Selection criteria for minimally invasive resection of intrahepatic cholangiocarcinoma-a word of caution: a propensity score matched analysis using the national cancer database.

BACKGROUND: While minimally invasive liver resection (MILR) vs. open approach (OLR) has been shown to be safe, the perioperative and oncologic safety for intrahepatic cholangiocarcinoma (ICC) specifically, necessitating often complex hepatectomy and extended lymphadenectomy, remains ill-defined. METHODS: The National Cancer Database was queried for patients with ICC undergoing liver resection from 2010 to 2016. After 1:1 Propensity Score Matching (PSM), Kruskal-Wallis and χ2 tests were applied to compare short-term outcomes. Kaplan-Meier survival analyses and Cox multivariable regression were performed. RESULTS: 988 patients met inclusion criteria: 140 (14.2%) MILR and 848 (85.8%) OLR resulting in 115 patients MILR and OLR after 1:1 PSM with c-index of 0.733. MILR had lower unplanned 30-day readmission [OR 0.075, P = 0.014] and positive margin rates [OR 0.361, P = 0.011] and shorter hospital length of stay (LOS) [OR 0.941, P = 0.026], but worse lymph node yield [1.52 vs 2.07, P = 0.001]. No difference was found for 30/90-day mortality. Moreover, multivariate analysis revealed that MILR was associated with poorer overall survival compared to OLR [HR 2.454, P = 0.001]. Subgroup analysis revealed that survival differences from approach were dependent on major hepatectomy, tumor size > 4 cm, or negative margins. CONCLUSION: MILR vs. OLR is associated with worse lymphadenectomy and survival in patients with ICC greater than 4 cm requiring major hepatectomy. Hence, MILR major hepatectomy for ICC should only be approached selectively and if surgeons are able to perform an appropriate lymphadenectomy.

Poorly differentiated hepatocellular carcinoma: resection is equivalent to transplantation in patients with low liver fibrosis.

BACKGROUND: Organ allocation criteria for liver transplantation focus on tumor size and multifocality while tumor differentiation and existing liver damage are omitted. This study analyzes the impact of hepatocellular carcinoma (HCC) grade and liver fibrosis comparing resection (SX) to transplantation (LT). METHODS: The National Cancer Database was queried between 2004 and 2016 for solitary HCC meeting Milan criteria undergoing SX vs LT. Two groups were created: low fibrosis (LF) vs high fibrosis (HF) and stratified by grade. Cox multivariable regression models, Kaplan-Meier survival analyses and log-rank tests were performed. RESULTS: 1515 patients were identified; 780 had LT and 735 had SX. Median overall survival (mOS) was 39.7 months; LT mOS was 47.9 months vs SX mOS of 34.9 months (P < .001). Multivariate analysis revealed SX, no chemotherapy, longer hospital stays, and age to be associated with worse survival. However, while transplantation conferred survival benefit for well-moderately differentiated tumors, SX vs LT did not impact survival for poorly differentiated HCC in LF patients, independent of tumor size. DISCUSSION: HCC differentiation and liver fibrosis, but not size, synergistically determine efficacy of SX vs LT. Therefore, current HCC transplantation criteria should incorporate tumor grade or liver fibrosis for optimal organ allocation.

Failure to Cure Patients with Colorectal Liver Metastases: The Impact of the Liver Surgeon.

