ASCO GU 2017: Blood Test Uncovers Potential New Treatment Targets in Advanced Prostate Cancer
Cell-free ctDNA provides comprehensive information about all the different genetic changes in the tumor. Today, treatments can sometimes be tailored to the genetic changes in a tumor, but these changes evolve over time. The cell-free ctDNA tests can be used to track new genetic changes, and this information can be used to stop treatment to which resistance is emerging and to switch the patient to another treatment.
In the study, researchers found genetic changes linked to poor outcomes, as well as changes that appear to arise as tumors become resistant to therapy. The changes in ctDNA found by the blood tests were similar to those previously reported in analyses of tumor tissue specimens, suggesting that ctDNA testing may be a viable alternative to tissue biopsy.
“This circulating tumor DNA test is now a valuable research tool to discover new molecular targets,” said lead study author Guru Sonpavde, MD, an associate professor of medicine at the University of Alabama in Birmingham, AL. “Eventually, it may also serve as a non-invasive alternative to the traditional tumor biopsy in cases where tissue biopsy is not safe or feasible. However, we’ll need a controlled, prospective clinical trial to confirm that selecting treatment based on the molecular information from this blood test improves patient outcomes.”
The Study
The researchers analyzed cell-free ctDNA from blood samples of 514 patients with metastatic castration-resistant prostate cancer. The blood test (Guardant360), which requires only two teaspoons of patient blood, examined changes in 70 cancer-related genes. The association between DNA changes and clinical outcomes was explored in 163 patients. In addition, the researchers explored how genomic changes evolved over time in 64 patients who underwent serial (periodic) blood tests.
Key Findings
Nearly all (94%) patients had at least one change detected in the ctDNA. A higher overall number of genetic changes, including changes in the androgen receptor (AR) gene, were associated with poorer treatment outcomes, such as a tendency towards shorter survival (although the difference in survival was not statistically significant).
The genes that were most often mutated included TP53 (36%); AR (22%); APC (10%); NF1 (9%); EGFR, CTNNB1 and ARID1A (6% each); and BRCA1, BRCA2, and PIK3CA (5% each). The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%) [increased cancer gene copy number can lead to overabundance of proteins that drive cancer growth]. Currently, there are no approved treatments for prostate cancer that target these specific genetic mutations, although several are being tested in clinical trials.
In the group of patients who underwent periodic blood tests, new changes in AR gene were particularly common. According to the researchers, this finding suggests that developing treatments that target AR mutations may hold promise.
About Prostate Cancer:
Prostate cancer is the most common type of cancer among U.S. men. An estimated 161,360 men will be diagnosed with prostate cancer in 2017 in the United States.1 Prostate cancer is also the third leading cause of death due to cancer, projected to take close to 27,000 lives this year.
This study was unfunded; de-identified data were provided by Guardant Health.
1 http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-048738.pdf
2017 Genitourinary Cancers Symposium: Presentation Information
Poster Session A
Thursday, February 16, 2017: 11:30 AM – 1:00 PM EST
Thursday, February 16, 2017: 5:15 PM – 6:15 PM EST
Rosen, Gatlin Ballroom B, Level 1
Guru Sonpavde, MD
University of Alabama at Birmingham
Comprehensive Cancer Center
Birmingham, Alabama
Abstract 149: Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy.
Authors: Guru Sonpavde, Rebecca J Nagy, A. Oliver Sartor, Gregory Russell Pond, Theodore Stewart Gourdin, Lakshminarayanan Nandagopal, Elisa M. Ledet, Neeraj Agarwal, Emma Carroll, Gurudatta Naik, Jue Wang, Mehmet Asim Bilen, Petros Grivas, Richard B. Lanman, AmirAli Talasaz, Michael B. Lilly; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Guardant Health, Inc., Redwood City, CA; Tulane University, New Orleans, LA; Ontario Clinical Oncology Group, Hamilton, ON; Hollings Cancer Center/Medical University of South Carolina, Charleston, SC; University of Alabama at Birmingham, Troy, MI; Tulane Cancer Center, New Orleans, LA; Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; University of Alabama at Birmingham, Birmingham, AL; University of Arizona Cancer Center at DH-SJHMC, Phoenix, AZ; Winship Cancer Institute at Emory University, Atlanta, GA; Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Medical University of South Carolina, Charleston, SC.
