From Then to Now: How Genomic Testing for Cancer Has Expanded

Balazs Halmos, MD, MS

The first biomarkers tests designed to determine eligibility for targeted treatments—those testing patients with breast cancer for estrogen receptor status—were introduced some 30 years ago and as a result of these achievements, routine biomarker testing has become a standard part of care for several common tumor types:

• In advanced breast cancer, aside from testing for estrogen receptor status, there were routine tests for progesterone receptors and the overexpression of HER2, which would determine eligibility for trastuzumab (Herceptin) or lapatinib (Tykerb).
• In acute lymphoblastic leukemia and chronic myelogenous leukemia, tests for the Philadelphia chromosome justified the use of imatinib (Gleevec) or dasatinib (Sprycel), or later nilotinib (Tasigna).
• In advanced colorectal cancer, there were tests for mutant RAS status to identify which patients might respond to cetuximab (Erbitux) or panitumumab (Vectibix).
• In advanced non–small cell lung cancer (NSCLC), EGFR mutation status qualified patients for treatment with anti-EGFR tyrosine kinase inhibitors (TKIs), such as the first-generation agents gefitinib (Iressa) or erlotinib (Tarceva).¹
• In metastatic melanoma, patients were tested for BRAF to determine eligibility for BRAF inhibitors like dabrafenib (Tafinlar),2 or later combinations of BRAF and MEK inhibitors.

Biomarkers started to be used more frequently about a decade ago to screen for some cancers. Trials supported the use of fecal occult blood testing to detect colorectal cancer,³ and prostate-specific antigen levels were sometimes used to screen for prostate cancer, though the value of those tests in extending survival was unclear.⁴

After a patient received an initial diagnosis, biomarkers could inform prognoses and improve surveillance after therapy. Prognostic markers were most frequently used in breast cancer, especially lymph node–negative disease. The Oncotype DX test measured the expression of 16 cancerassociated and 5 control genes in patients and was recommended by the American Society of Clinical Oncology (ASCO) to calculate a recurrence score, as were tests of uPA and PAI-1.⁵ As early as 2002, a microassay looking at a 70-gene expression profile, later known as MammaPrint, was used to predict the possibility of distant metastasis in young patients with breast cancer.⁶ The MammaPrint test was approved by the FDA in 2007.⁷

As for surveillance after treatment, ASCO recommended an intensive routine that included regular carcinoembryonic antigen measurements after curative surgery for patients with prostate cancer.8 Investigators, moreover, were already looking for ways to use circulating tumor DNA to monitor cancer.⁹

Biomarker testing thus was an important tool in the management of some tumor types, but the number of biomarkers used, particularly genomic biomarkers, and the treatment options that hinged upon test results were relatively small a decade ago.

Since then, biomarker tests have proliferated. Looking just at genetic mutations that can be targeted by approved therapies, there are currently at least 24 (^{TABLE 10)}. Numerous tests have been approved to detect these alterations, and the number continues to grow. There are currently 143 indications for approved companion diagnostic tests.¹¹ One such companion diagnostic test is FoundationOne CDx, which helps to identify patients with melanoma harboring BRAF V600E and/or V600K mutations who may benefit from several treatment options, as well as EGFR exon 19 deletions or exon 21 substitution mutations in patients with non–small cell lung cancer (NSCLC) who may benefit from an available EGFR TKI.

Robert L. Coleman, MD, FACOG, FACS

EGFR testing allowing for matching to EGFR-targeted therapies has led the charge for precision medicine in lung cancer as well as a shift in recommended testing for patients. In 2011, the American Society of Clinical Oncology first recommended that all patients with advanced NSCLC be tested for EGFR before deciding on first-line therapy.12 Since 2004, several generations of EGFR TKIs have been approved to treat patients with EGFR mutations.¹³ Treatment options more recently provide even greater specificity, and greater benefit. Patients with EGFR exon 20 insertion mutations can receive treatment with amivantamab (Rybrevant) or mobocertinib (Exkivity). Additionally, osimertinib (Tagrisso) is approved to treat previously treated patients with the acquired EGFR T790M mutation as well as in the frontline setting for EGFR-mutant patients.

“A decade ago, we were testing for 2 or 3 alterations in [patients with] lung cancer, beyond EGFR, ALK and ROS1 might have become standard of care,” said Balazs Halmos, MD, MS, director of thoracic oncology and clinical cancer genomics at Montefiore Medical Center and Albert Einstein College of Medicine in Bronx, New York. “Today, that number is not so easy to pinpoint because we don’t just have targeted therapies, we have immunotherapies as well where biomarkers factor into decision-making. Overall, we have at least 10 biomarkers we commonly use to drive treatment decisions in lung cancer.”

As of the 2018 updated guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology, the biomarkers necessary to test for in patients with nonsquamous NSCLC were determined to be EGFR, ALK, ROS1, and BRAF alterations plus PD-L1 expression by immunohistochemistry. Additional biomarkers recommended to test for in NSCLC included RET, MET exon 14, HER2, KRAS, and NTRK alterations.^13,14

The proliferation of tests has affected the management of some tumor types more than others though. In ovarian cancer, for example, the progression has been slower than for lung cancer.

