Tina M. Mayer

Plasma markers for identifying patients with metastatic melanoma

Purpose: With the rising incidence of melanoma, more patients are undergoing surveillance for disease recurrence. Our purpose was to study levels of proteins that might be secreted in the blood of patients with metastatic melanoma that can be used for monitoring these individuals. Methods: Genome-wide gene expression data were used to identify abundantly expressed genes in melanoma cells that encode for proteins likely to be present in the blood of cancer patients, based on high expression levels in tumors. ELISA assays were employed to measure proteins in plasma of 216 individuals; 108 metastatic melanoma patients and 108 age- and gender-matched patients with resected stage I/II disease split into equal-sized training and test cohorts. Results: Levels of seven markers, CEACAM (carcinoembryonic antigen–related cell adhesion molecule), ICAM-1 (intercellular adhesion molecule 1), osteopontin, MIA (melanoma inhibitory activity), GDF-15 (growth differentiation factor 15), TIMP-1 (tissue inhibitor of metalloproteinase 1), and S100B, were higher in patients with unresected stage IV disease than in patients with resected stage I/II disease. About 81% of the stage I/II patients in the training set had no marker elevation, whereas 69% of the stage IV patients had elevation of at least one marker (P < 0.0001). Receiver operating characteristic curves for the markers in combination in these two patient populations had an area under curve (AUC) of 0.79 in the training set and 0.8 in the test set. A CART (Classification and Regression Trees) model developed in the training set further improved the AUC in the test set to 0.898. Conclusions: Plasma markers, particularly when assessed in combination, can be used to monitor patients for disease recurrence and can compliment currently used lactate dehydrogenase and imaging studies; prospective validation is warranted. Clin Cancer Res; 17(8); 2417–25. ©2011 AACR.

First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163–9. ©2017 AACR.

Can We Predict Bevacizumab Responders in Patients With Glioblastoma

Glioblastoma is among the most devastating of oncologic diagnoses, with the disease being characterized by its aggressive recurrent nature and poor prognosis. Initial treatment with temozolomide in addition to radiation has been demonstrated to confer a modest survival benefit. 1 Since the US Food and Drug Administration approval of temozolomide in 2005, no other systemic therapies have been approved on the basis of demonstration of improvement in overall survival. Bevacizumab was approved by the US Food and Drug Administration in 2009 for monotherapy in patients with recurrent glioblastoma on the basis of two phase II trials that demonstrated durable objective response rates. 2,3 The hope was that the Radiation Therapy Oncology Group (RTOG) 0825 (Temozolomide and Radiation Therapy With or Without Bevacizumab in Treating Patients WithNewlyDiagnosedGlioblastoma)andAVAglio(AStudyofAvastin (Bevacizumab) in Combination With Temozolomide and Radiotherapy in Patients With Newly Diagnosed Glioblastoma) studies would demonstrate an overall survival benefit with the use of bevacizumab. Both of these studies included patients with newly diagnosed glioblastoma who were undergoing standard of care treatment with concurrenttemozolomideandradiationandwererandomlyassigned to either bevacizumab or placebo. They demonstrated benefits in progression-free survival favoring the bevacizumab arm, but no such benefit was demonstrated in overall survival. 4,5 Looking at the subgroup analysis in the AVAglio study population, clinical prognostic factors such as extent of resection, performance status, recursive partitioning analysis class, baseline steroid use, and O 6 -methylguanineDNA-methyltransferase analysis of tumor tissue, did not seem to be predictiveofresponse. 4 Patientsinthisstudydidseemtobenefitfrom bevacizumabintermsofmaintenanceofqualityoflife. 4 However,the RTOG 0825 study had conflicting results, with higher rates of neurocognitive decline in patients on the bevacizumab arm. 5

Muscadine Grape Skin Extract (MPX) in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial

Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy. Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics. Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7–83.1), low dose 1.5 months (n = 52; range, 10.3–87.2), high dose 0.9 months (n = 40; range, 27.3–88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3–4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25). Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306–15. ©2017 AACR.

Does Certificate of Need Minimize Intensity Modulated Radiation Therapy Use in Patients with Low Risk Prostate Cancer

Introduction: Certificate of need laws are optional from state to state, and are meant to limit the proliferation of certain unnecessary medical facilities. Theoretically, certificate of need laws should limit the use of intensity modulated radiation therapy in the population who likely would benefit from it the least, that is older or frail men with low risk prostate cancer. We evaluated the effect of certificate of need laws on the use of intensity modulated radiation therapy in these patients in a population based cohort. Methods: Using the SEER (Surveillance, Epidemiology, and End Results) database linked with Medicare files we identified male residents of SEER regions who were diagnosed in 2004 to 2009 with low risk prostate cancer (T1, Gleason 6 or less, prostate specific antigen less than 10 ng/ml), who were 70 years old or older, or 65 years old or older, with a Charlson comorbidity score of 2 or greater. The end point was percentage of newly diagnosed patients who were treated with intensity modulated radiation therapy within 12 months of cancer diagnosis. Logistic regression was used to assess the impact of certificate of need laws on the use of intensity modulated radiation therapy. Results: More than 37% (4,491) of the patients came from states with radiation oncology certificate of need laws whereas 63% (7,572) came from states without certificate of need laws. Intensity modulated radiation therapy was performed in 30% of certificate of need cases vs 28% of noncertificate of need cases. Logistic regression analysis revealed that intensity modulated radiation therapy was used more often in states with certificate of need laws than in states without certificate of need laws (OR 1.13, 95% CI 1.04–1.23, p=0.006). Conclusions: Certificate of need laws do not effectively limit the use of intensity modulated radiation therapy in older or frail patients with low risk prostate cancer.

