Entrectinib and larotrectinib have been approved to treat tumors with fusions in the neurotrophic tropomyosin receptor kinase (NTRK) gene – irrespective of the tumor’s site of origin.

These drugs are the second and third agents, overall, to have a tissue-agnostic indication approved by the FDA.

The first was pembrolizumab, an immunotherapy agent, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017.

Have we finally reached the point where tumor biology has become a more important consideration than site of origin?

Microsatellite instability testing in #colon #cancer has evolved considerably over the past several years. It began as a way to screen for Lynch #Syndrome, a heritable condition, which accounts for about 5% of colon cancers.

MSI subsequently has been shown to be a prognostic factor in colon cancer.

And in its most recent incarnation as a biomarker, it has been shown to be predictive for response to immunotherapy. Pembrolizumab has been approved for patients with microsatellite instability-high tumors.

Interestingly, or perhaps counter-intuitively, patients with microsatellite unstable tumors actually have a better prognosis. Why is this?

Diagnostic Testing can be thought of as occurring in three phases:

1. Pre-analytic phase - everything leading up to the actual testing, including properly filling out a requisition, blood draw, specimen handling, gross examination and tissue fixation

2. Analytic phase - the actual testing itself, which is “flashy” and most people understand

3. Post-analytic phase - results interpretation, report generation, communication with the ordering physician and planning for future testing

If the pre-analytic phase is suboptimal, everything that follows may be unreliable or uninformative.

Colloquially, this is known as “Garbage in, garbage out.”

It is not often we have a major paradigm shift in medicine.

Albert Broders, MD, was a pathologist at the Mayo Clinic. Early in his career, he described tumor grading, showing for the first time that features in cancer specimens observed under the microscope could predict outcomes.

This discovery was a massive paradigm shift, that quickly begat tumor staging and eventually the whole predictive biomarker field.

Rondell Graham, Head of GI and Liver Pathology at the Mayo Clinic, joins us this week on The Personalized Diagnostics Podcast, where we discuss predictive and prognostic markers in colon cancer, molecular diagnostics, digital pathology, the future of targeted therapies and much more.

We are introducing a new feature: "Hagenkord's Korner."

Jill Hagenkord, MD, FCAP is co-founder and CMO of MDisrupt, as well as previously serving as CMO at Invitae, Complete Genomics Inc., Color, and 23andMe.

This week we will be discussing how we have been hearing relatively little from experts such as physicians, epidemiologists, virologists and statisticians during the current pandemic.

We will also be discussing the pitfalls of testing and test development for SARS-CoV-2.

2020 marks the one hundredth anniversary of the publication of Albert Broder’s landmark paper on tumor grading.

The foundation of what is now called personalized medicine is the idea that not all tumors or all patients are the same. Differences in gene expression and phenotype correlate with outcome and inform how a patient is best treated.

Dr. Rondell Graham is head of gastrointestinal and liver pathology at the Mayo Clinic. He joins us to discuss predictive and prognostic markers in colon cancer - where we've been, the implications of new technologies such as artificial intelligence, as well as the future of targeted therapies.

Pharmacogenetics is the study of how people respond differently to drug therapy based on their unique genetic makeup. Genetic variations cause differences in the expression of various enzymes involved in drug metabolism.

Health #economic studies have shown that the use of pharmacogenetic testing in clinical practice results in better outcomes - by a variety of metrics.

Are payors interested in these data? Of course they are. Better outcomes generally save money as well.

Pharmacogenetics allows us to identify differences in how people respond to drugs based on their unique genetic makeup.

Genetic variations can affect the function of enzymes involved in drug metabolism, leading to both adverse drug events and toxicity as well as treatment failure.

Routine pharmacogenetic testing has been shown to improve outcomes and save costs but yet it is still underutilized.

Pharmacogenetics allows us to identify differences in how people respond to drugs based on their unique genetic makeup.

Genetic variations can affect the function of enzymes involved in drug metabolism, leading to both adverse drug events and toxicity as well as treatment failure.

Routine pharmacogenetic testing has been shown to improve outcomes and save costs but yet it is still underutilized.

How has pharmacogenetic testing evolved over the past 20 years?

We've moved from a very expensive single-gene testing model focused on drug - gene pairs to a more cost-effective multigene panel approach, which can provide significantly more information.

Kristine Ashcraft, CEO of YouScript, which offers a unique combination of pharmacogenetic information and EMR-integrated software, joins us this week on The Personalized Diagnostics Podcast.