Should there be universal molecular testing for all patients with gastrointestinal cancer?
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In February, ASCO named molecular profiling driving progress in gastrointestinal cancers as its “Advance of the Year.” According to the American Cancer Society, taken collectively, gastrointestinal cancers have the highest incidence in the U.S. and, after lung cancer, are the second leading cause of cancer-related death. Identifying smaller subsets of patients based on tumor-specific and tumor-agnostic alterations provides insight as to who will benefit from personalized therapies. These subsets ultimately end up being substantial in size and, thus, universal testing should indeed be standard of care for all patients with metastatic gastrointestinal cancer.
Since 2017, when the FDA approved the first tissue-agnostic drug for patients with microsatellite instability (MSI), there have been several other tissue-agnostic approvals, including larotrectinib (Vitrakvi, Bayer) and entrectinib (Rozlytrek, Genentech/Roche) for NTRK gene fusions as well as tissue-agnostic approval for high tumor mutational burden.
The precision oncology field has transformed as we are more readily available to identify the right treatment for the right patient at the right time. Identifying these patients is critical as the benefit can be dramatic. However, it is important to note that tissue-agnostic approvals still require prospective tumor context-dependent data as context will likely matter, as we have seen with tumor mutational burden or KRAS G12C, for example, where single-agent activity in colorectal cancer is not as robust as it is lung cancer.
Although context matters when identifying patients for currently available therapeutic approaches, clinical trials also matter. Another illustrative example is the BRAF V600E alteration. The development pathway was not as straightforward for patients with BRAF V600-mutated colorectal cancer as it was in melanoma. Acquired resistance happens rapidly in colorectal cancer, and single-agent BRAF V600E-targeted approaches had limited efficacy, unlike for melanoma. By understanding the context of the target and developing context-specific strategies, we now have an FDA-approved option for BRAF V600E-mutated colorectal cancer.
The BEACON regimen (binimetinib [Mektovi, Pfizer Oncology], encorafenib [Braftovi, Pfizer Oncology] and cetuximab [Erbitux, Eli Lilly]) took over 10 years to develop, but is now an option for these patients, who constitute 5% to 8% of the population. In colorectal cancer alone, accounting for the currently targetable alterations — MSI, BRAF V600E (and other BRAF non-V600E alterations), HER2 amplifications and, albeit rare but still detectable, fusions — collectively could constitute 20% of all colorectal cancers. With time, we will likely see progress with KRAS alterations, as well.
We have also seen dramatic progress in other gastrointestinal cancers, such as discovery of the FGFR fusions in both gastric cancers and cholangiocarcinoma and IDH mutations in cholangiocarcinoma, to name a few examples.
Given the high incidence and mortality of gastrointestinal cancers, there is an incredible opportunity for advancing the field of precision medicine given the availability of molecular targets. Molecular testing should indeed be the standard of care.
- Kopetz S, et al. Abstract 8. Presented at: Gastrointestinal Cancers Symposium; Jan. 23-25, 2020; San Francisco.
- Smith SM, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03420.
Aparna R. Parikh, MD, is assistant professor of medicine at Harvard Medical School. She can be reached at email@example.com.
The ethos of histology agnosticism informs the notion that we ought to consider cancer universally. But, within the narrower field of gastrointestinal oncology, there are taxonomies enumerating up to 13 different primary sites between the alimentary tract and its accessory organs. Our hard-won understanding of the differences in disease characteristics between these loci cannot be entirely jettisoned in favor of a one-size-fits-all mindset. For instance, in gastroesophageal cancer alone, there is tremendous divergence in management depending upon the tumor’s anatomic center relative to the gastroesophageal junction; if football is a game of inches, this is a matter of centimeters. The genomic landscape is, if anything, even more nuanced, speaking against a global approach.
