Ann Surg Treat Res.  2018 Dec;95(6):303-311. 10.4174/astr.2018.95.6.303.

Validation of the OncoHepa test, a multigene expression profile test, and the tumor marker-volume score to predict postresection outcome in small solitary hepatocellular carcinomas

• Ha SM
• Hwang S
• Park JY
• Lee YJ
• Kim KH
• Song GW
• Jung DH
• Yu YS
• Kim J
• Lee KJ
• Tak E
• Park YH
• Lee SG

• KMID: 2426761
• DOI: http://doi.org/10.4174/astr.2018.95.6.303

Abstract

PURPOSE
OncoHepa test is a multigene expression profile test developed for assessment of hepatocellular carcinoma (HCC) prognosis. Multiplication of α-FP, des-γ-carboxy prothrombin (DCP) and tumor volume (TV) gives the α-FP-DCP-volume (ADV) score, which is also developed for assessment of HCC prognosis.
METHODS
The predictive powers of OncoHepa test and ADV score were validated in 35 patients who underwent curative hepatic resection for naïve solitary HCCs ≤5 cm.
RESULTS
Median tumor diameter was 3.0 cm. Tumor recurrence and patient survival rates were 28.6% and 100% at 1 year, 48.6% and 82.9% at 3 years, and 54.3% and 71.4% at 5 years, respectively. The site of first tumor recurrence was the remnant liver in 18, lung in 1, and the peritoneum in 1. All patients with HCC recurrence received locoregional treatment. OncoHepa test showed marginal prognostic significance for tumor recurrence and patient survival. ADV score at 4log also showed marginal prognostic difference with respect to tumor recurrence and patient survival. Combination of these 2 tests resulted in greater prognostic significance for both tumor recurrence (P = 0.046) and patient survival (P = 0.048).
CONCLUSION
Both OncoHepa test and ADV score have considerably strong prognostic power, thus individual and combined findings of OncoHepa test and ADV score will be helpful to guide postresection surveillance in patients with solitary HCCs ≤5 cm.

Keyword

Recurrence; Survival; Prognosis; Genes

MeSH Terms

Carcinoma, Hepatocellular*
Humans
Liver
Lung
Peritoneum
Prognosis
Prothrombin
Recurrence
Survival Rate
Tumor Burden
Prothrombin

Figure

• 

  Fig. 1 Postresection cumulative tumor recurrence (A) and overall patient survival (B).

• 

  Fig. 2 Postresection cumulative tumor recurrence (A, C, E) and overall patient survival (B, D, F) according to microvascular invasion (A, B), the OncoHepa test (CbsBioscience Inc., Daejeon, Korea) (C, D), and the ADV score (E, F).

• 

  Fig. 3 Proportions of the patients in the indicated groups according to the OncoHepa test (CbsBioscience Inc., Daejeon, Korea) and the ADV score. The left-sided group indicates the combined low-risk group and the sum of the three right-sided groups indicates the combined high-risk group.

• 

  Fig. 4 Postresection cumulative tumor recurrence (A) and overall patient survival (B) according to the combined risk, determined from the combination of the OncoHepa test (CbsBioscience Inc., Daejeon, Korea) and the ADV score.

Reference

1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012; 379:1245–1255.

2. Hwang S, Lee YJ, Kim KH, Ahn CS, Moon DB, Ha TY, et al. The impact of tumor size on long-term survival outcomes after resection of solitary hepatocellular carcinoma: single-institution experience with 2558 patients. J Gastrointest Surg. 2015; 19:1281–1290.

3. Hwang S, Song GW, Lee YJ, Kim KH, Ahn CS, Moon DB, et al. Multiplication of tumor volume by two tumor markers is a post-resection prognostic predictor for solitary hepatocellular carcinoma. J Gastrointest Surg. 2016; 20:1807–1820.

4. Shindoh J, Andreou A, Aloia TA, Zimmitti G, Lauwers GY, Laurent A, et al. Microvascular invasion does not predict long-term survival in hepatocellular carcinoma up to 2 cm: reappraisal of the staging system for solitary tumors. Ann Surg Oncol. 2013; 20:1223–1229.

5. Shindoh J, Hasegawa K, Inoue Y, Ishizawa T, Nagata R, Aoki T, et al. Risk factors of post-operative recurrence and adequate surgical approach to improve long-term outcomes of hepatocellular carcinoma. HPB (Oxford). 2013; 15:31–39.

