SMAD4 Alterations are a Predictive Biomarker to Guide First-line Chemotherapy Selection for the Neoadjuvant Treatment of Localized Pancreatic Cancer : A Multicenter, Retrospective Cohort Study.

There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.

Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma.

Decision letter: Neutrophil-mediated fibroblast-tumor cell il-6/stat-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: A hybrid clinical-preclinical study

Neoadjuvant therapy is increasingly being used before surgery for localized pancreatic cancer. Given the importance of completing multimodal therapy, the aim of this study was to characterize surgical resection rates after neoadjuvant therapy as well as the reasons for, and long-term prognostic impact of, not undergoing resection. A systematic review and meta-analysis of prospective trials and high-quality retrospective studies since 2010 was performed to calculate pooled resection rates using a generalized random-effects model for potentially resectable, borderline resectable, and locally advanced pancreatic cancer. Median survival times were calculated using random-effects models for patients who did and did not undergo resection. In 125 studies that met the inclusion criteria, neoadjuvant therapy consisted of chemotherapy (36.8 per cent), chemoradiation (15.2 per cent), or chemotherapy and radiation (48.0 per cent). Among 11 713 patients, the pooled resection rates were 77.4 (95 per cent c.i. 71.3 to 82.5), 60.6 (54.8 to 66.1), and 22.2 (16.7 to 29.0) per cent for potentially resectable, borderline resectable, and locally advanced pancreatic cancer respectively. The most common reasons for not undergoing resection were distant progression for resectable and borderline resectable cancers, and local unresectability for locally advanced disease. Among 42 studies with survival data available, achieving surgical resection after neoadjuvant therapy was associated with improved survival for patients with potentially resectable (median 38.5 versus 13.3 months), borderline resectable (32.3 versus 13.9 months), and locally advanced (30.0 versus 14.6 months) pancreatic cancer (P < 0.001 for all). Although rates of surgical resection after neoadjuvant therapy vary based on anatomical stage, surgery is associated with improved survival for all patients with localized pancreatic cancer. These pooled resection and survival rates may inform patient-provider decision-making and serve as important benchmarks for future prospective trials.

This study evaluated the effect of neoadjuvant therapy (NAT) and the prognostic significance of carcinoembryonic antigen (CEA) levels in patients with non-elevated serum carbohydrate antigen (CA) 19-9 levels. The impact of NAT followed by surgical resection on oncologic outcomes in patients with localized pancreatic ductal adenocarcinoma (PDAC) remains unclear. This retrospective and propensity-score matched (PSM) study included primary and validation cohorts from four centers. Propensity scores were estimated using multivariable logistic regression and survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. overall survival (OS) and recurrence-free survival (RFS) were compared and univariable and multivariable Cox proportional hazards regression model were applied. Among 251 patients with PDAC with non-elevated CA 19-9 levels, 67 received NAT followed by surgical resection, and 184 underwent upfront surgery. Following PSM, NAT significantly improved OS (39.87 vs. 18.86 months, P=0.0175) and RFS (25.67 vs. 12.83 months, P=0.0197) compared to upfront surgery. These results validated in an independent external cohort. In the primary cohort after PSM, elevated CEA was associated with worse OS and RFS compared to non-elevated CEA (median OS: 18.86 months vs. 42.39 months, P=0.0014, and median RFS: 17.40 months vs. 28.60 months, P=0.0020). Furthermore, after adjusting for competing risk factors, elevated CEA was identified as an independent factor associated with both OS (hazard ratio (HR): 1.751, 95%CI: 1.087-2.821; P=0.021) and RFS (HR: 1.637, 95%CI: 1.046-2.561; P=0.031). These results were validated in an independent external cohort. NAT followed by surgical resection improves outcomes in patients with PDAC with non-elevated CA 19-9 levels. Elevated CEA levels were associated with adverse prognostic effects on both OS and RFS. These findings support the need for further evaluation of patients with non-elevated CA 19-9 levels and serum CEA levels in prospective settings.

Introduction: The utility of circulating tumor DNA (ctDNA) as a biomarker in localized pancreatic ductal adenocarcinoma (PDAC) remains unclear. We aimed to characterize the detection of ctDNA by targeted next-generation sequencing (NGS) during treatment for localized PDAC and to evaluate the clinical implication of detection. Methods: Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine Cancer Centers between September 2020 and May 2022. During treatment, blood was drawn for targeted NGS ctDNA assessment utilizing the Tempus xF 105 gene panel assay. Three timepoints during the course of treatment were evaluated: at diagnosis prior to treatment, after neoadjuvant chemotherapy (NAC), and after local therapy, which included surgery with or without radiotherapy, or radiotherapy alone. The effect of NAC and local therapy on ctDNA mutational status and its relationship with serum CA19-9 was analyzed. Results: 32 patients who underwent NAC were included in the analysis. 66% of patients received FOLFIRINOX and 34% received Gemcitabine/nab-paclitaxel. The mean length of NAC was 3.1 months. TP53 mutations were the most common mutation detected by targeted NGS (41%), followed by KRAS (G12D/V/R, 13%) and ATM mutations (13%). In 24 patients assessed prior to treatment, 10 (42%) were found to have detectable ctDNA. 11 of 32 (34%) patients had detectable ctDNA following completion of NAC. 22 patients underwent surgery, of which 6 (27%) had detectable ctDNA following NAC and surgery. Of the 10 patients who had detectable ctDNA prior to treatment, 4 (40%) cleared ctDNA after treatment. Patients with detectable ctDNA prior to treatment had higher CA19-9 levels following NAC compared with those with undetectable ctDNA prior to treatment (1244.83 U/ml vs 60.42 U/ml, p = 0.0299). Following NAC, patients with detectable ctDNA had higher CA19-9 levels than those with undetectable ctDNA after NAC (1121.05 U/ml vs 58.89 U/ml, p = 0.0231). 6 of 32 (19%) patients were found to have unresectable disease following NAC and underwent definitive radiotherapy for local control; none of these patients had ctDNA clearance. Conclusion: This is the first reported study demonstrating the value of targeted NGS as a biomarker in the treatment of localized pancreatic cancer. Treatment led to clearance of detectable ctDNA, although the effect was not seen in all patients. Patients with detectable ctDNA prior to treatment had higher levels of CA19-9 following NAC, suggesting that pre-therapy detection may be a predictor of poor serum CA19-9 response after NAC. Given that after NAC, patients with detectable ctDNA had significantly higher serum CA19-9 levels, ctDNA assessment by targeted NGS may be an additional biomarker of treatment response. Taken together, ctDNA detected by targeted NGS is a potential biomarker of treatment response in localized PDAC. Citation Format: Dhavan Shah, Amy Wells, Kevin Dawravoo, John Abad, Arlene D'Souza, Grace Suh, Robert Bayer, Sohail Chaudhry, David Bentrem, Akhil Chawla. Evaluating circulating tumor DNA by targeted next generation sequencing as a biomarker in the treatment of localized pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR014.

Nationwide trends over 10 years in epidemiology and management of pancreatic ductal adenocarcinoma: A real-world study from the French administrative database