BACKGROUND: Lack of a liver surgeon (LS) may lead to failure to cure in patients with possibly resectable colorectal liver metastases (CRLM). This study aims to quantify the failure-to-cure rate due to noninclusion of an LS. PATIENTS AND METHODS: All patients who underwent chemotherapy with palliative intent for CRLM at a community oncology network between 2010 and 2018 were identified from a prospectively maintained cancer registry. Two LS blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a newly developed resectability score. Nominal group technique and independent scores were combined to determine probability of curative-intent resection. Interobserver agreement was calculated using κ testing. RESULTS: This study included 72 palliative CRLM patients. Demographic factors were: 44 (59%) male, median age 68 years (range 36-94 years), 23 (32%) rectal primary, 24 (33%) receiving oxaliplatin-based chemotherapy. Of the 72 patients with CRLM, 6 had left-sided metastases only. The median number of CRLM was 6 (1-8). Agreement on resectability was achieved in 32 (44%) patients for the entire cohort and 17 (54%) in patients without extrahepatic disease. A lower median number of CRLM was found in the group considered to be resectable by the two LS (2 versus 8; p = 0.001). Substantial agreement was found between liver surgeons in the group of patients without extrahepatic disease (κ = 0.9043). CONCLUSIONS: Over 44% of patients who were assigned palliative chemotherapy at tumor boards without an LS were considered potentially resectable upon independent LS review.

Does a Laparoscopic Approach to Distal Pancreatectomy for Cancer Contribute to Optimal Adjuvant Chemotherapy Utilization?

BACKGROUND: Although laparoscopic distal pancreatectomy (LDP) versus open approaches (ODP) for pancreatic adenocarcinoma (PDAC) is associated with reduced morbidity, its impact on optimal adjuvant chemotherapy (AC) utilization remains unclear. Furthermore, it is uncertain whether oncologic resection quality markers are equivalent between approaches. METHODS: The National Cancer Database (NCDB) was queried between 2010 and 2016 for PDAC patients undergoing DP. Effect of LDP vs ODP and institutional case volumes on margin status, hospital stay, 30-day and 90-day mortality, administration of and delay to AC, and 30-day unplanned readmission were analyzed using binary and linear logistic regression. Cox multivariable regression was used to correct for confounders. RESULTS: The search yielded 3411 patients; 996 (29.2%) had LDP and 2415 (70.8%) had ODP. ODP had higher odds of readmission [odds ratio (OR) 1.681, p = 0.01] and longer hospital stay [ß 1.745, p = 0.004]. No difference was found for 30-day mortality [OR 1.689, p = 0.303], 90-day mortality [OR 1.936, p = 0.207], and overall survival [HR 1.231, p = 0.057]. The highest-volume centers had improved odds of AC [OR 1.275, p = 0.027] regardless of approach. LDP conferred lower margin positivity [OR 0.581, p = 0.005], increased AC use [3rd quartile: OR 1.844, p = 0.026; 4th quartile; OR 2.144, p = 0.045], and fewer AC delays [4th quartile: OR 0.786, p = 0.045] in higher-volume centers. CONCLUSIONS: In selected patients, LDP offers an oncologically safe alternative to ODP for PDAC independent of institutional volume. However, additional oncologic benefit due to optimal AC utilization and lower positive margin rates in higher volume centers suggests that LDP by experienced teams can achieve best possible cancer outcomes.

Laparoscopic Pancreatic Head Preserving Total Duodenectomy: The Parenchymal Sparing Alternative to a Whipple.

BACKGROUND: When endoscopic options fail, laparoscopic pancreatic head-preserving duodenectomy (LPHPD) for benign duodenal lesions is a parenchymal sparing and safe alternative to a pancreaticoduodenectomy.1-3 LPHPD may be the optimal "amount" of surgery, because such lesions are at risk for undertreatment (partial endoscopic resection associated with recurrence) or overtreatment (Whipple associated with morbidity and loss of pancreatic parenchyma).4,5 PATIENT: A 80-year-old, healthy female patient was diagnosed endoscopically with two, flat, symptomatic adenomas (7-cm D2; 2-cm D3). She had no family history of polyposis. Germline testing, tumor markers, and colonoscopy did not show any abnormality. TECHNIQUE: With the patient in French position, a wide laparoscopic Kocherization was performed past IVC and aorta. Following prepyloric gastric transection, the entire duodenum was carefully dissected off the pancreas. After transection of the proximal jejunum, the reconstruction begins. A two-layer, duct-to-mucosa, ampullary-jejunal anastomosis and a type II Billroth gastrojejunostomy were performed. CONCLUSIONS: LPHPD avoids under- or overtreatment of benign duodenal lesions unamenable to an endoscopic approach. If the stepwise approach described in this video is followed, LPHPD represents a safe and parenchymal-sparing alternative to pancreaticoduodenectomy for benign duodenal lesions with reduced morbidity.

