MOLDX General Questions V10 (M00086, v10) 20161024

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 MOLDX General Questions V10 (M00086, v10) 20161024

MolDX General Questions (M00086, V10)

     

 

Select the category of questions you would like to view:

• MolDX General Questions
• MolDX Registration
• Technical Assessment (TA)
• Billing and Coding
• Reimbursement
• Coverage Issues

MolDX General Questions

1. What is the purpose of the MolDX program?
To identify tests, determine coverage, and determine reimbursement.

2. How does this program help claim adjudication?
Once the required information is received and a unique identifier is assigned, Palmetto MolDX can determine coverage and payment without documentation review. This process removes the need for the provider to submit large amounts of additional information with every claim and expedites claim payment.

3. What laboratories will be affected?
All private, reference, and hospital laboratories that perform molecular diagnostic testing and submit claims to Medicare in JE, JF JM, J15 J5, or J8 on a CMS 1500 Claim Form or electronic claims on a 5010-837P are affected by this program. (Please reference the specific jurisdiction MDT policy for effective dates.)

4. What molecular diagnostic assays/tests are included in MolDX?
Tests that meet the description for CPT codes 81161-81383, Tier 2 CPT codes, 81400-81408, Genomic Sequencing Providers and Other Molecular Multianalyte Assays (MAA), 81410-81471, *MAA with Algorithmic Analyses, 81490-81595 microdissection codes, 88380-88381, HCPCS professional interpretation code, G0452, Proprietary MAA, 0001M-00010M , and not otherwise classified CPT codes (NOC), 81479, 81599, 84999, 85999, 86849, 87999, 88199, 88299, 88399, and 89398.  For more information review MolDX article Test Registration (M00019). Submit questions about specific tests/assays not described in this chart, to MolDX@PalmettoGBA.com.

5. Is the MolDX Program national in scope?
The MolDX Program currently covers JE (American Samoa, CA, Guam, HI, NV, North Mariana Islands), JF (AK, AZ, ID, MT, ND, OR, SD, UT, WA, WY), JM (NC, SC, VA, WV), J15 (KY, OH), J5 (IA, MO, KS, NE), and J8 (MI, IN). Labs that perform services for patients in those states, must register in order to submit a Medicare claim.

6. Will this project align with the AMA effort to publish CPT codes for MDT?
The AMA efforts and the MolDX program are not related or interdependent.

7. How does a lab register a test?  
Review MolDX Test Registration (M00019) for instructions and the registration link.

8. What is McKesson’s involvement in the MolDX program?
McKesson is the contracted technology provider for the MolDX program. Palmetto will leverage the McKesson Diagnostics Exchange™ (DEX) the online test registry and technical assessment components of the MolDX program. DEX is a web-based service designed to identify tests and help establish transparency in the evidence-based coverage of them. This tool enables labs to confidentially share test information with MolDX online

9. What information will be made available to the public?
MolDX information collected for the registry will only be available to those labs electing to submit a Z-Code Identifier application and is consistent with the public/private indications therein.

10. Will the MolDX Program expand to other jurisdictions?
At this time CMS has not determined how MolDX will be expanded. Palmetto GBA will continue to administer active LCDs and articles published in JM, Noridian will administer the MolDX in JE and JF, CGS will administer MolDX in J15, and WPS will administer MolDX in J5 and J8.

MolDX Registration (Z-Code applications)

1. Should the manufacturer or the performing lab register an FDA-approved, in vitro diagnostic test that utilizes a kit?
The manufacturer and the performing labs should submit an application. The MolDX team will review each submission for accuracy and assign each performing lab that reports the test without modifications the same code. The lab must submit an application in order to obtain an identifier for submission. Without the application information, MolDX cannot determine the kit is unmodified and the labs that intend to use the kit.

2. Should the manufacturer also register for Alternative Summary Reporting (ASR's) that have not been FDA approved?
No.

3. If multiple tests may be performed and billed within one assay, is the lab required to register each test within the assay?
A unique identifier application is required for a single assay that may involve multiple tests in order to produce a single result.

4. Is a unique identifier application required for each specimen source, i.e. blood and bone marrow, for the same test? 
No.

5. In addition to the unique identifier application, should labs send peer-reviewed articles to ensure MolDX has enough information to make a positive coverage determination?
No. Peer-reviewed literature used in coverage determination is  required only during the Technical Assessment (TA) process.

6. Is a unique identifier application required for an FDA-approved test?
The FDA approval process ensures only the clinical and analytical validity of the test. The FDA does not include clinical utility in their review, which is required to establish Medicare coverage.

7. Is a new unique identifier required for updated tests or a test expansion?
If the updated or expanded test is substantively different, you will need to submit an application and a new identifier will be assigned.

8. After a test is granted a unique identifier, can a hospital bill their respective MAC directly for the test using the assigned code? 
Yes. Although MolDX has NOT expanded to Part A, hospitals may add the Z-Code Identifier as additional information to help reviewers determine coverage.

9. If a pathologist plans to submit a claim for the professional component of a MolDX test, should the pathologist register the test?
No. In the rare instance when an additional and separate professional interpretation is needed, the pathologist must obtain the ID for the interpreted test from the performing lab. A G0452 claim service may ONLY be submitted when the clinician interprets the raw data for a test. The clinician must use the Z-Code Identifier assigned to the test interpreted.

Sample Claim:

Service	CPT Code	Z-Code Identifier
BCR-ABL, major breakpoint	81260	Z1234
Interpretation	G0452 (HCPCS)	Z1234

10. Is a unique identifier required for tests billed with a NOC code?
Yes. Review MolDX Test Registration (M00019)

11. Are labs expected to register tests sent to another lab to perform?
You are only required to register tests if you plan to submit claims to jurisdictions that implement MolDX.  Please indicate the referenced lab in the application.

12. If a lab performs the same exact test from two different locations, operating under two different CLIA numbers, will the lab be required to submit both tests for unique identifiers?
If the test process is standardized and the same method is used to acquire the results in both locations, labs will only have to submit one application for the test. However, if there is a difference in the method, an application will be required from both locations.

13. Should labs that provide lab products alert their lab customers about MolDX registration requirements? 
Yes.

14. If the kit used in an LDT is not FDA-approved, should the lab apply for a unique identifier for that kit?  
Yes.

15. How do labs identify test reagents in the MolDX unique identifier application forms?
Enter the information in the 'contributing component' field.

16. Are labs required to register tests that use a code in the MolDX code range and a code that is not listed in the MolDX range of codes (i.e., CPT codes 87001-87905)?
Yes.

17. When a laboratory modifies an FDA approved kit, will MolDX require a new unique identifier? 
Yes. If a lab modifies a registered test, the resulting test is considered an LDT and will require a separate application.

18.  If a California laboratory is billing for a test referred to a laboratory located outside of the jurisdiction, which lab is responsible for registering the test?
It is the responsibility of the billing provider to obtain a unique identifier.

19. If multiple laboratories purchase the same test and each lab registers the test, how will MolDX notify the laboratory regarding the assigned identifier?
MolDX will follow the registration process. A review of the MolDX database is performed to ensure a unique identifier has not been previously assigned. If a test has been registered, the lab will receive the assigned identifier. The only difference is the identifier for that particular test has already been established prior to the current lab’s application.

20.  Are hospital labs that file institutional claims and providers that file professional claims exempt from the requirement to obtain a unique identifier?
At this time the MolDX Program applies to JE, JF and JM Part B claim submission. J15 Part B claim submission starts in October 2015. Part B includes professional claims or claims submitted by a pathologist for the professional component of a test. Therefore, a pathologist submitting claims for a professional MolDX service would be required to register a test.

