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Baseline caspase levels may serve as biomarker in advanced SCCHN
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The presence of high serum caspase-3 activity predicted poor PFS and nonresponse to novel targeted treatments in patients with squamous cell cancer of the head and neck, according to study results.
Mounting evidence suggests that mTOR inhibitors might effectively treat advanced squamous cell carcinoma of the head and neck (SCCHN). However, noninvasive biomarkers for early prediction of treatment efficacy have not been identified, according to study background.
“The lack of appropriate methods for closely monitoring therapy response can result in prolonged ineffective treatment of patients,” Viktor Grünwald, MD, of the department of hematology, hemostasis, oncology and stem cell transplantation at the Medical School Hannover in Germany, and colleagues wrote. “Thus, there is a strong need for new strategies that allow for early identification of patients not responding to anti-cancer therapy.”
Highly proliferating tumors demonstrate enhanced cell turnover and apoptosis, according to the researchers. During apoptosis of epithelial cells, caspase-cleaved cytokeratin 18 (CK-18) is detectable in the blood.
Grünwald and colleagues collected sera from 29 patients with metastatic or relapsed SCCHN (mean age, 63 years; 79% male) and 15 healthy controls and used enzyme-linked immunosorbent assays to analyze for caspase-cleaved and total (caspase-cleaved and uncleaved) CK-18. Researchers also used a luminometric substrate assay to detect caspase-3 activity.
Patients received weekly IV temsirolimus (Torisel, Pfizer) until death, disease progression or unacceptable toxicity.
PFS served as the primary endpoint. Assessing the predictive role of caspase-cleaved CK-18 and caspase-3 or -7 served as secondary endpoints.
Compared with healthy controls, patients with SCCHN had higher baseline serum levels of caspase-cleaved CK-18 (mean, 181 ± 19.6 U/L vs. 139.3 ± 11.7 U/L), total CK-18 (mean, 503.8 ± 45.4 U/L vs. 348.1 ± 28.9 U/L) and caspase-3 activity (777.8 ± 145.5 reactive light units [RLU] vs. 424.8 ± 25.9 RLU). However, only the difference in total CK-18 levels reached statistical significance (P < .001).
The researchers then compared baseline serum levels in patients treated with temsirolimus who achieved a PFS of less than 2 months (n = 14) with those who achieved a PFS of at least 2 months (n = 15). Patients with shorter PFS had higher serum levels of caspase-cleaved CK-18 (200.2 ± 35.9 U/L vs. 163.1 ± 18 U/L) and total CK-18 (577.2 ± 78 U/L vs. 435.2 ± 44.6 U/L), as well as significantly increased caspase-3 activity (1,054.3 ± 252.5 RLU vs. 519.129.3 RLU; P < .01).
Further, the difference in caspase-3 activity increased when researchers compared patients who achieved a PFS of less than 3 months (n = 19) with those who achieved a PFS of 3 months or longer (n = 10; 1,000.7 ± 203.4 RLU vs. 354.3 ± 58.1 RLU).
In a regression analysis, caspase-3 activity inversely correlated with PFS (r = –0.42; P < .05) and OS (r = –0.19).
In a receiver operating characteristic analysis, caspase-3 activity baseline levels above 394 RLU accurately predicted PFS shorter than 2 months with a sensitivity of 86% and a specificity of 67% (area under the curve = 0.8; 95% CI, 0.62-0.96). Further, patients with caspase-3 activity of 394 RLU or greater achieved significantly prolonged PFS (P < .01).
“Increasing evidence exists indicating that activated caspases control a variety of pathways involved in tumor cell proliferation,” Grünwald and colleagues concluded. “Further large cohort studies analyzing the predictive value of serum caspase activity for treatment outcomes of SCCHN patients are warranted.” – by Cameron Kelsall
Disclosure: Grünwald reports an advisory role with Boehringer Ingelheim and Merck Serono. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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