Purpose:

Modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) remain standard first-line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC.

Experimental Design:

COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal χ2 statistic.

Results:

253 patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median overall survival (OS) was 10.0 months in hENT1high versus 7.9 months in hENT1low (P = 0.02). In patients receiving mFFX, there was no difference in overall response rate (ORR; 35% vs. 28%, P = 0.56) or median OS (10.6 vs. 10.5 months, P = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1high compared with hENT1low tumors (43% vs. 21%, P = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1high versus 6.7 months hENT1low (P < 0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction P = 0.002).

Conclusions:

In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP.

This article is featured in Highlights of This Issue, p. 3403

Translational Relevance

Biomarkers are urgently needed to select chemotherapy regimens in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether mRNA expression levels of human equilibrative nucleoside transporter (hENT1) predict responsiveness to gemcitabine/nab-paclitaxel (GnP) in patients with advanced PDAC. The results of this prospective observational clinical trial using tumor enriched RNA sequencing revealed higher response rates and improved survival in patients receiving GnP, when tumors were considered hENT1high compared with those that were hENT1low. No difference in response or survival were seen in patients receiving modified FOLFIRINOX. An interaction analysis confirmed hENT1 as a predictive biomarker for GnP response. This suggests that hENT1 expression can be used to identify patients who will respond to GnP.

Despite numerous phase III trials investigating novel agents, nonselective chemotherapy regimens remain the standard of care for most patients with unresectable or metastatic pancreatic cancer (1). Olaparib has been approved post induction platinum chemotherapy for the 5% to 7% of patients harboring germline alterations in BRCA1/2 who demonstrate disease control (2); while checkpoint inhibitors and other targeted biologics may be effective in a minority of patients. The regimens of modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) have never been compared head to head, and the choice between these two treatments is often based on a patient's performance status, as well as patient and physician preference.

The human equilibrative nucleoside transporter 1 (hENT1) encoded by the SLC29A1 gene belongs to a family of nucleoside transporters and plays a critical role in the uptake of gemcitabine into pancreatic ductal adenocarcinoma (PDAC) cells (3). Approximately 51% of human pancreatic and biliary cancers have been shown to display strong hENT1 expression by IHC (4). In early stage resected PDAC, hENT1 expression levels have been shown to predict benefit from adjuvant gemcitabine (3, 5).

RNA sequencing (RNA-seq) is increasingly integral to tumor profiling and can be used for fusion detection. In addition, signatures have documented a number of prognostic classifiers in PDAC, which are being evaluated in clinical trials (6).

We hypothesized that hENT1 mRNA expression would predict responsiveness to GnP in patients with advanced PDAC enrolled on the COMPASS trial (NCT02750657).

Patients

Patients with advanced PDAC had biopsies prior to commencing planned chemotherapy with mFFX or GnP as first-line treatment for advanced disease. All patients were Eastern Cooperative Oncology Group (ECOG) 0 to 1 and the choice of treatment was at the discretion of the treating medical oncologist. Response to therapy was assessed using CT scans and measured using RECIST 1.1. All patients were enrolled from December 2015 until June 2020 with follow-up censored on October 1, 2021. Patients on this study were enrolled at the Princess Margaret Cancer Centre (Toronto, Ontario, Canada), McGill University Health Centre (MUHC, Montreal, Quebec, Canada), and Kingston General Hospital (Kingston, Ontario, Canada), with written informed consent obtained prior to enrollment. The COMPASS trial has been approved by the Institutional Review Boards of the participating sites (University Health Network, Toronto, Ontario, Canada; MUHC Centre for Applied Ethics, Montreal, Quebec, Canada; and Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board, Kingston, Ontario, Canada); and was conducted in accordance with the Declaration of Helsinki.

RNA-seq

Frozen biospecimens underwent laser capture microdissection (LCM) for tumor enrichment. RNA-seq was performed at the Ontario Institute of Cancer Research as described previously (7). Briefly, reads were aligned to the human reference genome (hg38) and transcriptome (Ensembl v.84) using STAR v.2.5.2a (8), with duplicated reads marked using Picard v. 1.121 (https://github.com/broadinstitute/picard). Gene expression was calculated in fragments per kilobase of exon per million reads mapped using the cufflinks package v. 2.2.1 (9). A modified Moffitt classification (classical vs. basal-like) was applied to each sample with sufficient RNA for analysis (10). All RNA-seq data has been deposited in the European Genome-phenome Archive (EGA) at EGAD00001009409.