Technical Assessment (TA)

1. What types of tests may require a TA?

• Lab developed tests (LDT’s) performed using either established or novel technology with un-established clinical utility 
• Molecular or genetic testing that has not been validated for clinical and analytical validity
• Tests using modified versions of FDA registered kits
• Tests using a new molecular or genetic technological testing platform
• Genetic or molecular target with un-established clinical utility 
• Tests reported with one of the following CPT codes: 

Tier 2 CPT Codes	81400-81479
Genomic Sequencing Procedures and Other  Molecular Multianalyte Assays (MAA)	81410-81471
*MAA with Algorithmic Analyses	81500-81595
Not otherwise classified (NOC) CPT Codes	81479, 815999, 84999, 85999, 86849,87999, 88199, 88299, 88399, 89398

2. What tests may not require a TA?

• State of New York (NYS) certified tests that are industry accepted and have established clinical utility. However, MolDX may request the package used to determine the NYS certification to make a coverage decision. The approval letter or a copy of the NYS listing may be used to demonstrate NYS approval.
• Test that use FDA approved kits in an unmodified form
• New tests approved under a Premarket Approval (PMA)-(which under FDA policy from the early '90s requires evidence of clinical utility) and the test is reported with the stacking codes, a unique identifier is required, but a TA is not
• Tests that using existing or novel technology for molecular or genetic targets with established clinical utility

3. When should labs submit the clinical data dossier (TA) to MolDX? 
MolDX will accept a TA after an identifier has been assigned. MolDX will NOT accept any information prior to registration and assignment of a unique identifier. For labs that do not submit the clinical data, MolDX will prioritize according to claims data and make requests.

4. Where do I find guidance on creating a comprehensive TA dossier for submission? 
All guidance information for the creation of a TA dossier and the review process can be found under Technical Assessment (TA) Process (M00095) on the MolDX website.

5. Where do I find information on the level of evidence I need for a full review of my test?
The Clinical Test Evaluation Process (CTEP) (M00096) outlines a process used by the Subject Matter Experts (SME) and the MolDX Executive Committee (EC) to assess new tests.

6. Can I arrange a pre-submission meeting with MolDX to discuss my assay?
Yes. After you have registered your test and received a unique ID for the test, follow the steps outlined in the Pre-submission Review Process (M00117). 

7. How do I submit my dossier to MolDX?
The Technical Assessment Submission Instructions (M00115) provide the steps to submit your dossier through the registry.  

8. Why was an invalid determination issued on my TA submission?
A TA must be submitted with the test ID in the subject line. MolDX will not initiate a TA without an ID.  Additionally, all communication regarding tests MUST have the ID in the subject line. This enables the MolDX staff to accurately track test documents and avoid unnecessary delays and misplaced documents. 

9. How long will it take to complete the TA process and receive a coverage determination? 
Upon submission of the dossier, there is a 30 day period to determine if the submission is complete. Once the MolDX Team has determined that the dossier is complete, a 90 day review period begins.

10. The information requested by MolDX to support analytical validity may be considered proprietary intellectual property. How will MolDX assure the security and confidentiality of that information?
Only MolDX and its subject matter experts will have access to proprietary information submitted through the McKesson DEX account.

11. Are there options in lieu of two published articles that support clinical utility?
Review The MolDX clinical Test Evaluation Process (CTEP)-M00096

12. Who will perform the technical assessments (TA)?
Subject matter experts (SME) from academia and industry will assess the scientific literature. The MolDX team will perform the assessment for all other components.

13. Will MolDX share the conclusions of one SME with other SME?
No. An SME will only have access to their assigned TA. Also, each SME will only have access to the scientific literature submitted with the TA. All other components will be reviewed by the MolDX Team.  Only the MolDX Team will review proprietary information.

14. What are the conflict of interest principles that will guide MolDX in determining whether or not an SME should be permitted to conduct a technical assessment? 
The conflict of interest principles were developed by Blue Cross Blue Shield of South Carolina and are standard for the industry.

15. What types of disclosures will be required from the SMEs in order to facilitate a conflict of interest determination?
The disclosures required by the SME were developed by Blue Cross Blue Shield of South Carolina for government contractors and are standard for the industry.

16. Will there be an opportunity for a laboratory to comment on a TA report before it is finalized?
Yes. Questions/concerns that surface during the TA will be communicated with the test developer.

17. Will laboratories and/or manufacturers be allowed to resubmit a coverage request after they have received a non-coverage determination?
Yes. If substantive new information, not included in the initial submission, becomes available, a new request may be submitted 6 months after the initial non-coverage determination was issued.

18. What is the difference in the logistical steps to initiate a formal coverage determination and the process to initiate coverage determination with a TA? 
It is the same process.

19. When a manufacturer has a new test approved under a PMA (which under FDA policy from the early '90s requires evidence of clinical utility) and the test is reported with the stacking codes, a unique identifier is required, but a TA is not. If the lab billed the same test with an NOC code, both a unique identifier and TA would be required.
The NOC is not the only considered fact about the TA. If, as in your example, a test is vetted for science and clinical utility, the information can be collected at the time the unique identifier is assigned. At that time the lab may bill the NOC with the assigned unique identifier.

20. Since the clinical and economic utility data will be reviewed as part of the coverage determination (and not during the TA), will the clinical utility evidence be sent out for subject matter expert review or will that evidence be reviewed only within MolDX? What about the economic utility evidence? 
If the clinical utility and economic data are in the public domain (published), SME will review it. If it is proprietary, then MolDX Team will review it.

21. Is there a difference in the expected timeline for a coverage determination and a TA?
It is the same.

22. Can a lab provide services prior to the TA approval date in anticipation of a favorable determination and then submit the claims after the approval? 
To avoid overpayment requests, labs should freeze services until coverage is approved and appropriate billing and coding guidelines are published.

23. If a lab plans to submit a test for FDA approval, can the test be submitted for a TA first?
If the test is currently in the FDA process, please hold the TA request until the FDA has completed its determination. However, if you have not submitted the test to the FDA, you may request a TA. The FDA submission should be done prior to TA request. Once you receive an FDA determination, you may submit a TA request.

24. Should labs submit applications for Research Use Only Reagents (RUO)?
No.

25. Are manufacturers that provide items such as ASR or RUO used in an LDT required to register the items?
No. Only the LDT developer and biller of the LDT are required to register for a unique identifier. However, an LDT developer must disclose the ASR and RUO used in the developed LDT on the application.

26. How should labs outline test reagents in the TA?  
Submit the package insert for the kit with the materials.

27. When multiple large numbers of reagents are used in a test, how should labs identify the specific details for the reagents?
Provide sufficient information to identify the manufacturer and the product specifications (PI).

28. Should protocols for technical evaluation be included in the TA submission?
Yes.

29. Will a completed TA be made available on the MolDX website?
Only an approved TA will be published. However, MolDX may publish a coverage/non-coverage article or an LCD based on the TA.

30. How should a laboratory designate proprietary information on the TA submission?
MolDX will consider any information that is not publicly available to be proprietary information.

31. During the TA process, when should a laboratory submit pricing information to support a payment rate determination?
Any pricing information will be requested from the laboratory after a favorable coverage determination has been made.

32. How will MolDX determine reimbursement for a test?
Reimbursement is based on accurate submitted codes regardless of the cost of the platform used. For tests that are reported with an NOC code, pricing will be determined based on the information collected in the TA. Each test will be assessed on an individual basis and priced according to the most appropriate method. the MolDX Team will review the pricing method with the individual lab upon completion of the TA.

33. What is the TA process for labs performing and or submitting tests outside a MolDX jurisdiction?  
The TA process is open to all lab developers and their tests regardless of geographic location. In order to receive a coverage determination, it is the responsibility of the billing laboratory to submit a TA. Claims paid for tests that do not meet the mandated reasonable and necessary criteria may be subject to overpayment requests.

34. What resources are available to help me determine the best CPT code to bill my new test?      
All test applications are reviewed for correct CPT mapping by the MolDX Team. If an error or a disparity is identified, the Team will notify the test provider for clarification. After a TA is complete, the Team will notify the test provider with the final coding, billing, coverage, and if applicable allowed fee for the test.

