Deirdre Jill Cohen

Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

PURPOSE GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. PATIENTS AND METHODS Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. RESULTS A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. CONCLUSION Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

Purpose Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models. Patients and Methods Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied. Results No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model. Conclusion The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance

Purpose: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. Experimental Design: Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. Results: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. Conclusions: HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels. Clin Cancer Res; 20(15); 3974–88. ©2014 AACR.

Controversies in the Treatment of Local and Locally Advanced Gastric and Esophageal Cancers

Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched.

An expert opinion on esophageal cancer therapy

Introduction: Worldwide, esophageal cancer (EC) is the seventh leading cause of cancer-related death, with its incidence increasing in the US, where a change in its epidemiology has been noted. Most patients present with regional or distant disease and, therefore, have a very poor prognosis. Areas covered: Progress made over the last 20 years in the diagnosis, staging and management of EC is focused on in this review, with the emphasis on locally-advanced disease treated with curative intent. Evidence is reviewed from prospective randomized trials and meta-analyses and data are presented regarding new therapy with targeted agents. Although surgery has been the mainstay of treatment for EC, survival with this approach alone remains disappointing. As a result, combined modality treatment (CMT) including chemotherapy and radiation has been incorporated into the treatment paradigm for both operable and inoperable disease. The evidence supporting CMT for EC, the role of surgery at different stages, and how treatment strategies differ based on histology are outlined. Expert opinion: Trends in 5-year overall survival rates over the last 30 years have increased (from 5 to 17%), suggesting that small, yet significant, improvements in diagnosis, staging, treatment and supportive care are being made. Clearly, the choice of treatment should be guided by disease stage, histology and patient co-morbidities.

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.

BACKGROUND Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.

Mucinous tubular and spindle cell carcinoma of the kidney: Diagnosis by fine needle aspiration and review of the literature

Renal mucinous tubular and spindle cell carcinoma (MTSCC) was recently described as a distinct subtype of renal cell carcinoma (RCC) in the 2004 World Health Organization classification of kidney tumors. MTSCC is a rare low grade malignancy with < 100 cases reported in the literature. To the best of our knowledge, there are 5 case reports with a total of 6 patients describing its diagnosis by fine needle aspiration (FNA). All of these cases were diagnosed as conventional RCC on FNA. Subsequent excisions proved them to be MTSCC. We herein report a case in a 67-year-old male. He presented with abdominal pain and was found to have a new colon adenocarcinoma with metastasis to the liver and lungs. The extent of disease made the patient ineligible for surgical excision, and he received chemotherapy. Work-up also revealed a kidney mass which was later biopsied by FNA and core biopsy. The tumor was composed of epithelial and spindled cell components embedded in a myxoid background. It was positive for CK7, AMCAR, vimentin, and epithelial membrane antigen. The tumor was diagnosed as MTSCC. One year later the kidney mass remained stable. However, the patient developed new metastasis to the liver from colonic primary. The kidney mass was not resected. Although rarely encountered in FNA cytology of the kidney, we believe the cytologic features of this tumor are distinctive and are different from conventional and other subtypes of RCC. Therefore, its accurate diagnosis on FNA is possible once pathologists are aware that MTSCC should be considered in the differential diagnosis of kidney tumors.

Can we downstage locally advanced pancreatic cancer to resectable? A phase I/II study of induction oxaliplatin and 5-FU chemoradiation

Background Half of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemoradiation (CH-RT) is used in this setting in attempt to control local disease, and possibly downstage to resectable disease. We report a phase I/II trial of a combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with borderline resectable and locally advanced unresectable pancreatic cancer. Methods Patients with biopsy-proven borderline resectable or locally advanced unresectable PC were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) daily and oxaliplatin weekly for 5 weeks in dose escalation cohorts, ranging from 30 to 60 mg/m2. Concurrent radiation therapy consisted of 4,500 cGy in 25 fractions (180 cGy/fx/d) followed by a comedown to the tumor and margins for an additional 540 cGy ×3 (total dose 5,040 cGy in 28 fractions). Following completion of CH-RT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (SD, stable disease) received mFOLFOX6 ×6 cycles. Survival was calculated using Kaplan-Meier analysis. End-points of the phase II portion were resectability and overall survival. Results Overall, 24 subjects (15 men and 9 women, mean age 64.5 years) were enrolled between June 2004 and December 2009 and received CH-RT. Seventeen patients were enrolled in the Phase I component of the study, fifteen of whom completed neoadjuvant therapy. Reasons for not completing treatment included grade 3 toxicities (1 patient) and withdrawal of consent (1 patient). The highest dose of oxaliplatin (60 mg/m2) was well tolerated and it was used as the recommended phase II dose. An additional 7 patients were treated in the phase II portion, 5 of whom completed CH-RT; the remaining 2 patients did not complete treatment because of grade 3 toxicities. Overall, 4/24 did not complete CH-RT. Grade 4 toxicities related to initial CH-RT were observed during phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leukopenia and thrombocytopenia). Following restaging after completion of CH-RT, 4 patients had progressed (PD); 9 patients had SD and received additional chemotherapy with mFOLFOX6 (one of them had a dramatic response after two cycles and underwent curative resection); the remaining 7 patients (29.2%) were noted to have a response and were explored: 2 had PD, 4 had SD, still unresectable, and 1 patient was resected for cure with negative margins. Overall 2 patients (8.3%) in the study received curative resection following neoadjuvant therapy. Median overall survival for the entire study population was 11.4 months. Overall survival for the two resected patients was 41.7 and 21.6 months. Conclusions Combined modality treatment for borderline resectable and locally advanced unresectable pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen were comparable to others for locally advanced pancreas cancer, suggesting the need for more novel approaches.

