell receptor (TCR) repertoires from tumor infiltrating lymphocytes (TILs) could be distinguished from adjacent healthy tissue repertoires by the presence of TCRs bearing specific, biophysicochemical motifs in their antigen binding regions. We hypothesized that such motifs might allow development of a novel approach to cancer detection. The motifs were cancer specific and achieved high classification accuracy: we found distinct motifs for breast versus colorectal cancer-associated repertoires, and the colorectal cancer motif achieved 93% accuracy, while the breast cancer motif achieved 94% accuracy. In the current study, we sought to determine whether such motifs exist for ovarian cancer, a cancer type for which detection methods are urgently needed. We made two significant advances over the prior work. First, the prior study used patient-matched TILs and healthy repertoires, collecting healthy tissue adjacent to the tumors. The current study collected TILs from patients with high-grade serous ovarian carcinoma (HGSOC) and healthy ovary repertoires from cancer-free women undergoing hysterectomy/salpingo-oophorectomy for benign disease. Thus, the classification task is distinguishing women with cancer from women without cancer. Second, in the prior study, classification accuracy was measured by patient-hold-out cross-validation on the training data. In the current study, classification accuracy was additionally assessed on an independent cohort not used during model development to establish the generalizability of the motif to unseen data. Classification accuracy was 95% by patient-hold-out cross-validation on the training set and 80% when the model was applied to the blinded test set. The results on the blinded test set demonstrate a biophysicochemical TCR motif found overwhelmingly in women with HGSOC but rarely in women with healthy ovaries, strengthening the proposal that cancer detection approaches might benefit from incorporation of TCR motif-based biomarkers. Furthermore, these results call for studies on large cohorts to establish higher classification accuracies, as well as for studies in other cancer types.