Intra-abdominal seminoma found incidentally during trauma workup in a man with bilateral cryptorchidism

Bilateral cryptorchidism is a rare occurrence and seminoma is the most common germ cell tumor found in undescended testes when they occur. We present the case of a patient with bilateral cryptorchidism who presented to our trauma center after a motor vehicle collision and was found incidentally to have a 17-cm intra-abdominal mass. The mass was subsequently biopsied and proven to be seminoma. The patient completed three cycles of bleomycin/etoposide/cisplatin chemotherapy and successfully underwent a postchemo retroperitoneal lymph node dissection with no viable residual tumor or positive lymph nodes found in the surgical specimen. He also had an orchiopexy of the contralateral testicle. The patient recovered fully and has been found to be recurrence-free four months postoperatively. We highlight the importance of cisplatin-based chemotherapy and extensive tumor resection as the mainstay of initial cancer control.

A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. RESULTS We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69-97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. CONCLUSIONS In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

Results of Phase 1 Study on Cytoreductive Radical Prostatectomy in Men with Newly Diagnosed Metastatic Prostate Cancer

Background Preclinical and retrospective data suggest that cytoreductive radical prostatectomy may benefit a subset of men who present with metastatic prostate cancer (mPCa). Herein, we report the results of the first planned Phase 1 study on cytoreductive surgery. Methods From four institutions, 36 patients consented to the study. However, four did not complete surgery because of rapid disease progression (n = 3) and another because of an intraoperatively discovered pericolonic abscess. Men with newly diagnosed clinical mPCa to lymph nodes or bones were eligible. The primary endpoint was the rate of major perioperative complications (Clavien-Dindo Grade 3 or higher) occurring within 90 days of surgery. Results The mean age at surgery was 64.0 years. The 90-day overall complication rate was 31.2% (n = 10), of which two (6.25%) were considered major complications: one acute tubular necrosis requiring temporary dialysis and one death. In men with more than 6 months of follow-up, 67.9% had prostate specific antigen nadir ≤0.2 ng/mL, while one patient experienced a rapid rise in prostate specific antigen and another a widely disseminated disease that resulted in death 5 months after surgery. Altogether, these results demonstrate that cytoreductive radical prostatectomy is safe and surgically feasible in selected patients who present with mPCa . Yet, there may be a small subset of patients in whom surgery may cause a significant harm. Conclusion Therefore, cytoreductive surgery in men with mPCa should be limited to clinical trials until robust data are available.

Effect of alvimopan on gastrointestinal recovery and length of hospital stay after retroperitoneal lymph node dissection for testicular cancer

Objective: Alvimopan use has reduced the length of hospital stay in patients undergoing major abdominal surgeries and radical cystectomy. Retroperitoneal lymph node dissection for testicular cancer may be associated with delayed gastrointestinal recovery prolonging hospital length of stay. We evaluate whether alvimopan is associated with enhanced gastrointestinal recovery and shorter hospital length of stay in men undergoing retroperitoneal lymph node dissection for testicular cancer. Materials and methods: From 2010 to 2016, 29 patients underwent open, transperitoneal bilateral template retroperitoneal lymph node dissection. Data for patients who received alvimopan were prospectively collected and compared to a historical cohort of patients who did not receive alvimopan. Primary outcome measures were length of stay and recovery of gastrointestinal function. Descriptive statistics were reported. Time-to-event outcomes were evaluated using cumulative incidence curves and log rank test. Factors associated with length of stay were analyzed for correlation using multiple linear regression. Results: Of 29 men undergoing retroperitoneal lymph node dissection, eight received alvimopan and 21 did not. The two cohorts were well matched, with no significant differences. In the alvimopan cohort compared with those who did not receive alvimopan median time to return of flatus was 2 versus 4 days (p=0.0002), and median time to first bowel movement was 2.5 versus 5 days (p=0.046), respectively. Median length of stay in the alvimopan cohort was 4 days versus 6 days in those who did not receive alvimopan (p=0.074). In adjusted analyses, receipt of alvimopan did not influence length of stay. Conclusion: Alvimopan may facilitate gastrointestinal recovery after retroperitoneal lymph node dissection for testicular cancer. Whether this translates into reduced length of stay needs to be determined by randomized controlled trials using larger cohorts. Level of evidence: 3b.

Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma

Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-low ccRCC tumors. Similar results were observed in ER+/HER2- breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and πERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.