SAN FRANCISCO, CA USA (UroToday.com) - Dr. James Larkin presented data which had generated much discussion prior to the ASCO Cancers Symposium.
For decades, intratumoral heterogeneity has been demonstrated, but its significance has not really been investigated. His group set out to investigate whether driver mutation x at time point y actually predicted patient outcome or drug sensitivity. They performed exome sequencing to identify ubiquitous, shared primary, shared metastatic and “private” mutations from several regions within the primary tumor and from several resected metastatic sites. Curiously, they identified different mutations in SETD2, a recently described clear cell renal cell carcinoma, at different metastatic sites. Using a bioinformatics approach, they were able to show that the metastatic clones evolved in parallel, but separately, from the primary. These findings were extended to 10 patients now and will be available soon.
Much like Dr. Levi Garraway’s findings yesterday regarding the evolution of the prostate cancer genome, Dr Larkin’s findings have profound implications for therapy resistance. He went on to opine that evolving mutations as a result of selective pressure will not be overcome by that combination therapy, but rather that combinations will just delay the emergence of resistant clones. Further, he suggested that immunotherapy might be a better approach because it does not result in a fixed selective pressure like targeted therapy does, but rather the immune system can also evolve to match intratumoral heterogeneity.
Highlights of a presentation by James Larkin, MD, PhD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
The Royal Marsden, London England