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. 2008 Oct;10(10):1041-8.
doi: 10.1593/neo.08620.

Clinical evaluation of M30 and M65 ELISA cell death assays as circulating biomarkers in a drug-sensitive tumor, testicular cancer

Esther C de Haas  1 , Alessandra di Pietro, Kathryn L Simpson, Coby Meijer, Albert J H Suurmeijer, Lee J Lancashire, J Cummings, Steven de Jong, Elisabeth G E de Vries, Caroline Dive, Jourik A Gietema
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Free PMC article

Clinical evaluation of M30 and M65 ELISA cell death assays as circulating biomarkers in a drug-sensitive tumor, testicular cancer

Esther C de Haas et al. Neoplasia. 2008 Oct.
Free PMC article

Abstract

Circulating full-length and caspase-cleaved cytokeratin 18 (CK18) are considered biomarkers of chemotherapy-induced cell death measured using a combination of the M30 and M65 ELISAs. M30 measures caspase-cleaved CK18 produced during apoptosis and M65 measures the levels of both caspase-cleaved and intact CK18, the latter of which is released from cells undergoing necrosis. Previous studies have highlighted their potential as prognostic, predictive, and pharmacological tools in the treatment of cancer. Disseminated testicular germ cell cancer (TC) is a paradigm for a chemosensitive solid malignancy of epithelial origin and has a cure rate of 80% to 90%. We conducted M30/M65 analyses on 34 patients with TC before and during treatment with bleomycin, etoposide, and cisplatin and showed that prechemotherapy serum levels of M65 and M30 antigens are correlated with established TC tumor markers lactate dehydrogenase, alpha-fetoprotein, and beta-human chorionic gonadotropin, probably reflecting tumor load. Cumulative percentage change of M65 and M30 from baseline to end of study was highest in poor prognosis patients (P < .05). Moreover, area under the curve profiles of M65 and M30 during chemotherapy mirrored dynamic profiles for lactate dehydrogenase, alpha-fetoprotein, and beta-human chorionic gonadotropin. Consequently, M65 and M30 levels appear to reflect chemotherapy-induced changes that correlate with changes in markers routinely used in the clinic for management of patients with TC. This is the first clinical study where M65 and M30 antigen levels correlate with established prognostic markers and provides impetus for their exploration in other epithelial cancers where there is a pressing need for informative circulating biomarkers.

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Figures

Figure 1
Figure 1
Expression of CK18/CK8 (CAM5.2) and caspase-cleaved CK18 (M30) in different testicular germ cell tumor components. (A) Embryonal carcinoma (EC): positive for CK18/CK8 and apoptotic cells are positive for caspase-cleaved CK18. (B) Mature teratoma (MT): in general positive for CK18/CK8 and negative for caspase-cleaved CK18. (C) Seminoma (S): negative for both CK18/CK8 and caspase-cleaved CK18.
Figure 2
Figure 2
(A) Prechemotherapy serum levels of total CK18 (M65) and caspase-cleaved CK18 (M30) according to prognosis group (IGCCC) in all groups of analyzed patients (n = 34). (B) Cumulative percentage changes in total CK18 (M65) and caspase-cleaved CK18 (M30) levels over entire treatment period grouped by IGCCC prognosis for samples collected from serum bank (n = 23). *Significant difference from good-prognosis group (P < .05). **Significant difference from good and intermediate-prognosis group (P < .05).
Figure 3
Figure 3
Changes in circulating CK18 (M65) and caspase-cleaved CK18 (M30) in serum of patients with TC (n = 11) during the first course of BEP chemotherapy. The median values are connected by a line. *Median level significant different from baseline (P < .05).
Figure 4
Figure 4
M30 and M65 profiles in a patient from the three IGCCC-defined prognosis groups: (A) good prognosis, (B) intermediate prognosis, (C) poor prognosis. Serum from patients receiving standard chemotherapy for TC was analyzed for circulating CK18 (M65) and caspase-cleaved CK18 (M30). Arrows indicate the start of each chemotherapy course and error bars indicate 30% signal-to-noise ratio for each treatment cycle.
Figure 5
Figure 5
AUC data for (A) circulating CK18 (M65) and (B) caspase-cleaved CK18 (M30) according to IGCCC prognosis group. (C) Levels of M65, M30, and standard tumor markers LDH, αFP, and βHCG combined as normalized AUC data. The arrows indicate the start of each chemotherapy course.
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