The clinical management of patients with advanced cancers is often associated with treatment failure or relapse. Dissecting the molecular mechanisms leading to relapse at the patient level has been difficult and has been the missing link in patient management.
A tantalizing new study published in the September 17 issue ofScience Translational Medicine provides that link and, with it, glimpses into the future of oncology practice. It defines an approach to identify mechanisms that are associated with tumor cells evading drug treatment for men with castration-resistantprostate cancer that is resistance to abiraterone, all with a blood test.
In a press release, study leader Gerhardt Attard, MD, MRCP, PhD, Cancer Research UK Clinician Scientist at the Institute of Cancer Research, London, United Kingdom, said, "Our study showed that a steroid treatment given to patients with advanced prostate cancer and often initially effective started to activate harmful mutations and coincided with the cancer starting to grow again."
Researchers from the Institute of Cancer Research, the Royal Marsden National Health Service Foundation Trust, and the University of Trento in Italy collaborated on the study.
The researchers "deep sequenced" DNA extracted from biopsies and blood samples of 16 men with prostrate cancer, collected multiple times over the course of 12 months. DNA sequencing was targeted for common genetic aberrations in advanced prostate cancer to monitor emergence of cancer cell clones, linking them to treatment failure.
Significance of the Study
"One of the strengths of this study was the ability to serially monitor tumor dynamics by studying circulating tumor DNA in the bloodstream of patients," Emmanuel S. Antonarakis, MD, assistant professor of oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, toldMedscape Medical News.
This means that genetic analyses can be performed on tumor DNA without requiring invasive tumor biopsies, or even the need to capture circulating tumor cells. In addition, the beauty of studying circulating DNA is that this represents the full complement of tumor clones existing in a patient's body simultaneously," he added.
Trever Bivona, MD, PhD, from the Division of Hematology/Oncology and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, indicated to Medscape Medical News that the study "demonstrated the complexity and dynamic nature of the composition of prostate cancers in patients."
Although his emphasis is lung cancer, Dr. Bivona understands this complexity well, as he is very involved in investigating the presence and function of molecular alterations and evolution in human cancer.
Applicability to Clinical Practice
A press release from the Institute of Cancer Research indicated that "[the researchers] set out a new 'treatment paradigm' — the constant monitoring of patients using a blood test for signs that therapy is becoming counterproductive."
Dr. Bivona told Medscape Medical News, "The study makes the point, as have other studies, that real-time monitoring of the evolution of the biology of an individual patient's cancer is critical to guide clinical management."
Does that mean real-time monitoring is close to a cancer center near you? Not exactly. It would be difficult to do such genomics in a clinical time frame today, but there is continued progress toward that goal, Dr. Bivona said.
At this time, the techniques defined in the study for monitoring patients' response through genetic or genomic testing are available at research centers. In addition, the study was done in a small cohort of patients and requires confirmation from larger clinical studies.
"To take the study to the next level, a follow-up prospective study in a much larger set of patients is needed. This would help to further establish the changes in the clonal composition of the cancers over time and to link the specific changes to disease response and relapse on therapy in patients," Dr. Bivona toldMedscape Medical News.
Some Questions Raised
Tumors are multiclonal in nature, and a given therapy that works well initially typically stops working after killing susceptible clones, leaving nonsusceptible clones to thrive.
The study aimed to show that treatment failure was associated with specific genetic lesions in circulating clones of cancer cells in the blood of patients with metastatic prostate cancer. However, it also raised several questions.
"The most interesting feature of the study for me (and also potentially the most worrisome) was that tumor clonality was not conserved after development of metastatic disease, and in many cases, patients demonstrated continuously changing patterns and relative frequencies of genetic alterations in serial plasma samples," Dr. Antonarakis told Medscape Medical News.
Furthermore, some of these genetic changes (eg, point mutations in the ligand-binding domain of androgen receptor) became more or less abundant, depending on the particular therapy that a patient was receiving at that time, he added.
Dr. Antonarakis called out information from a patient in whom the AR-W742C mutation (a bicalutamide-activated mutation) was found in circulating tumor DNA during the course of therapy with bicalutamide but seemingly disappeared later, after bicalutamide had been stopped.
However, the study highlighted the exact mutations that were acquired/resided in cancer cell clones that remained unsusceptible to treatment. The mutations differ and may be unique to the treatment each patient received.
Does treatment become a disease driver? Or is it simply that clones that do not respond to therapy thrive? Can the study really identify that treatment has driven the emergence of the mutation or mutations? Or is it that clones that were originally in the minority now thrive because the susceptible clones have been destroyed? These questions remain to be answered.
Nonetheless, this approach, which is also being used to define therapeutic targets in other cancers, is helpful to provide pointers as to what treatment patients should next receive.
"In the future, we hope to routinely monitor genetic mutations in patients with advanced disease using just a blood test, enabling us to stop treatment when they become disease drivers and select the next best treatment option," Dr. Attard said.
Defining resistance to early in treatment failure is important in the clinical management of patients. "Drug resistance is the single biggest challenge we face in cancer research and treatment, and we are just beginning to understand how its development is driven by evolutionary pressures on tumours," Paul Workman, MD, interim chief executive at the Institute of Cancer Research, said in a news release.
This important discovery reveals how some cancer treatments can actually favor the survival of the nastiest cancer cells and sets out the rationale for repeated monitoring of patients, using blood tests to track and intervene in the evolution of their cancers, he added.
The study was funded by Prostate Cancer UK, Cancer Research UK, the National Cancer Institute, the Department of Defense, and the Prostate Cancer Foundation. The Institute of Cancer Research developed abiraterone and indicated it has a commercial interest in this agent. Multiple authors have identified ties with industry.
Sci Transl Med. 2014;6:254ra125. Abstract
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