Publications by authors named "Rana R McKay"

116 Publications

The renal clear cell carcinoma immune landscape.

Neoplasia 2022 Feb 4;24(2):145-154. Epub 2022 Jan 4.

Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

A comprehensive evaluation of the clear cell renal cell carcinoma (ccRCC) immune landscape was found using 584 RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), we identified 17 key dysregulated immune-associated genes in ccRCC based on association with clinical variables and important immune pathways. Of the numerous findings from our analyses, we found that several of the 17 key dysregulated genes are heavily involved in interleukin and NF-kB signaling and that somatic copy number alteration (SCNA) hotspots may be causally associated with gene dysregulation. More importantly, we also found that key immune-associated genes and pathways are strongly upregulated in ccRCC. Our study may lend novel insights into the clinical implications of immune dysregulation in ccRCC and suggests potential immunotherapeutic targets for further evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neo.2021.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8740459PMC
February 2022

Assessment of Regional Variability in COVID-19 Outcomes Among Patients With Cancer in the United States.

JAMA Netw Open 2022 01 4;5(1):e2142046. Epub 2022 Jan 4.

University of California, San Diego.

Importance: The COVID-19 pandemic has had a distinct spatiotemporal pattern in the United States. Patients with cancer are at higher risk of severe complications from COVID-19, but it is not well known whether COVID-19 outcomes in this patient population were associated with geography.

Objective: To quantify spatiotemporal variation in COVID-19 outcomes among patients with cancer.

Design, Setting, And Participants: This registry-based retrospective cohort study included patients with a historical diagnosis of invasive malignant neoplasm and laboratory-confirmed SARS-CoV-2 infection between March and November 2020. Data were collected from cancer care delivery centers in the United States.

Exposures: Patient residence was categorized into 9 US census divisions. Cancer center characteristics included academic or community classification, rural-urban continuum code (RUCC), and social vulnerability index.

Main Outcomes And Measures: The primary outcome was 30-day all-cause mortality. The secondary composite outcome consisted of receipt of mechanical ventilation, intensive care unit admission, and all-cause death. Multilevel mixed-effects models estimated associations of center-level and census division-level exposures with outcomes after adjustment for patient-level risk factors and quantified variation in adjusted outcomes across centers, census divisions, and calendar time.

Results: Data for 4749 patients (median [IQR] age, 66 [56-76] years; 2439 [51.4%] female individuals, 1079 [22.7%] non-Hispanic Black individuals, and 690 [14.5%] Hispanic individuals) were reported from 83 centers in the Northeast (1564 patients [32.9%]), Midwest (1638 [34.5%]), South (894 [18.8%]), and West (653 [13.8%]). After adjustment for patient characteristics, including month of COVID-19 diagnosis, estimated 30-day mortality rates ranged from 5.2% to 26.6% across centers. Patients from centers located in metropolitan areas with population less than 250 000 (RUCC 3) had lower odds of 30-day mortality compared with patients from centers in metropolitan areas with population at least 1 million (RUCC 1) (adjusted odds ratio [aOR], 0.31; 95% CI, 0.11-0.84). The type of center was not significantly associated with primary or secondary outcomes. There were no statistically significant differences in outcome rates across the 9 census divisions, but adjusted mortality rates significantly improved over time (eg, September to November vs March to May: aOR, 0.32; 95% CI, 0.17-0.58).

Conclusions And Relevance: In this registry-based cohort study, significant differences in COVID-19 outcomes across US census divisions were not observed. However, substantial heterogeneity in COVID-19 outcomes across cancer care delivery centers was found. Attention to implementing standardized guidelines for the care of patients with cancer and COVID-19 could improve outcomes for these vulnerable patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.42046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728628PMC
January 2022

Association of Healthcare System and Survival in African American and Non-Hispanic White Patients with Bladder Cancer.

J Natl Cancer Inst 2021 Dec 16. Epub 2021 Dec 16.

Veterans Affairs San Diego Healthcare System, San Diego, 92161, CA, USA.

Background: African American patients with bladder cancer have inferior outcomes compared to non-Hispanic White (White) patients. We hypothesize that access to health care is a primary determinant of this disparity. We compared outcomes by race for patients with bladder cancer receiving care within the predominant hybrid-payer healthcare model of the United States captured in the Surveillance, Epidemiology, and End Results (SEER) database to those receiving care within the equal-access model of the Veterans' Health Administration (VHA).

