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FDA or NOT? Not All LDTs are Alike

FDA or NOT? Not All LDTs are Alike. DAVID J. DABBS, M.D. Chief of Pathology Magee-Women ’ s Hospital of UPMC Pittsburgh, Pennsylvania ddabbs@upmc.edu @DAVIDJDABBSMD. Her2 Breast Cancer. 2000 generic recommendations ASCO/CAP Guidelines: 2007;2013 IVD ’ s Her2 IHC testing and FISH testing.

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FDA or NOT? Not All LDTs are Alike

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  1. FDA or NOT?Not All LDTs are Alike DAVID J. DABBS, M.D. Chief of Pathology Magee-Women’s Hospital of UPMC Pittsburgh, Pennsylvania ddabbs@upmc.edu @DAVIDJDABBSMD

  2. Her2 Breast Cancer • 2000 generic recommendations • ASCO/CAP Guidelines: 2007;2013 • IVD’s Her2 IHC testing and FISH testing

  3. Oncotype DX™ • qRT-PCR test shown to quantify distance recurrence for ER+, lymph node negative tumors • 668 patients in the NSABP trial B-14 (test set) • (Paik et al. N Engl J Med 2004;351:2817-2826) • Reported as distant disease recurrence score (RS) • Low-risk RS: 0-17 • Group average risk of recurrence = 7% (0-12%) • Intermediate risk RS: 18-30 • Group average risk of recurrence =14% (13-21%) • *RS= 25 (17% ROR) • High risk RS: 31-100 • Group average risk of recurrence =31%

  4. Oncotype DX Genes PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 HER2 GRB7 HER2 ESTROGEN ER PGR BCL2 SCUBE2 GSTM1 CD68 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC INVASION Stromelysin 3 Cathepsin L2 BAG 1

  5. Derivation of the Recurrence Score • RS (U) = + 0.47 x HER2 group score –0.34 x ER group score + 1.04 x proliferation group score+ 0.1 x invasion group score + 0.05 x CD68 – 0.08 x GSTM1 – 0.07 x BAG1.

  6. IVDMIA-LDT

  7. oncotype DX™ • 2004-2008, reported RS only • 2008-because of “oncologists demand”-started reporting ER, PR, Her2 by qRT-PCR. • No Her2 outcomes studies for qRT-PCR-(technical validation against IHC.) • -Laboratory developed test..Not FDA approved.

  8. 2010: Her2 of Odx QA Study: SPECIFIC AIMS • Perform a quality assurance study to ascertain if the Her2 qRT-PCR of the Oncotype dx (Odx) test meets the ASCO/CAP standards for Her2 testing, by comparing Odx qRT-PCR results with IHC/FISH testing at Magee-Women’s Pathology department. • Determine patient impact of the above.

  9. MWH QA Study- • Compare MWH IHC and FISH results on core needle biopsies to Her2 RT-PCR of the OncotypeDx test. • Compare MWH IHC and FISH results on FFPE that were used for Oncotype test.

  10. Verified all IHC data with FISH, performed on same block as ODx….. • Contacted 19 other labs. • 2 labs had data/willing to participate (Cleveland Clinic, Riverside Methodist Hospital, Columbus, Ohio).

  11. Take Home Message:Of 36UNEQUIVOCALPOSITIVE FISH CASES: • 14/36 GHI called NEGATIVE(39%) • 12/36 GHI called EQUIVOCAL (33%) • 10/36 GHI called POSITIVE(28%) Positive Percent Agreement (FDA). • CLIA-Richmond, CA

  12. MEDWATCH • The FDA Safety Information and Adverse Event Reporting Program

  13. Published Ahead of Print on October 11, 2011 as 10.1200/JCO.2011.34.7963 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.34.7963

  14. 28% Positive percent agreement with IVD reagents. • Why order Odx on Her2+ cases?

  15. Reasons for Discordance? • qRT-PCR process • Primers? • Probes? • Dilution artifact • Lack of proper target microdissection? • Other??

