Cancer-free Women Research Articles

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Breast Cancer: Evidence from a General Female Population and a Mammographic Screening Cohort in Sweden.

A link has been proposed between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of breast cancer. There is, however, insufficient data regarding the subtype and stage of breast cancer, and few studies have assessed the interaction between the use of NSAIDs and breast density or previous breast disorders. There is also a lack of data from population-based studies. We first conducted a nested case-control study within the general female population of Sweden, including 56,480 women with newly diagnosed breast cancer during 2006-2015 and five breast cancer-free women per case as controls, to assess the association of NSAID use with the risk of incident breast cancer, focusing on subtype and stage of breast cancer as well as the interaction between NSAID use and previous breast disorders. We then used the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma) cohort to assess the interaction between NSAID use and breast density in relation to the risk of breast cancer. Conditional logistic regression was used to estimate the hazard ratio (HR) and a 95% confidence interval (CI) was used for breast cancer in relation to the use of aspirin and non-aspirin NSAIDs. In the nested case-control study of the general population, exclusive use of aspirin was not associated with the risk of breast cancer, whereas exclusive use of non-aspirin NSAIDs was associated with a modestly higher risk of stage 0-2 breast cancer (HR: 1.05; 95% CI: 1.02-1.08) but a lower risk of stage 3-4 breast cancer (HR 0.80; 95% CI: 0.73-0.88). There was also a statistically significant interaction between the exclusive use of NSAIDs and previous breast disorders (p for interaction: <0.001). In the analysis of Karma participants, the exclusive use of non-aspirin NSAIDs was associated with a lower risk of breast cancer among women with a breast dense area of >40 cm2 (HR: 0.72; 95% CI: 0.59-0.89). However, the possibility of finding this by chance cannot be ruled out. Overall, we did not find strong evidence to support an association between the use of NSAIDs and the risk of breast cancer.

Development of mental health disorders in endometrial cancer survivors and the impact on overall survival—a population-based cohort study

To better understand the risk of developing a mental health disorder and the association on outcomes in endometrial cancer patients. Endometrial cancer patients ≥18 years old diagnosed between 1997–2012 were identified from the Utah Population Database and matched with up to 5 cancer free women from the general population. Mental health disorders were identified by International Classification of Diseases ICD-9 diagnostic codes. Endometrial cancer survivors with pre-existing mental health issues were excluded. Diagnosis of a mental health disorder in endometrial cancer patients was compared with the endemic rate. The impact of a mental health disorders on overall survival (OS) and cause specific survival (CSS) was evaluated. There were 2941 endometrial cancer patients and 12,192 general population matched subjects that met criteria with a median follow up time of 7.1 years (range 0–19.2) and 7.7 years (0.4–19.2) respectively. Within the first 1.5 years from diagnosis, there was an association of endometrial cancer patients being diagnosed with a mental health disorder (Hazard radio (HR) 3.09, 95% confidence interval (CI) 2.66–3.59). However, no association was found in endometrial cancer patients being diagnosed with a mental health disorder between 1.5–3 years (HR 1.07, 95% CI 0.83–1.38) and ≥3 years (HR 1.09, 95% CI 0.95–1.26). Treatment with tri-modality (surgery, radiation and chemotherapy) and advanced disease was associated with mental health disorders. OS was worse in endometrial cancer survivors who developed an anxiety disorder (p = 0.0265). CSS was worse in endometrial cancer patients diagnosed with all mental health disorders and anxiety disorders (p &lt; 0.0001, p = 0.002). Endometrial cancer patients have an increased diagnosis of mental health disorders within the first 1.5 years of cancer diagnosis compared to the general population. Endometrial cancer survivors with anxiety disorder have worse OS. Anxiety disorders and all mental health disorders have a worse CSS.

