Table 3.

Pharmacogenetic biomarkers and mutations identified

Gene	Frequency in these 14 patients	Pathway/action	Potential target therapy	FDA status of targeted therapies	Drug‐biomarker targeted clinical trials	References
AKT	5	PI3K/AKT/mTOR	AKT inhibitors. Akt inhibition may modulate platinum‐based therapy resistance	None approved	MK‐2206 in phase II clinical trials, alone, and in combination with platinum‐based chemotherapies. RX‐0201 plus gemcitabine in phase II in advanced PDAC	Cheaib et al. (2015), Nitulescu et al. (2016)
APC	8	Wnt/β‐catenin	WNT inhibitors	FDA‐approved, PDAC off‐label indication. Potentiation of chemotherapy agents by celecoxib and sulindac	Celecoxib with chemotherapy regimines in phase III trials in PDAC	Lesko et al. (2014), Lipton et al. (2010), Pino et al. (2009)
ATM	7	Protein kinase. Cell cycle, DNA repair, apoptosis	Associated with either increased or decreased survival when treated with Gemcitabine, depending on variant. Susceptibility to PARP inhibitors. Metformin pathway	Olaparib Metformin	No ATM inhibitors currently in clinical development. Olaparib and rucaparib in phase III trials in PDAC. Phase III trials metformin in combination with chemotherapy	Johnson et al. (2016), Mateo et al. (2015), Soo et al. (2012)
AURKA	3	Mediates mitosis	Aurora kinase inhibitors, potentiated by other microtubule‐targeting chemotherapies	None approved	Barasertib and danusertib in phase II clinical trials, SNS‐314 in phase I	Bavetsias and Linardopoulos (2015), Meulenbeld et al. (2013), Steeghs et al. (2009), VanderPorten et al. (2009)
BRAF	3	RAF/MEK/ERK signaling, MAPK	BRAF inhibitors, MEK inhibitors	FDA‐approved, PDAC off‐label indication. Vemurafenib and dabrafenib; trametinib. Sorafenib	Sorafenib with erlotinib and sorafenib with gemcitabine plus cisplatin failed phase II trials in advanced PDAC.	Cardin et al. (2014), Wilhelm et al. (2006)
BRCA1	10	DNA repair	Increased susceptability to PARP inhibitors and platinum‐based chemotherapies	FDA‐approved, PDAC off‐label indication for PARPi. Olaparib. Cisplatin och oxaliplatin are FDA‐approved for PDAC, not in monotherapy	Olaparib and rucaparib in phase III trials in PDAC. Veliparib in phase II trials as monotherapy and with gemcitabine and cisplatin	Bendell et al. (2015), Kaufman et al. (2015), Lowery et al. (2011)
CDA	1	pyrimidine salvaging, deamination of gemcitabine	Increased gemcitabine toxicity			Hung et al. (2012), Nakano et al. (2007), Soo et al. (2012)
CDKN2A	6	Cell cycle	CDK4/6 inhibitor	Palbociclib. FDA‐approved, PDAC off‐label indication	Palbociclib in phase I	Witkiewicz et al. (2015a,b)
DPYD	9	Inactivation of 5‐FU	Capecitabine, 5‐FU toxicity	FDA‐approved biomarker for adverse drug reaction		Lee et al. (2005), Stoehlmacher and Lenz (2003)
EGFR (ERBB‐1)	10	MAPK, JNK, PI3K/AKT/mTOR	Predictive role of EGFR intron length and response to anti‐EGFR therapies shown in other cancer types	Afatinib, cetuximab, panitumumab, temsirolimus. Erlotinib is FDA‐approved for use in PDAC, others off‐label in PDAC	Cetuximab in phase III trials no increase in overall survival. Afatinib phase II (togther with MEK inhibitor selumetinib)	Burtness et al. (2016), Soo et al. (2012)
