Rapidly Shifting Concepts Regarding Androgens and Prostate Cancer

There has been a recent dramatic shift in our understanding of the relationship between androgens and prostate cancer (PCa). Whereas for several decades it had been assumed that higher serum testosterone (T) concentrations would lead to ever-greater PCa growth, current literature indicates that PCa growth is unaffected by changes in serum T throughout most of the naturally occurring range. A Saturation Model has been proposed to explain how prostate tissue can be exquisitely sensitive to changes in serum T at the very low end of the concentration range, but appears indifferent to such changes above the near-castrate range. This has special applicability to T-deficient men, since this means that T therapy may not be nearly as risky as once assumed. Indeed, one of the more interesting changes over the last several years has been the growing acceptance of the use of T therapy in men with a prior history of PCa, with early data indicating minimal risk of cancer recurrence or progression. Provocative new evidence suggests that it is not high serum T that is problematic for PCa, butlowserum T that is associated with worrisome cancer features and outcomes, such as high Gleason score, advanced stage of presentation, and increased risk of biochemical recurrence after surgery. It will be interesting to see what changes will occur in this rapidly changing field over the next several years.

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Prostate brachytherapy: the impact of smoking on recurrence and overall survival of localized prostate cancer

American Journal of BioMedicine ◽

10.18081/ajbm/2333-5106-013-12/58-72 ◽

2013 ◽

Vol 2 (1) ◽

pp. 58-72

Author(s):

Edwin Cohen ◽

Justin Robinson ◽

Paul Margolis ◽

Marcia Gaut ◽

Amie Alperson ◽

...

Keyword(s):

Prostate Cancer ◽

Locally Advanced ◽

Cancer Recurrence ◽

Localized Prostate Cancer ◽

Smoking History ◽

Prostate Brachytherapy ◽

Cost Effective Treatment ◽

Increased Risk ◽

Risk Of Cancer ◽

The Impact

Brachytherapy has been shown to be an efficacious and cost-effective treatment among patients with localized prostate cancer. In this study, we examined the effects of smoking on prostate cancer recurrence and mortality in patients undergoing brachytherapy for locally advanced prostate cancer. The study population consisted of 405 patients with an average age of 73.4 years. Smoking history included 88 (21.7%) patients with no history of smoking, 108(26.6%) patients with one to twenty pack-years, and 209 (51.7%) patients with twenty-one or more pack-years. The impact of smoking history on OS relative to nonsmokers was hazards ratio 1.39 (CI: 0.81-2.64; P<0.05). In conclusion, the era of brachytherapy dose and treatment intensification strategies to improve upon prostate cancer outcomes, our study showed that smoking increases the risk of cancer recurrence and mortality. Patients who have smoked a higher number of pack-years are at increased risk of recurrence and mortality compared to those who smoked less.

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The role of genetic polymorphisms in endolysosomal ion channels TPC2 and P2RX4 in cancer pathogenesis, prognosis, and diagnosis: a genetic association in the UK Biobank

npj Genomic Medicine ◽

10.1038/s41525-021-00221-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Abeer F. Alharbi ◽

John Parrington

Keyword(s):

