Courtney Carmichael

Novel Therapies for Metastatic Renal Cell Carcinoma: Efforts to Expand beyond the VEGF/mTOR Signaling Paradigm

With six agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (i.e., axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of VEGF or mTOR signaling). The current review will focus on investigational agents that diverge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients with mRCCs, a surge above the current plateau with these agents will likely require exploring new avenues. Mol Cancer Ther; 11(3); 526–37. ©2012 AACR.

Detection and Phenotyping of Circulating Tumor Cells in High-Risk Localized Prostate Cancer

BACKGROUND In this study, we aimed to determine the feasibility of identifying CTCs in patients with HRLPC, using a modified isolation procedure using the CellSearch (Veridex) platform, and to assess the expression of stem cell and epithelial-mesenchymal transition (EMT) markers on the CTCs. PATIENTS AND METHODS Thirty-five patients with HRLPC who had chosen prostatectomy for definitive management were prospectively identified. After obtaining consent, four 30-mL blood draws were performed, 2 before surgery and 2 after surgery. The CTC-containing fraction was Ficoll-purified and transferred to a CellSave (Veridex) tube containing dilution buffer before standard enumeration using the CellSearch system. Loss of E-cadherin expression, a marker of EMT, and CD133, a putative prostate cancer stem cell marker, were characterized using the open channel of the CellSearch platform. CTC fragments were also enumerated. RESULTS Using the modified methodology, CTCs were detectable in 49% of patients before surgery. Although no correlation between CTC count and biochemical recurrence (BR) was observed, the percentages of CD133 and E-cadherin-positive CTC fragments were associated with BR at 1 year. CONCLUSION Our results suggest that further research into the development of CTCs as prognostic biomarkers in HRLPC is warranted.

Clinical outcome in patients receiving systemic therapy for metastatic sarcomatoid renal cell carcinoma: A retrospective analysis☆ ☆

OBJECTIVES Sarcomatoid metastatic renal cell carcinoma (mRCC) represents an aggressive subset of disease, and a definitive therapeutic strategy is lacking. We seek to define outcomes associated with systemic therapy (including immunotherapy, cytotoxic therapy, and targeted agents) for sarcomatoid mRCC, with attention to novel prognostic schema. MATERIALS AND METHODS From an institutional database including 270 patients with mRCC, we identified 34 patients with documented sarcomatoid features. Within this cohort, we assessed 21 patients who received systemic therapy. Survival was assessed in the overall cohort and in subgroups divided by clinicopathologic characteristics, including the extent of sarcomatoid features, Memorial Sloan-Kettering Cancer Center (MSKCC) risk criteria, Heng criteria, and the nature of systemic therapy rendered. RESULTS Of the 21 patients assessed, 2 patients received chemotherapy, 7 patients received immunotherapy, and 12 patients received targeted agents as their first line treatment. Median overall survival (OS) in the overall cohort was 18.0 months (95% CI 6.9-22.0). By MSKCC criteria, patients with poor-risk disease had a median OS of 4.7 months, compared with 20.1 months for patients with intermediate-risk disease [hazard ratio (HR) 0.02, 95%CI 0.003-0.15; P = 0.0001]. A similar difference in median OS was seen poor- and intermediate-risk groups when stratifying by Heng criteria (HR 0.17, 95%CI 0.001-0.12). There was no significant difference in survival in patients with sarcomatoid predominant disease vs. nonpredominant disease (HR 0.62, 95%CI 0.23-1.65; P = 0.34), nor was there a difference amongst patients who received targeted therapies vs. nontargeted therapies (HR 1.0, 95%CI 0.61-1.40; P = 0.36). CONCLUSIONS Compared with previous series and prospective trials assessing patients with sarcomatoid mRCC, the observed survival was prolonged. Although both Heng and MSKCC risk scores may be useful in determining prognosis, further studies are needed to identify relevant biomarkers and define the optimal therapeutic strategy for this disease.

Recent advances in the therapy of castration-resistant prostate cancer: the price of progress.

Within the past two years, three agents have garnered approval from the US FDA for the specific treatment of metastatic castration resistant prostate cancer (mCRPC) - (1) abiraterone, (2) cabazitaxel and (3) sipuleucel-T. In separate phase III studies, each agent led to an improvement in overall survival (OS) of 2-4 months over a suitable comparator. With these costly therapies all having potential application in the patient with mCRPC, multiple entities (industry, government, and the general public) must strategize to determine how the cost burden of these agents can be balanced with the potential gains for the individual patient. Herein, we provide a framework with which to approach this dilemma.

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer.

