Building Bridges, Transforming Pathology

Precision medicine has the potential to transform healthcare (1). If adopted seamlessly, it can quickly spotlight the ideal pathway for biopsies and biomarker-based testing to enable the use of the right treatment for the right patient at the right time – not only improving healthcare systems, but also patient outcomes (2,3). Unfortunately, despite the wide array of effective testing, many eligible patients may not receive targeted treatment due to barriers in the precision medicine pathway (4). Below, we explore how precision medicine can be used more effectively to bridge this gap and how it can transform pathology as a whole, with Umberto Malapelle, Chair of Predictive Molecular Pathology Laboratory, Department of Public Health, and Assistant Professor in Anatomic Pathology, School of Medicine, University Frederico II of Naples, Italy.

First, why is the adoption of precision medicine important for pathology? 
 

Often, when we’re thinking about precision medicine, we’re thinking about tailoring treatment. But to tailor treatment we need to tailor the test because each patient, type of tumor, tissue, and biometric characteristics are ultimately different (2, 5, 6, 11). Precision medicine is our best weapon in assessing molecular status and defining if a targetable alteration is present (7, 8). It’s a very important part of diagnosis because, in many cases, you need to integrate a morpho-molecular approach to better refine the diagnosis (2, 6). Once there, you can start the evaluation of predictive biomarkers and then start with a treatment process. In short, if we want to start precision treatment, we need to start with precision testing (9, 10). 

How can the application of precision medicine enhance current approaches to treatment?
 

Precision medicine is the direction of travel for medicine. It allows you to do work backstage – before and within clinical trials – where you are able to define biomarkers and predict treatment (5, 11). In the field of positive predictive biomarkers, you need to pay attention to the specific type of alterations, because it will determine the treatment path for the patient (12). Today, this means one gene is not one biomarker, but one mutation is one biomarker (13, 14, 15). Epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients, for example, can help define if patients are eligible to receive specific types of treatment (16, 17). There are many different types of EGFR mutation, with each responding to treatments differently, depending on the mutation (18). Depending on the types of mutations, patients may respond better to a particular type of treatment or show resistance to different classes of treatment (14). 

What does the current biomarker testing process look like for cancer patients? 
 

As mentioned, to start a precision oncology program, you need to start with precision biomarker testing (8, 9). And for different driver mutations in different settings, you may have different methodological and technological approaches (6, 19). For example, if we focus on NSCLC, we need to simultaneously test for more than 15 biomarkers (20). 

We need to use different types of methodologies to gain this information, but we have to prioritize next generation sequencing, as it is the best way to glean specific information about the single types of alteration we are searching for (21, 22, 23). Going back to the EGFR example, you can only analyze roughly 77 alterations with a PCR approach – but we know there are likely more in EGFR (18). So we need to use next generation sequencing (NGS) upfront. And when it’s possible, we need to start the biomarker assessment after we have the morphological diagnosis – without the need to wait for requests to test the other biomarkers (24, 25). 

This pathologist-initiated approach is known as reflex testing, and it reduces the likelihood of a suboptimal, non-targeted therapy being initiated prematurely, before determining the complete biomarker status of a patient (26). Furthermore, by standardizing the ordering of biomarker tests, fewer patients will be overlooked for testing, creating a more systematic and equitable system (19). 

Why do some patients drop out of the precision medicine pathway – or not have access at all? 
 

This is really difficult. Precision medicine is complex, with many stakeholders involved and points in the diagnostic and treatment pathway where patients could drop off (27, 28). If you look at the data coming from The European Society of Medical Oncology, there is a lack of equity in access to this type of assessment, in particular, for non-small cell lung cancer – where you need NGS (29, 30). 

One major barrier is the sample collection (4). When you need to test several biomarkers, you must have an appropriate quantity of tissue (21). Remember that we are not only looking for a morphological diagnosis, but rather a morpho-molecular characterization of our patients – and the quality and quantity of samples can hinder this approach (6, 21, 32). Another challenge is access to effective technology (5). As I mentioned before, if we use a real-time PCR test, we may have problems finding the entire spectrum of biomarkers that we need to test for (23). 

The third barrier is reimbursement; not every country has the same reimbursement for these types of tests. And that can quickly create a bottleneck for treatment (5). 

