Jamie Riches

Phase II Study of Sunitinib in Patients With Metastatic Urothelial Cancer

PURPOSE No standard therapy exists for metastatic urothelial cancer (UC) that has progressed after initial chemotherapy. This trial was designed to assess the efficacy and tolerability of sunitinib in patients with advanced, previously treated UC. PATIENTS AND METHODS In this phase II trial, 77 patients received sunitinib between September 2006 and January 2009 on one of two schedules (50 mg per day for 4 weeks on and 2 weeks off [cohort A], 37.5 mg per day continuously [cohort B]), using a Simon 2 stage design in each cohort separately. RESULTS A partial response was seen in three of 45 patients (95% CI, 1% to 18%) in cohort A, and in one of 32 patients (95% CI, 0% to 16%) in cohort B. Clinical regression or stable disease was achieved in 33 of 77 patients (43%). Tumor regression lasted between 0.6 and 23.4 months with 29% of patients achieving response lasting longer than 3 months. The progression-free survival (2.4 v 2.3 months; P = .4) and overall survival (7.1 v 6.0 months; P = .4) were similar in both cohorts. There was one treatment-related death, and 47 patients (33 cohort A, 24 cohort B) experienced grade 3 or 4 toxicity. CONCLUSION Sunitinib did not achieve the predetermined threshold of >or= 20% activity defined by Response Evaluation Criteria in Solid Tumors. However, antitumor responses were observed, identifying the vascular endothelial growth factor axis as a viable pathway for UC treatment. The reported clinical benefit in previously treated patients warrants further investigation in a disease for which there is no US Food and Drug Administration-approved treatment.

Clinical Value of Fluorine-18 2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography in Bladder Cancer

PURPOSE Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been approved for imaging in many malignancies but not for bladder cancer. This study investigated the value of FDG-PET/CT imaging in the management of patients with advanced bladder cancer. PATIENTS AND METHODS Between May 2006 and February 2008, 57 patients with bladder cancer at our center underwent FDG-PET/CT after CT (n = 52) or magnetic resonance imaging (MRI; n = 5). The accuracy of FDG-PET/CT was assessed using both organ-based and patient-based analyses. FDG-PET/CT findings were validated by either biopsy or serial CT/MRI. Clinician questionnaires performed before and after FDG-PET/CT assessed whether those scan results affected management. RESULTS One hundred thirty-five individual lesions were evaluable in 47 patients for the organ-based analysis. Overall sensitivity and specificity were 87% (95% CI, 76% to 94%) and 88% (95% CI, 78% to 95%), respectively. In the patient-based analysis, malignant disease was correctly diagnosed in 25 of 31 patients, resulting in a sensitivity of 81% (95% CI, 63% to 93%). FDG-PET/CT was negative in 15 of 16 patients without malignant lesions for a specificity of 94% (95% CI, 71% to 100%). Pre- and post-PET surveys revealed that FDG-PET/CT detected more malignant disease than conventional CT/MRI in 40% of patients. Post-PET surveys showed that clinicians changed their planned management in 68% of patients based on the FDG-PET/CT results. CONCLUSION FDG-PET/CT has excellent sensitivity and specificity in the detection of metastatic bladder cancer and provides additional diagnostic information that enhances clinical management more than CT/MRI alone. FDG-PET/CT scans may provide better accuracy in clinical information for directing therapy.

Detection of circulating tumor cells in patients with urothelial cancer

BACKGROUND Approximately 50% of patients with metastatic urothelial cancer (UC) respond to chemotherapy and several months of therapy is required to assess for radiographic response. Blood-based biomarkers may identify patients in whom a specific therapy provides clinical benefit, and this study sought to characterize circulating tumor cells (CTCs) in patients with metastatic UC. PATIENTS AND METHODS Peripheral blood from patients with metastatic UC was evaluated for CTCs using the CellSearch system. We assessed for associations between CTC counts and the number and sites of metastatic disease. RESULTS CTC evaluations were carried out in 33 patients with metastatic UC. Fourteen of 33 patients (44%; 95% confidence interval 27% to 59%) had a positive assay (range 0-87 cells/7.5 ml of blood) with 10 patients (31%) having five or more CTCs. A significantly higher number of CTCs was seen in patients with two or more sites of metastases compared with those with less than one or one site of metastases (3.5 versus 0, P = 0.04). CONCLUSIONS CTCs, detected by antibody capture technology, are present in 44% of patients with metastatic UC. Higher numbers of CTCs are seen in patients with a greater number of metastatic sites. One-third of patients have five or more CTCs providing a potential early marker to monitor response to chemotherapy.

Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma.

