Comprehensive Biomarker Testing

Kelly E. Goodwin, MSN, ANP-BC

Introduction

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer related deaths worldwide. Lung cancer rates vary significantly by sex, age, race/ethnicity, socioeconomic status and geography and lung cancer is found across all smoking histories.1 While patient characteristics are diverse, so is the disease itself. Lung cancer is broadly classified as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). NSCLC represents approximately 85% of total lung cancer diagnoses with adenocarcinoma (40%) and squamous cell carcinoma (25%) being the most commonly occurring histologies, or subtypes.2 Curative and palliative therapies for lung cancer include intravenous or orally administered systemic therapies, radiation therapy or surgery and are dependent on staging, pathology and patient considerations.

Systemic therapy for lung cancer historically consisted of chemotherapy.  Chemotherapy works by non-specifically killing cells that are growing or dividing and while it can help improve quality of life and survival in some patients it is also associated with significant toxicities due to the unintended effects on normal cells. Precision medicine, also known as personalized medicine, is a medical model that aims to customize treatments based on individual variability in genes, environment, and lifestyle. Through sequencing the genetic material of normal tissues and cancers scientists have been able to identify genetic alterations, often called mutations, that interfere with the normal functioning of cells. Some mutations change genes that control cell growth so that they are always active and promote unchecked cell growth. Some other cancer-promoting mutations inactivate genes whose normal function is to slow or stop cell growth. A better understanding of the molecular pathways that contribute to NSCLC and other malignancies since the early 2000s has led to the development of specific targeted therapies and immunotherapies that have helped to improve survival rates and decrease treatment-related toxicities for certain subsets of patients with NSCLC. More than a dozen new drugs for the treatment of NCSLC have been approved since 2013, marking an exciting and hopeful time in lung cancer research and care.3

Biomarkers

Biomarkers are molecules in the blood or tissue that can result from mutations in genes. Biomarkers help to link subsets of patients to certain therapies – they can serve as prognostic markers and can help predict response, resistance or toxicity to certain drugs.  Lung cancer biomarkers arise from somatic mutations, alterations in genes that occur in tissues. Somatic alterations are different from germline (noncancer) alterations in that they are not inherited from one’s parents and are not passed on to one’s offspring. Germline mutations occur in the sperm or egg and at a very early age in fetal development such that they are presumed to be present in all of a person’s cells. Somatic mutations are classified as driver mutations when they encode for proteins critical to cell growth, differentiation and survival. Passenger mutations are those genetic variants that are less essential to transforming or maintaining the change of a noncancerous cell into a malignant cell.4

Oncogenesis is the complex, multi-step process by which normal cells transform into cancer cells. Genetic changes in a group of cells can cause normally functioning cells which are usually controlled by inhibition loops or other physiologic signals – analogous to “on” or “off” switches – to grow and behave abnormally. Cells which have undergone oncogenic transformation as the result of a driver mutation are stuck in the “on” position and their survival is dependent on a signal from that driver in order to survive. Reliance on, or addiction to, the oncogenic driver mutation makes certain lung cancers more susceptible to targeted therapies.

The American Society of Clinical Oncology (ASCO), the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), the Association for Molecular Pathology (AMP) and the National Comprehensive Cancer Network (NCCN) have issued guidelines for biomarker testing for patients with lung cancer since the early 2010s.5 Cancer promoting mutations in NSCLC were historically thought to occur in patients with a never or light smoking history and an adenocarcinoma histology and earlier versions of these guidelines reflected this understanding by recommending biomarker testing for specific target populations.6 However, research has shown that cancer promoting mutations can be found across all lung cancer histologies and smoking histories.7 With improved biomarker testing techniques, an expanding list of molecular targets and more approved and emerging therapies, comprehensive biomarker testing is an essential part of the evaluation and management of all patients diagnosed with NSCLC.8

Biomarker Testing Methods

Somatic driver mutations in NSCLC can be the result of many different types of genetic changes – gene deletions, insertions and rearrangements are among the most common – and can be identified through a number of different testing modalities. Despite the importance of biomarker testing in the management of patients with NSCLC, there is wide variability in uptake in testing in clinical practice9, testing methodologies, resulting timelines, time to initiation of therapy and payor coverage. Surgeons, interventional radiologists, interventional pulmonologists and pathologists are crucial members of the multidisciplinary team caring for patients being evaluated for NSCLC.

