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ObjectivesA subset of laryngeal squamous cell carcinoma (LSCC) patients undergoing larynx preserving treatment ultimately require total laryngectomy (TL) for oncologic or functional reasons. This study aims to identify TL risk factors in these patients.MethodsRetrospective cohort study using Veterans Affairs (VA) database. T1-T4 LSCC cases treated with primary radiotherapy (XRT) or chemoradiotherapy (CRT) were assessed for TL and recurrence. Binary logistic and Cox regression and Kaplan-Meier analyses were implemented.ResultsOf 5390 cases, 863 (16.0%) underwent TL. On multivariable analysis, age (adjusted odds ratio: 0.97 [0.96-0.98]; p T1 disease (T2, 1.76 [1.44-2.17]; p

BackgroundThe US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.Patients and methodsParticipants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.Results and interpretationOn univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09,

Black Veterans have higher a incidence of localized and metastatic prostate cancer compared to White Veterans yet are underrepresented in reports of frequencies of somatic and germline alterations. This retrospective analysis of somatic and putative germline alterations was conducted in a large cohort of Veterans with prostate cancer (N = 835 Black, 1613 White) who underwent next generation sequencing through the VA Precision Oncology Program, which facilitates molecular testing for Veterans with metastatic cancer. No differences were observed in gene alterations for FDA approved targetable therapies (13.5% in Black Veterans vs. 15.5% in White Veterans, P = .21), nor in any potentially actionable alterations (25.5% vs. 28.7%, P =.1). Black Veterans had higher rates of BRAF (5.5% vs. 2.6%, P < .001) alterations, White Veterans TMPRSS2 fusions (27.2% vs. 11.7%, P < .0001). Putative germline alteration rates were higher in White Veterans (12.0% vs. 6.1%, P < .0001). Racial disparities in outcome are unlikely attributable to acquired somatic alterations in actionable pathways.

BackgroundGenetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.MethodsThis was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.ResultsA total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

ObjectiveTo analyse the effect of age at diagnosis on clinical outcomes of localized prostate cancer (PCa) treated with radiation therapy.Subjects and methodsWe identified 12 784 patients with intermediate- or high-risk localized PCa treated with radiation therapy (RT) and neoadjuvant androgen deprivation therapy (ADT) between 2000 and 2015 from nationwide Veterans Affairs data. Patients were grouped into three age categories (≤59, 60-69, and ≥70 years old). Outcomes included immediate PSA response (3-month post-RT PSA and 2-year PSA nadir, grouped into

BackgroundDisparities in prostate cancer-specific mortality (PCSM) between African American and non-Hispanic White (White) patients have been attributed to biological and systemic factors. We evaluated drivers of these disparities in the Surveillance, Epidemiology, and End Results (SEER) national registry and an equal-access system, the Veterans Health Administration (VHA).MethodsWe identified African American and White patients diagnosed with prostate cancer between 2004 and 2015 in SEER (n = 311 691) and the VHA (n = 90 749). We analyzed the association between race and metastatic disease at presentation using multivariable logistic regression adjusting for sociodemographic factors and PCSM using sequential competing-risks regression adjusting for disease and sociodemographic factors.ResultsThe median follow-up was 5.3 years in SEER and 4.7 years in the VHA. African American men were more likely than White men to present with metastatic disease in SEER (adjusted odds ratio = 1.23, 95% confidence interval [CI] = 1.17 to 1.30) but not in the VHA (adjusted odds ratio = 1.07, 95% CI = 0.98 to 1.17). African American vs White race was associated with an increased risk of PCSM in SEER (subdistribution hazard ratio [SHR] = 1.32, 95% CI = 1.10 to 1.60) but not in the VHA (SHR = 1.00, 95% CI = 0.93 to 1.08). Adjusting for disease extent, prostate-specific antigen, and Gleason score eliminated the association between race and PCSM in SEER (aSHR = 1.04, 95% CI = 0.93 to 1.16).ConclusionsRacial disparities in PCSM were present in a nationally representative registry but not in an equal-access health-care system, because of differences in advanced disease at presentation. Strategies to increase health-care access may bridge the racial disparity in outcomes. Longer follow-up is needed to fully assess mortality outcomes.

