The emerging role of comprehensive genomic profiling in cancer care

While our understanding of cancer has transformed in the last 20 years, it remains a leading cause of death worldwide.^1,2 It is estimated that around one in five people will develop cancer in their lifetime and that between 2020 and 2050 the global economic cost of cancer will be over $US 25 trillion.^2,3 Therefore a pressing need remains to find better ways to identify, treat, and overcome the disease.

New technologies such as comprehensive genomic profiling (CGP) are leading the way for cancer diagnostics by offering better ways to investigate and identify cancer, providing insights that can help to make personalized cancer care a reality.

Cancer was previously regarded as a single disease. However, it is now understood that cancer is a collection of hundreds of diseases, each driven by unique genomic characteristics. This means that even if the tumor location is the same, the DNA changes that caused the cancer may be making each cancer unique.⁴ There are now known to be around 250 types of cancers, around 350 genes that contribute to cancer development, and in some types of cancer there can be up to 100,000 mutations driving one unique cancer profile.^5,6,7 For example lung cancer, which was previously seen as one disease, is now categorized into at least 12 distinct subtypes based on molecular alterations that drive its growth.⁴

This knowledge about cancer and molecular information has the potential to offer cancer patients the best chance of personalized cancer care. It has triggered a shift away from a traditional ‘one-size-fits-all’ treatment approach (e.g. chemotherapy) towards therapy that targets the genetic changes that turn healthy cells into cancer cells.⁸ This shift looks is set to continue as it is estimated that targeted therapies will make up the majority of the oncology drugs market by 2031.⁹

In order to prescribe targeted therapies based on molecular information, physicians must rely on diagnostic testing. Existing companion diagnostics typically test for alterations to a single gene, or a small subset of somatic mutations which is known as ‘hot spot testing’. This approach helps pinpoint the best therapeutic options that may lead to better outcomes and inform clinicians about treatments that would be ineffective for patients. However, by focusing on narrow targets, these tests potentially miss other clinically relevant genomic alterations and signatures that may contribute to the patient’s disease.¹⁰

Next-generation sequencing (NGS), in which an individual’s full genetic sequence of three billion DNA base pairs (or genome) can be analyzed, has dramatically changed the way cancer can be diagnosed. NGS allows multiple tests to be performed on a single tissue sample. Millions of fragments of DNA are sequenced in parallel to enable genomic profiling within a rapid timeframe – typically in 2 to 3 weeks.⁴ 

Comprehensive genomic profiling (CGP) is an NGS approach that detects novel and known variants of the four main classes of genomic alterations and genomic signatures:¹¹

• Base substitutions: A DNA strand's amino acids are replaced with different ones
• Insertions and deletions: Extra amino acids are added to a DNA strand, or a section of DNA is removed
• Copy number alterations: Sections of DNA are repeated
• Rearrangements or fusions: The order of amino acids in a DNA strand is changed 

CGP can be applied to an individual’s genome to determine whether they are at higher risk than the general population to develop a certain type of cancer, or can be performed on a cancer biopsy to analyze the genetic drivers of that specific cancer. The results can provide complete information on common oncogenic drivers (like EGFR, KRAS, BRAF in non-small cell lung cancer) and new information on complex or rare biomarkers (like MET Exon 14, NTRK1, NTRK2, NTRK3 in non-small cell lung cancer, tumor mutational burden, microsatellite instability, genomic loss of heterozygosity and homologous recombination deficiency signatures that may apply to many cancers) all from a single test.^12,13

These insights can be thought of as helping to uncover the unique “fingerprint” of a cancer tumor. Such a deep understanding of what is driving the individual cancer is invaluable to physicians and can help them determine the best possible treatment for each patient, such as targeted therapies or clinical trials- that are tailored to the patient's tumor profile. They can even map their treatment journey to identify future courses of action should the disease progress.

Several studies have found that there are significant advantages to testing with CGP compared to traditional molecular tests for healthcare providers and patients:

• In non-small cell lung cancer (NSCLC), it was found that CGP can detect drug-sensitive EGFR exon 19 deletions better than conventional molecular tests, which are designed to detect specific deletions.¹⁰
• A Canadian study showed that replacing single-gene tests or hotspot panels with CGP could optimize treatment options and add life-years without significantly affecting cost.¹⁴
• A similar study from the US found that compared to conventional molecular diagnostic testing, increased use of CGP had a modest budgetary impact, which was attributable to increased survival due to effective treatments, in advanced NSCLC patients.¹⁵
• A growing number of studies demonstrate that sequential single-gene testing is less cost-effective than panel testing with CGP.^16,17
• Overall, data show that cancer patients treated with a targeted therapy, based on genomic mutations diagnosed via CGP, had better outcomes, including improved overall survival.¹⁸

While CGP testing has shown great promise, there are challenges to broad uptake such as turnaround times, confusion about test reimbursement, and limited access to targeted therapies outside the standard of care.¹⁹ The sheer amount of complex data provided by CGP testing can also mean physicians are faced with information overload and struggle with interpreting results, which may hinder actionable insights.^20,21 One way to address this challenge is with decision support software that can streamline the interpretation and reporting process for laboratories, enabling them to provide concise actionable reports to oncologists. In addition, as the knowledge base expands, software tools can continue to curate information from public databases, medical guidelines, and publications related to variants and signatures detected by NGS to support precision oncology.²²

Healthcare providers must also consider whether testing will be run in-house or outsourced. As this technology is still relatively new, the majority of cancer genomic profiling testing is outsourced. Outsourcing testing means labs don’t have to pay for equipment or expertise and is advantageous for smaller labs that may not have the capacity for additional testing. However, there are strong arguments to bring CGP in-house, such as ensuring safe and secure handling of specimens, the potential for quicker turnaround times, lower processing costs, and enabling research and development. As the CGP approach is adopted by more providers and the cost of sequencing drops, it is predicted that in-house sequencing will be implemented as a clinical laboratory test, particularly in specialist cancer centers.^23,24

Wherever testing is performed, it seems clear we are at a pivotal moment in healthcare history. A convergence of medical knowledge, technology, and data science is set to revolutionize patient care.