A Real-World Retrospective Analysis of the Management of Advanced Urothelial Carcinoma in Canada.

Locally advanced or metastatic urothelial carcinoma (aUC) presents a significant challenge with high mortality rates. Platinum-based chemotherapy remains the established frontline standard of care, and a switch-maintenance strategy with immunotherapy has now emerged as a new standard for aUC patients without disease progression, following initial platinum therapy. Examining the treatment patterns is imperative, given the evolving therapeutic landscape. In this study, we conducted a retrospective medical chart review of 17 Canadian oncologists treating patients with aUC to assess unmet needs in Canadian aUC patient care. Data from 146 patient charts were analyzed, revealing important clinical insights about the management of aUC. A substantial proportion of patients (53%) presented with de novo metastatic disease, which was possibly influenced by pandemic-related care disruptions. Variability was evident in the cisplatin eligibility criteria, with a majority (70%) of oncologists utilizing a 50 mL/min threshold. Most favored four cycles of platinum-based chemotherapy to spare the bone marrow for future therapies and prevent patient fatigue. Notably, some eligible patients were kept under surveillance rather than receiving maintenance therapy, suggesting a potential gap in awareness regarding evidence-based recommendations. Furthermore, managing treatment-related adverse events was found to be one of the biggest challenges in relation to maintenance immunotherapy. In conclusion, our findings provide the first comprehensive overview of aUC treatment patterns in Canada following the approval of maintenance immunotherapy, offering insights into the decision-making process and underscoring the importance of evidence-based guidelines in aUC patient management.

An in-depth analysis on the effects of body composition in patients receiving neoadjuvant chemotherapy for urothelial cell carcinoma.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is the standard of care for patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC); however, NAC can be associated with significant side effects and morbidity in some patients. NAC may contribute to sarcopenia, obesity, and the combination of the two. Our study examined the effects of NAC on body composition and the association between body composition and adverse events. METHODS: We created a retrospective database of patients with non-metastatic MIBC receiving NAC prior to RC. The change in skeletal muscle index (SMI) and fat mass index (FMI) was calculated using computed tomography (CT) scans done within three months prior to NAC and after the first two cycles. The association between body composition (sarcopenia, obesity, and sarcopenic obesity) and preoperative adverse events was investigated using a multivariable logistic regression. Changes in body composition were calculated using a paired Student's t-test. RESULTS: A total of 70 patients were included in our study. There was a mean decrease in SMI of 2.2±3.2 cm2/m2. Adiposity and FMI were unchanged by NAC. Sarcopenic obesity was found to be associated with adverse events among patients receiving NAC in the multivariable analysis. There were a total of 637 preoperative complications with grades 1-2 and 33 complications with grades 3-5. CONCLUSIONS: Based on our retrospective cohort study, NAC did not affect obesity and FMI, but there was a significant decrease in SMI. Sarcopenic obesity was associated with increased severity of NAC adverse events. As such, the presence of this factor may help predict tolerance of NAC.

Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer.

MicroRNAs (miRNAs) have emerged as key regulators of numerous biological processes, and increasing evidence suggests that circulating miRNAs may be useful biomarkers of clinical disease. In this study, we sought to identify plasma miRNAs that differentiate patients with metastatic castration resistant prostate cancer (mCRPC) from those with localized prostate cancer (PCa). Pooled plasma samples from patients with localized PCa or mCRPC (25 per group) were assayed using the Exiqon miRNA qPCR panel, and the differential expression of selected candidates was validated using qRT-PCR. We identified 63 miRNAs upregulated in mCRPC versus localized PCa, while only four were downregulated. Pearson's correlation analysis revealed two highly correlated groups: one consisting of miR-141, miR375 and miR-200c and the other including miR151-3p, miR423-3p, miR-126, miR152 and miR-21. A third group, containing miR-16 and miR-205, showed less correlation. One miRNA from each group (miR-141, miR151-3p and miR-16) was used for logistic regression analysis and proved to increase the sensitivity of the prostate-specific antigen (PSA) test alone. While no miRNA alone differentiated localized PCa and mCRPC, combinations had greater sensitivity and specificity. The expression of these 10 candidates was assayed for association with clinical parameters of disease progression through the cBio portal. Our results demonstrate that plasma levels of selected miRNAs are potential biomarkers to differentiate localized PCa and mCRPC.

Impact of the COVID-19 Pandemic on Medical Oncology Workload: A Provincial Review.

