Minimize Errors, Report with Accuracy

Molecular pathology is growing at an astonishing rate. It’s an area of medicine that continues to generate excitement, not only amongst health care professionals, but also the public. Rarely a week passes by without an announcement from the press about a medical ‘breakthrough’ and everyone appears to be sold on the merits and promise of personalized therapy. Often, these breakthroughs are the result of molecular research and many targeted drugs are now reaching the clinic.

This is an exciting time for medical research, but what does it mean for those involved in performing molecular pathology tests for cancer patients?

The new drugs require new testing processes and have challenging requirements for both equipment and staff. Inevitably, pathology laboratories are faced with greater workloads, greater resource requirements, greater training needs – and greater room for error.

Given the large number of processes and people involved – from the moment a molecular pathology report is first requested to its finalization – the importance of standardizing procedures and implementing guidelines is obvious. Progress is certainly being made in this regard. For example, in the US, the College of American Pathologists (CAP) in collaboration with the International Association for the Study of Lung Cancer and the Association for Molecular Pathology (AMP) have recently issued guidance for laboratories operating lung cancer molecular pathology services (1).

Recognizing the need to develop a more general guideline – or a best practice document – for laboratories performing molecular pathology tests in Europe, a large team made up of pathologists, geneticists, scientists, industry representatives, oncologists, quality assurance experts, and others, was assembled from across Europe. We focused our initial efforts on developing a guideline for those involved in performing tests for patients with cancer since the majority of advances in personalized medicine have been made in this therapy area.

We are now one year on and have produced a consensus document (2), which has been recognized and is supported by the European Society of Pathologists (ESP) and the UK Royal College of Pathologists (RCPath).

Beyond the obvious

The modern challenge to pathologists is to think beyond the diagnosis and classification of a disease, and to produce information that guides treatment more efficiently and accurately. To be effective, we must be clear about our responsibilities at every stage of the molecular pathology process – from requesting molecular analysis to pre-analytical sample handling to nucleic acid extraction and analysis to the reporting of results. Furthermore, the requirements for the laboratories offering those services need to be clearly outlined.

The infographics here summarizes all of the individual steps (and key considerations) involved in the molecular pathology process, which are discussed in more detail in the guidance (2). All steps (and factors or technologies related to them) share the risk that any deviation from standard operating procedures is likely to have a negative, knock-on impact on the overall process, leading to an inaccurate result. If this guidance is followed as a minimum precaution, we believe the resulting molecular pathology report will not only be accurate, but it will also provide the optimal treatment for the patient. With multiple stages and people involved, the catch is getting everyone on the same page.

Request or reflex

For those requesting a molecular pathology test, it’s very important to consider what type of test is needed; when the result is required and, perhaps most importantly, whether a test is needed at all. Currently, not everyone who would benefit from a cancer test is getting one. There will always be workload and budgetary concerns within pathology, but these can be better balanced through integration of molecular pathology with other departments. And while this is already happening (there are improvements across Europe), it is still very challenging. Our ultimate goal is to ensure that those in need have access to testing. A standard operating procedure that supports the multidisciplinary team (MDT) requesting process can help, but much comes down to good communication between the clinic and the laboratory.

Another way of tackling the problem is to consider reflex testing. In other words, pathologists are made directly responsible for the molecular analysis request based on a patient’s diagnosis and tissue availability. Given that more than 10 percent of patients with any particular diagnosis need molecular analysis, reflex testing has great potential. For example, we routinely do HER2 testing for all breast cancer, and a similar approach to EGFR mutation testing in lung cancer can save time in deciding treatment in patients who are often very ill at diagnosis. There are many circumstances where a pathologist should exercise his or her clinical judgment and simply order the test.

For the laboratory, reflex testing has a lot to offer in terms of speeding up the process. It is also financially attractive to hospitals in some instances, because it can reduce the number of MDT discussions and the number of outpatient appointments. It does, however, need to be balanced against unnecessary testing in patients who do not need further treatment. With that in mind, the RCPath and ABPI (Association of the British Pharmaceutical Industry) are in the process of developing planning tools that should help departments decide when reflex testing might be beneficial.

Common blunders

As you move along the pathway outlined in the infographics here, you will all see potential problem areas. From experience, the majority of issues that lead to inaccurate results occur during the pre-analytical stage, starting as early as the discussion about which biopsy to take.

Thereafter, DNA or RNA extraction can often be prone to errors. Many people still use manual processes, but there are good automated systems available that help eliminate some errors and help to achieve better consistency of extraction. Analytical methods vary, and comparative studies of these are needed. Such studies can generate economic data that not only convinces pathologists, but also – and more importantly – helps gain backing from national health care regulators.

Aside from processes, one very important aspect that is discussed throughout the guidance is the need for accreditation of laboratories in accordance with the External Quality Assessment (EQA) scheme, which is applicable to all laboratories in Europe. It is extremely important for laboratories offering molecular testing to participate. For those who do, I would advise that you look at the results of EQA schemes, and the mistakes made by others, which may help highlight areas where you might be introducing errors in your own lab.

Those laboratories who believe they can perform molecular pathology tests without the sort of oversight that accompanies EQA participation are taking big risks and should be aware of that fact.

Clearing clinician confusion

With the high (and growing) number of processes involved in performing a molecular test, it’s no surprise that the final complex report can result in clinicians scratching their heads in puzzlement. We must aim to produce coherent reports and accurate advice that guides treatment in the clearest possible way. We have provided recommendations in this area, but we will increasingly need to provide tools that will allow clinicians to easily and accurately interpret and act upon reports. The US is making a lot of headway in this regard. The CAP Cancer Committee has launched 70 cancer protocols in total that aim to standardize pathology reporting across a large range of cancers; these are now an integral part of routine pathology practice across the country. The RCPath and ICCR (International Collaboration on Cancer Reporting) minimum datasets are another part of the solution, but much depends on their implementation by the commercial providers of laboratory information systems.

Just the beginning

Here, we have only touched on a small number of points included within the overall guidance. The figure provides an overview of the critical considerations when conducting a molecular pathology test. The authors of the guidance certainly acknowledge that further guidance and standards can and should be developed for each of the separate elements of the process, but we’ve made a good start by covering all of the core processes.

While the new guidance is specific for cancer, there are many elements that are applicable to other facets of molecular pathology. Our scientific understanding and technology are evolving all the time, so we acknowledge that revisions will be needed in the future.

Where next? Well, work is ongoing to develop the guidance even further, and is currently focusing on internal quality assessment. In the meantime, the ESP and RCPath are disseminating the guidance as best practice for laboratories performing molecular pathology tests for cancer patients. Our ultimate goal is to support everyone working in molecular pathology laboratories to provide the right diagnosis and treatment for patients accurately and efficiently. If you share that goal, we hope you will join us on the journey.