Prostate Cancer ◽

Ion Channels ◽

Genetic Variants ◽

Cancer Recurrence ◽

Malignant Neoplasms ◽

Uk Biobank ◽

Cancer Subtypes ◽

Increased Risk ◽

The Uk ◽

Risk Of Cancer

AbstractRecent studies have implicated important roles for endolysosomal ion channels in cancer biology. We used UK Biobank data to characterise the relationships between genetic variants in two genes coding for endolysosomal ion channels—i.e. TPCN2 and P2RX4—and cancer in terms of the definition of tumour types, susceptibility, and prognosis. We investigated these relationships at both global and local levels with regard to specific types of cancer, including malignant neoplasms of the brain, breast, bronchus, lung, colon, lymphoid and haematopoietic systems, skin, ovary, prostate, rectum, thyroid gland, lip, oral cavity, pharynx, and urinary tract. Apart from rs3829241 (p value < 0.05), all the genetic variants were in Hardy–Weinberg equilibrium. We included 468,436 subjects in the analysis and stratified them into two major cohorts: cancer-free controls (385,253) and cancer cases (83,183). For the first time, we report novel associations between genetic variants of TPCN2 and P2RX4 and cancer/cancer subtypes in the UK Biobank’s population. Genotype GG in TPCN2 rs3750965 was significantly associated with a decreased risk of cancer and an increased risk of lip, oral cavity, and pharynx cancer and cancer recurrence in patients with prostate cancer, and genotypes GA/GG were associated with a significantly lower risk of developing various malignant neoplasms (involving melanoma, prostate, mesothelial, and soft tissues). rs35264875:TA was associated with a high risk of cancer at the global level, with subtypes of cancer at the local level (including breast, colon, prostate, and stated or presumed primary cancer of lymphoid, haematopoietic, and related tissue), and with a significantly low risk of cancer metastasis. rs72932540:GA was associated with a higher incidence of cancer/cancer subtypes (including breast, melanoma, and rectal cancer), and genotypes GA/GG were associated with an increased risk of prostate cancer. The P2RX4 rs25644 allele GG was associated with a high risk of prostate cancer, whereas it was associated with a low risk of cancer recurrence in patients with prostate cancer. Genotypes GA/GG in rs28360472 were associated with an increased risk of breast, mesothelial, and soft tissue cancers but with a decreased risk of colon cancer. We also provide insights into the pathophysiological contributions made by these significant polymorphisms to cancer/cancer subtypes and their effects on expression or channel activity. Further investigations of these genetic variants could help identify novel cancer biomarkers and facilitate the development of new diagnostic and therapeutic strategies. This would constitute a further step towards personalised cancer care.

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History of Diabetes, Clinical Features of Prostate Cancer, and Prostate Cancer Recurrence-Data from CaPSURETM (United States)

Cancer Causes & Control ◽

10.1007/s10552-005-3301-z ◽

2005 ◽

Vol 16 (7) ◽

pp. 789-797 ◽

Cited By ~ 39

Author(s):

J.M. Chan ◽

D.M. Latini ◽

J. Cowan ◽

J. DuChane ◽

P.R. Carroll

Keyword(s):

Prostate Cancer ◽

United States ◽

Clinical Features ◽

Cancer Recurrence ◽

Prostate Cancer Recurrence ◽

History Of

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CHEK2∗1100delC Mutation and Risk of Prostate Cancer

Prostate Cancer ◽

10.1155/2014/294575 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 24

Author(s):

Victoria Hale ◽

Maren Weischer ◽

Jong Y. Park

Keyword(s):

Prostate Cancer ◽

Current Knowledge ◽

Prostate Cancer Screening ◽

Critical Role ◽

Prostate Cancer Risk ◽

Conclusive Evidence ◽

Increased Risk ◽

History Of ◽

Cancer Studies

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

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Abstract 14: The Influence of Provider Specialty on Anticoagulation Prescription Fills and Stroke Risk in Atrial Fibrillation Patients With History of Cancer

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.11.suppl_1.14 ◽

2018 ◽

Vol 11 (suppl_1) ◽

Author(s):

Wesley T O’Neal ◽

J’Neka Claxton ◽

Richard MacLehose ◽

Lin Chen ◽

Lindsay G Bengtson ◽

...

Keyword(s):

