Publications by authors named "Timothy R Rebbeck"

298 Publications

The rising burden of cancer in low- and middle-human development index countries.

Cancer 2021 Jun 4. Epub 2021 Jun 4.

Dana-Farber Cancer Institute, Boston, Massachusetts.

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http://dx.doi.org/10.1002/cncr.33586DOI Listing
June 2021

Racial differences in the treatment and outcomes for prostate cancer in Massachusetts.

Cancer 2021 May 17. Epub 2021 May 17.

Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Massachusetts is a northeastern state with universally mandated health insurance since 2006. Although Black men have generally worse prostate cancer outcomes, emerging data suggest that they may experience equivalent outcomes within a fully insured system. In this setting, the authors analyzed treatments and outcomes of non-Hispanic White and Black men in Massachusetts.

Methods: White and Black men who were 20 years old or older and had been diagnosed with localized intermediate- or high-risk nonmetastatic prostate cancer in 2004-2015 were identified in the Massachusetts Cancer Registry. Adjusted logistic regression models were used to assess predictors of definitive therapy. Adjusted and unadjusted survival models compared cancer-specific mortality. Interaction terms were then used to assess whether the effect of race varied between counties.

Results: A total of 20,856 men were identified. Of these, 19,287 (92.5%) were White. There were significant county-level differences in the odds of receiving definitive therapy and survival. Survival was worse for those with high-risk cancer (adjusted hazard ratio [HR], 1.50; 95% CI, 1.4-1.60) and those with public insurance (adjusted HR for Medicaid, 1.69; 95% CI, 1.38-2.07; adjusted HR for Medicare, 1.2; 95% CI, 1.14-1.35). Black men were less likely to receive definitive therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.83) but had a 17% lower cancer-specific mortality (adjusted HR, 0.83; 95% CI, 0.7-0.99).

Conclusions: Despite lower odds of definitive treatment, Black men experience decreased cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.

Lay Summary: There is a growing body of evidence showing that the excess risk of death among Black men with prostate cancer may be caused by disparities in access to care, with few or no disparities seen in universally insured health systems such as the Veterans Affairs and US Military Health System. Therefore, the authors sought to assess racial disparities in prostate cancer in Massachusetts, which was the earliest US state to mandate universal insurance coverage (in 2006). Despite lower odds of definitive treatment, Black men with prostate cancer experience reduced cancer-specific mortality in comparison with White men in Massachusetts. These data support the growing body of research showing that Black men may achieve outcomes equivalent to or even better than those of White men within the context of a well-insured population.
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http://dx.doi.org/10.1002/cncr.33564DOI Listing
May 2021

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

Prostate 2021 Jul 6;81(10):683-693. Epub 2021 May 6.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).

Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.

Results: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.

Conclusions: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
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http://dx.doi.org/10.1002/pros.24148DOI Listing
July 2021

Computer extracted gland features from H&E predicts prostate cancer recurrence comparably to a genomic companion diagnostic test: a large multi-site study.

NPJ Precis Oncol 2021 May 3;5(1):35. Epub 2021 May 3.

Department of Urology, Case Western Reserve University, Cleveland, OH, USA.

Existing tools for post-radical prostatectomy (RP) prostate cancer biochemical recurrence (BCR) prognosis rely on human pathologist-derived parameters such as tumor grade, with the resulting inter-reviewer variability. Genomic companion diagnostic tests such as Decipher tend to be tissue destructive, expensive, and not routinely available in most centers. We present a tissue non-destructive method for automated BCR prognosis, termed "Histotyping", that employs computational image analysis of morphologic patterns of prostate tissue from a single, routinely acquired hematoxylin and eosin slide. Patients from two institutions (n = 214) were used to train Histotyping for identifying high-risk patients based on six features of glandular morphology extracted from RP specimens. Histotyping was validated for post-RP BCR prognosis on a separate set of n = 675 patients from five institutions and compared against Decipher on n = 167 patients. Histotyping was prognostic of BCR in the validation set (p < 0.001, univariable hazard ratio [HR] = 2.83, 95% confidence interval [CI]: 2.03-3.93, concordance index [c-index] = 0.68, median years-to-BCR: 1.7). Histotyping was also prognostic in clinically stratified subsets, such as patients with Gleason grade group 3 (HR = 4.09) and negative surgical margins (HR = 3.26). Histotyping was prognostic independent of grade group, margin status, pathological stage, and preoperative prostate-specific antigen (PSA) (multivariable p < 0.001, HR = 2.09, 95% CI: 1.40-3.10, n = 648). The combination of Histotyping, grade group, and preoperative PSA outperformed Decipher (c-index = 0.75 vs. 0.70, n = 167). These results suggest that a prognostic classifier for prostate cancer based on digital images could serve as an alternative or complement to molecular-based companion diagnostic tests.
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http://dx.doi.org/10.1038/s41698-021-00174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093226PMC
May 2021

