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The Importance of Registries in the Personalized Medicine Revolution: A Q&A With the President of CURE-1, Dane Dickson, MD
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The Importance of Registries in the Personalized Medicine Revolution: A Q&A With the President of CURE-1, Dane Dickson, MD

Dickson: It is a reality of medicine that, for a pharmaceutical company, you want to identify a group of patients who respond to a therapy, so you are going to appropriately enrich your patient population to show a benefit. To do that, you find a companion diagnostic, and you lock it down, and you do the test with those patients. We have done this with HER2 patients. HER2/HER3-positive patients or HER2 FISH–amplified patients will benefit from therapy. However, is it possible that patients with a lower level of HER2 will also respond? Probably, because the testing is not perfect. If you get better testing, we are going to identity patients with tests other than the companion diagnostics that the drug was approved with. Can we identify other patients who would respond that we know will have a benefit in those patients? Next-generation sequencing can allow us to find patients who will be missed. For example: EGFR and lung cancer. Original testing looked at very specific alterations such as exon 19 and some other areas. We know that we are missing patients who may have large translocations, insertions, and deletions that just were not picked up in the diagnostics that might be picked up in a more precise test such as next-generation sequencing. You can identify patients and put them on therapy that would not have been traditionally included, because they did not fit into that nice area that was determined by the companion diagnostics. Once we identify these patients who are not seen in traditional means, they also will benefit from therapy.

AJMC®: Currently, many payers limit coverage of genetic testing to companion diagnostics that are approved with medications. How is this likely to change as next-generation sequencing becomes less costly over time and potentially can offer, as you mentioned, a potentially more sensitive diagnosis in precision medicine?

Dickson: We can never talk about sensitivity without talking about specificity of testing. Sensitivity means that I can identify a patient who has a biomarker that will respond to a specific patient so I can personalize the medication to that patient. Specificity means how many patients do I test who are truly false-positives. The problem with false-positives is that we put people on very expensive therapies that will not benefit them because the testing is not good enough to be 100% sensitive and specific. One-hundred percent sensitive means you identify everyone who has the alterations that will respond to the treatment. One-hundred percent specific means that everyone negative is truly negative and that you do not miss anyone who can be treated. What we do not know in precision medicine is what the clinical specificity and sensitivity is for these patients. And so, with payers, we recognize that we have to find a balance. The testing will identify patients who will benefit at lower cost and lower hospitalization rates.

Treat those patients with broad-based chemotherapy. There is also a concern that some patients are false-positives. We put them on targeted therapy that is costly and not approved, and we increase costs. We need to find the right balance between the 2 groups—between sensitivity and specificity. The only way this is done is by collecting data and through registries.

AJMC®: How does precision medicine play into the shifting paradigm of drug review and potentially approval using real-world data, registries, and big data analytics to make real change happen in the field of medicine?

Dickson: I always tell people, you can completely digitize the complete works of Shakespeare, and you can analyze them in any way that you want and you will never find an answer to treat the common cold or common tumor. The size of the data does not matter. What matters is the quality of the data, the granularity of the data, and how well you can access it. When we start looking at big data, the hope is that we have enough granularity in that data that we can identify individual tests for individual patients. The problem that we are running into is that we do not have standardization of next-generation sequencing, so you have different sensitivities and specificity levels for next-generation sequencing. It is possible that you can look through 100 patients who were tested by next-generation sequencing by various methods, and you may say you didn’t see a substantial benefit for that testing—not because the testing didn’t work but because there were so many different variables in play that you didn’t understand the granularity of those variables to determine the benefit. What the FDA, payers, and laboratories are looking for is: “Tell us if it works,” and the only way we can do that is with this level of granularity. That means being able to look at the test and look at the patient and look at the treatments. As time goes on, registries are going to be great adjuncts to drug approvals, and registries can come back and answer questions that the pharmaceutical companies will not ask initially when they had to choose specific tests, like who are patients whom we are missing from therapy: Bristol-Myers Squibbs’ argument for lung cancer. They decided they were going to do PD-L1 [programmed death ligand 1] testing at such a low level that they did not meet significance. None of us really believed that it didn’t work—just that they chose the wrong biomarker and the wrong level. We could potentially identify patients whom, although the FDA approves with a companion diagnostic, we can also go through and find those other patients. Here is a crucial point about lung cancer, though: The problem we run into right now is that there are so many different tests you have to run on a lung cancer patient. When the patient has metastatic lung cancer disease, the patient has fine needle aspiration biopsy results. We estimate you can get 3 to 4 companion diagnostic tests out of 1 biopsy, and so anytime we rebiopsy a patient, we end up costing the payer significant money. By doing next-generation sequencing off tissue specimens up front, we can replace many of these companion diagnostics. This saves money for the payers by avoiding these rebiopsies. Or if it’s later, where you can do a liquid biopsy on these patients, then you can save money by avoiding a biopsy altogether. It is not so much the diagnostic testing as it is the procedure to get the tissue that could be saved initially, particularly in the lung cancer arena.

AJMC®: How does next-generation sequencing help address some of the heterogeneous features of individual cancers, in which cancer cells have multiple clones, each different mutations, and with clones evolving over time?

Dickson: This is the great question. If I have a tumor that has 5 different subtypes, and we identified 1 clone out of those subtypes, and that clone is only 3% of the tumor burden, for that specific patient, that really doesn’t matter. And so there is some elegance that we should be doing multiple biopsies to determine if we are checking for different types of clones. The initial biopsy may have showed only one type of biomarker. Maybe the initial biopsy did not show any biomarker because we missed the area that is now proliferating. The problem is I don’t know any data that show that being able to do sequential biomarkers other than in the lung cancer patients who fail anti-EGFR therapy after being diagnosed with an EGFR alteration are now developing P70M mutations. I think that’s the best example, where serial testing can have benefit but it may not require next-generation sequencing to show that 1 very specific alteration. As time goes on, we may begin to figure out how we need to be able to use this testing. Maybe we do need to be looking at several different biopsies or liquid biopsies in patients, but until we get more data on how that testing leads to treatments and outcomes, saying, “Let’s do multiple biopsies, but we aren’t sure if it’s going to make any difference to the patient,” is going to be something hard for the payers to swallow.

AJMC®: As a practicing clinician, how have you seen precision medicine already change in the way care is delivered, and what do you see for the future?

Dickson: One case report: A 45-year-old woman comes in with metastatic small cell lung cancer. All the major labs say that she is EGFR-negative. We order a test that wasn’t even paid for by her insurance company at the time and find that she had an EGFR-mutated lung cancer. We have given her 6 months of cytotoxic chemotherapy with no benefit so extensive that she was unable to work or do anything except come into the office, get treatment, and go home with the adverse effects of chemotherapy. Once we found that she had the EGFR alteration, and now 4 years out, she is still working and still feeling great. And so, from a quality standpoint, better testing led to better diagnosis and better treatment. We are seeing this all the time. When I started my career 17 years ago, almost 20 years from now, we were treating as if everyone were an average person. Now we are getting to the molecular era, where we are recognizing the start of agents that target estrogen receptors. Patients with tumors that tested positive for estrogen receptors are treated with drugs like tamoxifen; we can save them from additional treatment. First, selective estrogen receptor modulators, then HER2-targeting agents, and, now in the most recent 5 to 10 years, we have started to define malignancy based not on the tissue origin but on the molecular basis of that disease. As time goes on, I expect that it will not matter where the tumor comes from. For example, in pancreatic cancer, I might say, “This cancer is subtype 573,” and state the mutation burden with it. Also important, if anyone thinks sequencing is the endgame here, it is not. It is actually the starting point. We have to add proteins, we have to understand transcription, the epigenetics, the epibiome; we have to understand all these things together. We need to put them together to help identify what is going on in the patients. And so truly as molecular and precision medicine evolves, we have to be able to lock down areas that we don’t know. Now I know what sequencing does, and I can standardize that. Now let’s go down and look at proteins and see what we can learn by adding proteins to sequencing. Now let’s look at immune function. We have to be able to dissect the tumor from the molecular basis to really determine what we can do with that. We need to start to build standardized registries with testing that has been standardized or with outcomes that have been associated with that testing, to allow us to understand what that testing is doing and how to prove that testing. If we don’t use those standards to add further layers of precision medicine or precision diagnostics, we are likely to get a lot of information or a lot of big data, and we are never going to know what to do with it because it is way too complicated and none of it can be matched with other big data that’s out there.

Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
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