Atrial Fibrillation ◽

Oral Anticoagulant ◽

Cox Regression ◽

Prior History ◽

Cancer Type ◽

Patients With Cancer ◽

Increased Risk ◽

History Of ◽

Reduced Risk ◽

History Of Cancer

Background: Early cardiology involvement within 90 days of atrial fibrillation (AF) diagnosis is associated with greater likelihood of oral anticoagulant use and a reduced risk of stroke. Due to variation in cardiovascular care for patients with cancer, it is possible that a similar association does not exist for AF patients with cancer. Methods: We examined the association of early cardiology involvement with oral anticoagulation use among non-valvular AF patients with history of cancer (past or active), using data from 388,045 patients (mean age=68±15 years; 59% male) from the MarketScan database (2009-2014). ICD-9 codes in any position were used to identify cancer diagnosis prior to AF diagnosis. Provider specialty and filled anticoagulant prescriptions 3 months prior to and 6 months after AF diagnosis were obtained. Poisson regression models were used to compute the probability of an oral anticoagulant prescription fill and Cox regression was used to estimate the risk of stroke and major bleeding. Results: A total of 64,016 (17%) AF patients had a prior history of cancer. Cardiology involvement was less likely to occur among patients with history of cancer than those without (relative risk=0.92, 95% confidence interval (0.91, 0.93)). Similar differences were observed for cancers of the colon (0.90 (0.88, 0.92)), lung (0.76 (0.74, 0.78)), pancreas (0.74 (0.69, 0.80)), and hematologic system (0.88 (0.87, 0.90)), while no differences were observed for breast or prostate cancers. Patients with cancer were less likely to fill prescriptions for anticoagulants (0.89 (0.88, 0.90)) than those without cancer, and similar results were observed for cancers of the colon, lung, prostate, pancreas, and hematologic system. However, patients with cancer were more likely to fill prescriptions for anticoagulants (1.48 (1.45, 1.52)) if seen by a cardiology provider, regardless of cancer type. A reduced risk of stroke (hazard ratio=0.89 (0.81, 0.99)) was observed among all cancer patients who were seen by a cardiology provider than among those who were not, without an increased risk of bleeding (1.04 (0.95, 1.13)). Conclusion: AF patients with cancer were less likely to see a cardiologist, and less likely to fill an anticoagulant prescription than AF patients without cancer. However, cardiology involvement was associated with increased anticoagulant prescription fills and reduced risk of stroke, suggesting a beneficial role for cardiology providers to improve outcomes in AF patients with history of cancer.

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Abstract 27: Statin use and risk of hemorrhagic stroke in a community-based cohort of aging women: The Women’s Health Initiative

Circulation ◽

10.1161/circ.129.suppl_1.27 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Elena Salmoirago-Blotcher ◽

Kathleen M Hovey ◽

Judith K Ockene ◽

Chris A Andrews ◽

Jennifer Robinson ◽

...

Keyword(s):

Risk Factors ◽

Women's Health ◽

Hemorrhagic Stroke ◽

Extension Study ◽

Prior History ◽

Health Initiative ◽

Increased Risk ◽

History Of ◽

Statin Use ◽

The Women’S Health Initiative

Background: Statin therapy is recommended for treatment of hypercholesterolemia and prevention of cardiovascular events. Concerns have been raised about a potentially higher risk of hemorrhagic stroke in statin users; however, there is limited information in women and in older populations. We evaluated whether statin treatment was associated with increased risk of hemorrhagic stroke among women enrolled in the Women’s Health Initiative (WHI). Methods: This secondary data analysis was conducted among 68,132 women enrolled in the WHI Clinical Trials (CTs). Participants were 50 to 79 yrs old; postmenopausal; and were followed through 2005 (parent study) and for an additional 5 yrs (through September 30, 2010) in the WHI extension study. Statin use was assessed at baseline and at follow-up (FU) visits at 1, 3, 6, and 9 years. Women brought all medications in original containers for inventory. Strokes were self-reported annually and adjudicated by medical record review. Risk of hemorrhagic stroke by statin use (modeled as a time-varying covariate, with the “no use” category as the referent) was estimated from Cox proportional hazard regression models adjusted for age (model 1); risk factors for hemorrhagic stroke (model 2); and possible confounders by indication (model 3). All models adjusted for enrollment in the different CTs and in the extension study. Participants were censored at the date of last contact or loss to FU. Pre-specified subgroup analyses were conducted according to use or non-use of antiplatelet medications (including aspirin) or anticoagulants, and prior history of stroke. Results: Final models included 67,882 women (mean age at baseline 63 ± 7 yrs). Over a mean FU of 12 yrs, incidence rates of hemorrhagic stroke were 6.4/10,000 person-years among women on statins and 5.0/10,000 person-years among women not taking statins. The unadjusted risk of hemorrhagic stroke in statin users vs. non-users was 1.21 (CI: 0.96, 1.53). The HR was attenuated to 0.98 (CI: 0.76, 1.26) after adjusting for age, hypertension, and other risk factors for hemorrhagic stroke. Planned subgroups analyses showed that women taking both statins and antiplatelet agents had a higher risk of hemorrhagic stroke than women taking antiplatelet medications without statins (HR: 1.59; CI: 1.02, 2.46), whereas women not taking antiplatelet medications had no risk elevation with statins (HR=0.79; CI: 0.58-1.08); P for interaction = .01. No significant interactions were found for anticoagulant use or prior history of stroke, but the statistical power for these analyses was low. Conclusion: Statin use was not associated with an overall increased risk of hemorrhagic stroke among older community-dwelling women. However, women taking statins in conjunction with antiplatelet medications had elevated risk; a finding that warrants further study and potential incorporation into clinical decision making.