ERBB2	4	MAPK, PKC, JAK/STAT, PI3K/AKT/mTOR, phospolipase Cγ	Her 2/3 inhibitors and antibodies	Afatinib, lapatinib, pertuzumab, (ado‐)trastuzumab emtansine;temsirolimus. Everolimus is FDA‐approved for use in PDAC, others off‐label in PDAC	Trastuzumab with either gemcitabine or capcitabine showed no improval over gemcitabine alone in clinical trial in PDAC	Chou et al. (2013), Harder et al. (2012), Safran et al. (2004)
FGFR4	8	Tyrosine kinase receptors	Involved in proliferation and differentiation	FDA‐approved for metastatic melanoma with BRAFV600E mutation	Vemurafenib in phase I trials in PDAC	Hyman et al. (2015), Witkiewicz et al. (2015a,b)
KRAS	12	MAPK	RAF, MEK (KRAS V12 mutation and copy number variations are resistant to MEK inhibitors), PI3K or farnesyl transferase inhibitors. Decreased drug sensitivity to erlotinib	Trametinib; tipifarnib, Pantimumab, cetuximab. Selumetinib (orphan drug designation). FDA‐approved, PDAC off‐label indication	Selumetinib similar efficacy to capecitabine advanced PDAC phase II trials. Tipifarnib in phase III showed no improval over gemcitabine in PDAC. R115777 farnesyl transferase inhibitors failed phase II	Bramhall et al. (2002), Chiorean and Coveler (2015), Van Cutsem et al. (2004)
MAP3K1	2	MAPK	MAP3K1 mutation increases sensitivity to platinum‐based chemotherapy and taxanes	None approved	No MAP3K1 modulators currently in clinical development	Hu et al. (2014), Li et al. (2011)
MLH1	8	DNA repair	Decreased sensitivity to 5‐FU and doxorubicin with mismatch repair deficient tumors compared with proficient. Potential susceptibility to platinum‐based chemotherapy, PARP inhibitors	FDA‐approved, PDAC off‐label indication for PARP inhibitor. Olaparib. Cisplatin och oxaliplatin are FDA‐approved for PDAC, not in monotherapy	Olaparib and rucaparib in phase III trials in PDAC. Veliparib in phase II trials as monotherapy and with gemcitabine and cisplatin	Kawakami et al. (2015), Nakano et al. (2007)
MSH	10	DNA repair	Decreased sensitivity to 5‐FU and doxorubicin with mismatch repair deficient tumors compared with proficient. Potential susceptibility to platinum‐based chemotherapy, PARP inhibitors	FDA‐approved, PDAC off‐label indication for PARPi. Olaparib. Cisplatin och oxaliplatin are FDA‐approved for PDAC, not in monotherapy	Olaparib and rucaparib in phase III trials in PDAC. Veliparib in phase II trials as monotherapy and with gemcitabine and cisplatin	Kawakami et al. (2015), Nakano et al. (2007)
PALB2	4	DNA repair	PARP inhibitors	FDA‐approved, PDAC off‐label indication for PARPi. Olaparib. Cisplatin och oxaliplatin are FDA‐approved for PDAC, not in monotherapy	Olaparib and rucaparib in phase III trials in PDAC. Veliparib in phase II trials as monotherapy and with gemcitabine and cisplatin	Childs et al. (2016), Salo‐Mullen et al. (2015), Waddell et al. (2015)
PMS1	10	DNA repair	Decreased sensitivity to 5‐FU with mismatch repair deficient tumors compared with proficient			Kawakami et al. (2015)
PMS2	2	DNA repair	Decreased sensitivity to 5‐FU with mismatch repair deficient tumors compared with proficient			Kawakami et al. (2015)
STK11	2	Regulates polarity, tumor supressor	Metformin pathway	Metformin. FDA‐approved, PDAC off‐label indication	Phase III trials metformin in combination with chemotherapy	Bhaw‐Luximon and Jhurry (2016), Elmaci and Altinoz (2016)