Search

Key Points Question Given the higher COVID-19–related mortality rate observed among men than among women, is androgen deprivation therapy associated with decreased rate of 30-day mortality from COVID-19 among patients with prostate cancer? Findings In this cohort study of 1106 patients, no statistically significant difference was found in the rates of all cause 30-day mortality following COVID-19 infection among men with prostate cancer receiving androgen deprivation therapy (15%) vs those not receiving androgen deprivation therapy (14%). Meaning The findings of this cohort study do not support an association between androgen deprivation therapy and 30-day mortality among patients with COVID-19 infection., 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., This cohort study using data from the COVID-19 and Cancer Consortium registry examines whether androgen deprivation therapy is associated with decreased rates of mortality within 30 days of COVID-19 diagnosis among patients with prostate cancer.

Background: The impact of disease characteristics and androgen deprivation therapy (ADT) or other treatments for prostate cancer (PC) on severity of infection with Covid-19 has not been elucidated. We report results from our PC patients (pts) with Covid-19 in our registry of Covid-19 treated cancer patients at the Cleveland Clinic Foundation. Methods: We performed a retrospective analysis of PC pts who tested positive for Covid-19 between 3/16/2020 and 5/21/2020 at the Cleveland Clinic. Additional information including prostate specific antigen (PSA), Gleason score, disease extent, and current treatment were also obtained. Severe Covid-19 infection was defined as any pt requiring hospitalization, ICU care, and/or death. PSA values from prior to Covid-19 infection or first available after Covid-19 infected were collected. Analysis was carried out with Fisher’s exact test and Wilcoxon rank sum test, as applicable, and overall survival (OS) by log rank test. Results: A total of 54 pts with prostate cancer that tested positive for Covid-19 were identified, of which 4 were receiving active treatment (2 with metastatic disease and 2 with localized disease). Of the 2 pts with metastatic disease, 1 was on docetaxel with ADT and other on abiraterone/prednisone with ADT. Of the 2 pts with localized disease, 1 was on ADT and bicalutamide and other on ADT alone. A total of 40 patients had severe Covid-19 disease. There was no correlation with ADT and Covid-19 disease severity (p=0.67). There were 22 pts with Gleason 6, 20 pts with Gleason 7, 6 pts with Gleason 8, 4 pts with Gleason 9, 1 pt with Gleason 10, and 1 pt with Gleason unknown PC. There was no correlation between absolute (p=0.21) or divided (p=0.65) Gleason score with disease severity. There were 4 pts with metastatic disease and 46 with localized disease and no correlation was seen with extent of disease and Covid-19 severity (p>0.99). Fifty pts had PSA data available, and there was no correlation of PSA with Covid-19 disease severity (p=0.28). The mortality from Covid-19 was 26% (14 out of 54 pts) in our cohort. Out of the 14 pts who died, 2 were on active treatment that included ADT. There was no association between Gleason score (p=0.2649), extent of disease (p=0.9642), or treatment (p=0.5998) and OS. Conclusions: In our registry of Covid-19 treated cancer patients, we did not see any correlation between PC disease-risk factors and treatment with Covid-19 severity. While the results are limited by small patient population, they provide valuable information that PC treatment did not affect severity of Covid-19. Citation Format: Scott J. Dawsey, Nathan A. Pennell, Christopher Lemmon, Amanda Nizam, Wei Wei, Timothy D. Gilligan, Moshe C. Ornstein, Shilpa Gupta. Prostate cancer and COVID-19 outcomes: Results from the Cleveland Clinic registry of COVID-19 and cancer patients [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P25.