Computationally Derived Cribriform Area Index from Prostate Cancer Hematoxylin and Eosin Images Is Associated with Biochemical Recurrence Following Radical Prostatectomy and Is Most Prognostic in Gleason Grade Group 2.

Eur Urol Focus 2021 Apr 30. Epub 2021 Apr 30.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA. Electronic address:

Background: The presence of invasive cribriform adenocarcinoma (ICC), an expanse of cells containing punched-out lumina uninterrupted by stroma, in radical prostatectomy (RP) specimens has been associated with biochemical recurrence (BCR). However, ICC identification has only moderate inter-reviewer agreement.

Objective: To investigate quantitative machine-based assessment of the extent and prognostic utility of ICC, especially within individual Gleason grade groups.

Design, Setting, And Participants: A machine learning approach was developed for ICC segmentation using 70 RP patients and validated in a cohort of 749 patients from four sites whose median year of surgery was 2007 and with median follow-up of 28 mo. ICC was segmented on one representative hematoxylin and eosin RP slide per patient and the fraction of tumor area composed of ICC, the cribriform area index (CAI), was measured.

Outcome Measurements And Statistical Analysis: The association between CAI and BCR was measured in terms of the concordance index (c index) and hazard ratio (HR).

Results And Limitations: CAI was correlated with BCR (c index 0.62) in the validation set of 411 patients with ICC morphology, especially those with Gleason grade group 2 cancer (n = 192; c index 0.66), and was less prognostic when patients without ICC were included (c index 0.54). A doubling of CAI in the group with ICC morphology was prognostic after controlling for Gleason grade, surgical margin positivity, preoperative prostate-specific antigen level, pathological T stage, and age (HR 1.19, 95% confidence interval 1.03-1.38; p = 0.018).

Conclusions: Automated image analysis and machine learning could provide an objective, quantitative, reproducible, and high-throughput method of quantifying ICC area. The performance of CAI for grade group 2 cancer suggests that for patients with little Gleason 4 pattern, the ICC fraction has a strong prognostic role.

Patient Summary: Machine-based measurement of a specific cell pattern (cribriform; sieve-like, with lots of spaces) in images of prostate specimens could improve risk stratification for patients with prostate cancer. In the future, this could help in expanding the criteria for active surveillance.
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http://dx.doi.org/10.1016/j.euf.2021.04.016DOI Listing
April 2021

Trends in mortality among Black and White men with prostate cancer in Massachusetts and Pennsylvania: Race and neighborhood socioeconomic position.

Cancer 2021 Apr 2. Epub 2021 Apr 2.

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Reducing disparities in men with prostate cancer (PCa) that may be caused by racial and socioeconomic differences is a major public health priority. Few reports have studied whether these disparities have changed over time.

Methods: Men diagnosed with PCa from January 1, 2000 to December 31, 2015 were identified from the Massachusetts and Pennsylvania cancer registries. All-cause mortality and PCa and cardiovascular cause-specific mortality were assessed. To estimate neighborhood socioeconomic position (nSEP), a summary score was generated using census tract-level measures of income, wealth, educational attainment, and racial and income segregation. Participants were grouped by diagnosis year (2000-2003, 2004-2007, 2008-2011, or 2012-2015), and changing trends in the mortality rate ratio by race and nSEP were estimated using covariate-adjusted Cox models with follow-up for up to 10 years, until death, or until censoring on January 1, 2018.

