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What is Precision Medicine? Comprehensive genomic profiling

How do we realize the potential of precision medicine?

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Precision medicine

The shift towards precision medicine

Clinical practice is shifting towards an era of precision medicine where molecular insights enable treatment to be personalised to the unique genomic profile of a patient’s tumour.1–3 Cancer care is increasingly complex as more targetable genes are identified and treatment choice grows;4–8 in 2018, there were over 849 molecules in late-stage development, 91% of which were targeted treatments.9 An evolving approach to clinical diagnostics and decision-making is required if we are to manage this increasing complexity and realise the potential of precision medicine.4,10

Organ Based Biomarker Stratified Precision Medicine Chemotherapy Cancer is treated primarily according to its location in the body Personalised Treatment Molecular insights enable treatment to be personalised to the unique genomic profile  of a patient’s tumour Targeted Medicines Cancer therapy is selected based on both organ and biomarker 1990 2000 2010 2020 2030 1980
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Genomic insights

Capturing clinically relevant genomic insights

There are four main classes of genomic alterations: base substitutions, insertions or deletions, copy number alterations and gene rearrangements. But are current diagnostic approaches up to the task of identifying them all? Single biomarker tests, using common diagnostic techniques such as PCR/IHC/FISH, and multigene hotspot NGS tests risk missing genomic alterations that may be critical to patients’ treatment plans.4,11–13

Furthermore, complex pan-tumour genomic signatures, such as Tumour Mutational Burden (TMB), blood Tumour Mutational Burden (bTMB) and Microsatellite Instability (MSI), may provide further valuable insights to help personalise treatment plans. MSI informs eligibility for immunotherapy and is a cancer guideline-recommended signature.14-18 TMB and bTMB are exploratory genomic signatures that inform eligibility for immunotherapies independently of PD-Ll expression.19-24 Comprehensive genomic profiling is the only viable routine clinical option for measuring TMB and bTMB.19-22

MSITMB/bTMBBase substitutionsTumour Mutational Burden/blood Tumour Mutational Burden*Microsatellite Instability*RearrangementsFour main classes of genomic alterations12 12 34Genomic signatures

*TMB reported by FoundationOne CDx and FoundationOne Heme. bTMB reported by FoundationOne Liquid CDx. MSI reported by FoundationOne CDx and FoundationOne Heme, MSI-H reported by FoundationOne Liquid CDx.
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Evolving approach

An evolution in diagnostics and clinical decision-making

Ensuring that cancer patients can benefit from the latest treatment innovations requires an evolving approach to clinical diagnostics and decision-making, one that:

✓   Identifies clinically relevant genomic alterations and signatures

✓   Provides clinical decision-making support

✓   Personalises patients’ treatment plans

Comprehensive genomic profiling is important to ensure patients can benefit from the latest treatment innovations.1,10,20

"The NCCN NSCLC Guidelines panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC."

NCCN Guidelines for NSCLC Version 6, 202025

“Multiplexed genetic sequencing panels are preferred where available over multiple single gene tests to identify other treatment options beyond EGFR, ALK, BRAF and ROS1.”

ASCO endorsement of CAP/IASLC/AMP guidelines for lung cancer, 201826,27
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AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; bTMB, blood Tumour Mutational Burden; CAP, College of American Pathologists: FISH, fluorescence in situ hybridisation: IASLC, International Association for the Study of Lung Cancer; IHC, immunohistochemistry; MSI, Microsatellite Instability; NCCN, National Comprehensive Cancer Network; NGS, next generation sequencing; NSCLC, non-small cell lung cancer: PCR. polymerase chain reaction; TMB, Tumour Mutational Burden.
References
  1. Rozenblum AB et al. Clinical Impact of Hybrid Capture-Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer. J Thorac Oncol 2017; 12: 258–268. 2017
  2. Schwaederle M, Kurzrock R. Actionability and precision oncology.  Oncoscience 2015; 2: 779–780. 2015
  3. Mansinho A et al. The future of oncology therapeutics. Expert Rev Anticancer Ther 2017; 17: 563–565. 2017
  4. Frampton GM et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol; 31: 1023–1031. 2013
  5. Drilon A et al. Broad, Hybrid Capture–Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches. Clin Cancer Res ; 21: 3631–3639. 2015
  6. Hirsch FR et al. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet ; 388: 1012–1024. 2016
  7. Baumgart M. Diffuse large B-cell lymphoma with primary treatment failure: Ultra-high risk features and benchmarking for experimental therapies. Am J Hematol Oncol 2015; 11: 10–13. 2015
  8. Chakravarty D et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol ; doi: 10.1200/PO.17.00011. 2017
  9. Global Oncology Trends Report 2018. Report by IQVIA Institute for Human Data Science. Available at: https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/global-oncology-trends-2019.pdf (Accessed August 2020).
  10. Gagan J, Van Allen EM. Next-generation sequencing to guide cancer therapy. Genome Med 2015; 7: 80. 2015
  11. Schrock AB et al. Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing. Clin Cancer Res 2016; 22: 3281–3285. 2016
  12. Rankin A et al. Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer. Oncologist ; 21: 1306–1314. 2016
  13. Suh JH et al. Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials. Oncologist ; 21: 684–691. 2016
  14. Zhao P et al. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol; 12: 54. 2019
  15. Abida W et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol; 5: 471–478. 2019
  16. Kok M et al. How I treat MSI cancers with advanced disease. ESMO Open; 4(Suppl 2): e000511. 2019
  17. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 2.2020, May 2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (Accessed August 2020).
  18. FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. Available at: www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer (Accessed August 2020).
  19. FDA approves pembrolizumab for adults and children with TMB-H solid tumors, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors (Accessed August 2020).
  20. Gandara DR et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med; 24: 1441–1448. 2018
  21. Yarchoan M et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight; 4: e126908. 2019
  22. Marabelle A et al. Association of tumor mutational burden with outcomes in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158. Ann Oncol.;30(suppl_5):v475-v532. 2019
  23. Socinski M. Final efficacy results from B-F1RST, a prospective Phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC). Ann Oncol; 30(suppl_5): v851–v934. 2019
  24. Khagi Y et al. Hypermutated Circulating Tumor DNA: Correlation with Response to Checkpoint Inhibitor–Based Immunotherapy. Clin Cancer Res; 23: 5729–5736. 2017
  25. NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 6.2020, June 2020. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf (Accessed August 2020).
  26. Kalemkerian GP et al. Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Treatment With Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol ; 36: 911–919. 2018
  27. Lindeman NI et al. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn ; 20: 129–159. 2018