Prognostic and monitoring potential of circulating tumor DNA in resectable pancreatic cancer

Pancreatic cancer remains one of the most formidable challenges in oncology, often diagnosed at an advanced stage with a poor prognosis. For patients with resectable pancreatic cancer, upfront surgery followed by adjuvant chemotherapy is standard of care (1,2). Neoadjuvant and induction, systemic chemotherapy has shown promise in improving surgical outcomes and overall survival (OS) in borderline resectable and locally advanced disease (1,3-5). The modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) regimen, has emerged as a cornerstone in this paradigm (5). Concurrently, advancements in liquid biopsy techniques, particularly circulating tumor DNA (ctDNA) analysis, have opened new opportunities. The utility of ctDNA may span across multiple facets of cancer management, including early diagnosis, prognostication, monitoring, advanced genotyping and guiding therapeutic decisions (6).

In this editorial, neoadjuvant mFOLFIRINOX therapy and the use of ctDNA analysis in resectable pancreatic cancer is discussed, in light of the recently published study by Cecchini et al. (7). This non-randomized study included 46 patients with resectable pancreatic cancer receiving perioperative mFOLFIRINOX (6 preoperative cycles). A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery [27 patients (59%) per protocol]. The study’s definition of resectability included some patients with venous involvement that are considered borderline resectable based on contemporary guidelines. The 12-month progression-free survival (PFS) was 67%, meeting the trial’s primary endpoint. The study faced challenges in completing per-protocol perioperative treatments. This exposed the limitations of using PFS as an effective endpoint and emphasized the superiority of OS as a measure for neoadjuvant clinical trials in resectable pancreatic cancer. The study reported a 2-year OS rate of 59%, and OS of 37.2 months. For 37 patients who completed all 6 cycles per-protocol preoperative mFOLFIRINOX, the median OS reached 46.2 months. The difficulty with adhering to the protocol is evident in the fact that multiple patients discontinued protocol therapy for reasons other than disease progression or adverse events. This underscores the practical challenges of implementing neoadjuvant chemotherapy in resectable pancreatic cancer. It highlights the heterogeneity of the patient population and the challenges faced from inclusion through the treatment sequence when conducting a clinical trial on neoadjuvant chemotherapy for resectable pancreatic cancer. Although this is a single-center, non-randomized study, its detailed trial protocol and multi-disciplinary assessment help ensure consistency within the patient cohort. The lack of randomization and a comparative arm makes it challenging to conclusively advocate for a switch from adjuvant to perioperative mFOLFIRINOX in resectable pancreatic cancer without further evidence.

To date, neoadjuvant treatment has not demonstrated a survival advantage over upfront surgery for patients with resectable pancreatic cancer (8-13). In the phase-2 NORPACT-1 trial, 140 patients were randomized to neoadjuvant chemotherapy with 4 cycles fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or upfront surgery and adjuvant chemotherapy (12). Neoadjuvant FOLFIRINOX did not improve OS, neither in the intention-to-treat nor per-protocol analysis. The ongoing phase-3 trials PREOPANC-3 and ALLIANCE 021806 will provide further data regarding the efficacy and safety of neoadjuvant 8 cycles mFOLFIRINOX in resectable pancreatic cancer. Best practice guidelines have recently been developed focusing on the optimal standards for delivering neoadjuvant therapy to patients with localized pancreatic cancer (14). However, there is an urgent need of better prognostic and predictive biomarkers capable of guiding treatment sequencing, and determining the optimal chemotherapy regimens and duration.

In the context of pancreatic cancer, ctDNA offers a promising tool to overcome the limitations of traditional imaging and tissue biopsies, which often fail to capture the tumor’s molecular heterogeneity and are not suited for continuous monitoring (15,16). Cecchini et al. performed ctDNA testing with a clinically validated, personalized, tumor-informed assay, and only patients who underwent successful resection after completing preoperative therapy and had adequate tissue were amenable to testing. ctDNA data was available from 22 patients for evaluation. ctDNA levels were detected in 16 of 22 patients (73%) at baseline and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Postoperatively, ctDNA was detectable in 2 of 12 patients (17%), and after adjuvant mFOLFIRINOX, ctDNA was positive in 2 of 10 patients (20%). Importantly, postoperative undetectable ctDNA was significantly associated with improvement in PFS and OS, highlighting its potential as a prognostic biomarker. The detection of minimal levels of ctDNA may indicate a degree of tumor persistence shortly after surgery, even when radiographic methods fail to detect it. Moreover, detectable ctDNA levels may indicate the presence of occult disease during postoperative surveillance, which standard radiological assessments have not yet identified, potentially signifying a tumor relapse. In the field of liquid biopsies, this is often referred to as molecular residual disease and molecular relapse, respectively (6).

