A Conversation with Dr. Pashtoon Kasi

Dr. Pashtoon Kasi is the Englander Institute for Precision Medicine’s Director for Liquid Biopsy Research. He is an oncologist and researcher focused on treating patients with gastrointestinal cancers and other solid tumors using novel clinical trials and therapies. His focus has been on understanding the genomics and genetics of the underlying cancer, and to help treat these cancers in a more personalized fashion.

His research and utilization of non-invasive tests like circulating tumor DNA (ctDNA) testing, often referred to as “liquid biopsies,” allows him to not only understand the genetic makeup of his patients, but also to study the changes over time to identify the best treatments for his patients, including clinical trials with novel drugs as single agents or combinations (targeted therapies, immunotherapy, biologics, vaccines, etc.) besides or in addition to the traditional chemotherapy.

We hope you enjoy learning more about Dr. Kasi.

 

Question: You came to New York in the fall of 2021 to join WCM and the Englander Institute for Precision Medicine, can you tell our readers why you wanted to come here?

A: I wanted to come to New York to be part of two endeavors that I could lead. As an oncologist who treats gastrointestinal cancer, my focus has been the development of precision medicine-based therapies and trials. Coming to New York also allowed me to focus on colorectal cancer research, an area of increasing interest when it comes to precision medicine-based therapies. So, the opportunity to be a GI-oncologist focusing on research and trials for patients was very attractive, and the companion opportunity within the Englander Institute for Precision Medicine blends with the goals I have for my patients in the clinic as well as in the lab. Within the EIPM there are so many endeavors going on and I could be the director of the exciting area of research on liquid biopsies that I was particularly attracted to.

Q:        The field of liquid biopsy research has moved very quickly into the clinic and is already benefitting many patients. Can you tell our readers about this fast-evolving technology?

A: Liquid biopsies are already revolutionizing cancer care. It’s not something limited to research anymore, it’s very much in the clinic right now and it’s here to stay. Liquid biopsies are broadly having an impact in all phases of the journey of people who have cancer.  And it’s not only benefitting people with advanced or metastatic cancer, where there is a lot of shedding of cancer fragments that are circulating in the blood stream, often referred to as circulating tumor DNA or ctDNA. It’s also making its way into early-stage cancer diagnosis and treatment and helping to answer a patients question of ‘whether I’m cured or not,’ based on the surgery they had a few weeks ago. And helping to answer the holy grail of early detection, using liquid biopsies and blood testing to screen for a myriad of different cancers. So, this tool is already in the clinic and is part of my standard of care for all my patients depending upon their indication and their cancer type.

Q:        What hurdles need to be overcome to benefit more patients?

A: I think that’s a great question. Unlike technologies that focus on the genetic testing of an actual tumor, when it comes to liquid biopsies you must keep in mind that you’re relying on whatever is circulating in the blood at that precise time. Both the advantages and the disadvantages of a noninvasive blood draw is that it’s affected by clinical variables. So timing is of the essence, circulating tumor DNA has a very short half-life; it’s quickly cleared from circulation after an effective treatment or after cancer surgery.

One of the common misconceptions or initial mistrust in liquid biopsies came from its use in patients who started treatment that was working, and it was being ordered at a time when the tissue testing had failed. So, one important clinical variable that occurred in these patients is that they had started their treatment that cleared their ctDNA, so both the patients and the physicians alike were shown results that there wasn’t anything detectable, however the analyses couldn’t be completed because there wasn’t much cancer DNA, echoing the fact that it was important that the blood draws happen at the appropriate time.

Another clinical variable to consider is that different cancers shed different amounts of ctDNA; some cancers like GI malignancies and colorectal cancer can be called high-shedders, meaning they spill a lot of tumor DNA into the circulation, And conversely, there are low-shedders like slow growing tumors or pancreatic cancer that spill a lot less DNA into the circulation.

And finally, beyond the patient and the timing, it even matters as to where the cancer is located. There is research that shows that if there is a colorectal cancer in the lung, vs in the abdominal cavity, vs the liver, in that order, it would have increasing amounts of ctDNA detected.

So, beyond the technical issues with the various assays that look at cancer through different lenses, the most important question right now for the field of oncology is not necessarily which assay is most important but what is the clinical question for which patient and which tumor are we going to order an assay, and even more importantly, what are you going to do with that information?

Q:        Are you hearing directly from patients asking for liquid biopsies?

A: Yes, indeed. Patients and their caregivers alike are coming to us specifically asking for liquid biopsies to be done, or are already coming in with results of liquid biopsies ordered by another provider, and asking for our insights and next steps. It is important to realize that there are different kinds of liquid biopsies. Some liquid biopsies are meant for advanced/metastatic cancers when the cancer is still in the body. Whereas others are meant to be used after surgery has already been done to see if there is any leftover cancer DNA (something called minimal residual disease). So there are different kinds and uses of liquid biopsy assays. Patients and caregivers interested in liquid biopsies should speak with their physician.

There has been a learning curve for both providers and researchers, and for patients. No test is 100% of course, there are technical variables with the tests and patient-related variables that can affect the performance of the tests. One clinical example is using liquid biopsies in the immediate post-operative setting, there would be a lot of background noise from the inflammation of surgery that can make it difficult to find the needle in the bigger haystack.

