1. Perron, Michelle

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ORLANDO, Fla.-Circulating tumor DNA (ctDNA) is showing promise as a reliable marker for cancer that may allow oncologists to use less-invasive techniques to detect new cancers and make targeted treatment decisions about already diagnosed cancers. Whole genome sequencing in humans has identified the relationship among somatic mutations in oncogenes, tumor suppression genes, and cancer development. This knowledge was applied in a recent study of how ctDNA might identify potential new treatment targets in advanced prostate cancer (J Clin Oncol 2017:35(Suppl 6S; Abstract 149)).

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The research was performed by Guru Sonpavde, MD, and multiple coinvestigators. Sonpavde is Associate Professor of Medicine and Director of Urologic Malignancies at the University of Alabama at Birmingham School of Medicine. Sonpavde presented the findings in a presscast and a poster session at the 2017 Genitourinary Cancers Symposium, cosponsored by ASCO, the American Society for Radiation Oncology, and the Society of Urologic Oncology.



Cell-free ctDNA provides comprehensive information about genetic changes in tumors. Armed with this knowledge, oncologists can often tailor treatment according to these genetic alterations. Cell-free ctDNA tests can track new genetic changes and thus signal oncologists to stop treatments that are no longer effective due to resistance. Then, they can initiate a more tailored intervention, if available.


The ability to extract this information via blood sampling has many advantages. Molecular profiling of tumor DNA has traditionally been performed on samples obtained from a tumor biopsy or a surgical resection sample. The extraction of ctDNA from blood samples is associated with significantly less pain and is less invasive than a standard tissue biopsy procedure. Given these advantages, ctDNA may have an increasing utility in the clinical setting.



In this study, Sonpavde, et al, analyzed cell-free ctDNA from blood samples of 514 patients who had confirmed metastatic castration-resistant prostate cancer. They used a commercially available blood test that required only 2 teaspoons of blood and examined changes in 70 cancer-related genes.


The team found associations between DNA changes and clinical outcomes in 163 patients and explored them. In this group of 163 patients, 46 (28.8%) had not been treated for their metastatic castration-resistant prostate cancer prior to the study. Patients who had received prior therapy experienced new alterations in AR compared to untreated patients.


In a subset of patients, the researchers also sought to monitor tumor changes. In 64 patients, the research team used serial blood tests to examine genomic changes that evolved over time.



The team found that 94 percent of patients (482) experienced at least one change that was detected in the ctDNA. The median age of these patients was 70 years. The researchers identified a higher overall number of genetic changes, including alterations in the androgen receptor gene, that were associated with poorer treatment outcomes. This included a tendency toward shorter survival; however, the difference in survival was not statistically significant.


The most-often mutated genes were TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR (6%), CTNNB1 (6%), ARID1A (6%), BRCA1 (5%), BRCA2 (5%), and PIK3CA (5%). The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). This is noteworthy because an increased cancer gene copy number can produce an overabundance of proteins that drive cancer growth. At the time of the research and this article publication, no treatments that target these specific genetic mutations have been cleared by the FDA, but several are in clinical trials.


In the group of patients who underwent serial blood testing, new changes in the AR gene were especially common. The researchers identified the evolution of alterations in AR, BRCA1, and BRCA2 following therapy. They believe this finding suggests developing treatments that target AR mutations has great value and potential.


In summary, ctDNA was frequently detected in patients with metastatic castration-resistant prostate cancer, and alterations appeared similar to tumor tissue alterations. "A higher number of overall gene alterations and AR alterations appeared associated with poor clinical outcomes, and new AR and BRCA alterations appeared following therapy," the authors wrote. "These data suggest that developing salvage agents targeting AR alterations and PARP inhibitors holds promise."


The moderator of the presscast emphasized the potential applications for patients who are not candidates for biopsy, as in bone cancers. "As we work to tailor treatment to the molecular changes driving the growth of cancer in each patient, these blood tests appear very promising, especially for patients who are unable to undergo a tumor biopsy," said Sumanta Pal, MD, moderator for the presscast and an ASCO expert.


In an editorial published in European Urology in conjunction with other research on ctDNA, Sonpavde advocated for incorporation of circulating cell tumor (CTC) enumeration into clinical care and as a correlative endpoint and stratification factor in future research (Eur Assoc Urol 2017;71:172-173). But he and coauthor, Emmanuel S. Antonarakis, MD, of Johns Hopkins, point out the role of CTC in routine clinical care remains unclear. They urge a more spirited and directed approach to research on this issue.


"Vigorous collaboration within the urologic oncology community is imperative to incorporate panels of serially measured and rationally selected noninvasive molecular markers in large randomized trials," Sonpavde and Antonarakis wrote. "...It is imperative that biomarkers are integrated into every pivotal trial in the future."


Michelle Perron is a contributing writer.