Personalising pancreas cancer treatment: When tissue is the issue

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]

PC: Pancreatic cancers; EGFR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor; DFS: Disease-free survival; OS: Overall survival.