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Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS - or BRAF -mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS , RAF , and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53 , CDKN2A , PTEN , PIK3CA , and RB1 . Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers. Clinical exome and transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site, as part of the Michigan Oncology Sequencing (MI-ONCOSEQ) Program. Genomic landscape of metastatic cancer Cancer cells often gain new mutations as they spread through the body from the primary tumour site and develop into metastatic tumours. Arul Chinnaiyan and colleagues report clinical whole exome and transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineages and biopsy sites, as part of the Michigan Oncology Sequencing (MI-ONCOSEQ) Program. The authors characterize the landscape of genomic alterations across metastatic cancers, including recurrent somatic alterations in TP53 , CDKN2A , PTEN , PIK3CA and RB1 . They also used clinical RNA sequencing to characterize gene fusions, transcriptional signatures and the immune microenvironment of metastatic cancer. A timely analysis of the genomic and molecular profiles of metastatic tumours could help to tailor anticancer therapies to patients more precisely than can profiling only primary tumours.

Background Patients with advanced biliary tract cancers (BTCs) have poor prognoses and limited therapeutic options. Renin-angiotensin antagonists (ACE-I/ARBs), statins, and aspirin may have potential anti-tumorigenic effects and decrease mortality per retrospective analyses in some solid tumors. Objective To evaluate the efficacy of ACE-Is/ARBs, statins, and/or aspirin concurrent to first-line systemic therapy in patients with advanced or metastatic BTC. Methods Adult patients at University of Michigan with pathologic confirmation of BTC between January 2010 and December 2020 were included in this retrospective analysis. Results Of 1140 patients who met eligibility, a total of 509 patients received one or more concomitant medication(s) of interest in conjunction with systemic therapy for advanced cancer. In the total cohort, the overall survival for locally advanced patients (N = 305) was 16.3 months (95% CI: 12.1-18.6), and metastatic patients (N = 512) 8.6 months (95% CI: 7.6-9.5); P < .0001. Within this concomitant medication cohort, patients with locally advanced stage (n = 132) experienced significantly longer progression-free survival (9.8 vs 4.5; P < 0.0001), and overall survival (17.4 vs 10.6; P < 0.0001) than those with metastatic (n = 297) cancer, respectively. Patients who received ACE-Is/ARBs, statins, and/or aspirin (n = 245) versus not (n = 264) concurrent with systemic anti-cancer therapy did not experience improved progression-free (5.5 vs 5.5 months; hazard ratio (HR) 1.1; P = 0.51), or overall survival (12.3 vs 12.6 months; HR 1.1; P = 0.18), respectively. Conclusion In contrast to prior studies, no progression free or overall survival benefit in patients with advanced BTC from concurrent use of ACE-I/ARBs, statin, and/or aspirin with systemic therapy was observed when assessed by BTC subtype or specific systemic therapy regimen. Patients with advanced biliary tract cancers have poor prognoses and limited therapeutic options. This study evaluated the efficacy of renin-angiotensin antagonists (ACE-Is/ARBs), statins, and/or aspirin when given concurrently with first-line systemic therapy in patients with advanced or metastatic biliary tract cancer.

Abstract Background Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a “BRCAness” phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. Methods We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. Results Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. Conclusion This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA. This article reports an institutional case series in patients with advanced, IDH1 mutated cholangiocarcinoma treated with PARP inhibitor therapy.

Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae and has been implicated in oncogenic cell transformation, tumorigenesis and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models and patient samples and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models and human pancreatic tumors and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo , Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo) , is responsible for promoting resistance to therapies and may serve as a prognostic/predictive biomarker and target in PC.

Summary Background Cabozantinib and gemcitabine improve tumor control in pancreatic ductal adenocarcinoma (PDAC) in preclinical models through c-Met inhibition. We sought to determine the maximum tolerated dose (MTD) of this combination in patients with advanced PDAC. Methods Patients with ≤1 prior treatment and adequate performance status were eligible. Cabozantinib was given orally once daily, beginning day (−)7 and continued with gemcitabine given intravenously on days 1, 8, and 15 every 28 days. Dose level was assigned using Time to Event Continual Reassessment Method (TITE-CRM). Primary endpoint was MTD, defined as the highest dose level at which ≤25 % of patients incurred a dose-limiting toxicity (DLT). Secondary endpoints included response rate, progression-free survival (PFS), overall survival (OS) and urinary biomarker assessment. Results Twelve patients were enrolled and treated with 10 patients evaluable for DLT. The probability of DLT was >25 % for all dose levels tested, and thus an MTD was not determined. DLTs included grade 3 ALT/AST elevations and thrombocytopenia. Three patients had partial responses, but each discontinued therapy due to toxicity. Median PFS and OS were 4.7 (95 % CI: 1.4–9.7) and 10.1 months (95 % CI: 3.6–20.6). Exploratory biomarker analysis showed correlation of c-Met and VEGF levels with response. Conclusions An MTD for the combination was not established. Cabozantinib and gemcitabine appear impractical for further development due to DLT at low doses and continuing toxicities with ongoing therapy. Acknowledging the small sample size, responses were seen suggesting further investigation of c-Met inhibition in PDAC may be warranted.

