Susan G. Komen has been deeply invested in supporting researchers at New York cancer institutions since its founding in 1982. Over the last forty years, Komen has awarded 209 grants to New York-based researchers, totaling $58.4 million.
Pedram Ravazi, M.D., Ph.D., a medical oncologist at Memorial Sloan Kettering Cancer Center, is a Susan G. Komen grantee. He recently spoke with Komen about a three-part study he’s leading that analyzes circulating tumor cell DNA (ctDNA) from early-stage breast cancer patients to detect and monitor patients for microscopic breast cancer metastases. Metastatic breast cancer is when cancer spreads beyond the breast and becomes deadly.
Komen: Could you explain the focus of your research?
Razavi: We’re working with patients who have stage 1 to 3 high-risk breast cancers to identify early microscopic breast cancer metastasis, when it can potentially be treated more effectively with the goal of eradicating the residual cancer and preventing its progression to deadly metastatic breast cancer.
We know that neoadjuvant and adjuvant therapies work by eradiating microscopic metastatic tumors, and these therapies can almost double the chances for “curing” breast cancer. The problem is that we have no good way of knowing whether a patient’s tumor has already metastasized. Basically, we offer treatments almost blindly based on assessment of baseline risk of recurrence to all our high-risk patients.
This results in both over- and under-treatment of a certain population of patients. For example, in high-risk patients with aggressive breast cancers, such as triple-negative breast cancer, recurrences occur frequently despite our best efforts as there are subpopulations of metastatic cancer cells that are resistant to treatment. These cells have survived our treatment and will eventually progress to overt metastatic disease. So, there is a great potential to tailor our therapies if we have a robust method to identify these microscopic metastatic cells and monitor their responses to our therapies. Here the goal is to escalate care to eradicate these resistance residual tumor cells and prevent metastatic recurrence in the patients at highest risk for recurrence.
For estrogen receptor-positive (ER+) patients, the picture is more complex. We see a lot of recurrences in the first five years, especially in those with high-risk ER+ disease with microscopic metastatic tumors that may already be resistant to endocrine therapy. But some patients may be at risk for recurrence 10 or even 20 years after their diagnosis. We presume this happens because these patients have microscopic metastatic tumors that grow slowly during therapy or change to become resistant to treatment. The problem is that we really do not know which tumors are more prone to develop these resistant cells and have no good understanding of how tumors grow during therapy. So you can imagine that if we can identify the microscopic disease and monitor their growth and evolution, then we have an opportunity to intercept early and either prevent development of these resistance tumors or eradicate them with modifying our treatment approach.
In this study, we’re trying to tackle these very challenging problems and understand when and why these microscopic tumors become resistant to our best treatments and eventually grow to become overtly metastatic. Our ultimate goal is not achieving stable disease state, which is an acceptable outcome in the metastatic setting, but to devise approaches that can eradicate cancer. As a researcher and clinician, I want the tumors to be gone and that’s the focus of the first part of our three-part trial.
Komen: And how are you conducting your study to identify early metastasis?
Razavi: We know that tumor cells shed a small amount of their DNA into a person’s blood stream. We call this circulating tumor DNA (ctDNA). When a person’s breast cancer becomes metastatic, the amount of ctDNA is relatively high and we can use liquid biopsy (a blood test) to monitor the disease or identify alterations in the ctDNA that could contribute to treatment resistance.
Very early or microscopic metastatic cancers also shed ctDNA into the bloodstream. However, the amount of ctDNA coming from these microscopic tumors is often extremely small, and we don’t have sensitive methods to detect very low levels of ctDNA in the metastatic setting. In this study, we will develop and optimize an ultrasensitive method to detect low levels of ctDNA, and we will then use this method to detect and monitor ctDNA and metastatic residual disease (MRD) in patients with early-stage breast cancer.
We have been collecting blood samples before and after surgery and neoadjuvant or adjuvant chemotherapy from a large group of MSK patients with early-stage breast cancer who have admirably participated in our ctDNA monitoring study called MSK-LINC. We will use these samples to understand the rate and pattens of MRD detection in patients with early-stage breast cancer. All of this information will help inform the treatment strategies and design of new clinical trials that aim to identify metastasis early and eradicate MRD.
Komen: What might those treatment strategies look like for MRD positive patients?
Razavi: This is a fantastic opportunity to start bringing new treatment strategies and even new drugs in early stages of development into early-stage treatment. We have a lot of promising drugs such as antibody-drug conjugates, targeted therapies, and new endocrine therapies that are approved for or being developed in metastatic disease that I’d like to bring to early-stage patients. Some of these drugs are in Phase II clinical trials and show a lot of efficacy. Patients with early-stage breast cancer who are MRD positive are at very high risk of metastatic recurrence and, in my opinion, this justifies the use of such promising experimental therapies to give the patient the maximum possible chances of a cure. This could create a new model for drug development when new drugs can be developed and tested in such very high-risk patients, but with the goal of eradicating and curing breast cancer.
Komen: How does your research differ from other studies that focus on MRD in patients after a tumor is removed?
Razavi: What the studies are not showing at this point are the dynamics. How does MRD evolve, even in terms of detection, and what are the patterns?
There have been multiple studies on this, but all of them are on a smaller scale of maybe 50 patients or 100 patients. In this study, we have a very large cohort of more than 1,300 patients who have provided serial blood samples allowing us to comprehensively characterize and study MRD before and after surgery and while people are on treatment.
Our data is becoming mature – on average our patients have 5-6 years of follow up, which is a reasonable follow-up time for most of our high-risk patients, but not for some of the ER+ patients who are at risk of late recurrence. So now we’re looking for patients who are done with their recommended five years of hormone therapy, and my research team is asking if we can get baseline blood samples and follow them. We’d also like to get samples from patients who are 10 years out from treatment and might be at high risk for recurrence.
Komen: It sounds like the blood tests after treatment is complete are crucial in observing when and how microscopic disease evolves. How do you know when and how often to take a blood sample?
Razavi: We know some answers to that question, and the short answer is as soon as possible so that MRD does not become more advanced or more complex, which can negatively affect our chances of eradicating it. Having an extremely sensitive way to identify MRD very early is key here. It also depends on the aggressiveness and growth rate of the tumor, as well as the effectiveness of the therapies that we have available for that particular breast cancer. For example, triple-negative breast cancer is an aggressive tumor and if the MRD grows for two years, the patient might already have overt metastatic cancer that is not considered to be curable with our current treatments. For ER+ and HER2+ patients however, if you find growth within one to two years, it could still be possible to eradicate the tumors as we have effective therapies for these types of breast cancers.
Komen: What is the focus of Aim 2 and Aim 3, the second and third parts of your study
Razavi: The idea in Aim 2 is to sequence both the metastatic recurrence and the primary tumor and then construct the evolutionary tree of the cancer. The goal is to identify the subpopulation of cancer cells (subclones) that have existed in the primary tumor and were already resistant to therapy. These cells were fit enough to grow and ultimately form a metastatic recurrence or developed new features during treatment that allowed them to become resistant and ultimately metastatic. We will then develop patient- and tumor-specific ctDNA assays and analyze the serial ctDNA samples that we have from the time of diagnosis to when metastatic recurrence occurs. This has never been done before and would allow us to learn about early evolution of microscopic metastatic disease, as well as and when and how these small resistant metastatic tumors started to grow. This could teach us who are the patients at higher risk of developing metastatic disease and how these tumors become resistant to our drugs and progress to metastatic disease. We will then use all of this information for Aim 3, which is to create models to predict these outcomes based on clinical, genomic, and early ctDNA changes in primary tumors during treatment.
Some patients will develop resistance – either acquired resistance or resistance that already resided in the tumor – to therapies. We want to try to predict resistance before it happens. If we know when and how a tumor becomes resistant, it can potentially place us one step ahead of the tumor when we can escalate or modify our treatment strategy to kill it. Or if we see a tumor has responded to treatment, we can stay the course or in some instances deescalate treatment, so we don’t overtreat a patient. Aim 3 will hopefully give us a lot of information to personalize treatment and improve outcomes in the future for all patients.