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

New RAS-mutant pancreatic adenocarcinoma with combined BRAF and MEK inhibition for metastatic melanoma

No abstract available

Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy

Background: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. Patients and methods: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. Results: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. Conclusions: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial

Purpose: Personalized medicine strategies using genomic profiling are particularly pertinent for pancreas cancer. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial was initially designed to exploit results from genome sequencing of pancreatic cancer under the auspices of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed small subsets of patients with aberrations in their tumor genome that could be targeted with currently available therapies.<p></p> Experimental Design: The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumor specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable timeframe. We screened for three molecular targets: HER2 amplification; KRAS wild-type; and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM).<p></p> Results: Tumor biopsy and archived tumor samples were collected from 93 patients and 76 were screened. To date 22 candidate cases have been identified: 14 KRAS wild-type, 5 cases of HER2 amplification, 2 mutations in BRCA2, and 1 ATM mutation. Median time from consent to the return of validated results was 21.5 days. An inability to obtain a biopsy or insufficient tumor content in the available specimen were common reasons for patient exclusion from molecular analysis while deteriorating performance status prohibited a number of patients from proceeding in the study.<p></p> Conclusions: Documenting the feasibility of acquiring and screening biospecimens for actionable molecular targets in real time will aid other groups embarking on similar trials. Key elements include the need to better prescreen patients, screen more patients, and offer more attractive clinical trial options. <p></p&gt

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes