Personalizing Treatment With ctDNA in Prostate Cancer

Circulating tumor DNA (ctDNA) with at least one genetic alteration is present in up to 94 percent of patients with metastatic castration-resistant prostate cancer (mCRPC). This leads researchers to believe that ctDNA could be a noninvasive alternative to traditional tumor biopsies, which could lead to more personalized treatment plans.

The research, which was presented during a presscast held ahead of the 2017 Genitourinary Cancers Symposium, showed that a ctDNA assay identified potentially actionable molecular alterations in patients’ tumors. Further, higher overall numbers of genetic alterations, including changes in the androgen receptor (AR) gene, were associated with poorer treatment outcomes.

“ctDNA is frequently seen in patients with metastatic castration-resistant prostate cancer…so it looks rather promising for studying these tumors with ctDNA assays, which would be much easier than performing repeated bone biopsies from metastatic sites,” said lead study author Guru Sonpavde, M.D., an associate professor of medicine at the University of Alabama in Birmingham.

“The data with the AR alterations being associated with poor outcomes and the frequent evolution of AR alterations in patients who underwent ctDNA assays really suggests that it might be promising to keep looking at new drugs targeting this AR alteration…These data suggest that developing salvage therapy agents targeting AR alterations holds promise,” added Sonpavde.

Sonpavde et al assessed cell-free ctDNA from blood samples of 514 patients with mCRPC who received baseline ctDNA analysis for potentially actionable alterations using the Guardant360 assay, a 70-gene ctDNA next generation sequencing panel. According to Sonpavde et al’s abstract, the assay provides complete exon sequencing for 29 genes, critical exons in 39 genes and amplifications (16 genes), fusions (six genes) and indels (three genes) harvested from 10 mL of peripheral blood.

“[These results are] one of the largest clinically annotated data sets that we have describing features of circulating tumor DNA in patients with advanced prostate cancer,” ASCO expert Sumanta Pal, M.D., medical oncologist, assistant clinical professor, Department of Medical Oncology and Therapeutics Research, co-director, Kidney Cancer Program, City of Hope, said during the presscast.

Of the 514 patients, 94 percent (482) had at least one ctDNA alteration. The median age of these patients was 70 years (range, 39-91). The most frequently detected recurrent somatic mutations included TP53 (36 percent of patients), AR (22 percent), APC (10 percent), NF1 (9 percent), EGFR, CTNNB1, and ARID1A (6 percent each) and BRCA1, BRCA2 and PIK3CA (5 percent each). Additionally, the most common genes with increased copy numbers were AR (30 percent), MYC (20 percent) and BRAF (18 percent).

Clinical results were available for 163 patients, of whom 28.8 percent (46) were treatment-naive. There was an association between higher levels of ctDNA alterations and shorter time to failure. With AR alterations specifically, there were trends toward short TTF and survival. Further, the rates of new alterations in AR were higher in previously treated patients versus treatment-naive patients at 56 percent versus 37 percent, respectively.

“AR is the most common protein targeted by hormone therapies for prostate cancer. This suggests that developing new agents that target this protein more effectively is certainly a good direction for future research,” said Pal.

In his concluding remarks, Pal summarized the significance of Sonpavde et al’s findings.

“Circulating tumor DNA offers a simple and convenient way to assess an individual patient’s tumor DNA composition, and often, it can reveal new mutations that clinicians can use to personalize therapy. This is especially important in the setting of prostate cancer. The only other way we might be able to assess tumor DNA in real time is through a biopsy, which can be enormously challenging in prostate cancer, where most of the disease sits in bone. Bone biopsies can be expensive, painful, and also risky, with bleeding and other complications, and furthermore, the yield of tumor tissue from these biopsies can be quite low.”