HRDetect score

The HRDetect score was assigned as previously published (11) with minor modifications to enable installation in our computing environment as described in our prior study (12). The original feature coefficients published by Davies and colleagues (13) were employed with a score of ≥ 0.7 identifying HRD-PDAC.

Statistical analysis

Qualitative variables were compared by Fisher exact test, and quantitative variables by Wilcoxon rank-sum test for pairwise comparison and the Kruskal–Wallis test for multiple group comparison. Patients receiving at least one cycle of chemotherapy were included in the analysis of overall response rate (ORR). Overall survival (OS) was estimated using Kaplan–Meier curves and compared using the Cox proportional hazard regression with P values calculated using the Wald statistic. Spearman correlation coefficients were ascertained for evaluating gene expression. Cut-off thresholds for hENT1 expression were determined using both the median expression levels and the maximal χ2 statistic. The maximal χ2 statistic was chosen as it best reflected change in tumor size change with hENT1 expression. Tumors above this threshold were defined as hENT1high and those below classified as hENT1low. Statistical significance testing was two-tailed and set at P value less than 0.05. Statistical analysis was performed in R version 3.2. To correct for multiple tests, P values were adjusted using Benjamini and Hochberg method for independent tests or Benjamini and Yekutieli method for dependent tests, respectively.

Data availability

The RNA-seq data generated in this study are publicly available in the EGA at EGAD00001009409.

Baseline patient characteristics

In total, 268 eligible patients were enrolled with a median follow-up of 32 months. Median OS in the ITT population was 9.3 months. hENT1 expression levels were available for 253 cases. Of these, 138 patients received mFFX (55%) and 92 received GnP (36%). Two (1%) patients received cisplatin/gemcitabine and 5 (2%) gemcitabine only. Planned treatment was not given in 16 (6%). Baseline clinical characteristics are described in Table 1 and were well distributed between the mFFX and GnP groups, however those receiving GnP were significantly older than those who received mFFX (67 vs. 62 years, P < 0.001). On the basis of gene expression levels, 141 patients were classified as hENT1high and 112 as hENT1low.

Table 1.

Baseline characteristics of patients on COMPASS trial.

CategoriesFFX (N = 138)GnP (N = 97)a
Median age (years) 62*(P < 0.001) 67 
Sex 
 Male 89 (64.5%) 52 (53.6%) 
 Female 49 (35.5%) 45 (46.4%) 
ECOG performance status 
 0 52 (37.7%) 31 (32.0%) 
 1 86 (62.3%) 66 (68.0%) 
Prior surgery for resectable disease 
 Yes 14 (10.1%) 6 (6.2%) 
 No 124 (89.9%) 91 (93.8%) 
Metastatic disease 
 Yes 118 (85.5%) 85 (87.6%) 
 No 20 (14.5%) 12 (12.4%) 
Liver metastases 
 Yes 100 (72.5%) 70 (72.2%) 
 No 38 (27.5%) 27 (27.8%) 
Moffit signature 
 Classical 109 (79%) 80 (82.5%) 
 Basal-like 27 (19.6%) 17 (17.5%) 
 Unknown 2 (1.4%) 0 (0.0%) 
Location of biopsy 
 Pancreas 31 (22.5%) 29 (29.9%) 
 Liver 93 (67.4%) 56 (57.7%) 
 Other 14 (10.1%) 12 (12.4%) 
Median BMI (kg/m224.25 23.5 
Median CA 19–9 at baseline 1,916 1,133 
CategoriesFFX (N = 138)GnP (N = 97)a
Median age (years) 62*(P < 0.001) 67 
Sex 
 Male 89 (64.5%) 52 (53.6%) 
 Female 49 (35.5%) 45 (46.4%) 
ECOG performance status 
 0 52 (37.7%) 31 (32.0%) 
 1 86 (62.3%) 66 (68.0%) 
Prior surgery for resectable disease 
 Yes 14 (10.1%) 6 (6.2%) 
 No 124 (89.9%) 91 (93.8%) 
Metastatic disease 
 Yes 118 (85.5%) 85 (87.6%) 
 No 20 (14.5%) 12 (12.4%) 
Liver metastases 
 Yes 100 (72.5%) 70 (72.2%) 
 No 38 (27.5%) 27 (27.8%) 
Moffit signature 
 Classical 109 (79%) 80 (82.5%) 
 Basal-like 27 (19.6%) 17 (17.5%) 
 Unknown 2 (1.4%) 0 (0.0%) 
Location of biopsy 
 Pancreas 31 (22.5%) 29 (29.9%) 
 Liver 93 (67.4%) 56 (57.7%) 
 Other 14 (10.1%) 12 (12.4%) 
Median BMI (kg/m224.25 23.5 
Median CA 19–9 at baseline 1,916 1,133 

aIn the GnP group, 5 patients received gemcitabine alone.

