Dr. Park’s research at Johns Hopkins focuses on finding mutated or altered genes responsible for breast cancer initiation and growth or resistance to anti-cancer drugs. He received his first BCRF grant in 2008, which fueled his work on a gene called PIK3CA that is frequently mutated in breast cancer. With continued BCRF support, Dr. Park and his group developed anti-PIK3CA drugs and after successful laboratory experiments, needed to test the drugs in real patients with PIK3CA mutations. Over the next several years, he directed his efforts in applying a new technology called digital PCR to measure the PIK3CA mutation in the blood of breast cancer patients.
Inspired by the work of his former mentors, Burt Vogelstein and Ken Kinzler, and with support from BCRF, Dr. Park and his research team have led the field in refining the technology to measure tumor DNA in breast cancer patients with a simple blood draw. The concept of using blood as a liquid biopsy has emerged as a promising and exciting alternative to the more invasive methods of tissue biopsy for monitoring breast and other cancers. While there are currently challenges associated with capturing accurate information from blood samples, there is enormous potential—it could serve as a litmus test for how well a therapy is working, or identify patients who might benefit from targeted therapies available through clinical trials.
BCRF recently spoke to Dr. Park about the current status and the future of liquid biopsy.
BCRF: What are we talking about when we use the term liquid biopsy?
Dr. Park: The terminology is a little bit confusing because different people are doing different things that they consider a liquid biopsy, a term that can refer to any liquid biological sample, blood, urine, etc. Most of us in the cancer field are talking about blood and how we can use blood to gain information about a patient’s cancer.
In the cancer field, the concept of liquid biopsy as a replacement for tissue biopsy is focused on two biologic factors, circulating tumor cells (CTCs) and circulating tumor (ct)DNA (or more specifically plasma tumor (pt) DNA). We know that when solid tumors metastasize they have to travel through the blood to get to a distant site, so there’s an opportunity to capture those cells (CTCs) as they traverse from the breast to the various places in the body. Once isolated from other cells in the blood, CTCs can be analyzed for the types of proteins on the surface or inside the cells, as well as for mutations in genes. The second factor, ctDNA, is something our group has been working on and here we are focusing on DNA or RNA– the genetic material that is shed by the tumor cell into the circulation, rather than whole cells.
There are advantages and disadvantages to both concepts. ctDNA does not allow us to do protein analysis, such as measuring estrogen receptor or HER2, as we can with CTCs. On the other hand, while we can extract DNA from CTCs, because CTCs are single cells, it’s difficult to say how informative that will be regarding the tumor or a metastasis. While some researchers have a preference for one technology or the other, I view them as complementary tools in providing the best patient care we can.
The challenge for both of these concepts is that the relative amount of either tumor cells or tumor DNA compared to the normal constituents in blood, for instance normal blood cells and normal cellular plasma DNA, is quite small. In the case of circulating DNA, we know that all cells shed DNA into the blood stream, so much of what is circulating is going to be from normal, healthy cells.
BCRF: Why is there so much excitement around this idea?
Dr. Park: Liquid biopsy really provides an opportunity to use a relatively non-invasive method (simple blood draw) to analyze CTCs or ctDNA from a patient’s cancer. Before now, we didn’t have the technologies to be able to isolate cancer cells or cancer DNA from the normal constituents of blood; the analogy would be like searching for a needle in a haystack. It’s only been in the last decade or so that the technology has advanced to where it allows us to do this with pretty high accuracy.
Our hope is that we will be able to use ctDNA obtained through liquid biopsy to guide clinical decision making. For instance, rather than having to wait for a patient to complete a two or three cycles of chemotherapy–typically three months in duration–to do a CT scan to see if the tumor is still there, can we take a sample of blood after a week or so of therapy and use ctDNA as a surrogate marker of whether the therapy is working or not? If that were the case, it would allow us to monitor in real time what really happens when a patient starts therapy or changes to a different therapy.
Right now, the usefulness of the liquid biopsy is in research. One thing we want to establish is whether it can be used, not just for the purposes of measuring disease, but also to determine eligibility for clinical trials for targeted therapies. The way we conduct clinical trials is changing based on the knowledge we have about the tumor genome and our ability to sequence patient tumors. We can now match many patients with potential therapies based on mutations in their tumor. Our group recently completed a study where we showed that liquid biopsy was actually better than tissue biopsy in this regard, because we can find mutations that aren’t in a single site biopsy. So, we hope we’ll find that we can use ctDNA as a surrogate biomarker both for eligibility—to see if a patient has a mutation that makes them a good candidate for a targeted therapy—as well as in monitoring response to treatment. Ultimately we hope that this will be a widely adopted commercial test that is useful for our patients.
BCRF: Is liquid biopsy being used today as part of the usual care for cancer?
Dr. Park: Even though there are commercially available tests out there, I actually don’t think the technology is ready for prime time. For one thing, we don’t have enough targeted therapies for the mutations we may find. That will come in the future, but we’re not there. The second thing that we do not know is whether the liquid biopsy (ctDNA) will be as good as a tissue biopsy taken at the same time, and that is an important validation step.
Unfortunately, in the rush to make tests commercially available, no one has validated that these things are clinically useful and there are no standardized methods. Different groups are doing different things and standardization, especially in collection and storage of blood, is crucial to the accuracy of a liquid biopsy result.
To quote Dan Hayes, one of my heroes in the field, “A bad test can be just as dangerous as a bad drug.” What that statement implies is that the same rigorous testing that is applied to drug development has to be applied to biomarker development. We need the same level of clinical evidence, including prospective clinical trials to clinically validate a biomarker test.
Most academic scientists take a conservative, evidence-based approach and while we have the evidence that we can technically do this, the evidence for clinical application is still lacking. That is the critical next step and unfortunately, just as in clinical testing for new drugs, clinical testing for new biomarkers takes time. It will take years to prove with high-level evidence that these technologies are actually useful and as good as we think they are. If we don’t do this the right way, we’ll be taking two steps backwards before going ahead and could end up treating patients inappropriately.
BCRF: What has to happen before liquid biopsies become a part of usual care for cancer?
Dr. Park: We need time, resources and clinical trials to answer these questions and this is a huge focus of BCRF’s Evelyn Lauder Founder’s Fund, which I believe is going provide the clinical validation we urgently need.
The power of Founder’s Fund studies is having the opportunity to assess how the disease is changing over time and in response to therapy that will allow us to definitely say that the gene mutations found in ctDNA reflect the tumor mutation profile at the metastatic sites. In one project of the Founder’s Fund, we’re doing multiple blood draws from patients with metastatic breast cancer to look for mutations in the ctDNA that are not present in the original biopsy and will then match that with information about all their metastatic tumors obtained through rapid autopsy upon their passing.
This is an incredible gift from our patients, since they have generously donated their bodies to research to help future generations of breast cancer patients.
Our goal is to identify the malignant clone–the tumor population that is resistant to drugs and capable of metastasis. We can then monitor this population in future patients to assess the risk of metastasis while working to develop drugs to prevent it.
Our group is also in the process of initiating clinical trials that will begin to get at the level of evidence we need, including a trial that we hope to launch soon through the Translational Breast Cancer Research Consortium (TBCRC), also supported by BCRF. In this trial, which will involve multiple TBCRC clinical sites, we will be collecting blood in patients with early stage breast cancer to see whether or not the absence of ctDNA in the blood can predict response to neoadjuvant therapy, a concept I call liquid pathologic complete response (pCR) – pCR being a clinical measurement of no residual disease.
History is replete with examples where we’ve jumped the gun and made mistakes because intellectually something makes sense, or because a small group of patients does well. We have the opportunity to do this the right way, so let’s do it the right way, even if it takes more time, and it will. At the end of the day, we have to prove that liquid biopsy is as good as we think it is or maybe it won’t be and we can learn from that experience.
BCRF: You’ve talked about how liquid biopsy can be useful in monitoring advanced disease, but can it be used for early detection or risk assessment?
Dr. Park: That’s an important question. The technology continues to improve and is not limited to just late stage disease or metastasis, when you would expect there to be much more circulating tumor factors than in early disease when tumors are still small and localized. This is work we are actually doing. We recently published a paper showing that we could detect PIK3CA mutations in early stage breast cancers, with 93% sensitivity and 100% specificity. We’ve been working with industry partners to refine digital PCR technology to increase the sensitivity of the ctDNA assay. The new platform, called droplet digital (dd) PCR, allows us to quickly and relatively cheaply increase the number of DNA molecules we could assay by more than ten-fold.
This was an important proof of principle study. Many early stage breast cancers are over-treated, because we can’t actually determine which patients should receive systemic therapy after surgery (called adjuvant therapy) versus those who don’t need it since they are cured with surgery alone. It might take ten years to complete these studies, because we have to follow patients prospectively, but we really believe that someday we’ll be able to draw blood after a patient has her/his surgery and determine whether or not she/he needs adjuvant therapies.
When I see patients for follow up after surgery for early stage breast cancer, the biggest thing they face is uncertainty and living in fear that their breast cancer will come back. One of the things we hope to prove with this study is that by using ctDNA obtained from liquid biopsy, we can identify which group of patients is at risk of recurrence versus those who are not. That information would be hugely impactful for every woman who faces breast cancer. We believe that this technology will be paradigm changing for breast cancer patients.
BCRF: You’ve made reference to the work of the Founder’s Fund and your collaborations with the TBCRC, both of course receive major support from BCRF. How has BCRF impacted your ability to pursue this work?
Dr. Park: The major challenges in these studies continue to be funding and resources. BCRF’s support of my work over the years and its fostering of collaboration have really propelled not only my work, but the breast cancer field and I believe will continue to do so. As an example, when I started to think about how I could screen women for the PIK3CA mutations, I knew that it would be very difficult to obtain tissue biopsies. It was through “out of the box” thinking in collaboration with my BCRF colleague, Antonio Wolff, and Michaela Higgins a fellow in my lab at the time, that led to a study using the digital PCR technology to detect PIK3CA mutations in patient blood in 2010. Along multiple points, BCRF has propelled this research, from its support of our initial laboratory studies, to taking the work to the diagnostic level with droplet digital PCR. BCRF’s support of the TBCRC is a huge component of this because without the TBCRC we couldn’t do the type of trial I described in early stage breast cancer and in addition, the Founder’s Fund will allow us to launch this work in the metastatic setting.
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