Circulating tumor cells (CTCs), a population of cancer cells that represent the seeds of metastatic nodules, are a promising model system for studying metastasis. However, the expansion of ...patient-derived CTCs ex vivo is challenging and dependent on the collection of high numbers of CTCs, which are ultra-rare. Here we report the development of a combined CTC and cultured CTC-derived xenograft (CDX) platform for expanding and studying patient-derived CTCs from metastatic colon, lung, and pancreatic cancers. The propagated CTCs yielded a highly aggressive population of cells that could be used to routinely and robustly establish primary tumors and metastatic lesions in CDXs. Differential gene analysis of the resultant CTC models emphasized a role for NF-κB, EMT, and TGFβ signaling as pan-cancer signaling pathways involved in metastasis. Furthermore, metastatic CTCs were identified through a prospective five-gene signature (
,
,
,
, and
). Whole-exome sequencing of CDX models and metastases further identified mutations in constitutive photomorphogenesis protein 1 (
) as a potential driver of metastasis. These findings illustrate the utility of the combined patient-derived CTC model and provide a glimpse of the promise of CTCs in identifying drivers of cancer metastasis.
Biologics in bowel cancer Noel, Marcus S
Journal of gastrointestinal oncology
8, Issue:
3
Journal Article
Open access
Colorectal cancer is the third most common cancer in the United States and second leading cause of cancer death with over 50,000 patients expected to die from their disease in 2017. For patients who ...present at diagnosis with advanced disease the standard treatment is systemic chemotherapy. Over the last decade a number of biologic therapies have emerged as viable treatment options for advance colorectal cancer. When these new drugs are combined with chemotherapy survival is prolonged, often without a detriment to quality of life. In this chapter we will review the most active biologic options for treatment of colorectal cancer and place them in the context of a rapidly growing field.
Cutaneous metastasis resulting from internal primary tumors remains a rare phenomenon. The prompt recognition of these metastases is important, as they are an indicator of advanced disease and poor ...prognosis. We report the case of a 44-year-old Caucasian man presenting with a four-month history of multiple cutaneous nodules on the face, trunk, and upper extremities. Results from skin biopsy revealed strands and cords of atypical cells concerning for poorly differentiated metastatic carcinoma. An esophagogastroduodenoscopy was performed and a poorly differentiated signet-ring type invasive adenocarcinoma at the lesser curvature of the stomach was found. As the cancer had already metastasized to the skin and bones, the patient was started on chemotherapy with an oxaliplatin-based regimen and denosumab for the bone metastases, with resultant objective response and diagnostic control for greater than one year to the present date.
Background
This trial explores SM‐88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC)
Methods
Forty‐nine patients were ...randomized to daily 460 or 920 mg oral SM‐88 with MPS (SM‐88 Regimen). The primary endpoint was objective response rate (RECIST 1.1).
Results
Thirty‐seven patients completed ≥ one cycle of SM‐88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression‐free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality‐of‐life (QOL) was maintained and trended in favor of 920 mg. SM‐88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention‐to‐treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7–4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01).
Conclusions
SM‐88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second‐line treatment of patients with mPDAC.
ClinicalTrials.gov Identifier: NCT03512756.
This trial explores 460 or 920 mg oral SM‐88 daily, used with methoxsalen, phenytoin, and sirolimus (MPS) in previously treated patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). SM‐88 + MPS was well tolerated (1 of 49 patients had drug‐related grade 3/4 adverse events), patient quality‐of‐life was maintained, and overall survival trended toward being better for patients treated in the second (median overall survival mOS, 8.1 months; median progression‐free survival mPFS, 3.8 months) versus ≥ third line (mOS, 3.7 months; mPFS, 1.8 months). SM‐88 + MPS should be further explored in the second‐line treatment of patients with mPDAC.
Background
The role of neoadjuvant stereotactic body radiation therapy (SBRT) in the treatment of pancreatic adenocarcinoma (PDAC) is controversial and the optimal target volumes and ...dose-fractionation are unclear. The aim of this study is to report on treatment outcomes and patterns of failure of patients with borderline resectable (BL) or locally advanced (LA) pancreatic cancer following preoperative chemotherapy and SBRT.
Methods
We conducted a single-institution, retrospective study of patients with BL or LA PDAC. Patients received neoadjuvant chemotherapy and SBRT was prescribed to 30 Gy over 5 fractions to the pancreas planning tumor volume (PTV). A subset of patients received a simultaneous integrated boost to the high risk vascular PTV and/or elective nodal irradiation (ENI). Following neoadjuvant chemoradiation, all patients underwent subsequent resection. Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMPFS), and locoregional control (LRC) estimates were obtained using Kaplan-Meier analysis.
Results
Twenty-two patients with BL (18) or LA (4) PDAC were treated with neoadjuvant chemotherapy and SBRT followed by resection from 2011–2022. Following neoadjuvant treatment, 5 patients (23%) achieved a pathologic complete response (pCR) and 16 patients (73%) had R0 resection. At 24 months, there were no isolated locoregional recurrences (LRRs), 9 isolated distant recurrences (DRs), and 5 combined LRRs and DRs. Two LRRs were in-field, 2 LRRs were marginal, and 1 LRR was both in-field and marginal. 2-year median LRC, LRRFS, DMPFS, PFS, and OS were 77.3%, 45.5%, 31.8%, 31.8%, and 59.1%, respectively. For BL and LA cancers, 2-year LRC, DMPFS, and OS were 83% vs. 75%, (p = 0.423), 39% vs. 0% (p = 0.006), and 61% vs. 50% (p = 0.202), respectively. ENI was associated with improved LRC (p = 0.032) and LRRFS (p = 0.033). Borderline resectability (p = 0.018) and lower tumor grade (p = 0.027) were associated with improved DMPFS.
Conclusions
Following preoperative chemotherapy and SBRT, locoregional failure outside of the target volume occurred in 3 of 5 recurrences; ENI was associated with improved LRC and LRRFS. Further studies are necessary to define the optimal techniques for preoperative radiation therapy.
Abstract Purpose To evaluate and compare outcome of stereotactic body radiation therapy (SBRT), yttrium-90 radioembolization, radiofrequency ablation (RFA), or transarterial chemoembolization (TACE) ...as bridge to liver transplant (LT) in patients with hepatocellular carcinoma. Methods and materials We retrospectively reviewed patients treated at our institution with SBRT, TACE, RFA, or yttrium-90 as bridge to LT between 2006 and 2013. We analyzed radiologic and pathologic response and rate of failure after bridge therapy. Toxicities were reported using Common Terminology Criteria for Adverse Events, 4.0. Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival after LT. Results Sixty patients with a median age 57.5 years (range, 44-70) met inclusion criteria. Thirty-one patients (50.7%) had hepatitis C cirrhosis, 14 (23%) alcoholic cirrhosis, and 8 (13%) nonalcoholic steatohepatitis cirrhosis. Patients received a total of 79 bridge therapies: SBRT (n = 24), TACE (n = 37), RFA (n = 9), and Y90 (n = 9). Complete response (CR) was 25% for TACE, 8.6% for SBRT, 22% for RFA, and 33% for Y90. Grade 3 or 4 acute toxicity occurred following TACE (n = 4) and RFA (n = 2). Transplant occurred at a median of 7.4 months after bridge therapy. Pathological response among 57 patients was 100% necrosis (n = 23, 40%), >50% necrosis (n = 20, 35%), <50% necrosis (n = 9, 16%), and no necrosis (n = 5, 9%). Pathologic complete response was as follows: SBRT (28.5%), TACE (41%), RFA (60%), Y90 (75%), and multiple modalities (33%). At a median follow-up of 35 months, 7 patients had recurrence after LT. DFS was 85.8% and overall survival was 79% at 5 years. Conclusion All bridge therapies demonstrated good pathological response and DFS after LT. SBRT and Y90 demonstrated significantly less grade ≥3 acute toxicity. Choice of optimal modality depends on tumor size, pretreatment bilirubin level, Child-Pugh status, and patient preference. Such a decision is best made at a multidisciplinary tumor board as is done at our institution.
