Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC).
, a DDR and ...cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of
frequently lose a copy of tumor suppressor gene
; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.
We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of
and
in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to
studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of
and
in prostate cancer cells and patient-derived mCRPC organoids.
In human prostate cancer cell lines (LNCaP and LAPC4), loss of
leads to the castration-resistant phenotype. Co-loss of
-
in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.
Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor-based therapy.
.
PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, ...predominantly surgically treated cohort.
In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease. All statistical tests were two-sided.
On average, men were followed 11.7 years, during which there were 81 lethal events. Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores. After adjustment for clinical-pathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG-positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors.
PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.
Coffee consumption has been linked to lower risk of various health outcomes. However, the biological pathways mediating the associations remain poorly understood.
The aim of this study was to assess ...the association between coffee consumption and concentrations of plasma biomarkers in key metabolic and inflammatory pathways underlying common chronic diseases.
We investigated the associations of total, caffeinated, and decaffeinated coffee consumption with 14 plasma biomarkers, including C-peptide, insulin-like growth factor 1 (IGF-1), IGF binding protein (IGFBP) 1, IGFBP-3, estrone, total and free estradiol, total and free testosterone, sex hormone–binding globulin (SHBG), total adiponectin, high-molecular-weight (HMW) adiponectin, leptin, C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2). Data were derived from 2 cohorts of 15,551 women (Nurses’ Health Study) and 7397 men (Health Professionals Follow-Up Study), who provided detailed dietary data before blood draw and were free of diabetes, cardiovascular disease, or cancer at the time of blood draw. Multivariable linear regression was used to calculate the percentage difference of biomarker concentrations comparing coffee drinkers with nondrinkers, after adjusting for a variety of demographic, clinical, and lifestyle factors.
Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (−8.7%), IGFBP-3 (−2.2%), estrone (−6.4%), total estradiol (−5.7%), free estradiol (−8.1%), leptin (−6.4%), CRP (−16.6%), IL-6 (−8.1%), and sTNFR-2 (−5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee.
Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways. This trial was registered at clinicaltrials.gov as NCT03419455.
Multivitamin supplement is commonly used among older adults in the United States. Evidence on multivitamin use and prostate cancer risk is limited, and some suggested potential risk for clinically ...important subtypes of cancer.
A total of 48,137 men from the Health Professionals Follow-up Study were followed from 1986 to 2017. Multivitamin use and frequency were self-reported at baseline and updated biennially. Clinical features of prostate cancer included advanced, lethal, and high-grade outcomes. Cox proportional hazards models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of multivitamin use and incidence of prostate cancer.
The median follow-up for men without prostate cancer diagnosis or death was 30.7 years. We documented 7,108 incident prostate cancer cases including 564 advanced and 1,065 lethal. Overall, we observed a null association between multivitamin use and risk of prostate cancer. Compared to never-users, men who used multivitamin 10 or more tablets per week had similar risk of advanced (HR:1.14, 95% CI: 0.77-1.70, P
=0.46) or lethal (HR:1.07, 95% CI: 0.80-1.44, P
=0.59) prostate cancer, and multivitamin use of 15 years or more was not associated with risk of advanced (HR:1.10, 95% CI: 0.80-1.50, P
=0.46) or lethal (HR:1.04, 95% CI: 0.83-1.31, P
=0.13) prostate cancer.
Regular or long-duration multivitamin use among older generally well-nourished men was not associated with either increased or lower risk of overall or aggressive prostate cancer.
Abstract Background Robot-assisted laparoscopic radical prostatectomy (RALP) has become increasingly common; however, there have been no nationwide, population-based, non–claims-based studies to ...evaluate differences in outcomes between RALP and open radical retropubic prostatectomy (RRP). Objective To determine surgical, oncologic, and health-related quality of life (HRQOL) outcomes following RALP and RRP in a nationwide cohort. Design, setting, and participants We identified 903 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 2000 and 2010 who underwent radical prostatectomy using RALP ( n = 282) or RRP ( n = 621) as primary treatment. Intervention Radical prostatectomy. Outcome measurements and statistical analysis We compared patients undergoing RALP or RRP across a range of perioperative, oncologic, and HRQOL outcomes. Results and limitations Use of RALP increased during the study period, constituting 85.2% of study subjects in 2009, up from 4.5% in 2003. Patients undergoing RALP compared to RRP were less likely to have a lymph node dissection (51.5% vs 85.4%; p < 0.0001), had less blood loss (207.4 ml vs 852.3 ml; p < 0.0001), were less likely to receive blood transfusions (4.3% vs 30.3%; p < 0.0001), and had shorter hospital stays (1.8 d vs 2.9 d; p < 0.0001). Surgical, oncologic, and HRQOL outcomes did not differ significantly among the groups. In multivariate logistic regression models, there were no significant differences in 3- or 5-yr recurrence-free survival comparing RALP versus RRP (hazard ratios: 0.98 95% confidence interval (CI), 0.46–2.08 and 0.75 95% CI, 0.18–3.11, respectively). Conclusions In a nationwide cohort of patients undergoing surgical treatment for prostate cancer, RALP was associated with shorter hospital stay, and lower blood loss and transfusion rates than RRP. Surgical oncologic and HRQOL outcomes were similar between groups. Patient summary We studied men throughout the United States with prostate cancer who underwent surgical removal of the prostate. We found that robot-assisted laparoscopic radical prostatectomy resulted in shorter hospital stay, less blood loss, and fewer blood transfusions than radical retropubic prostatectomy. There were no differences in cancer control or health-related quality of life.
Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age.
To address this question, we undertook the world's largest ...prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability.
The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability heritability = 58% (95% confidence interval, 52%-63%) of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary.
Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age.
Findings affect the search for genetic and epigenetic markers and frame prevention efforts.
Multivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests ...potential harm.
We prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986-2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality.
We observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR 95% CI, 0.98 0.74-1.30) or all-cause mortality (1.00 0.88-1.12), after adjustment for potential confounders. Similarly, null associations were observed across various categories of use frequency. Compared to non-users, men who used multivitamins regularly (6-9 tablets/week) after cancer diagnosis had similar risk of lethal prostate cancer (0.96 0.72-1.28) and all-cause mortality (0.99 0.88-1.12).
We found no evidence that post-diagnostic multivitamin use among men with nonmetastatic prostate cancer was associated with better or worse survival in a well-nourished population.
Little is known about the development of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). We evaluated long-term outcomes of a large cohort of patients with BD-IPMNs to determine risk ...of malignancy and define a subset of low-risk BD-IPMNs.
We performed a retrospective analysis of data from 577 patients with suspected or presumed BD-IPMN under surveillance at the Massachusetts General Hospital. Patients underwent cross-sectional imaging analysis at 3 months or later after their initial diagnosis. The diagnosis of BD-IPMN was based on the presence of unilocular or multilocular cysts of the pancreas and a non-dilated main pancreatic duct (<5 mm). We collected demographic, clinical, and pathology data. Cysts were characterized at the time of diagnosis and during the follow-up period. Follow-up duration was time between initial cyst diagnosis and date of last visit or death for patients without development of pancreatic cancer, date of surgery for patients with histologically confirmed malignancy, or date of first discovery of malignancy by imaging analysis for patients with unresectable tumors or who underwent neoadjuvant treatment before surgery. The primary outcome was risk of malignancy, with a focus on patients followed for 5 years or more, compared with that of the US population, based on standardized incidence ratio.
Of the 577 patients studied, 479 (83%) were asymptomatic at diagnosis and 363 (63%) underwent endoscopic ultrasound at least once. The median follow-up time was 82 months (range, 6−329 months) for the entire study cohort; 363 patients (63%) underwent surveillance for more than 5 years, and 121 (21%) for more than 10 years. Malignancies (high-grade dysplasia or invasive neoplasm) developed after 5 years in 20 of 363 patients (5.5%), and invasive cancer developed in 16 of 363 patients (4.4%). The standardized incidence ratio for patients with BD-IPMNs without worrisome features of malignancy at 5 years was 18.8 (95% confidence interval, 9.7−32.8; P < .001). One hundred and eight patients had cysts ≤1.5 cm for more than 5 years of follow-up; only 1 of these patients (0.9%) developed a distinct ductal adenocarcinoma. By contrast, among the 255 patients with cysts >1.5 cm, 19 (7.5%) developed malignancy (P = .01).
In a retrospective analysis of patients with BD-IPMNs under surveillance, their overall risk of malignancy, almost 8%, lasted for 10 years or more, supporting continued surveillance after 5 years. Cysts that remain ≤1.5 cm for more than 5 years might be considered low-risk for progression to malignancy.
Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after ...diagnosis on prostate cancer survival in a human population is unknown.
We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage.
During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR 95% CI, 0.82 0.60-1.13) and significantly with all-cause mortality (0.84 0.74-0.96). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 0.32-0.96; all-cause mortality: 0.77 0.64-0.93), while higher dosage did not show a lower risk.
Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.
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