Molecular landscape of prostate cancer: implications for current clinical trials.

Castration-resistant prostate cancer (CRPC) is a lethal disease, and improvement with androgen-deprivation therapy has plateaued. Next-generation sequencing studies have led to significant advances in our understanding of genomic alterations in prostate cancer. The most common genomic aberrations in this malignancy are the transcription factor fusion of TMPRSS2-ETS, and mutations in TP53, AR, RB1 and PTEN/PIK3CA. Some of these alterations are actionable by drugs available in the clinic. In addition, it was recently shown that aberrations in DNA repair genes, such as BRCA2 and ATM, are present in both somatic and germline form in a significant minority of prostate cancer; these abnormalities can be targeted by drugs such as platinums and PARP inhibitors. In the era of tumour profiling, targeting molecular alterations may provide an opportunity for new therapeutic approaches. Although there are promising new agents to attack a variety of genomic signal abnormalities, biomarker-matched therapy (other than for androgens) have been utilised in only 2.0% of clinical trials (September 2011 through September 2014; https://clinicaltrials.gov) for prostate cancer. Enhanced efforts to define subsets of patients with prostate cancer based on their molecular anomalies, and match them with cognate therapies, warrant investigation

Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review

Pancreatic cancer has a dismal prognosis particularly in patients presenting with unresectable tumors. We performed a bibliometric analysis of clinical trials for pancreatic cancer conducted between 2014-2016 focusing on patients that presented with unresectable (locally advanced or metastatic) tumors. We discuss a range of studies that employed FOLFIRINOX, the gemcitabine + nab-paclitaxel combination and studies that used molecularly-targeted therapy. Major areas of focus have been dual targeting of EGFR and VEGFR, immunotherapy or a multimodal approach – combining chemotherapy with radiotherapy. We also point out the need for molecular selection for low prevalence subtypes. Key insights sourced from these pivotal trials should improve clinical outcomes for this devastating cancer

Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer.

BackgroundTreatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy.MethodsctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed.ResultsThe most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.ConclusionsOur findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival

Clinical and molecular characterization of HER2 amplified-pancreatic cancer

<p>Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies.</p> <p>Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC).</p> <p>Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum.</p> <p>Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types.</p&gt

Current Oncological Treatment of Patients with Pancreatic Cancer in Germany: Results from a National Survey on behalf of the Arbeitsgemeinschaft Internistische Onkologie and the Chirurgische Arbeitsgemeinschaft Onkologie of the Germany Cancer Society

Background: No data have previously been available regarding the current treatment of patients with pancreatic cancer (PC) in German hospitals and medical practices. Methods: Between February 2007 and March 2008 we conducted a national survey {[}on behalf of the Arbeitsgemeinschaft Internistische Onkologie (AIO) and the Chirurgische Arbeitsgemeinschaft Onkologie (CAO)] regarding the current surgical and oncological treatment of PC in Germany. Standardized questionnaires were sent via mailing lists to members of the AIO and CAO (n = 1,130). The data were analyzed using SPSS software (version 16.0). Pre-defined subgroup analysis was performed by grouping the results of each question with regard to the professional site of the responding physician and to the number of patients treated in their institution by year. Results: 181 (16%) of the oncological questionnaires were sent back. For 61% of the participating centers, a histological confirmation of PC diagnosis is obligatory. 21% of physicians offer neoadjuvant therapy to patients with potentially resectable PC. In the adjuvant treatment after curative-intent surgery, gemcitabine (Gem) is regarded as standard of care by 71% after R0 resection and 62% after R1 resection. For patients with locally advanced PC, 52% of the participating centers recommend systemic chemotherapy, 17% prefer combined primary chemoradiotherapy. Most centers (59%) base their decision of combination regimens for metastatic disease on the performance status of their patients. In patients with a good status, 28% apply single-agent Gem, 3% use Gem + capecitabine, 12% Gem + erlotinib, 16% Gem + oxaliplatin, and 8% Gem + cisplatin. Only 28% of the survey doctors offer second-line treatment to the majority of their patients with advanced PC. Conclusion: Not every PC patient in Germany is treated according to the present S3 guidelines. Diagnosis and treatment of PC in Germany still need to be improved. Copyright (C) 2009 S. Karger AG, Base

Updated management of malignant biliary tract tumors: an illustrative review

The management of malignant biliary tumors (MBTs) is complex and requires a multidisciplinary approach. Guidelines and methods of staging for biliary tumors have recently been released by main international societies, altering the clinical and radiologic approach to this pathologic condition. The aim of the present review is to detail the updated role of imaging in preoperative staging and follow-up and to illustrate clinical/therapeutic pathways. In addition, future perspectives on imaging and targeted/embolization therapies are outlined

Dynamic changes during the treatment of pancreatic cancer

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient\u27s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment

Challenges of drug resistance in the management of pancreatic cancer

The current treatment of choice for metastatic pancreatic cancer involves single agent gemcitabine or combination of gemcitabine with capecitabine and erlotinib (tyrosine kinase inhibitor). Only 25-30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activations of DNA repair pathways, resistance to apoptosis, and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, over expression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target, and/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments

Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers.

BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials

Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease