A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.
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ABSTRACT:
SUBMITTER: Jamison JK
PROVIDER: S-EPMC10994267 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.
Jamison Jacob K JK May Michael S MS Raufi Alexander G AG Luk Lyndon L Wong Winston W Mundi Prabhjot S PS Manji Gulam A GA
The oncologist 20240401 4
Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cance ...[more]
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Project description:BackgroundThere is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response.Study designConsecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012-2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed.ResultsAlterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15-0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44-7.60).ConclusionsSMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.
| S-EPMC9319357 | biostudies-literature
Project description:Pancreatic cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival of patients with this disease. However, the optimal chemotherapeutic regimen remains controversial. Recently, Conroy et al demonstrated the impressive benefits of modified FOLFIRINOX over gemcitabine alone in the multicenter Partenariat de Recherche en Oncologie Digestive 24 (PRODIGE-24) trial. The remarkable results mark a new milestone in treating resectable pancreatic cancer and have now changed the standard of care for this patient population. In this commentary, we discuss an issue of difference of tumor grade between the PRODIGE-24 trial and previous phase III trials. We also discuss potential biomarkers predicting therapeutic response to modified FOLFIRINOX. Finally, we summarize several ongoing clinical trials of replacing part of the FOLFIRINOX regimen with Xeloda/S-1/nanoliposomal irinotecan for pancreatic cancer.
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Project description:Background & objectivesFOLFIRINOX and gemcitabine plus nab-paclitaxel (GN) are the most commonly used regimens in advanced pancreatic ductal adenocarcinomas (PDACs). As there is limited data on comparison of these two regimens, the present study was aimed to compare survivals and tolerance for both regimens through a match-pair analysis.MethodsThe data of 350 patients with metastatic and locally advanced PDAC, treated between January 2013 and December 2019, were retrieved. A 1:1 matching, using age and performance status, without replacement was performed by using nearest neighbour matching method.ResultsA total of 260 patients (130 modified FOLFIRINOX and 130 GN) were matched. The median overall survival (OS) was 12.98 months [95% confidence interval (CI) 7.257-8.776 months] in modifications of FOLFIRINOX (mFOLFIRINOX) cohort and 12.06 months (95% CI 6.690-8.88 months) in GN group (P=0.080). The incidence of grade 3 and 4 infections, diarrhoea, oral mucositis, and fatigue was higher with mFOLFIRINOX. Patients who received second line therapy had improved OS as compared to those who did not (14.06 vs. 9.07 months, P<0.001).Interpretation & conclusionsGN and mFOLFIRINOX appear to have similar survival outcomes in an unselected match paired patient population with advanced PDAC. A markedly increased incidence of non-myelosuppressive grade 3 and grade 4 side-effects and lack of survival improvements suggest a need for nuanced use of the mFOLFIRINOX regimen. Administration of second-line chemotherapy improves OS in patients with advanced PDAC.
| S-EPMC10284354 | biostudies-literature
Project description:BackgroundDespite the scarcity of data based on randomized trials, FOLFIRINOX is widely used in the management of borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). We investigated the clinical outcomes of neoadjuvant FOLFIRINOX in patients with BRPC and LAPC.MethodsThis single-center retrospective analysis included a total of 199 consecutive patients with BRPC or LAPC who received conventional or modified FOLFIRINOX between February 2013 and January 2017. An independent radiologist reviewed all baseline computed tomography or magnetic resonance imaging scans were reviewed for vascular invasion status.ResultsWith median follow-up duration of 40.3 months [95% confidence interval (CI), 36.7-43.8] in surviving patients, median progression-free survival (PFS) and overall survival (OS) were 10.6 (95% CI, 9.5-11.7) and 18.1 (95% CI, 16.0-20.3) months, respectively. The 1-year PFS rate was 66.0% (95% CI, 65.3-66.7%), and the 2-year OS rate was 37.2% (95% CI, 36.5-37.9%). PFS and OS did not differ between BRPC and LAPC groups [median PFS, 11.1 months (95% CI, 8.8-13.5) versus 10.1 months (95% CI, 8.4-11.8), p = 0.47; median OS, 18.4 months (95% CI, 16.1-20.8) versus 17.1 months (95% CI, 13.2-20.9), p = 0.50]. Curative-intent conversion surgery (R0/R1) was performed in 63 patients (31.7%). C•A 19-9 response, objective tumor response to FOLFIRINOX, and conversion surgery were independent prognostic factors for OS.ConclusionFOLFIRINOX was effective for management of BRPC and LAPC. Given the potential for cure, a significant proportion of patients can undergo conversion curative-intent surgery following FOLFIRINOX.
| S-EPMC7498966 | biostudies-literature
Project description:ObjectivesPatients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX.MethodsAn institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated.ResultsThere were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4).ConclusionNearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.
| S-EPMC8933849 | biostudies-literature
Project description:BackgroundChemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting.MethodsThis was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D).ResultsAs of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9).ConclusionsFirst-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID.Trial registrationClinicalTrials.gov, NCT04228601.
