Podcast article: Biomarker testing in colorectal cancer

Abstract

Christopher Lieu, co-director of gastrointestinal medical oncology and the associate director for clinical research at the University of Colorado Cancer Center (CO, USA) discusses the importance of biomarker testing in metastatic colorectal cancer to inform personalized patient care.

Podcast

Keywords::

• biomarkers
• colorectal cancer
• patient-centric care
• personalized care
• predictive
• prognostic
• testing

“Molecular testing can play an important role in the patient journey by informing personalized patient care and supporting shared decision-making.”

Podcast talking points

My name is Dr Christopher Lieu, and I am the co-director of gastrointestinal medical oncology and the associate director for clinical research at the University of Colorado Cancer Center, in Aurora, Colorado, USA.

In today’s podcast, we will discuss the importance of biomarker testing in metastatic colorectal cancer and how molecular testing results can help inform personalized patient care decisions by clinicians and their teams.

Overview of metastatic colorectal cancer

Colorectal cancer is the third most common cancer worldwide.

It is the second most common cancer in women and the third most common in men, with a mortality rate of nine in 100,000 worldwide [1]. This rate can vary by geographic region and anatomic subsites.

In the USA, it is estimated that colorectal cancer will have caused over 50,000 deaths in 2022 [2].

Increasing the rate of colorectal cancer screening is critical to reduce mortality and morbidity [3].

The incidence of early onset colorectal cancer is also rising in people under the age of 50, raising awareness of the need to identify concerning signs and symptoms that will lead to appropriate screening and identification of patients who will benefit from early treatment initiation [3].

Metastatic colorectal cancer is a highly heterogeneous disease resulting from mutations in several pathways, including the Wnt, TGF-β, PI3K/AKT/mTOR and MAPK pathways, as well as other cellular mechanisms, including DNA repair and others [4]. These mutations define specific molecular subtypes of colorectal cancer and have both prognostic value in assessing patient outcomes, independent of treatment response, and predictive value in identifying treatment options for patients [4,5].

Molecular characterization of a patient’s tumor can therefore play an informative and critical role in the patient journey and foster timely initiation of targeted therapy or immunotherapy where appropriate [4,5].

While advances have been made in our understanding of the molecular drivers of metastatic colorectal cancer and in the development of targeted and immunotherapy treatments over the last few years, prognosis remains poor for patients as 5-year survival rates in the metastatic setting are low [4].

Several molecular subtypes of metastatic colorectal cancer exist, including those with KRAS mutations (~40%), NRAS mutations (~5–10%), high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) (~5%), BRAF mutations (~10–15%) and HER2 amplification (~3%), among others [4].

Among the different molecular subtypes of metastatic colorectal cancer, patients with BRAF_V600E-mutant disease have the worst prognosis due, in part, to the mutation resulting in the constitutive hyperactivation of the MAPK pathway, which is essential for cell growth and tumor progression [6,7]. BRAF_V600E mutations are identified in approximately 8–12% of patients with metastatic colorectal cancer globally [8], although incidence can vary by region and in different patient subgroups. In addition, approximately 20–30% of patients with BRAF_V600E-mutant metastatic colorectal cancer also have high levels of microsatellite instability and are deficient in mismatch repair, also referred to as MSI-H/dMMR tumors; in these cancers, the BRAF mutation status is thought to drive poor prognosis [8–10].

Defects in microsatellite stability and mismatch repair lead to the accumulation of genetic mutations, resulting in tumor growth [4].

While the incidence of each molecular subtype of metastatic colorectal cancer may vary by region and in different patient subgroups, molecular testing is essential and allows the timely identification of patients who will benefit from therapy with the potential to improve clinical outcomes [4].

Testing & treatment modalities

The diagnosis of metastatic colorectal cancer should be confirmed via imaging and histology of primary and metastatic tissue [5,11,12].

Treatment choices for patients with metastatic colorectal cancer may be made using a multidisciplinary team approach, as well as shared decision-making [5,11,12].