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Insulin Resistance and Inflammation in Black Women with and without Breast Cancer: Cause for Concern

Ethnicity & Disease ◽

10.18865/ed.26.4.513 ◽

2016 ◽

Vol 26 (4) ◽

pp. 513 ◽

Cited By ~ 2

Author(s):

Kathleen A. Griffith ◽

Seon Yoon Chung ◽

Shijun Zhu ◽

Alice S. Ryan

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Black Women ◽

White Women ◽

Cancer Recurrence ◽

Control Group ◽

Study Objective ◽

Increased Risk ◽

Tnf Α ◽

History Of

Objective: After chemotherapy for breast cancer, Black women gain more weight and have an increased mortality rate compared with White women. Our study objective was to compare biomarkers associated with obesity in Black women with and without a history of breast cancer.Design: Case-controlSetting: Academic/federal institutionParticipants: Black women with a history of breast cancer (cases) and age-matched controls.Methods: We compared insulin resistance, inflammation, and lipids in overweight and obese Black women with a history of breast cancer (n=19), age similar controls (n=25), and older controls (n=32). Groups did not differ on mean body mass index (BMI), which was 35.4 kg/m2, 36.0 kg/m2, and 33.0 kg/m2, respectively.Main Outcome Measures: Insulin resistance (HOMA-IR); inflammation (TNF-α, IL-1b, IL-6, IL-8, CRP); lipids (cholesterol, triglycerides).Results: Cases had 1.6 and 1.38 times higher HOMA-IR values compared with age similar and older controls, respectively (P≤.001 for both). TNF-α and IL-1b were significantly higher in cases compared with both control groups (P<.001 for both). IL-6 was also higher in cases compared with age-similar controls (P=.007), and IL-8 was lower in cases compared with older controls (P<.05). Lipids did not differ between cases and either control group.Conclusions: Black women with breast cancer were significantly more insulin resistant with increased inflammation compared not only with age similar controls but with women who were, on average, a decade older. These biomarkers of insulin resistance and inflammation may be associated with increased risk of breast cancer recurrence and require ongoing evaluation, especially given the relatively abnormal findings compared with the controls in this underserved group. Ethn Dis. 2016;26(4):513-520; doi:10.18865/ed.26.4.513

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Abstract 18516: Regional Dysfunction of Left Atrial Appendage and its Association with Stroke in Atrial Fibrillation

Circulation ◽

10.1161/circ.130.suppl_2.18516 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Abdullah A Alissa ◽

Yuko Inoue ◽

Jochen Cammin ◽

Qiulin Tang ◽

Elliot Fishman ◽

...

