Beyond the Micrometer

For many oncology indications, there are innovative treatments and management pathways that offer patients better outcomes than could have been expected even five years ago. But to realize the full potential of these advances, clinicians need to be able to route patients to the management pathway most likely to benefit them. 

At present, the clinical and pathologic factor-based staging systems that clinicians use to direct patients to and away from treatment pathways are limited in their prognostic accuracy. Precision medicine tools, such as next-generation sequencing or gene expression profiling (GEP), can provide invaluable, independent information about a patient’s tumor. Indeed, this molecular information complements clinicopathologic information obtained during staging to improve diagnostic accuracy, prognostic risk assessment and, in some instances, therapy response prediction.

For example, in melanoma a pathologist will assess histopathological characteristics – such as the depth of a tumor (Breslow depth measured with an ocular micrometer) and whether the lesion is ulcerated – to establish primary tumor stage. This is then used to route patients to a risk-appropriate management pathway. However, we now know that there are differences in gene expression between aggressive melanomas and melanomas that are unlikely to recur or metastasize, even if they have the same histological features. Here, optimized GEP testing results can be used to differentiate between higher- and lower-risk tumors – indistinguishable using gene sequencing panels or the clinical and pathologic factors used in staging.

However, there has been inconsistent evaluation and adoption of GEP testing across oncology. Disparities exist in how guidelines discuss advanced molecular testing across cancer types. In my opinion, careful evidentiary review, consideration, and discussion of GEP testing in cutaneous oncology is needed. 

Through my work as a dermatologist and a dermatopathologist, I have come to appreciate some key areas in which GEP testing is underutilized by some clinicians in cutaneous oncology. By clarifying these areas and reviewing the recent literature, I hope to encourage those who have not considered GEP to reassess its benefits for our patients.

How can GEP tests benefit patients?
 

In recent years, GEP tests have been used to improve diagnosis, risk assessment, or therapy response prediction, depending on the cancer and context. Of these, GEP testing for treatment prediction in breast cancer is the most well known, and it is often used as the only point of comparison for other GEP tests. However, it’s important to appreciate that the clinical application of therapy response prediction is different from the comparatively broad range of clinical applications for prognostic GEP tests.

GEP tests whose results directly inform therapy response prediction provide a single action point for clinicians – which systemic therapy to prescribe. Prognostic GEP tests, however, can inform a wide range of risk-aligned management decisions for clinicians who treat both early and more advanced stage cancers. These include frequency of clinical follow-up, sentinel lymph node biopsy decisions, surveillance imaging, and adjuvant radiation therapy. 

Both treatment prediction and prognostic risk assessment are critical to improving the lives of patients. For example, a study of more than 4,000 melanoma patients in 2023 demonstrated that patients who received prognostic GEP testing had better survival outcomes than similar patients who did not (1). The survival–benefit association observed by this large study is best understood when contextualized by additional studies focused on specific risk-aligned management decisions. 

One such study measured the clinical outcome of patients who were sentinel node negative and either did or did not receive GEP-guided surveillance imaging (2). Critically, this study found that patients with high-risk GEP results were directed by their treating clinician to receive imaging as part of their disease surveillance. As a result, melanoma recurrences were detected earlier, when their tumors were smaller, which led to improved survival compared to the no-GEP group. This study, performed independently from GEP test manufacturers, provides a clear example in which integrating the information from prognostic GEP testing improved patient risk stratification. It led to more closely risk aligned surveillance approaches that subsequently improved patient outcomes.

Of course, looking at survival outcomes alone does not account for the benefits observed from routing low-risk patients away from inappropriately intensive treatments or procedures – such as sentinel lymph node biopsy (SLNB). A 2023 multicenter, prospective study demonstrated how clinicians use GEP testing in the selection of patients for SLNB (3). Eighty-five percent of the decisions relating to SLNB were influenced by GEP results. And in patients identified as low risk for metastasis by GEP, SLNBs were reduced by 29 percent. Reduction of invasive surgical procedures for patients at low biological risk of metastasis is an important improvement in healthcare outcomes – and demonstrates the need to look beyond the improvement of survival.

It is time to leverage the power of precision
 

As a dermatologist and dermatopathologist, I recognize the limitations of risk stratification based on clinical and pathologic features alone. I also have confidence that the risk-aligned management decisions that doctors are making for their patients matter. So, when there is an opportunity to improve the accuracy of risk assessment at pivotal points in a patient’s care journey, it should be seriously considered. Precision medicine tests, such as GEP, can provide that opportunity when they layer additional, independent information on top of what is already known about a patient’s cancer. 

Ultimately, those who have not considered using GEP should question whether they are waiting for the future promise of precision medicine at the expense of its well-established current value. For indications such as breast cancer, uveal melanoma, prostate cancer, SCC, and melanoma, the tests are well validated with demonstrated clinical utility. GEP testing is no longer a future prospect – it is already here.