FGFR3 mutations are common in low‐grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high‐grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry‐based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low‐grade lesions. Retrospective pathological review of the class of FGFR3 mutant HGUC revealed unique histological features, characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histological appearance was confirmed using a prospective set of 49 additional HGUCs. Prospective histological review was able to correctly predict for the presence of an FGFR3 mutation in 13/24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histological features were FGFR3 wild‐type for a negative predictive value of 100%. Macrodissection of individual tumours confirmed the presence of the FGFR3 mutant allele in non‐invasive and invasive, low and high‐grade regions of individual tumours and in the lymph node metastases of patients whose tumours possessed the characteristic morphological signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histological screening of HGUCs followed by confirmatory genotyping can be used to enrich for the population of HGUCs most likely to harbour activating mutations in the FGFR‐3 receptor tyrosine kinase. Histological review could thus aid in the development of targeted inhibitors of FGFR‐3 by facilitating the identification of the subset of patients most likely to harbour activating mutations in the FGFR3 gene. Copyright

Final Results of Sequential Doxorubicin Plus Gemcitabine and Ifosfamide, Paclitaxel, and Cisplatin Chemotherapy in Patients With Metastatic or Locally Advanced Transitional Cell Carcinoma of the Urothelium

PURPOSE Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity. PATIENTS AND METHODS Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles. RESULTS Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to >or= 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free. CONCLUSION AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.

Genetic Predictors of Response to Systemic Therapy in Esophagogastric Cancer

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein-Barr virus-positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49-58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14See related article by Pectasides et al., p. 37This article is highlighted in the In This Issue feature, p. 1.

Sunitinib in urothelial cancer: clinical, pharmacokinetic, and immunohistochemical study of predictors of response.

BACKGROUND Sunitinib has activity in patients with metastatic urothelial cancer (UC), but most patients do not respond. OBJECTIVE To identify predictors of response to sunitinib. DESIGN, SETTING, AND PARTICIPANTS Seventy-seven patients with advanced UC received sunitinib on one of two schedules at a single institution. Blood pressure (BP), immunohistochemistry (IHC), and pharmacokinetic (PK) results were correlated with response to sunitinib. MEASUREMENTS BP was assessed on day 1 and 28 of each cycle and on day 14 of cycle 1. IHC was performed on 55 samples from 38 cases using mammalian target of rapamycin and hypoxia-inducible factor (HIF) pathway marker antibodies. Blood samples for PK analysis were collected from 15 patients at three time points. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria. RESULTS AND LIMITATIONS Sunitinib-induced hypertension predicted improved response when hypertension was categorized as a discrete (p = 0.02) or continuous variable (p = 0.005 [systolic BP] and p = 0.007 [diastolic BP]). The odds ratio of response was 12.5 (95% confidence interval, 1.95-246.8) for grade 3/4 hypertension compared with grade 0. Response was associated with low HIF-1α expression in primary (p = 0.07) tissue. A nonstatistically significant trend was seen for an association between greater drug concentration and best response. A correlation between expression markers within the same pathways was identified, phosphorylated-4EBP1 and phosphorylated-S6 (p = 6.5 × 10(-9)), and vascular endothelial growth factor receptor 2 and HIF-1α (p = 0.008). Results are limited by small numbers. CONCLUSIONS Clinical and molecular biomarkers of response to sunitinib may have clinical relevance and require prospective validation. There is an urgent need for predictive biomarkers to guide the management of UC.

Sequential adjuvant chemotherapy after surgical resection of high-risk urothelial carcinoma†‡

Despite definitive surgery, the survival of patients with high‐risk urothelial carcinoma (UC) is poor. Adjuvant cisplatin‐based chemotherapy may be beneficial, but it is restricted by the need for normal renal function (RF). Sequential administration of adjuvant chemotherapy facilitates drug delivery and improves survival in patients with breast cancer. The objective of this study was to evaluate the feasibility and survival impact of adjuvant, sequential chemotherapy in patients with high‐risk UC.

Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

BACKGROUND Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.

False elevation of human chorionic gonadotropin in a patient with testicular cancer

Background. A 44-year-old, HIV-positive man presented with a painless swelling of his left testicle. He underwent left radical orchiectomy for a pathological stage T1 nonseminomatous germ cell tumor (NSGCT). A persistently elevated postoperative human chorionic gonadotropin (hCG) level resulted in the patient being diagnosed as having low-risk, stage 1S disseminated NSGCT. He was treated with four cycles of etoposide and cisplatin chemotherapy, but his hCG level had not returned to normal at the end of the treatment. Postchemotherapy CT showed no evidence of metastatic disease.Investigations. Measurement of serum levels of tumor markers, including α-fetoprotein, hCG and lactate dehydrogenase, scrotal ultrasonography, HIV-1 reverse transcriptase polymerase chain reaction, CT of the thorax, abdomen and pelvis, assessment of kidney function, and measurement of follicle-stimulating hormone and luteinizing hormone levels.Diagnosis. Falsely elevated serum hCG level caused by heterophile antibody interference in the hCG immunoassay.Management. The patients postchemotherapy serum samples were reanalyzed using a heterophile antibody blocking agent, the results of which showed no detectable hCG. No salvage therapy was required, and the patient remains in complete remission.