Video 32 min

Building a Best-in-Class Precision Medicine Program

September 14th, 2017

The below text is a transcript from the webinar. Because it is a transcript, there may be oddities that arise from the process of translating speech into text. We recommend accessing the recording, above, to gain full context. 

Rakesh N.: Okay, why don't we go ahead and get started. Thank you everyone for joining our webinar today titled Building a Best-in-Class Precision Medicine Program, the Moffitt Cancer Center story. Joining me today from Moffitt Cancer Center is Dr. Tony Magliocco, he's the chair of Anatomic pathology, and the executive director of the Esoteric Laboratory services in a Morsani molecular diagnostic laboratory. I'm Rakesh Nagarajan, and chief informatics officer and founder of PierianDX.

Rakesh N.: Today we'll talk about Building a Best-in-Class Precision Medicine Program and Moffitt specific story. Before we get into that, I want to just give a few introductory slides, before, we let Tony steal the show. As you know, PierianDX supports molecular diagnostic laboratories, across a broad spectrum. So academic, medical centers, cancer centers, pediatric hospitals, commercial laboratories, reference laboratories and health systems.

Rakesh N.: Moffitt Cancer Center, was customer number one of ours as we became a company in May of 2014, and we will talk about their story today, and the journey that they've taken, and we've taken together with them since May of 2014. That story is really summarized here in this slide. So in May of 2014, Moffitt decided to partner with Pierian to address certain key needs, namely, laboratory workflow, support with secondary analysis, electronic medical record, integration, as well as access to a curated knowledge base that supported interpretation and reporting.

Rakesh N.: As we've expanded that relationship with Moffitt from May 2014 to date, one of our other key partnerships was with Illumina, where Moffitt chose Illumina as their vendor of choice for its sequencers as well as it's assays. So they started with the TruSight Tumor and a custom TruSeq myeloid assay, use the PierianDX validation services in order to support validation across both of those assays. And we'll talk a little bit about what that means near the end of the presentation.

Rakesh N.: Moffitt started then running, the first case in October of 2014. It added and used our gateway services in order to expand, in order to handle the expanded volume and heme. So this was a transitional model where technically sequencing was performed, within Pierian by partner laboratories and Moffitt then the professional review and sign out through that gateway offering. In January of 2016 Moffitt then formally moved to the official TruSight myeloid assay, expanded capacity.

Rakesh N.: And then in January of 2017, most recently, Moffitt added our interpretation services as well as the fusion acetate that Illumina offers. We're now working through with alumina and Moffitt to add the TruSight tumor 170 assay, that'll enable Moffitt to have a single report using DNA and RNA to report out on SNVs indels, copy number variance and structural variants include fusions including reporting of tumor mutation burden and micro satellite instability.

Rakesh N.: And again, these are themes and topics that, Tony will go into. I just want to give a brief on the clinical genomisis workspace, because that's the bedrock of all of the activities that has facilitated the workflow that I showed in the previous slide, namely the CGW or the clinical genomisis workspace is an end to end one space solution that allows molecular diagnostic laboratories to submit orders through HL7 messaging, or using our API in order to initiate the workflow within our system.

Rakesh N.: We integrate very tightly with sequencers, Illumina sequencers, the MiSeq, the HiSeq, the NextSeq among them, in order to then receive fast queue files as well as associated QC files that then get processed through secondary analysis to identify variants, classify variants, and annotate and interpret various using our knowledge base, draft reports and generated that can then be used for review and sign out by our laboratories or through our interpretation services.

Rakesh N.: The CGW as you know is assay and technology agnostic supporting wide variety of assays, amplicon hybrid capture based assays, as well as assays of different ... supporting different disease indications. Cancer end constitutional, our acquisition of two ... about a year ago, and it greatly enabled our constitutional capabilities including phenotype proven review and scoring, and our proprietary knowledge base, as a combination of both publicly available sources and highly curated sources including data from our partner sharing network where both clinical interpretations, and the identified aggregated patient data are shared.

Rakesh N.: Through this system, and the services that Moffitt has used at Pierian is now processed, almost 9,000 cases from October 2014 to date. So, with that brief introduction into the molecular diagnostic story and how Pierian supports that at Moffitt, I want to now hand it over to Tony who will talk about the precision medicine story and how everything got going at Moffitt awareness today, and where they'll be going in the future. Tony.

Dr. Tony M.: So thank you. Thanks Rakesh for that introduction and also thanks to PierianDX for accompanying us on that journey and enabling us to get our molecular lab launch so quickly into next generation. So, at Moffitt, it's really ... the focus that Moffitt is on cancer care. And, more recently the whole idea of precision medicine and personalized oncology has become paramount. And, this has led to actually some more strategic thinking at Moffitt in terms of what exactly do we mean by precision medicine and personalized oncology.

