Abstract
Today’s cancer pathology reports commonly refer to “driver mutations” that are either present in or absent from a tumor’s genome. Because of this, it has become vital for insurance company medical directors, underwriters, and claims professionals to acquire at least a basic understanding of genetics and mutations as well as targeted therapies and their mechanisms. With the price of whole genome, whole exome, and other genomic sequencing continuing to drop rapidly, more complicated pathology reports that contain significant amounts of genetic information will need to be correctly interpreted.
With advanced cancers, the use of targeted therapies is not likely to impact how life or critical illness insurance policies are underwritten in the short term, but they could significantly impact the approach to claims adjudication and cost of healthcare-related products.
This article will look at how genetics is contributing to cancer development, treatment, and prognosis. It will provide a brief overview of genetics, including commonly used terms, discuss some of the more common genetic mutations, and give examples of the mutations that occur in cancer.
The following is a terminal illness (TI) claim which will pay if death is expected within the next 12 months:
A 51-year-old male nonsmoker started afatinib (a tyrosine kinase inhibitor) four months ago for an adenocarcinoma subtype of non-small-cell lung cancer (NSCLC).
His pathology reports documented:
- Stage 4B, T3 N3 M1b disease based on PET–positive right hilum, mediastinal, and neck nodes and distant metastases in liver and bones.
- The tumor is ALK-IHC negative, ROS1-IHC negative, PD-L1 10%positive, EGFR ctDNA exon 19 deletion positive.
- First-line immunotherapy is not indicated as the level of PD-L1 is 10%. (Levels 50% or greater would support use.)
- The tumor is positive for EGFR mutation with an exon 19 deletion –hence prescribed afatinib.
This report utilizes molecular profiling of the cancer to a substantial degree. The several genetic mutations identified in the tumor may be therapeutically and prognostically relevant, and may potentially impact the assessment of the Insured’s life expectancy and eligibility for benefits.
Genetics Review
To grasp the impact of genetics on cancer development, treatment, and prognosis, it is important for medical directors, underwriters, and claims managers to review the essentials of genetics and the cancer genome.
- The basic unit of genetic information is the double-stranded molecule deoxyribonucleic acid (DNA). DNA’s building blocks are called nucleotides. Each nucleotide consists of a phosphate, a sugar, and one of four base molecules: adenine (A), cytosine (C), guanine (G), and thymine (T).
- DNA’s characteristic double helix is formed by pairs of these bases. Cytosine always pairs with guanine (C:G) and adenine with thymine (A:T). Human DNA contains about three billion base pairs, which represent the entire genome and codes for 20,000 to 25,000 genes.
- The nucleotides are grouped together in three-letter code words called codons. Each codon encodes for one amino acid. Amino acids are the building blocks of proteins. This encoding occurs via messenger ribonucleic acid (mRNA) which is “transcribed” from the DNA template and the mRNA is then “translated” into an amino acid.
- Only a small portion, approximately 3% of the human genome, is translated into proteins. This means the majority of the genome is selectively repressed. The portion of the genome that codes information for protein synthesis is called the exome, meaning all the protein coding genes are found in the exome. The actual portion of exome that contains the information used for protein synthesis is call the exon.
- Introns make up the rest of the exome and are found between the exons, but the introns do not contain any protein coding information.1
Alterations and mutations in DNA, mRNA and/or the end product protein can make each cancer slightly different.
This article will focus only on cancers caused by DNA-based alterations and mutations.
Driver Mutations
Specific genetic mutations are thought to drive the transformation of a cell from normal growth to invasive cancer. These mutations, which can either be inherited (germline) or acquired (somatic), are known as “driver mutations.”
Driver mutations within a gene lead to the formation of one or more mutant signaling proteins, which confers a selective growth advantage to the mutated cell. The advantage induces and sustains tumorigenesis (tumor development), thus promoting cancer development.2
The identification and presence of driver mutations occurring in multiple oncogenes (genes that can transform normal cells into tumor cells) allows the same histopathological type of cancer to be further subdivided at the molecular level, thus forming the basis of tumor heterogeneity.
Genes in cancerous cells generally contain multiple mutations. Studies have revealed approximately 140 genes that when altered by intragenic mutations can promote or drive tumorigenesis. A typical tumor will contain two to eight driver gene mutations. The rest of the mutations are alterations or “passengers” that may confer no selective growth advantage.3
In addition to the activating mutations of the proto-oncogenes that result in the formation of an oncogene, genetic alterations that lead to the inactivation of tumor suppressor genes have also been found. Testing for alterations and mutations in tumor suppressor genes is still not done widely due to its complexity, but there are tests that can look for altered protein expression due to inactivation of the suppressor genes.