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Background and purposeNeutrophil-lymphocyte ratio (NLR) has been associated with overall survival (OS) in non-small cell lung cancer (NSCLC). We aimed to assess the utility of NLR as a predictor of lung cancer-specific survival (LCS) and identify an optimal, pretreatment cutoff point in patients with localized NSCLC treated with stereotactic body radiotherapy (SBRT) within the Veterans Affairs' (VA) national database.Materials and methodsIn the VA database, we identified patients with biopsy-proven, clinical stage I NSCLC treated with SBRT between 2006 and 2015. Cutoff points for NLR were calculated using Contal/O'Quigley's and Cox Wald methods. Primary outcomes of OS, LCS, and non-lung cancer survival (NCS) were evaluated in Cox and Fine-Gray models.ResultsIn 389 patients, optimal NLR cutoff was identified as 4.0. In multivariable models, NLR > 4.0 was associated with decreased OS (HR 1.44, p = 0.01) and NCS (HR 1.68, p = 0.01) but not with LCS (HR 1.32, p = 0.09). In a subset analysis of 229 patients with pulmonary function tests, NLR > 4.0 remained associated with worse OS (HR 1.51, p = 0.02) and NCS (HR 2.18, p = 0.01) while the association with LCS decreased further (HR 1.22, p = 0.39).ConclusionNLR was associated with worse OS in patients with localized NSCLC treated with SBRT; however, NLR was only associated with NCS and not with LCS. Pretreatment NLR, with a cutoff of 4.0, offers potential as a marker of competing mortality risk which can aid in risk stratification in this typically frail and comorbid population. Further studies are needed to validate pretreatment NLR as a clinical tool in this setting.

Evidence supporting radical prostatectomy (RP) for men with clinically node-positive (cN+) prostate cancer (PC) is limited. In a US national database, we identified 741 men with cN+ nonmetastatic PC diagnosed during 2000-2015 who underwent definitive local therapy with RP (n=78), radiotherapy (RT) with neoadjuvant androgen deprivation therapy (ADT) (n=193), or nondefinitive therapy with ADT alone (n=445) or observation (n=25). We compared PC-specific mortality (PCSM) and all-cause mortality (ACM) using multivariable Fine-Gray competing risk regression and Cox regression, respectively. Compared to nondefinitive therapy, RP was associated with significantly better PCSM (subdistribution hazard ratio [SHR] 0.32, 95% confidence interval [CI] 0.16-0.66; p=0.002) and ACM (HR 0.36, 95% CI 0.21-0.61; p

PurposeThe survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared with ADT alone for clinically lymph node-positive prostate cancer remains controversial.Methods and materialsWe identified patients with clinically node-positive, nonmetastatic prostate cancer diagnosed between 2000 and 2015 and treated with ADT (n = 450) or ADT-RT (n = 198) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable competing-risks regression and Cox regression, respectively. An interaction term between ADT-RT and prostate-specific antigen (PSA) level (dichotomized about the median) was included in the multivariable models.ResultsADT-RT was associated with improved PCSM among patients with PSA levels less than the median of 26 ng/mL (sub-distribution hazard ratio, 0.50; 95% confidence interval [CI] 0.28-0.88; P = .02) but not greater than the median (hazard ratio [HR], 1.15; 95% CI 0.67-1.96; P = .62) (P = .038 for interaction). ADT-RT was also associated with improved ACM among patients with PSA levels less than the median (HR, 0.38; 95% CI 0.25-0.57; P

