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ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n?=?184) or gemcitabine monotherapy (n?=?188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p?

SUBMITTER: Veenstra VL

PROVIDER: S-EPMC6237826 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Veenstra V L VL Damhofer H H Waasdorp C C van Rijssen L B LB van de Vijver M J MJ Dijk F F Wilmink H W HW Besselink M G MG Busch O R OR Chang D K DK Bailey P J PJ Biankin A V AV Kocher H M HM Medema J P JP Li J S JS Jiang R R Pierce D W DW van Laarhoven H W M HWM Bijlsma M F MF

Oncogenesis 20181116 11

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic o ...[more]

PMID: 30442938

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Project description:BACKGROUND:In early-stage pancreatic cancer, there are currently no biomarkers to guide selection of therapeutic options. This prospective biomarker trial evaluated the feasibility and potential clinical utility of circulating tumor DNA (ctDNA) analysis to inform adjuvant therapy decision making. MATERIALS AND METHODS:Patients considered by the multidisciplinary team to have resectable pancreatic adenocarcinoma were enrolled. Pre- and post-operative samples for ctDNA analysis were collected. PCR-based-SafeSeqS assays were used to identify mutations at codon 12, 13 and 61 of KRAS in the primary pancreatic tumor and to detect ctDNA. Results of ctDNA analysis were correlated with CA19-9, recurrence-free and overall survival (OS). Patient management was per standard of care, blinded to ctDNA data. RESULTS:Of 112 patients consented pre-operatively, 81 (72%) underwent resection. KRAS mutations were identified in 91% (38/42) of available tumor samples. Of available plasma samples (N?=?42), KRAS mutated ctDNA was detected in 62% (23/37) pre-operative and 37% (13/35) post-operative cases. At a median follow-up of 38.4?months, ctDNA detection in the pre-operative setting was associated with inferior recurrence-free survival (RFS) [hazard ratio (HR) 4.1; P?=?0.002)] and OS (HR 4.1; P?=?0.015). Detectable ctDNA following curative intent resection was associated with inferior RFS (HR 5.4; P?<?0.0001) and OS (HR 4.0; P?=?0.003). Recurrence occurred in 13/13 (100%) patients with detectable ctDNA post-operatively, including in seven that received gemcitabine-based adjuvant chemotherapy. CONCLUSION:ctDNA studies in localized pancreatic cancer are challenging, with a substantial number of patients not able to undergo resection, not having sufficient tumor tissue for analysis or not completing per protocol sample collection. ctDNA analysis, pre- and/or post-surgery, is a promising prognostic marker. Studies of ctDNA guided therapy are justified, including of treatment intensification strategies for patients with detectable ctDNA post-operatively who appear at very high risk of recurrence despite gemcitabine-based adjuvant therapy.

Project description:BackgroundAs neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions.Materials and methodsA retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival.ResultsOne hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001).ConclusionPatients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort.Implications for practiceThis study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

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ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Publications

ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

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