Undifferentiated carcinoma (UC) is a rare subtype of pancreatic cancer distinguished from UC with osteoclast-like giant cells (UC-OGC) in 2019, affecting interpretation of literature that does not distinguish these subtypes. We sought to identify translationally relevant differences between these 2 variants and compared with pancreatic ductal adenocarcinoma. We characterized clinical and multiomic differences between UC (n = 32) and UC-OGC (n = 15) using DNA sequencing, RNA sequencing, and multiplex immunofluorescence and compared these findings with pancreatic ductal adenocarcinoma. Characteristics at diagnosis were similar between UC and UC-OGC, though the latter was more resectable (P = .009). Across all stages, median overall survival was shorter for UC than for UC-OGC (0.4 years vs 10.8 years, respectively; P = .003). This shorter survival was retained after stratification by resection, albeit without statistical significance (1.8 years vs 11.9 years, respectively; P = .08). In a subset of patients with available tissue, the genomic landscape was similar among UC (n = 9), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 159). Bulk RNA sequencing was deconvoluted and, along with multiplex immunofluorescence in UC (n = 13), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 16), demonstrated statistically significantly increased antigen-presenting cells, including M2 macrophages and natural killer cells, and decreased cytotoxic and regulatory T cells in UC and UC-OGC vs pancreatic ductal adenocarcinoma. Findings were similar between UC and UC-OGC , except for decreased regulatory T cells in UC-OGC (P = .04). In this series, UC was more aggressive than UC-OGC, with these variants having more antigen-presenting cells and fewer regulatory T cells than pancreatic ductal adenocarcinoma, suggesting potential for immune-modulating therapies in the treatment of these pancreatic cancer subtypes.

We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma. Patients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m2 intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion. There were 10 men and 10 women, with a median age of 58 years (range, 50-80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. Preoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.

Background Treatment for localized soft tissue sarcoma includes surgery and radiation, while the role of chemotherapy is controversial. Biomarkers that could predict therapeutic response or prognosticate overall survival (OS) are needed to define patients most likely to benefit from systemic treatment. Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling. Methods Using primary biopsy and resection specimens from patients with high-risk localized, soft tissue sarcoma treated on a neo/adjuvant chemotherapy study, SPARC expression was assessed and compared to patient and tumor characteristics, treatment, and outcomes. Survival functions were estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox model was used for multivariate analysis. Results Fifty patients had primary tumor specimens available. High, low, and no SPARC expression was found in 22, 13, and 15 patients, respectively. There was no significant difference in time to recurrence or OS between patients in these three groups. Comparing lack of SPARC expression with any SPARC expression, there was no significant difference in time to recurrence in patients without SPARC expression ( n  = 15) compared to patients with SPARC expression ( n  = 35). Likewise, there was no statistically significant difference in OS in patients without SPARC expression versus patients whose tumors expressed SPARC. Conclusions Although we did not find a statistically significant difference in time to recurrence and OS in patients with high-risk soft tissue sarcoma, we did identify a trend toward improved time to recurrence and OS in patients whose tumors lacked SPARC expression. However, SPARC did not demonstrate the ability to discern which high-risk patients may have a worse prognosis or greater benefit from chemotherapy. Trial registration The trial was registered on September 13, 2005 with ClinicalTrials.gov, number https://clinicaltrials.gov/ct2/show/NCT00189137?term=sarcoma&id=NCT00189137&state1=NA%3AUS%3AMI&phase=1&rank=1 .

Summary Tetrathiomolybdate (TM) is an oral copper chelator under development as an anti-angiogenic agent. We evaluated TM in combination with irinotecan, 5-fluorouracil, and leucovorin (IFL). Serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin 6 (IL-6), and IL-8 were measured to evaluate the anti-angiogenic effect. Twenty-four patients with metastatic colorectal cancer were treated. The combination with IFL was well tolerated and dose intensity of IFL was maintained during combination therapy with TM. By intention to treat analysis, the overall response rate (RR) was 25% (95% CI 9.8–46.7) and the median time to progression (TTP) was 5.6 months (95% CI 2.7–7.7). VEGF levels were correlated with TTP, as were changes in VEGF, IL-8, and IL-6. TM can be safely added to IFL without compromising dose intensity or diminishing the expected RR. Changes in serum VEGF, IL-8, and IL-6 after treatment may directly reflect changes in CRC tissue angiogenesis.