Evidence-based Molecular Profiling for Solid Tumours – The Future is Now

European Oncology & Haematology, 2012;8(4):242-7 DOI: http://doi.org/10.17925/EOH.2012.08.4.242

Abstract:

Advances in our understanding of the molecular basis of cancer have shown that biomarkers can help guide therapy in a growing number of cancer types and that targeted therapies are becoming increasingly integral to cancer management. However, how to interpret the rapidly expanding wealth of data on cancer genomics and ensure that the best evidence is effectively translated into an optimal individualised therapeutic strategy, remains a challenge. Caris Target Now™ is a well-established, evidence-based molecular profiling service provided by Caris Life Sciences (Basel, Switzerland). Caris Target Now utilises the latest diagnostic molecular assay technologies to determine the unique biomarkers of a patient’s tumour. This is combined with an extensive review of the published clinical evidence to correlate predictive biomarkers with drug response, in order to reveal the potential benefit (or lack of benefit) of specific therapeutic agents. By this process, Target Now provides tumour-specific information that can be used to help physicians personalise cancer therapy for their patients.
Keywords: Personalised care, targeted therapy, genomics, molecular profiling, biomarkers
Disclosure: Both authors are employees of Caris Life Sciences.
Received: August 22, 2012 Accepted September 12, 2012
Correspondence: Andreas Voss, Caris Life Sciences Europe, CityGate, St Jakobsstrasse 199, CH-4052 Basel, Switzerland. E: avoss@carisls.com
Support: The publication of this article was funded by Caris Life Sciences.

Personalised cancer care is becoming an increasingly important aspect of oncological practice. With the advent of high-throughput molecular profiling technology, it is now possible to identify the unique characteristics of a specific tumour and use this information to tailor treatment to the individual patient. Identification of relevant biomarkers, which include genes, proteins and other molecules, can help to ensure that specific treatments are targeted to those patients who are most likely to gain optimal benefit while avoiding the side effects of ineffective therapy. On a societal level, a personalised approach offers the potential to substantially reduce health care costs, by reducing treatment use in patients unlikely to benefit. This is especially important given the rapidly escalating economic burden of cancer that is, in part, driven by the expense of innovative new treatments.1

Most cancer therapies gain approval despite typical response rates of around only one-third of patients.2 Thus, a significant proportion of cancer patients receive treatment of limited clinical benefit. Better targeted clinical decision-making early in the disease course would improve outcomes for patients. More comprehensive and earlier use of molecular profiling could result in more patients receiving effective therapy at a stage where benefits may be optimal rather than after one or more lines of failed treatment, an especially important consideration in aggressive cancers for which the time window for effective intervention may be limited. It may also mean that patients with rare cancers, which have a limited evidence-base and fewtreatment options, may be able to benefit from existing targeted therapies. A more personalised approach to patient care, with targeted treatment directed by the molecular profile of the tumour rather than a ‘one-size-fits-all’ strategy, would also lead to more effective allocation of limited financial resources.

Over the past decade, an increasing number of targeted therapies to treat different types of cancer have been introduced and have contributed to improvements in survival rates. Among the first successful targeted agents in cancer were trastuzumab (Herceptin®) for breast cancer overexpressing the Human epidermal growth factor receptor 2 (HER2) receptor and imatinib mesylate (Gleevec®) for abnormal protein tyrosine kinase activity in chronic myeloid leukemia and gastrointestinal stromal tumours. Other examples of targeted therapies include erlotinib (Tarceva®) and gefitinib (Iressa®), both of which target epidermal growth factor receptor (EGFR)-expressing non-small-cell lung cancer (NSCLC), cetuximab (Erbitux®) for patients with EGFR-expressing metastatic colorectal cancer, crizotinib (Xalkori®) for patients with locally advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive, and vemurafenib (Zelboraf®) for BRAF V600E mutation-positive metastatic melanoma. These treatments, and many other targeted therapies, are changing the therapeutic landscape in oncology.