Purpose Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with low five-year survival rates. Currently, surgical resection is the only potentially curative treatment available to patients. However, few patients are eligible for surgery without receiving prior therapy due to disease progression. Of those that receive upfront surgery, up to 60% develop recurrent disease within 5 years. Therefore, there is a need to increase the rate of complete surgical resections and the number of eligible patients for surgery. In the last decade, neoadjuvant therapy or treatment prior to surgery has increased for patients diagnosed with borderline resectable and locally advanced PDAC. Often, this therapy consists of chemotherapy alone or chemoradiotherapy treatment intended to downstage the tumor and reduce micrometastatic disease. Fluorescence-guided surgery (FGS) is a potential tool to increase the rate of complete surgical resections by specifically targeting a protein biomarker upregulated in the tumor with a fluorescent dye conjugated probe. Previous in vitro and in vivo research from our lab has indicated that the transmembrane mucin, MUC16, is a promising target for FGS in PDAC. However, protein expression has the potential to deviate after chemotherapy treatment. Therefore, this research aimed to determine the effect of neoadjuvant chemotherapy treatment (NCT) on the FGS-targetable biomarker, MUC16, in PDAC patient specimens. Experimental Procedures Deidentified PDAC and matched adjacent patient specimens receiving the NCT regimen or surgery-first treatment were obtained from UNMC Pathology and the UNMC Paraffin Tissue Bank. Deidentified normal pancreas specimens were received from the Normal Organ Recovery program, UNMC. MUC16 expression was investigated in each specimen. The presence of PDAC tumor and MUC16 stain expression patterns were confirmed by a specimen-blinded, board-certified pathologist. The expression of MUC16 between the NCT, surgery-first, and normal pancreas specimens was compared via statistical analysis. Results MUC16 was expressed in both the NCT and surgery-first specimens. There was a significant difference in MUC16 expression between the NCT specimens and both the normal pancreas (P = 0.0450) and surgery-first (P = 0.0494) specimens. In matched adjacent tissue, MUC16 expression was found to be higher in the NCT (P = 0.0003) and surgery-first (P = 0.1446) tumor specimens allowing for distinct tumor margins; however, this difference was not significant in the surgery-first specimens. Conclusions MUC16 expression retention in NCT PDAC specimens may indicate that MUC16 is a stable biomarker after chemotherapy treatment. Distinct MUC16 expression between tumor and matched adjacent specimens indicates the ability to achieve distinguishable tumor margins allowing for complete tumor resection. Therefore, MUC16 remains targetable for FGS in chemotherapy-treated patients. This has the potential to broaden the benefiting patient population and increase the number of patients that may undergo a complete surgical resection. Citation Format: Kathryn M. Muilenburg, Evie G. Ehrhorn, Madeline T. Olson, Carly C. Isder, Kelsey A. Klute, Geoffrey A. Talmon, Mark A. Carlson, Quan P. Ly, Aaron M. Mohs. MUC16 expression in pancreatic ductal adenocarcinoma patient samples after neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C008.

Chronic immunosuppression does not potentiate the malignant progression of mucinous pancreatic cystic lesions

AimOrgan preserving treatment strategies and the introduction of a colorectal cancer-screening program have likely influenced the resection rates of rectal cancer. The aim of this study is to assess the influence of these developments on rectal cancer treatment and resection rates in the Netherlands. MethodsPatients diagnosed with non-metastatic rectal cancer between 2013 and 2018, were selected from the Netherlands Cancer Registry. The distribution of surgical and neo-adjuvant treatment and resection rates were analyzed and compared over time. ResultsBetween 2013 and 2018 22640 patients were diagnosed with non-metastatic rectal cancer. The incidence of early stage (cT1) disease increased from 141 (4%) in 2013 to 448 (12%) in 2018. The use of neoadjuvant radiotherapy and chemo-radiotherapy dropped from 39% to 21% and 34%–25%, respectively. A decrease in surgical resection rates (including TEM) was observed from 85% to 73%. The proportion of patients who underwent endoscopic resections increased from 3% to 10%. The decrease in surgical resection rates was larger in patients treated with neo-adjuvant chemo-radiotherapy. ConclusionAn increase in stage I disease is noted after the introduction of the screening program. Surgical resection rates for rectal cancer have fallen over time. Endoscopic resections due to more early-stage disease probably accounts for a large part of this decline. Furthermore, a watch and wait approach after neo-adjuvant chemo-radiotherapy may play an important role as well.

Short-term outcome of neoadjuvant immunotherapy and chemotherapy in non–small cell lung cancer: A systematic review and meta-analysis

PurposeThe role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy.MethodsThe PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events.ResultsA total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21–56) days and the median time of response evaluation was 45 (range, 42–56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%–71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%–94.5%) and 64.3% (95% CI, 43.8%–84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax.ConclusionNeoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