Results: There were 193,883 patients with PCa and 43,661 deaths over 1,404,131 person-years of follow-up. The Black-White adjusted hazard ratio (aHR) from 2000 to 2003 through 2012 to 2015 was stable for all-cause mortality (aHR, 1.14 to 0.97; P for heterogeneity = .42), decreased for PCa-specific mortality (aHR, 1.38 to 0.93; P for heterogeneity = .005), and increased for cardiovascular mortality (aHR, 1.09 to 1.28; P for heterogeneity = .034). The aHR comparing those in the lowest versus the highest nSEP quintile increased significantly for all-cause mortality (aHR, 1.54 to 1.79; P for heterogeneity = .008), but not for PCa-specific mortality (aHR, 1.60 to 1.72; P for heterogeneity = .40) or cardiovascular mortality (aHR, 1.72 to 1.89; P for heterogeneity = .085).

Conclusions: Although Black-White disparities in prostate mortality declined in Massachusetts and Pennsylvania over the study period, nSEP mortality disparity trends were stagnant or increased, warranting further attention.

Lay Summary: Few reports have examined whether racial and socioeconomic disparities in prostate cancer mortality have widened or narrowed in recent years. Using data from 2 state registries (Massachusetts and Pennsylvania) with differing intensities of government-mandated health insurance, trends in racial and neighborhood socioeconomic disparities were studied among Black and White men diagnosed from 2000 to 2015. Overall, trends in racial disparities were stagnant for all-cause mortality, shrank for prostate mortality, and widened for cardiovascular mortality. Disparities associated with neighborhood socioeconomic status either were stagnant or widened across all mortality end points. In general, disparities were more pronounced in Pennsylvania than in Massachusetts.
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http://dx.doi.org/10.1002/cncr.33506DOI Listing
April 2021

Corrigendum to "Precision prophylaxis: Identifying the optimal timing for risk-reducing salpingo-oophorectomy based on type of BRCA1 and BRCA2 cluster region mutations" [Gynecologic Oncology 156 (2020) 363-376].

Gynecol Oncol 2021 May 14;161(2):636. Epub 2021 Mar 14.

Harvard T.H. Chan School of Public Health, Boston, MA, United States of America; Dana Farber Cancer Institute, Boston, MA, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.ygyno.2021.03.005DOI Listing
May 2021

From COVID-19 to cancer, watching social determinants decide life: When will we stop spectating?

J Natl Med Assoc 2021 Mar 13. Epub 2021 Mar 13.

Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, United States.

The COVID-19 pandemic reminds us that African American, Latinx, Indigenous, and poor communities face significant healthcare disparities. Members of these communities have increased exposure to the virus due to higher rates of crowded living conditions and employment in essential occupations. Furthermore, news reports and public health data show that residents of these communities have more comorbidities, utilize hospitals with fewer resources, and experience greater treatment delays, all resulting in higher mortality related to COVID-19. The same social determinants contributing to the inequities seen in COVID-19 drive similar disparities in oncology. Oncologic inequities have long predated the inequities associated with COVID-19 and have led to considerably more deaths. These stark realities demand that we stop merely reporting the impact of adverse social determinants on the health of communities. We must instead target these causes of healthcare disparities. Here, we discuss proposed action items from the 2019 National Cancer Policy Forum workshop entitled "Applying Big Data to Address the Social Determinants of Health in Oncology." These actions are critical first steps to address adverse social determinants and thereby decrease unnecessary deaths in underserved communities.
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http://dx.doi.org/10.1016/j.jnma.2021.02.003DOI Listing
March 2021

Susceptibility-Associated Genetic Variation in Contributes to Prostate Cancer Initiation and Progression.

Cancer Res 2021 Feb 25. Epub 2021 Feb 25.

Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.

Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 () gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis and . Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities. SIGNIFICANCE: A prostate cancer susceptibility genetic variation in , which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3042DOI Listing
February 2021

Improved Prognostic Stratification Using Circulating Tumor Cell Clusters in Patients with Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2021 Jan 13;13(2). Epub 2021 Jan 13.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 baseline samples, and in 119 (52.4%) and 27 (11.9%) of 227 longitudinal samples, respectively. CTC counts were associated with both PFS and OS, but CTC-clusters were only independently associated with an increased risk of death. Among patients with unfavorable CTCs (≥5), the presence of CTC-clusters signified a worse survival (log-rank = 0.0185). mCRPC patients with both unfavorable CTCs and CTC-clusters had the highest risk for death (adjusted hazard ratio 19.84, = 0.0072), as compared to those with <5 CTCs. Analyses using longitudinal data yielded similar results. In conclusion, CTC-clusters provided additional prognostic information for further stratifying death risk among patients with unfavorable CTCs.
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http://dx.doi.org/10.3390/cancers13020268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828213PMC
January 2021

Novel Transcriptomic Interactions Between Immune Content and Genomic Classifier Predict Lethal Outcomes in High-grade Prostate Cancer.

Eur Urol 2020 Dec 7. Epub 2020 Dec 7.

University of California, San Francisco, CA, USA.

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICS/Decipher. Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICS/Decipher subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICS/Decipher subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤  0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤  0.0001) as compared with ICS/Decipher. The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities.
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http://dx.doi.org/10.1016/j.eururo.2020.11.038DOI Listing
December 2020

Discovering novel driver mutations from pan-cancer analysis of mutational and gene expression profiles.

PLoS One 2020 24;15(11):e0242780. Epub 2020 Nov 24.

Department of Digital Technologies, FoICDT, University of Mauritius, Réduit, Mauritius.

As the genomic profile across cancers varies from person to person, patient prognosis and treatment may differ based on the mutational signature of each tumour. Thus, it is critical to understand genomic drivers of cancer and identify potential mutational commonalities across tumors originating at diverse anatomical sites. Large-scale cancer genomics initiatives, such as TCGA, ICGC and GENIE have enabled the analysis of thousands of tumour genomes. Our goal was to identify new cancer-causing mutations that may be common across tumour sites using mutational and gene expression profiles. Genomic and transcriptomic data from breast, ovarian, and prostate cancers were aggregated and analysed using differential gene expression methods to identify the effect of specific mutations on the expression of multiple genes. Mutated genes associated with the most differentially expressed genes were considered to be novel candidates for driver mutations, and were validated through literature mining, pathway analysis and clinical data investigation. Our driver selection method successfully identified 116 probable novel cancer-causing genes, with 4 discovered in patients having no alterations in any known driver genes: MXRA5, OBSCN, RYR1, and TG. The candidate genes previously not officially classified as cancer-causing showed enrichment in cancer pathways and in cancer diseases. They also matched expectations pertaining to properties of cancer genes, for instance, showing larger gene and protein lengths, and having mutation patterns suggesting oncogenic or tumor suppressor properties. Our approach allows for the identification of novel putative driver genes that are common across cancer sites using an unbiased approach without any a priori knowledge on pathways or gene interactions and is therefore an agnostic approach to the identification of putative common driver genes acting at multiple cancer sites.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242780PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685479PMC
January 2021

Body Mass Index, Chemotherapy-Related Weight Changes, and Disease-Free Survival in Haitian Women With Nonmetastatic Breast Cancer.

JCO Glob Oncol 2020 10;6:1656-1665

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Few studies have explored the relationship between body habitus and breast cancer outcomes in Caribbean women of African ancestry. This study evaluates the association between body mass index (BMI) and disease-free survival (DFS) in a retrospective cohort of 224 female Haitian patients with nonmetastatic breast cancer.

Patients And Methods: BMI was obtained from the medical records and categorized as normal weight (< 25 kg/m), overweight (25-29.9 kg/m), and obese (≥ 30 kg/m). DFS was defined as time from surgical resection to disease recurrence, death, or censoring. Kaplan-Meier survival curves were generated, and the association between BMI and DFS was evaluated using Cox proportional hazard models to control for multiple confounders. Exploratory analyses were conducted on weight changes during adjuvant chemotherapy.

