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Diagnostics Oncology, Hematology, Training and education, Biochemistry and molecular biology, Liquid biopsy

Collaborate or Cave in?

At a Glance

  • With huge advances in the molecular understanding of disease and treatment, the role of the pathologist is changing rapidly
  • Research has provided compelling reasons for pathologists’ involvement in ongoing treatment decision-making and monitoring
  • Through assessing levels of circulating tumor DNA, liquid biopsy is showing real promise in tracking treatment success and disease progression
  • Pathologists need to take note of this and similar technological evolutions to become full partners in treatment monitoring

The profession of pathologist is an ever-evolving one, and has come far from the early pioneers who studied the nature and origin of disease. Today, the pathologist’s list of responsibilities is far longer, and it continues to grow. Disease screening and diagnosis are now an integral part of that list, but with knowledge of diseases (their genetics, various subclasses and mutations) increasing by the day, if pathologists aren’t already actively involved in treatment decision-making, monitoring and therapeutic tailoring, they soon will be. This is no simple task, but things are changing drastically, and I believe pathologists need to extend their traditional lab work to partner with other disciplines and fully enter this era of treatment evolution.

Don’t get me wrong, I know that involvement in treatment determination is not a new challenge, but with the advent of detailed molecular screening and advanced disease characterization, the nature of pathologists’ participation is changing. Tools like genetic and genomic profiling can now assist in selecting the most promising therapies for patients and eliminating inappropriate options. Though this is already happening, as an oncologist, I urge pathologists to collaborate even more with other disciplines. Now, more than ever, we need you. Certainly as an oncologist, I believe your knowledge and skills are critical in securing the most optimum outcome for patients. The situations listed below should help you to appreciate this at its best.

Targeting, testing, treating

Let's look at some examples of how our changing knowledge has impacted the traditional role of the pathologist. A good place to start would be the well-known EGFR signaling pathway in colorectal cancer. In many cancers of the colon, EGFR phosphorylation activates Ras, which stimulates Raf and the MAP kinase pathway to enhance cell proliferation and tumor invasion. Treating patients with an EGFR antibody blocks the pathway and induces a tumor response; but, in cases where the KRAS or NRAS genes are mutated – so that the protein can act without EGFR stimulation – an upstream blockage of the pathway will not yield any tumor response (1). So KRAS-NRAS is a useful negative predictive marker; patients who will respond poorly to treatment can be excluded from antibody therapy up front, and this will increase the percentage of positive responses in treated patients. It will also prevent the cost and toxicity of unnecessary therapy for others.

Pathologists also have an integral role in maximizing the effectiveness of targeted drugs and accelerating the development of new therapies by improving understanding of disease. Molecular classifications of disease allow us to distinguish between effective and ineffective treatments and make recommendations based on tumor gene profiles. In non-small-cell lung cancer (NSCLC), for instance, tumors that were previously separated into only three categories based on morphology and phenotype, can now be classified much more powerfully using genetic mutations. One recent study of crizotinib as a second-line treatment for NSCLC yielded a 57 percent response rate (2). This is almost unheard of for such a treatment and it’s thanks to the pre-screening of patients for the EML4-ALK translocation, which is a specific target of that drug and allows it to take effect. Numbers like this not only demonstrate to us the benefit of collaborating with pathologists to improve treatment performance, but also support drug development.

Parallel pros

There is also a new push toward parallel trial screening, a system in which patients undergo a single pre-screening and consent process for possible admission to multiple clinical trials, rather than repeated testing for each individual protocol (see “A Pioneering Approach to Trial Screening” Sidebar). By participating in more efficient screening strategies, we can build a better bridge between basic and clinical sciences, enabling laboratory studies to be more easily and efficiently translated into patient-based research. Avoiding repeated testing saves both time and money, as the cost for a single pre-screening is shared by several industrial partners, and may improve enrolment and optimize results by exposing a more diverse range of patients to many potential trial options.

A major research benefit of the parallel screening system is that all samples undergo the same handling, storage and quality assurance procedures, so that the collected data are more homogeneous and can be used for comparative evaluations, secondary “cross-trial” investigations and meta-analysis. Here, too, I believe the input of pathologists is key to developing the best and most efficient methods for patient sample screening, verification and preservation.

Mind the monitoring gap

The importance of collaboration between pathologists and clinicians does not end with screening and treatment determination, though. I see a vital new role for pathologists in ongoing patient monitoring and treatment modulation. Diseases are never at rest; they change throughout the treatment process, so patient therapies must change as well – and now, for the first time, there is a place for pathology in this process.

Cancerous tumors, for example, develop heterogeneity during treatment. This may occur as a natural consequence of metastasis, or it can be a result of treatment. Differential sensitivity to therapeutic agents can eliminate some tumor cells and allow others with different genetic characteristics to flourish; in some cases, even the treatment itself can induce mutagenesis. Clearly, such a significant issue must be addressed, it would, however, be impossible to biopsy every single metastasis in every patient. But without this ability, how can we investigate the changing nature of an individual patient’s disease?

cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer.