Methods: African American and White patients diagnosed with bladder cancer were identified in SEER and VHA. Stage at presentation, bladder cancer-specific mortality (BCM), and overall survival (OS) were compared by race within each healthcare system.

Results: SEER cohort included 122,449 patients (93.7% White, 6.3% African American). VHA cohort included 36,322 patients (91.0% White, 9.0% African American). In both cohorts, African American patients were more likely to present with muscle-invasive disease and metastases but the differences between races were statistically significantly smaller in VHA. In SEER multivariable models, African American patients had worse BCM (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.15-1.29) and OS (HR = 1.26, 95% CI = 1.20-1.31). In contrast within VHA, African American patients had similar BCM (HR = 0.97, 95% CI = 0.88-1.07) and OS (HR = 0.99, 95% CI = 0.93-1.05).

Conclusion: In this study of contrasting healthcare models, receiving medical care in an equal-access system was associated with reduced differences in stage at presentation and eliminated disparities in survival outcomes for African American patients with bladder cancer. Our findings highlight the importance of reducing financial barriers to care to notably improve health equity and oncologic outcomes for African American patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djab219DOI Listing
December 2021

Analysis of CDK12 alterations in a pan-cancer database.

Cancer Med 2021 Dec 12. Epub 2021 Dec 12.

Division of Hematology-Oncology, Department of Medicine, University of California San Diego, San Diego, California, USA.

Background: CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing.

Methods: This was a single-center retrospective analysis of 4994 cancer patients who underwent tissue or blood genomic profiling, including CDK12 assessment, conducted as part of routine care from December 2012 to January 2020. Prevalence, clinical characteristics, and treatment outcomes of patients with tumors with pathogenic CDK12 alterations were described.

Results: In all, 39 (0.78%, n = 39/4994) patients had pathogenic CDK12 alterations. Among CDK12-altered tumors, the most common organ site was prostate (n = 9, 23.1%) followed by colorectal (n = 5, 12.8%). Adenocarcinoma was the most common histology (n = 26, 66.7%). Median follow-up from time of diagnosis was 4.02 years. Median overall survival from time of metastasis was 4.43 years (95% CI: 3.11-5.74). Ten patients with CDK12-altered tumors received at least one immune checkpoint inhibitor-containing regimen. The majority of patients (n = 6/10, 60%) experienced an objective response. Progression-free survival for patients who had metastatic disease and received a checkpoint inhibitor-containing regimen was 1.16 years (95% CI: 0.32-2.00).

Conclusion: CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4483DOI Listing
December 2021

Learning through a Pandemic: The Current State of Knowledge on COVID-19 and Cancer.

Cancer Discov 2021 Dec 10. Epub 2021 Dec 10.

Vanderbilt University Medical Center, Nashville, Tennessee.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has left patients with current or past history of cancer facing disparate consequences at every stage of the cancer trajectory. This comprehensive review offers a landscape analysis of the current state of the literature on COVID-19 and cancer, including the immune response to COVID-19, risk factors for severe disease, and impact of anticancer therapies. We also review the latest data on treatment of COVID-19 and vaccination safety and efficacy in patients with cancer, as well as the impact of the pandemic on cancer care, including the urgent need for rapid evidence generation and real-world study designs. SIGNIFICANCE: Patients with cancer have faced severe consequences at every stage of the cancer journey due to the COVID-19 pandemic. This comprehensive review offers a landscape analysis of the current state of the field regarding COVID-19 and cancer. We cover the immune response, risk factors for severe disease, and implications for vaccination in patients with cancer, as well as the impact of the COVID-19 pandemic on cancer care delivery. Overall, this review provides an in-depth summary of the key issues facing patients with cancer during this unprecedented health crisis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-21-1368DOI Listing
December 2021

Disparities and trends in the participation of minorities, women, and the elderly in breast, colorectal, lung, and prostate cancer clinical trials.

Cancer 2021 Nov 22. Epub 2021 Nov 22.

Department of Urology, University of California San Diego School of Medicine, La Jolla, California.

Background: This study was done to determine the representation of minorities, women, and the elderly in National Cancer Institute (NCI) clinical trials.