Keyword(s):

Atrial Fibrillation ◽

Left Atrial ◽

Left Atrial Appendage ◽

Atrial Appendage ◽

Control Group ◽

Prior History ◽

Area Change ◽

Increased Risk ◽

History Of ◽

Regional Dysfunction

Background: Atrial Fibrillation (AF) is associated with an increased risk of cardioembolic stroke. Previous studies demonstrate that the Left atrial appendage (LAA) is the most common site of intracardiac thrombus, and the LAA morphology alone may determine the risk of stroke. We aimed to determine the association between LAA regional dysfunction using novel, noninvasive, image-based motion-estimation CT (iME) and prior history of stroke in patients with AF. Methods: Among the patients with history of AF referred for ablation who underwent pre-ablation CT with retrospective ECG gating, we identified 18 patients with a prior history of stroke or TIA, and 18 age- and gender-matched controls. The patients in AF at the time of CT were excluded. Four-dimensional motion vector field was estimated from reconstructed CT images using iME at every 5% RR interval. To assess myocardial deformation, area change ratio and area change rate were calculated over the endocardial surface of the LA and LAA. Univariate and multivariate comparisons were made by using binary logistic regression model. Results: A total of 36 patients (mean age 67.6 ± 8.1 years, 66.7% male, 16.7% persistent AF) were included in the study. Univariate analysis showed that the LA pre-atrial contraction area change ratio and LAA maximum area change ratio were significantly lower (P= 0.02 and 0.04, respectively) in the stroke/TIA group compared to the control group. These changes remained statistically significant in multivariate analysis (P=0.03 and 0.04, respectively) after adjusting for age, sex, body mass index, LV ejection fraction, type of AF, and CHADS score. Conclusions: LAA regional dysfunction is associated with stroke/TIA in patients with AF. LAA regional dysfunction detected by iME could represent a marker for stroke and a possible therapeutic target.

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Abstract 16083: Risk of Preserved versus Reduced Ejection Fraction in Women With and Without History of Breast Cancer: The Pathways Heart Study

Circulation ◽

10.1161/circ.142.suppl_3.16083 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jamal S Rana ◽

Heather Greenlee ◽

Richard Cheng ◽

Cecile A Laurent ◽

Hanjie Shen ◽

...

Keyword(s):

Breast Cancer ◽

Radiation Therapy ◽

Ejection Fraction ◽

Endocrine Therapy ◽

White Women ◽

Cox Regression ◽

Prior History ◽

Reduced Ejection Fraction ◽

Increased Risk ◽

History Of

Introduction: Incidence of heart failure (HF), specifically with preserved ejection fraction (HFpEF), is rising in the general population, yet is understudied. To provide a population-based estimate of HF in breast cancer (BC) survivors, we compared risk of HF in women with and without BC history in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed from 2005-2013 were identified and matched 1:5 with non-BC controls on birth year, race/ethnicity, and KPNC membership at BC diagnosis. Cox regression models assessed the hazard of HF by EF status: HFpEF (EF ≥ 45%), HF with reduced EF (HFrEF; EF < 45%), and unknown EF. Women with prior history of HF were excluded. Models were adjusted for factors known to affect BC risk or CVD and for prevalent CVD at BC diagnosis. We also examined case subgroups who received cardiotoxic chemotherapy, left-sided radiation therapy, and/or endocrine therapy, versus their controls. Results: A total of 14,804 women diagnosed with invasive BC and with no history of HF were identified and matched to 74,034 women without BC history. Women were on average 61 years at BC diagnosis and 65% white. Women with HFpEF were older and more likely to have hypertension (p<0.05). Among all cases vs. controls, there was increased risk of HFrEF (HR: 1.5, 95% CI: 1.18, 1.98) but not HFpEF or unknown EF (figure). Compared to their controls, women treated with chemotherapy were more than 3-times likely to develop HFrEF (HR: 3.26, 95% CI: 2.2, 4.8) and more than 1.5-times likely to develop HFpEF (HR=1.61, 95% CI: 1.15, 2.24). Women who received left-sided radiation therapy had nearly double the risk of developing HFrEF (HR=1.85, 95% CI: 1.20, 2.84). No associations were found among women who received endocrine therapy. Conclusions: Increased surveillance is warranted for women with BC receiving cardiotoxic chemotherapy for development of both HFrEF and HFpEF.

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