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©2014 Baishideng Publishing Group Inc.
World J Gastroenterol. Jun 28, 2014; 20(24): 7849-7863
Published online Jun 28, 2014. doi: 10.3748/wjg.v20.i24.7849
Published online Jun 28, 2014. doi: 10.3748/wjg.v20.i24.7849
Table 1 Potentially ''actionable'' phenotypes and supporting evidence
Actionable phenotype | Therapeutic | Rationale | Molecular characterization |
Gemcitabine responsive | Gemcitabine | In PC, Phase III trials showed benefit in adjuvant (DFS 13.4 mo vs 6.9 mo) and palliative setting (MS 5.65 vs 4.41)[6,87] | High hENT1, hCNT1, hCNT3 Phase III data suggested that hENT1 correlated with response to Gemcitabine in adjuvant setting in PC[65,88], however this was not shown in the metastatic population[89] |
Anti-EGFR responsive | Erlotinib, Cetuximab | A Phase III trial showed that Erlotinib plus Gemcitabine had an overall survival benefit (HR = 0.82) compared with Gemcitabine alone in PC[14] Phase III data did not show a difference in OS when Cetuximab was added to Gemcitabine in an unselected population with PC[16] | Classical subtypePC cell lines with a “classical” subtype were shown to be more sensitive to Erlotinib[90] EGFR expression did not correlate with response to Cetuximab in patients with PC[16] |
Taxane responsive | nab-Paclitaxel | Phase III data showed that the addition of nab-Paclitaxel to Gemcitabine increased PFS (HR = 0.69) and OS (HR = 0.72) in the metastatic PC population[13] | SPARC expression (stromal) A phase I/II study showed that SPARC expression in the stroma correlated with survival[71] |
5-FU responsive | 5-Fluorouracil | Small phase III trials showed activity of 5-FU containing regimens in the metastatic population in PC[91,92]5-FU was shown to prolong survival when used in the adjuvant setting in PC (HR = 0.7)[93] | Thymidylate SynthaseHigh intra-tumoural expression was shown to correlate with an increased benefit from 5-FU based chemotherapy in pre-clinical[94] and retrospective patient populations[95] |
Irinotecan responsive | Irinotecan | In PC, a small effect as monotherapy has been shown in the second-line setting[96], and a significant effect on OS was shown when used as part of FOLFIRINOX (HR = 0.57)[11] | Topoisomerase 1 expressionHigh topo 1 expression was associated with a larger benefit from Irinotecan containing regimens in metastatic colorectal cancer[97] |
HER2 amplified | Trastuzumab | Has shown activity in HER-2 overexpressing breast and gastric cancers[39,98,99]Phase II trials do not show a benefit of adding Trastuzumab to Gemcitabine in PC (OS = 7 mo), however, no standardised approach to FISH testing was used[41,70] | HER2 amplificationPre-clinical studies suggested that HER2 overexpression predicts a response to Trastuzumab in PC[100] |
m-TOR responsive | Everolimus, Temsirolimus | A phase III trial of Everolimus in renal cell cancer shows prolongation in PFS (PFS 4 mo vs 1.9 mo)[101]Phase II data showed minimal activity (OS = 4.5 mo) of Everolimus for second line treatment in an unselected population of patients with metastatic PC[102]A case study in a patient with PC and Peutz-Jeghers syndrome (SK11 deficient) responds to Everolimus[103] | P-TEN Deficient, High p-mTOR/p70S6, AKT amplified, STK11/LKB1 deficiency, PI3K mutation Pre clinical studies showed that p-TEN deficient cell lines are sensitive to m-TOR inhibitors[104]Retrospective studies suggested that SK11, p-MTOR, p-70S6, PI3K and AKT can select tumours that will respond to m-TOR inhibitors[103,104-110] |
VEGF inhibitor responsive | Sunitinib, Bevacizumab | Phase III trial showed no benefit with adding Bevacizumab to Gemcitabine in an unselected population of patients with PC[17]Phase II data showed that maintenance Sunitinib after primary chemotherapy improved 2 yr OS (22.9% vs 7%) in the metastatic PC population[109] | CSF1R up-regulation, High HIF-α expressionIn vitro studies showed CSF-1R up-regulation was associated with response to Sunitinib in AML[110]High HIF-α predicted response to Sunitinib in a retrospective cohort in renal cell cancer[111] |
DNA damage repair deficient | Platinum; MMC; PARP inhibitor | In vitro work showed that cells with defects in BRCA2 are preferentially sensitive to PARP inhibitors[112]Case reports of PC patients with BRCA2 deficient tumours respond to PARP[113,114]Multiple clinical trials are on-going assessing the effects of PARP inhibition | DDR signature; mutation of DDR genes,BRCA/ATM/PALB2Loss of BRCA1 was associated with sensitivity to DNA damaging agents[115]BRCA2 mutations were associated with improved response to platinum agents[116]In vivo studies showed PALB2 inactivation was a determinant of response to DNA damaging agents in PC[114] |
SMO inhibitor responsive | Saridegib, Vismodegib | A phase II trial found that Saridegib plus Gemcitabine was no better than Gemcitabine alone in an unselected population of metastatic PC patients (data not published)[117]In vivo studies show SMO inhibitors block metastasis formation in pancreatic cancer[118] | Gli1 and PTCH1 transcript levelsGLI1 mRNA may predict response to SMO inhibitors in pancreatic cancer in vivo[119]High Gli1/PTCH1 transcript levels were correlated with response to SMO inhibitors in CLL[120] |
