Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma

British Journal of Cancer ARTICLE www.nature.com/bjc OPEN Clinical Studies Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma Alimu Dayimu 1, Lorena Di Lisio2, Shubha Anand2, Isart Roca-Carreras2, Wendi Qian3, Abdulrahman Al-Mohammad4, Bristi Basu5, ✉ Juan W. Valle 6, Duncan Jodrell 5, Nikos Demiris3,7 and Pippa Corrie 4 1234567890();,: © The Author(s) 2023 BACKGROUND: Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) offers limited benefits, but survival outcomes vary. Reliable predictive response biomarkers to guide patient management are lacking. METHODS: Patient performance status, tumour burden (determined by the presence or absence of liver metastases), plasma protein biomarkers (CA19-9, albumin, C-reactive protein and neutrophils) and circulating tumour DNA (ctDNA) were assessed in 146 patients with metastatic PDAC prior to starting either concomitant or sequential nab-paclitaxel + gemcitabine chemotherapy in the SIEGE randomised prospective clinical trial, as well as during the first 8 weeks of treatment. Correlations were made with objective response, death within 1 year and overall survival (OS). RESULTS: Initial poor patient performance status, presence of liver metastases and detectable mutKRAS ctDNA all correlated with worse OS after adjusting for the different biomarkers of interest. Objective response at 8 weeks also correlated with OS (P = 0.026). Plasma biomarkers measured during treatment and prior to the first response assessment identified ≥10% decrease in albumin at 4 weeks predicted for worse OS (HR 4.75, 95% CI 1.43–16.94, P = 0.012), while any association of longitudinal evaluation of mutKRAS ctDNA with OS was unclear (β = 0.024, P = 0.057). CONCLUSIONS: Readily measurable patient variables can aid the prediction of outcomes from combination chemotherapy used to treat metastatic PDAC. The role of mutKRAS ctDNA as a tool to guide treatment warrants further exploration. CLINICAL TRIAL REGISTRATION: ISRCTN71070888; ClinialTrials.gov (NCT03529175). British Journal of Cancer; https://doi.org/10.1038/s41416-023-02170-9 BACKGROUND Patients diagnosed with metastatic pancreatic ductal adenocarcinoma (PDAC) generally have very poor overall survival, even with combination systemic therapy [1]. Nab-paclitaxel combined with gemcitabine (nabP+gemcitabine) is an international standard of care for metastatic PDAC, albeit offering modest improved outcomes for treated patients. The MPACT international registration randomised trial compared the efficacy of nabP+gemcitabine with gemcitabine alone and reported an overall response rate (ORR) of 23% [2] and median overall survival (OS) of 8.7 months [3] with the combination regimen. NabP + gemcitabine chemotherapy was associated with a significant risk of toxicities, with 50% of treated patients experiencing a serious adverse event and 38% having grade 3 or higher neutropenia. In 431 patients randomised to receive nabP +gemcitabine, 11 (3%) failed to start chemotherapy, while the median duration of treatment was 3.9 months, ranging between 0.1 and 21.9 months; 35% of patients were alive at 12 months. The UK SIEGE randomised phase 2 trial compared sequential scheduling of nabP + gemcitabine administered 24 h apart, with standard delivery of the 2 drugs on the same day, as a potential strategy to improve outcomes in patients with metastatic PDAC [4]. Although ORR was higher in the sequential scheduling arm compared with standard concomitant drug delivery (51% versus 31%, P = 0.023), the OS in both arms was not statistically different (10.1 and 8.2 months, P = 0.70). One-year OS was 32% (95% CI 25–40%): remarkably similar to the MPACT trial population. The median number of 4-weekly cycles of chemotherapy delivered in the SIEGE trial was 3 (range 0–12) in the concomitant and 4 (range 0–24) in the sequential arm. In this trial, 25 (18%) treated patients failed to reach their first response assessment at 8 weeks, which, in 76% of cases, was due to rapidly progressing disease. Both the MPACT and SIEGE trials demonstrate that, despite median OS times of 8–10 months, wide variation in individual outcomes is associated with the treatment of patients with metastatic PDAC. While chemotherapy currently represents the only treatment option associated with an extension in OS, treatment-related toxicity, impact on quality of life and limited survival gains means that selecting appropriate patients for 1 Clinical Trials Unit, Department of Oncology, University of Cambridge, Cambridge, UK. 2Cancer Molecular Diagnostics Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK. 3Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 4Oncology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 5Department of Oncology, University of Cambridge, Cambridge, UK. 6University of Manchester and The Christie NHS Foundation Trust, Manchester, UK. 7Department of Statistics, Athens University of Economics and Business, Athens, Greece. ✉email: Received: 14 August 2022 Revised: 5 January 2023 Accepted: 17 January 2023 A. Dayimu et al. 2 intervention is challenging. Reliable prognostic markers, as well as markers predictive of response to chemotherapy, could potentially aid patient management but are currently lacking [5, 6]. In clinical practice, poor performance status (using either the Eastern Cooperative Oncology Group [ECOG PS] or Karnofsky [KPS] scales) and the presence of liver metastases are known to predict for poor disease outcomes [3, 7], but also characterise the majority of patients diagnosed with metastatic PDAC. The Lewis blood group antigen, carbohydrate antigen 19–9 (CA19–9) is the most wellestablished circulating tumour marker associated with PDAC, with higher blood levels generally associated with poorer survival [3, 8]. However, while frequently measured, it is rarely used to guide treatment decisions. In a retrospective study, the MPACT investigators demonstrated that any decrease in pre-treatment CA19-9 at week 8 of chemotherapy treatment was an early predictor of efficacy with nabP+gem [9]. Since most patients with metastatic PDAC will have repeat imaging to assess response at 8 weeks, measuring CA19-9 at the same time point as imaging offers limited additional clinical utility. However, they also showed that CA19-9 decrease identified more patients with survival benefit than radiological response at an 8-week assessment time point and differentiated those patients with CT-defined stable disease likely to do well. Blood samples were not collected at earlier timepoints within the MPACT trial, so the predictive value of CA19-9 changes earlier than 8 weeks could not be evaluated. Alternative, readily measurable, soluble protein biomarkers have been proposed as showing potential prognostic significance when managing patients with both resectable and metastatic PD (...truncated)