*Statistically significant difference.

Tumor response according to hENT1 expression

Across all treatments received, ORR did not differ between the hENT1high and hENT1low groups (38% vs. 25%, P = 0.07). In patients receiving mFFX, there was no difference in ORR (35% in hENT1high and 28% in hENT1low, P = 0.56; Fig. 1A). However, in patients treated with GnP, ORR was significantly higher in hENT1high compared with those with hENT1low PDAC (43% vs. 21%, P = 0.038; Fig. 1B).

Figure 1.

A, Waterfall plot demonstrating response to mFFX according to hENT1 expression. B, Waterfall plot demonstrating response to GnP according to hENT1 expression.

Figure 1.

A, Waterfall plot demonstrating response to mFFX according to hENT1 expression. B, Waterfall plot demonstrating response to GnP according to hENT1 expression.

Close modal

OS according to hENT1 expression

In the intention to treat population, the median OS was 10.0 months in hENT1high versus 7.9 months in hENT1low [HR 1.35, 95% confidence interval (CI), 1.04–1.75; P = 0.02; Figure 2A]. In patients receiving mFFX, median OS was 10.6 in hENT1high and 10.5 in hENT1low groups (P = 0.45; Figure 2B). However, in patients treated with GnP median OS was 10.6 months in hENT1high versus 6.7 months hENT1low (P < 0.001; Fig. 2C).

Figure 2.

AC, Kaplan–Meier Survival curves of (A) intention to treat population (n = 253) according to hENT1 expression, (B) patients receiving mFFX, (C) patients receiving GnP.

Figure 2.

AC, Kaplan–Meier Survival curves of (A) intention to treat population (n = 253) according to hENT1 expression, (B) patients receiving mFFX, (C) patients receiving GnP.

Close modal

Classical tumors also showed elevated levels of hENT1 compared with basal-like tumors (82.5% vs. 17.5%, P < 0.0001). Patients with classical tumors and hENT1high expression had improved OS when treated with GnP, compared with those with classical tumors but hENT1low expression (Supplementary Figs. S1 and S2). Only four patients with basal-like and hENT1high PDAC were treated with GnP but had improved OS compared with those with hENT1low expression.

In multivariable analyses, tumors identified as classical PDAC (P = 0.001) and those that were homologous recombination deficient as defined by the HRDetect score (ref. 13; P = 0.007) were associated with improved OS (Fig. 3). Similarly receiving mFFX was associated with improved OS in this population (Fig. 3). In an interaction analysis, hENT1 expression was predictive of treatment response to GnP (P = 0.002).

Figure 3.

Multivariable analysis with HRs presented for OS. Only patients who received chemotherapy were used in this analysis.

Figure 3.

Multivariable analysis with HRs presented for OS. Only patients who received chemotherapy were used in this analysis.

Close modal

Changes in hENT1 expression at progression

On this trial 14 progression biopsies were available and median time to progression biopsy was 6 months (range 2–14 months). Of these 14 biopsies, 4 (29%) demonstrated a change in hENT1 expression levels. These include 2 patients treated with GnP that changed from hENT1high to hENT1low and 2 patients treated with mFFX that changed from hENT1low to hENT1high.

GnP is the backbone of many clinical trials and is a standard of care for advanced PDAC. Although mFFX is now the regimen of choice in the adjuvant setting with the APACT trial (22) failing to meet its primary endpoint, not all patients are suitable for this regimen. In addition, the SWOG 1505 trial did not demonstrate a ‘winner’ when comparing neoadjuvant GnP and mFFX with higher pathologic response rates in the GnP arm (14). Collectively, this suggests that there may be a cohort of patients that may benefit from gemcitabine-based treatments in the neoadjuvant/adjuvant settings. While hENT1 has previously been hypothesized to predict gemcitabine response, results have been conflicting. In this prospective observational clinical trial using tumor enriched RNA, patients with tumors that had high hENT1 expression demonstrated higher response rates (45% vs. 21%) and and improved survival (6.1 vs. 9.8 months) when treated with GnP compared with those with tumors that were hENT1low. No difference in response or survival were seen in patients receiving mFFX irrespective of hENT1 expression. The ORR to GnP and mFFX in our study is similar to the MPACT trial (23%; ref. 15) and PRODIGE4/ACCORD 11 (31.6%; ref. 16).While cross trial comparisons are limited, the ORR of 45% and improved survival seen in patients with hENT high tumors is important given lack of predictive biomarkers to dictate choice of chemotherapy. This is notable given that chemotherapy selection was by physician, with patients receiving GnP being significantly older than those receiving mFFX. Not all patients will be suitable for triplet therapy and the ability to use a potentially more tolerable regimen with a predictive biomarker is important. This has also recently been highlighted in adjuvant studies incorporating biomarkers of gemcitabine response (17, 18).

