Functional Testing for Personalized Cancer Treatment Beyond Standard of Care

•Best drug for you : Testing the response of your cancer cells to drugs is valuable because during your course of treatment you are only able to take a relatively small number of drugs, generally sequentially, with effects (such as side-effects on your body, or effects on the cancer itself) that may alter your body’s ability to tolerate other drugs or impact the cancer’s response to future drugs. Some drugs may not be generally used for your type of cancer, and locating such drugs from the myriad of possibilities is hard. In addition, a drug that is targeted at a mutation that you don’t have, such as EGFR, may hit more than one target, so you might respond unexpectedly. Or there may be seven EGFR inhibitor drugs, and one will work better, but not the others.

•Complement to other tests : Assuming that you do want to get a test, you should think about what type of test to get (although subject to cost and sample availability, you can often do more than one test). A standard test uses gene sequences taken from your cancer cells to make its predictions. But biology is complex – and much more than just genetics – and predicting a drug’s utility from the genetics of a cancer cell alone can be hard, particularly when the drug is not one designed specifically for a particular genetic aberration. Compounding that problem is the fact that a cancer population, like a region of garden overgrown by weeds, is often a heterogeneous collection of somewhat different cells. A genetic test might be able to give you information about how a drug will work in a particular cell type in your cancer, but may be less good at predicting the effect of a drug in the overall broader population of your cells. Other tests, such as RNA sequencing and proteomics arrive at their results using different techniques, can provide different information, and they may not all agree. For example, a genomic test might tell you more about the makeup of your cancer and its course, which is information outside the scope of Travera’s test, which seeks to provide insights on specific drugs. If you are interested in obtaining a fuller picture of your cancer – and have sufficient samples and funds – it may be reasonable to use a variety of “standard” tests at the same time. You can repeat many of these tests, including Travera’s, multiple times (subject of course to tumor volume amounts and insurance) in the event your cancer was not adequately treated or it recurs. The tests may have different results and be of higher utility as the disease progresses. A functional test doesn’t seek to predict by theory what might work. Instead it just tries the drug on a group of cells to see what happens.

•Large scale testing : The Travera test enables the large-scale testing of many drugs, and even drug combinations, limited only by the number of tumor cells in your sample and your testing budget. Why might you not want to get a “functional test”?

•Cost: Many functional tests (like Travera’s) are in a research phase at the time, so their tests are free so that they can gather data to support becoming standard. As tests move from research to commercial acceptance, the test could become expensive. This may pose a financial burden, particularly if it is not covered by insurance.

•Sample availability : It might be hard for you to obtain fresh tumor tissue, or sufficient volumes of tumor tissue to test as many drugs as you would like. Keep in mind that unlike many other test types, which can work with very small samples and can provide a comprehensive report based on that sample, the more drugs you wish to functionally test, the larger the sample you will need to provide.

•Predictive accuracy : While exciting and very sophisticated technically, there remain significant questions as to how well Travera’s test and functional testing in general works. The Travera test is not yet FDA-approved or cleared, and has not been extensively tested in clinical trials. It is thus hard to gauge how accurate their results may be. Specifically, they may give you suggestions that are less beneficial than the recommendations of your care team or other tests you may obtain. These recommendations may take you on costly detours from optimal treatment. Here are a few of the potential issues behind concerns about predictive accuracy:

•Creation of samples: Travera separates malignant from non-malignant cells using certain markers present on the surface of the cells. But for particular patients with particular cancers, this sorting may be less complete or wholly ineffective. The result is that certain parts of the tumor may not be separated out as malignant and thus not tested. That can be a significant problem if, for example, these unsorted cells are particularly numerous or particularly aggressive.

•Ex Vivo (out of the body) vs. In Vivo (in the body): Despite many attempts over many years, there is no way to mirror in ex-vivo wells the behavior of cells in their native environment in the body. So for example, an in-vivo cell has a complex environment with other cells near it that may provide nutrients, signals or protection. Outside the body, such cells may be significantly weakened and much easier for certain drugs to kill.

•Drug effects: Applying a drug directly to a cell ex-vivo is not the same as the drug getting to the cell through the in-vivo route of a patient swallowing a pill or via IV. To give just two examples, different drugs can be metabolized or excreted very differently by different patients and what might work well in one patient could have a dramatically different effect in another, even though the ex-vivo functional tests would not reveal this. When should you get a functional test? 1.Early (at initial diagnosis) : In an ideal world getting this test as early as possible could have important benefits. First, at the initial biopsy it might be easier to obtain a large volume of tumor cells to test. Additionally, each round of treatment has effects on your body and effects on the cancer. So it seems plausible that using the most effective treatments earliest is the best strategy for fighting your cancer. 2.At change points (advanced cancer) : Assuming your cancer is advanced, the next best time to get a functional test is when you're planning to change your therapy. If there's a recurrence, this could mean the cells have changed from the original specimen, and there might be different drugs you could identify, and ones that were identified that are no longer actionable. 3.To build on information from other tests : The benefits of novel tests like functional testing must be weighed against the often well-validated vast corpus of accumulated oncology knowledge with more standard tests and the treatments associated with them. Especially if you have a treatable (or highly treatable) cancer with known effective early treatments, using a non-standard test which might recommend something that is not in the standard of care potentially exposes you to a level of risk that may be high compared to the benefits. But alternatively, if there are multiple possible known effective treatments and you are trying to select the best first one to try, you may want specific guidance. The risks and benefits are a tradeoff. What are the barriers to getting “functional testing”?

•Input: You will need to get fresh tumor tissue or fluids on which to run the functional tests. If you have malignant fluids, you're commonly getting that drained at regular intervals, which is an easy point to get a specimen. When it comes to getting biopsies from a surgical procedure, it’s easiest to piggyback on biopsies that are being gathered for other tests.

•Physician acceptance : You will need your doctor’s order for most functional tests. Many oncologists won't accept the guidance from unvalidated functional tests such as these. The more open-minded oncologists may ask for clinical trial data and articles, but some might not be interested in anything but a product that has successfully been through the FDA regulatory process.You may well wish to discuss this with your clinician early in your journey.

•Reimbursement: Tests which are not standard can be free if the test provider is gathering research evidence, but it can be quite difficult to obtain reimbursement from health insurers for non-standard tests, and if they won’t pay, you may have to. It is a long road for a test provider to have a product which is reimbursed by insurers. At a minimum, insurers, including Medicare, want to see evidence of both clinical validity (proof that the test does what it says) and clinical utility (proof that the test changes treatment and improves patient outcomes). For example, Travera is trying to prove their test works for a variety of different cancer types and stages, making their demonstration of validity and utility harder. Sometimes you can make arrangements with test providers for reduced payments, but the time to have that discussion is early, not after your claim has been refused. How can you overcome the barriers to accessing functional tests? Functional test providers can help you with accessing their services. For example, Travera has had good success in getting doctors to order their test, with only a few flatly refusing. They provide a draft email for you to send to your doctor to request the test. Dennis Watson will provide you with personalized support throughout the process, including connecting with your doctor and collecting follow-up data. How can you access this technology and help Travera’s expanding validation efforts? Travera offers a free genetic test for cancer patients through cancer patient groups like Cancer Commons, xCures, and Cancer Patient Lab. They plan to continue research and partnerships to improve the accuracy and validate the test. They are prioritizing the list of drugs based on patient and doctor input, focusing on gynecologic and lung malignancies to build data, but also accept patients with other cancers. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Meeting Notes SUMMARY KEYWORDS drug, cells, work, patient, specimen, cancer cells, test, cancer, data, measuring, heterogeneity, CLIA, biopsy, response, assay, therapy, case, mass, call, process SPEAKERS Dennis Watson (66%), Rob Kimmerling (13%), Brian McCloskey (5%), Richard Anders (5%), Rick Stanton (3%), Gitte Pedersen (3%), Saed Sayad (2%), Alexis Hall (1%), Mark Stevens (1%) OUTLINE 1.Cancer patient data and technology. (0:00) 2.Personalized cancer treatment using ex vivo drug testing. (2:14) 3.Improving ex vivo drug testing using a new technology. (6:35) 4.Using mass measurement to detect cancer drug effectiveness. (11:50) 5.Cancer treatment personalized with live cell testing. (16:45) 6.Biopsy testing for cancer treatment. (23:43) 7.Cancer treatment and testing with a new approach. (29:14) 8.Cancer diagnosis and treatment using single-cell analysis. (34:17) 9.Drug testing and tumor cell isolation. (39:02) 10.Cancer drug response analysis and genomics. (44:05) 11.Liquid biopsy technology for cancer diagnosis and treatment. (48:06) 12.Analyzing cancer cell responses to drugs. (53:21) SUMMARY

•Cancer patient data and technology. 0:00

•Dennis Watson introduces himself and Rob Kimmerling and Mark Stevens, and explains the technology they will be presenting.

•Challenges in finding effective cancer treatment due to limited success with current guidelines.

•Dennis Watson highlights personalized drug testing for cancer patients, using a combination of single agents and drug combinations.

•Travera has developed a novel approach to ex vivo drug testing that measures the drug's impact on patient cells without the need to keep them alive.

•This approach is clinically available for the first time in 70+ years of research, allowing for more accurate testing of drug response in patient cells.

•Dennis Watson explains how the SMR invention at MIT allows for accurate mass measurement of individual cells, with a precision of 10 parts in 10 billion.

•The SMR technology can measure mass changes in cells as small as 5 nanometers, which is 100 times smaller than the wavelength of visible light.

•MIT researchers use precise measurement tool to detect cancer cell death in real-time, with potential to revolutionize cancer treatment.

•Dennis Watson discusses using a test kit to isolate cancer cells from a patient's tissue sample, then measuring the cells' response to a drug treatment.

•The predictive accuracy of the assay is currently 85%, but the Dennis Watson plans to continue research and partnerships to improve the validation.