(1) Background: Cancer is the leading cause of death in Canada, with significant resource limitation impacting the delivery of cancer care nationwide. The onset of the COVID-19 pandemic forced additional resource restriction and diversion, further impacting care delivery. Our intention is to analyze the impact COVID-19 on a provincial medical oncology workload and bring attention to the limitations of the current workload metric for oncologists. (2) Methods: All medical oncology patient encounters were extracted and compared, collected by year and encounter type, from April 2014 through March 2022. (3) Results: There was an increase in all patient encounters by an average of 9.5% per year, including during the strictest COVID-19 restrictions. There was an increase in virtual care encounters from 37.9% to 52.1%. (4) Conclusions: Medical Oncology workloads have increased over time and estimates suggest growing demand. Little data exist to inform workforce requirements and actual workload is not captured by the current metric. Though volume of new consults continues to increase, COVID-19 has highlighted additional changes in the delivery of care, likely with lasting impact, little of which are included in the current workload metric.

Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease.

Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.

The impact of kidney function on the outcome of metastatic renal cell carcinoma patients treated with vascular endothelial growth factor-targeted therapy.

BACKGROUND: A study was undertaken to investigate the effect of baseline renal function on treatment outcome in patients treated with vascular endothelial growth factor (VEGF)-targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: Retrospective data from 6 North American cancer centers (3 US and 3 Canadian) were pooled to identify patients with mRCC treated with VEGF-targeted therapy. Patient characteristics, response rate, time to treatment failure, and overall survival were collected. The Modification of Diet in Renal Disease formula was used at therapy initiation for calculation of glomerular filtration rate (GFR). RESULTS: Five hundred twenty-nine patients with mRCC who received sunitinib (n = 323), sorafenib (n = 165), or bevacizumab (n = 41) were included in this analysis. Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1 mL/min/1.73 m(2) (range, 6.5-174.2). On univariate analysis, patients with a GFR <60 (n = 262) were more likely to have had a previous nephrectomy (P < .0001) and to be older (P < .0001), but were less likely to have poor prognostic features such as anemia (P = .041), hypercalcemia (P = .008), neutrophilia (P = .039), thrombocytosis (P < .0001), short diagnosis to treatment interval (P = .007), and low Karnofsky performance status (P = .051). GFR <60, when adjusted for poor risk factors, did not have an impact on type of objective response (odds ratio, 1.31; 95% confidence interval [CI], 0.74-2.32; P = .359), time to treatment failure (hazard ratio [HR], 0.97; 95% CI, 0.79-1.19; P = .772), or overall survival (HR, 0.90; 95% CI, 0.69-1.17; P = .439). CONCLUSIONS: Renal function at therapy initiation does not adversely affect the efficacy of VEGF-targeted therapy in mRCC. Clinicians should not avoid treating patients with impaired baseline renal function.

Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor.

BACKGROUND: Metastatic breast cancers have historically been presumed to have the same predictive biomarkers as the initial primary tumor. We compared the expression of these biomarkers in a large paired tissue microarray (TMA) series of primary and subsequent relapsed tumors. METHODS: Using the British Columbia Cancer Agency Breast Cancer Outcomes Unit database, patients with biopsy-proven relapses were identified and linked to a large TMA series of primary breast cancers from 1986-1992. Charts were reviewed, and tissue blocks of the metastatic cancer were collected to create a separate TMA. Immunohistochemical assessment with the same antibodies and conditions was performed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2 on both the primary and relapsed tumors. RESULTS: One hundred sixty cases were received that had tumor adequate for analyses. Of these, 71.9% had no changes in either the ER or PR status or HER-2 status. Of the 45 (28.1%; 95% confidence interval [CI], 21.2%-35.1%) tumors that did have changes in receptor status, 7.5% were in-breast recurrences or new breast primaries, 4.4% had changes in PR status only and were therefore deemed clinically irrelevant, and 19.4% (95% CI, 13.3%-25.5%) had changes in either the ER or HER-2 status from regional or distant relapses. Five percent of tumors had a receptor status change going from ER(+) or PR(+) to ER(-) or PR(-); 9.4% went from ER(-) or PR(-) to ER(+) or PR(+). With regard to HER-2 status, 3.8% of tumors went from positive to negative and 1.3% went from negative to positive. For all discordant cases, biopsies of the relapsed lesion were obtained prior to initiation of first-line treatment for metastatic disease. In the primary tumors that were ER(+), time to relapse was significantly shorter in the discordant relapsed cases than in the concordant ones (p = .0002). Changes in loss or gain of either biomarker were seen across the discordant cases. CONCLUSIONS: A significant proportion of relapsed tumors had changes in either ER or HER-2 status, which would dramatically alter treatment recommendations and clinical behavior. This study suggests that biopsies of relapsed and metastatic breast cancers should be performed routinely in clinical practice.

Micrometastatic node-positive breast cancer: long-term outcomes and identification of high-risk subsets in a large population-based series.