Results: Eighty-three patients (37.1%) were normal weight, 66 (29.5%) were overweight, and 75 (33.5%) were obese. There were no statistical differences in baseline characteristics or treatments received by BMI group. Twenty-six patients died and 73 had disease recurrence. Median DFS was 41.1 months. Kaplan-Meier estimates showed no significant DFS differences by BMI categories. After controlling for confounders, normal weight patients, when compared with overweight and obese patients, had adjusted hazard ratios of 0.85 (95% CI, 0.49 to 1.49) and 0.90 (95% CI, 0.52 to 1.55), respectively. Overall, mean weight loss of 2% of body weight was noted over the course of adjuvant chemotherapy. Patients who were postmenopausal ( = .007) and obese ( = .05) lost more weight than other groups. However, chemotherapy-related weight changes did not have an impact on DFS.

Conclusion: Baseline BMI and weight changes during adjuvant chemotherapy did not have an impact on DFS in this cohort. Future prospective studies in similar Caribbean breast cancer cohorts are needed to verify study findings.
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http://dx.doi.org/10.1200/GO.20.00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713562PMC
October 2020

Racial and Ethnic Variation in PSA Testing and Prostate Cancer Incidence Following the 2012 USPSTF Recommendation.

J Natl Cancer Inst 2021 Jun;113(6):719-726

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: The 2012 US Preventive Services Task Force recommendation against routine prostate-specific antigen (PSA) testing led to a decrease in prostate cancer screening, but the heterogeneity of its impact by race and ethnicity remains unclear.

Methods: The proportion of 40- to 74-year-old men who self-reported receiving a routine PSA test in the past year was estimated in the Behavioral Risk Factor Surveillance System (2012-2018). Odds ratios (ORs) of undergoing screening by race and ethnicity were estimated, adjusting for healthcare-related factors. Prostate cancer incidence rates and rate ratios (IRRs) by race and ethnicity were estimated using Surveillance, Epidemiology, and End Results registry data (2004-2017).

Results: PSA testing frequencies were 32.3% (95% confidence interval [CI] = 31.7% to 32.8%) among non-Hispanic White (NHW), 30.3% (95% CI = 28.3% to 32.3%) among non-Hispanic Black (NHB), 21.8% (95% CI = 19.9% to 23.7%) among Hispanic, and 17.7% (95% CI = 14.1% to 21.3%) among Asian and Pacific Islander men in 2012. The absolute screening frequency declined by 9.5% from 2012 to 2018, with a larger decline among NHB (11.6%) than NHW men (9.3%). The relative annual decrease was greater among NHB (OR = 0.86, 95% CI = 0.84 to 0.88) than NHW men (OR = 0.89, 95% CI = 0.89 to 0.90; Pheterogeneity = .005), driven by a larger decline among NHB men ages 40-54 years. The NHB to NHW IRR for total prostate cancer increased from 1.73 (95% CI = 1.69 to 1.76) in 2011 to 1.87 (95% CI = 1.83 to 1.92) in 2012 and has remained elevated, driven by differences in localized tumor incidence. Metastatic disease incidence is rising across all racial and ethnic groups.

Conclusions: The frequency of prostate cancer screening varies by race and ethnicity, and there was a modestly steeper decline in PSA testing among younger NHB men relative to NHW men since 2012. The NHB to NHW IRR for localized prostate cancer modestly increased following 2012.
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http://dx.doi.org/10.1093/jnci/djaa171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168268PMC
June 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

Prostate 2021 02 3;81(2):109-117. Epub 2020 Nov 3.

Dana Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied.

Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections.

Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG 81.4% vs. ERG 18.6%; p = .005) and EAM (ERG 60.4% vs. ERG 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC).

Conclusions: ERG tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.
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http://dx.doi.org/10.1002/pros.24086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810127PMC
February 2021

Neighborhood greenness and burden of non-communicable diseases in Sub-Saharan Africa: A multi-country cross-sectional study.

Environ Res 2021 05 31;196:110397. Epub 2020 Oct 31.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, USA.

