Cancer in the Era of Personalized Medicine and Next Generation Sequencing

Dr. Neha Sabnis, Product Manager, CORE Diagnostics Headquartered in Gurgaon, CORE Diagnostics is a clinical laboratory which offers services in the areas of Cardiology, Oncology, Reproductive disorders, Endocrinology, and Infectious diseases.

What is the first thought that crosses your mind when you hear the word ‘cancer’? I am sure most people would think of it as a slow, painful and an inhumane way of dying, and I agree, this would have been true a few decades ago, when we were still trying to decipher the etiology of the disease. Howeve, rapid, scientific & technological advances have significantly enhanced our understanding of this deadly disease and completely changed our outlook towards managing this deadly disease.

A few decades ago, chemotherapy & radiation therapy were the only available treatments for all advanced cancers. However, with the advent of personalized therapy, it was soon realized that the ‘one-size-fits-all’ umbrella approach may not be effective, particularly in a disease like cancer which is characterized by inter-individual variability. Personalized therapy is the individualization of therapy based on the molecular characteristics of an individual’s tumor. In fact, personalized therapy has completely revolutionized the management of lung, melanoma, breast, and colorectal cancers.

In order to personalize therapy, it is vital to unlock the genetic code and unravel the biological complexity of tumors. While a few decades back, this seemed like an impossible task, rapid advances in the field have made it possible to sequence the entire human genome rapidly at a fraction of a cost. DNA sequencing dates back to 1977, when Fredrick Sanger & colleagues developed what is called as the Sanger sequencing method to sequence DNA. Sanger sequencing, although very accurate, had very low throughput, as a result of which sequencing was both labor & cost intensive. Despite its obvious flaws, it was the most widely sequencing method for approximately 39 years. In fact, the Human Genome Project, which was an international scientific research effort aimed to sequence and map human genes utilized the Sanger sequencing method and cost ~$3 billion. Recent advances in science have very
efficiently replaced the Sanger sequencing method with Next-Generation Sequencing (NGS), which is both accurate, has high throughput and is much cheaper. In a span of just 10 years, the cost to sequence an entire genome dropped own from ~$3 billion to less than $1000!

"The advent of NGS has opened the doors to cost-effective personalized therapy, which is where medicine & research is headed"

In order to simplify and comprehend what genome sequencing is, let’s dive a little further into the basics. Genes are made up of deoxyribo nucleic acid (DNA), which is a double helix composed of two strands twisted around each other, similar to a spiral staircase. The sides are sugar & phosphate molecules and the rings are pairs of chemicals called ‘nitrogenous bases’. There are four types of nitrogenous bases, adenine (A), thymine (T), guanine (G)and cytosines(C)that make-up the DNA and the order of the bases along a strand is a code - a code for synthesizing proteins, which control most of our body processes. Every gene has a specific code and an error in the code (mutation) can lead to a dysfunctional protein, which may play an important role in the process of cancer initiation. Thus, to put it simply, genome sequencing helps us unlock the complex genetic code and facilitates the identification of genetic mutations.

So how will unlocking genetic code helps predict one’s health outcome or identify what disease one will or won’t get? In most cases, a disease’s phenotype is directly linked to an individual’s genotype. Several debilitating diseases such as cancer, cardiovascular diseases, diabetes, neurodegenerative diseases and many more are associated with an underlying genetic component. Identifying mutant variants through genome sequencing can thus have a multitude of applications such as predicting the risk of getting a disease, early screening, diagnosis, predicting individual response to therapy, designing effective therapy and characterizing drug resistance. With the advent of NGS, it is now possible to identify patients at an elevated risk for developing cancers such as breast, ovarian, prostate, colorectal, melanoma and pancreatic cancer with a simple non-invasive blood draw. For instance, women with a faulty BRCA1/2 gene are at an increased risk of developing Hereditary Breast & Ovarian Cancer. If diagnosed with clinically relevant mutations in BRCA1/2, women have the option of either undergoing prophylactic surgery or undergoing regular screening procedures, which can help detect cancer at a very early stage when it is still easily manageable. Apart from cancer risk prediction, NGS can also help detect cancers at a very early stage, earlier than conventional imaging technologies. Although this application of NGS is still in preclinical stages, it will not be long before blood tests become the mainstay in cancer screening.

DNA sequencing by NGS has changed our outlook to cancer management and has become an indispensable precursor to deciding optimal targeted therapy. For instance, several international regulatory bodies state that a metastatic lung adenocarcinoma patient must undergo broad molecular profiling that consists of testing for mutations in genes such as EGFR, ALK, ROS1, BRAF, KRAS, RET and MET to determine the next course of therapy. Similarly, a metastatic colorectal cancer patient must undergo extended RAS testing in order to determine the eligibility for anti-EGFR therapy.

In conclusion, the advent of NGS has opened the doors to cost-effective personalized therapy, which is where medicine & research is headed. There will soon be a day when personalized medicine becomes a common place, a day when we can bid adieu to cancer-related mortalities due to better risk prediction, early screening, early diagnosis and effective therapeutics.