Methods: This is an analysis in the NCI Clinical Data Update System. Patients were evaluated in breast, colorectal, lung, and prostate cancer trials from 2000 to 2019. Representation in a trial was determined by race/ethnicity, sex, and age. Secondarily, the change in trial participation by multivariable analysis by comparing years 2000 through 2004 to 2015 through 2019 was evaluated.

Results: The cohort included 242,720 participants: 197,320 Non-Hispanic White (81.3%), 21,190 Black (8.7%), 11,587 Hispanic (4.8%), and 6880 Asian/Pacific Islander (2.8%). Black and Hispanic patients were underrepresented for colorectal (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001 and OR, 0.74; 95% CI, 0.64-0.87; P < .001, respectively), lung (OR, 0.83; 95% CI, 0.76-0.91; P < .001 and 0.66; 95% CI, 0.57-0.77; P < .001, respectively), and prostate cancer trials (OR, 0.85; 95% CI, 0.79-0.92; P < .001 and OR, 0.58; 95% CI, 0.51-0.66; P < .001) between 2015 and 2019. The odds of participation in 2015 to 2019 increased among Black patients in breast (OR, 2.19; 95% CI, 2.07-%2.32; P < .001), lung (OR, 1.54; 95% CI, 1.38-1.73; P < .001), and prostate cancer trials (OR, 1.14; 95% CI, 1.04-1.26; P < .001). The odds of participation in a trial among Hispanic patients increased for breast (OR, 3.32; 95% CI, 3.09-3.56; P < .001), colorectal (OR, 2.46; 95% CI, 2.04-2.96; P < .001), lung (OR, 3.88; 95% CI, 3.20-4.69; P < .001), and prostate cancer (OR, 1.70; 95% CI, 1.42-2.04; P = .005).

Conclusions: This study identified that Black and Hispanic patients remain underrepresented in trials, but in recent years, participation has increased. These findings indicate that minority participation has increased over time, but further efforts are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33991DOI Listing
November 2021

Disparities in germline testing among racial minorities with prostate cancer.

Prostate Cancer Prostatic Dis 2021 Nov 13. Epub 2021 Nov 13.

University of California San Diego, San Diego, CA, USA.

Germline testing is becoming increasingly relevant in prostate cancer (PCa) screening, prognosis, and management. A subset of patients with PCa harbor pathogenic/likely pathogenic variants (P/LPVs) in genes mediating DNA-repair processes, and these P/LPVs have implications for cancer screening, treatment, and cascade testing. As a result, it is recommended that all men with high-risk localized and metastatic PCa undergo routine germline testing. As more PCa patients undergo germline testing, it is important that clinicians and genetics experts recognize current disparities in germline testing rates among racial/ethnic minorities in the United States. The reasons for these disparities are multiple and require similarly manifold consideration to close the germline testing gap and reduce inequities in PCa screening, management, and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-021-00469-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590439PMC
November 2021

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19.

JAMA Netw Open 2021 11 1;4(11):e2134330. Epub 2021 Nov 1.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2).

Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer.

Design, Setting, And Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease.

Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19.

Main Outcomes And Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching.

Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).

Conclusions And Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.34330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590166PMC
November 2021

Asymptomatic detection of SARS-CoV-2 among cancer patients receiving infusional anti-cancer therapy.

Cancer Med 2021 12 28;10(24):8763-8767. Epub 2021 Oct 28.

University of California San Diego Moores Cancer Center, La Jolla, California, USA.

Background: Little is known regarding the rate and clinical outcomes of asymptomatic carriers of SARS-CoV-2 among patients with cancer. Detection of asymptomatic carriers is important in this population given the use of myelosuppressive and immunomodulating therapies. Understanding the asymptomatic carrier rate will help to develop mitigation strategies in this high-risk cohort.

Methods: Retrospective cohort analysis of an asymptomatic screening protocol which required patients receiving infusional anti-cancer therapy to undergo a symptom/exposure screen and SARS-CoV-2 PCR testing 24-96 h prior to their infusion. The primary outcome of this analysis was the rate of asymptomatic SARS-CoV-2 infection. Secondary outcomes included the rate of COVID-19-related hospitalization and mortality and delays in oncologic therapy.