The answer lies in new, efficient and less invasive technologies, and I believe that liquid biopsies could be the key. Already in development as a prognostic survival tool and early-identification technique, liquid biopsy technology could potentially be used to monitor patient treatment by screening for new mutations that arise during therapy. This screening is conducted on the DNA shed by tumors into the bloodstream, known as circulating cell-free DNA (cfDNA) (3,4). According to research, this cfDNA can be detected in the blood of over 50 percent of patients with localized tumors and over 80 percent of those presenting with metastatic disease (5). In the same study of 24 colorectal cancer patients, who did not initially present with any KRAS mutation and who were treated successfully with anti-EGFR therapy before progressing, 23 developed mutations that were revealed by liquid biopsy. These mutations coincided with patients’ development of resistance to the treatment (4). Another very recent study reports on the detection of KRAS and BRAF mutations in cfDNA in 95 patients, comparing assessment by liquid biopsy with traditional assessment on classic pathologic material (6). With 100 percent specificity and sensitivity for the BRAF V600E mutation and a concordance value of 96 percent with the results obtained from tumor material, the study authors came to a compelling conclusion: “cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer.”

Liquid biopsies could also potentially evaluate tumor burden and detect residual tumor cells after surgery, in addition to resistance monitoring and the identification of specific mutations. For the latter, liquid biopsy is actually the only appropriate method currently available to us, considering vast tumor heterogeneity and the impossibility of taking biopsies of every single lesion in metastatic disease!

I would strongly encourage pathologists to get involved and continue building on the amazing work you already do.
Who should be taking responsibility?

With new technologies come new opportunities for pathologists, but it’s important to proactively take the opportunities that are available. The liquid biopsy, for instance, is not a true biopsy but a blood draw, which means that responsibility for the technique is as yet unclaimed – will it lie with pathologists, with molecular biologists, or elsewhere? Each institution will need to make a call on this, but I would strongly encourage pathologists to get involved and continue building on the amazing work you already do. Collaborations with clinical researchers are on the rise and should continue to increase as long as the power of prognostic and predictive markers remains an important part of the selection and administration of patient therapies. Now more than ever, pathologists are working at the interface of basic and clinical science, and their job is not that of the static diagnostician of years past, but a dynamic and integral participant in patient care. In a changing situation like this, then, pathologists can play an active part in redefining the role. I, for one, am looking forward to growing my partnerships with my pathologist colleagues – I truly believe this is the best option for both of our professions and, ultimately, should lead to the best outcome for our patients.

A Pioneering Approach to Trial Screening

What? SPECTAcolor, or Screening Platform for Efficient Clinical Trial Access for patients with pathologically confirmed metastatic colorectal cancer (CRC), is an initiative led by the European Organization for Research and Treatment of Cancer (EORTC).

Why? SPECTAcolor is a pioneering clinical research model that hopes to revolutionize the approach to cancer research and treatment. Instead of screening each patient for each available trial separately, patients are prescreened once and then invited to participate in trials with drugs selected according to their prescreened profile. The idea is to give these patients the best chance of accessing the most suitable clinical trials with new, molecularly defined approaches.
When? SPECTAcolor prescreening began in October 2013 and is currently increasing its accrual speed, while trials with new targeted drugs (antibodies, tyrosine kinase inhibitors, etc.) are in preparation.

Who? Supported by a network of 29 clinical centers in 10 countries, the ultimate goal of this initiative is to enable better access to new treatment options. Between 600 and 1,000 patients with advanced CRC are expected to enroll each year. SPECTAcolor is supported by the EORTC Charitable Trust and the corporate social responsibility program of Alliance Boots. It is also actively supported by the European Society of Pathology (ESP) and the Sanger Institute.

Key achievements? As of 14 October 2014, 440 adult patients had already given their informed consent to be tested for mutations in CRC biomarkers. Next-generation sequencing is being used to identify genetic alterations that may intrinsically drive cancer cells and could therefore be targeted by new therapies.

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  1. R. G. Amado et al., “Wild-Type KRAS is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer”, J. Clin. Oncol. 26, 1626–1634 (2008). doi: 10.1200/JCO.2007.14.7116.
  2. E. L. Kwak et al., “Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer”, N. Engl. J. Med. 363, 1693–1703 (2010). doi:10/1056/NEJMoa1006448.
  3. L. A. Diaz Jr. et al., “Liquid Biopsies: Genotyping Circulating Tumor DNA”, J. Clin. Oncol. 32, 579–586 (2014). doi: 10.1200/JCO.2012.45.2011.
  4. F. Mouliere et al., “Multi-marker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer”, Mol. Oncol., 8, 927-941, (2014).
  5. C. Bettegowda et al., “Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies”, Sci. Transl. Med. 6, 224ra24. doi:10.1126/scitranslmed.3007094.
  6. A. R. Thierry et al., “Clinical Validation of the Detection of KRAS and BRAF Mutations from Circulating Tumor DNA”, Nat. Med. 20, 430–435 (2014). doi:10.1038/nm.3511.
About the Author
Arnaud Roth

Arnaud Roth is head of unit physician at the digestive tumor unit, HUG, Geneva, Switzerland

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