Food as medicine: A randomized controlled trial (RCT) of home delivered, medically tailored meals (HDMTM) on quality of life (QoL) in metastatic lung and non-colorectal GI cancer patients.

155 Background: Malnutrition incidence in cancer approaches 85%, disproportionately burdening those with lung, GI, and advanced stage cancers. Malnourished patients have impaired chemotherapy response, shorter survival, longer hospital stays, and decreased QoL. Home delivered meals are nutritional interventions that improve patient well-being, nutrition, and lower healthcare costs in the elderly but have not been studied as an intervention in cancer patients. HDMTM are nutritionist prescribed home delivered meals tailored to patients symptoms, co-morbidities, and health needs. Preliminary data in 211 cancer patients showed with HDMTM 87% ate more than half of meals, 91% lived more independently, 89% ate more nutritiously, and 70% had less fatigue. HDMTM may be a strategy to reduce financial toxicity and healthcare utilization and improve QoL in cancer patients, but no primary data exists evaluating its efficacy. METHODS We sought to develop the first RCT evaluating patient-centered QoL improvement from nutritional intervention with HDMTM in those with metastatic lung and non-colorectal GI cancer. We established a partnership with Gods Love We Deliver, a 501c3 non-profit specializing in HDMTM. RESULTS We developed a protocol for a single-institution RCT of standard of care (SoC) versus SoC and HDMTM in metastatic lung and non-colorectal GI cancer patients with primary aim comparing QoL between arms at 12 weeks using the FACT-G questionnaire. Sample size is 180. Secondary aims assess HDMTMs impact on nutritional status, weight, mood, survival, food security, financial toxicity, healthcare utilization, and cost effectiveness. Eligible patients tolerate oral alimentation, have PS 0-3, and newly diagnosed (< 6 weeks) metastatic cancer. All patients have pre-randomization nutritional evaluation by an oncologic dietician. CONCLUSIONS We present the first PRMC reviewed and IRB approved RCT evaluating the efficacy of HDMTM in metastatic cancer patients with primary endpoint of patient reported QoL. Investigating HDMTM expands our knowledge of nutrition as an effective arm of palliative oncology.

Abstract 3873: Hedgehog signaling maintains gastric cancer stem cells and promotes chemotherapy resistance: results from laboratory and clinical studies

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Gastric cancers may harbor a small subset of cancer stem cells (CSCs) with the exclusive ability to self-renew and differentiate into heterogenous cell types. These CSCs may also contribute to chemotherapy resistance. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. However in a recent randomized phase II trial of chemotherapy with or without the small molecule HH inhibitor vismodegib for advanced gastric cancers, the addition of vismodegib did not increase progression-free survival (PFS) or overall survival (OS). In this study, we examine the role of HH signaling in gastric CSC maintenance and chemotherapy resistance. Methods and Results: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 were grown as spheroids to enrich for CSCs. Spheroid cells were found to have upregulation of the putative gastric CSC marker CD44 along with HH pathway proteins Shh, Ptch1, Smo, and Gli1. Inhibition of the HH signaling using Smo shRNA or vismodegib decreased spheroid formation by 70.3-78.4% or 66.9-70.8%, respectively, and attentuated another CSC phenotype, single cell colony formation, by 66.9-78.4%. Transformation phenotypes such as migration, invasion, and anchorage-independent colony formation were also inhibited in gastric CSCs by 50.2-65.6%, 57.4-66.3%, and 3.8-4.6 fold, respectively. CD44(+) gastric CSCs from all 3 cell lines were resistant to 5-fluorouracil or cisplatin chemotherapy, and this resistance was reversed with the addition of Smo shRNA or vismodegib. The combination of Smo shRNA and cisplatin synergistically blocked the growth of MKN-45 xenografts, and treated tumors demonstrated a 1.8-2.6 fold increase in tumor cell apoptosis compared to tumors treated with cisplatin alone. Clinical tumor samples from the phase II vismodegib trial were analyzed for CD44 expression (as a surrogate to levels of CSCs). In the chemotherapy alone group, high CD44 expression was associated with worse PFS and OS. However in the chemotherapy with vismodegib group, high CD44 expression was associated with improved PFS and OS. For two patients in the vismodegib arm of the study who had a complete response, CD44 levels were 6.1-fold higher than the other patients in the group (p=0.001). Conclusions: HH signaling is required to maintain gastric CSC phenotypes such as spheroid formation and colony formation from single cells as well malignant transformation phenotypes such as migration, invasion, and anchorage-independent growth. Gastric CSCs are resistant to chemotherapy compared to unselected cells, and HH inhibition can reverse this resistance. Given gastric cancer is a heterogeneous disease, the strategy of combining chemotherapy with HH inhibition may only be effective in a subset of gastric cancer patients with high levels of CD44(+) gastric CSCs. Citation Format: Changhwan Yoon, Do Joong Park, Benjamin Schmidt, Nicholas J. Thomas, Hae-June Lee, Teresa S. Kim, Yelena Y. Janjigian, Deirdre J. Cohen, Sam S. Yoon. Hedgehog signaling maintains gastric cancer stem cells and promotes chemotherapy resistance: results from laboratory and clinical studies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3873. doi:10.1158/1538-7445.AM2014-3873