Compared with normal cells, tumour cells contain elevated levels of reactive oxygen species (ROS). Increased levels of the antioxidant protein NAD(P)H:quinone oxidoreductase 1 (NQO1) and ...phosphorylated signal transducer and activator of transcription 3 (pSTAT3) correlate negatively with the survival of patients with pancreatic cancer. Napabucasin is an investigational, orally administered ROS generator bioactivated by NQO1.
In the open-label, phase 3 CanStem111P study (NCT02993731), adults with previously untreated metastatic pancreatic adenocarcinoma (mPDAC) were randomised (1:1) to napabucasin plus nab-paclitaxel with gemcitabine or nab-paclitaxel with gemcitabine alone. The primary endpoint was overall survival (OS). In exploratory analyses, OS was evaluated in the subgroup of patients with tumours positive for pSTAT3 (biomarker-positive).
Between 30 January 2017 and 20 February 2019, a total of 1779 patients were screened across 165 study sites in Austria, Australia, Belgium, Canada, China, Czech Republic, France, Germany, Italy, Japan, Korea, Netherlands, Poland, Portugal, Russia, Singapore, Spain, Taiwan, Ukraine, and the US. Of the 565 and 569 patients randomised to the napabucasin and control treatment arms, respectively, 206 and 176 were biomarker-positive. Median (95% confidence interval CI) OS in the napabucasin and control treatment arms was 11.4 (10.5–12.2) and 11.7 (10.7–12.7) months, respectively (hazard ratio, 1.07; 95% CI, 0.93–1.23). Due to the lack of OS improvement in the napabucasin arm, CanStem111P was terminated due to futility. In the biomarker-positive subgroup, no difference between treatment arms was found for OS. Grade ≥3 adverse events were reported in 85.4% and 83.9% of napabucasin-treated and control-treated patients, respectively. The incidence of gastrointestinal-related grade ≥3 events was higher with napabucasin (diarrhoea: 11.6% vs 4.9%; abdominal pain: 10.0% vs 4.8%).
Our findings suggested that although the addition of napabucasin to nab-paclitaxel with gemcitabine did not improve efficacy in patients with previously untreated mPDAC, the safety profile of napabucasin was consistent with previous reports. CanStem111P represents the largest cohort of patients with mPDAC administered nab-paclitaxel with gemcitabine in the clinical trial setting. Our data reinforce the value of nab-paclitaxel plus gemcitabine as a platform for novel therapeutics approaches in mPDAC.
The Sumitomo Pharma Oncology, Inc.
Biliary tract cancer (BTC) is a group of relatively rare tumors with a poor prognosis. The current standard of care consists of doublet chemotherapy (platinum plus gemcitabine); however, even with ...cytotoxic therapy, the median overall survival is less than 1 year. The genetic basis of BTC is now more clearly understood, allowing for the investigation of targeted therapy. Combinations of doublet chemotherapy with antiepidermal growth factor receptor agents have provided modest results in Phase II and Phase III setting, and responses with small molecule inhibitors are limited. Moving forward as we continue to characterize the genetic hallmarks of BTC, a stepwise, strategic, and cooperative approach will allow us to make progress when developing new treatments.
Novel agents in mantle cell lymphoma Noel, Marcus S., MD; Friedberg, Jonathan W., MD; Barr, Paul M., MD, MMSc
Best practice & research. Clinical haematology,
06/2012, Volume:
25, Issue:
2
Journal Article
Peer reviewed
Open access
Mantle cell lymphoma is a mature B cell neoplasm constituting 5–7% of all non-Hodgkin lymphoma. Overall prognosis with current therapeutics remains poor, thus numerous novel agents are currently ...under investigation. In this review we focus on early phase trials that have demonstrated promise in mantle cell. Constitutive activation of signaling components downstream of the B cell receptor play an important role in the pathobiology of mantle cell lymphoma. Targeting of this signaling pathway has become a focus with specific agents under development including inhibitors of spleen tyrosine kinase, phosphoinositide 3-kinase and Bruton's tyrosine kinase. Promising data also supports further development of BH-3 mimetics, a crucial component of anti-apoptotic signaling. Histone deacetylase inhibitors have an established role in cutaneous T-cell lymphoma and are now under investigation in mantle cell lymphoma as well. With further understanding of cellular signaling, the armamentarium of treatment options will be enhanced, with the hope of improving the prognosis of this disease.
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