While there is no single standard platform for molecular testing, tissue-based testing remains the gold standard. Because driver mutations develop early in the process of transformation from normal cell to malignant cell tumor samples from either the primary tumor or a metastatic lesion are appropriate for molecular testing.10 Once tissue has been procured through a diagnostic biopsy, confirmation of adequate tumor cellularity occurs and histology has been determined (squamous versus non-squamous), the tissue sample may undergo biomarker testing.

Clinically useful biomarker tests are those which can be performed on available samples, are at least semi-automated, do not rely on a single operator or interpreter, are cost effective and have a fast turnaround time (two weeks or less).11 The type of testing employed depends on the type of mutation under investigation – DNA mutations, chromosome abnormalities or gene expression.

The most common testing techniques include, but are not limited to, polymerase chain reaction testing (PCR) of DNA or RNA (the genetic material that converts DNA into proteins), Fluorescence in-situ testing (FISH), Immunohistochemistry (IHC) and Next Generation Sequencing (NGS). These tests are collectively referred to as companion diagnostics because they help to match a patient to a specific drug or therapy. Testing can be performed through a hospital based, accredited laboratory or a number of commercial services.

DNA sequencing and DNA allele-specific testing are forms of single gene tests which use PCR to examine either the entire length of a gene or a specific region of a chromosome for the presence of a pre-specified mutation. While a relatively quick turnaround time of less than one week is an advantage to these testing techniques there are several disadvantages including lower sensitivity (a higher probability of a false negative), the potential to exhaust the tissue sample through multiple single gene tests, low cost effectiveness and the inability to identify new abnormalities.12

Fluorescence in-situ testing (FISH) is a testing technique which allows for the detection of gene rearrangements, translocations, amplifications or deletions through visualizing and mapping the genetic materials in cells. FISH is useful for examining specific genes, portions of genes or for understanding larger chromosomal abnormalities. Short sequences of single stranded DNA called “probes” are created to match a portion of the gene under evaluation; each probe is “labelled” with a fluorescent dye. As DNA is double stranded, identifying rearrangements uses hybridizing DNA probes of different colors that separate when two parts of a gene have broken apart.13 FISH testing can only detect a pre-specified mutation, requires significant technical expertise to perform and interpret and requires a minimum of 50-100 well preserved tumor cells within the tissue sample.  FISH results are typically available in about 6 days.14

Immunohistochemistry (IHC) testing is used to detect the presence of certain proteins in cells or tissues that may be overexpressed, whether or not there is an alteration in the genes. This technique preserves the spatial context or architecture of the tissue sample. The role of IHC testing in NSCLC continues to evolve but it is a rapid (one day) and reliable test for several of the most common driver mutations found in NSCLC15

Next generation sequencing (NGS) is a broad-based testing technique which allows for the analysis of multiple genetic alterations at the same time. DNA fragments from the biopsied sample are purified, amplified, isolated, and then compared to a known mutation “library” and a normal reference sample. Several hospital-based and commercial targeted lung cancer NGS tests are available which can test for 10s-100 alterations.16 Single gene testing requires “purer” cancer samples for adequate sensitivity and can exhaust tissue when run sequentially. NGS can be financially expensive though more cost effective than a la carte testing and the median turnaround time for results is close to 2-3 weeks. Rapid and ultra-rapid testing of some of the most common mutation types can be added as an adjunct to NGS testing for patients with significant symptoms and certain pathologic or clinical features. These rapid or ultra-rapid testing pathways can return results in 9 days or less than 2 days respectively and can significantly shorten the time between diagnosis and initiation of a life sustaining therapy.17 NGS reports can contain a large amount of information and require careful interpretation before finalizing a treatment plan. Acknowledging the importance of comprehensive biomarker testing for patients with recurrent, metastatic, refractory or stages III or IV cancer, the Centers for Medicare and Medicaid finalized a National Coverage Determination in 2018 that covers diagnostic laboratory tests using NSG in order to assist oncologists and patients in making more appropriate and timely treatment decisions and determining candidacy for clinical trials.18 Private payor reimbursement is variable but many oncologists, pathology departments and commercial labs have processes to advocate for reduced out of pocket costs to the patient.