Background: Existing data on the impact of Hispanic ethnicity on outcomes for patients with renal cell carcinoma (RCC) is mixed. The authors investigated outcomes of Hispanic and non‐Hispanic White (NHW) patients with advanced RCC receiving systemic therapy at large academic cancer centers using the International Metastatic Renal Cell Carcinoma Database (IMDC). Methods: Eligible patients included non‐Black Hispanic and NHW patients with locally advanced or metastatic RCC initiating systemic therapy. Overall survival (OS) and time to first‐line treatment failure (TTF) were calculated using the Kaplan–Meier method. The effect of ethnicity on OS and TTF were estimated by Cox regression hazard ratios (HRs). Results: A total of 1563 patients (181 Hispanic and 1382 NHW) (mostly males [73.8%] with clear cell RCC [81.5%] treated with tyrosine kinase inhibitor [TKI] monotherapy [69.9%]) were included. IMDC risk groups were similar between groups. Hispanic patients were younger at initial diagnosis (median 57 vs. 59 years, p =.015) and less likely to have greater than one metastatic site (60.8% vs. 76.8%, p <.001) or bone metastases (23.8% vs. 33.4%, p =.009). Median OS and TTF was 38.0 months (95% confidence interval [CI], 28.1–59.2) versus 35.7 months (95% CI, 31.9–39.2) and 7.8 months (95% CI, 6.2–9.0) versus 7.5 months (95% CI, 6.9–8.1), respectively, in Hispanic versus NHW patients. In multivariable Cox regression analysis, no statistically significant differences were observed in OS (adjusted hazard ratio [HR], 1.07; 95% CI, 0.86–1.31, p =.56) or TTF (adjusted HR, 1.06; 95% CI, 0.89–1.26, p =.50). Conclusions: The authors did not observe statistically significant differences in OS or TTF between Hispanic and NHW patients with advanced RCC. Receiving treatment at tertiary cancer centers may mitigate observed disparities in cancer outcomes. The authors demonstrate that there were no statistically significant differences in overall survival or time to first‐line treatment failure between non‐Black Hispanic and non‐Hispanic White patients with advanced renal cell carcinoma (RCC) treated at these large academic cancer centers. Our findings suggest that receiving treatment at a tertiary cancer center may mitigate previously observed disparities in cancer outcomes for non‐Black Hispanic patients with advanced RCC. [ABSTRACT FROM AUTHOR]

Despite differences in prostate cancer risk across ancestry groups, relative performance of prostate cancer genetic risks scores (GRS) for positive biopsy prediction in different ancestry groups is unknown. This cross-sectional retrospective analysis examines the association between a polygenic hazard score (PHS290) and risk of prostate cancer diagnosis upon first biopsy in male veterans using 2-sided tests. Our analysis included 36 717 veterans (10 297 of African ancestry). Unadjusted rates of positive first prostate biopsy increased with higher genetic risk (low risk: 34%, high risk: 58%; P  < .001). Among men of African ancestry, higher genetic risk was associated with increased prostate cancer detection on first biopsy (odds ratio = 2.18, 95% confidence interval = 1.93 to 2.47), but the effect was stronger among men of European descent (odds ratio = 3.89, 95% confidence interval = 3.62 to 4.18). These findings suggest that incorporating genetic risk into prediction models could better personalize biopsy decisions, although further study is needed to achieve equitable genetic risk stratification among ancestry groups. [ABSTRACT FROM AUTHOR]

PurposeTo compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events.MethodsWe identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion.ResultsIn each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8.ConclusionCompared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.