Population growth, demographic transitions and urbanization in sub-Saharan Africa (SSA) will increase non-communicable disease (NCD) burden. We studied the association between neighborhood greenness and NCDs in a multi-country cross-sectional study. Among 1178 participants, in adjusted models, a 0.11 unit NDVI increase was associated with lower BMI (β: -1.01, 95% CI: -1.35, -0.67), and lower odds of overweight/obesity (aOR: 0.73, 95% CI: 0.62, 0.85), diabetes (aOR: 0.77, 95% CI: 0.62, 0.96), and having ≥3 allostatic load components compared to none (aOR: 0.66, 95% CI: 0.52, 0.85). Except for diabetes, these remained statistically significant after Bonferroni correction. We observed no association between NDVI and hypertension or cholesterol. Our findings are consistent with health benefits of neighborhood greenness reported in other countries, suggesting greening strategies could be considered as part of broader public health interventions for NCDs.
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http://dx.doi.org/10.1016/j.envres.2020.110397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085185PMC
May 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 May 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Geospatial evaluation of trade-offs between equity in physical access to healthcare and health systems efficiency.

BMJ Glob Health 2020 10;5(10)

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Introduction: Decisions regarding the geographical placement of healthcare services require consideration of trade-offs between equity and efficiency, but few empirical assessments are available. We applied a novel geospatial framework to study these trade-offs in four African countries.

Methods: Geolocation data on population density (a surrogate for efficiency), health centres and cancer referral centres in Kenya, Malawi, Tanzania and Rwanda were obtained from online databases. Travel time to the closest facility (a surrogate for equity) was estimated with 1 km resolution using the Access Mod 5 least cost distance algorithm. We studied associations between district-level average population density and travel time to closest facility for each country using Pearson's correlation, and spatial autocorrelation using the Global Moran's I statistic. Geographical clusters of districts with inefficient resource allocation were identified using the bivariate local indicator of spatial autocorrelation.

Results: Population density was inversely associated with travel time for all countries and levels of the health system (Pearson's correlation range, health centres: -0.89 to -0.71; cancer referral centres: -0.92 to -0.43), favouring efficiency. For health centres, negative spatial autocorrelation (geographical clustering of dissimilar values of population density and travel time) was weaker in Rwanda (-0.310) and Tanzania (-0.292), countries with explicit policies supporting equitable access to rural healthcare, relative to Kenya (-0.579) and Malawi (-0.543). Stronger spatial autocorrelation was observed for cancer referral centres (Rwanda: -0.341; Tanzania: -0.259; Kenya: -0.595; Malawi: -0.666). Significant geographical clusters of sparsely populated districts with long travel times to care were identified across countries.

Conclusion: Negative spatial correlations suggested that the geographical distribution of health services favoured efficiency over equity, but spatial autocorrelation measures revealed more equitable geographical distribution of facilities in certain countries. These findings suggest that even when prioritising efficiency, thoughtful decisions regarding geographical allocation could increase equitable physical access to services.
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http://dx.doi.org/10.1136/bmjgh-2020-003493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580044PMC
October 2020

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 Jan 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042600PMC
January 2021

Rethinking Environmental Carcinogenesis.

Cancer Epidemiol Biomarkers Prev 2020 10;29(10):1870-1875

Dana-Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, Massachusetts.

The 2010 report of the President's Cancer Panel concluded that the burden of cancer from chemical exposures is substantial, while the programs for testing and regulation of carcinogens remain inadequate. New research on the role of early life exposures and the ability of chemicals to act via multiple biological pathways, including immunosuppression, inflammation, and endocrine disruption as well as mutagenesis, further supports the potential for chemicals and chemical mixtures to influence disease. Epidemiologic observations, such as higher leukemia incidence in children living near roadways and industrial sources of air pollution, and new technologies that decode carcinogenesis at the molecular level, illustrate the diverse evidence that primary prevention of some cancers may be achieved by reducing harmful chemical exposures. The path forward requires cross-disciplinary approaches, increased environmental research investment, system-wide collaboration to develop safer economic alternatives, and community engagement to support evidence-informed action. Engagement by cancer researchers to integrate environmental risk factors into prevention initiatives holds tremendous promise for reducing the rates of disease.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0541DOI Listing
October 2020

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
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http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

Penetrance of Breast and Ovarian Cancer in Women Who Carry a Mutation and Do Not Use Risk-Reducing Salpingo-Oophorectomy: An Updated Meta-Analysis.

JNCI Cancer Spectr 2020 Aug 23;4(4):pkaa029. Epub 2020 Apr 23.