Dr. Tony M.: At Moffitt, we believe that it's more than just about measuring DNA mutations, and taking action on targeted or actionable targets, it's really about the whole precision medicine, and managing each patient as an individual, and to have optimal management of a patient of the cancer patient, we believe that you need a correct diagnosis, a correct treatment, at the correct time, and also to be able to monitor that in real time to be able to adjust as necessary. Next, please.

Dr. Tony M.: So the personalized oncology service at Moffitt really has three components that we're focusing on currently. The first is the development of advanced molecular diagnostic capabilities through in house testing and also partnerships with external reference labs, to be able to provide the molecular data that we need. The second component is the development of a strategy to use this data in an effective way for all of the tumor boards, in terms of creating personalized tumor boards for patients around disease sites.

Dr. Tony M.: And thirdly, is to try to do this in a financially prudent and efficient manner so that we don't bankrupt ourselves doing this, that this is a challenge to be able to do this in an efficient way that enables us to maintain financial responsibility. Next. Now, we believe that molecular diagnostics at this time is really central to the pillars of what we call precision medicine at Moffitt, and we've actually created four separate groups at Moffitt that focus on different aspects of precision medicine.

Dr. Tony M.: The first is targeted therapy in terms of matching molecular mutations to key drugs that have been identified for that. For example, EGFR mutations to tyrosine kinase inhibitors. The second area that's become more important is immunotherapy, that clearly and revolutionary changes in cancer treatment are happening right now, and we understand that immuno therapy is both toxic but highly effective and that there are new emerging molecular diagnostics that can guide this. Such things as measuring PDL 1, We're looking at mutational loads, so this is another area.

Dr. Tony M.: The third area is radiation therapy that we have some thought leaders in radiation oncology at Moffitt, particularly Lou Harrison. He's created a program called the future of radiation therapy or FORT, where we're really looking at how do we more effectively deliver radiation therapy. Over 70% of cancer patients get radiation therapy at some time in their treatment, but in many it's ineffective. So how do we identify patients who are intrinsically radio resistant, and those that respond best to therapy.

Dr. Tony M.: Another area at Moffitt where there's clear leadership with Dr. Bob Gatenby, is evolutionary oncology that we're applying principles of mathematical oncology and evolutionary dynamics to understand that sometimes if you over treat a tumor, you may actually push it into resistance and escape leading into a worse outcome. So there's some visionary trials that are underway trying to manage tumors and turn them into a chronicity state, where we can actually treat these tumors over much longer periods of time with less therapy, but the key is delivering the therapy at the correct intervals and that the correct dosage, to ensure a longterm outcome. Next, please.

Dr. Tony M.: Moffitt cancer center, Moffitt is a relatively young cancer center, was first initiated in 1981 through efforts of the H. Lee Moffitt, who was a speaker of the house in Florida at that time. And Lee Moffitt during his campaign, that tragedy struck and some of his closest advisors, I believe he lost two of them, to cancer very shortly after he was elected. And this prompted him to note that there is very or that Florida lacked having a comprehensive cancer center, and caused him to begin a bipartisan crusade to actually build a new cancer center in Florida, which he initiated back in 1981.

Dr. Tony M.: And he lobbied and successfully created funds through tobacco tax revenues, to create this new Center. And part of the challenge or part of the vision that he had at that time, was he ran around cancer centers around the country to determine what is the best model for a new cancer center when you're creating it from scratch. And, he determined, and his advisors determined that the best model was to have a freestanding cancer center, one that had a singular focus on cancer care, and that one that was multidisciplinary from the inception.

Dr. Tony M.: So that was the genesis and the vision of Moffitt and it rapidly grew, it rapidly attained NCI designation and continues to grow at a fairly healthy rate at over 12% per year. So currently we have over 4,000 faculty, we have over 17,000 new patients a year. We see up to 59,000 unique patients a year. There's over 200 beds and there's a well over $1.2 billion impact in that Tampa region, from the Moffitt Cancer Center, and Moffitt continues to grow today. Next.

Dr. Tony M.: So, as I noted, Moffitt is multidisciplinary. So there are not traditional departments of surgery or medicine. The teams are actually organized around tumor sites, so there are 13 separate tumor sites with practitioners that include radiation oncologists, surgeons, internal medicine experts, nursing staff, radiologists et cetera, around each tumor site. And these tumors sites have tumor board grounds, at least once a week. So at Moffitt, their tumor board rounds occurring every day. There are multiple ones occurring at any given time.

Dr. Tony M.: About half of our patients come from outside, so Moffitt is really focused on not providing community level cancer care, but really providing high level complex cancer care. So we have a feeder network from around the state that sends us the most complicated cases. As a policy for every case that comes in, there's a complete review of external material, presentation of tumor boards, and consensus diagnosis in terms of what the correct therapy strategies should be with continuous monitoring from those teams.

Dr. Tony M.: Moffitt also has a five scientific programs, cancer biology and evolution, immunology, molecular medicine, epidemiology, health outcomes and behavior. And this is what makes it a comprehensive cancer center covering all pillars of research and cancer care. Next. So some of the unique aspects of the Moffitt cancer center is that, Moffitt is the only NCI designated cancer center in Florida. It's organized around the tumor groups, and it has a really central commitment to personalized medicine. And this vision was first initiated back in 2003 with something called Total Cancer Care, where there was a program, a banking program, and a gene profile [inaudible 00:14:45] program where today over 150,000 patients have been enrolled in it.

Dr. Tony M.: In this program, the patients have given voluntary consent to have their medical data extracted, their tumors banked, and to undergo molecular testing. This program has really led to the foundation of an advanced banking program, and the data that's necessary to understand how a molecular changes in tumors, impact outcome and responses to therapy. This has led to the creation of a company called M2Gen, and now a much broader network called Orion that includes 13 medical centers around the country. Moffitt is also a pioneer in ACO and has formed one of the first ACOs with Florida blue.

Dr. Tony M.: As noted, all patients received tumor boards and pathology review. Some of the key areas that Moffitt works in are hematological malignancies, and has one of the largest bone marrow transplant programs in the country. It also has an innovative CAR T-cell therapy program, and a manufacturing FDA approved facility, one of the only ones in the nation, creating new CAR T-cell therapies. Moffitt has lead several immuno-oncology trials and has a national MDF tissue bank. In addition, there were spores in Melanoma and also in Thoracic oncology or their intensive research efforts. Next.

Dr. Tony M.: So, moving forward with personal medicine, the key components to creating a successful strategy or to first of all, have a clearly defined vision, to have a multidisciplinary team approach, and the willingness to share data and to develop best practices. So, this activity led to Moffitt creating a strategic initiative to create a world class next generation sequencing lab at Moffitt. And, I was recruited back in 2011 to help put this program together.

Dr. Tony M.: So, at that time Moffitt was very committed to building a lab and really structuring that lab, to support it's personalized vision. And this led to a lot of challenges in terms of a bad time. The future wasn't really that clear. We have to decide what is the correct technology platform, what assets should we run, how are we going to pay for it, what patients should be tested and so on. So, back in those days, it was quite a challenge. Next.

Dr. Tony M.: So here are some of the challenges there in terms of how do we organize all of this, what do we do about operational and quality control because there weren't any FDA approved devices that we could just take off the shelf and plug in and build. And essentially running next generation sequencing is almost like running a mini human genome project in a hospital lab. It was an extremely daunting and challenging activity.

Dr. Tony M.: So, these are some of the challenges that we had had to consider. And we actually spent about a year going over all of this, talking to our colleagues, visiting centers, and one of the visits we did go up to St Louis, to visit the University of Washington and looked at how they provided next generation sequencing services for their patients, and learned about period PierianDX at that time.

Dr. Tony M.: And that actually led to our partnership in terms of helping us figure out how to implement some of this technology. At this time, we also decided to go along with the Illumina, as we felt that they were leaders in the world and next generation sequencing and probably had some of the most robust technology at the time, and we decided to launch some of the TruSight tumor panels, the 26, and the myeloid panels that were available off the shelf at that time. And that's ... now one of the real drivers of creating this whole program is clinical champions.

Dr. Tony M.: And I'd mentioned this to other labs that are trying to get started in molecular diagnostics at academic medical centers. At Moffitt, we have three clear leaders that were really pushing the boundaries, leading clinical trials. They're Eric Haura, who leads the thoracic oncology spore, and we know that in solid tumors lung really push the field in terms of developing targeted therapies, requiring molecular diagnostics, creating a need for being able to sequence EGFR etc.

Dr. Tony M.: Dr. Weber, led many programs in melanoma and likewise their targeted therapies against the BRAF, also determined that we had to make these tests available, and make them at a CLIA standards, so they can be used for treatment of melanoma patients. And Dr. Alan List, who's now grown on to become CEO, was a clear visionary in terms of hematal, he's a hematal oncologist, a world renowned expert in myelodysplastic syndrome and has been completely supportive of bringing us the technologies that we need to be able to accept the diagnosis of malignant heme tumors.

Dr. Tony M.: So having these clinical leaders really facilitated the process and being able to get the institution behind the program to make the necessary investments to make the vision a reality. Next. Now, if we look at the evolution of personalized medicine over the last 20 years, some of the key global events where the development of the human genome project, and the complete human skeletons sequences back in 2000. Some of the other advances came from clinical trials and pharmacology where therapeutics against EGFRs, became approved, necessitating the need of molecular testing of tumors as the use of these agents, were contingent on patients having a demonstrable mutations, neither BRAF or EGFR or not having a K-Ras mutation.

Dr. Tony M.: The next advance was the development of next generation sequencing, which really commoditize the ability to do high throughput, massive parallel sequencing, at a reasonable cost, so that this could actually be performed in a clinical environment on real patients. And then most recently the immuno oncology revolution has transformed the way we think about treating cancer, so that we both have opportunities with targeted therapy and regulation of the immune system. Paralleling that at Moffitt, Moffitt was established initially as a multidisciplinary cancer center.

Dr. Tony M.: Total cancer care paralleled the development of the human genome project and created a foundation where there was infrastructure in place to be able to collect tumors, to be able to extract DNA and be able to perform sequencing in a research great facility. A lot of that was done in conjunction with Merck at the time, and there's quite a significant investment to the tune of about $150 million into that core infrastructure. So that really positioned Moffitt at a position where they felt comfortable bringing on a molecular diagnostic strategic plan, and building the molecular diagnostic labs.

Dr. Tony M.: It really kicked into play in 2011. The next most important aspect that happened was down the development of a personalized medicine service to really bring all of that molecular data and put it into practice in the clinics. And the key thing that happened there was the recruitment of Dr. Howard McLeod, who has revolutionized our personalized medicine service at Moffitt. So the molecular diagnostic labs were ... had to be put in a separate facility.

Dr. Tony M.: So these are created at the M2Gen's site, the Morsani molecular labs are a suite of labs that they're actually five labs, that are located in a floor of this building. So, the building was a shell building, part of it was occupied by M2Gen but Moffitt had it available. These labs operate under the hospital CLIA license, and they were constructed in this facility using about 20,000 feet of space. Next. The governance of the labs are actually five labs that were put into this building.

Dr. Tony M.: Each one has a separate medical director, a separate menu, but they all work in coordination with each other, as there are shared managers, shared administrators and the two chairs, myself and Dr. Lynn Moscinski provide executive oversight to these facilities. Now the two most important labs in my opinion in terms of moving the personalized services forward, are the routine molecular lab, and then you asked a development lab. We broke these labs into two separate labs to facilitate the process of innovation where new assets are basically evaluated and worked up the CLIA grade in the new asset development lab.

Dr. Tony M.: And once they are ready for routine use, they're transferred into the routine molecular lab where they become routine, order or both and are basically run through the EHR, and the results are ordered and delivered back to the physicians as required. Next. There are a number of devices, I won't go over all of them, but the lab is equipped with a classical sequencing, next generation sequencing, and also expression technologies such as nano string and asset metrics. We also have an advanced digital imaging lab that I won't really talk about today.

Dr. Tony M.: Next. So the governance is, as I said, there are two main labs in production and the development lab. There are two medical directors and an administrator. And one thing that we use to a CLIA PhD scientists in the innovation lab. We have a team of five scientists, each one of them is assigned to a different technology platform, and they've been really instrumental in helping us develop these assets and bring them up to CLIA grade. Once they're CLIA grade they're then transferred over to more. To technology staff and more routine operations where routine quality assurance practices go into place and so on.

Dr. Tony M.: Now the overall lab is governed by an operational committee that basically reviews the priority of new tests. So you can imagine there's a lot of demand on creating new tests, so we have to manage that demand and also look at what are we sending out. So we use a suite of reference Labs. We monitor that, if the use of reference lab becomes extremely heavy, we consider repatriating those tests and bringing those tests in house. We're also generating, as Rakesh mentioned, over 9,000 cases.

Dr. Tony M.: That data is going into the central data research repositories at Moffitt, that's something we call the HFRI or the data warehouse, and data from the electronic medical record goes in there, data from total cancer care, from Orien and also from a reference lab such as foundation and genoptixs and now there's populate this research warehouse, and that data is really available to both the hospital administrators and also researchers who want to access that data to look at frequency of mutations, or link it to data outcomes or treatments or trials, et cetera. Next.

Dr. Tony M.: Now I want to highlight that one of the key jewels of Moffitt is the personalized medicine service, and this is a creation and ambition of Dr. Howard McCloed and there's several components to this program. So Howard was recruited a few years ago. He's a deform, so he's an expert in clinical trials and then therapeutics. And one of the key components that was credited with the personalized medicine consultation. So whenever an advanced molecular test is ordered, for example, foundation or a very large panel, the results come back to the oncologist.

Dr. Tony M.: But it also triggers an automatic personalized medicine consultation where the personalized medicine service we'll review that, much like the radiologist will review a CT Scan, they'll make a recommendation and assist the oncologists with what that external report means. They will facilitate the oncologist accessing a standard treatment, access to a clinical trial, and also potentially access to an off label treatment. The team will also work closely with payers to ensure that the patient gets the best quality care and also that they can get reimbursed for the treatments that they receive.

Dr. Tony M.: And we've had considerable success working with our local reimbursers and pairs, well through this program. The other components of the personalized medicine service include the molecular tumor boards. These are held on a weekly basis for particularly complex cases. So I'm essentially three or four cases per week, that have particular complexity to them or discussed their molecular tumor boards. We'll talk a little bit more in depth or a multidisciplinary boards, and they facilitate analyzing this complex information.

Dr. Tony M.: Another important aspect of the program is a training program. So it's a fellowship training program that's three years long and that recruits fellows from a variety of disciplines, so, there are pharmacists in it, but they're also pathologists have gone through this program and medical oncologists. So a variety of trainings go through this program. The vision of the program is to create experts in personalized medicine that will either stay at Moffitt or could go to other medical centers in the United States, or even a community practices to help those centers build their own personalized medicine services.

Dr. Tony M.: One of the other things that the personalized medicine service does is pathway development. So at Moffitt, we have a program, we're creating pathways of treatments for each cancer condition that we see. And this is an important payer strategy. So we've negotiated with our payers that, we will follow best evidence. So basically NCCN guidelines, clinical trials, and Moffitt continues to contribute to those trials and update them, but that we document that we practice oncology in an evidence based way, and that it's predictable in how we will manage cases.

Dr. Tony M.: So personalized medicine helps develop these pathways. They're updated on a frequent basis, at least every six months as to when certain molecular tests should be done, what the indications are, when they should be repeated, when alternate therapies should be considered, and so on. So pathways are a very important component to manage how we do personalized medicine, and how we allocate resources and treatment. The other services I mentioned is clinical trial matching, so the personalized medicine who keeps an updated list of all trials in terms of where they're occurring, the ones that are in house, the ones that are in Florida and they work closely with the patients to determine which trials might be suitable for them.

Dr. Tony M.: Next, the genomics action committee is basically our molecular tumor board rounds, but it's not just a molecular rounds. It includes genetics, review of complex cases by personalized medicine experts, and it actually leads to a treatment strategy. So it's not just looking at the mutations. There is an effort to actually provide useful direction for patients that come to this, in terms of whether the patient can be assigned to a clinical trial, or whether an off label use should be considered, and there's close work with the patient's insurance, and others to ensure that we can potentially get reimbursed for these treatment decisions.

Dr. Tony M.: And that the board has had significant success in achieving that. Next. So clearly putting this into practice involves a multidisciplinary team, that includes pathologist, fellows, even bench scientists are coming on board. We also have bond pharmaticians on the team, because sometimes we've determined that from some of the external labs that data's sheltered, that the dry lab can sometimes be erroneous, if incorrect filters have been applied, and there's opportunities to do new bioinformatics analysis and so on. So, the team is always central to this, and this is clearly a work in progress, but the message is, is that you need help from all corners.

Dr. Tony M.: Everything from basic scientists, bond pharmaticians, pathologists and billing experts to really make this work. Next. So, as alluded to earlier, that the pathways of care a really central of Moffitt, these are living documents, so they're not really shizzled and stone telling our oncologist, you must follow this. These are guidelines of what we believe is the best current evidence based practice around particular tumor sites. And we continuously update these, and we make these available in terms of NCCN, and contribute to it. So it's a work in progress.

Dr. Tony M.: At Moffitt, there's anywhere up to 300 open clinical trials at any one time. So we get a lot of experience in terms of new agents, in terms of what the complications are, in terms of what are the best patients and so on to select for these new compounds that are being evaluated. Next. Now, some comments on how our test development lab works. So as noted, we have a team of PhD scientists. The scientists are CLIA certified. So not only do they have a PhD and some of them with many years of research experience at prestigious centers, they have also undergone CLIA certification to enable them to work, and provide test results.

Dr. Tony M.: We've organized them around the various test platforms such as next generation sequencing, expression technology, liquid biopsy, bioinformatics, et cetera. And so they work individually with the team of technicians, and as assays are proposed, they're handed off to these scientists to help lead projects around each assay to really design what will be the validation process, what specimens do they need, how are they going to implement that, analyze the data, overcome the concerns, and really get those assays packaged as LDTs.

Dr. Tony M.: Once they're packaged they're then handed off to the production lab. The production lab then runs them. If they assay fails or runs into some difficulty, the scientists are there to review and determine if there's any opportunities to learn from problems with the assays to troubleshoot, etc. And this has been a continuously growing process. We continually recruit additional scientists, we add new platforms, and we continuously extend our capability. And I believe that's somewhat essential to keep the two components separate, the diagnostic routine lab versus the test development lab.

Dr. Tony M.: They actually use the same equipment, but organizationally they run somewhat independently, but they still overall run as a team. So sometimes the technologists will rotate, so they may be working on a routine case one week, the next week they may be working on the test development lab, running basically validation samples. So the team is integrated, but the projects are clearly identified, and separated with clear milestones. Our managers help shepherd these projects through these teams. Next. Next. Next. Hello? Next.

Rakesh N.: So it seemed like we had a network issue in the middle there. Tony, are you still on the line?

Dr. Tony M.: Can you hear me?

Rakesh N.: Yeah. Perfect. So I'm sorry, about three minutes ago we got cut out. So you were right near the end of the discussion of the scientific teams, and keeping the routine molecular lab separate from the test development component.

Dr. Tony M.: Okay, let's go on to the next slide. Yeah and for those on the line, clearly most of these molecular tests are not available as FDA approved tests. So we have to work them up as lab developed tests, and this is a significant challenge. As you know that the lab must prove that these tests have accuracy, precision, we must develop the reportable range, and reference range, reproducibility, etc. For every one of these tests, and that can take anywhere from six months to longer to get a test launched.

Dr. Tony M.: Next. Now thinking about when we're developing our initial panels, there was a question as to whether we should have a small panel versus a large panel. There's certain advantages to having a smaller panel and that the workflow is sometimes easier. The results, there's less variance of uncertain significance. It can be easier to sign out. Sometimes you may have an increased sensitivity. The trade off with moving to a greater panel, is that there's more treatment options become available. However, the complexity of the data becomes more daunting.

Dr. Tony M.: However, we're being driven more and more to a more complex panel, because simply there's more treatment options available for patients. And also now we're seeing that with immuno oncology that using mutational load and micro satellite instability as indicators for therapy across tumor sites, that these calculations are best done on much larger panels such as TST170, that has about a half a mega base of data available to be able to do more accurate calculation of mutational load. Next. So I'll turn it back over to Rakesh to discuss how Pierian is helping with managing these complex pipelines.

Rakesh N.: Great. Thanks so much Tony. So as Tony talked about really the assay and the informatics are tied together, and the two together then become in cap proficiency, the total challenge, although there are wet and dry lab challenges as well in cap proficiency testing. You know, we recognize that at Pierian and our validated informatics pipelines are really tied to assays that our partner laboratories develop and implement. So for example, at Moffitt, as they brought on new assays through the test development laboratory, we've partnered with them to validate the informatics side by side as the assay is validated with appropriate samples.

Rakesh N.: And those may be samples that are methods based as well as previously characterized samples in a clinical setting that then comprise the entire validation strategy. The last piece of proficiency testing and a challenge in next generation sequencing is the actual clinical interpretation, and in order to support those components, Pierian in January launched the interpretation services, and we truly believe that it takes the right mix of technology, and platform along with human medical expertise to interpret variance in final reporting.

Rakesh N.: You know as you guys know, the technology and platforms through the CGW allows for a comprehensive workflow as well as the knowledge base, that I'll talk about in a few slides that enables automated classification of variance as well as in a constitutional setting, semi automated approaches to evaluate a subset of the ACMG evidence codes. The CGW dust synthesizes information, makes that available for various scientists, medical directors to then perform report finalization.

Rakesh N.: That report finalization then, that's the human medical expertise in the interpretation service that's provided by Pierian really then hones in on clinical trial matching based on molecular findings, and this could be tuned at a site by site level based on their specific SOPs and trials that are open as Tony mentioned. Of course, being able to fully edit the report to draft clinical interpretations and reclassify variants based on the newest available knowledge, including potentially even cutting edge trials that are available, as Tony mentioned, to refine the variant classification using established guidelines and evidence codes to really complete that ACMG classification in the constitutional workflow, and then really to evaluate pathway crosstalk in order to make final recommendations and match the trials as well.

Rakesh N.: As Tony mentioned, the field of precision medicine is really daunting from a data point of view. This slide really just summarizes the data generated in a laboratory, whether that's molecular diagnostics, pharmaco kinetics, the immune response, radio mix, pharmacogenomics, liquid biopsy and genetics, and these data ... and majority of these data Pierian's platform supports already today. So obviously molecular diagnostics with our expansion of supporting side of genetic testing and the chromosomal micro-array that's coming out at the end of this month, genetic testing, pharmacogenomic testing through next generation or prior technologies as well as working again with Moffitt and Illumina on liquid biopsy approaches are all part of our portfolio.

Rakesh N.: The knowledge challenge really has been summarized here where we've got to marry up that primary data that we talked about on the previous slide, with a knowledge base that can enable and facilitate the human professional team, whether our team or a combination of our team and our laboratories team, to make final interpretations, and that knowledge base is really composed of publicly available sources as well as sources that are available publicly but are clean and curated to normalized oncologies that we have within our system, as well as very highly curated proprietary data sets including ACMG evidence code determination, NCCN, and ASCO guidelines and [inaudible 00:44:06] breaking abstract curation, FDA approved labels, clinical trials for more precise molecular matching.

Rakesh N.: The final component of our knowledge base and a key bedrock are shared clinical interpretations from our partner. So close to 50 partners now that are sharing thousands of interpretations, and these are their prior experience as they're evaluating interpretation .... I'm sorry, variants in the context of one or more tumor types of other diseases in the constitutional setting. These are all key components of the knowledge base and again, the network effect of that knowledge base is growing with the number of partners that we've got. I'm going to hand it back to Tony then to really conclude on what's next. Where's Moffitt Cancer Center going on this journey and precision medicine.

Dr. Tony M.: I agree. Thanks Rakesh and again, thank you to Pierian for really assisting with pulling of this data together. And as I noted, we're moving towards larger and larger panels, and this creates a huge challenge for the molecular pathologist. So being able to rapidly analyze these complex panels, to sift through variance of uncertain significance and of no one significance, and of almost known significance. And also to understand the implication the germline alterations, is becoming more and more challenging.

Dr. Tony M.: We also know that the reimbursements are very limited for the professional components of doing this work, so it's an extraordinarily labor-some task with very little reimbursement. So the ability to streamline those pipelines are really important. Now thinking about next generation sequencing, I think next generation sequencing, I like to think of it as, you know, it's an incredible tool that can be applied to many different aspects of pathology and oncology much like the microscope transformed our understanding of cancer.

Dr. Tony M.: I think next generation sequencing can really revolutionize our understanding of the very fabric of these tumors. So for next generation sequencing, we can sequence a tumor and identify the targets of therapy. We can understand germline inherited, so looking at risk, but now we also know that things such as BRAF gene mutations may predict responsiveness to pap inhibitors or achieving platinum. For large clinical trials where there are multiple targets, in the past we might have to take a very small specimen, submit it to 20 different tests and run out of specimens by running a large multiplex panel, we can screen a patient for dozens of trials and treatments simultaneously with one assay, such as the mask ... the match trials and the basket trials.

Dr. Tony M.: Pharmaco genomics is an emerging area as well that some patients devolved neurotoxicity and toxicities, certain therapies. So we certainly don't want to treat a patient that will experience severe toxicity. So understanding pharmacogenomics is also a key aspect of personalized medicine. Not to forget that in pathology certain rare tumors, so like certain types of rare sarcomas, or salivary gland tumors are actually defined by underlying translocations. So even though these translocations or specific mutations may not be specifically actionable, they help with the correct classification of a tumor.

Dr. Tony M.: And to me that's also vitally important because you really need to know what is the diagnosis before you embark on a set of treatments. So improving classification is also a very important step. And we also now know that cancers evolve. So we see them at one snapshot in time, but more and more patients are seeing multiple cycles of therapy. They're having recurrent tumors, they're being enrolled on evolutionary trials where there's adaptive therapy administrated. So there's the new challenge of monitoring what is happening to a tumor in real time. Is it responding? We now know it's mind boggling that in immuno oncology there something like 600 open trials at anyone time.

Dr. Tony M.: It seems like the phase three trial of the futures will probably become nonexistent. It won't be possible to do that. That really, we're going to have to do individualized trials and that means selecting the best combinations of therapy for a patient, but also monitoring them in real time, and adjusting treatments as necessary, determining whether a patient is responding or not responding, because there is no possible way to test every possible combination of immunotherapy with targeted therapy with dosing.

Dr. Tony M.: So it's a huge challenge trying to manage that, and I think that a treatment response monitoring will become a fundamental component of that in the future. Next. So bringing it back, we can think of at the beginning, a lot of people think of personalized medicine as basically doing mutational analysis, and matching patients to a targeted therapy, at Moffitt, we believe it's much more than that, that molecular diagnostics, personalized medicine, precision medicine, and personalized oncology applies to all aspects of the cancer treatment spectrum. In surgery which patients benefit from surgery, who should be operated on, are the margins clear? What's the molecular staging?

Dr. Tony M.: Even classical cytotoxics, we now know that certain molecular mutations such as BRCA mutations may predict response to things like platinum therapy, so that we can avoid toxicity, renal failure, etc, by better selecting patients. Targeted therapy, it's obvious that this is what really drove molecular diagnostics, forcing us to classify tumors, identify those that will respond to BRAF inhibitors, and track be BRCA etc. Immunotherapy, huge revolution, and now we're seeing that things like mutational load is independent of tumor site, and is becoming, a basically an indicator, an FDA approved indicator for selection of therapy.

Dr. Tony M.: And now we're learning more about evolution, being able to monitor tumors as they respond to therapy and change, adjusting our therapy to achieve ultimate and optimal outcomes in our patients by avoiding toxicity. Next. So at Moffitt we're continually advancing in all of these fronts. So immuno oncology an area of great interest, huge amount of effort, and as I noted, there's over 800 open trials currently evaluating immuno oncology agents. I think it's important that we identify which patients will benefit from immunotherapies, which patients are toxic to it, how to add in other types of treatment along with immuno therapy. So this is an area of considerable research.

Dr. Tony M.: We're looking at even Ex Vivo models, PDX models, Ex Vivo graphs, etc. To try to understand this space better. Going back to looking at gene expression. So this can be done by next generation sequencing as well by RNA seek or by using gene expression platforms such as nano string RAF metrics. Understanding the gene expression can give us a clue about what's in the microenvironment, what inflammatory cells are there. Is a tumor more likely to respond to immunotherapy, etc, and I think you'll see more use of gene expression in the future.

Dr. Tony M.: In addition, some of the radiation response signatures, RSI, which was developed at Moffitt, and is now going into some clinical trials, is based on a signature of 12 genes that can predict whether a tumor will be likely to respond to radiation treatment or not. The the other aspect is liquid biopsies. We're seeing more and more challenges and demands from our clinical teams. For example, the neuro oncology team is asking us can we measure mutations in CSF and this led us to a challenge when we determined, "Wow, when we set up our original platforms, we really only validated next gen sequencing for formal and fixed paraffin embedded material," and this is a cautionary note to other labs.

Dr. Tony M.: Consider other types of specimens that you might receive. You could be receiving cystic fluids, CSF, urine, blood, etc. And you need to think about qualifying those samples at the time you set up your assay, and we're seeing more and more demands on this. We're also looking at ultra sensitive technologies to be able to look for mutations such as digital PCR, and other methods so that we can monitor on an ongoing basis response to therapy in a cost effective way. Another area of great interest is the microbiome.

Dr. Tony M.: Certainly we know that human papillomavirus is an important indicator of response in many tumor types, particularly have neck tumors, so understanding how viruses play a role as a factor, but also more information is coming up as how to bacteria in the GI system cause the patient to respond to therapies, immunotherapy, etc. So an area of great research in terms of looking at microbiome and also other types of molecules as well, such as micro RNA, long noncoding RNA, exosomes, etc. Finally, pharmacogenomics is an important area of investigation in terms of finding patients who are potentially toxic to a therapy, so that we can avoid triggering a toxic reaction in patients is very important as well.

Dr. Tony M.: Next. So bringing it back together. That today a patient's journey with cancer is very complicated, that basically they go through ... There may be a high risk patient, they go through screening programs, they have a diagnosis, they might have to select from a variety of treatments. They get their treatments, and they may have different types of response. In fact, their tumor may change after treatment, and may have to reconsider. So it's an ongoing process. A patient may go through two or three cycles of therapy.

Dr. Tony M.: They may go away for several years and come back again. So there's really a ... a patient's journey with cancer is becoming more, and more complex. And I think it comes back to that, in terms of oncology that treating patients, it's really about information, about understanding the disease, about understanding how to integrate different aspects of the patient's own genome. The genome or the cancer, how the cancer is evolving, how the patient's immune system is responding to the cancer, and how the cancer's responding to different treatments. So it's becoming more and more complex, and there are many, many more, healthcare professionals being involved.

Dr. Tony M.: So we see that it's really a daunting challenge synthesizing all of this information and bringing it together. A further complicating factor that a patient may go to multiple different medical centers, they may be being treated at a family doctor, they may go to a local surgery center, or a community cancer center. They may go to a major academic cancer center, they may get involved in an industry trial, they may go to a different cancer center, etc. So we've got many, many different sources of information that we need to track, and synthesize to really provide the best possible care for our patients. Next. And, an overview of the biology of cancer.

Dr. Tony M.: Cancer's a four dimensional disease. Essentially, there's tumor heterogeneity, cells evolve, cells react to treatments such as radiation, targeted therapies, etc. Distant metastasis change. And this is an ongoing challenge as we learn more more about the disease. We need ways to monitor this. We need ways to better select patients, and their treatment and to avoid toxicity. And this is really the heart of personalized medicine, precision medicine. Next. So I want to acknowledge all of the people that have made the journey of Moffitt possible.

Dr. Tony M.: Certainly Pierian and MBX who were our partners all along and helping us get our assays up and running reported, and all of the teams of scientists that have participated in developing these assays and particularly Moffitt leadership who has put molecular diagnostics as a key strategic initiative, and I'd also like to acknowledge the Morsani family, who have given philanthropic donations to help support development of key programs as well. So thank you for your attention, I'll turn it back over to Rakesh.

Rakesh N.: Great. Thank you so much Tony for that comprehensive review of how things started at Moffitt, and that deep story. I greatly appreciate the opportunity that you've given us Pierian and partnering with you on that journey, and we look forward to continuing on that journey together. For the audience, thank you so much for attending the webinar today. We have a few logistical things before we send you off. One is that the webinar is being recorded, and will be available on our website for others to review.

Rakesh N.: I know a few of you, in the questions said you'd have to drop off early. We'll send you that information. I also want to put a plug in for our next webinar on October 12th at noon central time where, we'll highlight the TruSight Tumor 170 assay, and our implementation of that assay along with three of our major partners, including Moffitt. Thanks again for attending today. And tony, thanks again for presenting such an educational webinar.

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