Preclinical studies have suggested that VEGFR1-positive cells potentially foster the development of metastases by establishing a “premetastatic niche.” We sought to test this hypothesis in high-risk localized prostate cancer and assess potential niche modulation by the VEGFR1-targeting drug axitinib. Formalin-fixed, paraffin-embedded tissue derived from benign lymph nodes was collected and VEGFR1-positive cell clustering was assessed in benign lymph nodes via IHC. Recursive partitioning was used to define a threshold for VEGFR1 clustering that could segregate patients based on time to biochemical recurrence (TTBR). Multivariate analyses were used to determine whether VEGFR1 clustering, age, pathologic T-stage, Gleason score, or baseline PSA could independently predict TTBR. A randomized, phase II clinical trial comparing axitinib for 28 days followed by radical prostatectomy and pelvic lymph node dissection (RP/PLND) to RP/LND alone was then conducted, with the primary endpoint of demonstrating downregulation of VEGFR1-positve cell clustering in benign lymph nodes. Our retrospective analysis assessed a cohort of 46 patients. A threshold of 1.65 VEGFR1-positive cells per high power field was identified, below which TTBR was delayed. VEGFR1 clustering was an independent predictor of TTBR in a multivariate analysis. Only 11 out of the planned 44 patients were accrued to the phase II trial. While preoperative axitinib was safe and well tolerated, there was no sign of clinical activity or VEGFR1 downregulation. Our results validate previous findings that suggest VEGFR1-positive cells in benign lymph nodes can predict clinical outcome. Further work is needed to develop a viable clinical strategy for modulating VEGFR1 in these tissues. Mol Cancer Ther; 14(12); 2896–900. ©2015 AACR.

Quality of Life in Patients With Metastatic Renal Cell Carcinoma: Assessment of Long-Term Survivors

BACKGROUND An emerging literature describes the potential for long-term survival with targeted agents, but the health-related quality of life (HR-QOL) in patients who receive chronic therapy with these agents is poorly defined. METHODS From an institutional database including 562 patients with renal cell carcinoma (RCC), patients were identified who (1) were alive 3 years beyond initiation of systemic therapy for metastatic renal cell carcinoma (mRCC) and (2) received a targeted therapy as a component of their treatment. European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 36 (QLQ-C30) and Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-15) questionnaires were administered by telephone survey. Data from questionnaires were compared with historical estimates derived from pivotal studies evaluating targeted agents. RESULTS A total of 38 patients met eligibility criteria for the study, and 28 patients participated in the telephone survey. Most were male patients and had clear cell histologic type (75% for both). All patients had either good- or intermediate-risk disease by Heng criteria. The mean QLQ-C30 Global QOL score in the present cohort was higher than the mean score among patients evaluated at baseline in the phase III evaluations of pazopanib (73.5 vs. 65.8; P = .07) and everolimus (73.5 vs. 61.0; P = .007). The FKSI-15 score in the present cohort was similar to the mean score among patients evaluated at baseline in the phase III evaluation of sunitinib (45.1 and 46.5, respectively; P = .41). CONCLUSION In this small pilot study, long-term survivors with mRCC who received targeted therapies appear to have an HR-QOL comparable to that of patients who participated in relevant phase III studies. Given the many emerging treatment options for mRCC, the HR-QOL of long-term survivors warrants greater attention.

Paclitaxel-Based High-Dose Chemotherapy with Autologous Stem Cell Rescue for Relapsed Germ Cell Tumor: Clinical Outcome and Quality of Life in Long-Term Survivors

BACKGROUND High-dose chemotherapy (HDCT) is a viable and potentially curative approach for patients with relapsed or refractory germ cell tumors (GCTs). However, no comparative data exist to define the optimal chemotherapeutic strategy, and little is known about the quality of life (QOL) of long-term survivors. Herein we attempt to characterize the QOL in long-term survivors who received high-dose paclitaxel, etoposide, carboplatin, and ifosfamide (TECTIC). PATIENTS AND METHODS Details of the TECTIC regimen and clinical outcomes for the initial 33 patients have been reported. In the present study, we report the clinical data for 15 additional patients. Using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Functional Assessment of Cancer Therapy-Taxane (FACT-T) questionnaires, we surveyed all patients who survived at least 4 years after HDCT. RESULTS Forty-eight patients were enrolled and 46 patients received protocol therapy. For all 48 patients, the median progression-free survival (PFS) and overall survival (OS) were 11.8 months (range, 5.8-not reached) and 21.7 months (range, 12.7-not reached), respectively. Seventeen patients were progression free at a median of 123.2 months (51.6-170.2 months), and 6 patients remain alive after progression with a median OS of 68.8 months (47.6-147.1 months). Of the 23 surviving patients, 18 were accessible and consented to telephone interviews. Compared with historical cohorts, survivors had a higher global health scale score (87.04 vs. 75.62; P = .02) but a lower physical functioning score (68.89 vs. 92.66; P = .0001) by the QLQ-C30 scale. CONCLUSIONS HDCT with the TECTIC regimen produces durable remissions in patients with relapsed or refractory GCTs with acceptable QOL in long-term survivors.

