The Tissue Is Still The Issue
For ASCO 2014, my colleague Dietmar Berger noted that we need new tumor tissue tests to continue to deliver a future of personalized medicine. He’s right, and there are other reasons why tumor tissue is incredibly important.
Over the past 15 years, more and more personalized cancer medicines—targeted agents with corresponding biomarker tests that predict efficacy—are being approved across cancer types. Alongside that, genomic profiling technologies are evolving, making large-scale genetic information on someone’s cancer more readily obtainable.
Taken together, this has led to the idea that we should start to reclassify cancers based on the mutations that drive their growth, rather than where they originated in the body. That is to say, we should start to think about cancers first as “HER2-positive” and “EGFR-positive” rather than as “breast” or “colon” cancer.
The potential implication is our targeted medicines that address a particular mutation could be used across tumor types. However, as it stands today, ignoring the tissue of origin and focusing only on a genomic view of cancer is likely not in the best interest of advancing cancer treatment.
“…today, ignoring the tissue of origin and focusing only on a genomic view of cancer is likely not in the best interest of advancing cancer treatment.”
Tissue Context: Just As Important As Biomarker Theory
We can’t rely on theory alone; we have to follow the data. And so far the data have been mixed. Take for example the BRAF mutation, which is found in about half of metastatic melanoma cases. The BRAF mutation is also found in about five to eight percent of colorectal cancers. Yet early clinical testing of approved BRAF inhibitors in colorectal cancer has been disappointing thus far. In fact, we now know that other signaling pathways can bypass the BRAF mutation.
What this means is that biomarkers need to be looked at in the context of the tissue where they are found. Even though one type of cancer may be “addicted” to a particular mutation, that doesn’t mean the same mutation has the same role in other cancers.
A biomarker-only approach, if widely instituted, runs the risk of neglecting proven disease management strategies. This includes local therapies and coordinated care from oncologists, surgeons and radiotherapists who may specialize in a certain organ system. A cancer’s tissue of origin is equally important to the biomarker that it harbors.
When it comes to drug development, “basket trials” that group participants by mutation status also may prove of limited use today. Since there’s likely to be considerable variability in efficacy across tumor types, it may be very difficult to generate the statistically powered data set required for regulatory approvals. Basket trials may instead be best suited to assess feasibility issues in specialized cases rather than a method for generating “approvable” data.
“A cancer’s tissue of origin is equally important to the biomarker that it harbors.”
A “Grassroots” Approach Is Needed
It’s undeniable that genomic profiling is a key part of our efforts against cancer. But we need a “grassroots” approach to continue advancing personalized cancer treatments. A critical first step is that it must become routine practice for pathologists’ reports to include genetic information about known cancer drivers and “actionable” mutations in tumor biopsies. Such genomic information can guide clinical decisions for people with highly advanced disease where treatment options are limited and the use of an experimental medicine is justified.
From those clinical experiences, we can start to generate correlations that guide pilot studies for additional uses of personalized medicines and for trials that can form the basis for regulatory approvals.
Broad-scale genomic sequencing of individual tumor samples is also important. This is how the recurrent BRAF mutation was originally identified in metastatic melanoma, and more recently in virtually all cases of a rare blood cancer called hairy cell leukemia. With the right infrastructure in place, “mining” emerging clinical experience can help us understand the complex interplay between a mutation and the tissues in which it arises.
We’ve learned a lot from our collective experience with personalized cancer medicines. One important lesson is that standards of care can change quickly in response to strong clinical information. Take for example the impact of HER2 amplification status in breast cancer or EGFR and ALK mutation status in lung cancer. We have also learned that there’s no singular approach that will necessarily be useful in every situation.
“With the right infrastructure in place, “mining” emerging clinical experience can help us understand the complex interplay between a mutation and the tissues in which it arises.”
As “personalized” or “precision” medicine becomes an increasingly important feature of our lexicon in healthcare, particularly oncology, it will be essential to resist the temptation to broadly reclassify cancer. Rather, the more pressing opportunity remains in discovering the unique approaches that deliver the best science and medicine.
Read more about these important findings in our Cell publication, "From Cancer Genomics to Precision Oncology—Tissue’s Still an Issue."