Background: Cell-free ctDNA may be prognostic and evolve following therapy. We report ctDNA profiling of patients (pts) with mCRPC and their association with clinical outcomes and evolution with therapy. Methods: Pts with mCRPC that underwent baseline ctDNA analysis for potentially actionable alterations using Guardant360 before new systemic therapy were identified. Data were requested for clinical factors, current and prior therapy, TTF (time to failure) and survival. A 70-gene cfDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of alterations with outcomes and prior therapy was examined. Results: Of 514 with confirmed mCRPC, 482 (94%) had ≥ 1 ctDNA alteration. The median age was 70 years (range 39-91). The most common recurrent somatic mutations were in TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR, CTNNB1 and ARID1A (6% each) and BRCA1, BRCA2 and PIK3CA (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%) and BRAF (18%). Clinical outcomes were available for 163 pts, of whom 46 (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations was associated with shorter TTF (HR: 1.05, p = 0.026). AR alterations had a trend for shorter TTF (HR: 1.42, p = 0.053) and survival (HR: 2.51, p = 0.09). Pts who received prior therapy had new alterations in AR (56% vs. 37%, p = 0.028) compared to untreated pts. Serial ctDNA profiling of 64 pts revealed the evolution of alterations in AR, BRCA1 and BRCA2 following therapy. Conclusions: ctDNA was frequently detected in patients with mCRPC, and alterations appear 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. These data suggest that developing salvage agents targeting AR alterations and PARP inhibitors hold promise.
About the American Society for Radiation Oncology:
The American Society for Radiation Oncology (ASTRO) is the premier radiation oncology society in the world, with more than 10,000 members who are physicians, nurses, biologist, physicists, radiation therapists, dosimetrists and other health care professionals that specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, the Society is dedicated to improving patient care through professional education and training, support for clinical practice and health policy standards, advancement of science and research, and advocacy. ASTRO publishes three medical journals, International Journal of Radiation Oncology, Biology, Physics, Practical Radiation Oncology, and Advances in Radiation Oncology, developed and maintains an extensive patient website; and created the Radiation Oncology Institute, a non-profit foundation to support research and education efforts around the world that enhance and confirm the critical role of radiation therapy in improving cancer treatment. Learn more about ASTRO.
About the American Society of Clinical Oncology:
Founded in 1964, the American Society of Clinical Oncology, Inc. (ASCO®) is committed to making a world of difference in cancer care. As the world’s leading organization of its kind, ASCO represents more than 40,000 oncology professionals who care for people living with cancer. Through research, education, and promotion of the highest-quality patient care, ASCO works to conquer cancer and create a world where cancer is prevented or cured, and every survivor is healthy. ASCO is supported by its affiliate organization, the Conquer Cancer Foundation. Learn more at www.ASCO.org, explore patient education resources at www.Cancer.Net, and follow us on Facebook, Twitter, LinkedIn, and YouTube.
About the Society of Urologic Oncology:
The Society of Urologic Oncology (SUO) was created in 1984 to enable qualified members primarily interested in the care of patients with malignant genitourinary diseases to meet for the purpose of discussion, development, and implementation of ideas to improve care. The Society and its bylaws conform to the guidelines and bylaws of the American Urological Association (AUA). The purpose of the SUO is to develop educational and research initiatives and to study issues in urologic oncology and provide physician statements that represent a state of the art assessment of these issues to other organizations. The Society also provides a forum for identifying the urologic oncologist as a physician with specific expertise in the study and treatment of genitourinary malignancies. In recognition of the multidisciplinary efforts involved in the study and treatment of genitourinary malignancies, the Society seeks to incorporate multiple disciplines in achieving these goals. The Society supports the activities of multiple disciplines in the common objectives of seeking an increased understanding and successful treatment of genitourinary malignancies. The SUO seeks to improve the care of patients with malignant urologic disease and to provide a forum for the discussion of problems relating to malignant urologic disease. Our objectives include: 1) Stimulating research in and the teaching of urologic oncology, 2) Disseminating the principles of urologic oncology to the medical profession at large, 3) Bringing urologists into a Society whose work is entirely, or principally with malignant disease, 4) Being identified as the most qualified organization on matters relating to urologic oncology, and 5) Standardize fellowship training in urologic oncology.
2017 GU Cancers Symposium News Planning Team Sumanta K. Pal, MD, American Society of Clinical Oncology (ASCO); Daniel A. Hamstra, MD, PhD, American Society for Radiation Oncology (ASTRO); and Marc Dall’Era, MD, Society of Surgical Oncology (SSO)