Determinants of gemcitabine response in pancreatic cancer: are we there?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer mortality in developed countries, but despite its rising prevalence, the prognosis has remained largely static over the past two decades (1). Genomic efforts in PDAC have led to a deep understanding of the mutational and structural landscape, dominated by oncogenic mutations in KRAS mutations in 90% of patients. The latter has been considered undruggable until recently. Renewed efforts have led to several trials evaluating KRAS mutant allele-specific inhibitors, together with pan-RAS inhibitors and vaccine strategies. Nevertheless, resistance to these agents is likely to develop and chemotherapy will ultimately continue to have a role in PDAC management, underscoring the need to identify biomarkers.

The NAPOLI-3 trial has demonstrated superiority of NALIRIFOX over Gemcitabine and nab-Paclitaxel (GnP) (2), representing the first positive trial in PDAC in over 12 years. Disappointingly, however, survival remains less than 1 year, and many physicians will continue to use modified FOLFIRINOX given the substantial differences in cost and the similar survival achieved.

Biomarkers for the aforementioned regimens are lacking aside from germline or somatic alterations in BRCA1/2 or PALB2 (3,4). This is important given concerns regarding the addition of experimental agents to the triplet regimen of mFOLFIRINOX which has meant a reliance on GnP as a backbone (5).

Given a largely immunosuppressive tumour microenvironment and the heterogeneity associated with PDAC, efforts have focussed on tumour subtypes and dissecting the stromal and immune compartments for a more informed approach to trial design (6). Liquid biopsy has seen exponential growth in recent years in other malignancies, and its non-invasive approach has been utilised to identify targetable mutations, provide prognostic information including the identification of minimal residual disease. The ease of acquisition longitudinally can also identify resistance mechanisms while on therapy (7).

Piquemal et al. first published on their blood-based RNA signatures for gemcitabine response in advanced PDAC in 2020 (8). Using qualitative real-time PCR to identify 62 genes of interest, prognostic signatures were identified for both overall survival (OS) and progression-free survival (PFS). This information was used to create a unique nine-gene based score (8). This blood-based RNA signature known as the GemciTest, appears to identify those most likely to benefit from a gemcitabine-based treatment (8,9).

In this issue, authors provide clinical validation of the GemciTest in 336 patients with samples acquired prior to the initiation of chemotherapy in treatment-naïve patients (9). The chemotherapy regimens were either gemcitabine-based or fluoropyrimidine-based, specifically gemcitabine monotherapy, GnP, FOLFIRINOX or FOLFOX. The physiological roles of each of the selected genes have previously been described and include the ATP Binding Cassette Subfamily C Member 1 (ABCC1) which is linked to chemotherapy resistance, due to efflux of treatment from the cells induced by the expression of membrane drug transporters (10). ADP Ribosylation Factor Like GTPase 4C (ARL4C) expression is associated with cell proliferation, drug resistance, and pancreatic stellate cell activation, which further enhance cancer stem cell properties (11). LYN Proto-Oncogene, Src Family Tyrosine Kinase (LYN) and NME/NM23 Nucleoside Diphosphate Kinase 4 (NME4) which contribute to cell proliferation and migration. The remainder of genes examined in this panel included Peptidylprolyl Isomerase B (PPIB), Ubiquitin Conjugating Enzyme E2 H (UBE2H), Aldolase, Fructose-Bisphosphate A (ALDOA), GRB2 Associated Binding Protein 3 (GAB3), and transporters like Solute Carrier Family 35 Member E2B (SLC35E2B).

Piquemal et al. have shown that use of their GE test can identify patients with advanced PDAC who may have a clinical response, defined as PFS ≥3.5 months and OS >8.7 months. Patients with advanced PDAC treated with a gemcitabine-based protocol, with a positive GemciTest had both a longer PFS (5.3 vs. 2.8 months) and OS (10.4 vs. 4.8 months) compared to those with a negative GemciTest. This study has also shown that patients with a positive GemciTest treated with a gemcitabine-based regimen had a similar median PFS (5.6 months for 5FU-based patients vs. 5.3 months for gemcitabine-based ones) and OS (10.1 vs. 10.4 months) to patients treated with a 5FU-based regimen.

The model developed here is based on prospective observational studies, and is currently awaiting validation from a randomised phase III trial: GEMFOX 233, comparing FOLFOX versus gemcitabine monotherapy in patients unsuitable for FOLFIRINOX (NCT04167007). This may provide additional information on this test, especially if patients who are considered GemciTest positive have similar outcomes on single-agent gemcitabine compared to FOLFOX.

In this regard, the GemciTest is not the first tool developed to assess response to Gemcitabine. The “GemPred” signature, derived from FFPE tissue, was developed to identify patients who would respond to Gemcitabine in the adjuvant setting, and has been validated to predict both OS and PFS (12,13). Notably in a retrospective analysis of PRODIGE-24, patients considered GemPred positive and treated with single-agent gemcitabine had very similar OS to those receiving modified FOLFIRINOX. If validated in prospective studies these gemcitabine signatures may be very powerful in eliminating the toxicity seen with the triplet regimen.

Human equilibrative nucleoside transporter 1 (hENT1) was investigated as a predictive marker of objective response rates and OS in patients receiving GnP in pancreatic cancer (12,13). In a retrospective analysis of the ESPAC-3 trial, hENT1 low patients, using immunohistochemistry, did not derive benefit from adjuvant gemcitabine (14). The COMPASS trial evaluated RNAseq expression data in treatment naïve patients with advanced pancreatic cancer and found hENT1 expression to predictive for GnP (15). Further validation and assessment of these biomarkers, accounting for variation in expression throughout the tumour microenvironment, will provide further answers in determining chemotherapy resistance (16). Each of these studies assessing prognostic and predictive biomarkers, with multi-omic approaches contribute toward better understanding of pathological processes and accelerate the implementation of precision oncology. In this regard the PASS-01 trial (NCT04469556) randomizing patients to mFOLFIRINOX vs. GnP with in depth correlative analyses may provide a further platform for biomarkers.

Novel therapeutics in PDAC are desperately needed, Piquemal et al. (9) have provided a potential new tool to identify patients with advanced PDAC to predict outcomes with gemcitabine-based protocols and its validation is eagerly awaited.

Acknowledgments

Funding: Dr. Grainne M. O’Kane was funded by the Irish Cancer Society as part of the Irish Cancer Society Trinity St James Cancer Institute Strategic Partnership through the Research Grant (No. TSJCI22OKA).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2023-04/coif). GMO has received Honoraria/Consulting fees from AstraZeneca, Roche, Servier, MSD, Incyte and Eisai. She has received grant funding from Roche. OMF has no conflicts of interest to report.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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