CIO Spotlight: Dr Tam on the Role of Biopsy in 2017
Dr Alda Tam presented the session Understanding the Role of Biopsy at the 2017 Clinical Interventional Oncology Symposium. In this article, Dr Tam provides the reader with a full deciphering of her presentation. Here she explains the role of biopsy in the drug development timeline, the challenges faced by the medical community, and how these challenges can be overcome.
In the opening slides of her presentation Dr Tam, as professor and clinical medical director at the M.D. Anderson Cancer Center in Houston, joins efforts to “make cancer history”, and calls on Bob Dylan in her opening slides to state that “the times, they are a-changing”.
As collaborator for tissue acquisition for several Moon Shot initiatives, she then echoes the White House’s #AmericaLeads presentation from 2015 that states that “where drugs used to be designed with the average patient in mind, now they can be tailored to patients’ specific genetics, microbes and genetic compositions”.
I – Role of biopsy in the drug development timeline
Current research aims to deliver personalized therapy based on genomic characteristics. From a drug development perspective, any potential agent has to end in a biomarker driven clinical trial before approval. This drug development pipeline relies on image-guided biopsies to determine which patients have the necessary genetic alterations, to look at tumor response, and to study pharmacodynamic relationships. Dancey and colleagues in 2010 demonstrate the various roles that a biopsy can play in clinical trial design and the roles are stratified by order of importance. An integral biopsy will be used to make trial decisions, such as randomization into a treatment arm, and occurs in real time. An integrated biopsy looks at biomarkers for predictive potential or effects of dosing and an exploratory biopsy is used for hypothesis generating analyses. Dr. Tam goes on to give two clinical examples of why mutations matter. The Amado et al. study in 2008 demonstrated that only metastatic colorectal (mCRC) patients who were KRAS wild type (WT) derived benefit from panitumamab monotherapy thereby indicating a role for pre-treatment biopsies to predict response. The second example argues for using image-guided biopsies to determine mechanisms of drug resistance in a BRAF positive melanoma patient with an initial remarkable response to therapy who recurred due to an acquired MEK1 mutation (Wagle et al. 2011).
At this point in the presentation, Dr Tam has shown her audience that biomarkers are relevant, both in drug development and in the clinical practice setting. However, there are challenges in conducting the biopsies in both these settings which she goes on to explore.
II – Technical and biological challenges met with solutions, described
There are three broad challenges when image-guided biopsies are used to drive clinical trials. The first is a problem with heterogeneity. The landmark paper in the NEJM nicely illustrated the complex issue of intra-tumoral heterogeneity: different mutations exist in different parts of the tumor and in different metastatic sites. Sampling strategies beyond just taking more samples or taking samples at random from different places in the tumor will be needed to overcome this issue.
The second challenge is more global and relates to researchers having to prioritize how to use these small biopsy samples. At this point in time precision medicine may mean very different things to different researchers and decisions on the molecular analyses that will be the most important for that particular clinical trial should be determined to allow for planning of how much tissue should be acquired and how the tissue will be distributed to fulfill the molecular testing requirements in order of priority.
The third challenge is related to obtaining adequate tissue which is a problem we have to actively address. The Freeman et al. study (2012) looking at trials that obtained biopsies for pharmacodynamics analyses found that in 53% of the resulting publications, either no pharmacodynamics data or incomplete pharmacodynamic data was reported. A survey sent out to the senior authors determined that inadequate tissue hindered reporting in a significant percentage of studies. More recently, similar feedback was received from the NIH precision medicine MATCH trial on suboptimal biopsy quality and argues for greater involvement of interventional radiologists in clinical trials. The M.D. Anderson Cancer Center BATTLE trial experience highlights the benefits of using a multi-disciplinary operational approach, dedicating 2 IR’s to supporting the trial through lesion selection and risk assessment for each patient. They were also responsible for consistently communicating with the oncology and pathology teams. The BATTLE trial was a metastatic NSCLC clinical trial conducted at MD Anderson where for the first time the results from real-time biopsies were used to randomize patients to treatment. The biopsies had to be adequate for running 12 different test ranging from gene mutations to protein analyses. It showed we were successful 83% of time which set a bench mark.
The take-home message is that as we embark on this biopsy driven biomarker era of research, providing tissue that is sufficient only for a histologic diagnosis is no longer satisfactory and interventional radiologists must embrace a critical, clinical role for these patients as they are the most qualified to select the best lesion for biopsy and to determine the potential risk for related procedural complications. Overcoming intra-tumor tissue heterogeneity and evolution with more aggressive sampling from multiple sites and time-points, coupled with appropriate integrative analysis within a framework of free exchange of information between disciplines will allow the best setting for an optimal use of tissue biopsy in 2017.
Dr Alda Tam is dedicated to determining strategies for optimizing image-guided biopsy in the age of genomic medicine. She seeks to establish the standard for these image-guided procedures and many of her publications regard the safety and optimal use of tissue biopsy in clinical trials. She discloses research grants from AngioDynamics and Medical Monitor—Galil and reports no off-label/unapproved use or uses of drugs and/or devices.