6.7 FDA Approved ‘Companion Diagnostic’ Tests
6.8 Molecular Techniques in Lung Cancer Diagnosis
The U.S. Food and Drug Administration (FDA) has a role in the approval of ‘companion diagnostics’ that provide biomarker information that is required for the effective use of a corresponding therapeutic product or tumor treatment.
By regulating these ‘companion’ diagnostic tests for each therapeutic biomarker, and by requiring standardized use and interpretation, there is an assurance for the patient that the most appropriate ‘targeted therapy‘ will be given for their lung tumor.
Fluorescence in-situ hybridization (FISH) is one of the diagnostic, tissue-based tests that may be used. When compared to IHC, FISH is more expensive and requires laboratories with expertise in fluorescence microscopy. Polymerase chain reaction (PCR) gene identification also requires laboratory expertise.
The current status of FDA-approved ‘companion diagnostics’ in lung cancer (NSCLC) is:
1) EGFR Companion Diagnostics:
- Cetuximab (Erbitux®) / gefitinib (Iressa®): DAKO EGFR PharmaDx kit (IHC).
- Afatinib (Gilotrif®): Qiagen, therascreen EGFR RGQ PCR kit (PCR).
- Erlotinib (Tarceva®): Roche Molecular Systems Inc, Cobas® EGFR mutation kit, (PCR test for exon 19 deletions and exon 21 (L858R) substitution mutations of the EGFR gene in DNA derived from FFPE tissue.
2) HER2 Companion Diagnostics:
- Trastuzumab (Herceptin®):Ventana Medical Systems, INFORM HER-2/NEU (FISH).
- Trastuzumab (Herceptin®): Abbott Molecular Inc, PATHVYSION HER-2 DNA Probe Kit (FISH).
- Trastuzumab (Herceptin®): Biogenex Laboratories Inc, INSITE HER-2/NEU KIT (Mouse McAb for IHC).
3) ALK Companion Diagnostics:
- Crizotinib (Xalkori®): Abbott Molecular Inc, VYSIS ALK Break Apart FISH Probe Kit to detect rearrangements involving the ALK gene via FISH in FFPE tissue.
4) KRAS Companion Diagnostics:
- Cetuximab (Erbitux®): Qiagen therascreen KRAS RGQ PCR kit.
5) BRAF Companion Diagnostics:
- Dabrafenib (Tafinlar®) & tramatenib (Mekinist®): bioMerieux Inc. THxID BRAF for detection of BRAF V600E and V600K mutations in tissue DNA.
- Vemurafenib (Zelboraf®): Roche Molecular Systems, Cobas® 4800 BRAF V600 Mutation Test, an in vitro diagnostic device intended for the qualitative detection of the BRAF V600E mutation in DNA extracted from FFPE tissue.
6.8 Molecular Techniques in Lung Cancer Diagnosis
Mutation testing is done on DNA, and quantitative PCR is done on mRNA extracted from lung tumor samples. These molecular techniques require specialized technology, which is not usually available in routine diagnostic clinical laboratories.
The Pathologist is required to assess the lung tumor tissue used for nucleic acid extraction and has a role in the storage and preparation of lung tissue. Translocations and increase in gene copy number are commonly assessed using fluorescence in-situ hybridization (FISH), which also requires adequate lung tumor tissue assessment and preparation and requires fluorescence microscopy facilities.
Figure 6.15 FISH detection of ALK gene re-arrangements.
A. Red and green FISH probes adjacent to the common break
point in the native ALK gene. B. When no rearrangement is
present, the probes appear fused together (yellow).
In 2013, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) put together evidence-based recommendations for the molecular analysis of lung cancer tissue (Lindeman et al, 2013).
These recommendations were developed to guide EGFR- and ALK-directed targeted therapy and direct which patients and tissue samples should be tested, and when and how the molecular testing should be performed. These guidelines may be found here.
In 2014, a set of guidelines were developed from the European Society for Molecular Oncology (ESMO) Consensus Conference on Lung Cancer, to address several questions on the management of patients with Non-Small Cell Lung Cancer (NSCLC) (Kerr et al., 2014). The ESMO guidelines cover four areas: pathology and molecular biomarkers, early-stage NSCLC, locally advanced disease and advanced (metastatic) NSCLC. These guidelines can be found here.
It is anticipated that these U.S. and European recommendations will be updated regularly, as more molecular targets become identified for the treatment of advanced lung cancer.
Kerr KM, Bubendorf L, Edelman MJ, et al. Panel Members. (2014). Second ESMO consensus conference on lung cancer: pathology and molecular biomarkers for non-small-cell lung cancer. Ann Oncol 25(9), 1681-90. (Retrieved 20th Feb 2015): http://annonc.oxfordjournals.org/content/25/9/1681.full.pdf+html
Lindeman NI, Cagle PT, Beasley MB, et al. (2013). Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137(6),828-860. (Retrieved 19th Feb 2015): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162344/
National Cancer Institute Targeted Cancer Therapies (Retrieved 29th April 2015): http://www.cancer.gov/cancertopics/treatment/types/targeted-therapies/targeted-therapies-fact-sheet
FDA: US Food and Drug Administration Personalized Medicine and Companion Diagnostics Go Hand-in-Hand (Retrieved 19th Feb 2015): http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm407328.htm