BackgroundClinical trial costs may be reduced by identifying enriched subpopulations of patients with favorable risk profiles for the events of interest. However, increased selectivity affects accrual rates, with uncertain impact on clinical trial cost.MethodsWe conducted a secondary analysis of Southwest Oncology Group (SWOG) 8794 randomized trial of adjuvant radiotherapy for high-risk prostate cancer. The primary endpoint was metastasis-free survival (MFS), defined as time to metastasis or death from any cause (competing mortality). We used competing risks regression models to identify an enriched subgroup at high risk for metastasis and low risk for competing mortality. We applied a cost model to estimate the impact of enrichment on trial cost and duration.ResultsThe treatment effect on metastasis was similar in the enriched subgroup (HR, 0.42; 95% CI, 0.23-0.76) compared to the whole cohort (HR, 0.50; 95% CI, 0.30-0.81) while the effect on competing mortality was not significant in the subgroup or the whole cohort (HR 0.70; 95% CI 0.39-1.23, vs. HR 0.94; 95% CI, 0.68-1.31). Due to the higher incidence of metastasis relative to competing mortality in the enriched subgroup, the treatment effect on MFS was greater in the subgroup compared to the whole cohort (HR 0.55; 95% CI 0.36-0.82, vs. HR 0.77; 95% CI, 0.58-1.01). Trial cost was 75% less in the subgroup compared to the whole cohort ($1.7 million vs. $6.8 million), and the trial duration was 30% shorter (8.4 vs. 12.0 years).ConclusionCompeting event enrichment can reduce clinical trial cost and duration, without sacrificing generalizability.

Purpose/objectives(s)Early-stage endometrial cancer patients are at higher risk of noncancer mortality than of cancer mortality. Competing event models incorporating comorbidity could help identify women most likely to benefit from treatment intensification.Methods and materials67,397 women with stage I-II endometrioid adenocarcinoma after total hysterectomy diagnosed from 1988 to 2009 were identified in Surveillance, Epidemiology, and End Results (SEER) and linked SEER-Medicare databases. Using demographic and clinical information, including comorbidity, we sought to develop and validate a risk score to predict the incidence of competing mortality.ResultsIn the validation cohort, increasing competing mortality risk score was associated with increased risk of noncancer mortality (subdistribution hazard ratio [SDHR], 1.92; 95% confidence interval [CI], 1.60-2.30) and decreased risk of endometrial cancer mortality (SDHR, 0.61; 95% CI, 0.55-0.78). Controlling for other variables, Charlson Comorbidity Index (CCI) = 1 (SDHR, 1.62; 95% CI, 1.45-1.82) and CCI >1 (SDHR, 3.31; 95% CI, 2.74-4.01) were associated with increased risk of noncancer mortality. The 10-year cumulative incidences of competing mortality within low-, medium-, and high-risk strata were 27.3% (95% CI, 25.2%-29.4%), 34.6% (95% CI, 32.5%-36.7%), and 50.3% (95% CI, 48.2%-52.6%), respectively. With increasing competing mortality risk score, we observed a significant decline in omega (ω), indicating a diminishing likelihood of benefit from treatment intensification.ConclusionComorbidity and other factors influence the risk of competing mortality among patients with early-stage endometrial cancer. Competing event models could improve our ability to identify patients likely to benefit from treatment intensification.

Background Opioid tapering in the general population is linked to increases in hospitalizations or emergency department visits related to psychiatric or drug-related diagnoses. Cancer survivors represent a unique population with different opioid indications, prescription patterns, and more frequent follow-up care. This study sought to describe patterns of opioid tapering among older cancer survivors and to test the hypothesis of whether older cancer survivors face increased risks of adverse events with opioid tapering. Methods Using the Surveillance, Epidemiology and End Results Medicare–linked database, we identified 15 002 Medicare-beneficiary cancer survivors diagnosed between 2010 and 2017 prescribed opioids consistently for at least 6 months after their cancer diagnosis. Tapering was defined as a binary time-varying event occurring with any monthly oral morphine equivalent reduction of 15% or more from the previous month. Primary diagnostic billing codes associated with emergency room or hospital admissions were used for the composite endpoint of psychiatric- or drug-related event(s). Results There were 3.86 events per 100 patient-months, with 97.8% events being mental health emergencies, 1.91% events being overdose emergencies, and 0.25% involving both. Using a generalized estimating equation for repeated measure time-based analysis, opioid tapering was not statistically associated with acute events in the 3-month posttaper period (odds ratio [OR] = 1.02; P  = .62) or at any point in the future (OR = 0.96; P  = .46). Conclusions Opioid tapering in older cancer survivors does not appear to be linked to a higher risk of acute psychiatric- or drug-related events, in contrast to prior research in the general population. [ABSTRACT FROM AUTHOR]