Polymorphisms May Offer Clues to Treatment Outcomes in HCC

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Two polymorphisms of a vasodilatory enzyme had significant associations with improved survival in liver cancer treated with an inhibitor of vascular endothelial growth factor receptor (VEGFR), data from a retrospective study reported at the 2015 Gastrointestinal Cancers Symposium showed.

Photo by © ASCO/Todd Buchanan 2015

Andrea Casadei Gardini, MD

Carriers of one or two alleles of the endothelial nitric oxide synthase (eNOS) VNTR polymorphism lived two to four times longer with sorafenib treatment as compared with patients who did not have the alleles. Median survival increased from 5.7 months in patients who had no copies of the VNTR allele to 23.6 months with two copies.

Carriers of the T allele of eNOS—786 had a modest 2-month gain in overall survival, which nevertheless achieved statistical significance compared with patients who did not have the allele. Progression-free survival (PFS) did not change by polymorphism status.

“The eNOS VNTR and eNOS—786 polymorphisms could represent prognostic markers in patients with hepatocellular carcinoma treated with sorafenib,” said Andrea Casadei Gardini, MD, a medical oncologist at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori in Meldola, Italy. “The results are limited by the small sample size and should be considered hypothesis-generating for future studies.”

Cancer cells survive in a hypoxic microenvironment by activating various molecules to counteract hypoxia. The molecules include the vasodilatory enzyme eNOS. Sorafenib induces inhibition of eNOS by blocking several VEGFRs. In carcinogenesis, nitric oxide facilitates tumor angiogenesis, invasion, and metastasis. Whether eNOS polymorphism influences clinical outcome in hepatocellular carcinoma (HCC) had not been investigated.

Casadei Gardini and colleagues retrospectively analyzed data for 257 patients with newly diagnosed HCC from 2004 to 2014, and they identified 54 patients treated with sorafenib. Peripheral blood or tissue samples were available in all 54 cases for DNA extraction and genotyping. Their primary objective was to determine the prognostic and predictive associations of eNOS polymorphisms in patients with advanced HCC treated with sorafenib.

Investigators examined the association between survival and three types of eNOS polymorphisms: +894 G/T, VNTR 27bp 4a/b, and —786 C/T. They identified 21 patients with the VNTR 4 a/b polymorphism, 32 with the –786 C/T polymorphism, and 29 patients with the +894 G/T polymorphism.

Overall, the patients had a median PFS of 5.3 months and a median overall survival of 14.9 months.

The analyses showed that patients with the VNTR b allele (5 repetitions of 27 bp) had better survival, as compared with patients who were not carriers of the b allele. Patients who were neither heterozygous (a/b) nor homozygous (b/b) had a median overall survival of 5.7 months, which increased to 13.9 months in patients who were a/b, and 23.6 months in those who were b/b (P = .016).

Overall survival remained significantly higher for patients who were homozygous for the VNTR polymorphism when the a/b and a/a groups were combined (23.6 versus 10.4 months, P = .016). Analysis of the —786 C/T polymorphism showed that patients who were heterozygous (C/T) or homozygous (T/T) for the T allele had a median overall survival of 15.6 months compared with 13.9 months for patients who were homozygous C/C (P = .031).

Analysis of PFS showed a median of 5.8 months for the VNTR a/b and a/a groups combined versus 4.6 months for the b/b group combined. The —786 analysis showed a median PFS of 5.7 months for the C/C group and 5.2 months for the C/T and TT groups combined.

The genotype did not significantly influence survival or PFS in the +894 G/T group treated with sorafenib.

Reference: Casadei Gardini A, Marisi G, Scarpi E, et al. eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 230.

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