Molecular Markers

Molecular Markers

Despite of many medical and surgical advances over the past decades, mortality from liver and pancreas cancers have been increasing1. Many patients with hepatopancreatobiliary (HPB) cancers have a poor prognosis not only because of aggressive cancer biology but also because of challenges with timely diagnosis and treatment2,3. HPB cancers are often diagnosed at a late stage due to vague symptoms and lack of routine screening tests. In selected patients who are diagnosed early enough for curative resection or converted on neoadjuvant therapies, their prognosis may still vary widely given their tumor biology and responsiveness to adjuvant therapies. Our HPB service has spearheaded many genetic and epigenetic studies to identify markers that are diagnostic and/or prognostic for patients with HPB cancers. Given our high surgical volume, we are uniquely poised to study these rare cancers.

Integrated Mutation Profiling for Actionable Cancer Targets (IMPACT) for HPB cancers

To date, we have enrolled over 1101 patients with primary and metastatic HPB cancers to have their tumor and blood undergo targeted sequencing through our institutional MSK-IMPACT™ (Integrated Mutation Profiling of Actionable Cancer Targets). IMPACT panel sequences over 400 oncogenes and tumor suppressor genes, and evaluates single-nucleotide variants, copy number amplification and deletions, and fusions. These genetic data is then available to MSKCC research community through the cBio Cancer Genomics Portal (Figure 1)4,5.

Dr. William Jarnagin and Dr. Amber Simpson are spearheading research studies among patients with gallbladder carcinoma, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. We analyze genomic data to better elucidate tumor biology and may potentially provide actionable therapeutic targets. It is also key to utilize this rich genomic data to correspond to clinical, pathological, and radiographical data to further examine their interplay on cancer recurrence and overall survival.

Figure 1. cBio Cancer Genomic Portal is an interactive platform available for researchers to study genetic alterations in different pathways and in association with different outcomes.

Gene Signature in Colorectal Liver Metastasis

Resection of colorectal liver metastasis (CRLM) may be curative for 20% of patients, but predicting which patients may benefit from resection remains challenging. Our group evaluated 1001 consecutive patients and created a clinical risk score which predicted outcome after CRLM resection6. However, we found that clinical risk score does not validate well on external data and also that clinical variables lose its prognostic significance after patients survive for several years after resection7,8.

Dr. Balachandran and Dr. D’Angelica looked beyond clinical risk score and created a 20-gene molecular risk score to better risk stratify patients9. Molecular risk score was found to not only be prognostic among 96 patients from MSKCC but also it was externally validated on 119 European patients (Figure 2). This was the first externally validated prognostic multigene signature for CRLM and it warrants prospective validation in clinical trials.

Figure 2. Patients with high molecular risk score (stratified at median) had significantly higher recurrence-free survival compared to patients with low molecular risk score at both MSKCC and Europe.

MicroRNA Profiling for Colorectal Liver Metastasis

In addition to developing a molecular risk score to predict outcome following resection of CRLM, Dr. Kingham in collaboration with Dr. Sohail Tavazoie at the Rockefeller University to profile tumor microRNAs. In recent years, microRNAs have shown to become deregulated in cancers, facilitate cancer progression and metastasis, and thus microRNA can also be a promising prognostic marker in patients following CRLM resection. MicroRNAs (miRNA) are 19-25 nucleotide non-coding RNAs that can regulate gene expression by targeting the complementary sequences in the 3′ untranslated regions of transcripts10.

This collaborative effort has led to the identification of miR-203, for which expression levels were found to be significantly higher in tumors of 91 patients who were short-term survivors compared to long-term survivors (Figure 3).  In addition, we can also detect significant differences between the miR-203 levels of 46 patients from their preoperative sera, highlighting the potential utility of this prognostic biomarker as a non-invasive clinical test. We are working towards integrating this test into future trials in order to validate its utility.

Figure 3. Next-generation sequencing of small-RNAs showed 16 miRNAs (squares and triangles) that were significantly differentially expressed, of which 10 miRNAs (triangles) exhibited an absolute fold change of 2 or above. MiR-203 expression levels were significantly different between short-term vs. long-term survivors (log2Foldchange=1.02, p=0.006).
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.
  2. Hidalgo M, Cascinu S, Kleeff J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology. 2015;15(1):8-18.
  3. Bruix J, Han KH, Gores G, Llovet JM, Mazzaferro V. Liver cancer: Approaching a personalized care. Journal of hepatology. 2015;62(1 Suppl):S144-156.
  4. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404.
  5. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.
  6. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Annals of surgery. 1999;230(3):309-318; discussion 318-321.
  7. Tan MC, Butte JM, Gonen M, et al. Prognostic significance of early recurrence: a conditional survival analysis in patients with resected colorectal liver metastasis. HPB : the official journal of the International Hepato Pancreato Biliary Association. 2013;15(10):803-813.
  8. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection for colorectal metastases: value for risk scoring systems? Annals of surgery. 2007;246(2):183-191.
  9. Balachandran VP, Arora A, Gonen M, et al. A Validated Prognostic Multigene Expression Assay for Overall Survival in Resected Colorectal Cancer Liver Metastases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016.
  10. Kanaan Z, Roberts H, Eichenberger MR, et al. A plasma microRNA panel for detection of colorectal adenomas: a step toward more precise screening for colorectal cancer. Annals of surgery. 2013;258(3):400-408.