It’s Going to Be in the Genes

When I was asked to write a commentary on liver-directed treatments for hepatic colorectal metastases, my first thought was that we in no way needed another review of this subject, which has been beaten to death in the literature over the last decade. However, at the outset, let me state that this review[1] by Dr. Yuman Fong, the senior author, and his colleagues should be mandatory reading for residents and fellows in training in any specialty of oncology. Dr. Fong is one of several talented US investigators in the field of surgical oncology who has extensive experience with the treatment of liver metastases from colorectal cancer. It would be a waste of my time to criticize this review, since it is up to date on liver-directed treatments for colorectal hepatic metastases. The sections on tumor ablation and radiation therapy (which includes external beam, proton beam, and regional brachytherapy/radioembolization) are excellent discussions. The same goes for the section on clinical staging. There is no fluff in any of the descriptions, but rather straight-to-the-point discussions, with excellent references for further in-depth reading.

I would like to focus this commentary on the section entitled “Need for Useful Clinical Staging Criteria.” The authors state-and rightly so-that the population of patients with colorectal metastases who are offered hepatectomy is clearly a heterogeneous group of individuals. Hence, developing a scoring system for staging patients with hepatic colorectal metastases is important, both for purposes of prognosis and to identify patients who will benefit from additional systemic therapy, either following hepatic resection or in the neoadjuvant setting. The Clinical Risk Score (CRS), as illustrated in Table 3 of the article, is widely utilized, and this system has been verified by several investigators. The CRS can predict prognosis both for patients who undergo hepatic resection and those treated with ablative procedures. However, I am sure that Dr. Fong and colleagues would agree that the CRS is not optimal, and that a better means of predicting prognosis and identifying patients who will benefit from additional systemic therapy, either following hepatic resection or prior to resection, needs to be developed.

It will also not surprise Dr. Fong and his colleagues that this leads us to a mention of the genetics of colorectal cancer. This area of research was jump-started by the Cancer Genome Atlas Project, which conducted a genome-scale analysis of 276 colon and rectal cancer samples, analyzing exome sequence, DNA copy number, promoter methylation, and messenger RNA and micro RNA expression.[2] The Cancer Genome Atlas Project demonstrated that not all colon and rectal cancers are the same at the molecular level. For example, tumors from the ascending colon are more likely to be hypermethylated and to have elevated mutation rates than are other colorectal cancers located in the large intestine. Other researchers[3] have demonstrated that about half of the hepatic metastases from colorectal cancer that they investigated had the same clonal origin as their primary colorectal carcinomas, whereas in the remaining cases the metastases were genetically distinct from their primary carcinomas. These latter investigators emphasized the need to evaluate the genetics of hepatic metastases separately for optimized therapy rather than extrapolating from the primary colon or rectal cancer. It is important to note that our knowledge of the molecular events underlying colorectal cancer is greater than for other common solid tumors.

One of the points I am trying to make is that one can foresee a time when the CRS will be replaced by a patient’s genomic profile, which will allow the oncologist not only to determine the prognosis of someone who presents with resectable hepatic metastases from colorectal cancer, but also make possible the identification of effective systemic therapy that would add to the survival benefit from surgical resection or any liver-ablative procedures. And ultimately, this line of investigation will lead to the identification of those genes that are involved in promoting tumor cells to metastasize to the liver from the primary colon or rectal cancer. It is hoped that utilizing the scientific technologies that we have today will not only increase our understanding of hepatic metastases, but also, at some point in the future, identify molecular targets that, when treated, can actually prevent metastases to the liver, obviating the need to treat metastases at all.

I congratulate Dr. Fong and his colleagues on their fine review. Conceivably the day will arrive when a review article on this topic describes genomic profiling that will key a drug or vaccine or gene therapy that will actually prevent the development of primary colorectal cancer, and the development of hepatic metastases will only be of historical interest.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Park J, Chen Y-J, Lu W-P, Fong Y. The evolution of liver-directed treatments for hepatic colorectal metastasis. Oncology (Williston Park). 2014;28:991-1003.

2. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-7.

3. Lee SY, Haq F, Kim D, et al. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS ONE. 2014;9: e90459.