Western population-based study of oncologic surgical quality and outcomes of laparoscopic versus open gastrectomy for gastric adenocarcinoma.

BACKGROUND: While studies have reported improved morbidity of laparoscopic (LG) compared with open gastrectomy (OG), it remains unclear whether comparable oncologic outcomes can be achieved. This study aims at comparing not only short-term outcomes, including 30- and 90-day mortality, but also survival of LG vs OG. METHODS: The National Cancer Database was searched for adult patients with histologically proven gastric cancer and complete information regarding M0 disease, tumor size, differentiation grade, T stage, nodal status, comorbidities, type of hospital, hospital stay, type of surgery, oncological treatment and survival data were included. Logistic regression analyses were performed to analyze margin status, 30- and 90-day mortality, and 30-day re-admission rate. Linear regression was performed for length of hospital stay and lymph node yield. Kaplan-Meier survival analyses were performed to evaluate median survival. Cox multivariable regression models were created to correct for confounders and identify factors affecting survival. RESULTS: A query of the National Cancer Database identified 13,538 patients with complete dataset. A significant regression equation favoring LG for lymph node yield, hospital stay, and unplanned re-admission rate was identified. There was no significant effect of surgical approach on R1 margin rate, 30-day mortality, or 90-day mortality. Median survival was comparable between LG and OG (44.8 vs 40.2 months, p = 0.804). CONCLUSION: LG offers a safe surgical approach to gastric cancer with shorter hospital stay and lower re-admission rates than OG, and also similar and sometimes improved operative oncologic quality parameters (margin, lymph node yield). More importantly, this Western series demonstrates that equivalent long-term outcomes of LG vs. OG are being achieved.

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

BACKGROUND: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma. METHODS: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999. FINDINGS: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths. INTERPRETATION: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies. FUNDING: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.

Lack of Impact of Robotic Assisted Laparoscopic Radical Prostatectomy on Intraoperative Levels of Prostate Cancer Circulating Tumor Cells.

PURPOSE: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. MATERIALS AND METHODS: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. RESULTS: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21-month followup. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding.

COVID-19's Impact on Cancer Care: Increased Emotional Stress in Patients and High Risk of Provider Burnout.

BACKGROUND: COVID-19's precise impact on cancer patients and their oncologic care providers remains poorly understood. This study aims at comparatively analyzing COVID-19's effect on cancer care from both patient and provider perspectives. METHODS: A multi-institutional survey was developed to assess COVID-19-specific concerns regarding treatment, safety, and emotional stress through 5-point Likert-type prompts and open-ended questions before and during the pandemic. Wilcoxon signed-rank and rank-sum tests were used to analyze before/during answers for providers and patients independently. Open-ended responses were assessed using inductive thematic analysis. RESULTS: The survey was completed by 104 (69.3%) patients and 50 (50%) providers. Patients demonstrated a significant change in only 1 of 15 Likert prompts. Most significant were increased concern regarding susceptibility to infection [z = 2.536, p = 0.011] and concerns regarding their cancer outcome [z = 4.572, p < 0.001]. Non-physician providers demonstrated significant change in 8 of 13 Likert prompts, whereas physicians had all 13 Likert prompts change in the COVID-19 setting. Physicians believed care to be more poorly planned [z = -3.857, p ≤ 0.001], availability of protective personal equipment to be more limited [z = -4.082, p < 0.001], and were significantly concerned infecting family members [z = 4.965, p < 0.001]. CONCLUSIONS: While patients had more difficulty coping with their cancer, they did not perceive significant differences in their actual treatment. This suggests the need for a renewed focus on patients coping with cancer. Among providers, physicians more than any other provider group had a strong negative perception of COVID-19's impact on healthcare, suggesting the need for novel approaches to target physician burnout.