Results: Among a cohort of 2691 cancer patients who underwent asymptomatic screening, 1.6% (N = 43/2691) of patients were found to be SARS-CoV-2 positive on asymptomatic screening. 11.6% (N = 5/43) of the cohort ultimately developed COVID-19-related symptoms. Four patients required hospitalization for complications of COVID-19 infection. No patient died from COVID-related complications. 97.7% (N = 42/43) had their anti-cancer therapy delayed or deferred with a median delay of 21 days (range: 7-77 days).

Conclusions: Overall, among a cohort of active cancer patients receiving anti-cancer therapy, an asymptomatic SARS-CoV2 PCR-based screening protocol detected a small cohort of asymptomatic carriers. The majority of these patients remained asymptomatic on long-term follow-up and outcomes were much more favorable compared to previously described outcomes of cancer patients with symptomatic COVID-19 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8646446PMC
December 2021

Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients With Renal Cell Carcinoma.

JAMA Oncol 2021 Dec;7(12):1815-1823

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Patients with brain metastases from renal cell carcinoma (RCC) have been underrepresented in clinical trials, and effective systemic therapy is lacking. Cabozantinib shows robust clinical activity in metastatic RCC, but its effect on brain metastases remains unclear.

Objective: To assess the clinical activity and toxic effects of cabozantinib to treat brain metastases in patients with metastatic RCC.

Design, Setting, And Participants: This retrospective cohort study included patients with metastatic RCC and brain metastases treated in 15 international institutions (US, Belgium, France, and Spain) between January 2014 and October 2020. Cohort A comprised patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy.

Exposures: Receipt of cabozantinib monotherapy at any line of treatment.

Main Outcomes And Measures: Intracranial radiological response rate by modified Response Evaluation Criteria in Solid Tumors, version 1.1, and toxic effects of cabozantinib.

Results: Of the 88 patients with brain metastases from RCC included in the study, 33 (38%) were in cohort A and 55 (62%) were in cohort B; the majority of patients were men (n = 69; 78%), and the median age at cabozantinib initiation was 61 years (range, 34-81 years). Median follow-up was 17 months (range, 2-74 months). The intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively. In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months). In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months). Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed.

Conclusions And Relevance: In this cohort study, cabozantinib showed considerable intracranial activity and an acceptable safety profile in patients with RCC and brain metastases. Support of prospective studies evaluating the efficacy of cabozantinib for brain metastases in patients with RCC is critical.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.4544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532040PMC
December 2021

Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.

Genome Med 2021 10 4;13(1):155. Epub 2021 Oct 4.

Center for Personalized Cancer Therapy, Moores Cancer Center, UC San Diego Health, 3855 Health Sciences Drive, Mail Code 0658, La Jolla, CA, 92093-0658, USA.

Background: Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study.

Methods: A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS).

Results: Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0-15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01-10.83), P = 0.048], PFS [HR 0.55 (0.28-1.07), P = 0.08], and OS [HR 0.42 (0.21-0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups.

Conclusions: Personalized combination therapies targeting a majority of a patient's molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies.

Trial Registration: I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00969-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491393PMC
October 2021

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

BJU Int 2021 Oct 1. Epub 2021 Oct 1.

Department of Oncology and Nuclear Medicine, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia.

Objectives: To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease.

Patients And Methods: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors.

Results: We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately.

Conclusion: Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.15603DOI Listing
October 2021

Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer.

Cell Rep 2021 09;36(10):109665

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address:

High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109665DOI Listing
September 2021

Cabozantinib in Combination With Atezolizumab for Advanced Renal Cell Carcinoma: Results From the COSMIC-021 Study.

J Clin Oncol 2021 11 7;39(33):3725-3736. Epub 2021 Sep 7.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.

Purpose: COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma (RCC).

Methods: This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety.

Results: A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs.

Conclusion: The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601305PMC
November 2021

Analysis of the Prognostic Significance of Circulating Tumor DNA in Metastatic Castrate Resistant Prostate Cancer.

Clin Genitourin Cancer 2021 Dec 31;19(6):564.e1-564.e10. Epub 2021 Jul 31.

Division of Hematology-Oncology, Department of Medicine, University of California San Diego, San Diego, CA. Electronic address:

Background: There has been considerable interest in ctDNA next generation sequencing platforms to assess genomic alterations in mCRPC given its accessibility and identification of temporal genomic data.