Targeted Cancer Therapies
Targeted cancer therapies are designed to interfere with specific molecular targets involved with the growth of cancers. These therapies are meant to have no effect on normal cells and to be cytostatic (i.e., aimed at blocking tumor cell proliferation) rather than cytotoxic (i.e., aimed at killing tumor cells).
Several different targeted agents are used to treat cancers, including hormone therapies, signal transduction inhibitors, gene expression modulators, apoptosis (cell death) inducers, angiogenesis inhibitors, immunotherapies, and toxin delivery molecules.
The targeted therapies can be divided into these two classes:4
- Monoclonal antibody therapies, which target specific antigens on cell surfaces. The names of these agents contain the suffix “mab” (for monoclonal antibody).
- Small molecule therapies, which can penetrate the cell membrane and interfere with the activity of a certain protein inside the cell. The names of these agents ends with “-ib,” indicating protein inhibitory properties.
Genetic Alterations in Cancer
Many genetic alterations occur in cancers. These alterations can lead to the formation of driver mutations, which can serve as molecular targets of therapies. Some common types of mutations are discussed below.
- Point Mutations
In point mutations, also known as single nucleotide variations (SNVs), a base substitution occurs, which may or may not result in an alteration of an encoded amino acid. Testing for an SNV in a gene is one of the simpler tests to perform.
An example of an SNV is the BRAF c.1799T>A (V600E) mutation. This is a specific mutation in the protein kinase BRAF, which is a member of the RAF family of kinases (ARAF, BRAF and CRAF [RAF1]). It is downstream of RAS in the RAS/RAF/MEK/ERK pathway and its mutation leads to uncontrolled cell proliferation. This mutation accounts for 80% to 90% of all BRAF mutations at the V600 position and occurs in 40% of all malignant melanomas.5
In the V600E mutation, thymine substitutes for adenine at position c.1799, which results in the substitution of the amino acid glutamic acid for valine at position 600 in BRAF and leads to increased kinase activity.6
In individuals with malignant melanoma, the BRAF V600E mutation confers increased sensitivity to targeted therapy with BRAF inhibitors. Trials of the BRAF kinase inhibitor vemurafenib have shown response rates of more than 50% in patients with the BRAF V600E mutation who have metastatic melanoma. The problem is that resistance to treatment and tumor progression occurs in nearly all patients in the first year of therapy.7 Studies are showing that combination therapy may be more durable than single-agent treatment.8
- Gene Insertions/Deletions
In this type of alteration, nucleotides are inserted in or deleted in the coding (exons) of the genome. These abnormalities are usually detected through whole exome sequencing, which sequences the exon rather than only a select few genes. This differs from whole genome sequencing, in which all of the nucleotides in an individual’s DNA are sequenced and can determine variations in any part of the genome.
Some cancers may show both an insertion and deletion mutation. For example, NSCLC can have an EGFR (epidermal growth factor receptor) exon 19 deletion and a human epidermal growth factor receptor (HER2) exon 20 insertion. EFGR is a receptor tyrosine kinase (RTK). The exon 19 deletion occurs with a frequency of 48% in EGFR-mutated lung cancers.9
Driver mutation screening of NSCLC has shown that approximately 10% of U.S. patients and 35% of East Asian patients have tumor-associated mutation of the EGFR. EGFR activation drives the pathways involved in cell survivaland proliferation.
In advanced NSCLC, the presence of an EGFR mutation confers a more favorable prognosis and strongly predicts for sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, afatinib, and osimertinib.10
The insertion mutation seen with NSCLC is related to the HER2 gene, which also belongs to the family of receptor tyrosine kinases (RTKs). In this instance, a G776(YVMA) insertion in exon 20 results in increased HER2 kinase activity, leading to increased cell survival, invasiveness, and tumorigenicity. The role of this mutation in regards to targeted therapy is being investigated.11
The presence of targetable driver mutations may result in first-line usage of targeted therapies vs. standard chemotherapy in the treatment of NSCLC. In a 2016 study conducted in France, molecular profiling of known oncogenic drivers was performed for patients with advanced NSCLC. Genetic mutations were found in about 50% of the analyses: EGFR mutations were reported in 11%, HER2 mutations in 1%, KRAS mutations in 29%, and BRAF mutations in 2%. The presence of a genetic mutation affected first-line therapy choice for 51% of patients and resulted in improved first-line progression-free survival (10 months versus 7.1 months) and overall survival (16.5 months versus 11.8 months).12
- Gene Amplification
This mutation occurs when there is an increase in the number of copies of a gene. If an oncogene is involved in the amplified region of the gene, the resulting overexpression of the oncogene can lead to tumorigenesis.