“In 2012, there were no genetic tests recommended for all [patients with] ovarian cancer in clinical care. Olaparib [Lynparza] wasn’t approved for BRCA-mutated cancers until 2014, and even then, standard of care was to test only those people whose family history indicated more than a 10% chance of mutation,” said Robert L. Coleman, MD, FACOG, FACS, the chief scientific officer of The US Oncology Network and a gynecologic oncologist at Texas Oncology.

"We knew we were missing [individuals] who had de novo mutations, but it wasn’t until several years later that enough evidence piled up to justify standards of care that called for everyone to be tested. Even now some claim we shouldn’t be testing for a wide variety of biomarkers because so few actionable biomarkers are common in ovarian cancer.”

Then vs Now

In addition to the growing number of single biomarker tests, there is also a growing number of next-generation sequencing (NGS) tests that can identify large numbers of biomarkers from a single tissue sample. FoundationOne CDx and MSK-IMPACT were among the first of these tests and were approved by the FDA in November 2017.¹⁵ FoundationOne CDx tests for 324 genes and 2 genomic signatures, whereas MSK-IMPACT tests for 468 genes. In 2020, the FDA approved the first NGS test for liquid biopsies, the Guardant360 CDx assay.¹⁶ Other NGS tests relying on either liquid or standard biopsies have been approved since, such as Oncomine Dx Target.

NGS tests have several advantages over single-biomarker assays in patients with appropriate tumor types. In addition to the convenience of sending a single sample to a single lab, multigene panels allow caregivers to identify mutational signatures, groups of mutations that often cluster and can guide treatment choices collectively.¹⁷ Multigene panels also enable the identification of tumor mutational burden, which can predict response to immunotherapy.¹⁸ Technological improvements have dramatically reduced the cost of genetic testing over the past 2 decades, but they are not the only factor driving costs down. A unanimous ruling by the US Supreme Court in 2013 held that genes are not patentable¹⁹ and ended the monopoly Myriad Genetics had on testing for BRCA1 and BRCA2 mutations. This decision allowed any company to develop tests for any gene (although these tests still have to be approved by regulators) and greatly increased competition in the testing market.²⁰

NGS testing remains expensive. Different payers negotiate different rates, but tests generally cost thousands of dollars. They can, however, be cost-effective in patients with some tumor types, particularly when the alternative is many single-gene tests.²¹ Additionally, costs have reduced over time as the technology became more accessible.

Practices and Opinions Differ

Experts have long disagreed over which patients should receive NGS assays. Some have argued that NGS, although suitable for trials, tends to be costly overkill because few cancers have more than a handful of actionable mutations.²² Others have argued that NGS should be performed on nearly all patients with limited options under current standards of care, as test results could support an unexpected treatment or render patients eligible for clinical trials.²³

In addition to witnessing an explosion in genomic testing, the past decade has also seen a rise in the use of assays that measure tumor protein expression, particularly PD-L1. Such tests often decide which patients are eligible for checkpoint inhibitor immunotherapies, and they are indicated for patients with a wide range of tumor types. One such drug, the PD-1 inhibitor pembrolizumab (Keytruda), has received nearly 40 separate indications from the FDA,²⁴ and 2 of those approvals are for tumor-agnostic indications with certain genomic biomarkers (high tumor mutational burden²⁵ or microsatellite instability–high or mismatch repair deficient²⁶) and limited alternative treatments.

Despite the growing body of evidence supporting tests for genomic mutations and other cancer biomarkers, such tests traditionally have been underused in ordinary clinical practice. A retrospective study of 1497 patients with metastatic colorectal cancer from 23 practices found that about half or fewer patients were tested as recommended by current guidelines for RAS (41%), BRAF (43%), and microsatellite instability/ mismatch repair deficiency (51%). The same study also found that many patients received targeted therapy without ever being properly tested for the relevant target. Among those who received anti-EGFR therapy (12%), only 28% of these patients had undergone guideline- aligned biomarker testing.²⁷

A study presented at European Lung Cancer Congress 2022 in March used registry data from Spain to show that 85% of patients with nonsquamous NSCLC and 56.3% with squamous histology received tumor marker testing since September 2016. Testing rates were higher for EGFR (78.9%) than for ALK (64.7%) or ROS1 (35.6%), and rates for PD-L1 expression testing were low overall at 46.9% but increased to over 85% when looking just at the past 3 years. A total of 44.5% of tested patients did have a positive result for either EGFR, ALK, KRAS, BRAF, or ROS1 alterations, or PD-L1 expression.²⁸

Conversely, many patients who undergo proper testing do not receive the treatment that test results indicate is needed. A 2018 study of multigene panel sequencing in advanced NSCLC found that between 25% and 40% of all patients with targetable mutations never received a proper targeted treatment.²⁹ The reasons for the underuse (and misuse) of tests are unclear. Cost is a potential barrier for patients whose insurance won’t cover the tests, but coverage is increasing as more studies show the value of testing and more societies add biomarker tests to their standards of care.

“Coverage is an ongoing battle, but we typically win those battles. We just need to provide appropriate justification,” Halmos said. “Many times, that justification comes in the form of national guidelines advocating the integration of a particular type of test up front or at the time of progression. It’s very hard for an insurance company not to feel that they need to listen to that guidance. That’s why we will continue to make sure that these guidelines are up to date and that they provide prudent guidance as to the use of these assays.”

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