Stool Bacteriomic Profiling in Patients with Metastatic Renal Cell Carcinoma Receiving Vascular Endothelial Growth Factor–Tyrosine Kinase Inhibitors

Purpose: Diarrhea occurs in approximately half of patients with metastatic renal cell carcinoma (mRCC) receiving vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKI). We evaluated the relationship between VEGF-TKI–related diarrhea and stool microbiota. Experimental Design: Stool samples were collected from 20 mRCC patients receiving VEGF-TKIs. 16S rRNA sequencing was used to characterize the stool bacteriomic profiling of patients. Assay validation with Salmonella typhimurium spike-in experiments suggested greatest speciation with use of the V5 region. Results: Higher levels of Bacteroides spp. and lower levels of Prevotella spp. were found in patients with diarrhea. In addition, patients receiving VEGF-TKIs with mRCC appeared to have less relative abundance of Bifidobacterium spp. as compared with previous reports based on healthy subjects. Conclusions: We have thus demonstrated interplay between microbiota and VEGF-TKI–induced diarrhea. Further studies are warranted to evaluate the potential causative role of preexisting dysbiosis in VEGF-TKI–related diarrhea. Clin Cancer Res; 21(23); 5286–93. ©2015 AACR.

Comparison of radiographic characteristics of renal cell carcinoma (RCC) brain metastases treated with vascular endothelial growth factor (VEGF)-directed therapies or radiotherapy.

479 Background: With improvements in systemic therapy for metastatic RCC (mRCC), an increased frequency of brain metastases (BM) has been observed, perhaps owing to the central nervous system (CNS) serving as a sanctuary site. The response of BM to VEGF-directed therapies has been poorly characterized. Methods: Patients (pts) with mRCC BM were identified from an institutional database. Selection of pts was further refined to pts who had received either VEGF-directed therapy during their diagnosis with BM or radiotherapy directed to their BM. Only those pts with brain MRI straddling systemic therapy and radiotherapy were selected for analysis. Imaging studies were anonymized and transmitted to an independent radiologist for review. Descriptive statistics were applied to characterize the change in sum of long axis dimensions (SLD) in two separate groups: (1) pts treated with VEGF-directed therapy and (2) pts treated with radiotherapy. Results: Of 276 pts with mRCC in our institutional database, 34 pts with ...

Elevated pS6K levels in the sarcomatoid component of tumors derived from patients with metastatic renal cell carcinoma (mRCC).

475 Background: Consistent with other retrospective analyses, data from our institutional experience indicates that patients (pts) with sarcomatoid mRCC have a poorer outcome as compared to pts that lack sarcomatoid features (Pal SK, et al. Urol Oncol 2012). The preponderance of correlative studies to date focused on epithelial-to-mesenchymal transition (EMT) as a driver of sarcomatoid disease; however, the role of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling is poorly understood. METHODS Of 270 pts with mRCC in our institutional database, 21 pts were noted to have sarcomatoid features. Thirteen of these pts had available tissue from nephrectomy or diagnostic biopsy. An additional 13 pts with mRCC and available tissue were identified from the database who had a similar MSKCC risk stratification but lacked sarcomatoid features. Immunohistochemical staining were performed for moieties related to VEGF-mediated signaling (pS6K) and EMT (Twist, E-cadherin and N-cadherin). RESULTS Among matched pts with and without sarcomatoid features (n=13 for each group), 9 pts (69.2%) in each group had poor risk disease by MSKCC criteria, while the remainder had intermediate risk disease. Given our risk-matching approach, median survival was similar in both groups (6 mos in pts with no sarcomatoid features vs. 9 mos in pts with sarcomatoid features, p = NS). In evaluable specimens from pts with no sarcomatoid features, the proportion of cell staining positively for pS6K was 24.4%. A higher proportion of pS6K staining was found in pts with sarcomatoid mRCC, both in sarcomatoid components (60.0%) and non-sarcomatoid components (52.5%). Staining for N-cadherin, E-cadherin, and Twist were highly variable, and no observable differences between groups were identified. CONCLUSIONS Although chemotherapeutic strategies are a common 1st-line approach to sarcomatoid mRCC, the finding of higher pS6K staining in this population suggest the potential for currently approved targeted therapies in this disease. Prospective assessment of VEGF- and mTOR-directed therapies for sarcomatoid mRCC, as in ECOG 1808 (NCT01164228), should be encouraged.