While tissue based biomarker testing remains the gold standard for genetic analysis of NSCLC, “liquid biopsies” can be considered when a tumor is inaccessible, or a tissue biopsy is considered too high risk. Liquid biopsies detect fragments of circulating tumor DNA (ctDNA) that is shed into the bloodstream when the cancer is most active (at the time of diagnosis or when cancer is progressing on a therapy). ctDNA testing has significant benefits – it is less invasive than a traditional tissue biopsy, it is quick (7-10 days) and easily repeatable. The sensitivity of detecting target mutations with ctDNA is 60-80% and depends on tumor location, size, blood supply and detection method used (PCR vs NGS).19 Because of the increased risk of false negative ctDNA tests, liquid biopsies should not serve as stand-alone testing – tissue based testing should be considered if clinical suspicion for an activating mutation is high. The US FDA has approved ctDNA tests to identify EGFR mutation positive patients and one of the tests uses NGS to also identify genetic abnormalities in 55 genes.20 It is likely that as more data emerge the use of liquid biopsies to assess other molecular abnormalities will become more widespread.21

Lung Cancer Biomarkers

Lung cancer is one of the most genetically complex cancer types according to data from The Cancer Genome Atlas (TCGA) with genetic alterations identified in up to two-thirds of newly diagnosed advanced lung cancers. Historically driver mutations have been thought to occur primarily in non-squamous tumors and to be mutually exclusive.22 However, recent studies have shown clinically significant, actionable mutations in approximately 10% of squamous cell tumors23 and overlapping driver mutations in up to 12% of non-squamous NSCLC.24 Coexistence of driver mutations is clinically relevant because it may provide targets for additional or combination therapy and may help to identify potential sensitivity or resistance to a particular type of targeted therapy.

In 2020 and 2021 the NCCN updated their guidelines for routine molecular testing in newly diagnosed NSCLC recommending  testing be performed via a broad, panel-based approach, most typically performed by NGS, so that testing is done for all of the actionable biomarkers at the same time, including the established and emerging biomarkers. The expert panel recommended that smoking status, small biopsy specimens, and mixed histology should no longer be used when considering whether to perform biomarker testing. Furthermore, while acknowledging the lower incidence of driver mutations in advanced squamous cell NSCLC, the panel cited the cumulative incidence of actional alternations in squamous cell tumors and the effectiveness of targeted therapies as justification for recommending comprehensive biomarker testing for tumors of squamous histology. The goal of these expanded guidelines is to identify rarer mutations for which effective drugs may be available and to identify patients for appropriate clinical trials to advance the care of all patients with NSCLC.25

Common biomarkers in NSCLC

EGFR (Epidermal Growth Factor Receptor) mutations are the most common targetable mutations found in lung adenocarcinomas accounting for nearly 20% of NSCLC and are often found in younger patients, Asian patients and patients with a never or light smoking history. EGFR mutations can be detected with PCR or NGS testing. EGFR exon 19 deletions, L858R point mutations and some exon 19 insertions are associated with responsiveness to multiple oral EGFR targeted therapies. Targeted therapies for these EGFR mutations have been less effective for EGFR exon20 insertion mutant NSCLC, which represents about 10% of EGFR mutations and only 2% of overall lung adenocarcinomas, but two new therapeutic options to be used after initial treatment with chemotherapy (one oral and one administered by infusion) are expected to be available for this variant in 2021.26