The impact of chemotherapy sequencing on resectable pancreatic cancer by stage.

INTRODUCTION: While chemotherapy is an important therapeutic modality for pancreatic cancer (PDAC), the optimal sequence of chemotherapy to surgery remains unclear. Further, the precise added benefit of including chemotherapy at each (especially early) stage has not been quantified. METHODS: The National Cancer Database (NCDB) was queried for patients with PDAC who underwent pancreaticoduodenectomy between 2004 and 2016. Cox multivariable and Kaplan-Meier survival analyses were performed for disease-specific survival (DSS) and overall survival (OS) after correcting for confounders. Permutations of chemotherapy/surgery were compared: preoperative only (NCT), postoperative only (ACT), pre- and post-operative (perioperative, PCT), and no therapy (NoT). RESULTS: 22975 patients met inclusion criteria. 13944(61%) received ACT, 1793(8%) received NCT and 946(4%) received PCT, while 6292(27%) did not receive chemotherapy. Log-rank test showed inferior survival in the NoT group compared to NCT, ACT, and PCT. Compared to the NoT group, PCT had the lowest rate of death (HR 0.704, p < 0.001) followed by NCT (HR 0.721, p < 0.001) and ACT (HR 0.759, p < 0.001).). CONCLUSION: PDAC patients receiving chemotherapy, independent of their stage, will result in better DSS and OS. NCT should be given consideration for resectable disease including early stage PDAC and ideally complemented with postoperative chemotherapy. While there was a trend towards improved survival for PCT, NCT and ACT are reasonable options for stages IB-III.

Clinical Prognosticators of Metastatic Potential in Patients with Small Pancreatic Neuroendocrine Tumors.

BACKGROUND: While observation of T1(≤2cm) nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) is an accepted practice, an ill-defined subgroup of patients with T1 tumors develops metastases. This study aimed to identify those patients via clinical factors. METHODS: Patients from the Surveillance, Epidemiology, and End Results (SEER) registry who were diagnosed with NF-PanNET with size ≤2cm between 1998 and 2014 and who underwent primary tumor resection were identified. Binary logistic regression analyses were performed to evaluate factors associated with pathological nodal and systemic metastatic disease. RESULTS: A total of 612 patients with T1 NF-PanNETs were identified. Of those, 72 (11.7%) developed nodal metastasis and 35 (5.7%) distant metastasis (M1). In the multivariable analysis, tumor location in the pancreatic body (OR 1.903, p=0.03) (OR 1.407, p=0.038) or tail (OR 1.258, p=0.04) (OR 1.612, p=0.021); tumor grade III-IV (OR 2.042, p=0.022) (OR 5.379, p≤0.001); and younger age (OR 0.963, p=0.01) (OR 0.919, p=0.009) were associated with nodal metastases and the presence of M1 disease, respectively. CONCLUSION: While the low metastatic potential of ≤2cm NF-PanNET implies watchful waiting to be an appropriate strategy for most patients, the increased risk of metastatic disease in younger patients with high grade (III-IV) body/tail tumors suggests individualized risk stratification to be optimal.

Race, Age, Gender, and Insurance Status: A Comparative Analysis of Access to and Quality of Gastrointestinal Cancer Care.