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References:
  1. Malik NN, Controlling the cost of innovative cancer therapeutics, Nat Rev Clin Oncol, 2009;6:550–2.
  2. Jackson DB, Clinical and economic impact of the nonresponder phenomenon--implications for systems based discovery, Drug Discov Today, 2009;14:380–5.
  3. De Roock W, Piessevaux H, De Schutter J, et al., KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab, Ann Oncol, 2008;19:508–15.
  4. Amado RG, Wolf M, Peeters M, et al., Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer, J Clin Oncol, 2008;26:1626–34.
  5. Bokemeyer C, Bondarenko I, Makhson A, et al., Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer, J Clin Oncol, 2009;27:663–71.
  6. Wong R, Cunningham D, Using predictive biomarkers to select patients with advanced colorectal cancer for treatment with epidermal growth factor receptor antibodies, J Clin Oncol, 2008;26:5668–70.
  7. Di Nicolantonio F, Martini M, Molinari F, et al., Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer, J Clin Oncol, 2008;26:5705–12.
  8. Herreros-Villanueva M, Gomez-Manero N, Muñiz P,et al., PIK3CA mutations in KRAS and BRAF wild type colorectal cancer patients. A study of Spanish population, Mol Biol Rep, 2011;38:1347–51.
  9. Sartore-Bianchi A, Martini M, Molinari F, et al., PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies, Cancer Res, 2009;69:1851–7.
  10. Sood A, McClain D, Maitra R, et al., PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer, Clin Colorectal Cancer, 2012;11:143–50.
  11. Ashfaq R, Arguello D, Feldman RA, et al., Frequency and distribution of HER2 overexpression in advanced malignancies, J Clin Oncol, 2011;29(Suppl):abstract e21153.
  12. Shacham-Shmueli E, Beny A, Geva R, et al., Response to temozolomide in patients with metastatic colorectal cancer with loss of MGMT expression: a new approach in the era of personalized medicine?, J Clin Oncol, 2011;29:e262–5.
  13. Tsao MS, Sakurada A, Cutz JC, et al., Erlotinib in lung cancer - molecular and clinical predictors of outcome, N Engl J Med, 2005;353:133–44.
  14. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al., Molecular predictors of outcome with gefitinib in a phase III placebocontrolled study in advanced non-small-cell lung cancer, J Clin Oncol, 2006;24:5034–42.
  15. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al., Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib, Ann Oncol, 2007;18:752–60.
  16. Fukuoka M, Wu Y, Thongprasert S, et al., Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib (G) versus carboplatin/paclitaxel (C/P) in clinically selected patients (pts) with advanced non-small cell lung cancer (NSCLC) in Asia (IPASS), J Clin Oncol, 2009;27:15s (Suppl; abstract 8006).
  17. Pirker R, Pereira JR, von Pawel J, et al., EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study, Lancet Oncol, 2012;13:33–42.
  18. Jackson AL, Loeb LA, The mutation rate and cancer, Genetics, 1998;148:1483–90.
  19. Balak MN, Gong Y, Riely GJ, et al., Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors, Clin Cancer Res, 2006;12:6494–501.
  20. Misale S, Yaeger R, Hobor S, et al., Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer, Nature, 2012;486:532–6.
  21. Von Hoff DD, Penny R, Shack S, et al., Frequency of potential therapeutic targets identified by immunohistochemistry (IHC) and DNA microarray (DMA) in tumours from patients who have progressed on multiple therapeutic agents, J Clin Oncol, 2006;24:138s (abstract 3071).
  22. Von Hoff DD, Stephenson JJ Jr, Rosen P, et al., Pilot study using molecular profiling of patients' tumours to find potential targets and select treatments for their refractory cancers, J Clin Oncol, 2010;28:4877–83.
  23. Dean A, Zeps N, Multi-targeted molecular profiling of advanced refractory solid tumour cancers: influence on treatment choice and outcomes, Asia-Pacific J Clin Oncol, 2012;8(Suppl S2):49.
  24. Popovtzer A. Bio-marker driven tailored treatment for metastatic adenoid cystic carcinoma. 8th International Conference on Head and Neck Cancer, Meeting Abstracts. S172 http://ahns.jnabstracts.com/Detail.aspx?ID=0172. Accessed August 2012.
  25. Henary HA, Hong DS, Falchook GS, et al., Targeted agents matched with tumour molecular aberrations: Review of 160 patients with advanced melanoma treated in a phase I clinic, J Clin Oncol, 2012;30(Suppl):abstract 8551.
Keywords: Personalised care, targeted therapy, genomics, molecular profiling, biomarkers