A recent meta-analysis of 29 studies in pancreatobiliary cancers showed that higher protein expression of hENT1 was prognostic for OS in patients treated with adjuvant gemcitabine (pooled HR, 0.67; 95% CI, 0.51–0.89), however this was largely antibody dependent (4). Among studies using the murine 10D7G2 antibody, 88% demonstrated this association, while studies with other antibodies, in particular those of rabbit SP120 antibody were less consistent. In addition, in a recent study of five hENT1 antibodies in 472 patients with resected PDAC, the 10D7G2 was the only antibody associated with a prolonged PFS and OS in patients who received adjuvant gemcitabine (19). Unfortunately, the 10D7G2 antibody is currently not validated for commercial use. Using the 10D7G2 antibody in patients on the ESPAC-3 trial receiving adjuvant gemcitabine demonstrated improved median survival of 26.2 months (95% CI, 21.2–31.4) when hENT1 expression was high, compared with 17.1 months (95% CI, 14.3–23.8) when hENT1 expression was low (5). While this predictive benefit was confirmed with the multivariable analysis, no such effect was seen with patient treated with 5-fluorouracil. The reasons for the discrepancies between the different antibodies is not clear but it has been proposed that this may be secondary to the antibodies recognizing distinct epitopes or isoforms of glycosylated hENT1 (19).

Of the prior studies evaluating mRNA expression, four showed a correlation between hENT1 mRNA levels and improved survival (4). Limited studies of advanced disease were included and to our knowledge, no studies have evaluated hENT1 prospectively in the advanced PDAC setting. Although criteria for defining high hENT1 mRNA expression have varied between studies, there is a consistent trend. A study of 164 patients in the adjuvant setting, found a trend toward a predictive value when comparing the patients with the top versus lowest quartiles of hENT1 expression (19). Further increasing the threshold to the top 10% of hENT1 expressors allowed for the identification of group of patients with exceptional response to gemcitabine. Another study of 102 resected cases reported significantly longer survival when expression levels were analyzed by medians versus tertiles (20). Importantly in the latter study, samples underwent LCM, which allowed for enrichment of tumor tissue similar to our study. In the absence of clinically validated antibodies, mRNA expression–based analyses offers a viable, robust alternative to evaluate hENT1 expression, especially given that RNA-seq is increasingly integral to tumor profiling.

We have previously confirmed the poor prognostic impact of the basal-like subtype in PDAC (21). This was again observed in this study where classical tumors were associated with improved OS in multivariable analysis. Despite this favorable prognosis, classical tumors with hENT1low expression had worse survival outcomes than those with hENT1high expression, indicating the importance of hENT1 in dictating response to gemcitabine-based chemotherapy. In addition, while small numbers of basal-like PDAC were included in these analyses we hypothesize that in patients with basal-like tumors and high hENT1 expression, outcomes may be improved if treated with GnP.

We also document in a small sample of matched progression biopsies that hENT1 expression changed only in a subset of patients. While our ability to interpret this data is limited by sample size, this does suggest that hENT1 expression may evolve depending on type of treatment received and warrants further evaluation.

One of the main limitations of our study is the non-randomized design, with choice of chemotherapy regimen dictated by the treating physician. While this likely impacts the results of the study, the median OS with mFFX and GnP treatment observed in this study are similar to the MPACT trial (8.5 months; ref. 15) and PRODIGE4/ACCORD 11 (11.1 months; ref. 16) respectively. Moreover, it is possible that there is heterogeneity in hENT1 gene expression between the primary and metastatic sites. It should be noted that hENT1 expression between primaries and metastases have a high concordance when evaluated by IHC (19) suggesting reproducibility regardless of site biopsied. While, this situation likely holds true with regards to mRNA expression as well, it has never been directly evaluated. Furthermore, based on our current understanding of hENT1 activity, we do not believe it should impact activity or uptake of nab-paclitaxel, but rather promote the activity of gemcitabine within the doublet.