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Project description:Serine hydrolases (SHs) are among the largest classes of enzymes in humans and play crucial role in many pathophysiological processes of cancer. We have undertaken a comprehensive proteomic analysis to assess the differential expression and cellular localization of SHs, which uncovered distinctive expression of Carboxylesterase 2 (CES2), the most efficient carboxyl esterase in activating the prodrug irinotecan into SN-38, in pancreatic ductal adenocarcinoma (PDAC). We therefore assessed the extent of heterogeneity in CES2 expression in PDAC and its potential relevance to irinotecan based therapy. CES2 expression in PDAC and paired nontumor tissues was evaluated by immunohistochemistry. CES2 activity was assessed by monitoring the hydrolysis of the substrate p-NPA and correlated with irinotecan IC50 values by means of Pearson's correlation. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CES2 expression in patients who underwent neoadjuvant FOLFIRINOX treatment. All statistical tests were two-sided. Statistically significant overexpression of CES2, both at the mRNA and protein levels, was observed in PDAC compared with paired nontumor tissue (P < .001), with 48 of 118 (40.7%) tumors exhibiting high CES2 expression. CES2 activity in 11 PDAC cell lines was inversely correlated with irinotecan IC50 values (R = -0.68, P = .02). High CES2 expression in tumor tissue was associated with longer overall survival in resectable and borderline resectable patients who underwent neoadjuvant FOLFIRINOX treatment (hazard ratio = 0.14, 95% confidence interval = 0.04 to 0.51, P = .02). Our findings suggest that CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy.
| S-EPMC4554193 | biostudies-literature
Project description:5-Fluorouracile, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) has not been extensively used in the neoadjuvant setting because of concerns with safety and toxicity. We evaluated our institutional experience with neoadjuvant FOLFIRINOX in borderline resectable pancreatic adenocarcinoma (BRPAC). The primary endpoints were completion of therapy to surgery and negative resection margin (R0) rate. Patients with BRPAC treated with neoadjuvant FOLFIRINOX were retrospectively analyzed. Between August 2011 and September 2013, 20 patients with BRPAC treated with neoadjuvant FOLFIRINOX were identified. Most patients (88.8%) completed FOLFIRINOX therapy and underwent resection. Abutment of venous structures was identified in 13 cases (72.2%), while short segment portal vein encasement in 3 cases (16.6%) with concomitant arterial involvement in 3 cases (16.6%). Isolated superior mesenteric artery abutment was identified in 2 cases (11.2%). Patients received a median of 4 cycles of FOLFIRINOX. There was 1 case of progression. Vascular resection was performed in 9 cases (52.9%). Preoperative radiation therapy was used in 8 patients (44%). All patients underwent margin negative resection (R0). Histopathologic treatment response was evident in 10 cases (58.8%). Neoadjuvant FOLFIRINOX was generally safe and the expected toxicity did not prevent surgery allowing for a high rate of R0 resection.
| S-EPMC4602784 | biostudies-other
Project description:ImportancePancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection.ObjectiveTo assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival.Design, setting, and participantsThis open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023.InterventionsPatients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression.Main outcomes and measuresThe primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator.ResultsOf 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07).Conclusions and relevanceThis nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies.Trial registrationClinicalTrials.gov Identifier: NCT02047474.
| S-EPMC11190830 | biostudies-literature
Project description:BackgroundMost patients with advanced pancreatic adenocarcinoma (PA) treated with FOLFIRINOX experience adverse events requiring dose reduction. We aimed to assess the association between relative dose intensity (RDI) and disease control in a European setting.MethodsWe retrospectively included patients with advanced PA treated with three or more cycles of FOLFIRINOX between 2011 and 2018 in six French centers. We computed the cumulative single-agent RDI (csRDI) before the first reassessment for each FOLFIRINOX agent (oxaliplatin, irinotecan, 5FU bolus, and 5FU intravenous infusion) and the cumulative multi-drug RDI (cmRDI) of their combination. The association between RDI and disease control or objective response at first reassessment was evaluated using multivariable logistic regression models controlling for performance status, liver metastases, and center.ResultsWe included 243 patients. Median csRDIs were 81%, 79%, 75%, and 85% for oxaliplatin, irinotecan, 5FU bolus, and 5FU intravenous infusion, respectively. Median cmRDI was 80%. None of the RDIs was significantly associated with disease control or objective response. Including RDI in a clinical model did not improve its ability to predict disease control; the area under the curve was 0.79 (95% CI: 0.73-0.85) with RDI versus 0.78 (95% CI: 0.72-0.85) without. Similar results were observed for the objective response.ConclusionPragmatic dose adjustments of FOLFIRINOX should be made by oncologists without considering a loss of effect.
| S-EPMC8287268 | biostudies-literature