PURPOSE: The prognostic implication of breast cancer with nodal micrometastases measuring >0.2 mm but < or =2 mm (pNmic) is unclear. This study evaluates survival in pNmic relative to node-negative (N0) and macroscopic node-positive (pNmac) disease in a large population-based series. METHODS: Subjects were 9,637 women diagnosed between 1989 and 1999, referred to the British Columbia Cancer Agency with pT1-2, node-negative and node-positive, M0 breast cancer. Kaplan-Meier breast-cancer-specific survival (BCSS) and overall survival (OS) were compared between patients with pN0 (n = 7,988), pNmic (n = 491), and pNmac disease (n = 1,158), according to the number of positive nodes and the lymph node ratio (LNR) of positive to excised nodes. Cox regression and recursive partitioning analyses were performed to identify significant factors associated with survival. RESULTS: Median follow-up was 8.2 years. Patients with pNmic disease had significantly poorer outcomes compared with pN0 cancers, with progressively lower BCSS and OS with increasing number of positive nodes and with LNR > 0.25. On multivariable analysis, histologic subtype, T stage, number of positive nodes, LNR, grade, lymphovascular invasion, estrogen receptor status, and systemic therapy use were factors significantly associated with BCSS and OS. Recursive partitioning trees for BCSS and OS both selected the pN/LNR variable at the first split, indicating that this variable provided the strongest prognostic separation. CONCLUSION: Patients with nodal micrometastases are a heterogeneous population with varying breast cancer mortality risks. The number of positive nodes and the LNR should be considered in conjunction with tumor factors in risk estimates and treatment decisions for patients with nodal micrometastatic breast cancer.

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial.

BACKGROUND: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01499121.

A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205.

BACKGROUND: In PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B). PATIENTS AND METHODS: The primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B). RESULTS: A total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen. CONCLUSIONS: PX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.

Lapatinib for breast cancer: a review of the current literature.

IMPORTANCE OF THE FIELD: The identification of HER-2 expression as a predictive and prognostic marker revolutionized breast cancer. Trastuzumab, a humanized mAb, improves survival in both early and advanced HER-2 overexpressing breast cancer. However, many cancers either do not respond or develop resistance to this agent. Lapatinib is an oral tyrosine kinase inhibitor which has both HER-1 and -2 activities and has been licensed for use in recurrent breast cancer that overexpresses HER-2. Studies of lapatinib in early breast cancer are ongoing. AREAS COVERED IN THIS REVIEW: A PubMed search was conducted using 'lapatinib' and 'breast cancer' as the key words. All published works up to July 2010 were reviewed. A manual review of abstracts presented at the ASCO Annual meeting and the San Antonio Breast Cancer Symposium was conducted for the last 2 years. In this review, we summarize the current knowledge of lapatinib and pose questions which need to be addressed as we further expand our knowledge of the HER-2 subtypes of breast cancer. WHAT THE READER WILL GAIN: The reader will gain an up-to-date and comprehensive review of the current literature as it pertains to the safety and efficacy of lapatinib in the treatment of breast cancer. TAKE HOME MESSAGE: Lapatinib has provided an alternative for the treatment of advanced HER-2 overexpressing breast cancer and is currently being assessed in early disease.

Novel targeted therapies for prostate cancer.

This article reviews the concepts and rationale behind targeted agents that are currently in clinical testing for patients with castration resistant prostate cancer (CRPC). Advances in our understanding of the molecular mechanisms underlying prostate cancer progression has translated into a variety of treatment approaches. Agents targeting androgen receptor activation and local steroidogenesis, angiogenesis, apoptosis, chaperone proteins, the insulinlike growth factor pathway, RANK ligand, endothelin receptors, and Src family kinases are entering, or have recently completed, accrual to phase III trials for patients with CRPC. There has also been interest generated by data from early-phase studies evaluating multitargeted tyrosine kinase inhibitors, agents effecting signal transduction pathways, and novel cytotoxics.

Rasburicase prevents tumor lysis syndrome despite extreme hyperleukocytosis.

Hyperleukocytosis [white blood cell count (WBC) >100 x 10(9)/l] occurs in 5%-22% of pediatric patients with acute leukemia. Rasburicase (recombinant urate oxidase) is very effective for the prophylaxis and treatment of hyperuricemia, but its efficacy in marked hyperleukocytosis (WBC >200 x 10(9)/l) is not well known. We describe three children with marked hyperleukocytosis (WBC of 508, 320, and 242 x 10(9)/l) at initiation of induction chemotherapy. All three received rasburicase. Minimal metabolic disturbance occurred in all patients. We conclude that WBC reduction strategies may not be required solely for the risk of tumor lysis syndrome in patients with very high WBC (>200 x 10(9)/l) who are treated with rasburicase.