This cancer epidemiology study uses SEER data to examine US trends in use of active surveillance, watchful waiting, radiotherapy, and surgical management of localized prostate cancer among men with ...low-, intermediate-, and high-risk disease treated between 2010 and 2015.
The Gleason score is the best independent predictor of prostate cancer outcomes.1 The principle distinction between Gleason 6 disease vs Gleason 7 to 10 disease is that Gleason 6 disease does not ...necessarily need definitive treatment.2 Nevertheless, the implications of Gleason score are less clear in black men because of disparate prostate cancer outcomes, particularly for Gleason 6 disease, in which risk assessment and management of disease in black men is controversial.2,3 We investigated prostate cancer–specific mortality by Gleason score and race.
The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer ...based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer.
For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater.
75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7–10·6). Biochemical failure (R2 0·38 95% CI 0·11–0·64), biochemical failure-free survival (R2 0·12 0·0030–0·33), biochemical failure and clinical failure (R2 0·28 0·0045–0·65), and local failure (R2 0·085 0·00–0·37) correlated poorly with overall survival. Progression-free survival (R2 0·46 95% CI 0·22–0·67) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 0·59–0·89) correlated strongly.
Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.
Prostate Cancer Foundation and National Institutes of Health.
Purpose
Although breast cancer (BC) risk increases with age, BC in younger women is more aggressive with higher mortality compared with older women. We characterize the genomic landscape of BCs in ...younger women.
Methods
Clinicopathologic, molecular, and genomic differences across age groups (< 40 years, 40–60 years, > 60 years) in female BC patients were investigated in two large cohorts AACR-GENIE8.1 (
n
= 11,594) and METABRIC (
n
= 2509). Cox-proportional regression analyzed the prognostic impact of age groups for disease-specific survival (DSS) and recurrence-free survival (RFS) in METABRIC and progression-free survival (PFS) in GENIE cohorts. Chi-squared test was used to assess statistical associations between genomic alterations and age groups.
Results
Survival analysis showed that women < 40 years had shorter DSS hazard ratio (HR): 1.52,
p
= 0.005, RFS (HR: 1.4,
p
= 0.006), and PFS (HR: 1.82,
p
= 0.0003) compared with women 40–60 years, and shorter RFS (HR: 1.5,
p
= 0.001) and PFS (HR: 2.95,
p
< 0.0001) compared with women > 60 years. Molecular subtypes in the METABRIC cohort showed women < 40 years were enriched with basal, and HER2+ subtypes, and less enriched with luminal A and B subtype (
p
< 0.0001). Characterization of genomic alterations in both cohorts demonstrated that BCs in women < 40 years were more enriched with
TP53
mutations (FDR < 0.0001),
BRCA1
mutations (FDR = 0.01),
ERBB2
amplifications (FDR < 0.001),
CDK12
amplifications (FDR < 0.001), and
PPM1D
amplifications (FDR < 0.001). In contrast, BCs in older women (> 60 years) were more enriched with
PIK3CA
,
KMT2C
, and
CDH1
mutations (FDR < 0.0001).
Conclusions
BCs in young women are associated with shorter survival and more aggressive genomic features, including mutations in
TP53
and
BRCA1
, and amplifications in
ERBB2
and
CDK12
. These findings have the potential to impact clinical trial design and treatment.
Black men are disproportionately affected by prostate cancer (PCa), with earlier presentation, more aggressive disease, and higher mortality rates versus White men. Furthermore, Black men have less ...access to PCa treatment and experience longer delays between diagnosis and treatment. In this review, the authors discuss the factors contributing to racial disparities and present solutions to improve access to care and increase clinical trial participation among Black men with PCa. Racial disparities observed among Black men with PCa are multifaceted, evolving from institutional racism. Cultural factors include generalized mistrust of the health care system, poor physician‐patient communication, lack of information on PCa and treatment options, fear of PCa diagnosis, and perceived societal stigma of the disease. In the United States, geographic trends in racial disparities have been observed. Economic factors, e.g., cost of care, recovery time, and cancer debt, play an important role in racial disparities observed in PCa treatment and outcomes. Racial diversity is often lacking in genomic and precision medicine studies. Black men are largely underrepresented in key phase 3 PCa trials and may be less willing to enroll in clinical trials due to lack of awareness, lack of diversity in clinical trial research teams, and bias of health care providers to recommend clinical research. The authors propose solutions to address these factors that include educating clinicians and institutions on the barriers Black men experience, increasing the diversity of health care providers and clinical research teams, and empowering Black men to be involved in their treatment, which are keys to creating equity for Black men with PCa.
