[Column] A game changer in colorectal cancer treatment: the evolution of ...

Hong Joo-hyun, a specialist at the Korean Society of Medical Oncology and the Department of Hematology-Oncology at the National Cancer Center

Colorectal cancer, which includes both colon cancer and rectal cancer, can be broadly classified into colon and rectal cancer, but it may also be divided into left-sided and right-sided colorectal cancer based on the splenic flexure. (Credit: Getty Images)

According to statistics released by the National Cancer Information Center in April, colorectal cancer ranked third in both incidence in 2023 and mortality in 2024, consistently remaining among the country’s most common cancers.

While the number of younger colorectal cancer patients had previously declined, recent data suggest a slight increase. However, because colorectal cancer predominantly affects older adults, its burden is expected to remain high in Korea, which has now entered a super-aged society.

The five-year relative survival rate for localized or locally advanced colorectal cancer exceeds 80 percent, but drops to only around 20 percent in cases with distant metastasis. This sharp contrast underscores the importance of early screening, and Korea’s national screening program is also moving toward improvements in response.

Colorectal cancer, which includes both colon cancer and rectal cancer, is often broadly classified into these two categories. It can also be divided into left-sided and right-sided colorectal cancer based on the splenic flexure. In general, localized or locally advanced colon cancer is treated with surgery followed by adjuvant chemotherapy to reduce recurrence risk.

In contrast, locally advanced rectal cancer is commonly treated with neoadjuvant chemoradiotherapy before surgery due to the rectum’s narrow and anatomically complex location within the pelvis. This approach aims to improve anal preservation and reduce local recurrence.

However, not all colon and rectal cancers are the same. Advances in molecular classification have led to efforts to categorize colorectal cancer into left-sided and right-sided disease, as studies revealed significant differences in genetic alterations, clinical course, treatment response, and prognosis. Beyond this binary classification, precision medicine has continued to evolve through targeted therapies tailored to specific genetic mutations.

Dr. Hong Joo-hyun

One of the most remarkable biomarkers in colorectal cancer is mismatch repair deficiency (dMMR) or microsatellite instability (MSI), which gained prominence with the emergence of immunotherapy. Immune checkpoint inhibitors have already transformed treatment paradigms in several cancer types, but colorectal cancer has traditionally been considered less responsive to immunotherapy.

Yet some colorectal cancers harboring these genetic alterations have shown dramatically different outcomes, with even metastatic disease occasionally achieving complete remission or cure. As a result, testing for dMMR or MSI has become an essential biomarker assessment in colorectal cancer.

The significance of this biomarker is also increasing in locally advanced disease, not just metastatic cancer. Although rare, occurring in fewer than 5 percent of cases, studies published in the 2025 edition of the New England Journal of Medicine reported that patients with locally advanced rectal cancer harboring these mutations demonstrated exceptionally favorable responses to immunotherapy, including clinical complete response rates reaching 100 percent.

As mentioned earlier, neoadjuvant chemoradiotherapy followed by surgery is one of the standard treatments for locally advanced rectal cancer. Even when surgery is successful and recurrence is prevented, patients may still experience urinary, sexual, and bowel dysfunction. Identifying these genetic alterations and treating patients with immunotherapy instead could significantly reduce treatment-related complications and long-term sequelae while dramatically improving outcomes.

Although the burden of chemoradiotherapy and surgery is generally lower in colon cancer than in rectal cancer, these genetic alterations remain highly important in locally advanced colon cancer as well. Perioperative immunotherapy, whether neoadjuvant or adjuvant, may play a major role in reducing the risk of recurrence.

Additionally, although even rarer at less than 1 percent, POLE/POLD1 mutations associated with high tumor mutational burden (TMB-high) are also known to predict particularly strong responses to immunotherapy. Detecting these mutations can therefore help guide treatment decisions. Because these are uncommon alterations, comprehensive next-generation sequencing (NGS) that analyzes hundreds of genes simultaneously is necessary.

Adjuvant chemotherapy is generally administered after surgery for stage 2 and 3 colorectal cancer. A study published in the 2025 New England Journal of Medicine reported that patients with PI3K pathway mutations who took aspirin for three years experienced recurrence rates reduced by more than half compared to those who did not.

Aspirin is an old, well-known medication with relatively manageable side effects, making these findings particularly encouraging. However, identifying PI3K pathway mutations also requires NGS testing capable of evaluating hundreds of genes simultaneously. These mutations are estimated to occur in approximately 37 percent of colorectal cancer patients.

In stage 4 metastatic colorectal cancer, multiple genetic tests are essential for selecting appropriate therapies. In addition to dMMR/MSI testing, mutations such as KRAS/NRAS and BRAF V600E must be identified to guide targeted treatment decisions. Patients with these mutations are often treated with the targeted therapy bevacizumab, while those without mutations and with left-sided colorectal cancer may receive Erbitux (cetuximab).

Among these mutations, BRAF V600E has historically been associated with poor prognosis, with a median overall survival of approximately 15 months. However, recent studies have shown that first-line treatment with cetuximab and the targeted therapy Encorafenib can nearly double median overall survival to around 30 months, providing an important new treatment option.

Patients with KRAS G12C mutations may also benefit from targeted therapies, such as Lumakras (sotorasib), or from participation in clinical trials.

Even in third-line or later treatment settings, cetuximab may still be considered, particularly in patients without KRAS/NRAS or BRAF V600E mutations.

Because tumors can acquire resistance mechanisms, including new mutations during chemotherapy, repeat genetic testing before cetuximab administration is advisable. Repeated tissue biopsies may be difficult, however, making liquid biopsy—blood testing for circulating tumor DNA—a useful alternative.

Additional actionable targets, such as HER2 overexpression and NTRK or RET gene fusions, may also allow for mutation-specific targeted therapies.

Colorectal cancer is not a single disease. Its clinical behavior and prognosis vary significantly depending on genetic mutations. Therefore, identifying dMMR/MSI status as well as KRAS/NRAS and BRAF V600E mutations is now essential.

Furthermore, it is important to identify additional rare but clinically meaningful genetic alterations that may influence treatment decisions and prognosis.

Because tissue samples can be limited, NGS testing, which evaluates hundreds of genetic alterations simultaneously, is strongly recommended despite its high cost burden.

When tissue biopsy is difficult, NGS can also be performed through liquid biopsy blood tests. These technologies make it increasingly possible to implement personalized precision medicine tailored to each patient, ultimately improving outcomes.

Hong Joo-hyun