In summary, in this study we demonstrate that hENT1 mRNA levels serve as a predictive biomarker of GnP in advanced PDAC patients. These results will be further validated in the ongoing PASS-01 trial (NCT04469556).

S. Perera reports personal fees from Eisai outside the submitted work. M. Tehfe reports personal fees from BMS, Merck, Taiho, and Pfizer outside the submitted work. R. Ramjeesingh reports grants from Craig's Cause Pancreatic Cancer Society during the conduct of the study; grants from AstraZeneca, Eisai, Amgen, Pfizer, Ipsen; and other support from Incyte outside the submitted work. R.C. Grant reports other support from Pfizer outside the submitted work. J.J. Knox reports grants from Ontario Institute of Cancer Research, Pancreas Cancer Canada, and Princess Margaret Cancer Centre Foundation during the conduct of the study. G.M. O'Kane reports grants from Ontario Institute for Cancer Research during the conduct of the study; personal fees from AstraZeneca, Roche, Incyte; and grants from Roche outside the submitted work. No disclosures were reported by the other authors.

S. Perera: Data curation, methodology, writing–original draft, writing–review and editing. G.H. Jang: Formal analysis. Y. Wang: Writing–review and editing. D. Kelly: Writing–review and editing. M. Allen: Writing–review and editing. A. Zhang: Data curation, software. R.E. Denroche: Data curation, formal analysis. A. Dodd: Project administration. S. Ramotar: Project administration. S. Hutchinson: Project administration. M. Tehfe: Visualization, writing–review and editing. R. Ramjeesingh: Resources, funding acquisition, visualization, writing–review and editing. J. Biagi: Visualization, methodology. B. Lam: Data curation, methodology. J. Wilson: Data curation, methodology. S.E. Fischer: Resources, investigation, methodology. G. Zogopoulos: Investigation, visualization. F. Notta: Data curation, investigation, visualization. S. Gallinger: Conceptualization, resources, supervision, funding acquisition, visualization, writing–review and editing. R.C. Grant: Conceptualization, resources, supervision, validation, investigation, visualization. J.J. Knox: Conceptualization, resources, supervision, funding acquisition, visualization, writing–review and editing. G.M. O'Kane: Conceptualization, resources, supervision, methodology, writing–review and editing.

This study was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative, I.PANC 399985, to S. Gallinger) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, Pancreatic Cancer Canada, the Terry Fox Research Institute (TFRI 1078, to S. Gallinger), Craig's Cause Pancreatic Cancer Society and the QEII Foundation (to R. Ramjeesingh) and the Canadian Cancer Society Research Institute (702316, to S. Gallinger).

