The Role of Physician Specialty in the Underutilization of Standard-of-Care Treatment Intensification in Patients With Metastatic Castration-sensitive Prostate Cancer.

PURPOSE: We evaluate utilization of treatment intensification of androgen deprivation therapy with androgen receptor pathway inhibitor/docetaxel for metastatic castration-sensitive prostate cancer patients across physician specialties. MATERIALS AND METHODS: This retrospective study identified patients with metastatic castration-sensitive prostate cancer in the Optum Research Database between 2014 and 2019. Adult men with ≥1 claim for metastatic disease within 90 days before or any time after the first prostate cancer claim who received androgen deprivation therapy were included. Physician specialty, determined from medical/pharmacy claims during each line of therapy, was categorized as urologist only, oncologist only, both (urologists and oncologists), or other (other specialties). Treatment intensification and patient characteristics were analyzed descriptively. RESULTS: Of 4,675 patients, 16% were treated by urologists only, 20% by oncologists only, 63% by both, and 1.1% by others. The most frequent first line of therapy was androgen deprivation therapy ± first-generation nonsteroidal antiandrogens (>50%). Androgen deprivation therapy + docetaxel use declined over time, while androgen deprivation therapy + androgen receptor pathway inhibitor use increased. Patients seen by oncologists or both were younger, had fewer comorbidities, and were likelier to receive treatment intensification compared to those treated by urologists. By 2019, however, treatment intensification remained <40% from oncologists only or both, and <15% from urologists only. In the second and third lines of therapy, androgen deprivation therapy + androgen receptor pathway inhibitor was the most prescribed regimen across specialties (>50%). CONCLUSIONS: Treatment intensification was underused in first lines of therapy across urology and oncology specialties despite evidence of improved survival. In subsequent lines, androgen deprivation therapy + androgen receptor pathway inhibitor was prescribed more frequently across specialties. These results underscore the need for earlier treatment intensification by urologists and oncologists.

Comparative international incidence of Ewing sarcoma 1988 to 2012.

Ewing sarcoma (ES) is the second most common primary bone tumor in children and adolescents. There are few known epidemiological or genetic risk factors for ES. Numerous reports describe incidence rates and trends within the United States, but international comparisons are sparse. We used the Cancer Incidence in Five Continents (CI5) data to estimate age standardized incidence rates (ASRs; cases per million) and 95% confidence intervals (95% CIs), male-to-female incidence rate ratios (IRRs; 95% CI), and the average annual percent change in incidence (AAPC; 95% CI) for ES by geographic region for children and adults aged 0 to 49 years. We also estimated the ASR for each country or country subpopulation among the 10- to 19-year-old age range; capturing the peak incidence of ES. In total, 15 874 ES cases ages 0 to 49 were reported in the CI5 series between 1988 and 2012. AAPC estimates varied by age group and geographic region. Most of the statistically significant AAPCs showed an increased incidence over time; the only statistically significant decreases in incidence were observed among 20- to 29-year-olds and 30- to 39-year-olds in Southern Asia at -1.93% and -1.67%. When categorized by predominant ancestry, we observed countries and subpopulations with predominately African, East Asian, and Southeast Asian ancestry had the lowest incidence rates, whereas Pacific Islanders and populations with predominantly European and North African/Middle Eastern ancestry had the highest. An excess incidence in males was observed in most regions. Our results highlight substantial variation in ES incidence across geographic populations, reflecting potential ancestral influence on disease risk.

International trends in incidence of osteosarcoma (1988-2012).

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. The etiology of OS is largely unknown but may be informed by comparisons of incidence and trends between geographic regions. Using the Cancer Incidence in Five Continents (CI5) data from 1988 to 2012, we present OS age-standardized incidence rates (ASRs; cases/million) and average annual percent change (AAPC) and 95% confidence interval (CI) by geographic region among the age groups 0-9, 10-19, 20-29, 30-59, 60-79, 0-79. Among the 10-19 age group, we also used the most recent data (2008-2012) to present the ASRs for each country. We observed little variation in OS incidence between geographic regions in 2008-2012 across all age groups. Overall, the ASR for 0-79 ranged from 2 cases per million in Southern Asia to 4.2 in Sub-Saharan Africa. A bimodal distribution in incidence was observed with peaks in the 10-19 and 60-79 age groups across all regions over time. Overall, OS incidence was relatively stable across 1988-2012 with the only statistically significant increases in the 0-79 age group observed in Eastern Asia (AAPC: 1.8; 95% CI: 0.6, 1.9) and Sub-Saharan Africa (AAPC: 3.1; 95% CI: 0.5, 5.8). The small variation in incidence between regions and the stability in incidence over time suggests that OS carcinogenesis is not influenced by environmental or time-varying exposures.

Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children's Oncology Group.

PURPOSE: To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. METHODS: The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. RESULTS: Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION: Apart from TP53, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered.

Racial and Ethnic Differences in Sarcoma Incidence Are Independent of Census-Tract Socioeconomic Status.

BACKGROUND: Epidemiologic analyses of sarcoma are limited by the heterogeneity and rarity of the disease. Utilizing population-based surveillance data enabled us to evaluate the contribution of census tract-level socioeconomic status (CT-SES) and race/ethnicity on sarcoma incidence rates. METHODS: We utilized the Surveillance, Epidemiology, and End Results program to evaluate associations between CT-SES and race/ethnicity on the incidence rates of sarcoma. Incidence rate ratios and 99% confidence intervals were estimated from quasi-Poisson models. All models were stratified by broad age groups (pediatric: <20 years, adult: 20-65 years, older adult: 65+ years) and adjusted for sex, age, and year of diagnosis. Within each age group, we conducted analyses stratified by somatic genome (fusion-positive and fusion-negative sarcomas) and for subtypes with >200 total cases. A P value less than 0.01 was considered statistically significant. RESULTS: We included 55,415 sarcoma cases in 35 sarcoma subtype-age group combinations. Increasing CT-SES was statistically significantly associated with 11 subtype-age group combinations, primarily in the older age group strata (8 subtypes), whereas malignant peripheral nerve sheath tumors in adults were associated with decreasing CT-SES. Nearly every sarcoma subtype-age group combination displayed racial/ethnic disparities in incidence that were independent of CT-SES. CONCLUSIONS: We found race/ethnicity to be more frequently associated with sarcoma incidence than CT-SES. Our findings suggest that genetic variation associated with ancestry may play a stronger role than area-level SES-related factors in the etiology of sarcoma. IMPACT: These findings provide direction for future etiologic studies of sarcomas.

Associations of Socioeconomic Status, Public vs Private Insurance, and Race/Ethnicity With Metastatic Sarcoma at Diagnosis.

Importance: Approximately 10% to 30% of patients with sarcoma present with detectable metastases at diagnosis. However, the extent to which presentation with metastases is due to delayed diagnosis vs other factors remains unclear. Objective: To evaluate whether socioeconomic status, insurance status, or race/ethnicity were associated with the presence of metastases at diagnosis of sarcoma. Design, Setting, and Participants: This cross-sectional study used data from the population-based Surveillance, Epidemiology, and End Results program. Adult and pediatric patients with an initial diagnosis of soft-tissue and bone sarcoma between 2001 and 2015 were stratified by age group (pediatric, <20 years; adult, 20-65 years; older adult, >65 years) and sarcoma subtype. Statistical analyses were performed between August 2019 and January 2020. Exposures: Surveillance, Epidemiology, and End Results Census tract-level socioeconomic status index, insurance status, and race/ethnicity. Main Outcomes and Measures: The odds of presenting with metastases at diagnosis were calculated. Results: A total of 47 337 patients with first primary malignant sarcoma were included (24 343 male patients [51.4%]), with 29 975 non-Hispanic White patients (63.3%), 5673 non-Hispanic Black patients (12.0%), 7504 Hispanic patients (15.8%), and 4185 American Indian-Alaskan Native and Asian Pacific Islander patients (8.8%). Liposarcoma in adults was the only subtype and age group combination that demonstrated a significant trend in incidence across socioeconomic status levels (odds ratio, 0.85; 99% CI, 0.76-0.96; P = .001). However, compared with having non-Medicaid insurance, having Medicaid or no insurance in adults was associated with an increased odds of metastases at diagnosis for 6 of the 8 sarcoma subtypes evaluated; osteosarcoma and Ewing sarcoma were the only 2 subtypes in adults for which metastases were not associated with insurance status. In addition, there was an increased risk of presenting with metastases among non-Hispanic Black adults diagnosed with leiomyosarcoma (odds ratio, 1.87; 99% CI, 1.41-2.48) and unclassified sarcomas (odds ratio, 1.65; 99% CI, 1.01-2.67) compared with non-Hispanic White adults that was independent of socioeconomic and insurance status. Conclusions and Relevance: These findings suggest that delayed access to care is associated with advanced stage at diagnosis for several soft-tissue sarcoma subtypes in adults, whereas other factors may be associated with the metastatic progression of osteosarcoma and Ewing sarcoma, as well as the racial disparities observed with metastatic leiomyosarcoma and unclassified sarcomas.