  16. ASCO June 2011

  17. July 25, 2011 Meeting with Shak/Baehner at MWH-with independent observer. • Outcome….

  18. 8Laboratories World-Wide have documented the Her2 single gene flaw in OncotypeDx • Dvorak L, Dolan M, Fink J, Varghese L, Henriksen J, Gulbahce HE. Correlation Between HER2 Determined by Fluorescence In Situ Hybridization and Reverse Transcription-Polymerase Chain Reaction of the Oncotype DX Test. Appl Immunohistochem Mol Morphol. 2012 Aug 20. • Christgen M, Harbeck N, Gluz O, Nitz U, and Kreipe H. Recognition and handling of discordant negative human epidermal growth factor receptor 2 classification by Oncotype DX in patients with breast cancer.J Clin Oncol 2012 May 29 Epub ahead of print • Dabbs DJ, Klein M, Mohsin S, Tubbs R, Shuai Y, Bhargava R. High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the Oncotype DX test: an independent quality assurance study.JCO 2011 29(32):4279-85

  19. Conclusions • In the real world, Her2 in ODx fails to recognize significant number (>70%) of IHC/FISH positive and misses 100% of equivocal cases. • Even after excluding IHC/FISH equivocal cases, GHI HER2 has an unacceptable false negative rate of 72% • Can potentially lead to mismanagement of breast cancer patients

  20. Patient Safety Issue • IVDMIAs are inherently different from other LDTs in that they have… • – “Complex unique interpretation functions, the verification of which is not available to the end user” • -LDT IVDMIAs “high risk, high impact assays that raise significant issues of safety and effectiveness”

  21. Issues • The financial toxicities associated with: giving the drug to someone who does not need it, OR, not giving the drug to someone who needs it. • Patient harms associated with the above. • GHI should have rejected Her2+ cases. • GHI continues to offer the Her2 test.

  22. >Soon, Dave Dabbs and I have had a multi year running argument about the utility of Oncotype Dx in Her2 positive, ER positive, node negative breast cancer, as you can see below. • > Can you shed any light on this issue? Thanks in advance for your time and thoughts.

  23. Soon Paik: All HER2 positive cases were mostly high RS or at least intermediate RS. Therefore I simply do not recommend performing OncotypeDx on HER2 positive tumors.

  24. the issue of OncotypeDx being inaccurate about HER2 status - yes it is - since HER2 mRNA levels of HER2 positive and negative tumors overlap. Therefore you will have false negative cases if you rely on HER2 mRNA levels only (even if you use GRB7 or other genes around HER2, same situation). The only time HER2 mRNA levels reported as part of OncotypeDx can be useful is to rule out false negative cases. I guess if the Genomic Health has been marketing otherwise, then they should not do that. Hope this makes sense. Sincerely, Soon Paik

  25. Isabel Pinhel, Margaret Hills, Suzanne Drury, Janine Salter, Georges Sumo, Roger A’Hern, Judith M Bliss, Ivana Sestak, Jack Cuzick, Peter Barrett-Lee, Adrian Harris and Mitch Dowsett,* on behalf of the NCRI Adjuvant Breast Cancer Trial Management Group*

  26. Overlap of mRNA in Her+ve and Her2-veER+ Breast Cancers

  27. Comments/Questions

  28. Human Epidermal Growth Factor Receptor 2 Assessment in aCase-Control Study: Comparison of Fluorescence In SituHybridization and Quantitative Reverse TranscriptionPolymerase Chain Reaction Performed by Central LaboratoriesFrederick L. Baehner, NinahAchacoso, Tara Maddala, Steve Shak, Charles P. QuesenberryJr,LynnC. Goldstein, Allen M. Gown, and Laurel A. HabelJ ClinOncol 28:4300-4306:2010 • HER2 concordance by central FISH and central qRT-PCR (Odx) was 98%.

  29. GHI has a 98% PPA for Her2 FISH-RT-PCR

  30. Shak, Baehner, Gown et al

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