Table 2 Ongoing biomarker directed therapy trials in pancreatic carcinoma
Trial identifier1 | Name of study | Phase | Sponsor | Arms | Primary outcome | Biomarker |
ACTRN12612000777897 | The IMPACT trial: Individualised Molecular Pancreatic Cancer Therapy A randomised open label phase II study of standard first line treatment or personalised treatment in patients with recurrent or metastatic pancreatic cancer | II | The Australasian Gastro-Intestinal Trials Group Collaborating groups:Australian Pancreatic Cancer Genome Initiative Sydney Catalyst; the Translational Cancer Research Centre of Central Sydney and Regional NSW | Patients with actionable phenotypes randomised 1:1 to Standard -gemcitabine aloneORPersonalised Treatment -allocated based on molecular phenotype:HER2 positive sub-group - gemcitabine plus trastuzumab Homologous recombinant defects subgroup: 5FU plus MMCantiEGFR responsive sub-group: gemcitabine plus erlotinib | Progression free survival (initial pilot phase will assess feasibility of personalised approach) | Identification of actionable phenotypes based on molecular phenotype in tumour tissue in one of 3 subgroups:HER2 positive (HER2/neu amplification) subgroupHomologous recombination defects (BRCA1, BRCA2 or PALB2 mutation)AntiEGFR phenotype subgroup (KRAS wildtype or KRAS codon 13 mutation) |
NCT01188109 | Gemcitabine/cisplatin for resected pancreas cancer: Establishing the role of ERCC1 in treatment decision | II | Emory University | Gemcitabine and cisplatin | Progression free survival and overall survival | Immunohistochemistry, rt-PCR, and single nucleotide polymorphism assessment to determine status of ERCC1 expression and gene |
NCT01488552 | A Phase II study of induction consolidation and maintenance approach for patients with advanced pancreatic cancer | I/II | Pancreatic Cancer Research Team | Gemcitabine + Nab-paclitaxel inductionFOLFIRINOX consolidative Metformin + targeted agent selected by biomarkers for maintenance | Complete response rate | IHC Analysis will be performed on a fresh tissue biopsy of the tumor after chemotherapy has been administered. A targeted-based regimen will be determined from the results of the IHC analysis for the next therapy given to the patient in the maintenance phase of the study |
NCT01524575 | Gemcitabine and oxaliplatin in the management of metastatic pancreatic cancers with low expression of ERCC1 | Phase II | University of Hawaii | Gemcitabine+oxaliplatin | 6 mo overall survival | Low expression of ERCC1 protein and mRNA expression |
NCT01888978 | A Pilot Study of Molecularly Tailored Therapy for Patients With Metastatic Pancreatic Cancer | Phase II | Georgetown University | Gemcitabine+oxaliplatinGemcitabine + 5FUGemcitabine + docetaxelFOLFOX6Oxaliplatin + docetaxelFOLFIRIDocetaxel-irinotecan | Timing of biopsy and treatmentNumber of days from study entry to biopsy to molecular results to first dose | Selection of doublet treatment on basis of molecular analysis of tumour |
NCT01585805 | Gemcitabine Hydrochloride and Cisplatin With or Without Veliparib or Veliparib Alone in Patients With Locally Advanced or Metastatic Pancreatic Cancer | Randomised phase II | National Cancer Institute | Cisplatin+gemcitabine+/-veliparib | Optimal dose of veliparibResponse rate | BRCA1 or BRCA2 mutation carrier |
NCT01586611 | Study of Gemcitabine vs FOLFOX in the First Line Setting for Metastatic Pancreatic Cancer Patients Using Human Equilibrative Nucleoside Transporter 1 (hENT1) Biomarker Testing | Phase III | AHS Cancer Control Alberta | FOLFOXGemcitabine | PFS between arms in hENT1 high and hENT1 low patients | hENT1 |
NCT01454180 | Study of Individualized Selection of Chemotherapy in Patients With Advanced Pancreatic Carcinoma According to Therapeutic Targets | Phase II | Centro Nacional de Investigaciones Oncologicas CARLOS III | Arm A: Physician discretionArm B: Therapeutic target guidedGemcitabineGemcitabine + capecitabineGemcitabine + erlotinibFOLFOXIRIFOLFOXFOLFIRI | Overall survival | Therapeutic targets expressed in tumour tissue |
NCT01726582 | Molecular Profiling to Guide Neoadjuvant Therapy for Resectable and Borderline Resectable Adenocarcinoma of the Pancreas | Phase II | Medical College of Wisconsin | Targeted chemotherapy prior to surgeryStandard FOLFIRINOX chemotherapy prior to surgeryGemcitabine after surgeryNo additional therapy after surgeryTargeted chemotherapy after surgeryChemoradiotherapy | Resectability rate | Molecular profile of tumour will point to particular chemotherapy treatment |
(Targeted chemotherapy include the following schedules: FOLFIRINOX, FOLFIRI, gemcitabine+irinotecan, gemcitabine + oxliplatin, gemcitabine + cisplatin, gemcitabine+nab-paclitaxel, capecitabine + nab-paclitaxel, gemcitabine, capecitabine, 5FU) |
- Citation: Sjoquist KM, Chin VT, Chantrill LA, O’Connor C, Hemmings C, Chang DK, Chou A, Pajic M, Johns AL, Nagrial AM, Biankin AV, Yip D. Personalising pancreas cancer treatment: When tissue is the issue. World J Gastroenterol 2014; 20(24): 7849-7863
- URL: https://www.wjgnet.com/1007-9327/full/v20/i24/7849.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i24.7849