6. Roayaie S, Obeidat K, Sposito C, Mariani L, Bhoori S, Pellegrinelli A, et al. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013; 57:1426–1435.

7. Kim J, Hong SJ, Park JY, Park JH, Yu YS, Park SY, et al. Epithelial-mesenchymal transition gene signature to predict clinical outcome of hepatocellular carcinoma. Cancer Sci. 2010; 101:1521–1528.

8. Hwang S, Ha TY, Song GW, Jung DH, Ahn CS, Moon DB, et al. Quantified Risk assessment for major hepatectomy via the indocyanine green clearance rate and liver volumetry combined with standard liver volume. J Gastrointest Surg. 2015; 19:1305–1314.

9. Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol. 2016; 22:18–75.

10. Jung DH, Hwang S, Lee YJ, Kim KH, Song GW, Ahn CS, et al. Small hepatocellular carcinoma with low tumor marker expression benefits more from anatomical resection than tumors with aggressive biology. Ann Surg. 2017; 08. 23. [Epub]. DOI: 10.1097/SLA.0000000000002486.

11. Kim J, Hong SJ, Lim EK, Yu YS, Kim SW, Roh JH, et al. Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exp Clin Cancer Res. 2009; 28:20.

12. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3:RESEARCH0034.

13. Pawlik TM, Delman KA, Vauthey JN, Nagorney DM, Ng IO, Ikai I, et al. Tumor size predicts vascular invasion and histologic grade: implications for selection of surgical treatment for hepatocellular carcinoma. Liver Transpl. 2005; 11:1086–1092.

14. Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 2009; 1796:75–90.

15. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology. 2009; 50:1464–1474.

16. Kowanetz M, Valcourt U, Bergstrom R, Heldin CH, Moustakas A. Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein. Mol Cell Biol. 2004; 24:4241–4254.

17. Tsunedomi R, Iizuka N, Tamesa T, Sakamoto K, Hamaguchi T, Somura H, et al. Decreased ID2 promotes metastatic potentials of hepatocellular carcinoma by altering secretion of vascular endothelial growth factor. Clin Cancer Res. 2008; 14:1025–1031.

18. Damdinsuren B, Nagano H, Kondo M, Yamamoto H, Hiraoka N, Yamamoto T, et al. Expression of Id proteins in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Int J Oncol. 2005; 26:319–327.

19. Mohamed MM, Sloane BF. Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer. 2006; 6:764–775.

20. Przybylo JA, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail's pace. Int J Biochem Cell Biol. 2007; 39:1082–1088.

21. Sakamoto Y, Mafune K, Mori M, Shiraishi T, Imamura H, Mori M, et al. Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma. Int J Oncol. 2000; 17:237–243.

22. Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol. 2002; 8:385–392.

23. Hayasaka A, Suzuki N, Fujimoto N, Iwama S, Fukuyama E, Kanda Y, et al. Elevated plasma levels of matrix metalloproteinase-9 (92-kd type IV collagenase/gelatinase B) in hepatocellular carcinoma. Hepatology. 1996; 24:1058–1062.

24. Chen ZB, Shen SQ, Ding YM, Wang WX, Tao JP, Liang LJ, et al. The angiogenic and prognostic implications of VEGF, Ang-1, Ang-2, and MMP-9 for hepatocellular carcinoma with background of hepatitis B virus. Med Oncol. 2009; 26:365–371.

25. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem. 2001; 276:27424–27431.

26. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004; 117:927–939.

27. Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol. 2017; 35:2838–2847.

28. Delahaye LJ, Drukker CA, Dreezen C, Witteveen A, Chan B, Snel M, et al. A breast cancer gene signature for indolent disease. Breast Cancer Res Treat. 2017; 164:461–466.

29. Vaira V, Roncalli M, Carnaghi C, Faversani A, Maggioni M, Augello C, et al. MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma. Liver Int. 2015; 35:1077–1086.

30. Chen R, Guan Q, Cheng J, He J, Liu H, Cai H, et al. Robust transcriptional tumor signatures applicable to both formalin-fixed paraffin-embedded and fresh-frozen samples. Oncotarget. 2017; 8:6652–6662.