Policy Guidelines
Advances in sequencing technology have facilitated the identification of crucial genetic alterations that drive cancer cell growth by constitutive activation of cell signaling/cell cycling pathways or by inactivation of critical negative regulators of these networks (Bos, 1989; Davies et al., 2002; Levine & Oren, 2009; Soda et al., 2007). Compared with protein biomarkers, cancer genetic markers are more reproducible and less subject to intrinsic and extrinsic stimuli (M. Kalia, 2013; Li, Kung, Mack, & Gandara, 2016). The use of this information in personalized medicine has changed the paradigms in oncology because it is now based on understanding molecular carcinogenesis, pharmacogenomics, and individual genetic differences that determine the response to chemotherapeutics (Grullich & von Kalle, 2012; Madhu Kalia, 2015; Nalejska, Maczynska, & Lewandowska, 2014).
Small molecule inhibitors and antibodies have been developed that target particular oncogenic drivers (Chapman et al., 2011; Druker et al., 2001; Shaw et al., 2013; Slamon et al., 2001; Zhou et al., 2011). These targeted agents may be equivalent or even inferior to standard therapy in an unselected population but frequently induce dramatic regression in tumors harboring the target, demonstrating the value of precision medicine (Flaherty et al., 2010; Karapetis et al., 2008; Mok et al., 2009). Many agents are also now demonstrating signs of efficacy, even in previously difficult to target pathways involving activated RAS, impaired p53, and loss of cyclin-dependent kinase regulation(Ascierto et al., 2013; Dickson et al., 2013; Janne et al., 2013; Lehmann et al., 2012). Therefore, the ability to identify potentially actionable genetic alterations is imperative to exploiting the molecular vulnerabilities of cancer. (Johnson et al., 2014)
Figure from: (Dietel et al., 2015) See Appendix 1.
Currently, a variety of molecular diagnostic platforms are available (Meador et al., 2014). The most common clinically used sequencing platforms assess a limited number of the most extensively validated mutations (hotspots)(Dias-Santagata et al., 2010; Halait et al., 2012; Lovly et al., 2012; Shaw et al., 2013). These range from polymerase chain reaction (PCR)-based assays of a single point mutation to more extensive PCR- or mass spectrometry-based platforms assessing multiple point mutations across several genes (SNaPshot or Sequenom) (Halait et al., 2012; Lovly et al., 2012). However, activating mutations at non-hotspot locations that confer sensitivity to approved therapies (Bahadoran et al., 2013; Dahlman et al., 2012) and other clinically relevant gene fusions are not detected with hotspot testing methods (Drilon et al., 2013). A proportion of patients may therefore be excluded from potentially effective therapeutics based on incomplete genetic profiling(Johnson et al., 2014).
Whole genome and whole exome sequencing (WGS/WES) are available, however practical considerations related to data analysis, cost, and delay have constrained the widespread use of WGS/WES in clinics (Ulahannan, Kovac, Mulholland, Cazier, & Tomlinson, 2013).
Targeted NGS (i.e. FoundationOne) sequences the entire coding region of a large number of preselected genes with clinical or preclinical relevance in cancer (Wagle et al., 2012). Although less comprehensive than WGS/WES, targeted NGS does provide a comprehensive analysis of known genes with potential therapeutic and prognostic importance, a quick turnaround time (2–3 weeks in this case), and a standardized analytics pipeline (Frampton et al., 2013; Johnson et al., 2014).
The clinical utility of targeted therapy was examined by Kamps et al (2017)—See Appendix 2
Harada et al (2017) found that in 132 cases selected by a tumor board for comprehensive next generation sequencing, Forty-six cases (34.8%) had driver mutations that were associated with an active targeted therapeutic agent, including BRAF, PIK3CA, IDH1, KRAS, and BRCA1. An additional 56 cases (42.4%) had driver mutations previously reported in some type of cancer. Twenty-two cases (16.7%) did not have any clinically significant mutations. Eight cases did not yield adequate DNA. 15 cases were considered for targeted therapy, 13 of which received targeted therapy. One patient experienced a near complete response. Seven of 13 had stable disease or a partial response.
This approach of determining therapy based on genetic abnormalities rather than tissue of origin is increasingly important, as indicated by drugs such as pembrolizumab being developed and approved based on molecular indications (MSI-high or MMR deficient) independent of anatomical site of cancer origin (Hulick, 2018). However, the clinical utility and cost effectiveness of multigene panels versus broader sequencing methods is still in need of further study.
