Editor’s Note: We asked MBC advocate and fellow Chicagoan Martha Carlson to attend ASCO 2018. In this article she looks at some liquid biopsy developments; in Part 1 she shared her thoughts on being at one of the world’s largest oncology conferences . –Katherine O’Brien, MBCN
By Martha Carlson
Current clinical recommended practice is to biopsy metastatic sites of progression in breast cancer, but that isn’t always practical. Tumor location, inadequate tissue selection, patient resistance, fear and anxiety, as well as the risk of complications all combine to make tissue biopsies less than perfect.
It makes sense that researchers and oncologists would like to prove that liquid biopsies can meet the “gold standard” of tissue biopsies in treatment of metastatic breast cancer. Minetta Liu, of the Mayo Clinic in Minnesota, is such a person. She opened her presentation at the recent ASCO meeting in Chicago by acknowledging, “If you’ve ever been on the receiving end of a needle biopsy, you could argue that they’re never practical.” Still, to make the best treatment decisions, clinicians need to know what’s happening with an individual cancer. Breast cancer can mutate between types, moving from ER+ to triple-negative, for instance, and it can have mutations within the DNA even when the overall type remains the same. In addition, because of our expanding knowledge about genes and genetic mutations, biopsy at a site of progression may give information on actionable targets that didn’t exist at the time of an earlier biopsy.
All this to say, again, that every site of progression should be biopsied and we need a better, less invasive way to do that. Patients, perhaps better than clinicians, understand that liquid biopsies hold that promise. At the recent ASCO meeting, University of Toronto’s Min Joon Lee presented research showing a 9-to-1 patient preference for liquid biopsies despite limited understanding of cancer-specific blood-based biomarkers.
What Is A Liquid Biopsy?
A liquid biopsy typically looks at blood for signs of circulating cancer cells. These circulating tumor cells (CTCs) are believed to be microscopic disease that can eventually lead to metastatic recurrence or progression. Researchers studying CTCs use the word “shed” to describe how these cells come to be circulating in a patient’s blood because the tumor is believed to shed them. Levels of CTCs in a person’s blood have been shown to change depending on tumor response to treatment, and the number of them correlates with prognosis. As reported here, patients with CTCs above 5 per 7.5 ml of whole blood before and after starting a new therapy had worse clinical outcomes than patients whose CTCs were, at some point, less than 5.
In addition to CTCs, a liquid biopsy can look for more specific genetic information that could increase the chance of finding a treatment match:
1) circulating tumor DNA (ctDNA), which refers to DNA shed specifically by tumor cells into the circulation;
2) circulating cell-free DNA (cfDNA), which are small DNA fragments shed by ALL cells–not just tumor cells–into the circulation;
3) plasma tumor DNA (ptDNA), which is the plasma component of ctDNA; and
4) circulating cell-free nucleic acids (CNA), which is DNA in the blood that is not inside a cell and can be “naked” (alone), bound to protein, or maybe inside a little vessicle.
Precision Medicine & Liquid Biopsies
Given all the potential methods of discovering signs of cancer and genetic information about an individual’s specific cancer, the focus on improving the clinical usefulness of liquid biopsies is understandable. However, in breast cancer, CTCs have not yet been shown to improve the overall survival, so tissue biopsies remain the primary source of metastatic tumor information. Of course, tissue biopsies can only happen when a scan, such as a CT or PET scan, reveals a tumor and that tumor has to be needle-accessible. In effect, patients and their doctors don’t know if treatments are working and are just waiting for treatment to fail.
Blood, though? Blood could tell you today what a scan might need months to reveal.
This information, collected possibly on a routine basis with metastatic breast cancer patients and definitely when there is progression shown on scans, could allow better prognoses but it might also help oncologists find the best treatment for an individual patient at a specific time during their disease. As Dr. Liu asked at ASCO, “If you’ve made the decision to start a particular agent or combination of agents, can we better predict treatment resistance? Not only to outsmart that resistance, but to not waste time with ineffective therapies that are giving our patients toxicity without benefit.”
Theoretically liquid biopsies hold great promise for overcoming many of the limitations associated with tissue biopsies. In practice, much work remains to be done--but as the accompanying graphics demonstrate, lung cancer is a prime example of how oncology professionals are harnessing the benefits of liquid biopsies.
As BiopharmaDive’s Ned Pagliarulo reports, one immediate challenge with liquid biopsies is detection. Circulating tumor DNA is relatively rare compared to the number of hematological molecules found in a blood sample. Circulating tumor cells are even less common. The sensitivity of a liquid biopsy to detect ctDNA or CTCs at extremely low concentrations, then, is a crucial factor for proving the test’s utility. Improved sample preparation and sequencing capabilities are helping researchers overcome these potential hurdles.
What We Heard at ASCO 2018
Stage IVindolent As explained in this article, recent research using CTCs has found that patients with less than 5 CTCs per 7.5 ml of whole blood have a less aggressive form of metastatic breast cancer. This research by Andrew A Davis, Massimo Cristofanilli, both of Northwestern University, and others, found that these StageIVindolent patients comprise up to 60% of the metastatic breast cancer population. By using CTCs and the FDA-approved CellSearch system, the researchers say that more accurate staging and patient care is possible for all subtypes of breast cancer. The indolent group had a median overall survival of 36.3 months, while overall survival of those diagnosed de novo with indolent metastatic breast cancer was over 5 1/2 years. Because this finding could impact clinical treatment of the patient, it is possible that insurance would pay for a liquid biopsy to determine CTC levels–but this remains to be seen.