A comparison of risk factors for metastasis at diagnosis in humans and dogs with osteosarcoma.

BACKGROUND: Canine osteosarcoma (OS) is a relevant spontaneous model for human OS. Identifying similarities in clinical characteristics associated with metastasis at diagnosis in both species may substantiate research aimed at using canine OS as a model for identifying mechanisms driving distant spread in the human disease. METHODS: This retrospective study included dog OS cases from three academic veterinary hospitals and human OS cases from the Surveillance, Epidemiology, and End Results program. Associations between clinical factors and metastasis at diagnosis were estimated using logistic regression models. RESULTS: In humans, those with trunk tumors had higher odds of metastasis at diagnosis compared to those with lower limb tumors (OR = 2.38, 95% CI: 1.51, 3.69). A similar observation was seen in dogs with trunk tumors compared to dogs with forelimb tumors (OR = 3.28, 95% CI 1.36, 7.50). Other associations were observed in humans but not in dogs. Humans aged 20-29 years had lower odds of metastasis at diagnosis compared to those aged 10-14 years (OR = 0.67, 95% CI: 0.47, 0.96); every 1-cm increase in tumor size was associated with a 6% increase in the odds of metastasis at diagnosis (95% CI: 1.04, 1.08); compared to those with a white, non-Hispanic race, higher odds were observed among those with a black, non-Hispanic race (OR: 1.51, 95% CI: 1.04, 2.16), and those with a Hispanic origin (OR 1.35, 95% CI: 1.00, 1.81). CONCLUSION: A common mechanism may be driving trunk tumors to progress to detectable metastasis prior to diagnosis in both species.

Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma.

Osteosarcoma is the most common primary bone tumor, with metastatic disease responsible for most treatment failure and patient death. A forward genetic screen utilizing Sleeping Beauty mutagenesis in mice previously identified potential genetic drivers of osteosarcoma metastasis, including Slit-Robo GTPase-Activating Protein 2 (Srgap2). This study evaluates the potential role of SRGAP2 in metastases-associated properties of osteosarcoma cell lines through Srgap2 knockout via the CRISPR/Cas9 nuclease system and conditional overexpression in the murine osteosarcoma cell lines K12 and K7M2. Proliferation, migration, and anchorage independent growth were evaluated. RNA sequencing and immunohistochemistry of human osteosarcoma tissue samples were used to further evaluate the potential role of the Slit-Robo pathway in osteosarcoma. The effects of Srgap2 expression modulation in the murine OS cell lines support the hypothesis that SRGAP2 may have a role as a suppressor of metastases in osteosarcoma. Additionally, SRGAP2 and other genes in the Slit-Robo pathway have altered transcript levels in a subset of mouse and human osteosarcoma, and SRGAP2 protein expression is reduced or absent in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in osteosarcoma metastasis, with loss of SRGAP2 potentially contributing to a more aggressive phenotype.

Prevalence of Metastasis at Diagnosis of Osteosarcoma: An International Comparison.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in many countries, with metastatic disease responsible for most patient deaths. This study compares the prevalence of metastatic OS at diagnosis across countries to inform the critical question of whether diagnostic delay or tumor biology drives metastases development prior to diagnosis. PROCEDURE: A literature search of the PubMed database was conducted to compare the prevalence of metastatic disease at the time of OS diagnosis between countries. A pooled prevalence with 95% confidence intervals was calculated for each study meeting inclusion criteria. Studies were grouped for analysis based on human development index (HDI) scores. RESULTS: Our analysis found an 18% (95% confidence interval [CI]: 15%, 20%) average global pooled proportion of metastasis at OS diagnosis. The average prevalence of metastasis at diagnosis increased as HDI groupings decreased, with very high HDI, high HDI, and medium/low HDI groups found to be 15% (95% CI: 13%, 17%), 20% (95% CI: 14%, 28%), and 31% (95% CI: 15%, 52%), respectively. CONCLUSIONS: Our evidence suggests there is a biological baseline for metastatic OS at diagnosis, which is observed in countries with very high HDI. In countries with medium/low HDI, where there are more barriers to accessing healthcare, the higher prevalence of metastasis may result from treatment delay or an artificial prevalence inflation due to patients with less severe symptoms not presenting to clinic. Additional research in countries with medium/low HDI may reveal that earlier detection and treatment could improve patient outcomes in those countries.