Billing and Coding

1. What are the effective dates of the codes ZSB01 and ZB728?
Z-Code Identifiers are effective at time of assignment.

2. What action should a lab take if they believe they may have incorrectly billed for a MolDX service?
If you believe your practice has made a MolDX billing/coding error, you may take the following corrective actions:

• Complete a Self-Audit
• Identify incorrect submissions
• Prevent further claim submission errors
• Consider Self-Disclosure Protocol
• Self-disclosure guidelines available on the OIG website  

3. Where do I enter the assigned MolDX test identifier on my claim?
If you are submitting a paper claim, this information would be placed in Block 19 of the CMS 1500 claim form. For Electronic claims (5010)837P (Physician/Professional),use the SV101-7 field adjacent to each CPT code used to report the service. This field maps to the Line item Description (This field is required for NOC codes to avoid rejection by the Common Edit Module Front end).

4. If the lab submits a MolDX covered test without a unique identifier after the implementation date, will MolDX reject the claim as 'unprocessable' with no appeal rights or send a denial with a specific or new claim denial message?  
Claims received without additional information required to adjudicate the claim will be rejected.

5. If a laboratory performs multiple assays/tests on a single patient on one date of service, will the lab have to split the different assays/tests into multiple claims? 
MolDX considers the performance of multiple molecular biomarkers, regardless of whether the test requisition lists the tests as a panel or individually, and completed on a single sample to be a 'panel' of tests. Therefore, each panel should be registered and billed with a single CPT code and a unique MolDX identifier.

6. If a CPT code appears on the claim more than once to report an additional test, is a modifier required?
Yes. Append with CPT modifier 91. See the claim example for question 8.

7. How do I submit a claim for ONLY the professional interpretation of a test?
Although rare, when an additional and separate professional interpretation is needed, the pathologist must obtain the ID for the interpreted test from the performing lab.

Sample Claim:
Lab A performed BCR-ABL, major breakpoint assigned with Z1234.

Clinician interpretation should be submitted as follows:

Service	HCPCS Code	Z-Code Identifier
Interpretation	G0452	Z1234

8. Will CCI edits continue to be in effect on MolDX services?
Yes. Because the Z-Code Identifier only acts to label the specific test and is not a code set, MolDX service providers must append CPT codes within the CCI edits with a 59 CPT modifier to indicate the CCI Column II code is a different test.

Note: The 59 CPT modifier should ONLY be appended to CCI Column II codes.

9. There is only one Box 19 on my paper claim form. How do I identify more than one test or assay on my claim? 
Due to the limitations of the paper claim, labs using this form will be limited to only one test/assay/unique identifier per claim. To bill a MolDX test on a paper claim, enter the unique identifier in Box 19 and then enter only the CPT code(s) for that identifier on the claim. Remember: You may only file one test per paper claim submission.

10. I registered a single gene test performed on a Next Generation Sequencing (NGS) platform that is listed on the MolDX approved gene test list. Why is my claim denied?
MolDX does NOT consider the T1 and T2 descriptions appropriate for genes interrogated on an NGS platform. Please reference the coding and billing guidelines in reference article M00130.

Reimbursement

1. Will a microarray service be reimbursed at the same rate for all microarrays or will the diagnosis differentiate payment? For example, will 1800+ genes of one array be viewed differently than an 1800+ array with a different algorithm?
Diagnosis will not differentiate payment. Payment is based on the accurate CPT/HCPCS codes submitted. However, if there are less than 500 probes in an array, CPT code 83999 must be used and MolDX will price the NOC code.

2. Does the DRG segregate the CPT code to a different payment?
No.

3. Will ABN’s be valid with the unique identifier? 
The unique identifier is only additional information, not a billing code.

4. Will MolDX pay test services provided prior to the TA approval date?
All new test services will be denied as noncovered until the test completes the TA process and reasonable and necessary criteria is established. Claims submission for tests in the TA process should be suspended until a final coverage determination is made.

5. If I already have a PTI for my test, how do I switch to a Z-Code Identifier so I can use the online TA feature? 
Send a request to switch the ID to MolDX@PalmettoGBA.com.

6. Is the reimbursement for a flow cytometry affected by MolDX?
Palmetto GBA has an active LCD for Flow Cytometry and will continue to administer coverage as published in that policy the same as any other active policy.

Coverage Issues

1. Is a confirmatory FISH test a covered benefit?
Confirmatory testing is considered a quality check and is not a covered Medicare benefit.

2. If a lab needs a denial for a noncovered test in order to bill a secondary payor, should they submit the test for MolDX registration?
Yes.

FOCR Hill Hearing FDA IVD LDT October 13, 2016

http://www.focr.org/events/friends-cancer-research-senate-briefing-future-precision-medicine-patient-care

Friends of Cancer Research Senate Briefing: The Future of Precision Medicine & Patient Care

Senate Briefing

The Future of Precision Medicine & Patient Care:

Current Landscape in Genomic Testing

Thursday, October 13th, 2016 - 12:00pm-1:00pm

430 Dirksen Senate Office Building

Washington, DC

 

 

Panelists: 

Jonathan Leff, Chairman, Deerfield Institute

Mike Pellini, Chief Executive Officer, Foundation Medicine

Jeff Allen, President and CEO, Friends of Cancer Research

Andrea Ferris, President and Chairman, LUNGevity

John Iafrate, Associate in Pathology, Massachusetts General Hospital

Jeff Shuren, Director, Center for Devices and Radiological Health, FDA

About the issue: Recent years have seen a proliferation in genomic testing options in oncology as more and more treatments are developed to target genetic alterations only present in subsets of the overall population. 

Additionally, advances in genomic medicine are taking place within a complex regulatory environment, with oversight split between the Food and Drug Administration (FDA) and the Centers for Medicare & Medicaid Services (CMS).

In order to promote progress in genomic testing in the field of oncology, this discussion will address:

• The current regulatory landscape for genomic tests
• Trends in the use of genomic tests in clinical practice
• Strategies to enhance patient safety and access to innovative, high quality tests
• Development of new technologies to advance precision medicine

Friends, in partnership with The Deerfield Institute, recently released the results of a comprehensive medical chart audit, which elucidated the trends of genomic testing in oncology. These results were published in the September issue of Personalized Medicine in Oncology, entitled "Use of FDA-Approved and Laboratory-Developed Tests in Advanced Non-Small Cell Lung Cancer: Results of a Retrospective Market Analysis."

Jeff Allen, Friends' President and CEO, also recently testified at the Senate Health, Education, Labor, and Pensions Committee hearing titled, "Laboratory Testing in the Era of Precision Medicine." His full testimony can be read by clicking HERE.

Lunch will be provided. This is a widely attended event.

www.focr.org        @CancerResrch

"Use of FDA-Approved and Laboratory-Developed Tests in Advanced Non-Small Cell Lung Cancer: Results of a Retrospective Market Analysis."

Date: 

Thursday, October 13, 2016 -

12:00pm to 1:00pm

Event Type: 

Congressional Briefing

https://events.r20.constantcontact.com/register/eventReg?llr=kwe6axbab&oeidk=a07ed8t7uas416d0d86

Invited Speakers of NCI 9/29-9/30/2016 Workshop on ctDNA. (Online Archive)

Invited Speakers of NCI 9/29-9/30/2016 Workshop on ctDNA.

https://ncifrederick.cancer.gov/events/circulatingtumorDNA/invited_speakers.asp

  

Invited Speakers

Luis Alberto Diaz, Jr, M.D.

Associate Professor of Oncology, Johns Hopkins University

Dr. Luis Diaz is a leading authority in oncology, having pioneered several genomic diagnostic and therapeutic approaches for cancer. He is an attending physician at the Johns Hopkins Hospital where he specializes in the treatment of pancreatic and colorectal cancers. He is currently a member of the Ludwig Center for Cancer Genetics and Therapeutics where he directs translational medicine and is the Director of the Swim Across America Lab. D r. Diaz has undergraduate and medical degrees from the University of Michigan, and completed residency training at the Osler Medical Service at Johns Hopkins and medical oncology training at the Sidney Kimmel Cancer Center at Johns Hopkins.

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Maximilian Diehn MD, PhD.

Assistant Professor of Radiology Oncology Stanford University

is an Assistant Professor of Radiation Oncology at Stanford University, with co-appointments in the Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine. He is a board certified Radiation Oncologist and specializes in the treatment of lung cancers. Dr. Diehn's current research program spans laboratory, translational, and clinical studies. His areas of interest include cancer genomics, stem cell biology, and lung cancer biology. His group has developed an ultrasensitive and specific method for detection of circulating tumor DNA called Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Current work is focused on applying CAPP-Seq to a range of tumor types and clinical contexts, with a particular emphasis on analyses of tumor heterogeneity and detection of minimal residual disease. He received his Bachelor's Degree in Biochemical Sciences from Harvard College and his M.D./Ph.D. in Biophysics from Stanford University.

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Peter Kuhn, PhD.

Dean's Professor of Biological Sciences and Professor of Medicine, Biomedical Engineering, University of Southern California

Dr. Kuhn is a scientist and entrepreneur with a career long commitment in personalized medicine and individualized patient care. He is focused on the redesign of cancer care. Dr. Kuhn is the Dean's Professor of Biological Sciences and Professor of Medicine and Engineering at USC, a founding member of the Michelson Center for Convergent Biosciences, a co-founder of the BRIDGE @ USC and director of the Southern California Physics Oncology Center. Prof. Kuhn's strategy is to advance our understanding of the human body to improve the human condition. His research is shedding new light at how cancer spreads through the body. This new science will lead to a personalized care strategy that is biologically informed and clinically actionable. Dr. Kuhn is a physicist who trained initially at the Julius Maximilians Universität Würzburg, Germany, before receiving his Masters in Physics at the University of Albany, Albany, NY in 1993 and his Ph.D. in 1995. He then moved to Stanford University where he later joined the faculties of Medicine and Accelerator Physics. From 2002 to 2014 he established a translational science program at the Scripps Research in La Jolla, CA that brought together over forty scientists from basic, engineering and medical sciences to work on understanding the spread of cancer in the human body. He has published over 200 peer scientific articles and patents as a result of his research. He founded Epic Sciences, Inc. in 2009 to develop cancer diagnostic products. Today Epic Sciences is a premier partner to most pharmaceutical and biotech companies in the development of precision companion diagnostics for cancer care. The University of Southern California (USC) recruited Dr. Kuhn in 2014 to advance the next frontier of human scale science that can improve the human condition. At the convergence of biological, engineering and medical sciences will we learn how major diseases from cancer to neurodegenerative to autoimmune diseases evolve in and how we can improve the outcomes for patients.

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Tony E. Godfrey, PhD

Associate Chair, Surgical Research and Associate Professor of Surgery, Boston University

Dr. Godfrey earned a bachelor's of science degree in biochemistry from Brunel University in England, followed by a doctorate in molecular biology and biochemistry, also from Brunel. He attended the University of California, San Francisco, for postdoctoral fellowships and managed UCSF's Genome Analysis Core Facility before taking his first faculty position at the University of Pittsburgh in 1999. Dr. Godfrey's research is focused on cancer genetics and molecular pathology. Research projects use state-of-the-art genetic and genomic approaches to address clinical needs in the areas of cancer diagnosis, prognosis and therapy. Currently the major focus of Dr. Godfrey's research is on Barrett's esophagus and esophageal adenocarcinoma; a tumor with rapidly increasing incidence in the United States and other western countries. The Godfrey lab works closely with translational research teams comprised of surgeons, pathologists and oncologists in order to develop new molecular approaches to cancer detection, staging and treatment.

Abstract Title: Detection of Tumor-specific Mutations in Circulating, Cell-free DNA: Potential for a Biomarker in Esophageal Adenocarcinoma

Recent studies have shown that tumor-specific DNA from multiple types of tumors can be detected circulating in plasma and this has raised the possibility of “liquid biopsies” using mutated tumor DNA as a potential diagnostic and prognostic biomarker. Detection of mutations with allele frequencies below 0.1% remains challenging however given that circulating cell-free DNA is highly degraded and in low abundance. Detection of multiple different mutations in the same sample presents an additional challenge particularly when the mutation panel may change from patient to patient. We have developed a novel approach, called SimSen-Seq, to introduce molecular barcodes into sequencing libraries with DNA inputs as low as 5ng. Barcodes enable differentiation of true mutants from background noise introduced by Taq polymerase errors and permits detection of variant alleles with frequencies below 0.1%. The barcodes are protected from mis-priming using a hairpin structure which permits a high degree of multiplexing and flexibility for detection of multiple mutations from one plasma sample. We are using this technology to test the utility of liquid biopsy as a biomarker for esophageal adenocarcinoma (EAC) diagnosis and disease monitoring.

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Tza-Huei (Jeff) Wang

Professor, Department of Mechanical Engineering, Department of Biomedical Engineering, Institute for NanoBioTechnology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University

Dr. Wang's primary research focus is the development of new technologies and methods for molecular analysis of diseases and biomedical research via advances in micro- and nano-scale sciences. He has contributed to developments in single-molecule fluorescence spectroscopy, microfluidics and nano-biosensors for genetic and epigenetic biomarker-based diagnostics of cancer, infectious disease and an array of other diseases. Wang also has taken the leading role in the development of quantum dot-fluorescence resonance energy transfer (QD-FRET) DNA nanosensors, which have been used to detect a variety of cancer biomarkers, including point mutations, DNA methylation and gene copy variations in clinical laboratories. In addition, he has pioneered the development of single molecule detection (SMD) technologies for biomarker screening. Wang is an inventor of 20 patents, and has authored > 150 research articles and delivered > 90 invited talks. He received the NSF CAREER Award in 2006, CSR Jorge Heller Award in 2007, ASGR Excellence in Research Award in 2007, JALA Ten Award in 2011, JHU Discover Award in 2015 and several Best Paper Awards in technical conferences and workshops.

Abstract Title: Translating Nanotechnology and Microfluidics for Analysis of DNA Methylation

Tumorigenesis is a multi-step process resulting from gain-of-function or loss-of-function alterations, occurring through genetic or epigenetic abnormalities. The most well-studied epigenetic alteration is the transcriptional silencing of tumor suppressor genes associated with aberrant CpG DNA hypermethylation of gene promoter regions. Numerous reports demonstrate promoter hypermethylation as a promising biomarker for different types of cancer. The use of tumor-specific methylated circulating DNA as a biomarker is particularly attractive for cancer screening and companion diagnostics, as blood is obtained through a simple, relatively noninvasive procedure. While promising, reliable detection of methylation as marker is hampered by the limited quantity of circulating DNA in blood. This talk describes the development of new technology platforms using micro and nanotechnologies to enhance the both the sample preparation and detection sensitivity for analyzing circulating methylated DNA. Examples includes the use of the quantum dot (QD)-FRET technology to improve the limit of detection and the use of combined digital detection and high precision melt analysis to distinguish individual copies of epiallelic species at single-CpG-site resolution. The talk also describes a silica superparamagnetic particles-based single-tube sample preparation process that enhances the efficiency of recovery of circulating DNA and subsequent bisulfite conversion. The streamlined process has led to the development of a microfluidic droplet platform of sample preparation that promises for robust DNA methylation analysis in the point of care settings.

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Julie E. Lang, MD, FACS

Director, USC Breast Cancer Program
Associate Professor of Surgery, University of Southern California

Julie Lang, MD, FACS is an Associate Professor at the Keck School of Medicine of USC. She earned her medical degree from the University of North Carolina, Chapel Hill. She then went on to complete a Surgery residency and a postdoctoral research fellowship in breast cancer research at the University of California, San Francisco. She completed her breast surgical oncology fellowship at the UT-MD Anderson Cancer Center in 2007. She served as the Director of Breast Surgical Oncology at the Arizona Cancer Center for 5 years, then joined the faculty of USC in 2012. Dr. Lang is an expert in the field of breast surgical oncology, with strong expertise in both clinical care and research in the field of breast cancer. She is experienced with advanced breast surgical techniques, such as skin sparing, nipple sparing mastectomies, and coordinating reconstructive surgery with colleagues in Plastic Surgery. Her research focuses, clinical trials, locally advanced/inflammatory breast cancer and radiation-induced sarcoma. Dr. Lang is an avid breast cancer researcher and leads the Breast Surgical Oncology Translational Research Laboratory at the Norris Comprehensive Cancer Center. Dr. Lang is very patient centered and strives to utilize technology and evidenced based medicine to the benefit of her patients. She has published numerous peer reviewed articles and book chapters on the topic of breast cancer.

Abstract Title: Advantages and Disadvantages of ctDNA vs CTC Assays

Circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) assays have each been demonstrated to be prognostic in breast cancer. CTCs and ctDNA research have made great progress demonstrating correlation with clinical grade biomarkers/tumor growth and sequencing of tumors. There is a compelling case for studying these circulating biomarkers to predict treatment response. Specific advantages and disadvantages for applying these two types of liquid biopsies towards prospective translational studies will be discussed.

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Geoffrey R. Oxnard, MD.

Assistant Professor of Medicine, Harvard Medical School

Dr. Oxnard is a thoracic oncologist at the Dana-Farber Cancer Institute and an Assistant Professor of Medicine at Harvard Medical School. He is a clinic-based translational investigator whose research focuses on the development of biomarkers and targeted therapies for management of genotype-defined NSCLC populations and drug resistance. He was previously awarded with a Young Investigator Award and Career Development Award from the Conquer Cancer Foundation of ASCO, a Career Development Award from the US Department of Defense, and has recently been named a Damon Runyon Clinical Investigator. He leads or co-leads a number of ongoing correlative studies including the NCI's ALCHEMIST study aiming to genomically characterize resected NSCLC, the INHERIT EGFR study of germline EGFR T790M mutations, and the FNIH VOL-PACT study of advanced imaging metrics for efficient clinical trial design.

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Katherine Varley, PhD

Assistant Professor, Oncological Sciences, University of Utah

Katherine (K-T) Varley, PhD, is an investigator at Huntsman Cancer Institute and an assistant professor in the Department of Oncological Sciences at the University of Utah. Dr. Varley's research focuses on using next-generation sequencing assays and computational analyses to study the gene expression, transcription factor binding and DNA methylation patterns in breast cancer. Her goals are to answer fundamental questions about how epigenetic gene regulation is disrupted in cancer cells as well as to discover drug targets and biomarkers that may have a more immediate impact on breast cancer treatment. Research in her lab involves the development of new molecular methods and bioinformatics approaches to explore the cancer genome and to translate discoveries into clinical tools that improve patient care. Recently Dr. Varley's lab has modified the targeted sequencing method she developed, called Patch PCR, in order to quantify low frequency mutations and DNA methylation. They are applying this approach to measure rare circulating tumor DNA molecules in blood plasma from breast cancer patients

Abstract Title: Patch PCR: A targeted sequencing approach to quantify breast cancer ctDNA

Monitoring for disease recurrence is an essential component of the clinical management of breast cancer. Approximately 1.5 million breast cancer survivors will see their oncologists for follow-up physical exams and imaging tests this year. Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive monitoring for breast cancer recurrence because it can be detected early, several months before imaging-based detection of metastasis. Additionally, tumor mutations that confer resistance to hormone therapy can be detected in ctDNA, which can help inform treatment decisions. Our goal is to develop a clinical-scale ctDNA test that can be used to monitor breast cancer patients for disease recurrence and determine if a recurrent tumor is resistant to hormone therapy. Several years ago we developed Patch PCR, a method for targeted sequencing that utilizes thermo-stable ligation and PCR to capture up to 1,000 targeted loci in parallel for sequencing on next-generation instruments. Recently, we have enhanced Patch PCR by incorporating unique molecule indexes during the ligation-based capture, which enables the accurate quantification of rare ctDNA molecules in cell free DNA isolated from blood plasma. We designed a breast cancer mutation panel that covers enough loci so that ctDNA from most patients’ tumors can be detected. We have also designed a breast cancer DNA methylation panel, which enables the quantification of ctDNA based upon the detection of breast cancer-specific DNA methylation patterns. We have reduced the cost, time, and complexity of the test so that it can be performed routinely and reliably in a CLIA laboratory environment. We will describe the development, evaluation, and optimization of these tests.

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Muhammed Murtaza MD, PhD

Translational Genomics Research Institute, Mayo Clinic Arizona

Dr. Muhammed Murtaza received his medical degree from Aga Khan University in Karachi, Pakistan before moving to Trinity College and Cancer Research UK Cambridge Institute to get a PhD from the University of Cambridge. He started his research career investigating germline determinants of disease predisposition in South Asians before moving into development of cancer diagnostics through cell-free DNA analysis. He moved to Arizona in 2014 as Assistant Professor and Co-Director of the Center for Noninvasive Diagnostics at TGen and Mayo Clinic Arizona, where he setup a research program focused on liquid biopsies for patients with cancer. Dr. Murtaza’s current research focuses on developing novel methods to leverage circulating tumor DNA analysis as a longitudinal diagnostic tool for patients with localized and metastatic cancers.

Abstract Title: Capturing tumor heterogeneity and clonal evolution using ctDNA analysis

ctDNA analysis is moving rapidly towards clinical applications such as noninvasive tumor genotyping, re-biopsies and monitoring of treatment response. However, there is little evidence evaluating the extent of tumor heterogeneity that can be captured in plasma DNA and we don't yet understand how to make sense of discordant results between plasma and tumor samples. In this talk, I will share insights gained from targeted and exome-wide comparisons between tumor biopsies and longitudinal plasma samples in patients with breast and ovarian cancer.

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Jamie Holloway, PhD

Breast cancer Survivor, patient Advocate

As a graduate student at Georgetown University, Jamie Holloway studied breast cancer progression while gaining an appreciation for the impact of research on patients. Nearly ten years after earning her PhD, she was diagnosed with triple negative breast cancer. Following treatment and with no evidence of disease, she now provides a patient's perspective to researchers as a member of Georgetown Breast Cancer Advocates and bridges the gap between scientists and patients as a Precision Medicine Advocate for Cure Forward and the Patient Advocate for the Metastatic Breast Cancer Project at the Broad Institute of MIT and Harvard.

Abstract Title: Patient advocacy perspective in the use of ctDNA in clinical trials and beyond

This talk will focus on the patient's perspective of the utilization of ctDNA in the clinical trials process and beyond, into clinical practice. Specifically, the need to validate the procedure will be discussed, as will some problems that may be encountered. Significant benefits of utilizing ctDNA within the scope of a clinical trial will be considered, and additional discussion will focus on patient benefits that can be derived from the incorporation of this technology into the standard of care. Furthermore, the promise for the use of ctDNA in the monitoring of disease progression in the in-treatment and the NED populations will be explored.

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Theresa Zhang, PhD

Vice President, Research Services, Personal Genome Diagnostics

Dr. Theresa Zhang joined PGDx after a decade at Merck Research Laboratories, where she led the molecular profiling group supporting Oncology drug development at all stages. During her tenure at Merck, Dr. Zhang oversaw large scale efforts for identifying patient selection biomarkers, advanced multiple candidate biomarkers for clinical validation and led the development of specially designed CLIA assays for use in cancer clinical trials. Dr. Zhang received B.S. degrees from Peking University and Bridgewater College and a Ph.D. from the University of Virginia. She completed a Post-doctoral Fellowship in bioinformatics at Cold Spring Harbor Laboratories. Dr. Zhang is a co-author of numerous scientific publications and a frequent presenter at scientific meetings.

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Kelli Bramlett

Director, R&D, Thermo Fisher Scientific

Kelli Bramlett leads a team of scientists in the Clinical Sequencing Division of Life Sciences Solutions, Thermo Fisher Scientific. She guides the Research and Development effort focused on creating innovation sequencing and data analysis solutions for cfDNA analysis and liquid biopsy with next generation sequencing. The team has also developed many sequencing products and applications for RNA analysis using next generation sequencing. Prior to joining Thermo Fisher Scientific, Ms. Bramlett was a drug development scientist at Ely Lilly and Company where she led a team of scientists specializing in gene regulation and nuclear receptor biology to identify novel drug targets. Ms. Bramlett built her background and experience in gene regulation through prior academic positions at Baylor College of Medicine and M.D. Anderson Cancer Center. Kelli holds an undergraduate degree in Chemistry from Rice University in Houston, TX and a Master's Degree in Pharmacology from Indiana University School of Medicine in Indianapolis, IN.

Abstract Title: Oncomine™ cfDNA Assays – experiences in development and technical validation

Ms. Bramlett will present work done to develop the new Oncomine cfDNA assays for research use in detecting somatic variation from cfDNA. The focus will be on the technology utilized in these new targeted sequencing methods as well as the testing used to technically validate these research materials. She will also present some results from clinical research samples and discuss the early customer experience.

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Travis Clark, PhD

Principal Scientist, Molecular Biology and Sequencing, Foundation Medicine.

Dr. Clark received his PhD at the University of Toronto and post doctoral training at Yale University. He took his first position in industry as a senior scientist at RainDance Technologies developing genomics assays on their microfluidic, digital droplet based platform. He then moved to be on the founding team of Ion Torrent Systems as a Senior Research Scientist and was on the team that developed a new next-gen sequencing instrument, the Personal Genome Machine. He went to Vanderbilt-Ingram Cancer Center and Vanderbilt University Medical Center as the Technical Director of the Vanderbilt Technologies for Advanced Genomics center. In 2014Dr. Clark joined Foundation Medicine on the Molecular Biology and Sequencing to lead a lab team focused on taking the circulating tumor DNA assay through feasibility, development, analytical validation, and commercial launch.

Abstract Title: Development of a Clinical Cell-Free Circulating Tumor DNA Assay for Cancer Molecular Profiling

Dr. Clark will be presenting a brief introduction on the clinical requirements (genomic alterations, sample types, accuracy specifications) that led to the assay requirements and design. He will also discuss the design and result of their analytical validation of the ctDNA assay, with focus on precision, accuracy, and orthogonal validation.

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Martin Horlitz

Manager Molecular Diagnostic Development, Qiagen

Dr. Horlitz has been working with QIAGEN since 2007 and is currently the head of the Liquid Biopsy competence center within the Technology Center Diagnostic Sample Preparation & Stabilization (part of QIAGEN's MDx R&D organization). He earned a masters in biology and a PhD in Physical and Molecular Biology from the University of Düsseldorf, Germany. Before coming to QIAGEN, Dr. Horlitz was doing a postdoctoral fellowship at Stanford University School of Medicine (basic research work on eukaryotic translation using single-molecule techniques). His major fields of expertise at QIAGEN include:

• Extraction of circulating nucleic acids from plasma and serum for applications in prenatal diagnosis and cancer detection ("Liquid Biopsy")
• Stabilization technologies for circulating nucleic acids in blood in clinical workflows "between blood draw and nucleic acid extraction"
• Viral nucleic acid extraction for diagnostic applications.
• Automated pre-analytical workflows for NGS, including liquid biopsy analysis
• Development of manual and automated nucleic acid purification solutions under Design Control, as required for IVD application development

Dr. Horlitz will present their technological approaches and solutions for blood sample stabilization and manual/automated ccfDNA extraction for molecular diagnostic workflows. This will include showing the importance of pre-analytical steps (i.e., sample stabilization and DNA isolation) to ensure accurate results for rapidly expanding ccfDNA applications in cancer profiling and detection alongside the application of ccfDNA-based testing in noninvasive prenatal diagnostics.

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Reena Philip, PhD

Division Director, CDRH/OIR/DMGP, FDA

Dr. Philip currently holds the position of Director in the Division of Molecular Genetics and Pathology in the Office of In Vitro Diagnostic Devices and Radiological Health, at Center for Devices and Radiologic Health at the FDA. At the FDA, she has been involved in many diverse activities including premarket clearance/approval, manufacturer assistance, post market regulatory compliance actions, and the development of FDA Guidance on In Vitro Companion Diagnostic Devices. In addition, she has been an ongoing participant in FDA multi-center reviews in companion diagnostics. Dr. Philip received her Ph.D. in Molecular Biology from The University of Illinois at Urbana-Champaign

Abstract Title: Regulatory considerations: cfDNA IVD as a companion diagnostic

As a noninvasive means to detect genetic alterations in tumor DNA, detection of cell-free tumor DNA in plasma holds much promise for improving cancer diagnosis, monitoring and drug development. Recently The US Food and Drug Administration approved first blood test to detect gene mutation associated with non-small cell lung cancer as a companion diagnostic for the cancer drug Tarceva (erlotinib). Even though FDA approved one liquid biopsy test for lung cancer, there are still lots of challenges in advancing additional liquid biopsy cancer tests. This talk will cover some of these challenges & developments regarding the analytical and clinical validation of liquid biopsy cancer tests.

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Lisa M McShane, PhD

Chief of the Biostatistics Branch, Biometric Research Program
Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).

Dr. McShane advises programs in DCTD and NCI on matters relating to development and use of tumor markers for prognosis, therapy selection, and disease monitoring. She holds a Ph.D. in Statistics from Cornell University and is a Fellow of the American Statistical Association. Her statistical research interests include biomarker-driven clinical trial design, analysis methods for high-dimensional omics data, multiple comparisons methods, surrogate endpoints, measurement error adjustment methods, and biomarker assay analytical performance assessment. She co-led efforts to develop “Reporting guidelines for tumor marker prognostic studies (REMARK)” and "Criteria for the use of omics-based predictors in clinical trials." She is a coauthor of numerous statistical and biomedical papers and the book Statistical Design and Analysis of DNA Microarray Investigations. Dr. McShane serves on the Scientific Advisory Board for Science Translational Medicine and is a member of the Editorial Board for BMC Medicine. She has served on several American Society of Clinical Oncology panels and committees, including those that developed guidelines for HER2 and hormone receptor testing in breast cancer, EGFR mutation testing in lung cancer, and use of tumor biomarkers in early stage breast cancer. She has served as a member of the Institute of Medicine Committee for Management of the Air Force Health Study Data and Specimens, the Consensus Committee on Management of the Air Force Health Study Data and Specimens-Report to Congress, and the Committee on the State of the Science in Ovarian Cancer Research.

Abstract Title: Statistical Considerations for Trials Designed to Determine Clinical Utility of cfDNA Assays

Advances in technologies to detect cell-free DNA (cfDNA) in plasma, serum or other body fluids have generated interest in using these assays as clinical tools for early detection or diagnosis of cancer, and for assessing prognosis, selecting therapy, and monitoring tumor status before, during or after delivery of anti-cancer therapy. Advancement from proof-of-principle studies which demonstrate associations between presence of cfDNA and various clinical endpoints to demonstration that a cfDNA-based test has clinical utility, meaning that its use in clinical practice leads to net benefit for patients, requires appropriately designed clinical studies.
This talk will focus on statistical design principles for clinical studies which aim to establish that a cfDNA test has clinical utility when intended for use in one of three ways: assessing prognosis, selection of therapy, or disease monitoring. General initial considerations include the intended clinical use setting, analytical performance of the specific test to be used, how the test results will be interpreted, and how those results will be used to guide clinical decisions. Statistical design issues common to all three clinical uses include selection of cutpoints for clinical decisions, and consideration of whether the test is proposed as a standalone test absent availability of an alternative test, to replace an existing test, or to use in combination with an existing test. Additional considerations discussed for prognostic test utility evaluation are the distinction between relative and absolute risks, how they are influenced by characteristics of the intended use population, and whether there are therapies available to improve outcome. For assessment of a test’s utility for therapy selection different study designs may be considered depending on the preliminary level of evidence supporting the association between the target DNA alteration(s) and the therapies of interest, but usually some treatment randomization will be required to distinguish prognostic and predictive effects on time-to-event outcomes. Many of the considerations for design of clinical studies to assess a test’s utility in monitoring overlap with those for therapy selection, although timing of the testing occasions and the possibility to monitor for indicators of therapy resistance as well as sensitivity add complexity to the decision making process and study design. Carefully designed clinical studies taking into account all of the aspects discussed and tailored to the specific intended use will be essential to the successful translation of these promising new cfDNA technologies to clinical tests with established medical utility.

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Paul "Mickey" Williams, PhD

Director, Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research

Dr. Williams received his doctorate from the University of Virginia, and did postdoctoral work at Stanford University. He spent thirteen years at Genentech, where he developed novel assays to support clinical studies and discover new therapeutic targets and contributed to the development of “real-time” PCR technology. Prior to joining CDP in 2010, he was a senior research group leader at Roche Molecular Diagnostics, managing two large multi-national clinical assay studies: The MILE Study (microarray innovations in leukemia) and a collaboration with the LLMPP (leukemia and lymphoma molecular profiling project) and also led projects that led to two FDA approved companion diagnostic tests. In his current position he continues to make contributions to the use of molecular technologies for use as clinical assays

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Christopher D. Gocke, M.D.

Associate Professor of Pathology, Director of Molecular Pathology Division ,Johns Hopkins University

Dr. Christopher Gocke is an Associate Professor of Pathology and Oncology at the Johns Hopkins University School of Medicine. He is Director of the Division of Molecular Pathology, Deputy Director (Vice Chairman) of Personalized Medicine for the Department of Pathology, and co-director of Johns Hopkins Genomics.He received his M.D. in 1985 from Rutgers Medical School. His residency training in pathology was at the University of Rochester and Stanford University. He completed a fellowship in pathology at Stanford. Dr. Gocke has co-authored over 100 peer-reviewed publications in the area of cancer diagnostics. He is a past Councilor on the Program Directors’ Council of the Association of Molecular Pathology and a member of the NCI’s Investigational Drug Steering Committee. He is co-principle investigator on two NIH research project cooperative agreements. He is board certified in Molecular Genetic Pathology and Anatomic Pathology.

Abstract Title: Challenges for the validation of ctDNA for use in clinical trials

Dr. Christopher Gocke, will speak on “Challenges for the validation of ctDNA for use in clinical trials”. He is director of the Division of Molecular Pathology and an associate professor of pathology and oncology at the Johns Hopkins School of Medicine. He will provide a brief historical overview of ctDNA, discuss some of the limitations of ctDNA assays reported to date, and provide suggestions to overcome validation issues in ctDNA testing.

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Shivaani Kummar, MD, FACP

Director, Phase I Clinical Research Program, Division of Oncology, Stanford School of Medicine

Upon completing her medical degree from Lady Hardinge Medical College in New Delhi, India, Dr. Kummar moved to the United States to train in Internal Medicine at Emory University in Atlanta, Georgia. Following this she was selected to pursue her fellowship training at the National Institutes of Health in Medical Oncology and Hematology, which culminated in her being offered a faculty position at Yale University, New Haven CT. After spending four years as Assistant Professor of Medicine at Yale Cancer Center, Yale University School of Medicine, she moved back to the National Cancer Institute (NCI), NIH, as staff clinician in the Developmental Therapeutics Section. She developed a clinical research program in novel cancer therapeutics and in 2011 became Head of Early Clinical Trials Development in the Office of the Director, Division of Cancer Treatment and Diagnosis, NCI. She moved to Stanford University in 2015 as Professor of Medicine, Director of the Phase I Clinical Research Program, and Chair of the Translational Oncology Program at Stanford, Stanford Cancer Institute. Her research interests focus on developing novel therapies for cancer. She specializes in conducting pharmacokinetic and pharmacodynamic driven first-in-human trials tailored to make early, informed decisions regarding novel molecular agents. The clinical studies integrate genomics and laboratory correlates into early phase trials. She serves on multiple national and international committees and her work has been published in numerous peer reviewed journals.

Abstract Title: Role of Circulating Tumor DNA Profiling in Cancer Management

Increasing application of molecular profiling in the selection of cancer treatment, especially in diseases such as lung cancer, has highlighted the need to safely and repeatedly obtain tumor DNA samples throughout the disease course. The ability to isolate tumor DNA from blood presents a safe, simple method that lends itself to longitudinal assessments. Circulating tumor DNA analysis is being studied as a means to detect recurrence, assess tumor burden, determine early response, and to evaluate emergence of resistance. More data needs to be generated to correlate findings in circulating tumor DNA with those obtained from actual tumor biopsies and the overall clinical utility of this approach needs to established. Ongoing studies will better define the role of circulating tumor DNA profiling in cancer management.

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David Polsky, MD, PHD

Professor of Dermatologic Oncology, Director of the Pigmented Lesion of the Department of Dermatology, New York University School of Medicine

Dr. David Polsky is the Alfred W. Kopf MD Professor of Dermatologic Oncology, Director of the Pigmented Lesion Clinic in The Ronald O. Perelman Department of Dermatology, and member of The Laura and Isaac Perlmutter Cancer Center at the New York University School of Medicine Langone Medical Center. He graduated cum laude from Bucknell University, received his MD and PhD degrees from the Albert Einstein College of Medicine, completed his medical internship at Montefiore Medical Center, and his Dermatology training at NYU. He subsequently completed a post-doctoral fellowship in the Division of Molecular Pathology at Memorial Sloan-Kettering Cancer Center and then returned to NYU to establish a melanoma translational research laboratory. As a physician-scientist, Dr. Polsky's laboratory is focused primarily on biomarker research. In particular the lab is interested in the development of blood-based markers to monitor melanoma disease activity; the identification of patients with loco-regional melanoma who are at high risk for developing metastases; and the development of genetic approaches to identify patients at increased risk of developing melanoma. Dr. Polsky's primary clinical interests are melanoma and atypical nevi.

Abstract Title: Utility of ctDNA monitoring in metastatic melanoma disease surveillance

While several highly effective immune checkpoint blocking agents and small molecule inhibitors of the mitogen activating protein kinase (MAPK) pathway are now available for metastatic melanoma, strategies for changing therapies in patients with progressing disease are not established. Currently there is no clinically useful blood-based biomarker to guide patient management. Serum lactate dehydrogenase (LDH) is part of the melanoma staging system, and is the only serologic marker used for monitoring advanced melanoma in the United States; however, its sensitivity and specificity to detect disease progression are low. Unlike the management of asymptomatic patients with prostate, ovarian, colon, and breast cancer, where serial measurements of serologic markers are the mainstay of follow-up, in melanoma radiologic imaging studies are obtained every 3 to 6 months in asymptomatic patients with metastatic disease since LDH is not a sufficiently useful biomarker. This talk will describe our work investigating droplet digital PCR measurements of cell-free, circulating tumor DNA (ctDNA) as biomarkers of disease activity in metastatic melanoma patients undergoing treatment with MAPK-targeted therapies and immune checkpoint blocking agents.

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Gary Spitzer, MD

Director Clinical Validity and Clinical Utility Evaluation MolDx Palmetto GBA

Dr. Gary Spitzer presently evaluates the clinical utility of precision medicine testing for potential full coverage or possible coverage with data development under the requirement of a well-designed, prospectively developed outcome protocol and associated registry or trial. He is a Medical Oncologist by training. He graduated medical school in Melbourne Australia and received his medical oncology training and clinical research experience at MD Anderson Hospital Houston Texas. His present interests focus on the evidence-based clinical utility of precision medicine tests, and particularly cell-free DNA and other liquid biopsies techniques.

Abstract Title: Clinical Utility Needs of ctDNA Assays Versus Research Utility

This presentation will focus on the design of prospective transparent registries to validate the clinical utility of a test in a clear intent to study patient population. He will also discuss obstacles of existing registries and trial design and present ideas on how costs can be diminished through non-traditional data extraction techniques, but with an emphasis on transparency, scientific independence, and open data collection. The presentation will also address concerns regarding discordant liquid and tissue results from a clinical perspective and discuss possible methods to solve these concerns with data collection. These findings, are not uncommon with mutations derived under drug pressure. Although these findings are probably real, secondary to tumor heterogeneity, they may be best described as a clonally insignificant false positive. Where is the right balance between sensitivity and relevance when used to direct clinical decisions? Can we agree on performance guidelines, so no patient harm occurs Determining clinical utility will require a separate evaluation of this subgroup of patients?

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David Wong, DMD, DMSc.

Professor, Associate Dean for Research, UCLA

Dr. Wong is Felix & Mildred Yip Endowed Professor, Associate Dean of Research and Director of the Oral/Head and Neck Oncology Research Center at UCLA. Dr. Wong is an active scientist in oral cancer and saliva diagnostics research. He has authored over 280 peer reviewed scientific publications. He is a fellow of the American Association for the Advancement of Sciences (AAAS), past member of the ADA Council of Scientific Affairs and the past president of American Association of Dental Research (AADR).

Abstract Title: EFIRM Liquid Biopsy (eLB)

Liquid biopsy is a rapidly emerging field to address this unmet clinical need as diagnostics based on cell-free circulating tumor DNA (ctDNA) can be a surrogate for the tumor genome. The use of ctDNA via liquid biopsy will facilitate analysis of tumor genomics that is urgently needed for molecular targeted therapy. Currently, most targeted approaches are based on PCR and/or next generation sequencing (NGS) for liquid biopsy applications with performance concordance in the 70-80% range with biopsy-based genotyping.

We have developed a liquid biopsy technology “Electric Field Induced Release and Measurement (EFIRM)- Liquid Biopsy (eLB)” provides the most accurate detection that can assist clinical treatment decisions for the most common subtype of lung cancer, non-small cell lung cancer (NSCLC), with tyrosine kinase inhibitors (TKI) that can extend the disease progress free survival period of these patients. eLB can detection ctDNA at single copy level. In addition eLB requires only 40 µl of sample volume, no sample processing, reaction time is 15min and can be performed at the point-of-care or high throughput reference lab using plasma or saliva. In two blinded independent clinical studies, eLB detects actionable EGFR mutations in NSCLC patients with >90% concordance with biopsy-based genotyping (1, 2). eLB is minimally/ non-invasive detecting the most common EGFR gene mutations that are treatable with TKI such as Gefitinib or Erlotinib to effectively extend the progression free survival of lung cancer patients (3). eLB offers both a high throughput reference lab as well as point-of-care platform that can provide real time feedback in a physician’s office.

1. D. Pu et al., Evaluation of a novel saliva-based EGFR mutation detection for lung cancer: a pilot study. Thoracic Cancer, 1-8 (2016).
2. F. Wei et al., Noninvasive saliva-based EGFR gene mutation detection in patients with lung cancer. Am J Respir Crit Care Med 190, 1117-1126 (2014).
3. L. M. Sholl et al., Liquid Biopsy in Lung Cancer: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med, (2016).

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Nitzan Rosenfeld, PhD

Senior Group Leader, University of Cambridge, UK; CSO, Inivata Ltd. UK

Dr. Nitzan Rosenfeld is a recognized expert in cell-free DNA analysis and its application for non-invasive cancer genomics. Originally trained in Physics, Dr. Rosenfeld specialized in quantitative molecular biology, obtaining a Ph.D. from the Weizmann Institute of Science. In 2005 he joined Rosetta Genomics Ltd, where he was head of Computational Biology and led development of molecular tests that are commercially available for clinical use in oncology. Since 2009 he has been focusing on applications of circulating tumor DNA (ctDNA), as a group leader at the Cancer Research UK Cambridge Institute (University of Cambridge). His research group pioneered the use of Next-Generation Sequencing of ctDNA, demonstrating its potential as a liquid biopsy, and produced seminal publications establishing molecular techniques for ctDNA analysis including whole exome, hybrid capture, and tagged-amplicon sequencing (TAm-Seq). In 2013 Dr. Rosenfeld was awarded the CRUK Future Leaders in Cancer Research prize, the British Association for Cancer Research Translational Research Award, and an ERC Starting Grant. In 2015 he was awarded the Foulkes Foundation Medal for outstanding achievements in medical science and significant impact on UK bioscience. In 2014, Dr. Rosenfeld and colleagues founded Inivata, to harness the emerging potential of circulating DNA analysis to improve testing and treatment for oncologists and their patients.

Abstract Title: Genomic analysis of circulating tumor DNA: pushing the limits for cancer applications

Cancer is driven by genomic alterations, and can evolve in response to selective pressures. Sampling of tumor material however is a limiting factor for both diagnostics and research. Circulating tumor DNA can be found in plasma and other body fluids, and with advanced genomic techniques it can be used as an effective source of information for oncology. Targeted molecular profiling tests of “liquid biopsies” in blood plasma are now entering clinical use to support treatment selection, and are emerging as an informative clinical research tool to track response to treatment, cancer progression and emergence of resistance to therapy. Wider-scale analysis can be used to study new drivers and mechanisms of resistance. In parallel, the specificity of genomic alterations makes these excellent markers to quantify cancer dynamics and disease burden. Improved methods and strategies can allow us to stretch the boundaries of analysis to detect smaller amounts of tumor DNA and to obtain more information from limited samples. These can be used to support an expanding range of applications for both earlier and later stage cancers.

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Richard B. Lanman, MD

Chief Medical Officer, Guardant Health, Inc

Dr. Lanman was appointed as Chief Medical Officer of Guardant Health INC in 2014. Dr. Lanman earned his medical degree from Northwestern University - The Feinberg School of Medicine and complete his residency at the University of California San Francisco. Prior to joining Guardant Health, Dr. Lanman was chief medical officer for Veracyte where he successfully conducted several large multicenter clinical utility and validity studies in endocrinology and pulmonology. He led collaborations with key academic and community-based opinion leaders that led to broad managed care coverage for the Afirma™ thyroid cancer test. He has held CMO and Executive Vice President roles at several cardiovascular diagnostics companies, including diaDexus, Inc. and Atherotech. Earlier in his career, he served in various physician practice management roles. Dr. Lanman is also currently on the board of advisors for Compass Technology Partners.

Abstract Title: Lessons Learned from ctDNA NGS Testing in 25,000 Advanced Cancer Patients in Clinical Practice

Dr. Lanman will discuss the test performance requirements for a ctDNA predictive diagnostic, the importance of comprehensive genomic plasma testing covering all four major alteration classes, and the use of outcomes studies to validate low variant allele fractions and alteration classes where robust reference standards do not exist.
The primary clinical utility of cell-free circulating tumor DNA (ctDNA) is as a predictive diagnostic for matched therapies in advanced cancers. Because tissue is required for histopathological classification, it cannot routinely replace tissue-based genotyping at initial diagnosis; however, it is indicated for use at disease progression (2nd line and higher) and also at diagnosis (1st line) for the 25%-50% of tissue biopsies that are quantity not sufficient (QNS) for genotyping or undergenotyped. Put simply, the clinical utility of ctDNA genotyping is inherent when it is used to obviate a repeat invasive tissue biopsy.
The utility of the test provides a guide to the diagnostic test performance characteristics required. As a predictive diagnostic, the critical performance criterion is high specificity, so that false positive results do not lead to prescription of matched therapies in a patient who will not benefit. As high sensitivity is difficult to achieve due to low concentrations of ctDNA, extant liquid biopsy hotspots tests cannot be used as rule-out tests. In addition to qualitative accuracy, ctDNA-based diagnostics must also demonstrate a high degree of quantitative accuracy for understanding whether resistance mutations are subclonal or truncal (and thus targetable). Lastly, all four major types of genomic alterations must be reported in order to capture the eleven somatic genomic alterations mentioned in NCCN guidelines as matched therapy targets.
Validation of ctDNA NGS versus tissue testing is challenged by spatial and tumor heterogeneity, where a needle biopsy may not capture actionable alterations not present in all lesions or parts of a lesion, or where archival tissue will not detect actionable alterations acquired under treatment pressure. Also, since reference standards for copy number amplifications and fusions are not robust and FDA CDx tests for point mutations and indels are of insufficient sensitivity, single-arm outcome studies with objective response endpoints will be required for validation for these situations