NEW YORK – Metastatic colon cancer patients are being undertested for guidelines-backed genomic markers, which means that many of them are losing out on the chance to receive precision therapies, a recently published study suggests.
It has been known for well over a decade that metastatic colorectal cancer patients who harbor certain KRAS mutations shouldn't receive monoclonal antibodies directed at EGFR. Despite this knowledge, a substantial number of colon cancer patients are still not being tested for KRAS mutations and other guidelines-recommended predictive biomarkers that could help them avoid ineffective treatments or receive therapies they would benefit from, according to a recently published study in JCO Precision Oncology from researchers at Hackensack University Medical Center in New Jersey, data analytics company Cota Healthcare, and the liquid biopsy testing firm Guardant Health.
The analysis, which was also highlighted last week at the Precision Medicine World Conference in Santa Clara, California, drew on a real-world database that contained diagnostic and treatment information on cancer patients treated at 23 practices and found that only 40 percent of metastatic colon cancer patients diagnosed between 2013 and 2017 were getting tested for predictive biomarkers recommended in guidelines. Given the testing rates identified in the study, the authors concluded that metastatic colon cancer patients who likely harbor non-response mutations, but haven't been genetically tested, are receiving anti-EGFR treatments that they are unlikely to respond to.
"The undergenotyping problem is something we need to shine a bright light on," Rebecca Nagy, senior director of medical affairs at Guardant and an author on the paper, said at the PMWC meeting highlighting the data from the study.
According to the authors, their findings should encourage oncology practices to survey testing rates among their own metastatic colon cancer patients and address barriers that may exist, such as tissue availability, test turnaround time, and physician education. "My own practice didn't do as well as I would want" in terms of testing rates, admitted Stuart Goldberg, chief of the outcomes and value research division at the John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, and senior author of the study. "It caused us to go back and take a look at where the breakdowns and the problems are."
Goldberg is also chief scientific officer at Cota, and Hackensack Meridian Health, the healthcare network that Hackensack University Medical College is a part of, is an investor in the company. Goldberg's research team previously used Cota's database to identify undertesting rates in lung cancer. "After that study, we did go to the individual practices and show them what their testing rates were … so they could see what they were missing," Goldberg said, adding that this information has been useful in improving the genomic testing program within his cancer center.
After the lung cancer analysis, Goldberg and his colleagues wanted to use Cota's database to investigate testing rates in other tumor types. Colorectal cancer, like lung cancer, was a setting where guidelines have evolved in recent years to recommend testing for multiple genomic markers.
In 2009, the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommended testing metastatic colorectal cancer patients for KRAS exon 2 mutations in codons 12 and 13. In 40 percent who harbor such mutations, the guidelines say to avoid anti-EGFR monocolonal antibodies, such as cetuximab (Eli Lilly's Erbitux) and panitumumab (Amgen's Vectibix), since patients are unlikely to respond.
More recently, expert groups have expanded guidelines to recommend testing for other KRAS, NRAS, BRAF mutations, and ERBB2 amplification, which together account for an additional 20 percent of metastatic colorectal cancer patients who don't respond well to anti-EGFR drugs.
The guidelines also recommend testing for markers that can be useful for predicting whether a colorectal cancer patient will respond to treatment. For example, patients who have a BRAF V600E mutation or have HER2 overexpression, but are RAS wildtype, could receive combination targeted treatments. Meanwhile, patients who have mismatch repair deficiency (dMMR) or microsatellite instability (MSI) are now eligible for checkpoint inhibitors, such as pembrolizumab (Merck's Keytruda) and nivolumab (Bristol-Myers Squibb's Opdivo). Testing for MSI and dMMR is also included in guidelines as a prognostic marker for colorectal cancer and for assessing risk of Lynch syndrome, a hereditary cancer condition.
Goldberg's team wanted to know whether testing rates were improving in line with evolving guidelines. Using Cota's real-world database, they retrospectively identified nearly 1,500 patients with pathologically confirmed metastatic colon cancer who were diagnosed between Jan. 1, 2013 and Dec. 1, 2017.
Cota's database includes deidentified demographic, diagnostic, and treatment information culled from electronic health records from 23 practices in five states (Arkansas, Maryland, Michigan, New Jersey, New York, and Tennessee.) Trained data abstractors searched EHRs for mention of biomarker testing and deemed if the performed testing was in line with what the guidelines recommended for a given year.
The researchers found that during the study period, because of expanding testing guidelines, more patients were tested for individual markers, but the number of patients receiving guidelines-aligned testing for all the biomarkers in 2017 was lower than in 2013, the first year of the study. This indicates a lag in oncologists' awareness and adoption of testing guidelines, and the need for physician education, Goldberg said. "If you ask oncologists if they're doing genomic testing, they might say, ‘Yes,' but they might be doing the testing in guidelines from two years ago," he said.
Overall, 60 percent of nearly 1,500 patients were still missing out on the chance to be tested, the study showed. Guidelines-aligned RAS, BRAF, and MSI/MMR testing occurred in 41 percent, 43 percent, and 51 percent, respectively.
Goldberg and colleagues reported a trend toward increasing guideline-aligned testing from 2015 to 2017, which they attributed to the growing use of next-generation sequencing panels. For example, at the start of the study period in 2013, PCR testing was the most common method of assessing KRAS mutations. But after that year, NGS was the main method for detecting KRAS, NRAS, and BRAF mutations, and the proportion of patients who received NGS testing for all three genes increased each year.
However, the undertesting found in the study has important implications for patient care. Nearly 180 patients received cetuximab or panitumumab, but only 50 patients, or 28 percent, had RAS or BRAF testing. That suggests that more than 70 percent of those who received anti-EGFR treatment may have received these drugs without knowing their biomarker status.
The undertesting rates suggest multiple barriers exist, among which access to tissue samples is probably the most pervasive problem. For example, Goldberg noted that patients are often referred to an academic cancer center like the one at Hackensack University from a community practice, but they got biopsied at the community practice. "It's not a coordinated system and it's sometimes difficult to get the sample," he said.
This study also suggested that metastatic colon cancer patients were more likely to have guidelines-aligned testing if they presented first with de novo metastatic disease, rather than being diagnosed with early-stage disease first and then progressing to metastases. Goldberg noted that there might be reluctance on the part of physicians to put a metastatic patient through another invasive procedure if they already had a colonoscopy when they presented with early-stage cancer. In these cases, rather than doing another biopsy for tissue based NGS, a liquid biopsy might be useful, Goldberg said.
As the developer of liquid biopsy testing, Guardant's interest in doing this type of analysis is undoubtedly to demonstrate the benefits of plasma-based NGS in situations where tissue ascertainment is a problem and the advantages of multi-gene analysis over single-gene testing. The authors point out in their paper that if every patient in this study who had testing for at least one biomarker received a tissue or plasma-based NGS panel that analyzed RAS, BRAF, and MSI, it would have increased the guidelines-aligned testing rate by almost 50 percent.
"We know people are being inappropriately tested, which is important because this gets into value and economics," said Goldberg, noting that while some insurers may balk at the $4,000 price tag for NGS profiling, by covering this testing more broadly, they can avoid the higher costs of treatments that are unlikely to benefit patients or cause them adverse events. "If only 40 percent of patients are getting the testing they're supposed to be [getting], there's a serious knowledge gap [and] an economic gap that we need to correct."
This study in metastatic colon cancer, along with the earlier analysis on lung cancer, should be eye-opening findings for cancer centers, in Goldberg's view. "These are the common cancers," he said. "What happens when you get to the rare cancers? We still have a ways to go."