Marijo Bilusic

Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

BACKGROUND Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

A phase II randomized clinical trial of samarium-153 EDTMP (Sm-153) with or without PSA-TRICOM vaccine in metastatic castration-resistant prostate cancer (mCRPC) after docetaxel.

102 Background: A prior randomized, placebo-controlled, multi-center phase 2 trial of PSA-TRICOM demonstrated survival benefit. Sm-153 is a radiopharmaceutical that targets osteoblastic lesions. Preclinical data indicated that Sm-153 could alter tumor phenotype, causing upregulation of Fas, MHC Class I, and tumor-associated antigens, making tumor cells more amenable to immune-mediated killing. This trial was intended to examine the safety and efficacy of the Sm-153 with PSA-TRICOM vs. Sm-153 alone. METHODS This phase 2 multi-center trial was designed to randomize 68 pts to Sm-153 with or without PSA-TRICOM. Eligibility included mCRPC, bone metastases, no visceral disease, prior docetaxel, ECOG ≤2, and normal organ function. Sm-153 was given at 1mCi/kg IV on day 8 and then every 12 weeks. PSA-TRICOM was given on days 1, 15, 29, then every 4 weeks. The 1° endpoint was comparison of progression-free survival at 4 months (mo) utilizing PCCWG, but not PSA criteria. A Fishers exact test, assuming a one-tailed alpha = 0.10, was used to compare these fractions. 2° endpoints were OS, ORR, PSA changes, immunologic, and toxicity. RESULTS 44 pts were enrolled, 5 were not evaluable for the 1° endpoint due to withdrawal prior to 4 mos (4 on Arm A, 1 on Arm B). PFS and PSA findings are provided below. Hematologic toxicities were most common, and were well matched. CONCLUSIONS This final analysis suggests the combination of PSA-TRICOM and Sm-153 has a similar toxicity profile to Sm-153 alone. Despite early closure of this trial due to poor accrual, which may be related to recent approval of multiple agents for mCRPC, this analysis appears to demonstrate improvement in PFS with the combination. This may indicate synergy between PSA-TRICOM and bone-seeking radiopharmaceuticals. Based on the data presented here, we are exploring the potential to combine PSA-TRICOM with alpharadin (radium-223), a next generation bone-seeking radiopharmaceutical. CLINICAL TRIAL INFORMATION NCT00450619. [Table: see text].

Therapeutic cancer vaccines: the latest advancement in targeted therapy.

Therapeutic cancer vaccines represent an emerging therapeutic modality that may play a more prominent role in cancer treatment in the future. Therapeutic cancer vaccines are designed to generate a targeted, immune-mediated antitumor response. There are 2 main types of therapeutic vaccines: patient-specific (generated either from a patients own cells or tumor) and patient- nonspecific, where a peptide- or vector-based vaccine induces an immune response in vivo against specific tumor-associated antigens. Studies are currently underway to investigate methods to enhance vaccine strategies, including combinations with standard anticancer therapies or immune-modulating agents. Cancer vaccines are usually well tolerated, with minimal toxicity compared with chemotherapy. This review summarizes selected therapeutic cancer vaccines in late clinical development.

Relationships Among Financial Distress, Emotional Distress, and Overall Distress in Insured Patients With Cancer.

PURPOSE Recent studies have demonstrated increasing rates of financial toxicities and emotional distress related to cancer treatment. This study assessed and characterized the relationships among financial distress, emotional symptoms, and overall distress in patients with cancer. METHODS A cross-sectional sample of patients with cancer who visited our outpatient medical oncology and psychiatry clinics completed a pen-and-paper survey. The survey assessed demographics; cost concerns; and financial, emotional, and overall distress. RESULTS One hundred twenty insured patients completed the survey. Sixty-five percent reported clinically significant overall distress scores, with the same percentage reporting at least one emotional problem (worry, anxiety, depression, etc). Twenty-nine percent scored in the range of high to overwhelming financial distress. By using structural equation modeling, we found that financial distress was associated with overall distress. This association was both direct (accounting for 76% of the effect) and indirect (accounting for 24% of the effect) via mediation by emotional distress. CONCLUSION This cohort of patients with cancer reported significant levels of emotional distress, financial distress, and overall distress. These factors were interrelated, with both financial and emotional distress contributing to overall distress. Interventions targeted at alleviating financial distress may help to decrease levels of overall distress.

Is extended pharmacologic venous thromboembolism prophylaxis uniformly safe after radical cystectomy

OBJECTIVE To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. METHODS Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. RESULTS Three hundred four patients with eGFR >30 mL/min/1.73 m(2) at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m(2) threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m(2) was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR ≥60 mL/min/1.73 m(2) with those with a discharge GFR <60 mL/min/1.73 m(2). CONCLUSION More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC.

A review of interventional clinical trials in renal cell carcinoma: a status report from the ClinicalTrials.gov WebSite.

