The dense stroma of PDAC promotes tumor growth and impedes delivery of cytotoxic drugs. We assessed the utility of ADAM12, a circulating biomarker of PDAC stroma identified in our preclinical models, to non-invasively measure stromal activation in patients (pts) and predict outcomes.
The prognostic and predictive value of ADAM12 was determined in an institutional cohort from the Academic Medical Center (AMC), which included 144 pts with PDAC (58 resected and 86 non-resected pts) and 38 non-age–matched healthy controls, and in a cohort of 372 pts with metastatic PDAC treated with nab-paclitaxel plus gemcitabine (nab-P/Gem) or Gem alone in the MPACT trial.
For the AMC cohort, higher serum ADAM12 levels (median, 372 pg/mL; P < .01) were found in pts with PDAC vs healthy controls (median, 154 pg/mL). High ADAM12 levels (> median) were significantly associated with poor survival (P = .04) in resected pts but not in non-resected pts (P = .67). In the pooled MPACT analysis, median overall survival (OS) was significantly longer (9.3 vs 6.9 months; log-rank P = .01) in pts with no detectable (ND; n = 95) vs detectable (n = 277) serum ADAM12 levels at baseline (BL). Median OS was longer in pts with ADAM12 decrease (fold change [FC] < 1) vs increase (FC > 1) from BL to cycle 2, but both OS values were significantly shorter than that in pts with ND ADAM12 levels at either time point (Table). In a multivariate analysis, baseline ADAM12 levels (0 vs > 0; P = .02), treatment (nab-P/Gem vs Gem; P = .02), and Karnofsky performance status (90-100 vs 70-80; P < .01) were significant predictors of OS. Table. OS in pts with ADAM12 measured at both BL and cycle 2 in the MPACT studyTable:
|Overall Population||nab-P/Gem Arm||Gem Arm|
|Deaths, n/N (%)||Median OS (95% CI), mo||Deaths, n/N (%)||Median OS (95% CI), mo||Deaths, n/N (%)||Median OS (95% CI), mo|
|FC 1||54/58 (93)||8.1 (6.5 - 9.9)||25/27 (93)||8.3 (6.5 - 11.3)||29/31 (94)||6.9 (5.5 - 9.3)|
|ND||30/38 (79)||13.2 (9.3 - 16.4)||17/22 (77)||14.4 (8.5 - 19.2)||13/16 (81)||12.0 (6.8 - 14.9)|
|HR (95% CI); P value|
|FC 1 vs ND FC 1||1.5 (1.0 - 2.3); < .05 2.3 (1.4 - 3.6); < .01 0.7 (0.5 - 0.9); .02||1.8 (1.0 - 3.2); .04 2.8 (1.5 - 5.4); < .01 0.6 (0.4 - 1.0); .07||1.3 (0.7 - 2.3); .48 1.7 (0.9 - 3.3); .11 0.7 (0.5 - 1.2); .19|
BL, baseline; FC, fold change; HR, hazard ratio; nab-P/Gem, nab-paclitaxel plus gemcitabine; ND, no detectable; OS, overall survival; pt, patient.
Low serum levels of ADAM12 at baseline were associated with longer OS in pts with PDAC, as were decreases in ADAM12 during treatment. ADAM12 may be a valuable biomarker to predict long-term outcomes in pts treated with nab-P/Gem.
Clinical trial identification
Legal entity responsible for the study
H.W. van Laarhoven: Advisory role, Lilly, Nordic. Research funding to institution: Bayer, BMS, Celgene, Lilly, MDS, Nordic, Roche. J.P. Medema: Employment (family member) Sanofi, Abbott/Abbvie; stock ownership (family member), Sanofi; advisory role, Bionovion; patents, royalties, other IP, Aduro Biotech. J. Shiansong Li, R. Jiang, D.W. Pierce: Employment, stock ownership, Celgene. M.F. Bijlsma: Research funding, Celgene; travel & accommodations, Biouniversa. All other authors have declared no conflicts of interest.