39 Background: The presence of progressing cancer, male sex and advanced age have been shown to increase the severity of coronavirus disease 2019 (COVID-19). Given that the androgen regulated gene TMPRSS2 has been implicated in SARS-CoV-2 viral entry, we hypothesized that ADT may improve COVID-19 outcomes. This analysis evaluated clinical outcomes of pts with PCa with concurrent SARS-CoV-2 infection and investigated the impact of ADT on occurrence of severe-COVID-19 and mortality. Methods: Data was obtained via the COVID-19 and Cancer Consortium (CCC19), a multicenter registry including >120 cancer centers with de-identified data from pts with COVID-19 and cancer. Men with confirmed SARS-CoV-2 infection and a primary diagnosis of prostate cancer were included: data cutoff of July 31, 2020. The primary endpoint was the development of severe-COVID-19 (death, ICU admission, or mechanical ventilation) among pts on ADT vs. those not on ADT at time of COVID-19 infection. Secondary endpoints included 30-day mortality based on ADT use. Mortality and development of severe-COVID-19 were assessed in Pts grouped by therapy: 1st generation androgen receptor inhibitor (ARI-1), 2nd generation ARI (darolutamide, enzalutamide, apalutamide, ARI-2), abiraterone/prednisone, and chemotherapy. Propensity score matching was utilized. Logistic regression was utilized to adjust for age, ECOG PS, comorbidities, and race. Results: 589 pts were included; median follow-up was 42 days (IQR 25-90) and 62% (363/589) were hospitalized. Severe-COVID-19 developed in 28% of pts and the all-cause 30-day mortality rate was 19%. There was no significant difference in the development of severe-COVID-19 or 30-day mortality between Pts on ADT vs not on ADT, whether using descriptive statistics with the entire population or using the propensity score matched population (Table). Among the descriptive population, the numerical rates of severe-COVID-19 and mortality were lowest in Pts receiving ARI-2, but sample size was low. Conclusions: The overall 30-day mortality rate and percentage developing severe-COVID-19 were high. There was no statistical difference in the development of severe-COVID-19 or mortality based on receipt of ADT; however, this analysis is limited by the retrospective nature and small N after propensity-matching. [Table: see text]

BACKGROUND Epidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated. METHODS Patients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m2) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints. RESULTS Eighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death. CONCLUSIONS GC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes. Cancer 2014;120:2684–2693. © 2014 American Cancer Society.

Although current breast cancer treatment guidelines limit the use of HER2-blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Using breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we show that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell (CSC) population in estrogen receptor-positive (ER+), HER2− luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from patients with breast cancer as compared with matched primary tumors. Furthermore, this increase in HER2 protein expression was not due to gene amplification but rather was mediated by receptor activator of NF-κB (RANK)-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the CSC population in a process that does not require HER2 gene amplification. Furthermore, these studies support a CSC model in which maximal clinical benefit is achieved when CSC targeting agents are administered in the adjuvant setting. Cancer Res; 73(5); 1635–46. ©2012 AACR.

Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites. Cancer Res; 77(1); 74–85. ©2016 AACR.

A clinical appraisal and clinical application of Koch KL, Karafin MS, Simpson P, Field JJ. Intensive management of high-utilizing adults with sickle cell disease lowers admissions. Am J Hematol. 2015 Jan;90(3):215-219. doi:10.1002/ajh.23912

4506 Background: In UCpts EGFR over-expression correlates with high grade, stage, progression, short survival. Preclinical data show enhanced anti-tumor effect with CET + chemotherapy (CT). In several solid tumors CET added to CT improved survival. CET is hypothesized to improve UC response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, unresectable, locally recurrent or metastatic UC were stratified by disease state and randomized (1:2) to C 70mg/m2 d1, G 1000mg/m2 d1, d8, d15 (Arm A) or same CT + CET 500mg/m2 d1, d15 (Arm B) q28 days. Due to high thromboembolic events rate in Arm B, G dose was reduced to 800 mg/m2. 6 GC cycles were planned. Arm A pts progressing after 2 GC cycles had CET added. Arm B pts were to continue on CET monotherapy after 4-6 CT cycles. Imaging was q8 weeks. Primary endpoint: RECIST response rate (RR); secondary: safety, PFS, survival. Since E-cadherin impacts UC response to CET in vitro, serum level (sE-cad) was assessed at baseline, after 2 cycles, end of CT and at progression. With 1-stage design, assuming RR 50% (Arm A) and at least 65% (Arm B), planned sample size was 27/54 pts. RR improvement of 5% has 81% probability if true difference is 15%. Results: 88 pts were eligible and randomized, Arm A/B: median age 66/61 years; bladder primary 71.4%/77.2%; metastatic disease 92.9%/89.5%, median CT cycles number 6/5. 28 Arm B pts continued CET (median 3 cycles, range 1-29); 1 Arm A pt had CET added. Most common G3/4 adverse events (AEs) (Arm A, B): neutropenia (34.5%, 33.9%), anemia (10.3%, 5.1%), thrombocytopenia (27.6%, 22%), thromboembolism (6.9%, 18.6%), hyponatremia (3.5%, 10.2%); Arm B only: rash 28.8%, fatigue 11.9%, hypomagnesemia 11.9% and 2 deaths. 84 pts were response evaluable (see table below). sE-cad did not correlate with outcome. sE-cad increased in Arm A, but decreased in Arm B over time. Conclusions: GC/CET was feasible with no outcome improvement but higher AEs. sE-cad did not correlate with outcome. Decreased sE-cad in Arm B suggests potential EGFR-mediated E-cad proteolysis. [Table: see text]