Lay summary
Prostate cancer negatively affects Black men more than men of other races.
The history of segregation and mistreatment in the health care system may contribute to mistrust among Black men.
Outcomes are worse for Black men because they are less likely to be screened or to receive treatment for prostate cancer.
Black men also are unlikely to participate in clinical research, making it difficult for investigators to understand how Black men are affected by prostate cancer.
Suggestions for addressing these differences include teaching physicians and nurses about the issues Black men experience getting treatment and improving how Black men get information on prostate cancer.
Racial disparities seen within prostate cancer diagnosis, treatment, and outcomes are multifaceted and evolve from institutional racism. The disparities can be addressed by educating physicians about the barriers faced by Black men receiving health care, identifying the best practices for conveying information on treatments and clinical trials, and increasing diversity among health care professionals.
Utilization of stereotactic body radiation therapy (SBRT) for treatment of localized prostate cancer is increasing. Guidelines and payers variably support the use of prostate SBRT. We therefore ...sought to systematically analyze biochemical recurrence-free survival (bRFS), physician-reported toxicity, and patient-reported outcomes after prostate SBRT.
A systematic search leveraging Medline via PubMed and EMBASE for original articles published between January 1990 and January 2018 was performed. This was supplemented by abstracts with sufficient extractable data from January 2013 to March 2018. All prospective series assessing curative-intent prostate SBRT for localized prostate cancer reporting bRFS, physician-reported toxicity, and patient-reported quality of life with a minimum of 1-year follow-up were included. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined by the I
and Cochran's Q tests. Meta-regression was performed using Hartung-Knapp methods.
Thirty-eight unique prospective series were identified comprising 6116 patients. Median follow-up was 39 months across all patients (range, 12-115 months). Ninety-two percent, 78%, and 38% of studies included low, intermediate, and high-risk patients. Overall, 5- and 7-year bRFS rates were 95.3% (95% confidence interval CI, 91.3%-97.5%) and 93.7% (95% CI, 91.4%-95.5%), respectively. Estimated late grade ≥3 genitourinary and gastrointestinal toxicity rates were 2.0% (95% CI, 1.4%-2.8%) and 1.1% (95% CI, 0.6%-2.0%), respectively. By 2 years post-SBRT, Expanded Prostate Cancer Index Composite urinary and bowel domain scores returned to baseline. Increasing dose of SBRT was associated with improved biochemical control (P = .018) but worse late grade ≥3 GU toxicity (P = .014).
Prostate SBRT has substantial prospective evidence supporting its use, with favorable tumor control, patient-reported quality of life, and levels of toxicity demonstrated. SBRT has sufficient evidence to be supported as a standard treatment option for localized prostate cancer while ongoing trials assess its potential superiority.
Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown ...whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival.
We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models.
One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses >5 fractions (P = .003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio OR, 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P < .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03).
Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.
Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ...ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities.
Display omitted
•The genetic ancestry of TCGA patients was estimated at global and local levels•The Cancer Genetic Ancestry Atlas, a publicly accessible resource, was developed•The frequencies of TP53 mutations and CCNE1 amplification were higher among AAs•The frequencies of the alterations in the PI3K pathway were lower among AAs
By analyzing TCGA cohorts, Yuan et al. show that breast, head and neck, and endometrial cancers of African Americans (AA) have higher levels of chromosomal instability than those of European Americans whereas the frequency of genetic alternations in the PI3K pathway in AA patients is lower across cancers.
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