BACKGROUND: Socioeconomics, demographics, and insurance status play roles in healthcare access. Considering the limited resources available, understanding the relative impact of disparities helps prioritize programs designed to overcome them. This study evaluates gastrointestinal cancer care disparity by comparing the impact of different patient factors across oncologic care metrices. METHODS: A multi-institutional prospectively maintained cancer database was reviewed retrospectively for gastrointestinal cancers (esophagus, stomach, liver, pancreas, colorectal, and hepato-pancreato-biliary) from 2007 to 2017 to assess quality of care provided. Quality of care was defined by clinical course following national guidelines for the respective cancer. This included surgical intervention, chemotherapy, palliative care, and minimal delay to treatment/diagnosis. Logistic regression was used to adjust for confounders and identify factors associated with quality of care. Kaplan-Meier survival curves were compared using log-rank test. RESULTS: One thousand seventy-two patients were identified. Survival improved in patients with private insurance compared to government-funded options [median overall survival (mOS) 57.8 vs. 21.2 months; P < .001]. Private insurance also correlated with earlier stage at diagnosis [stages I-II = 50.9% vs. 37.5%, stages III-IV = 37.7% vs. 49.1%, P < .001], increased chemotherapy use [44.2% vs. 37.1%, P < .001], and more surgical intervention [62.4% vs. 48.8%, P < .001]. Outcomes were inferior for Black Americans, including trend towards lower rate of surgical treatment [42% vs. 54%, P = .058] and worse survival in private insurance carriers [mOS 7.8 vs. 57.8 months, P = .021] and those with early stage disease [mOS 39.2 vs. 81.5 months, P = .045] compared to White counterparts. CONCLUSIONS: Insurance status has the strongest impact on the quality of gastrointestinal oncologic care with negative synergistic negative effect of race for Black Americans. While governmental programs aim to improve equality of care, there remains significant disparity compared to private insurance. Moreover, private insurance doesn't correct disparity for Black Americans, suggesting the need to address racial imbalances in cancer care.

Preoperative Chemotherapy for Pancreatic Cancer Improves Survival and R0 Rate Even in Early Stage I.

BACKGROUND: While preoperative chemotherapy for patients with stage II-III pancreatic adenocarcinoma (PDAC) is frequently practiced, its impact on very early PDAC (stage I) remains unclear today. MATERIAL AND METHODS: Patients undergoing pancreatectomy for PDAC between 2010 and 2016 were identified in the National Cancer Database. Early-stage patients (IA-IB) with complete oncologic and clinical information and more than 30-day survival were included. The effect of preoperative chemotherapy on margin status was assessed with binary logistic regression. Following correction for confounders, the effect of therapy sequencing was assessed via comparison of preoperative, postoperative, perioperative (pre- and post-operative) chemotherapy, and surgery only using Cox regression. RESULTS: Of 4785 patients, 688 (14.4%) were stage IA, and 4197 (87.7%) IB. The rate of preoperative chemotherapy was only 8.8%. Rate of margin positivity was lower for preoperative chemotherapy (12.3% vs 19.7%). After correcting for confounders, the risk of a positive margin was lower in preoperative chemotherapy (odd ratio [OR] 0.703, p = 0.042). Cox regression showed a significant overall survival advantage for preoperative (hazard ratio [HR] 0.784, p = 0.002), postoperative (HR 0.618, p < 0.001), and perioperative (HR 0.601, p < 0.001) chemotherapy compared with surgery alone. There was no significant difference in survival between chemotherapy groups but a trend towards optimal survival for preoperative chemotherapy. CONCLUSION: Despite preoperative chemotherapy vs surgery alone resulting in improved R0 rates and overall survival even in stage I PDAC, it is rarely practiced. The results presented here suggest that preoperative chemotherapy should be strongly considered in all patients with resectable PDAC, including very early PDAC.

A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma.

