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Diagnostics Oncology, Profession, Genetics and epigenetics, Omics

On The Road Less Well Traveled

What drew you to GI tract and hepatobiliary (HPB) cancer?

As a resident at Yale, I encountered a rare case of pancreatic acinar cell carcinoma. It was a challenging diagnosis, and required electron microscopy to confirm at that time. My mentor, Juan Rosai, told me that there were no comprehensive studies on this tumor type, and no immunohistochemical markers available to establish the diagnosis. He suggested that I assemble a series of cases, and arranged for me to review the collection of the US Armed Forces Institute of Pathology. After I completed my study, I realized that there were very few American pathologists studying pancreatic neoplasia – and I decided to make this a focus of my research.

Coincidentally, not long after this, I joined Memorial Sloan Kettering Cancer Center (MSKCC), where I assisted the pathologist responsible for GI neoplasms, Stephen Sternberg. I was asked to establish GI pathology as my subspecialty, and over the next 25 years, my close collaborations with the clinical and research teams working in HPB/GI cancers at MSKCC cemented my interest in this area of pathology.

What have been the most significant advances during your time in the field?

There have been many, both in tumor pathology in general, and in HPB and GI pathology. More specifically, in pancreatic and colorectal carcinomas (CRC) – two of the most prevalent cancers in the HPB/GI areas – we have taken a major step forward in understanding their molecular underpinnings. They have both been sequenced at the whole genome level, and results from the Cancer Genome Atlas project have also provided many new insights into the genetic events that lead to cancer formation and progression. This new information has clarified that molecularly distinct subtypes exist within these broad tumor categories, which the heterogeneity of histomorphology we encounter when studying them pathologically predicts. In addition to providing information about cancer development, genetic alterations have the potential to reveal therapeutic targets, and to aid in the development of biomarkers for tumor detection and monitoring.

How big an impact has the advent of “omics” had?

The effect of gene sequencing of HPB and GI cancers is huge. With the amazing reductions in the costs of sequencing has come the ability to study these cancers routinely at the genetic level. Now, rather than having a general understanding of the spectrum of mutations and other alterations that can occur in a specific type of cancer, we can study each individual patient’s tumor, and the resulting genetic alterations can be specifically used to enhance diagnosis, treatment, and follow-up. We are still unraveling the complexities of the epigenetic changes that modify the transcription of DNA and the translation of mRNA, and comprehensive “omic” analysis of tumors, with integration of data related to genomics, transcriptomics, and proteomics, may be necessary to fully understand the genetic key to successful treatment. Technology is advancing very quickly, along with sophisticated bioinformatic analysis of the data, to allow this sort of pan-omic analysis.

Survival rates for GI and HPB tumors remain low – why?

In these highly aggressive cancers, a better understanding of precursor lesions, to allow detection before invasive carcinoma develops, remains the best chance for a cure. Being able to identify these lesions, and knowing their risk of progression, would allow more effective screening, and earlier detection. Despite technical advances though, surgery remains a significant clinical intervention, and only with a thorough understanding of a patient’s risk can the best treatment decisions be made.

A lot of progress has been made in understanding the pathologic and molecular features of precursors in the colorectum, pancreas, gallbladder, biliary tree, and stomach. This has already impacted CRC mortality. However, similar advances in pancreatic carcinoma remain elusive.  Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor to invasive pancreatic carcinoma. We now know the histologic features of each grade of PanIN, and their molecular alterations have also been determined. But we know very little about the absolute risk that any particular PanIN lesion may progress to cancer. So even if we had a perfect means to detect PanIN, it would remain unclear when surgical intervention would be justified. Developing highly sensitive, noninvasive methods to identify PanIN and other precursors – especially in sites that are difficult to biopsy – is the key to defining their natural history and determining when, and how, to intervene.

At the other end of the neoplastic process, our knowledge of how GI and HPB cancers spread and cause death is still lacking. Research has predominantly focused on relatively early stage cancers, but the later stages of these diseases are less well studied. The occurrence of genetic heterogeneity is well-known, and techniques to identify the full range of genomic alterations in advanced disease, as well as the mechanisms of metastasis, will be needed in order to develop and apply targeted therapy.

Why is funding a problem in GI and HPB cancers?

Some of these cancers are relatively uncommon in the US, and fewer advocacy groups have been formed to sponsor and support research. I also think there is a level of nihilism about the likelihood of major progress for cancers with a particularly dismal outcome (such as, pancreatic cancer). Unfortunately, many creative ideas remain unexploited, especially now that federal research funding has become particularly challenging to obtain. I believe it is important for researchers working in these fields to work with advocacy groups to raise awareness, and to pursue great ideas collaboratively within the research community. We must ensure we use our existing resources in the most effective ways, in order to make the greatest impact possible. Having said that, progress is being made, thanks to increasing awareness, and the existence of some specific funding sources that target uncommon cancers.

What are the next potential game-changers?

The ability to detect targetable genetic alterations, and tailor medical therapy would be a huge advance, and there are multiple examples of how this is already happening in GI cancers (colorectal and gastric in particular). Finding actionable targets in HPB cancers would be a further step forward, and our improved understanding of the genomic landscapes of several major tumor types has promised to accelerate this discovery. But most therapeutic targets identified so far do not allow curative treatment, so further understanding of all of the oncogenic pathways involved in these cancers is needed to move beyond the modest survival gains we have seen so far.

Another potential advance would be the ability to turn an understanding of molecular alterations in cancer into measurable biomarkers of very early (even preinvasive) neoplasia. Screening for CRC was a huge advance, but we are currently unable to screen effectively for cancers of most other GI and HPB organs – even in known high risk groups. Identifying specific biomarkers that can be measured in the blood (such as circulating tumor cells, or cell-free DNA), or by highly sensitive imaging techniques, is a crucial part of improving the early detection of most GI and HPB cancers.

How important is pathology in GI/HPB oncology research?

Pathology is the key to understanding tumors. Proper diagnosis and subclassification is the first step to studying the biology, outcome, treatment response, and all other clinical aspects of different tumor types. Unraveling the genetic basis for cancer has helped us understand many of the pathologic findings we previously regarded as largely descriptive. Now, we can begin to appreciate the basis for the morphologic features pathologists have long recognized as characteristic of carcinomas, and their precursors, grade, subtype and biology. The end results of genomic and epigenetic alterations are changes in proteins, which contribute to the histomorphologic appearance of the tumors. Increasingly, we are learning that specific microscopic findings reflect a predictable underlying genetic alteration, and informed pathologic analysis is needed to draw conclusions about the mechanisms of morphologic alterations. To define tumor characteristics, and to understand how tumor alterations translate into specific morphologies, you need pathologists!

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About the Author
David Klimstra

David Klimstra is Chair, Department of Pathology, James Ewing Alumni Chair of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.

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