INTRODUCTION The treatment of renal cell carcinoma (RCC) has undergone a major shift over the past 10 years and continues to evolve. The objective of this study was to assess the current landscape of clinical trials (CTs) in RCC to identify areas of strength and opportunities for improvement. MATERIALS AND METHODS ClinicalTrials.gov was queried using 17 prespecified search criteria. Only open, RCC-dedicated, interventional CTs in adult patients were included. Descriptive statistics and Fisher exact tests were used to compare features of CTs. RESULTS The study cohort consisted of 169 trials. Phase II trials were the most common (67, 39.6%) and 52.7% (89) of CTs examined patients with stage IV disease. Only 26.6% (45) were randomized and 64.5% (109) were single-arm. Targeted therapies (TTs) were studied in 47.9% (81) of CTs overall and 71.1% (81 of 114) of the systemic therapy trials. Immunotherapies (ITs) were the next most common systemic therapy accounting for 5.9% (10) of trials. The primary end point of feasibility or biomarker analysis, progression-free survival, or overall survival was noted in 27.8%, 51.5%, and 2.1% of TT CTs (27, 50, 2 trials, respectively) and 42.9%, 35.7%, and 14.3% of IT CTs (6, 5, 2 trials respectively; P = .037). Biomarkers were assessed in 45% (76) of CTs overall and were more frequently examined in TT and IT CTs (53.6% [52/97] and 64.3% [9/14]) than in surgery and other CTs (22.2% [4/18] and 27.5% [11/40]; P = .002). Sponsorship differed according to treatment type (P = .003). CONCLUSION Clinical trials in RCC are largely nonrandomized, single-arm, with minimal focus on non-clear-cell RCC. Significant differences were noted in the primary end point, sponsorship, and biomarker assessment between treatment types.

Spontaneous Tumor Lysis Syndrome in Renal Cell Carcinoma: A Case Report

Spontaneous tumor lysis syndrome (STLS) is a rare oncologic emergency caused by acute and massive death of tumor cells before the initiation of any anticancer therapy. It is commonly associated with aggressive hematological malignancies; however, it has been more frequently recognized in multiple solid tumors. Our literature search of STLS in solid tumors revealed common characteristics including extensive metastatic disease and increased levels of uric acid and lactate dehydrogenase. In this report, we describe, to our knowledge, the first case of STLS caused by a renal cell carcinoma and discuss the need for developing screening guidelines for this deadly syndrome.

Anti-angiogenesis in prostate cancer: knocked down but not out

Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors (stimulators and inhibitors). This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms: by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration (FDA) approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and promising area of prostate cancer research.

Effect of Talactoferrin Alfa on the Immune System in Adults With Non-Small Cell Lung Cancer

BACKGROUND Talactoferrin alfa (talactoferrin), an agent with immune-stimulating properties, has demonstrated safety and preliminary efficacy in clinical trials. METHODS Ten patients (five males and five females) with stage IV non-small cell lung cancer (NSCLC) in a single-arm pilot study received orally administered talactoferrin (1.5 g, b.i.d.) for up to 24 weeks. Radiographic and immunologic studies were performed at baseline and at weeks 6 and 12. Circulating immune cells (natural killer cells [NKCs], CD4+, CD8+, and regulatory T cells) and systemic cytokine levels were measured to assess immune response. RESULTS Patients enrolled in the study had received a median of four prior chemotherapy regimens, and all patients were symptomatic. Talactoferrin was well tolerated, with no grade 3 or 4 toxicities. Median time to progression (TTP) and overall survival were 6 weeks and 14.5 weeks, respectively. The four patients with ≥9 weeks TTP had evidence of immunologic activity (three with increased NKC activity). CONCLUSIONS The median of four previous chemotherapy regimens, with elevated levels of interleukin (IL) 6 and tumor necrosis factor-alfa in most patients, suggests these patients were poor candidates for immunotherapy.

Therapeutic Cancer Vaccines in Prostate Cancer: The Quest for Intermediate Markers of Response

Despite recent advances in cancer immunotherapy, no prospectively validated intermediate biomarkers exist to predict response. These biomarkers are highly desirable given modern immunotherapy’s paradoxical pattern of clinical benefit; that is, improvement in overall survival without short-term change in progression. Immunotherapy clinical trials have evaluated biomarkers that may correlate with clinical outcomes. Many of them are performed on peripheral blood to evaluate the systemic response, such as tumor-targeted humoral and cellular immunity, and cytokine responses. Accumulating evidence suggests that immune infiltrates in tumors may suggest evidence for the therapy’s mechanism of action, and have greater potential for providing prognostic and predictive information. In addition, a non-immunologic biomarker, such as tumor growth kinetics, may explain this paradoxical pattern of clinical benefit, and predict survival in patients treated with an immunotherapy. Prospective assessment and validation of these and other intermediate markers would be required to better understand their potential clinical role.