Colorectal cancer: Recent research and insight

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. The Stanford Cancer Institute has labeled it a priority cancer. In observance of Colorectal Cancer Awareness Month and to learn more about recent advancements in the treatment and knowledge of CRC, we talked to SCI members George A. Fisher Jr., MD, Colleen Haas chair in the Stanford School of Medicine, and Steven M. Corsello, MD, Stanford assistant professor of Medicine and, by courtesy, of Chemical and Systems Biology and principal investigator of the Corsello Laboratory.

Mismatch repair (MMR) deficient CRC

“There is now a proof of concept that the immune system can cure advanced disease,” says Fisher.

Stanford was part of the first trial demonstrating the superiority of immunotherapy to chemotherapy in CRC patients with MMR deficiency, also known as microsatellite instability, which is now the first-line treatment for these patients. Further supporting this, a Memorial Sloan Kettering Cancer Center study showed 37 complete clinical responses to immune checkpoint inhibitors in patients with newly diagnosed mismatch-repair deficient rectal cancer. 

“This is remarkable because these are patients who otherwise may be treated with an aggressive combination of chemotherapy, radiation, and surgery,” Corsello says.

While only 5% of metastatic CRC is related to MMR deficiency, nearly 20% of patients with early stage (II or III) disease have MMR deficiency. Fisher says that the challenge is now to find a way to activate the immune system of patients who do not have MMR deficiency, which is a key focus of current research. 

HER2-amplified CRC

The accelerated approval of the combination of tucatinib and trastuzumab for advanced HER2-amplified CRC is a notable advancement in treating CRC patients. The drugs work in tandem as an antibody and a small molecule kinase inhibitor against HER2. Corsello notes that screening CRC tumors for HER2 expression is important to identify these tumors..

HER2-positive tumors are present in 3-5% of CRC patients, but finding HER2 amplification can have great implications for patient care. The combination improves progression-free survival compared to chemotherapy with a 38% objective response rate and 12.4 months median duration of response.

Fisher notes that SCI member Edgar Engelman, MD, identified a strategy targeting HER2 with an antibody that could generate an immune response, which is now in clinical trials with SCI members Chris Chen, MD, and Mark Pegram, MD, with Bolt Therapeutics as a sponsor. 

RAS mutations

Forty to 50% of CRC tumors harbor RAS mutations with KRAS being a well-established and key culprit oncogene across multiple tumor types. Recent drug discovery advances have enabled the specific inhibition of cancers with the G12C mutation, a point mutation that changes an amino acid from glycine to cysteine at position12 on the KRAS protein. Cysteine residues can react with certain drugs to form covalent adducts and inhibit protein function. These drugs first showed efficacy in non-small cell lung cancer with KRAS G12C mutations, and now researchers are seeing evidence of activity among other cancer types, including CRC, of which up to 3% have KRAS G12C mutations. Specifically, adagrasib has shown anti-tumor activity for CRC patients with the G12C mutation.

“It’s a compound that inhibits the mutant form of KRAS, so it’s highly selective,” Corsello explains.

Further, a recent study in the New England Journal of Medicine demonstrated that the combination of adagrasib and cetuximab, an epidermal growth factor receptor antibody, increased the response rate compared to adagrasib alone.

While the response rates are not as high as lung cancer, Corsello is optimistic about the potential of these medications. 

“We’re hopeful that KRAS-targeted therapy will benefit colorectal cancer patients and that we’ll figure out how to use those medications and combinations to further improve the response rate.”

Fisher says that several companies have pipelines with drugs that target G12D and other more common alterations of the KRAS gene that occur in colorectal and pancreas cancers. “We are excited to bring these now KRAS inhibitor to clinical trials for our colorectal and pancreas patients”.

Identifying patients and strategies that could avoid aggressive therapies and surgeries

A challenge in treating CRC patients is identifying who will benefit from adjuvant therapy, which is chemotherapy after surgery, and who can be spared chemotherapy’s risk of toxicity. In the past, providers have relied on the tumor’s clinicopathologic characteristics alone to make this decision, but clinicians are increasingly using the presence of circulating tumor DNA after surgery to identify patients at highest risk who may merit additional treatment.

Circulating tumor DNA can also be used to monitor for recurrence, as tumor DNA may be detectable in a patient before cancer is observable by a CT scan. Clinical trials are now ongoing to see if circulating tumor DNA alone is informative in terms of when to start treatment.

Meta-analyses have also shown that certain colorectal cancer patients, such as those with early stage 3 colon cancer or patients who have a tumor but only one or two positive lymph nodes, may have similar outcomes if they are treated with three months of chemotherapy compared to the standard six months. Shorter exposure to chemotherapy drugs decreases the chance of side effects, such as the risk of sensory neuropathy associated with longer exposure to the chemotherapy drug oxaliplatin

Additionally, a current study being conducted by Stanford professor in radiation oncology  Erqi Pollum is examining if a more intensive regimen of radiation and chemotherapy can achieve a complete clinical response potentially allowing patients to avoid an operation with life altering consequence and only undergo surveillance. 

Prevention and early detection of colorectal cancer remain key

The US Preventive Services Task Force recommends screening for colorectal cancer in adults starting at age 45. Per the American College of Gastroenterology, earlier screening may also be recommended, especially for individuals with a history of colorectal cancer or advanced polyp in a first-degree relative. Colorectal cancer incidence has increased in younger adults, so close attention to lower gastrointestinal symptoms and low threshold for diagnostic testing is merited, even in younger patients.

Patients who have MMR deficiency are now universally tested to see if the deficiency is from an inherited gene to inform treatment and so that family members are aware of their risk. Lynch syndrome is a genetic defect associated with an increased risk of colorectal cancer, as well as endometrial, ovarian, pancreas, gastric, small intestine, and bile duct cancers. A third of patients with MMR deficiency have inherited Lynch syndrome. Fisher points to the importance of increasing awareness of Lynch syndrome and notes that it’s actually more common than the well-known BRCA mutation associated with breast cancer.

Additionally, tumor molecular profiling is of increasing importance in treatment selection for patients with advanced disease. 

Avenues for future breakthroughs

Corsello notes there remains strong interest in combining immune checkpoint inhibitors with additional immunotherapies or targeted therapies to increase response rates in the most common form of colon cancer.

He also believes there are exciting opportunities to use new patient-derived models in cancer research. 

“There are ways to take patient tumors and grow them directly in the lab by generating what are called organoids.”

The idea is to make personalized models from patient tumors and use them to understand cancer biology and perform drug discovery experiments. He points to SCI member Calvin Kuo, MD, PhD, as specializing in this field.

Fisher is hopeful about future advancements in colon cancer treatment.

“When I started working as a faculty member at Stanford, there was no treatment that had been proven to prolong survival in colon cancer. Now we know that not only can we improve survival, but in some patients, we can cure what used to be considered incurable.”

March 2023