My colleagues and I have shown the same amount of ctDNA detected significantly improves over time after the operation. Also, as you mentioned, we are confident that when the tests show there is cancer DNA circulating in the body, that these patients in 1-2 years will experience a resurgence of their cancer and are not cured. A key limitation is that when an assay comes back as negative that could mean that maybe the patient is cured, or maybe the test didn’t pick it up because the numbers were just below the threshold of detection or whatever bioinformatics processing was developing and we’re recognizing that there are false positives like any tests for any indication. While technologies have improved significantly, there is never such a thing as a perfect test.

Q:        What is the potential for the field of liquid biopsy, where will it be in 5-10 years?

A: What excites me is not the future, but the present! Already in our clinic, and across institutions, in the last few years we have seen an endorsement of using liquid biopsy as an effective alternative to tissue-based testing in front line genomics for conditions like colorectal cancer where the guidelines have shifted towards liquid biopsy as an alternative to tissue biopsy, even if the tissue biopsy is available. The advantage is that it’s noninvasive and the turnaround is key, we’re getting results in ten days vs. up to 4-6 weeks for tissue-based biopsy results. And during the worst stages of the Covid pandemic, patients could even get their blood drawn from the comfort and safety of their own home via a phlebotomy service, making the process truly noninvasive, feasible, practical and with a rapid turnaround.

I don’t often echo the argument that liquid biopsies are a replacement for tissue biopsy; they can be complimentary and be easily repeated over time. The other big indication is the evolution of cancer treatment, especially with targeted therapies and immune therapies, you can use some of these assays to see what changed and how it changed in a non-invasive and feasible manner, taking fresh tissue samples are not always safe, practical and feasible, which asks an awful lot from a patient when we can get many of the same results from a simple blood draw that we can easily repeat a number of times.

The huge area of interest that has exploded over the last year or two could be called minimal or molecular residual disease or MRB which seeks to answer the question, ‘do I have any leftover cancer after treatment?’ Right now, we kind of guesstimate the probability assessment of who should or shouldn’t be getting chemotherapy to mop up any leftover cancer based on the pathology report.

We do know that a fair proportion of these patients probably could be spared the toxicity of chemo because they are probably already cured vs some patients who might actually need intensive follow-up treatment because they still have a lot of cancer in their systems. In these cases, liquid biopsies can be especially helpful in determining if a future course of treatment is necessary. The question now being asked in trials is, can we closely monitor but potentially forego or delay invasive treatment in a patient who’s already cured of cancer. Liquid biopsy is another tool in the toolbox, it doesn’t replace the clinical acumen and decision making; if someone should be getting chemotherapy because they are a very high risk the new tests won’t negate that.

For healthy people who should be screened for cancer, many blood tests are now commercially available and many more are already in clinical trials. Some of these are cancer-specific, or can even detect high-risk polyps, and are making great strides in early detection of cancer. The other broad category are multi-cancer tests, these screen for many types of cancer from one blood draw. There have been a lot of news reports of a specific single test that can screen for up to 50 different types of cancer. These can measure how much DNA is detected for specific types of cancer. Patients and doctors need to be reminded that every test has its own limitations.

Q:        What are the financial implications of these new tests?

A: That’s an important question. There are a lot of potential downstream costs to patients, providers, and insurance companies: Who gets tested, how frequently, do they become limited to high-risk populations over time? These can lead to uncomfortable questions of access to cancer treatment and care as costs continue to rise.

In the long run it will be more cost-effective to screen more often, especially as the cost of cancer care continues to increase, and especially for those with advanced cancer or cancer metastases. We can keep those long-term care costs down by getting more people screened for cancer as early as possible, especially for high-risk populations. And noninvasive tests like liquid biopsies will become more attractive to patients, and less expensive and more accurate over time.

Q:        How did you get interested in this field?

A: My mentors and patients motivated me down this path. I had a young patient with colorectal cancer seven years ago who asked if he could get a blood test instead of a liver biopsy because he didn’t want yet another invasive procedure. That made me question why we didn’t have better alternative procedures. I’d heard about liquid biopsies and some of the limitations with those earlier tests, but his question and others I subsequently encountered made me ask why we didn’t have better alternative tests and ask myself what I could do to bring about better, less invasive tests for my patients and others.

So serendipitously, I started my own journey down this path with liquid biopsies, which took me from the clinic to the research world, and back again to the clinic for patients in the form of new trials and new tests. Of course, my mentors who punctuated my career and have played such an important role in my life, helped me solidify my interest in this field and run with this research focus, and niche. My journey started with an interest in medicine, then oncology, then GI cancers and a focus on liquid biopsies, in tandem with patient care, flowed very naturally. My parents, both of whom are physicians, have been instrumental throughout the whole process.

Q:        What do you like to do when not working?

A: My personal time revolves around my kids and my better half Maryam; our whole universe is focused on a five-year-old boy Rafay and a 1-year-old girl Zuha. It seems all our hobbies and interests have taken a back seat to the children!

For more information about Dr. Kasi’s research please visit “ASCO Daily News: ctDNA Assays: Exploring Their Clinical Use in Oncology Care,” and “ASCO Daily News: Kinetics of Liquid Biopsies in Predicting Response to Immunotherapy.” [Graphic images in this article come from ASCO Daily]. Dr. Kasi was a recent guest on Dr. John Leonard’s CancerCast podcast, “The Promise of Liquid Biopsies.”

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