Background: Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Toxicities during NT are common, often leading to the inability to undergo surgical resection, yet risk factors for attrition are poorly understood. Therefore, we sought to evaluate the impact of baseline frailty on outcomes of patients with PDAC undergoing NT. Methods: All patients with potentially resectable (PR) or borderline resectable (BR) PDAC who initiated neoadjuvant chemotherapy and/or chemoradiation between 2019 and 2025 at a single institution were assessed retrospectively in an intention-to-treat fashion. The association between frailty as defined by the modified 11-item frailty index (mFI-11) and receipt of surgical resection as well as other secondary endpoints was assessed. Comprehensive functional frailty assessments were prospectively obtained in a subset of patients. Results: Among 252 eligible patients, the median age was 67 years, 56.7% were male, 90.9% were White, 49.6% had PR disease, and 5.2% were frail according to mFI-11. After a median 3.6 months of NT, 62.7% underwent surgical resection. Frail individuals had worse performance status and increased comorbidities compared with non-frail patients. On multivariable analysis, male sex, BR anatomic staging, initial use of Gemcitabine + nab-paclitaxel, and frailty (OR 0.09; 95%CI 0.02-0.44) were associated with reduced odds of undergoing resection. Along with increased baseline CA 19-9 levels, frailty was independently associated with worse overall survival (HR 3.00; 95%CI 1.46-6.20). Among 39 patients who underwent formal functional frailty assessment, only abnormal posture was associated with lower odds of surgical resection following NT (OR, 0.22; 95% CI, 0.05-0.92), and no aspects of functional frailty were associated with overall survival. Conclusions: Among patients with localized PDAC initiating NT, frailty as assessed by mFI-11 was associated with reduced odds of undergoing surgical resection and worse overall survival. Future research should focus on efforts to improve functional status during NT.

Patients with localized (that is non-metastatic) pancreatic ductal adenocarcinoma with an inadequate response or toxicity to first-line chemotherapy may benefit from chemotherapy switch. The aim was to explore the available data on the use and effect of chemotherapy switch, as reported in the literature. A systematic search was conducted in Embase, MEDLINE (Ovid), the Web of Science, Cochrane, and Google Scholar on 1 December 2023. The main outcomes were the proportion of patients who underwent chemotherapy switch and the carbohydrate antigen 19-9 response and resection, R0 resection, and ypN0 resection rates after chemotherapy switch. Data were pooled using a random-effects model. A total of five retrospective studies, representing 863 patients with localized pancreatic ductal adenocarcinoma, were included and 226 of the 863 patients underwent chemotherapy switch. In four studies, first-line chemotherapy consisted of 5-fluorouracil/leucovorin/irinotecan with oxaliplatin ('FOLFIRINOX') and patients were switched to gemcitabine with nab-paclitaxel. Reasons for chemotherapy switch included an inadequate biochemical, clinical, or radiological response, or toxicity. Three studies compared patients who underwent chemotherapy switch with patients who only received first-line chemotherapy and found that the proportion of patients who underwent chemotherapy switch was 20.5% (95% c.i. 10.5% to 36.3%). The pooled resection rate after chemotherapy switch was 42.0% (95% c.i. 16.6% to 72.5%). Two studies compared the chance of resection after chemotherapy switch versus first-line chemotherapy alone and found a risk ratio of 0.88 (95% c.i. 0.65 to 1.18). Two studies, with a combined total of 576 patients, found similar postoperative survival for patients who underwent chemotherapy switch and patients who only received first-line chemotherapy. One in five patients with localized pancreatic ductal adenocarcinoma underwent chemotherapy switch after an inadequate response or toxicity to first-line chemotherapy. The pooled resection rate after chemotherapy switch was 42% and similar in overall survival compared with first-line chemotherapy only. Three ongoing trials are investigating chemotherapy switch in patients with an inadequate radiological or carbohydrate antigen 19-9 response.

Simple SummaryPatients diagnosed with pancreatic cancer have a poor prognosis at time of diagnosis, with a 5-year survival rate of merely 10%. The only treatment with curative intent is surgical resection of the tumor and adjacent tumor-containing lymph nodes. To improve surgical outcome and survival, additional (imaging) tools are needed that support complete surgical tumor resection. Firstly, more accurate monitoring of tumor response to neoadjuvant treatment and subsequent determination of resectability is needed. Secondly, an imaging tool is needed for intraoperative guidance allowing accurate identification, delineation, and complete resection of the tumor and suspected lymph nodes. Therefore, both tumor-targeted PET/CT before surgery and real time fluorescence-guidance during surgery could be helpful to improve patient outcome. This review focusses on literature considering tumor-targeted PET/CT and near-infrared fluorescence (NIRF) imaging. Several tumor-targeted agents are under clinical evaluation, and several other promising agents are currently tested preclinically, both with promising results. Their additional diagnostic value and feasibility for future implementation in standard clinical care of PDAC has yet to be established in phase III clinical trials.Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient’s treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins. Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers.