In some ways, the concept of a liquid biopsy extends back to some of the earliest modern systemic cancer treatments: childhood leukemias were among the first cancers to be treated, and leukemic cells circulate in the blood. Decades later, circulating protein markers such as carcinoembryonic antigen, CA 19-9, prostate-specific antigen, and others began to be used to assess cancer burden, followed more recently by circulating tumor cells (CTCs) and plasma tumor DNA (ptDNA). In the modern era of oncology, liquid biopsies are increasingly being studied and used to help understand cancer biology, guide treatment, and limit some of the risks associated with more traditional methods of diagnostics.
On June 3, an Education Session, “ASCO/American Association for Cancer Research (AACR) Joint Session: Liquid Biopsies” will examine the current state of research on various types of these tests, focusing on CTCs and ptDNA, and how they are used today and will be used in clinical practice in the future.*
Dr. Nancy Davidson, credit Robert Hood
The advantages to a liquid biopsy listed by Dr. Hayes do carry some caveats, but, in general, a blood test is simpler in comparison to a needle biopsy. There are risks inherent to needle biopsies, and the more involved procedure costs substantially more. And because many cancers carry substantial intratumor heterogeneity, a biopsy of only a single site can be misleading.
“The flip side of this is, do we actually know that what we see in blood reflects what’s going on in the tissue? That’s a big issue,” Dr. Hayes said.
Research is ongoing, but certain types of liquid biopsy are now known to reflect tumor biology and tumor burden to varying degrees. The use of CTCs can offer information on a number of malignancies including breast cancer, and ptDNA can help focus in on the genetics of a patient’s disease.
Although research has proliferated on liquid biopsy approaches, many questions remain about the clinical utility of the information these tests can gather. “We have many interesting tools available to us, but a fool with a tool is still a fool,” Dr. Davidson said. “Fortunately, critical work is going on to help us understand how best to these new tools.”
Dr. Klaus Pantel, credit Monika Lutz
Dr. Hayes agreed and provided an example. The Southwest Oncology Group S0500 trial tested whether CTCs could be used to help guide chemotherapy decisions in 595 patients with metastatic breast cancer.1 It found that, although levels of CTCs are prognostic for outcome, using those CTC levels and the presence or absence of CTC response to determine whether switching chemotherapy regimens improves outcome was not effective. The CTC assay could offer a prognosis but could not yet guide clinicians to help improve that prognosis. Ongoing research is now focused on what other therapies might be offered to such patients instead of chemotherapy, which appears to be largely ineffective.
Klaus Pantel, MD, PhD, of the University Medical Center Hamburg-Eppendorf, in Germany, will speak specifically about the latest research on CTCs during the session. He pointed out that, even if CTCs cannot yet determine specific therapy options, their prognostic value can still be very high. That same SWOG trial found that patients who did not have elevated CTCs at baseline had a median overall survival of 35 months, compared to only 13 months in patients who had elevated CTCs and saw no improvement after one cycle of therapy (p < 0.001).
“For CTCs, the largest databases exist for breast cancer and prostate cancer, demonstrating that sequential monitoring of CTC counts can predict after only a few weeks of systemic therapy whether a patient with metastatic disease responds or not,” he said. “Tumor cells from various primary or metastatic sites and their products are released into the blood, and the analysis of blood as a pool could be more representative than the analysis of a single lesion by needle biopsy.”
He added that CTCs can be analyzed for therapeutic targets or mechanisms of resistance at the DNA, RNA, and protein level, and that functional studies on viable cells are now feasible. Such strategies may help pinpoint appropriate therapies for patients with high CTC counts and poor prognosis.
CTCs, ctDNA, and the Regulatory Perspective
Dr. Pantel, who Dr. Hayes credited with coining the term “liquid biopsy,” will also discuss ongoing trials that are building on the SWOG trial’s experience and looking for ways that liquid biopsy tests can guide treatment and improve outcomes. For example, the German DETECT III trial will assess the use of lapatinib in patients with metastatic breast cancer with HER2-negative tumors but HER2-positive CTCs (NCT01619111). Dr. Pantel said much work remains to be done to make these tests effective in practice. “In order to bring liquid biopsies into the clinic, an international effort on standardization and quality assurance of the plethora of current assays is required.” Such an effort is underway in Europe with the CANCER-ID project.2
Nicholas C. Turner, MBBS, PhD, of the Institute of Cancer Research, in London, will also speak during the session, offering a similar update on the research into ctDNA. Finally, Reena Philip, PhD, of the U.S. Food and Drug Administration, will speak about FDA perspectives on liquid biopsy.
“This is a timely session because it is operating at the interface between great science and clinical practice,” Dr. Davidson said. “There is a lot of optimism and a lot of hope, and we should make sure that both of those are maintained, but I think we also have to have our hope tempered with a little bit of reality.”
*Program information updated as of March 6. For session time and location information, please refer to the ASCO iPlanner on the Attendee Resource Center.