Bringing Cancer Genome Diagnostics into Clinical Routine
How to Quickly and Reliably Analyze the Molecular Tumor Profile of Individual Patients
Martin Lindner | 2016-11-02
Growth in the field of cancer genomics has created a dramatic shift toward demand for personalized tumor diagnostics in routine settings. Today, patients are eligible to receive individualized therapy options tailored to fit their genetic tumor profile, based on a single blood withdrawal or tumor sample.
Challenge: Increasing knowledge in the field of cancer genomics enables targeted tumor therapies and promises new treatment approaches for the future. However, this requires testing methods that allow doctors to quickly and reliably analyze the molecular tumor profile of individual patients in a clinical setting.
Solution: A variety of genomic alterations can now be detected in a single test using special next-generation sequencing methods that also significantly reduce analysis and material costs. In some cases, a molecular tumor profile can be created using a single blood withdrawal.
Results: Targeted cancer treatment based on tumor-specific genomic alterations is increasingly being used in clinical practice. This allows tailored approaches that optimize treatment.
Precision medicine promises thorough, genome-based tumor evaluations which can then provide treatment options tailored to the patient’s genetic profile.1 The aim of this approach is to treat patients with targeted drugs known to have fewer side effects than conventional chemotherapy. The popularity of efficient and highly individualized therapy has, in turn, created an increasing demand for cancer genomics to be integrated into routine clinical settings.
Tackling Tumor-specific Mutations
Well-known examples include the use of specific antibodies to target breast cancer. In up to 20% of breast cancer patients, a faulty HER2 gene makes multiple copies of itself, thereby leading to an abundance of HER2 protein, which in turn results in aggressive cancer growth. Currently, breast cancer patients are routinely tested for their HER2 protein status to identify individuals who would benefit from therapies targeting the protein. A HER2-positive patient is then treated with an antibody to block the protein’s activity. Statistics have shown that patients treated with HER2-targeted therapies had a five-year survival rate of over 85%.2
Targeted drugs have long been available for several tumor types.3 For the most common type of lung cancer, non-small cell lung carcinoma, it is considered the diagnostic standard to screen for changes in EGFR and ALK genes. Mutations in both genes are known tumor drivers in lung cancer, with 10% to 35% of all patients harboring a mutation in the EGFR gene, and up to 5% of all patients having an altered version of the ALK gene.4 Thus, the life expectancy of a patient with a proven alteration in either gene can be substantially prolonged using targeted agents.5
About Siemens Healthineers and NEO New Oncology
Siemens Healthineers recently acquired NEO New Oncology GmbH, a growing diagnostics company with 34 employees headquartered in Cologne, Germany. NEO New Oncology has developed a molecular diagnostics platform for tumor profiling to support targeted treatment decisions for cancer patients.
The NEO platform* works reliably on clinical routine specimens, such as formalin-fixed, paraffin-embedded tissue and whole blood, to detect circulating tumor DNA.
NEO New Oncology is part of Siemens Healthineers’ Molecular Services business, which plans to provide physicians, hospitals, and laboratories with testing and enablement services that include access to the latest medical knowledge and technologies.
*NEO is not commercially available except for research use. Due to regulatory reasons, its future availability cannot be guaranteed. Please contact your local Siemens organization for further details. Not for sale in the U.S.
Diagnostic Challenges in Clinical Practice
With advances in cancer research, the understanding of molecular cancer mechanisms will continue to grow rapidly in the future, thereby raising the question of how this knowledge can be incorporated into a clinical setting.6
The present challenges being faced in routine testing centers require researchers to keep abreast of recent developments in order to thoroughly test patient samples. The need to perform multiple tests can lead to extended turnaround times, which in turn delay patient treatment. Furthermore, the limited availability of tissue samples poses a predicament for doctors, especially if several tests are needed for a comprehensive diagnosis.7
However, various technological developments in the past few years can help overcome these challenges. For example, clinically relevant genetic alterations can be detected even in small tumor samples using powerful high-throughput sequencing technologies, such as gene panels enriched for cancer-relevant genes. This process is called “hybrid capture-based next-generation sequencing.” The key is that this method can detect various genomic alterations – from simple point mutations to complex structural alterations, such as gene fusions or amplifications/deletions – using a single test and thus significantly reducing analysis and material costs.8
Liquid Biopsies Support Therapeutic Decision-making
One of the most appealing prospects of the hybrid capture-based next-generation sequencing assay is that it can be performed not only on tumor tissue, but also using a blood sample, in what is known as a “liquid biopsy.” Tumors continuously release tumor cells and fragments of their DNA (circulating DNA) into the bloodstream. These are captured and sequenced to create a patient’s tumor molecular profile.9
Liquid biopsies offer several advantages. Unlike tissue biopsies, blood sampling presents very little risk to patients and can easily be repeated when necessary. Additionally, liquid biopsies are a diagnostic alternative when the location of a tumor cannot be accurately determined or when a tissue biopsy cannot be performed.
Liquid biopsies are not expected to replace established tissue analyses and imaging methods in the future. However, the method is a promising addition, especially for monitoring progress and the effectiveness of a therapy. It is, therefore, now possible to use circulating tumor DNA to verify treatment success10 and detect resistance to drugs in the blood at an early stage.11 A recent case report shows how valuable this is for the therapeutic decision-making process. A liquid biopsy from a lung cancer patient revealed that the tumor had become resistant to a previously effective cancer drug, but would respond to a newer drug in the same drug class. Switching therapies quickly shrank the tumor and significantly improved the patient's condition.12
1Collins F, Varmus H (2015) A new initiative on precision medicine. N Engl J Med 372:793-5
2Gallagher CM, More K, Masaquel A, et al. (2016) Survival in patients with non-metastatic breast cancer treated with adjuvant trastuzumab in clinical practice. Springerplus 5:395
3U.S. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm), accessed July 7, 2016
4Lynch TJ, Bell DW, Sordella R, et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-39;
Paez JG, Jänne PA, Lee JC, et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497-500;
Pao W, Miller V, Zakowski M, et al. (2004) EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-11;
Soda M, Choi YL, Enomoto M, et al. (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448:561-6
5Seidel D, Zander T, Heukamp LC, et al. (2013) A genomics-based classification of human lung tumors. Sci Transl Med 5:209ra153
6Roychowdhury S, Chinnaiyan AM (2016) Translating cancer genomes and transcriptomes for precision oncology. CA Cancer J Clin 66:75-88
7Heuckmann JM, Thomas RK (2015) A new generation of cancer genome diagnostics for routine clinical use: overcoming the roadblocks to personalized cancer medicine. Ann Oncol 26:1830-7
8Frampton GM, Fichtenholtz A, Otto GA, et al. (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023-31
9Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10:472-84
10Newman AM, Bratman SV, To J, et al. (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20:548-54
11Misale S, Yaeger R, Hobor S, et al. (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486:532-6
Chabon JJ, Simmons AD, Lovejoy AF, et al. (2016) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7:11815
12Gautschi O, Aebi S, Heukamp LC (2015) Successful AZD9291 Therapy Based on Circulating T790M. J Thorac Oncol 10:e122-3
The statements by Siemens’ customers described herein are based on results that were achieved in the customer's unique setting. Since there is no "typical" hospital and many variables exist (e.g., hospital size, case mix, level of IT adoption) there can be no guarantee that other customers will achieve the same results.