Previously, as part of a company we founded—Applied Genomics, Inc—we created multivariate panels of antibodies for immunohistochemistry, including Mammostrat and Pulmotype:

  • Mammostrat consisted of five antibodies where the binary score for each antibody was placed into a weighted algorithm to create a single index for predicting whether women with ER+/HER2- could be treated with tamoxifen alone or should have chemotherapy added to their regimen(1). It validated on multiple cohorts, including two clinical trial cohorts.

    • the NSABP B14 and B20, the same cohorts used by Genomic Health for OncotypeDX®(2), and

    • the TEAM trial, an international trial comprised of 1800 patients(3), of which 1390 were included in the Mammostrat study.

  • Pulmotype likewise consisted of five antibodies to determine whether a lung cancer sample was adenocarcinoma versus squamous cell carcinoma in samples too small for definitive classification by histology alone. It validated on several large studies(4)

Both of these tests were commercialized as laboratory developed test (LDTs). Applied Genomics was acquired by Clarient Inc. in 2009, which in turn was acquired by GE Healthcare in 2010.

Later, with Insight Genetics, Inc., we took large scale genomic data and, working with Jennifer Pietenpol and Brian Lehmann of Vanderbilt University, converted a classifier for triple negative breast cancer, TNBCtype, which used thousands of genes, into a much smaller classifier, InsightTNBCtype(5-8). InsightTNBCtype has proven to be highly innovative, for two key reasons:

  • This classifier has proven to be able to describe the tumor immune microenvironment in a manner very useful for understanding how and when immunotherapy may be appropriate (9,10).

  • This classification method in turn gave rise to DetermaIO a 27 gene predictor for response to immune checkpoint inhibitors and runs on an RT-PCR platform.

DetermaIO has validated in over 13 studies (including two randomized clinical trials) comprising four different ICI’s and six different tissue types(9-21). It is being used in a prospectively designed biomarker study (SWOG S1418 phase III clinical trial) to identify responders treated with the immune, checkpoint inhibitor, pembrolizumab, in triple negative breast cancer22.

In 2019 Insight Genetics was acquired by Oncocyte, which offers DetermaIO as an LDT and is currently working to make it a distributable test on a PCR platform.

  1. Ring, B. Z. et al. Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer. J Clin Oncol 24, 3039-3047 (2006). https://doi.org:10.1200/jco.2006.05.6564

  2. Ross, D. T. et al. Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials. Clin Cancer Res 14, 6602-6609 (2008). https://doi.org:10.1158/1078-0432.Ccr-08-0647

  3. Bartlett, J. M. et al. Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy. Breast Cancer Res 12, R47 (2010). https://doi.org:10.1186/bcr2604

  4. Ring, B. Z. et al. A novel five-antibody immunohistochemical test for subclassification of lung carcinoma. Mod Pathol 22, 1032-1043 (2009). https://doi.org:10.1038/modpathol.2009.60

  5. Lehmann, B. D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121, 2750-2767 (2011). https://doi.org:10.1172/JCI45014

  6. Lehmann, B. D. et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 11, e0157368 (2016). https://doi.org:10.1371/journal.pone.0157368

  7. Ring, B. Z. et al. Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients. BMC Cancer 16, 143 (2016). https://doi.org:10.1186/s12885-016-2198-0

  8. Stecklein, S. R. et al. Dual Prognostic Classification of Triple-Negative Breast Cancer by DNA Damage Immune Response and Homologous Recombination Deficiency. JCO Precision Oncology, e2300197 (2023). https://doi.org:10.1200/PO.23.00197

  9. Nielsen, T. J., Ring, B. Z., Seitz, R. S., Hout, D. R. & Schweitzer, B. L. A novel immuno-oncology algorithm measuring tumor microenvironment to predict response to immunotherapies. Heliyon 7, e06438 (2021). https://doi.org:10.1016/j.heliyon.2021.e06438

  10. Seitz, R. S. et al. Translation of the 27-gene immuno-oncology test (IO score) to predict outcomes in immune checkpoint inhibitor treated metastatic urothelial cancer patients. Journal of Translational Medicine 20, 370 (2022). https://doi.org:10.1186/s12967-022-03563-9

  11. Iwase, T. et al. A Novel Immunomodulatory 27-Gene Signature to Predict Response to Neoadjuvant Immunochemotherapy for Primary Triple-Negative Breast Cancer. Cancers (Basel) 13 (2021). https://doi.org:10.3390/cancers13194839

  12. Ranganath, H. et al. Association of a novel 27-gene immuno-oncology assay with efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer. BMC Cancer 22, 407 (2022). https://doi.org:10.1186/s12885-022-09470-y

  13. Dugo, M. et al. Abstract P2-07-12: Triple negative breast cancer subtypes and early dynamics of the 27-gene IO score predict pCR in the NeoTRIPaPDL1 trial. Cancer Research 82, P2-07-12-P02-07-12 (2022). https://doi.org:10.1158/1538-7445.SABCS21-P2-07-12

  14. Saltman, D. L. et al. 27-gene Immuno-Oncology (IO) Score is Associated With Efficacy of Checkpoint Immunotherapy in Advanced NSCLC: A Retrospective BC Cancer Study. Clin Lung Cancer 24, 137-144 (2023). https://doi.org:10.1016/j.cllc.2022.11.009

  15. Antoniotti, C. et al. An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer. Clinical Cancer Research 29, 2291-2298 (2023). https://doi.org:10.1158/1078-0432.CCR-22-3878

  16. Nielsen, T. J. et al. The 27-gene IO score is associated with efficacy of PD-1/L1 inhibitors independent of FGFR expression in a real-world metastatic urothelial carcinoma cohort. Cancer Immunol Immunother 72, 2075-2086 (2023). https://doi.org:10.1007/s00262-023-03401-x

  17. Sharma, P. et al. Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer: NeoPACT Phase 2 Clinical Trial. JAMA Oncology (2023). https://doi.org:10.1001/jamaoncol.2023.5033

  18. Seitz, R. et al. Association with immune checkpoint inhibitor efficacy of a 27-gene classifier in renal cell cancer. Journal of Clinical Oncology 39, 4575-4575 (2021). https://doi.org:10.1200/JCO.2021.39.15_suppl.4575

  19. Varga, M. G. et al. The 27-gene IO score is associated with molecular features and response to immune checkpoint inhibitors (ICI) in patients with gastric cancer. Journal of Clinical Oncology 40, 4058-4058 (2022). https://doi.org:10.1200/JCO.2022.40.16_suppl.4058

  20. Seitz, R. S. et al. Abstract P5-02-26: The 27-gene IO score is associated with pathologic complete response (pCR) in HR+/HER2- breast cancer patients treated with pembrolizumab in the I-SPY2 Trial. Cancer Research 83, P5-02-26-P05-02-26 (2023). https://doi.org:10.1158/1538-7445.SABCS22-P5-02-26

  21. Page, D. B. et al. Association of 27-gene IO score with outcome in a phase Ib trial of pembrolizumab (pembro) plus chemotherapy (CT) in metastatic triple-negative breast cancer (mTNBC). Journal of Clinical Oncology 40, 1082-1082 (2022). https://doi.org:10.1200/JCO.2022.40.16_suppl.1082

  22. Oncocyte SWOG Press Release. Oncocyte.com News Releases (https://investors.oncocyte.com/news-releases/2022/10-06-2022-130437596, 2022).

Our ability to evaluate novel molecular tools and to help make informed business and clinical decisions stems from our own experience in taking large scale genomic data and reducing it to clinical problems and clinical practice.

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