Patientsand Methods: In this retrospective analysis, we analyzed 63 patients who underwent ctDNA genomic profiling during their mCRPC disease course using a CLIA-certified commercial assay. The primary objective was to assess the feasibility of commercial ctDNA analysis in a real world mCRPC cohort. Key secondary objectives included assessment of the landscape of pathogenic ctDNA alterations and the prognostic significance of ctDNA detection on overall survival (OS).

Results: Among the cohort, at the time of ctDNA collection, median age was 70 years, and 47.6% (N = 30/63) had bone-only metastases. ctDNA was detected in the majority of patients with at least 1 pathogenic alteration detected in 90.5% (N = 57/63) of individuals. The most common alterations detected were in AR, TP53, and PIK3CA. Actionable alterations with FDA-approved therapies were found in 15.8% (N = 10) of the cohort. The presence of ≤ 1 versus > 1 alteration on ctDNA analysis was strongly associated with inferior OS with a median OS of 26.1 versus 8.8 months, respectively (HR = 7.0, 95% CI, 2.2-23.1, P < .001). In multivariate analysis, the number of detected alterations remained a significant predictor for OS. Lastly, there was weak correlation between Prostate-Specific Antigen (PSA), and ctDNA characteristics.

Conclusion: ctDNA is a viable next generation sequencing (NGS) platform in mCRPC and can be utilized to identify actionable alterations. The presence and extent of ctDNA alterations appear to be prognostic of OS in mCRPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2021.07.012DOI Listing
December 2021

The Promise of Adjuvant Immunotherapy in Renal-Cell Carcinoma.

Authors:
Rana R McKay

N Engl J Med 2021 08;385(8):756-758

From the University of California, San Diego, La Jolla.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMe2109354DOI Listing
August 2021

Outcomes for Muscle-invasive Bladder Cancer with Radical Cystectomy or Trimodal Therapy in US Veterans.

Eur Urol Open Sci 2021 Aug 9;30:1-10. Epub 2021 Jun 9.

Division of Hematology-Oncology, Department of Internal Medicine, University of California San Diego, La Jolla, CA, USA.

Background: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments.

Objective: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline-preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT).

Design Setting And Participants: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied.

Outcome Measurements And Statistical Analysis: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review.

Results And Limitations: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94-1.50;  = 0.15) and BCSM (HR 1.34; 95% CI 0.99-1.83;  = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04-1.61;  = 0.02) and BCSM (HR 1.45; 95% CI 1.09-1.94;  = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95-1.24;  = 0.24) and BCSM (HR 1.02; 95% CI 0.86-1.21;  = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87-1.50;  = 0.35) and BCSM (HR 1.11; 95% CI 0.76-1.62;  = 0.60). Among patients <65 yr of age, pTMT was associated with worse OM (HR 1.82; 95% CI 1.14-2.91;  = 0.01) and BCSM (HR 2.51; 95% CI 1.52-4.13;  < 0.01). The 5-yr cumulative incidence of salvage cystectomy in the TMT group was 3.6%.

Conclusions: In MIBC, patients receiving pTMT have comparable survival in RC-NAC patients ≥65 yr and inferior survival in RC-NAC patients <65 yr. Salvage cystectomy rates were low.

Patient Summary: Management of muscle-invasive bladder cancer is a multidisciplinary effort requiring thoughtful discussions with patients about treatment options, including trimodal therapy, which is an effective treatment option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.euros.2021.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317783PMC
August 2021

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study.

EClinicalMedicine 2021 Jun 6;36:100887. Epub 2021 May 6.

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Background: Androgen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk.

Methods: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.

Findings: We identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48-1•71), myocardial infarction (1•35, 1•16-1•58), arrythmia (2•04, 1•82-2•30), and heart failure (3•02, 2•60-3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12-1•30), myocardial infarction (1•80, 1•61-2•03) and heart failure (2•06, 1•76-2•41).

Interpretation: We found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone.

Funding: None.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257986PMC
June 2021

The microbiome and prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jul 15. Epub 2021 Jul 15.

Janssen Research and Development, San Diego, CA, USA.

There is growing evidence that the microbiome is involved in development and treatment of many human diseases, including prostate cancer. There are several potential pathways for microbiome-based mechanisms for the development of prostate cancer: direct impacts of microbes or microbial products in the prostate or the urine, and indirect impacts from microbes or microbial products in the gastrointestinal tract. Unique microbial signatures have been identified within the stool, oral cavity, tissue, urine, and blood of prostate cancer patients, but studies vary in their findings. Recent studies describe potential diagnostic and therapeutic applications of the microbiome, but further clinical investigation is needed. In this review, we explore the existing literature on the discovery of the human microbiome and its relationship to prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-021-00413-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767983PMC
July 2021

The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID-19.

J Thromb Haemost 2021 10 13;19(10):2522-2532. Epub 2021 Aug 13.

Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

Background: Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking.

Objectives: To assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID-19.

Methods: Among patients with cancer in the COVID-19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19-associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.

Results: From March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n = 1423 vs. high-risk, 3+ points, n = 1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% confidence interval 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.

Conclusions: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420489PMC
October 2021

Prospective Evaluation of Clinical Outcomes Using a Multiplex Liquid Biopsy Targeting Diverse Resistance Mechanisms in Metastatic Prostate Cancer.

J Clin Oncol 2021 09 1;39(26):2926-2937. Epub 2021 Jul 1.

Department of Medicine, Carbone Cancer Center, University of Wisconsin, Madison, WI.

Purpose: Nearly all men with prostate cancer treated with androgen receptor (AR) signaling inhibitors (ARSIs) develop resistance via diverse mechanisms including constitutive activation of the AR pathway, driven by AR genomic structural alterations, expression of AR splice variants (AR-Vs), or loss of AR dependence and lineage plasticity termed neuroendocrine prostate cancer. Understanding these de novo acquired ARSI resistance mechanisms is critical for optimizing therapy.

Materials And Methods: A novel liquid biopsy technology was used to collect mRNA from circulating tumor cells (CTCs) to measure expression of AR-Vs, AR targets, and neuroendocrine prostate cancer markers. An institutional review board-approved prospective cohort (N = 99) was used to identify patterns of gene expression. Two prospective multicenter phase II clinical trials of ARSIs for men with castration-resistant prostate cancer (ClinicalTrials.gov: NCT01942837 [enzalutamide, N = 21] and NCT02025010 [abiraterone, N = 27]) were used to further validate these findings.

Results: Hierarchical clustering of CTC transcripts identified two distinct clusters. Cluster 2 (C2) exhibited increased expression of AR-regulated genes and was associated with worse overall survival (median 8.6 22.4 months; < .01; hazard ratio [HR] = 3.45 [1.9 to 6.14]). In multivariable analysis, C2 was prognostic independent of other clinicopathologic variables. AR-V status was not significant when accounting for C2. Upon further validation in pooled multicenter phase II trials, C2 was associated with worse overall survival (15.2 months not reached; < .01; HR = 8.43 [2.74 to 25.92]), prostate-specific antigen progression-free survival (3.6 12 months; < .01; HR = 4.64 [1.53 to 14.11]), and radiographic progression-free survival (2.7 40.6 months; < .01; HR = 4.64 [1.82 to 17.41]).

Conclusion: We demonstrate that a transcriptional profile detectable in CTCs obtained from liquid biopsies can serve as an independent prognostic marker beyond AR-V7 in patients with metastatic prostate cancer and can be used to identify the emergence of multiple ARSI resistance mechanisms. This is currently being investigated in additional prospective trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425833PMC
September 2021

Prognostic Significance of Pancreatic Metastases in Patients With Advanced Renal Cell Carcinoma Treated With Systemic Therapy.

Clin Genitourin Cancer 2021 Dec 19;19(6):e367-e373. Epub 2021 Apr 19.

Department of Medicine, Division of Hematology-Oncology, University of California San Diego, La Jolla, CA. Electronic address:

Background: Pancreatic metastases (PM) are rare in renal cell carcinoma. It has been suggested that patients with metastases to the pancreas have a more favorable prognosis, but little is known about the long-term outcomes with systemic therapy. We sought to understand the outcomes of patients with metastatic renal cell carcinoma with PM treated with systemic therapy.

Patients And Methods: We conducted a pooled analysis of 4736 patients with metastatic renal cell carcinoma treated on phase II/III clinical trials. Systemic therapies included anti-vascular endothelial growth factor targeted therapy, mammalian target of rapamycin-targeted therapy, and cytokine therapy.