Cecchini et al. did not find that baseline undetectable ctDNA versus detectable ctDNA was associated with improved OS, likely due to the small sample size. Baseline ctDNA has shown to be an independent predictor of decreased PFS and OS in resected pancreatic cancer (16). In advanced pancreatic cancer, baseline levels of ctDNA are also associated with shorter PFS and OS (17). Additionally, tracking ctDNA over time predict disease progression through rising levels (17). Traditional imaging modalities like computed tomography (CT) and magnetic resonance imaging (MRI) are often inadequate in accurately assessing early therapeutic response. Thus, ctDNA can provide early indications of response or resistance to systemic chemotherapy, enabling timely modifications in the therapeutic regimen during neoadjuvant or adjuvant therapy. This may be particularly relevant during total neoadjuvant chemotherapy. Thalji et al. demonstrated that a lack of biochemical carbohydrate antigen 19-9 (CA19-9) response to first-line mFOLFIRINOX identifies a subgroup of patients with operable pancreatic cancer who exhibit a very high response rate to second-line gemcitabine/nab-paclitaxel (18). ctDNA analysis could offer additional insights when implementing adaptive modifications to chemotherapy (chemotherapeutic switch) during total neoadjuvant chemotherapy (19).

Cecchini et al. found that tumor K17 expression was associated with numerically decreased survival whether detected at diagnosis in fine needle aspirations or in the postneoadjuvant setting using surgical specimens, although these exploratory observations were not statistically significant. When combining ctDNA to K17 expression by interaction analyses, the authors suggest that K17 expression may enhance survival stratification with clinical response and ctDNA status. However, the study was limited by a relatively high dropout rate, and small sample sizes when combining ctDNA positive/negative and low/high K17 patients in subgroup analyses. The authors did not combine ctDNA analyses with CA19-9, currently the only clinically available prognostic biochemical biomarker in pancreatic cancer. Interestingly, Shah et al. recently found that detection of baseline ctDNA is correlated with CA19-9 levels and is predictive of CA19-9 response to neoadjuvant chemotherapy, with specific circulating mutational profiles in KRAS exhibiting worse prognosis (20). They found that patients (n=56) with localized pancreatic cancer without detectable ctDNA pretreatment experienced significant reductions in post-neoadjuvant CA19-9 levels. In contrast, those with detectable ctDNA at diagnosis showed no significant change in CA19-9 levels. The PANACHE01-PRODIGE48 study randomized patients with resectable pancreatic cancer to upfront surgery and adjuvant chemotherapy or 4 cycles of neoadjuvant chemotherapy with either FOLFOX or mFOLFIRINOX (13). In an ancillary study from this trial, including 92 of 132 patients who were available for ctDNA status at diagnosis, three distinct patient groups were identified [“CA19-9 high and ctDNA positive”, “CA19-9 high or ctDNA positive”, and “CA19-9 low and ctDNA negative”, (CA19-9 low/high; cutoff =80 UI)], with median OS of 19.4, 30.2 and not reached (NR) [95% confidence interval (CI): 39.3 months–NR], respectively (P=0.0069) (21).

ctDNA presents a promising tool in the perioperative management of resectable pancreatic cancer. In the paper by Cecchini et al. its potential as a prognostic (i.e., predicting PFS or OS) or monitoring (i.e., detecting molecular residual disease) biomarker, was evaluated (7). The latter finding highlights its potential in detecting residual tumor tissue and tumor recurrence. Using ctDNA for advanced genotyping to identify actionable mutations to direct targeted therapy is also feasible in some cancer types (6). The ultimate goal of using ctDNA is in cancer screening by detecting early-stage cancers and precancerous conditions in individuals without symptoms (6). This may lead to interventions aimed at increasing cure rates or even preventing the development of invasive cancers. However, several knowledge gaps remain in using ctDNA, including the lack of standardized methods for ctDNA collection and analysis. Standardizing ctDNA methodologies will ensure consistency and reliability across various clinical contexts. Additionally, the absence of established criteria for interpreting ctDNA results complicates the evaluation of its potential survival benefits for patients. Thus, to fully utilize ctDNA’s potential, several important steps need to be undertaken. Conducting prospective interventional studies is crucial to determining how ctDNA can be effectively used in clinical settings and its impact on patient outcomes. Multiple clinical trials are underway that may provide the evidence base to adopt ctDNA assays for clinical decision making. Finally, developing clear guidelines for ctDNA result interpretation is essential to provide clinicians with actionable insights and improve decision-making in the management of resectable pancreatic cancer.

Acknowledgments

None.

Footnote

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