The fourth barrier is the skillset of the professional (5). This is a complex treatment approach, so you need to have skilled people who have undergone specialized training in data interpretation, data management, and working within a multidisciplinary context to understand how this will impact treatment decisions, all whilst ensuring standardization of the reporting (33, 34, 35). For me, this step is integral, as we pull together the expertise from a number of experts to ensure that patients are given the best treatment for them. Regular communication between members of the multidisciplinary team helps to prevent disconnect between the specialists, working to provide timely treatment recommendations (35). 

Unfortunately, there is a very human price to pay when eligible patients do not get the appropriate diagnostics and subsequently do not receive the appropriate treatment (36). Patients who find themselves in this situation may undergo treatment that has a lower chance of positive outcomes and overcoming disease (1). They may also have to undergo repeated rounds of treatment, which is not only inefficient for hospital care, with financial implications, but also a physically and mentally exhausting experience for the patient (1). And of course, in the worst case scenario, it can lead to suboptimal outcomes, where precision medicine could have been effective for those eligible patients (1). 

What role can pathologists play in ensuring precision medicine for all eligible patients?
 

Pathologists must play a really important role. After all, pathologists are involved in every stage – from sample collection to analysis (22, 37). They are involved in the extraction of nucleic acids from samples, tissues, and liquid biopsies (38). Next, they must analyze the extracted nucleic acids, define molecular characterization, interpret data, and – most importantly – discuss with the oncologist and the other clinicians on the best course of action (39).

An important point to consider is how the anatomic pathology department can be a place where morphological and molecular evaluation coexist. To reemphasize, it’s not a morphological diagnosis or a molecular characterisation – it is both (32). This new type of molecular pathologist is – and will continue to be – a key player. 

What key stages of the precision medicine journey involve pathologists?
 

Several key stages involve pathologists – basic research, first clinical phase trials, evaluation in larger trials, approval in clinical practice, biomarker evaluation from patients, and, finally, treatment decisions (40). It’s important to remember that the prescription of the treatment today is not only in the hands of the oncologist, but also supported by the pathologist after discussing the data (3, 41). 

Pathologists, in clinical practice, are also involved in a number of key stages in the precision medicine pathway, from biospecimen collection to treatment decision making (4, 41, 42). [Figure 1] outlines this in more detail, as well as highlighting the breadth of the multidisciplinary team involved (42). 

What obstacles currently prevent seamless precision medicine integration?
 

There are many barriers that we should – and can – begin to overcome. One of these is the standardization of guidelines – including reports – as this is not currently widespread (5, 43). If we are to adopt precision medicine at scale, we need stringent and widely accepted standards (5). In my view, without standardization, clinicians do not have a recommended pathway to treatment decision-making (5). But standardization doesn’t just end there; it also requires digital tools that can host an accredited platform where we can all access standardized guidelines and best practices, regardless of location in the world (44). This approach can even extend to what people refer to as “centers of excellence” – institutions that have outstanding records of care that can offer training and education to other labs (44, 45). 

Other barriers are also tied to geographical location – for example, availability of facilities or cost barriers (3). It is not uncommon to see delays or outright rejections in receiving test results across Europe because of the logistics required to facilitate them (3, 5). And that often means treatment decisions are made before results are received (3, 5). From experience, misdiagnosis can also occur when testing needs to be outsourced because of the added risk that accrues as more (unnecessary) links are added to the treatment pathway (3, 5). 

In my opinion, us molecular pathologists must change our perspective. We need to obtain the largest amount of data possible and we need to use all the tools at our disposal – not just one. For example, we need to consider a marriage between tissue biopsy and liquid biopsy. We don’t need to have a hard stance on whether liquid biopsy is better than tissue biopsy or vice versa; by using a combined approach, we are able to get more information from both. We have the ability to fully exploit the power of the data. In this sense, we need to be helped by other types of tools, not only technical tools, but also clinical ones, as well as mathematical modeling, digital imaging, integrative analysis, data collection, and administration. In my mind, this is the future. 

Our biggest goal must be to challenge standard ways of thinking and usher in this new, more effective approach.

Janssen Pharmaceutica NV has funded the development and publication of this article, including a consultancy fee for Professor Umberto Malapelle. The views expressed in the article are those of the authors and publisher, and do not necessarily reflect the views of Janssen Pharmaceutica NV. CP-402581. August 2023.