Abstract A113: Insight into cervical cancer prevention awareness, experiences, and attitudes among Southern Vietnamese women

Abstract Background At least 80% of new cervical cancer cases and deaths occur in low- and middle-income countries. Vietnam is a middle-income country where cervical cancer is the second most common and the deadliest gynecologic cancer. Cervical cancer incidence in Southern Vietnam has been shown to be 1.5-4 times higher than that in Northern Vietnam. However, less than 10% of Southern Vietnamese women have received the Human papillomavirus (HPV) vaccine and only 50% have ever been screened for cervical cancer. No study has examined the perceptions toward cervical cancer prevention and screening in Southern Vietnamese women. Hence, this study aimed to explore cervical cancer awareness, barriers to screening, and acceptability of HPV self-sampling for cervical cancer screening among rural and urban women in Southern Vietnam. Methods In October-November 2021, three focus groups were conducted in the rural district of Can Gio (n=21 participants) and three were conducted in the urban District Four (n=23 participants) in Ho Chi Minh City, Southern Vietnam. All participants were cervical cancer-free women aged 30-65 years. Awareness of, attitudes toward, and experience with cervical cancer prevention and screening were explored using audio-recorded, semi-structured discussions in Vietnamese. During the focus groups, participants also watched four short videos with Vietnamese subtitles and voiceover about cervical cancer screening methods and discussed their views on each. The recordings were transcribed, translated into English, and coded and analyzed using Dedoose 9.0.46. Results Four main themes emerged. First, women showed low awareness, but high acceptance of cervical cancer screening and HPV vaccination. Second, screening barriers were related to logistics (e.g., cost, time, travel distance), psychology (e.g., fear of pain, embarrassment, fear of the test revealing they had cancer), and healthcare providers (e.g., doctors’ impolite manners, male doctors). Third, women were concerned about self-sampling incorrectly and pain, but believed HPV self-sampling to be a feasible screening tool in some circumstances (e.g., during the COVID-19 pandemic, those living in remote areas). Fourth, women related cervical cancer prevention to COVID-19 prevention; they believed strategies that have been successful for COVID-19 control in Vietnam could be applied to cervical cancer. No differences in themes emerged by rural/urban areas. Conclusions Southern Vietnamese women showed low awareness but high acceptance of cervical cancer screening despite barriers. Strategies for successful COVID-19 control in Vietnam, including campaigns to increase public awareness, advocacy from the government and doctors, and efforts to increase access to screening and vaccination, should be applied to cervical cancer control. Health education programs to address HPV self-sampling concerns and promote it as a cervical cancer screening tool are warranted given its potential to improve screening uptake in this low-resource setting. Citation Format: Minh Tung Phung, Pham Le An, Lilah Khoja, Pham Duong Uyen Binh, Hong H.T.C. Le, Karen McLean, Bhramar Mukherjee, Rafael Meza, Alice W. Lee, Celeste Leigh Pearce. Insight into cervical cancer prevention awareness, experiences, and attitudes among Southern Vietnamese women [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A113.

Sexual dysfunction among gynecologic cancer survivors in a population-based cohort study.

Treatment for gynecologic cancer is associated with sexual dysfunction, which may present during and/or after treatment. The aim of this study was to investigate the risk of sexual dysfunction among gynecologic cancer survivors compared to cancer-free women in a population-based cohort study. We identified a cohort of 4863 endometrial, ovarian, and cervical cancer survivors diagnosed between 1997 and 2012 in the Utah Cancer Registry. Up to five cancer-free women were matched to cancer survivors (N = 22,693). We used ICD-9 codes to identify sexual dysfunction. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for sexual dysfunction with adjustment for potential confounders. Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1-5years after cancer diagnosis. Gynecologic cancer survivors had higher risks of overall sexual dysfunction (HR: 2.51, 95% CI: 2.16, 2.93), dyspareunia (HR: 3.27, 95% CI: 2.63, 4.06), and vaginal dryness (HR: 2.63, 95% CI: 2.21, 3.12) compared to a general population of women, 1-5years after cancer diagnosis. Sexual dysfunction was associated with advance cancer stage (HRRegional vs. Localized: 1.61, 95% CI: 1.19, 2.31), radiation therapy (HR: 1.73, 95% CI: 1.29, 2.31), and chemotherapy (HR: 1.80, 95% CI: 1.30, 2.50). This large cohort study confirms that there is an increased risk of sexual dysfunction among gynecologic cancer survivors when compared to the general population. Further investigation is needed to address the risk factors for sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction among gynecologic cancer survivors.

Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis.