An example of an amplification mutation is HER2 overexpression in breast cancer. Amplification of the HER2-containing region of chromosome 17 (i.e., q11-12) leads to overexpression of the HER2 oncogene, which occurs in 18% to 20% of all breast cancers. Other mechanisms can also result in HER2 gene overexpression, but gene amplification is the most common.13
As mentioned before, HER2 (ERBB2) encodes for one of the tyrosine kinases receptors (RTKs). Its overexpression in breast cancer is associated with higher rates of breast cancer recurrence and death. As a result, effective anti-HER2 targeted drugs, specifically monoclonal antibodies, are recommended
for early and late stage breast cancer. (Specifically, trastuzumab for both early and late stage, and pertuzumab, ado-trastuzumab emtansine, and lapatinib for late stage are indicated.)
In addition to gene amplification, several other single nucleotide variations (point mutations) have been identified in 1.6% to 2.0% of breast cancers. These activating mutations appear to also drive tumorigenesis and may lead to resistance or sensitivity to some of the HER2-targeted monoclonal antibodies listed above.14
- Gene Fusion
Fusion is the genetic recombination of the parts of two or more genes where regions of DNA not normally next to each other become fused together. This can result in different and/or added regulatory regions. This oncogene fusion includes at least one oncogene as one of the partners, the result of which is the translation of oncogene fusion proteins.
The classic example of a fusion gene is the translocation that results in an abnormal chromosome 22, known as the Philadelphia (Ph) chromosome. The Ph chromosome results from a balanced translocation between chromosomes 9 and 22, denoted t(9;22) (q34.1;q11.21). This translocation of the ABL1 gene on chromosome 9q34 to chromosome 22 results in a fusion between the BCR gene and the ABL1 gene and the formation of the BCR-ABL1 leukemic oncogene. ABL1 is a tyrosine kinase and the BCR-ACL1 fusion gene leads to the unique BCR-ACL1 fusion protein, a constitutively active deregulated tyrosine kinase that leads to uncontrolled proliferation.15 In 95% of cases, a t(9;22) (q34.1;q11.21) translocation results in the BCR-ABL1 fusion gene, which is necessary for the pathogenesis and diagnosis of chronic myeloid leukemia (CML).16
Other translocations also result in the creation of the BCR-ABL1 fusion gene and may be associated with distinct leukemia phenotypes.17
ABL1 kinase inhibitors are being used as targeted therapies against BCR-ABL1 positive malignancies. Imatinib was the first tyrosine kinase inhibitor (TKI) developed for CML. It works by inhibiting the activity of the oncogenic BCR-ABL1 fusion protein.18 High rates of complete cytogenic response (no Ph chromosome cells measured) and improved survival have occurred with imatinib, but 30% to 40% of patients will develop resistance or intolerance to the drug.19
Some of this resistance is due to single nucleotide variations (i.e. point mutations) in the tyrosine kinase domain of the BCR-ABL 1 fusion gene. Second generation TKIs have been developed to treat these resistant forms of CML.20
Financial Considerations
The cost of targeted therapy is significant and cure rates are still lower than expected. Standard chemotherapy with dacarbazine in metastatic melanoma, for example, has a median overall survival of 5.6 to 7.8 months. Vemurafenib, the BRAF kinase inhibitor used in metastatic melanoma, costs U.S. $13,000 per month and leads to a 15.9 month median survival rate. Patients for whom vemurafenib fails are often given ipilimumab, an immunomodulatory drug which costs U.S. $150,000 per course and has a relatively limited response in only 10% to 15% of patients and a median survival of 19.9 months.21, 22 Based on this, societies and healthcare systems will need to determine how limited medical resources will be allocated and distributed as more targeted therapies are developed and made available.
Conclusion
Cancers appear to be due to the mutation of a number of genes that alter pathways responsible for cell proliferation, survival, and suppression. Each cancer appears to have numerous mutations associated with it, all of which may have an effect on the sensitivity and/or resistance to targeted molecular therapy.
Targeted therapies are not likely to have a significant impact on the underwriting of traditional life and critical illness products in the near term, especially in regard to advanced tumors. However, they could significantly impact the approach to claims adjudication (as in the terminal illness claim above) and will certainly result in a significant increase in the cost of healthcare-related products.
Note: The website “My Cancer Genome” (www.mycancergenome.org) can be an invaluable reference for information on the genetic mutations provided in pathology reports.