I do, in fact, advocate for molecular testing in biliary tract cancer, but a disease like intrahepatic cholangiocarcinoma is the example par excellence whereby the tissue volume available for traditional histopathologic analysis may be scant and where, just as importantly, newer diagnostics can be paired to newer therapies. Accordingly, the paradigm for second-line treatment of biliary tract cancer has evolved rapidly; while traditional cytotoxic regimens like FOLFOX and, more recently, 5-FU/nanoliposomal irinotecan (Onivyde, Ipsen) can be considered on the basis of the ABC-06 and NIFTY trials, the discerning oncologist may also be able to discover an IDH1 mutation targetable with ivosidenib (Tibsovo, Servier) or an FGFR2 amplification rendering their patient eligible for pemigatinib (Pemazyre, Incyte).
This lock-and-key hypothesis of uncovering mutations and matching them to targeted therapies holds great appeal. But its biological plausibility must be sacrificed on the altar of data, whereby across all genomically informed drug choices the therapeutic response rate is modest at best (by several estimates in the single-digit percentage range). This disappointingly low figure has many explanations, including conceptual oversimplification in yoking cancer growth to a single driver mutation, as well as the staggering diversity to be found in intra- and intertumoral heterogeneity; a phylogenetic analysis of a single patient’s multiple liver metastases from colorectal cancer can reveal enormously complex spatiotemporal influences on one subclone’s evolution vs. another, despite seeding of the same organ from the same ancestral cells. Further complicating the matter is the treating oncologist potentially diversifying tumor clades through selective antineoplastic pressures.
Although proponents of universal testing will posit that one cannot know a priori what mutations will be unsurfaced by next-generation sequencing, there is a counterargument that we can still maintain a Bayesian approach to our orders. Pancreatic ductal adenocarcinoma is one of the most lethal cancers I treat in my practice and yet its menace seldom arises from a high tumor mutational burden, nor is its largely predictable dependence on KRAS, considered conventionally actionable at the time of this writing. Further, the simple step of taking a comprehensive family history may reveal the pattern of Lynch syndrome or of a BRCA kindred in a more discriminating, less costly fashion that can trigger genetic counseling and focused testing for germline defects, rather than casting a wide somatic net.
During my training I was taught this maxim of diagnostic pragmatism: “Never order a test unless you are prepared to act upon the result.” This is advice that becomes impossible to follow when an assay yields variants of unknown significance; that phraseology itself is an admission of the iterative nature of our genomic understanding, and it will remain largely in the domain of clinical trials to demonstrate in a rigorous fashion that mutation-treatment dyads make effective pairings. To that end, the widespread use of genomic testing outside research settings may impede our progress toward greater comprehension of what is truly actionable.
Finally, the true “universality” of said testing is questionable given known gaps in cancer care delivery. In the wake of a practice-changing trial, such as KEYNOTE-177, it is nearly unthinkable that a metastatic colon cancer would not be tested for MSI or mismatch repair (MMR) defects to ensure we were capturing every candidate for immunotherapy. Yet, as recently as 2020, a survey of more than 20 U.S. oncology practices showed that fewer than 60% of patients’ tumors were being tested for MSI-high status or MMR deficiency, let alone for KRAS, NRAS or BRAF V600E mutations. The greatest barrier to next-generation sequencing may therefore be our inability to demonstrate consistent adherence to the standards of current-generation diagnostics.
In conclusion, the principles of biological diversity (both within and between tumors), pretest probability and equity cannot be abandoned in favor of irrational exuberance toward novel testing before it is proved to provide benefit for all patients.
- Lamarca A, et al. Abstract 4003. Presented at: ASCO Annual Meeting; May 31 to June 4, 2019; Chicago.
- Shiu KK, et al. Abstract 6. Presented at: Gastrointestinal Cancers Symposium (virtual meeting); Jan. 15-17, 2021.
- Yoo C, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdz247.155.
Mark A. Lewis, MD, is director of gastrointestinal oncology at Intermountain Healthcare in Utah. He can be reached at firstname.lastname@example.org.