The data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman. We included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses' Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, >0-<1, 1-10, >10-50, and >50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma). Spearman correlation between pathologist and Definiens ranged between 0.40-0.64 for stroma and 0.66-0.68 for epithelium in normal TDLUs cores and between 0.24-0.60 for stroma and 0.61-0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92-0.95 and 0.24-0.60, respectively, with 1% cut-off and between 0.43-0.88 and 0.73-0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74-0.80). ICC for CD24 and ALDH1A ranged between 0.42-0.63 and 0.44-0.55, respectively. Our findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.

Changes in cigarette smoking behavior among breast cancer and unaffected women – A prospective study in the MARIE cohort

BackgroundSmoking cessation after a cancer diagnosis can reduce adverse cancer treatment outcomes. Whether a breast cancer diagnosis, a cancer commonly seen as unrelated to smoking cigarettes, motivates changes in smoking behavior is not fully understood. We aimed to compare long-term changes at three follow-up times of cigarette smoking behavior in women with breast cancer and baseline age- and region-matched unaffected women. MethodsWe used longitudinal data from the population-based case-control study MARIE (Mamma Carcinoma Risk Factor Investigation). Women with breast cancer (N = 3813) and unaffected women (N = 7341) aged 50–74 years were recruited from 2002 to 2005. Analyses on changes in smoking were based on data from those who also completed follow-up 1 in 2009–2012, follow-up 2 in 2014–2016 and follow-up 3 in 2020. Multinomial logistic regression for changes (quitting, stable, or start smoking) adjusted for age, study region, education, comorbidities, living situation, and follow-up time, was applied to examine the associations between breast cancer status and changes in smoking behavior. ResultsWomen with breast cancer had significantly higher odds than unaffected women of quitting smoking (OR = 1.38, 95 % CI: 1.01–1.89) and lower odds of returning to smoking (OR = 0.29, 95 % CI: 0.09–0.94) at follow-up 1, but were more likely to start or return to smoking at follow-up 2 (OR = 2.11, 95 % CI 1.08–4.15). No significant group differences were found for changes in smoking behavior at follow-up 3. ConclusionOur findings indicate that short-term changes in smoking behavior can be attributed to a breast cancer diagnosis, but that over time the effect diminishes and changes in smoking no longer differ between breast cancer and breast cancer-free women. To support smoking cessation and to prevent relapse, guidelines to address smoking in cancer care, as well as comprehensive tobacco treatment services, are needed.

Reproductive Factors in Relation to Incidence of Lung and Colorectal Cancers in a Cohort of Norwegian Women: The HUNT Study.

The roles of reproductive factors in the etiology of lung and colorectal cancers, among the most common cancers in women, are unclear. We aimed to explore whether female reproductive factors were associated with the incidence of lung and colorectal cancers. We followed up 33 314 cancer-free women who participated in the HUNT Study in Norway from 1995-1997 to 2018. A large panel of reproductive factors were self-reported at baseline. Incident lung and colorectal cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% CIs after adjustment for important confounders. During a median follow-up interval of 22.2 years, 467 women developed lung cancer (including 169 lung adenocarcinoma), 660 developed colon cancer, and 211 had rectal cancer. Early menarche (≤12 years) was associated with an increased incidence of lung adenocarcinoma (HR 1.43; 95% CI, 1.02-2.03). Women with one or no child had an increased colon cancer incidence (HR 1.26; 95% CI, 1.03-1.54). Hormone therapy appeared to be associated with a decreased incidence of rectal cancer (HR 0.68; 95% CI, 0.44-1.04). Results in the subgroup of postmenopausal women were similar or strengthened. Other reproductive factors were not related to the risk of lung, colon, and rectal cancers. Certain reproductive factors might play a role in the etiology of lung and colorectal cancers. Further investigations are warranted to study if they are causal associations.

Reproductive Outcomes in Young Breast Cancer Survivors Treated (15-39) in Ontario, Canada.

