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

V. L. Veenstra; H. Damhofer; C. Waasdorp; L. B. van Rijssen; M. J. van de Vijver; F. Dijk; H. W. Wilmink; M. G. Besselink; O. R. Busch; D. K. Chang; P. J. Bailey; A. V. Biankin; H. M. Kocher; J. P. Medema; J. S. Li; R. Jiang; D. W. Pierce; H. W.M. van Laarhoven; M. F. Bijlsma

doi:https://doi.org/10.1038/s41389-018-0096-9

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

V. L. Veenstra, H. Damhofer, C. Waasdorp, L. B. van Rijssen, M. J. van de Vijver, F. Dijk, H. W. Wilmink, M. G. Besselink, O. R. Busch, D. K. Chang, P. J. Bailey, A. V. Biankin, H. M. Kocher, J. P. Medema, J. S. Li, R. Jiang, D. W. Pierce, H. W.M. van Laarhoven, M. F. Bijlsma

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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 < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Original language	English
Article number	87
Journal	Oncogenesis
Volume	7
Issue number	11
DOIs	https://doi.org/10.1038/s41389-018-0096-9
Publication status	Published - 1 Nov 2018

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Veenstra, V. L., Damhofer, H., Waasdorp, C., van Rijssen, L. B., van de Vijver, M. J., Dijk, F., Wilmink, H. W., Besselink, M. G., Busch, O. R., Chang, D. K., Bailey, P. J., Biankin, A. V., Kocher, H. M., Medema, J. P., Li, J. S., Jiang, R., Pierce, D. W., van Laarhoven, H. W. M., & Bijlsma, M. F. (2018). ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy. Oncogenesis, 7(11), Article 87. https://doi.org/10.1038/s41389-018-0096-9

@article{169a0c7366f14e279dcd15690e10dc68,

title = "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 < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.",

author = "Veenstra, {V. L.} and H. Damhofer and C. Waasdorp and {van Rijssen}, {L. B.} and {van de Vijver}, {M. J.} and F. Dijk and Wilmink, {H. W.} and Besselink, {M. G.} and Busch, {O. R.} and Chang, {D. K.} and Bailey, {P. J.} and Biankin, {A. V.} and Kocher, {H. M.} and Medema, {J. P.} and Li, {J. S.} and R. Jiang and Pierce, {D. W.} and {van Laarhoven}, {H. W.M.} and Bijlsma, {M. F.}",

note = "Funding Information: We thank Tom van Leusden for technical assistance, and all patients for participating. This work was supported by KWF Dutch Cancer Society (UVA 2012–5607 and UVA 2013–5932). Funding Information: M.F.B. has received research funding from Celgene. H.W.L. has acted as a consultant for Celgene, Eli Lilly and Company, Nordic Pharma Group and Philips, has received research grants from, Amgen, Bayer Schering Pharma AG, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, Nordic Pharma Group, Philips, Roche Pharmaceuticals. D.W.P., R.J., and J.S.L. are Celgene employees. Other than Celgene, none were involved in drafting of the manuscript. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = nov,

day = "1",

doi = "https://doi.org/10.1038/s41389-018-0096-9",

language = "English",

volume = "7",

journal = "Oncogenesis",

issn = "2157-9024",

publisher = "Nature Publishing Group",

number = "11",

}

Veenstra, VL, Damhofer, H, Waasdorp, C, van Rijssen, LB , van de Vijver, MJ , Dijk, F , Wilmink, HW , Besselink, MG , Busch, OR, Chang, DK, Bailey, PJ, Biankin, AV, Kocher, HM, Medema, JP, Li, JS, Jiang, R, Pierce, DW, van Laarhoven, HWM & Bijlsma, MF 2018, 'ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy', Oncogenesis, vol. 7, no. 11, 87. https://doi.org/10.1038/s41389-018-0096-9

TY - JOUR

T1 - ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy

AU - Veenstra, V. L.

AU - Damhofer, H.

AU - Waasdorp, C.

AU - van Rijssen, L. B.

AU - van de Vijver, M. J.

AU - Dijk, F.

AU - Wilmink, H. W.

AU - Besselink, M. G.

AU - Busch, O. R.

AU - Chang, D. K.

AU - Bailey, P. J.

AU - Biankin, A. V.

AU - Kocher, H. M.

AU - Medema, J. P.

AU - Li, J. S.

AU - Jiang, R.

AU - Pierce, D. W.

AU - van Laarhoven, H. W.M.

AU - Bijlsma, M. F.

N1 - Funding Information: We thank Tom van Leusden for technical assistance, and all patients for participating. This work was supported by KWF Dutch Cancer Society (UVA 2012–5607 and UVA 2013–5932). Funding Information: M.F.B. has received research funding from Celgene. H.W.L. has acted as a consultant for Celgene, Eli Lilly and Company, Nordic Pharma Group and Philips, has received research grants from, Amgen, Bayer Schering Pharma AG, Celgene, Eli Lilly and Company, GlaxoSmithKline Pharmaceuticals, Nordic Pharma Group, Philips, Roche Pharmaceuticals. D.W.P., R.J., and J.S.L. are Celgene employees. Other than Celgene, none were involved in drafting of the manuscript. Publisher Copyright: © 2018, The Author(s).

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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 < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

AB - 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 < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30442938

U2 - https://doi.org/10.1038/s41389-018-0096-9

DO - https://doi.org/10.1038/s41389-018-0096-9

M3 - Article

C2 - 30442938

SN - 2157-9024

VL - 7

JO - Oncogenesis

JF - Oncogenesis

IS - 11

M1 - 87

ER -

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

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