KRAS and NRAS in Metastatic Colon Cancer

A pathologist-in-training explains in simple terms how KRAS and NRAS mutation testing can give a ray of hope for patients with metastatic colorectal cancer to identify the most suitable therapy to prolong survival

By Thaddeus C. Hinunangan, MD

As a freshman of the University of the Philippines Diliman, I was a naive sixteen year old straight from Tacloban. I did not think I would have survived without my uncle’s guidance. During my first few days in Manila in the summer of 1997, my father left me in the care of his older brother. They lived in a house an hour’s commute from UP Diliman in Quezon City.

My uncle was a simple family man who worked at a large company and had a modest three-bedroom house with a car. My aunt was a college instructor at St. Paul’s. They had an only son. For the first few months when school started, my uncle was my go-to person. My father sent my allowance through him, and he was a strict but fair disciplinarian.

KRAS and NRAS in Metastatic Colon Cancer 4On late afternoons after a day’s commute, I would find him puffing a smoke near the gate, sometimes while fixing his car. He would always ask how my day was. Like my dad, he was not really an affectionate father, but I appreciated his efforts in making me feel at home. By my second year in UP, I decided to live on campus and my uncle gave his blessing. He said I was better off spending hours studying rather than commuting. I would still visit during weekends or staying at length like the time I had chickenpox.

Five years later, I was shocked to learn that my uncle had colon cancer. A mass was growing which had begun to obstruct his bowels. Regretfully, at the time I was already busy working in an office so I could not keep tabs with his condition except when my father would update me. Uncle had surgery to remove the mass and had a colostomy. Even then he had been able to make jokes about his condition, he said he now had a “cellphone” (referring to his colostomy bag) attached to his belly. The doctors said he had other masses noted on computed tomography scan.

Last I saw him, he was visibly thinner than usual. His smile seemed to hide the pain that he probably felt, still puffing on his cigarette. I felt a pang of sadness as I talked with him, with a lighted cigarette burning between his fingers. I was not in the medical profession then, but I knew no good came out of smoking. He did not undergo further treatment.

One evening I was asleep in my apartment when my mother called me- I was shocked to find out that my uncle had passed away. I was taken aback at how rapid the course of his illness was, and what the risks would be for our family, knowing our history. My father and his two siblings all had surgery for polyps and external hemorrhoids. What was the future for me health-wise? Would I meet the same fate? I asked myself.

Steps to dreaded cancer

Many years later, as a medical student and later as a Pathologist-in-Training, I became more aware of the advancements in medicine, Clinical Pathology in particular. I learned that cancers result from a series of multiple mutations in people’s genes that lead to malignant tumors. For instance, in colorectal cancers inherited or acquired mutations can cause inactivation of tumor suppressor genes particularly the APC (Adenomatous polyposis coli) gene, followed by activation of RAS (a protein involved in cell signaling). In mutations of the RAS protein, KRAS is the most important, found in 40% of colon cancers. The sum of the inactivation of tumor suppressor, RAS activation, loss of tumor suppressor gene at Chromosome 18q21, and loss of p53 (another tumor suppressor gene) ultimately drives the adenoma to carcinoma sequence.

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The implication of these well studied developments is that we can now detect these mutations by means of immunohistochemistry and molecular testing. In the same vein, advancements in immunohistochemistry in breast cancers have enabled doctors to determine if the patient’s breast cancer is Estrogen receptor (ER) and Progesterone receptor (PR) positive (usually in two thirds of breast cancers) and it helps determine the patient’s risk for recurrence and predict whether the cancer can be treated with hormone therapy. The same concept is applied when testing for Human Epidermal Growth Factor Receptor 2 (Her2) to check if the patient can benefit from targeted or biological therapies.

What are KRAS and NRAS?

KRAS is a proto-oncogene which was first identified in Kirsten rat sarcoma virus. The KRAS protein is involved in Epidermal Growth Factor (EGFR) pathway, and a mutation in the KRAS gene is a vital step in colon cancer transformation. Neuroblastoma RAS (NRAS) is also a part of the RAS oncogene family. NRAS mutations are usually noted in aggressive, leftsided colon primary tumors. To simplify, think of our cells as having a means of regulating themselves, when subjected to stresses and they are damaged, they are able to repair themselves and replace the damaged cells. The way these cells communicate with each other is through signaling pathways, but when there are mutations or derangements, this will result in cells proliferating beyond the control of regulatory mechanisms.

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Approximately 20% of colon cancer patients present with metastasis (or spread to other organs or sites), with a 5-year survival rate of only 11% in metastatic colorectal cancer. Although surgery is usually the first line treatment for early stage colorectal carcinoma, the American Society of Clinical Oncology and the National Comprehensive Cancer Network (NCCN) recommends the determination of KRAS and NRAS mutation status in patients with metastatic colorectal cancer.

A biopsy of the tumor is done to get a sample of the tumor tissue. The KRAS and NRAS tests check for mutations in the DNA of tumor cells to determine the treatment for patients with metastatic colon cancer. These patients with no identified KRAS or NRAS mutations are described as RAS wild-type and would benefit from anti-EGFR therapy, such as Cetuximab or Panitumumab. On the other hand, tumors with KRAS and NRAS mutations do not benefit anti-EGFR therapy. These patients would benefit from chemotherapy with or without anti-VEGF (anti-vascular endothelial growth factor) therapy. Treatment is always individualized per patient, hence it is essential to be guided by one’s oncologist.

Currently, The Medical City is the institution providing KRAS and NRAS mutation testing in the Philippines.

Hope for patients with colorectal cancer

Of course, back in the day when my uncle had been battling colon cancer, the diagnostics and therapies available were not as advanced as today. Cancer is such an insidious enemy that lurks around quietly while we live our day to day lives, waiting for that day our cells mutate and proliferate to become deadly invasive cancers. Lucky for us now, we have the technology to test for these biomarkers and be given the appropriate therapy.

Today, I am able to give more sound medical advice to family members and relatives, especially given our health history. We may never hear my uncle’s booming laughter again, but at least we learned lessons as to what we should do when a loved one battles the Big C again.

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“Although a colectomy or surgical treatment is still the mainstay of therapy per the National Comprehensive Cancer Network (NCCN) Guidelines 2017, the American Society of Clinical Oncology and NCCN recommends the determination of KRAS mutation status in patients with metastatic colorectal cancer”