We conducted a population-based, retrospective, matched-cohort study to examine the impact of breast cancer diagnosis and treatment on fertility outcomes. Relative risks of infertility, childbirth, premature ovarian insufficiency (POI; age < 40) and early menopause (age < 45) were calculated using modified Poisson regression. Our primary cohort included young women (15-39) with early stage BC diagnosed 1995-2014. Five cancer-free patients were matched to each BC patient by birth year and census subdivision. The BC cohort was further divided by treatment with chemotherapy vs. no chemotherapy treatment. 3903 BC patients and 19,515 cancer-free women. BC patients treated with chemotherapy were at increased risk of infertility (RR 1.81; 95% CI 1.60-2.04), and POI (RR 6.25; 95% CI 5.15-7.58) and decreased childbirth (RR 0.85; 95% CI 0.75-0.96), compared to women without cancer. BC patients who did not receive chemotherapy were also at increased risk of infertility (RR 1.80 95% CI 1.48-2.18) and POI (RR 2.12 95% CI 1.37-3.28). All young BC survivors face an increased risk of diagnosed infertility and POI relative to women without cancer, independent of chemotherapy. These results emphasize the importance of pre-treatment fertility counselling for young women diagnosed with BC.

Matrix Metalloproteinase Gene Polymorphisms Are Associated with Breast Cancer in the Caucasian Women of Russia.

We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) and 746 unaffected (cancer-free) women were included in this case-control retrospective study. From BC-related genes in previous studies, ten single nucleotide polymorphisms (SNPs) in five MMP genes (MMP1, 2, 3, 8, 9) were genotyped. The BC risk was calculated by logistic regression (to evaluate the SNPs’ independent effects) and model-based multifactor dimensionality reduction (MB-MDR) (to identify SNP–SNP interactions) methods. The allelic variants’ distribution of c.836 A > G (rs17576) and c. 1721 C > G (rs2250889) MMP9 was significantly different between BC and cancer-free women: for G minor alleles, these SNPs manifested disorder protective effects (OR 0.82 and OR 0.67–0.71, respectively, pperm ≤ 0.035). Eleven haplotypes of six SNPs MMP9 were involved in BC risk (nine haplotypes) and protective (two haplotypes) effects. All 10 SNPs of the MMP genes examined were associated with BC within the 13 SNP–SNP interaction simulated models, with a pivotal role of the two-locus (rs17577 × rs3918242) MMP9 epistatic interaction (defined as 1.81% BC entropy within more than 60% of the genetic models). Under in silico bioinformatics, BC susceptibility MMP polymorphic loci are located in functionally active genome regions and impact genes expression and splicing “regulators” in the mammary gland. The biological pathways of BC MMP candidate genes are mainly realized due to metalloendopeptidase activity and extracellular matrix organization (structure, disassembly, metabolic process, etc.). In conclusion, our data show that MMP gene polymorphisms are related to BC susceptibility in the Caucasian women of Russia.

HPV16 E7 Nucleotide Variants Found in Cancer-Free Subjects Affect E7 Protein Expression and Transformation.

Simple SummaryHuman papillomaviruses (HPV) are one of the deadliest viruses causing cancer resulting in over 300,000 deaths annually in the world. HPV16 is the most oncogenic form of HPV and is responsible for over half of all HPV-driven tumors. The viral E7 gene encodes a powerful oncoprotein that can cause infected cells to have uncontrolled growth. A previous study showed that HPV16 isolates with amino acid alterations in the E7 gene were nearly always found in women with HPV infection but no cancer. To study the role of these variants, we expressed them in cultured cells. Most variants produced lower levels of protein, and selected variants had reduced activity in allowing cells to grow in assays that measure tumor cell invasiveness. The data indicate that inhibition of E7 could be a practical approach to treating HPV-driven cancers.The human papillomavirus (HPV) type 16 E7 oncogene is critical to carcinogenesis and highly conserved. Previous studies identified a preponderance of non-synonymous E7 variants amongst HPV16-positive cancer-free controls compared to those with cervical cancer. To investigate the function of E7 variants, we constructed full-length HPV16 E7 genes and tested variants at positions H9R, D21N, N29S, E33K, T56I, D62N, S63F, S63P, T64M, E80K, D81N, P92L, and P92S (found only in controls); D14E, N29H cervical intraepithelial neoplasia (CIN2), and P6L, H51N, R77S (CIN3). We determined the steady-state level of cytoplasmic and nuclear HPV16 E7 protein. All variants from controls showed a reduced level of E7 protein, with 7/13 variants having lower protein levels. In contrast, 2/3 variants from the CIN3 precancer group had near-wild type E7 levels. We assayed the activity of representative variants in stably transfected NIH3T3 cells. The H9R, E33K, P92L, and P92S variants found in control subjects had lower transforming activity than D14E and N29H variants (CIN2), and the R77S (CIN3) had activity only slightly reduced from wild-type E7. In addition, R77S and WT E7 caused increased migration of NIH3T3 cells in a wound-healing assay compared with H9R, E33K, P92L, and P92S (controls) and D14E (CIN2). These data provide evidence that the E7 variants found in HPV16-positive cancer-free women are partially defective for transformation and cell migration, further demonstrating the importance of fully active E7 in cancer development.

The Association Between Metabolic Syndrome and Colorectal Cancer Risk by Obesity Status in Korean Women: A Nationwide Cohort Study.

ObjectivesThis study aimed to determine the association between metabolic syndrome (MetS) and the incidence of colorectal cancer (CRC) in Korean women with obesity.MethodsCancer-free women (n=6 142 486) aged 40–79 years, who underwent National Health Insurance Service health examinations in 2009 and 2010 were included. The incidence of CRC was followed until 2018. The hazard ratio (HR) of MetS for the incidence of colon and rectal cancer was analyzed according to body mass index (BMI) categories, adjusting for confounders such as women’s reproductive factors. In addition, the heterogeneity of associations across BMI categories was assessed.ResultsWomen with MetS were at increased risk of colon and rectal cancer compared to women without MetS (HR, 1.20; 95% confidence interval [CI], 1.16 to 1.23 and HR,1.15; 95% CI, 1.11 to 1.20), respectively. The HR of MetS for colon cancer across BMI categories was 1.12 (95% CI, 1.06 to 1.19), 1.14 (95% CI, 1.08 to 1.20), and 1.16 (95% CI, 1.12 to 1.21) in women with BMIs <23.0 kg/m2, 23.0–24.9 kg/m2, and ≥25.0 kg/m2, respectively. The HR of MetS for rectal cancer across corresponding BMI categories was 1.16 (95% CI, 1.06 to 1.26), 1.14 (95% CI, 1.05 to 1.23), and 1.13 (95% CI, 1.06 to 1.20). The heterogeneity of associations across BMI categories was not significant in either colon or rectal cancer (p=0.587 for colon cancer and p=0.927 for rectal cancer).ConclusionsWomen with MetS were at increased risk of colon and rectal cancer. Clinical and public health strategies should be considered for primary CRC prevention with an emphasis on improving women’s metabolic health across all BMI groups.

Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study

PurposeEpidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism impacts survival outcomes in breast cancer patients. We aimed to determine the association between hypothyroidism and breast cancer-specific and all-cause mortality.MethodsWe conducted a population-based study using the Scottish Cancer Registry to identify women diagnosed with breast cancer between 2010 and 2017. A matched comparison cohort of breast cancer-free women was also identified. Using hospital diagnoses and dispensed prescriptions for levothyroxine, we identified hypothyroidism diagnosed before and after breast cancer diagnosis and determined associations with breast cancer-specific and all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for potential confounders.ResultsA total of 33,500 breast cancer patients were identified, of which 3,802 had hypothyroidism before breast cancer diagnosis and 565 patients went on to develop hypothyroidism after. Breast cancer patients had higher rates of hypothyroidism compared with cancer-free controls (HR 1.14, 95% CI 1.01–1.30). Among breast cancer patients, we found no association between hypothyroidism (diagnosed before or after) and cancer-specific mortality (before: HR 0.99, 95% CI 0.88–1.12, after: HR 0.97, 95% CI 0.63–1.49). Similar associations were seen for all-cause mortality.ConclusionIn a large contemporary breast cancer cohort, there was little evidence that hypothyroidism, either at diagnosis or diagnosed after breast cancer, was associated with cancer-specific or all-cause mortality.

Body Mass Index Is Inversely Associated with Risk of Postmenopausal Interval Breast Cancer: Results from the Women's Health Initiative.