Dana FarberCancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Use of risk-reducing Salpingo-oophorectomy (RRSO) substantially reduces the risk of ovarian and breast cancer for women who carry a mutation. It is important to adjust for RRSO use in the estimation of penetrance of breast and ovarian cancer.

Methods: We searched PubMed for penetrance estimates of breast and ovarian cancer from studies that genotyped individual patients and explicitly adjusted for RRSO use by censoring follow-up at the age of RRSO. We meta-analyzed penetrance estimates from 7 identified studies. We implemented the resulting penetrance estimates in a Mendelian risk prediction model as iplemented in the software package BRCAPRO, which we applied to estimate carrier probabilities in 2 cohorts.

Results: Penetrance estimates by age 70 years for breast cancer were 64.6% (95% confidence interval [CI] = 59.5% to 69.4%) for BRCA1 mutation carriers and 61.0% (95% CI = 48.1% to 72.5%) for BRCA2 mutation carriers, and for ovarian cancer they were 48.3% (95% CI = 38.8% to 57.9%) and 20.0% (95% CI = 13.3% to 29.0%), respectively. When integrated into BRCAPRO, our estimates led to good calibration and different estimates of carrier probabilities for some individuals when evaluating the models in 2 cohorts.

Conclusions: The report updates penetrance estimates for BRCA1/2-associated cancer. We report higher estimates than previously reported, which did not adjust for RRSO. Differential use of RRSO may partially explain heterogeneity in the currently available penetrance estimates. For some individuals, using our estimates in BRCAPRO may result in changes in estimated carrier probabilities, which warrants validation in future studies.
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http://dx.doi.org/10.1093/jncics/pkaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353955PMC
August 2020

The association between neighborhood greenness and incidence of lethal prostate cancer: A prospective cohort study.

Environ Epidemiol 2020 Apr 9;4(2):e091. Epub 2020 Apr 9.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Background: Growing evidence suggests that neighborhood contextual environment could influence risk factors and, therefore, incidence of lethal prostate cancer. We studied the association between neighborhood greenness and lethal prostate cancer incidence and assessed mediation by vigorous physical activity.

Methods: A total of 47,958 participants were followed in the Health Professionals Follow-up Study from 1986 to 2014. Neighborhood greenness exposure was estimated using normalized difference vegetation index (NDVI) with 1 km resolution, assigned to home or work addresses at start of follow-up. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using sequentially adjusted Cox models with individual and contextual prostate cancer risk factors as covariates. Analyses were compared among those whose addresses were constant over follow-up and stratified by population density and address type.

Results: We observed 898 cases over 1,054,743 person-years. An interquartile range increase in NDVI was associated with 5% lower rate of lethal prostate cancer (aHR = 0.95, 95% CI = 0.88, 1.03), with stronger associations in nonmovers (aHR = 0.92, 95% CI = 0.85, 1.01). Inverse associations were observed among men in high (aHR = 0.90, 95% CI = 0.82, 0.99) but not low (aHR = 1.11, 95% CI = 0.95, 1.29, = 0.086) population density areas, and those reporting from work (aHR = 0.87, 95% CI = 0.75, 1.01) but not home (aHR = 1.04, 95% CI = 0.91, 1.17, = 0.10) addresses. There was no evidence of mediation by vigorous physical activity.

Conclusion: We report inverse associations between neighborhood greenness and lethal prostate cancer when restricting to nonmovers and in high population density areas. Replication could confirm findings and clarify mechanisms.
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http://dx.doi.org/10.1097/EE9.0000000000000091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319229PMC
April 2020

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

JAMA Oncol 2020 08;6(8):1218-1230

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, And Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes And Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions And Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
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http://dx.doi.org/10.1001/jamaoncol.2020.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333177PMC
August 2020

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

J Clin Oncol 2020 08 9;38(24):2798-2811. Epub 2020 Jun 9.

Advocate Aurora Health, Milwaukee, WI.

Purpose: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.

Methods: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).

Results: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included and mismatch repair genes, with broader testing, such as , for clinical trial eligibility. was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for carriers, with consideration in , and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.

Conclusion: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
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http://dx.doi.org/10.1200/JCO.20.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430215PMC
August 2020

A Custom Genotyping Array Reveals Population-Level Heterogeneity for the Genetic Risks of Prostate Cancer and Other Cancers in Africa.

