Kidney Cancer Journal – 2018 – Number 3
GUEST EDITOR’S MEMO
Predictive Biomarkers in Kidney Cancer- The Last Crusade or the Temple of Doom?
My mission as Guest Editor for this issue of the Kidney Cancer Journal has a twofold purpose. The first is to alert readers to the upcoming 17th International Kidney Cancer Symposium (IKCS) in Miami, November 2-3- a fantastic scientific program highlighting some of the outstanding progress in conquering kidney cancer this year and the exciting work expected in 2019. In my welcoming remarks at this year’s scientific sessions, sponsored by the Kidney Cancer Association, I will highlight an exciting agenda with arguably the broadest spectrum of topics related to renal cell carcinoma at any oncology symposium this year. The second message in this Guest Editor’s Memo is to mention how one of our topics covered in this issue touches upon a segment of the program at the IKCS—biomarkers.
Biomarkers continue to evolve in RCC; from protein markers to genomic alterations and even recently, the stool microbiome. One of the planned sessions at the IKCS meeting involves where we stand for prognostic and predictive biomarkers including a discussion of the past, the present, and the future. As the headline above suggests, the search for a reliable and predictive biomarker has been exhaustive over the last decade and feels more like a plot line to an Indiana Jones movie. How many meetings have you attended where abstracts have proposed new exciting biomarkers yet validation studies became trapped and failed to meet their promise or the investigators strayed from their path and didn’t pursue clinical utility studies? Nonetheless, there are positive signs that the “Quest for the Holy Grail” is beginning to move a bit closer to the goal of identifying biomarkers to select therapy in view of a whole host of clinical studies pursuing testable hypotheses.
The ultimate goal of a candidate biomarker is demonstration of validity as an integral or integrated biomarker in the clinical trial setting. Several biomarker driven trials are currently open in phase III trials evaluating non-clear cell RCC using alterations in the MET pathway as either integral or integrated biomarkers. SAVOIR explores the role of potent MET inhibitor savolitinib vs sunitib in papillary RCC. In this trial, MET alterations (mutation or MET/HGF amplication) serve as an integral biomarker dictating trial eligibility. PAPMET (SWOG S1500) is looking at various MET inhibitors in all papillary RCC. In this trial, MET alterations and papillary subtype (1, 2, or unclassified) by central path review are used as integrated biomarkers with the hypothesis these influence progression-free survival and response. These protocols build upon prior work from the CREATE trial with crizotinib and a phase II trial of savolitinib (NCT02127710). These larger phase III studies will be useful to determine if this biomarker has clinical utility or is a forged relic.
Tumor sequencing is now readily available in house at some institutions or by engaging commercial companies. However, how tumor profiling influences decision making and outcome in RCC is unclear. The issues of heterogeneity and tumor evolution also remain a trap on our journey to treatment, as often analyzed specimens come from a small component from the archival nephrectomy specimen. To overcome these barriers, understanding the disease at time of treatment decisions may be critical to determine if new mutations have developed and been selected for.
In a hypothesis-generating report Pal, et. al. looked at circulating tumor DNA (ctDNA) from a nationwide cohort of 220 consecutive patients with mRCC. Results suggest that the acquisition of additional genomic alterations can be a mechanism of resistance to therapy that hopefully could be targeted in the future. The noninvasive nature of ctDNA testing makes it an attractive method of obtaining real time genomic data as compared to serial biopsies of metastatic sites progressing through therapy. It also provides insight into acquisition of additional driver alterations during the course of tyrosine kinase therapy, which if confirmed may suggest a role for therapy prior to checkpoint inhibitors to increase immunogenicity and perhaps improve response to therapy. As increased genomic alterations can be a surrogate for mutational burden, shown to be correlated with increased neoantigen formation and improved response to immunotherapies, these insights may suggest a role for TKI prior to immune checkpoint inhibitors. The article in this issue by Drs. McGregor, Choueiri, and Flippot briefly covers this topic and reports and explores how this emerging biomarker may be an exciting avenue for further biomarker work.
I hope I have provided you a taste of some of the exciting topics to be covered in depth at the IKCS in November. Attendees at the symposium will come away with not only new insights on this subject but on many other findings with translational impact. These include point-counterpoint discussions and Q&A sessions on highly controversial areas, from the bench to the bedside. There is still time to register and make plans to attend the most comprehensive kidney cancer meeting of the year. You can find details by going to the Kidney Cancer Association website: https://www.kidneycancer.org/event/17th-international-kidney-cancer-symposium. See you in Miami!
Brian M. Shuch, MD