Simple SummaryBreast cancer diagnosed between a negative screening mammogram and the next regularly scheduled mammographic exam is called interval breast cancer. It is often diagnosed at more advanced stages than screening-detected cancers. While body mass index (BMI) is a risk factor for postmenopausal breast cancer overall and can influence the accuracy of mammography, the association of BMI with postmenopausal interval breast cancer is unclear. Using data from the Women’s Health Initiative, a national study among postmenopausal women, we found that lower BMI was significantly associated with a higher risk of interval breast cancers diagnosed within 1 year of a negative mammogram after adjustment for multiple risk factors. These findings suggest that obesity is associated with a lower risk of postmenopausal interval breast cancer. Future research using body composition measures is warranted to confirm our findings.Interval breast cancer refers to cancer diagnosed after a negative screening mammogram and before the next scheduled screening mammogram. Interval breast cancer has worse prognosis than screening-detected cancer. Body mass index (BMI) influences the accuracy of mammography and overall postmenopausal breast cancer risk, yet how is obesity associated with postmenopausal interval breast cancer incidence is unclear. The current study included cancer-free postmenopausal women aged 50–79 years at enrollment in the Women’s Health Initiative who were diagnosed with breast cancer during follow-up. Analyses include 324 interval breast cancer cases diagnosed within one year after the participant’s last negative screening mammogram and 1969 screening-detected breast cancer patients. Obesity (BMI ≥ 30 kg/m2) was measured at baseline. Associations between obesity and incidence of interval cancer were determined by sequential logistic regression analyses. In multivariable-adjusted models, obesity was inversely associated with interval breast cancer risk [OR (95% CI) = 0.65 (0.46, 0.92)]. The inverse association persisted after excluding women diagnosed within 2 years [OR (95% CI) = 0.60 (0.42, 0.87)] or 4 years [OR (95% CI) = 0.56 (0.37, 0.86)] of enrollment, suggesting consistency of the association regardless of screening practices prior to trial entry. These findings warrant confirmation in studies with body composition measures.

Use of hypnotics among women diagnosed with cervical cancer – A population-based cohort study

ObjectivePrevious studies suggest that sleeping problems are frequent after cervical cancer. However, the evidence on the use of hypnotics is sparse. We investigated if women diagnosed with cervical cancer have an increased risk of using hypnotics and identified risk factors for prolonged use. MethodsIn this nationwide register-based cohort study, 4264 women diagnosed with cervical cancer from 1997 to 2013 and 36,632 cancer-free women were followed in registers until 2016. Prolonged use of hypnotics was defined as more than three prescriptions with no more than three months in between. Data were analysed using Cox proportional hazards regression models and multistate Markov models separately for women with localized and advanced cervical cancer. ResultsThe rate of first use of hypnotics was substantially increased during the first year after cervical cancer diagnosis compared to cancer-free women (HRlocalized 4.4, 95% CI 3.9–5.1; HRadvanced 8.9, 95% CI 7.5–10.6) and remained markedly increased for up to five years after diagnosis. Dependent on stage of disease and age, 1.4 to 4.7 excess women per 100 with cervical cancer were prolonged users of hypnotics compared to cancer-free women one year after diagnosis. Risk factors for prolonged use of hypnotics were higher age, short education, previous use of antidepressants or anxiolytics, and advanced disease. ConclusionsWomen diagnosed with cervical cancer are at increased risk of prolonged use of hypnotics. For the majority, treatment with hypnotics is initiated within the first year after cancer diagnosis, but the rate of first use is increased for up to five years.

A Multi-State Survival Model for Time to Breast Cancer Mortality among a Cohort of Initially Disease-Free Women.

Identifying risk factors for aggressive forms of breast cancer is important. Tumor factors (e.g., stage) are important predictors of prognosis, but may be intermediates between prediagnosis risk factors and mortality. Typically, separate models are fit for incidence and mortality postdiagnosis. These models have not been previously integrated to identify risk factors for lethal breast cancer in cancer-free women. We combined models for breast cancer incidence and breast cancer-specific mortality among cases into a multi-state survival model for lethal breast cancer. We derived the model from cancer-free postmenopausal Nurses' Health Study women in 1990 using baseline risk factors. A total of 4,391 invasive breast cancer cases were diagnosed from 1990 to 2014 of which 549 died because of breast cancer over the same period. Some established risk factors (e.g., family history, estrogen plus progestin therapy) were not associated with lethal breast cancer. Controlling for age, the strongest risk factors for lethal breast cancer were weight gain since age 18: &gt; 30 kg versus ± 5 kg, RR = 1.94 [95% confidence interval (CI) = 1.38-2.74], nulliparity versus age at first birth (AAFB) &lt; 25, RR = 1.60 (95% CI = 1.16-2.22), and current smoking ≥ 15 cigarettes/day versus never, RR = 1.42 (95% CI = 1.07-1.89). Some breast cancer incidence risk factors are not associated with lethal breast cancer; other risk factors for lethal breast cancer are not associated with disease incidence. This multi-state survival model may be useful for identifying prediagnosis factors that lead to more aggressive and ultimately lethal breast cancer.