Cancer Res 2020 07 11;80(13):2956-2966. Epub 2020 May 11.

Thermo Fisher Scientific, Santa Clara, California.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. SIGNIFICANCE: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335354PMC
July 2020

The contribution of residential greenness to mortality among men with prostate cancer: a registry-based cohort study of Black and White men.

Environ Epidemiol 2020 Apr 9;4(2):e087. Epub 2020 Apr 9.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Background: Black men with prostate cancer (CaP) experience excess mortality compared with White men. Residential greenness, a health promoting contextual factor, could explain racial disparities in mortality among men with CaP.

Methods: We identified Pennsylvania Cancer Registry cases diagnosed between January 2000 and December 2015. Totally, 128,568 participants were followed until death or 1 January 2018, whichever occurred first. Residential exposure at diagnosis was characterized using the Normalized Difference Vegetation Index (NDVI) with 250 m resolution. We estimated hazard ratios (HRs) using Cox models, adjusting for area-level socioeconomic status, geographic healthcare access, and segregation. To determine whether increasing residential greenness could reduce racial disparities, we compared standardized 10-year mortality Black-White risk differences under a hypothetical intervention fixing NDVI to the 75th percentile of NDVI experienced by White men.

Results: We observed 29,978 deaths over 916,590 person-years. Comparing men in the highest to lowest NDVI quintile, all-cause (adjusted HR [aHR]: 0.88, 95% confidence interval [CI]: 0.84, 0.92, < 0.0001), prostate-specific (aHR: 0.88, 95% CI: 0.80, 0.99, = 0.0021), and cardiovascular-specific (aHR: 0.82, 95% CI: 0.74, 0.90, < 0.0001) mortality were lower. Inverse associations between an interquartile range increase in NDVI and cardiovascular-specific mortality were observed in White (aHR: 0.90, 95% CI: 0.86, 0.93) but not Black men (aHR: 0.97, 95% CI: 0.89, 1.06; = 0.067). Hypothetical interventions to increase NDVI led to nonsignificant reductions in all-cause (-5.3%) and prostate-specific (-23.2%), but not cardiovascular-specific mortality disparities (+50.5%).

Discussion: Residential greenness was associated with lower mortality among men with CaP, but findings suggest that increasing residential greenness would have limited impact on racial disparities in mortality.
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http://dx.doi.org/10.1097/EE9.0000000000000087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147390PMC
April 2020

Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients.

Clin Cancer Res 2020 04 5;26(8):1915-1923. Epub 2020 Mar 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Purpose: Between 30%-40% of patients with prostate cancer experience disease recurrence following radical prostatectomy. Existing clinical models for recurrence risk prediction do not account for population-based variation in the tumor phenotype, despite recent evidence suggesting the presence of a unique, more aggressive prostate cancer phenotype in African American (AA) patients. We investigated the capacity of digitally measured, population-specific phenotypes of the intratumoral stroma to create improved models for prediction of recurrence following radical prostatectomy.

Experimental Design: This study included 334 radical prostatectomy patients subdivided into training (V, = 127), validation 1 (V, = 62), and validation 2 (V, = 145). Hematoxylin and eosin-stained slides from resected prostates were digitized, and 242 quantitative descriptors of the intratumoral stroma were calculated using a computational algorithm. Machine learning and elastic net Cox regression models were constructed using V to predict biochemical recurrence-free survival based on these features. Performance of these models was assessed using V and V, both overall and in population-specific cohorts.

Results: An AA-specific, automated stromal signature, AAstro, was prognostic of recurrence risk in both independent validation datasets [V: AUC = 0.87, HR = 4.71 (95% confidence interval (CI), 1.65-13.4), = 0.003; V: AUC = 0.77, HR = 5.7 (95% CI, 1.48-21.90), = 0.01]. AAstro outperformed clinical standard Kattan and CAPRA-S nomograms, and the underlying stromal descriptors were strongly associated with IHC measurements of specific tumor biomarker expression levels.

Conclusions: Our results suggest that considering population-specific information and stromal morphology has the potential to substantially improve accuracy of prognosis and risk stratification in AA patients with prostate cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165025PMC
April 2020