Assessment of the resectability of limited oligometastatic disease is important for possible multidisciplinary management that may lead to surgical resection, ablation, or other liver-directed therapies [5,11,12].

Cytoreductive surgery in combination with chemotherapy may be recommended in experienced centers for selected patients with colon cancer with limited peritoneal metastases [5,11].

For patients who are candidates for curative resection of liver metastases, neoadjuvant/adjuvant chemotherapy or surgery alone can be offered [13].

Advances in our understanding of prognostic and predictive biomarkers in colorectal cancer are leading to the emergence of molecular testing practices in earlier disease settings, such as the use of circulating tumor DNA to test for molecular residual disease, which may hold promise for assessing recurrence risk and response to treatment [13].

While geographical differences may exist in molecular testing recommendations, several tumor tissue- or blood-based testing modalities exist which can help inform the treatment pathway for patients with metastatic colorectal cancer [4,5,11,12].

Biomarker-guided treatment is recommended as standard practice for the management of metastatic colorectal cancer [4,5,11,12].

Per the colorectal diagnostic and management guidelines, all patients should undergo RAS and BRAF testing, either as individual tests (e.g., Sanger sequencing, digital PCR) or as part of a next-generation sequencing (NGS) panel; immunohistochemistry (IHC) is also an option for BRAF_V600E testing [4,5,11,12].

For patients whose tumors are positive for RAS mutations, anti-EGFR therapy should be avoided, as these tumors have mutations downstream of EGFR which constitutively activate the signaling pathway irrespective of receptor blockade [4,5,11,12, 14]. This leads to harm, as patients will experience side effects of these agents, without antitumor benefit.

For patients with BRAF_V600E mutation-positive tumors, targeted therapies are available in the second-line setting and beyond [4,5,11,12, 14].

Mismatch repair testing via IHC and microsatellite instability testing via PCR or as part of an NGS panel are also recommended in newly diagnosed patients with metastatic colorectal cancer [4,5,11,12, 14]. MSI-H/dMMR is a predictive biomarker of response to anti-PD-1 therapy in metastatic colorectal cancer [4].

Molecular testing can also include HER2 testing, via IHC, FISH or NGS [4,5]. For those patients with HER2-amplified and RAS/BRAF wild-type tumors, anti-HER2 therapies are available [4,5].

Additional considerations include NTRK, ALK or ROS1 fusion testing via Sanger sequencing or NGS; IHC and FISH can also help detect NTRK fusions [4,5]. Note that NTRK, ALK and ROS1 fusions are very rare in metastatic colorectal cancer [4].

Personalized care for patients

Molecular testing can play an important role in the patient journey by helping treatment and management decisions [3,4,9].

While the incidence of each molecular subtype of metastatic colorectal cancer may vary by region and in different patient subgroups, molecular testing allows the timely identification of patients who will benefit from therapy, with the potential to improve clinical outcomes [4].

Patient journey considerations

Despite existing guidelines to leverage molecular testing to guide treatment decisions for patients with metastatic colorectal cancer, current testing rates can vary widely depending on access to relevant testing technology [15,16].

Patients and their caregivers are critical members of the treatment team. It is critical that they feel comfortable asking ‘has my tumor been tested for biomarkers? If so, how will these results impact my treatment? If not, please tell me why my tumor has not been tested for biomarkers.’

In addition, tissue and coverage limitations, as well as limited access to technology equipment, can hinder widespread use of molecular testing [15,16]. This is why raising awareness of the importance of and modalities involved in biomarker testing for metastatic colorectal cancer remains essential. Molecular testing can play an important role in the patient journey by informing personalized patient care and supporting shared decision-making.

Closing

Thank you for listening to this podcast.

I hope you have found the information discussed today helpful.

Disclaimer

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd.

Financial & competing interests disclosure

C Lieu reports a consulting role with Pfizer. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support for this podcast was provided by A Erden at Health Interactions, Nucleus Global, and was funded by Pfizer, Inc.

Supplementary data

To view the supplementary podcast that accompanies this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/fon-2022-1293

Additional information

Funding

C Lieu reports a consulting role with Pfizer. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.