Cardiovascular disease risk in long-term breast cancer survivors: A population-based cohort study.

Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD. A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for >10 to 15 and >15years. Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors. Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.

Accelerated Epigenetic Age Among Women with Invasive Cervical Cancer and HIV-Infection in Nigeria.

BackgroundInvasive cervical cancer (ICC) is a serious public health burden in Nigeria, where human immunodeficiency virus (HIV) remains highly prevalent. Previous research suggested that epigenetic age acceleration (EAA) could play a role in detection of HIV-associated ICC. However, little research has been conducted on this topic in Africa where the population is most severely affected by HIV-associated ICC. Here, we investigated the association between ICC and EAA using cervical tissues of ICC-diagnosed Nigerian women living with HIV.MethodsWe included 116 cervical tissue samples from three groups of Nigerian women in this study: (1) HIV+/ICC+ (n = 39); (2) HIV+/ICC- (n = 53); and (3) HIV-/ICC + (n = 24). We utilized four DNA methylation-based EAA estimators; IEAA, EEAA, GrimAA, and PhenoAA. We compared EAA measurements across the 3 HIV/ICC groups using multiple linear regression models. We also compared EAA between 26 tumor tissues and their surrounding normal tissues using paired t-tests. We additionally performed a receiver operating characteristics (ROC) curve analysis to illustrate the area under the curve (AUC) of EAA in ICC.ResultsWe found the most striking associations between HIV/ICC status and PhenoAge acceleration (PhenoAA). Among HIV-positive women, PhenoAA was on average 13.4 years higher in women with ICC compared to cancer-free women (P = 0.005). PhenoAA was 20.7 and 7.1 years higher in tumor tissues compared to surrounding normal tissues among HIV-positive women (P = 0.009) and HIV-negative women (P = 0.284), respectively. We did not find substantial differences in PhenoAA between HIV-positive and HIV-negative women with ICC.ConclusionPhenoAA is associated with ICC in HIV-infected women in our study. Our findings suggest that PhenoAA may serve as a potential biomarker for further risk stratification of HIV-associated ICC in Nigeria and similar resource-constrained settings.

Contribution of large genomic rearrangements in PALB2 to familial breast cancer: implications for genetic testing

BackgroundPALB2 is the most important contributor to familial breast cancer after BRCA1 and BRCA2. Large genomic rearrangements (LGRs) in BRCA1 and BRCA2 are routinely assessed in clinical testing and are...

Genetic variation in progesterone receptor gene and ovarian cancer risk: A case control study.

Previous studies examined the association of genetic variation in progesterone receptor (PR) gene (PGR) with ovarian cancer, possibly by altering the expression of PR-B isoform, but with mixed outcome. This study evaluated the association of PGR variants with ovarian cancer and associated features. This was a retrospective case-control study, which involved 82 women with ovarian cancer and 95 cancer-free women who served as controls. Genotyping was done by Taqman® SNP genotyping by qRT-PCR. The PGR variants tested were rs471767 (A>G), rs590688 (G>C), and rs10895068 (G>A). Stratification analyses were used for testing the correlation between the PGR variants with ovarian cancer susceptibility according to menstruation status, FIGO classification, pathological grade, and chemotherapy. Significantly lower minor allele frequency (MAF) of rs10895068 was seen among ovarian cancer patients, thereby imparting disease protective nature to this variant. Significant association of rs10895068 genotypes with ovarian cancer was seen under the dominant model, but not other genetic models. FIGO classification correlated positively with rs471767 and rs10895068, while rs10895068 correlated positively with lymph node positivity. Three-locus haplotype analysis identified ACA and HCG haplotypes to be negatively associated with the risk of ovarian cancer. This report confirms the contribution of PGR variants, specifically the rs10895068 (+331G/A) the etiology of ovarian cancer.

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

ObjectiveAberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma. MethodsDNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. 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 OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma 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. ResultsThirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (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 the 5 stage I/II HGS OCs included, all were correctly identified. ConclusionsWhole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.