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

1.
O'Kane
GMFS
,
Denroche
R
,
Jang
GH
,
Zhang
A
,
Dodd
A
,
Grant
RC
, et al
.
Integrative molecular profiling and response to chemotherapy on the COMPASS trial
.
J Clin Oncol
2019
;
37
:
88
.
2.
Golan
T
,
Hammel
P
,
Reni
M
,
Van Cutsem
E
,
Macarulla
T
,
Hall
MJ
, et al
.
Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer
.
N Engl J Med
2019
;
381
:
317
27
.
3.
Spratlin
J
,
Sangha
R
,
Glubrecht
D
,
Dabbagh
L
,
Young
JD
,
Dumontet
C
, et al
.
The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma
.
Clin Cancer Res
2004
;
10
:
6956
61
.
4.
Vos
LJ
,
Yusuf
D
,
Lui
A
,
Abdelaziz
Z
,
Ghosh
S
,
Spratlin
JL
, et al
.
Predictive and prognostic properties of human equilibrative nucleoside transporter 1 expression in gemcitabine-treated pancreatobiliary cancer: a meta-analysis
.
JCO Precision Oncology
2019
;
3
:
1
22
.
5.
Greenhalf
W
,
Ghaneh
P
,
Neoptolemos
JP
,
Palmer
DH
,
Cox
TF
,
Lamb
RF
, et al
.
Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial
.
J Natl Cancer Inst
2014
;
106
:
djt347
.
6.
Collisson
EA
,
Bailey
P
,
Chang
DK
,
Biankin
AV
.
Molecular subtypes of pancreatic cancer
.
Nat Rev Gastroenterol Hepatol
2019
;
16
:
207
20
.
7.
Connor
AA
,
Denroche
RE
,
Jang
GH
,
Timms
L
,
Kalimuthu
SN
,
Selander
I
, et al
.
Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma
.
JAMA Oncol
2017
;
3
:
774
.
8.
Dobin
A
,
Davis
CA
,
Schlesinger
F
,
Drenkow
J
,
Zaleski
C
,
Jha
S
, et al
.
STAR: ultrafast universal RNA-seq aligner
.
Bioinformatics
2013
;
29
:
15
21
.
9.
Trapnell
C
,
Williams
BA
,
Pertea
G
,
Mortazavi
A
,
Kwan
G
,
van Baren
MJ
, et al
.
Transcript assembly and quantification by RNA-seq reveals unannotated transcripts and isoform switching during cell differentiation
.
Nat Biotechnol
2010
;
28
:
511
5
.
10.
Moffitt
RA
,
Marayati
R
,
Flate
EL
,
Volmar
KE
,
Loeza
SGH
,
Hoadley
KA
, et al
.
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
.
Nat Genet
2015
;
47
:
1168
78
.
11.
Zhao
EY
,
Shen
Y
,
Pleasance
E
,
Kasaian
K
,
Leelakumari
S
,
Jones
M
, et al
.
Homologous recombination deficiency and platinum-based therapy outcomes in advanced breast cancer
.
Clin Cancer Res
2017
;
23
:
7521
30
.
12.
Golan
T
,
O'Kane
GM
,
Denroche
RE
,
Raitses-Gurevich
M
,
Grant
RC
,
Holter
S
, et al
.
Genomic features and classification of homologous recombination deficient pancreatic ductal adenocarcinoma
.
Gastroenterology
2021
;
160
:
2119
32
.
13.
Davies
H
,
Glodzik
D
,
Morganella
S
,
Yates
LR
,
Staaf
J
,
Zou
X
, et al
.
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures
.
Nat Med
2017
;
23
:
517
25
.
14.
Sohal
D
,
Duong
MT
,
Ahmad
SA
,
Gandhi
N
,
Beg
MS
,
Wang-Gillam
A
, et al
.
SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA)
.
J Clin Oncol
2020
;
38
:
4504
.
15.
Von Hoff
DD
,
Ervin
T
,
Arena
FP
,
Chiorean
EG
,
Infante
J
,
Moore
M
, et al
.
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
.
N Engl J Med
2013
;
369
:
1691
703
.
16.
Conroy
T
,
Desseigne
F§O
,
Ychou
M
,
Bouché
O
,
Guimbaud
R
,
Bécouarn
Y
, et al
.
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer
.
N Engl J Med
2011
;
364
:
1817
25
.
17.
Nicolle
R
,
Gayet
O
,
Duconseil
P
,
Vanbrugghe
C
,
Roques
J
,
Bigonnet
M
, et al
.
A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma
.
Ann Oncol
2021
;
32
:
250
60
.
18.
Nicolle
RBJ
,
Harlé
A
,
Iovanna
JL
,
Hammel
P
,
Rebours
V
,
Turpin
A
, et al
.
Adjuvant gemcitabine is as efficient as mFOLFIRINOX in patients with GemPred+ tumor signature and resected pancreatic adenocarcinoma (PDAC): an ancillary study of the PRODIGE-24 clinical trial
.
Presented at the ESMO Congress
2022
.
19.
Raffenne
J
,
Nicolle
R
,
Puleo
F
,
Le Corre
D
,
Boyez
C
,
Marechal
R
, et al
.
hENT1 testing in pancreatic ductal adenocarcinoma: Are we ready? A multimodal evaluation of hENT1 status
.
Cancers
2019
;
11
:
1808
.
20.
Giovannetti
E
,
Del Tacca
M
,
Mey
V
,
Funel
N
,
Nannizzi
S
,
Ricci
S
, et al
.
Transcription analysis of human equilibrative nucleoside transporter 1 predicts survival in pancreas cancer patients treated with gemcitabine
.
Cancer Res
2006
;
66
:
3928
35
.
21.
O'Kane
GM
,
Grünwald
BT
,
Jang
G-H
,
Masoomian
M
,
Picardo
S
,
Grant
RC
, et al
.
GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer
.
Clin Cancer Res
2020
;
26
:
4901
10
.
22.
Tempero
MA
,
Reni
M
,
Riess
H
,
Pelzer
U
,
O'Reilly
EM
,
Winter
JM
, et al .
APACT: phase III, multicenter, international, openlabel, randomized trial of adjuvant nabpaclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma
.
J Clin Oncol
2019
;
37
:
4000
.