Results: The primary end point was overall survival (OS) in patients with versus without PM. Statistical analyses were performed using Kaplan-Meier analysis and Cox regression. Among 4736 patients, 235 (5.0%) were identified to have baseline PM at therapy initiation. The median OS in patients with PM was significantly prolonged with OS of 41.7 months versus 19.0 months (adjusted hazard ratio, 0.52; P < .0001). Similarly, progression-free survival was significantly prolonged in patients with PM (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P = .004). The effect of PM on OS and progression-free survival was independent of other sites of metastasis or International mRCC Database Consortium risk group.

Conclusion: The presence of PM in RCC is an independent positive predictor for survival and improved response to systemic therapy. These findings suggest RCC with PM is associated with favorable outcomes and further work to understand the underlying disease biology of these patients is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2021.04.006DOI Listing
December 2021

Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.

Eur Urol 2021 09 19;80(3):295-303. Epub 2021 Apr 19.

Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Background: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.

Objective: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.

Design, Setting, And Participants: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.

Intervention: Intense neoadjuvant ADT followed by RP.

Outcome Measurements And Statistical Analysis: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.

Results And Limitations: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations.

Conclusions: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.

Patient Summary: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2021.03.031DOI Listing
September 2021

Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance.

Clin Cancer Res 2021 07 13;27(13):3610-3619. Epub 2021 Apr 13.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.

Patients And Methods: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.

Results: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in (mutations, amplifications) and tumor suppression genes (, and ), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased amplifications (64.7% at progression vs. 53.9% at baseline) and alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression.

Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-4616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254786PMC
July 2021

Tackling Diversity in Prostate Cancer Clinical Trials: A Report From the Diversity Working Group of the IRONMAN Registry.

JCO Glob Oncol 2021 04;7:495-505

Moffitt Cancer Center, Tampa, FL.

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/GO.20.00571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162521PMC
April 2021

Next Steps: Sequencing Therapies in Metastatic Kidney Cancer in the Contemporary Era.

Am Soc Clin Oncol Educ Book 2021 Mar;41:1-11

Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA.

Systemic therapy for first-line metastatic renal cell carcinoma has evolved toward immune checkpoint blockade combinations incorporating a PD-1/L1 inhibitor along with CTLA-4 inhibition or VEGF-targeted therapy. The new treatment paradigm that integrates immunotherapy for treatment-naïve advanced metastatic renal cell carcinoma creates a new therapeutic challenge for clinicians including the optimal way to integrate multidisciplinary care involving surgery, radiotherapy, and application of contemporaneous systemic treatment in subsequent lines of therapy following discontinuation of combination therapy. We outline the available data for the multidisciplinary management of metastatic renal cell carcinoma, systemic therapy options in the post-immune checkpoint blockade setting, and novel therapies in development for advanced renal cell carcinoma. We provide practical considerations to assist clinicians in treatment choice and map future directions for progress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/EDBK_320785DOI Listing
March 2021

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

Prostate 2021 05 1;81(7):433-439. Epub 2021 Apr 1.

Department of Medicine, Tulane Cancer Center, Tulane University, New Orleans, Louisiana, USA.

Background: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations.

Methods: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed.

Results: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men.

Conclusions: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.24123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252583PMC
May 2021

Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer.

J Urol 2021 07 8;206(1):80-87. Epub 2021 Mar 8.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Materials And Methods: Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.

Results: The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.

Conclusions: Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor 5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001702DOI Listing
July 2021

Temporal Trends and Predictors in the Use of Stereotactic Body Radiotherapy for Treatment of Metastatic Renal Cell Carcinoma in the U.S.

Oncologist 2021 05 24;26(5):e905-e906. Epub 2021 Mar 24.

Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100555PMC
May 2021

Development and initial clinical testing of a multiplexed circulating tumor cell assay in patients with clear cell renal cell carcinoma.

Mol Oncol 2021 09 3;15(9):2330-2344. Epub 2021 Mar 3.

Carbone Cancer Center, University of Wisconsin-Madison, WI, USA.

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC-specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD-L1 and HLA-I expression and correlated with patient response to therapy. CTC enumeration and expression of PD-L1 and HLA-I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1878-0261.12931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410529PMC
September 2021
-->