Precision medicine aims to define and identify meaningful subgroups and develop tailored screening and treatment approaches for disease. However, existing evidence reveals that precision medicine for colorectal cancer (CRC) prevention may be misleading in regard to cancer risk, especially since this concept is based on the broad targeting of a disease or just a few risk factors. Researchers discussed the status of precision medicine for the prevention of CRC and evaluated whether this clinical application may be generating more hope than hype among the general public, according to a study published in Gastroenterology.

Hope in CRC Treatment and Screening

Precision medicine in CRC may be most promising in disease prediction and therapy. The 3 key molecular phenomena in CRC are high-level microsatellite instability (MSI-H) and somatic mutations in BRAF and RAS oncogenes.1 MSI-H is a favorable prognostic biomarker for every stage of CRC, and predicts for lack of benefit from fluoropyrimidine chemotherapy as monotherapy following initial treatment. Additionally, the activation of somatic mutations in BRAF has been found to result in poor prognoses in CRC, while RAS oncogenes may predict for lack of benefit from anti–epidermal growth factor receptor (EGFR) therapy using cetuximab or panitumumab. However, immune checkpoint inhibitor therapy for refractory MSI-H CRC has been recognized as the most notable development in precision medicine for advanced cases.

The researchers noted that single-agent PD-1 inhibitor therapy has demonstrated disease control rates of between 69% and 77% in patients with advanced CRC even after therapy has been discontinued.1 Combination immune checkpoint inhibitor therapy for MSI-H CRC with nivolumab and ipilimumab may provide an even greater benefit, with reduced toxicity. At present, clinical trials are examining the effects of immune checkpoint inhibitor therapy at other stages of CRC.

A growing number of potential therapies for other oncogenic pathways are being identified for CRC with RAS or BRAF wildtype. For example, CRC with ERBB2 amplification may benefit greatly from anti-HER2 therapies such as trastuzumab and lapatinib, which are used to treat ERBB2-amplified breast cancer. In chemotherapy-refractory, BRAF-mutated CRC, targeted therapies with combined RAF/MEK/EGFR inhibitor therapy are producing positive outcomes in 48% of patients, with median overall survival of more than than 15 months.1

The use of multigene panel testing and clinical criteria are widely recommended to identify patients at highest risk of CRC due to inherited genetic mutations. However, despite access to these tools, patients and their relatives remain undiagnosed.

The researchers stressed that 4 key considerations must be considered before implementing precision medicine for CRC, including measurable benefits to the patient, cost-effective delivery of precision medicine, savings due to the omission of unnecessary interventions, and the ability to implement precision medicine for the general population.2 Precision medicine may also be more effective with prevention strategies that involve molecular profiling, biomarkers, environment, and personal lifestyle.2

Hype in CRC Treatment and Screening

Many personalized treatment approaches for CRC are pending validation. According to researchers, systematic CRC molecular profiling with tumor tissue sequencing and/or circulating cell-free DNA have claimed high rates of therapeutic actionability in anywhere from 37-66% of all cases tested; however, these results have not been proven.1 For example, more than half of the actionable findings in 66% of tested CRCs were found to activate actionable KRAS mutations, though they predicted for lack of benefit from anti–EGFR-based therapies. Therefore, the concept of potential therapeutic actionability may be misleading, raising false hope and potentially causing psychological harm in patients with CRC.

Risk models that guide individualized screening for CRC are other precision medicine approaches that require further assessment and validation. At present, the only risk factors recommended to inform optimal screening for CRC are age and family history; however, there is no evidence to support the appropriate age at which patients should be screened. The American Cancer Society recommends starting CRC screening at age 45, but lack of evidence surrounding this recommendation has raised controversy between other organizations.1

Potential applications of precision medicine for CRC risk stratification may include predictive models that combine multiple risk factors and biomarkers. Genetic variants known as single nucleotide polymorphisms (SNPs) have been associated with CRC and have a small effect on disease risk, but when taken in aggregate, can predict a significant amount of variation in CRC risk and can therefore impact screening recommendations.

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According to researchers, models combining polygenic risk scores and environmental risk factors have the potential to increase performance compared with that produced by either model by itself.1 Combining risk scores with objective markers such as fecal immunochemical testing may also improve detection of CRC, though these approaches require further validation and have yet to be tested on non-European populations.

The CRC screening strategies currently being used rely on screening uptake, patient interactions, and patient questionnaires, even though questionnaires are subject to recall bias. Other potential barriers to these strategies include concerns surrounding ethics, privacy, and cost, which may be magnified in minority populations. Additionally, existing polygenic risk models have overwhelmingly consisted of patients with European genetic backgrounds.

Lastly, direct-to-consumer (DTC) testing for several indications has gained momentum for personalized medicine among the general public, though such testing has raised concerns  utility, validity and privacy that may outweigh the benefits of reduced cost, accessibility, and greater awareness of genetic conditions. Furthermore, current DTC panels for CRC risk assessment may produce negative outcomes, including misinterpretation and false reassurance based on race, ethnicity, and personal or family history of cancer. The American College of Medical Genetics recommends that consumers of DTC genetic tests be informed about the validity of testing and what it can and cannot reveal about their health conditions.

Conclusion

Though precision medicine may have great potential for preventing and treating CRC, and despite the fact that targeted therapies have produced positive outcomes for some patients, further validation is required for tailored screening, risk predictive models, and clinical application of precision medicine approaches. Until the healthcare industry can more adequately handle big data, adapt to artificial intelligence, and gather more evidence surrounding the efficacy of precision medicine for CRC, healthcare providers and patients must remain aware of hype, while also remaining optimistic about the hope of the individualized treatment and prevention of CRC.

References

1. Muller C, Yurgelun M, Kupfer SS. Precision treatment and prevention of colorectal cancer-hope or hype? [published online October 14, 2019]. Gastroenterology. doi: 10.1053/j.gastro.2019.09.046

2. Aziz MA. Precision medicine in colorectal cancer. Saudi J Gastroenterol. 2019;25:139-140.