BACKGROUND: In this trial we assessed the efficacy and tolerability of TRC105, a chimeric monoclonal antibody that targets CD105 (endoglin) in patients with advanced, previously treated urothelial carcinoma (UC). PATIENTS AND METHODS: Patients received TRC105 15 mg/kg every 2 weeks on days 1 and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) at 6 months. Secondary end points included safety, toxicity, and overall survival (OS). CD105 expression was evaluated using immunohistochemistry (IHC) in a separate cohort of 50 UC patients. Biomarker studies included immune subsets, circulating tumor cells (CTCs), circulating endothelial cells (CECs), circulating endothelial progenitor cells (CEPs), and osteopontin. RESULTS: Of 13 patients enrolled, 12 were evaluable for OS and PFS. The 3-month PFS probability was 18.2% (median PFS, 1.9 months [95% confidence interval (CI), 1.8-2.1 months). This met the criterion for ending accrual on the basis of the 2-stage design. Median OS was 8.3 months (95% CI, 3.3-17.0 months). IHC for CD105 scores was not associated with T stage (P = .26) or presence of lymph nodes (P = .64). Baseline levels of regulatory T and B cells, CEPs, and changes in CEC level after TRC105 exhibited trends toward an association with PFS or OS. CTCs pre- and post-TRC105 were detected in 4 of 4 patients. CONCLUSION: Although TRC105 was well tolerated, it did not improve 6-month PFS in heavily pretreated patients with advanced UC. CD105 staining was present in 50% of UC tumors at different intensities. Our observations on the pharmacodynamic significance of immune subsets, CECs, and CTCs warrant further study.

Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants.

The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90ß, fold, assemble and maintain the three-dimensional structure of numerous client proteins. Because many HSP90 clients are important in cancer, several HSP90 inhibitors have been evaluated in the clinic. However, little is known concerning possible unique isoform or conformational preferences of either individual HSP90 clients or inhibitors. In this report, we compare the relative interaction strength of both HSP90α and HSP90ß with the transcription factors HSF1 and HIF1α, the kinases ERBB2 and MET, the E3-ubiquitin ligases KEAP1 and RHOBTB2, and the HSP90 inhibitors geldanamycin and ganetespib. We observed unexpected differences in relative client and drug preferences for the two HSP90 isoforms, with HSP90α binding each client protein with greater apparent affinity compared to HSP90ß, while HSP90ß bound each inhibitor with greater relative interaction strength compared to HSP90α. Stable HSP90 interaction was associated with reduced client activity. Using a defined set of HSP90 conformational mutants, we found that some clients interact strongly with a single, ATP-stabilized HSP90 conformation, only transiently populated during the dynamic HSP90 chaperone cycle, while other clients interact equally with multiple HSP90 conformations. These data suggest different functional requirements among HSP90 clientele that, for some clients, are likely to be ATP-independent. Lastly, the two inhibitors examined, although sharing the same binding site, were differentially able to access distinct HSP90 conformational states.

A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas.

PURPOSE: A multi-cohort phase II study of fostamatinib, an oral multi-kinase inhibitor, was conducted to determine the response rate in patients with advanced colorectal (CRC), thyroid, non-small cell lung, head and neck, and renal cell carcinomas, and pheochromocytomas. METHODS: Patients received 200 mg fostamatinib BID in 4-week cycles with response assessed every 2 cycles. Blood was collected for pharmacokinetic analysis and measurements of circulating tumor cells and circulating endothelial (progenitor) cells (CE(P)Cs). RESULTS: A total of 37 patients (22 CRC), median of 4 prior therapies, were enrolled. Due to toxicities in four of the first five patients, the study was amended to incorporate a dose escalation phase for each histology. The maximum-tolerated dose was established at 50 mg BID in CRC but was not established for the other cancers. Common grade 3/4 toxicities included transaminitis, hyperbilirubinemia, and hypertension. Pharmacokinetic profile was similar to previous reports. Seventy-three percent of CRC patients had liver involvement and 91 % had prior anti-angiogenic therapy. Patients with abnormal liver tests at baseline were more likely to experience grade ≥ 2 hepatotoxicity than those with normal tests (44 vs. 0 %). No responses were observed; disease stabilization rate was 27 % in CRC. Reduction in CECs following treatment was associated with a better disease stabilization rate (75 vs. 0 %) in CRC. CONCLUSION: Fostamatinib had limited anti-tumor activity in this first clinical trial in patients with advanced refractory solid tumors; reduction in CECs and CEPs was indicative of anti-angiogenic effects. Abnormal liver testing at baseline appeared to influence drug tolerability.

A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. METHODS: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. RESULTS: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m(2) administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. CONCLUSIONS: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study.