ALK (Anaplastic Lymphoma Kinase) gene rearrangements have been found in 3-5% of patients with NSCLC and can be found using FISH, IHC and numerous NGS methods. ALK rearrangements are more frequently found in younger, male, never smokers with adenocarcinoma histology and ALK positive disease is associated with responsiveness to multiple oral ALK inhibitors.27

ROS1 (ROS proto-oncogene 1) rearrangements, typically genetic translocations, have been identified by FISH or NGS though some variants may be under reported.ROS1 mutations act as the driver mutation in 1-2% of NSCLCs and are more frequently identified in younger, Asian, never smokers with adenocarcinoma histology. The presence of ROS1 rearrangement predicts responsiveness to oral ROS1 targeted therapies. 28

BRAF (B-raf proto-oncogene) mutations, detected through PCR and NGS methods, are found in up to 4% of NSCLC though only the V600E variant has been associated with responses to BRAF inhibition given in combination with another class of drugs targeted the MEK pathway. BRAF + MEK inhibition is an oral therapy. BRAF mutations are most commonly found in patients with a smoking history.29

MET (mesenchymal-epithelial transition) exon 14 skipping mutations or MET gene amplifications are found in approximately 2-4% of NSCLC through RNA based NGS testing. Variants in MET are associated with response to oral therapies which inhibit MET. MET exon 14 skipping mutations are more frequently identified in patients with nonsquamous tumor histology, older, female and are less likely to be non-smokers.30

RET (rearranged during transfection) rearrangements are detected by FISH, RNA based NGS or PCR testing in 1-2% of lung adenocarcinomas and are associated with responses to oral RET inhibitors. RET rearrangement occur more frequently in younger patients and in never smokers.31

KRAS (Kirsten rat sarcoma) mutations are found in approximately 25% of patients with lung adenocarcinoma and is generally associated with smoking. KRAS G12C is the most common KRAS mutation found in lung cancers and is responsible for approximately 1 in every 8 lung adenocarcinomas. The first KRAS G12C inhibitor was approved in June 2021 for the treatment of disease following progression on or intolerance of first line treatment for advanced disease.32

NTRK 1/2/3 (neurotrophic tyrosine receptor kinase) gene fusions have been found in approximately 1% of NSCLC via FISH, IHC, PCR and NGS testing and is associated with sensitivity to oral NTRK inhibitors. NTRK fusions occur in NSCLCs across sexes, ages, smoking histories, and histologies.33

PD-L1 (programmed death-ligand 1) is a protein found on cancer cells, including NSCLC, which helps the cancer to hide from the immune system. PD-L1 expression can be detected using IHC and is reported as the proportion of tumor cells exhibiting staining. The proportion of PD-L1 informs the decision to pursue immunotherapy alone (PD-L1>50%) or chemotherapy plus immunotherapy combinations (PD-L1>1%) in patients with newly diagnosed NSCLC.34

TMB (tumor mutational burden) is not currently recommended for NSCLC but is emerging as an independent predictor of response to immunotherapy.35

HER2 (human epidermal growth factor receptor 2) mutations have been reported in 1-3% of NSCLC tumors, are most frequently detected using PCR or NSG testing and predominantly affect never smokers. The majority of HER2 mutations occur in women with adenocarcinomas. Anti-HER2 therapies are currently in development and may be accessed through clinical trial participation.36

Additional emerging biomarkers include PTEN, FGFR1, PDGFRA and DDR2. These alterations are most commonly found in squamous cell lung cancers. Multiple therapies directed at these variations are currently in development.37

Conclusion

As our understanding of genetic drivers in NSCLC evolves and more therapeutic options become available, patients are living longer and challenging the traditional concept of cancer survivorship. A collaborative, multidisciplinary approach to the evaluation and management of NSCLC that utilizes comprehensive biomarker testing for all patients with newly diagnosed NSCLC regardless of age, gender, smoking history or histology and for patients with identified actionable mutations whose cancer is acquiring resistance to targeted therapies is critical to ensuring that patients receive the therapy that is most likely to improve their survival and quality of life.38

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