Applicable Federal Regulations
The FDA has approved more than 50 companion diagnostic devices to detect mutations in 12 different genes for the targeted treatment of cancer. Methodologies include immunohistochemistry, real-time or multiplex PCR, FISH, and next generation sequencing. The FDA has also approved additional nucleic acid based tests for cancer, not specifically as companion diagnostics.
On June 22, 2017 the FDA approved the Oncomine™ Dx Target Test (Thermo Fisher Scientific) as a next generation sequencing (NGS) test to detect multiple gene mutations for lung cancer in a single test from a single tissue specimen. This test detects the presence of BRAF, ROS1, and EGFR gene mutations or alterations in tumor tissue of patients with NSCLC. This test can be used to select patients with NSCLC with the BRAF V600E mutation for treatment with the combination of dabrafenib and trametinib.
On June 30, 2017 the FDA approved the Praxis Extended RAS Panel as a qualitative in vitro diagnostic test using targeted high throughput parallel sequencing for the detection of 56 specific mutations in RAS genes [KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4)] in DNA extracted from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer (CRC) tissue samples. The Praxis™ Extended RAS Panel is indicated to aid in the identification of patients with colorectal cancer for treatment with Vectibix® (panitumumab) based on a no mutation detected test result. The test is intended to be used on the Illumina MiSeqDx® instrument.
In November 2017 the FDA approved the marketing of the MSK-IMPACT assay as a qualitative in vitro diagnostic test that uses targeted next generation sequencing of formalin-fixed paraffin-embedded tumor tissue matched with normal specimens from patients with solid malignant neoplasms to detect tumor gene alterations in a broad multi gene panel. The test is intended to provide information on somatic mutations (point mutations and small insertions and deletions) and microsatellite instability for use by qualified health care professionals in accordance with professional guidelines, and is not conclusive or prescriptive for labeled use of any specific therapeutic product. MSK-IMPACT is a single-site assay performed at Memorial Sloan Kettering Cancer Center.
On November 30, 2017 the FDA approved FoundationOne CDx™ (F1CDx) as a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies in accordance with the approved therapeutic product labeling. Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms. The F1CDx assay is a single-site assay performed at Foundation Medicine, Inc.
Guidelines and Recommendations
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN)
NCCN guidelines for hereditary forms of cancers state that multi-gene testing should be offered to patients and families in the context of professional genetic expertise for pre- and post-test counseling. NCCN recommends that “patients who have a personal or family history suggestive of a single inherited cancer syndrome are most appropriately managed by genetic testing for that specific syndrome. When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/or cost-effective.” The guidelines state that “there may be a role for multi-gene testing in individuals who have tested negative (indeterminate) for a single syndrome, but whose personal or family history remains suggestive of an inherited susceptibility.” NCCN further recommends that “multi-gene testing can include intermediate penetrant (moderate-risk) genes”, but cautions that “not all genes included on available multi-gene tests are necessarily clinically actionable”.
Center for Medical Technology Policy (CMTP): Green Park Collaborative
In 2015, the Green Park Collaborative recommended that panels containing from 5 to 50 genes should be covered when the following criteria are met:
- A subset of at least 5 constituent genes or variants is cited in the label of an FDA-approved companion diagnostic indicated for the treatment of the patient; OR
- A subset of at least 5 constituent genes or variants is recommended for decision-making for the underlying diagnosis in nationally recognized clinical guidelines, such as those of the National Cancer Comprehensive Network (NCCN), or the American Society of Clinical Oncology (ASCO) or other guidelines that meet the IOM criteria for clinical guidelines; 10 OR
- A subset of at least 5 constituent genes are designated as standard of care for the underlying condition by the molecular testing committees of at least 3 NCCN member institutions; OR
- The provider has submitted two peer-reviewed journal articles of studies designed to demonstrate the safety and effectiveness of using the genomic information in question for clinical management of the patient’s diagnosis and support the conclusion that use of the information is reasonably likely to provide a health benefit for the patient.
AND, in all cases:
- The cost of analysis by NGS does not exceed the cost of individual sequencing of the target genes by other methods, AND
- The laboratory conducting the analysis is CLIA-certified and accredited by CAP for NGS testing.