Guiding Therapy It has also been found, as presented at ASCO by researchers led by Neelima Vidula and Aditya Bardia, that cfDNA genome typing can result in more actionable targets than that found through tissue genome typing (47% vs 28%; although the samples were not taken from the same patients). In this study, patients receiving matched therapy based on the results of their cfDNA testing, excluding those with matched standard of care therapies, had improved overall survival. This is exciting information because it suggests that treatment can be guided by liquid biopsy results, given actionable targets and mutations and access to either standard treatment or clinical trials/expanded access through the FDA or Right-to-Try.
Profiling Patients Because of the advances in genomic-typing, looking at liquid biopsies, particularly ptDNA and ctDNA, and the relative ease of having new and more accurate information when it’s needed–because it’s much easier to draw blood than to take a tissue sample–researchers have found that mutations that might not show up in a particular piece of tumor tissue can be found in the plasma, for example, well before a treatment failure means moving on to a more effective drug or adding a drug that could decrease resistance. Increasing levels of mutations, such as p53, and CTCs have been shown to correspond with risk of relapse or progression, long before a scan would pick that up, allowing more timely treatment.
Surprise Findings Sometimes, blood-based biopsies provide insights that go far beyond the idea that oncologists will be able to find what will work for an individual patient. At ASCO, work by Medford et al showed the potential value of ctDNA in finding novel targets when researchers found that molecular alterations in the MAPK pathway, which is considered rare in HR+ breast cancer, occurred in 25% of the metastatic HR+ breast cancer sample. These alterations included known treatment targets and again suggest real clinical value for liquid biopsies.
Additional research, from The Netherlands and also presented at ASCO, suggested the potential usefulness of CTCs to determine androgen-receptor status of metastatic breast cancer patients. The androgen receptor has been associated with endocrine resistance and could be an additional treatment target. This work is preliminary but showed discordance between AR status found in CTCs and that found in tumor tissue samples. Patient outcomes on ER-targeting therapy in this study were unaffected by CTC-AR status, but the authors point out that use of CTCs would allow clinicians to select metastatic breast cancer patients for AR-inhibiting treatment, which could potentially impact treatment outcomes.
Liquid Biopsies & You
All that research looks promising and there is much more currently underway but, because clinical usefulness needs to show a survival benefit, widespread use of liquid biopsies in metastatic breast cancer isn’t here yet. Current research tells us circulating biomarkers can provide prognostic information and that current molecular profiling is possible from those circulating cells and DNA. Now we need to show that the information gained from liquid biopsies can truly benefit patients by avoiding drugs that won’t work given molecular profile, leading clinicians to better combinations of drugs in precision treatment, and, essentially, driving the treatment to better patient outcomes.
Words To Know
Liquid biopsy Alternative to surgical/needle biopsies that uses blood (or urine, cerebral spinal fluid, etc) to reveal information about a tumor
Circulating tumor cells (CTC) Cells that have shed into the vasculature or lymphatics from a primary tumor and are carried around the body in the circulation
Cell-free DNA (cfDNA) Small fragments of DNA shed by all cells into circulation. For example, pregnant women have DNA from their baby’s placenta in their blood. People who’ve had a heart attack or stroke may also have DNA fragments in their blood. Collectively, all those DNA fragments are called cell-free DNA. So, researchers need to be able to accurately identify ctDNA among all the other types of DNA in blood to avoid false alarms, telling someone they have cancer when they don’t.
Circulating tumor DNA (ctDNA) DNA shed specifically by tumor cells into circulation
Plasma tumor DNA (ptDNA) The plasma component of ctDNA
Circulating cell-free nucleic acid (CNA) A component of the plasma
Next-Generation sequencing (NGS) The technologies that allow quicker, cheaper analysis of DNA, RNA, mRNA
Blood-based biomarker A measurable substance that is indicative of some phenomenon such as disease, infection, or environmental exposure.
For Further Reading…
“Liquid Biopsies, Past, Present and Future.” Len Lichtenfeld, MD, deputy chief medical officer at the American Cancer Society on a key liquid biopsy challenge: “With cancer, you’re looking for a very small quantity of ctDNA in a sea of unrelated proteins.”
“Liquid Biopsies What We Do Not Know Yet.” How molecular analyses of ctDNA and CTCs can contribute to better understand therapy resistance and potentially improve personalized treatment for metastatic breast cancer and other cancers.
“Case for Testing Cancer in Blood.” This 2015 Reuters story reports that at least 38 companies are working on liquid biopsies for cancer, according to analysts at investment bank PiperJaffray, who think the U.S. market alone could eventually reach $29 billion a year.
This infographic shows how liquid biopsies potentially can work in Lung Cancer…liquid biopsies currently are not routinely done for Breast Cancer patients…as detailed in the preceding article, work is ongoing.
Martha contributes a regular blog on MBC issues to Cure Magazine. She’s also active with Living Beyond Breast Cancer (LBBC). Learn more about Martha’s role in LBBC’s Hear My Voice Program in this issue of Conquer Cancer Magazine.