Mutated gene influencing metastatic colorectal cancer survival rate

In a first ever reported study, researchers revealed better treatment prognosis for certain types of advanced colorectal cancer

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atari scientists have recently discovered that that an unmutated specific gene marker tends to indicate better prognosis for patients of metastatic colorectal cancer undergoing certain regiment of targeted therapies.

In a first published report of its kind on the subject, the study found that metastatic colorectal cancer patients with wild-type Kirsten Ras (KRAS) gene will likely have better survival rate upon receiving anti-epithelial growth factor receptors (EGFR) targeted therapy.

Meanwhile, the mutated-type KRAS metastatic colorectal cancer patients receiving anti-vascular endothelial growth factor (VEGF) therapy tend to have poorer survival outcomes, according to authors Kakil Ibrahim Rasul, Hind Elmalik, Mini Satheesh and Prem Chandra from National Center for Cancer Care and Research (NCCCR) in Doha, Qatar.

The state of KRAS gene, whether wild-type (normal) or mutated (abnormal), is already known to predict the metastatic colorectal cancer patients’ treatment response to anti-EGFR targeted therapy, a treatment inhibiting cell membrane growth factor receptors that are crucial in the control of key cellular transduction pathways and that are often over-expressed in various human tumors including colorectal cancers.

No study, however, had correlated KRAS with the survival rate of metastatic colorectal cancer patients. “To our best knowledge, this is the first known report of KRAS status and its impact on the prognosis of metastatic colorectal cancer,” they noted in a case report published by the open-access peer-reviewed journal of Advances in Modern Oncology Research (AMOR).

Mutated gene factor

KRAS, a coding gene, produces protein that primarily regulates cell division. “Its major signal transduction pathway…leads to the expression of proteins involved in cell proliferation, differentiation, and apoptosis,” explained the researchers.

KRAS mutation occurs in 30%–50% of colorectal cancers. Against the EGFR-targeted monoclonal antibody therapy, when applied across all treatment lines either as a single agent or in combination with chemotherapy, the mutation could indicate the therapy’s non-responsiveness.

As the third most common cancer worldwide and a disease responsible for the second highest cancer-related death in the industrialized world, colorectal cancer (CRC) afflicts more than one million people every year globally, despite its overall rate declining in recent years. While a majority of new CRC cases still involved older patients (age 50 and above, men more than women), the rate of colorectal cancer continues to increase in the younger generation.

The cancer often presents no symptom and would likely remain undetected by tests, developing slowly over several years, until past its initial stage. When it becomes advanced, the cancer can metastasize to other organs, most frequently the liver and lungs, while still presenting no noticeable symptoms. If caught early, CRC cases come with decent prognoses (stage I colon cancer have 92% survival rate); however, late-stage colorectal cancer patients, for instance those with metastatic or stage IV colon cancers, have relatively very poor five-year survival rate of about only 11%.

Response rate

It is therefore vital that researchers search for ways to improve the odds of survival for colorectal cancer patients. For the Qatari scientists, they foresaw that the clues could be embedded in the link between KRAS abnormalities and treatment outcomes.

“CRC biology and carcinogenesis have recently been recognized as a multistep process that involves the accumulation of molecular alterations. In addition, it has also been suggested that there is a potential association between many of these abnormalities with a patient’s survival rate,” they said.

According to the authors, significant improvements have been made in the last decade regarding CRC treatments in terms of response rates (RR), progression-free survival (PFS) and overall survival (OS). “These significant improvements are mainly from the development of a combination of standard chemotherapy using fluorouracil, irinotecan, and oxaliplatin, and therapeutic agents that target molecular events involved in colorectal carcinogenesis, with EGFR inhibitors being the most effective,” they reported.

The researchers examined the KRAS status of patients admitted at NCCR from 2009 to 2013 who were diagnosed with metastatic colorectal cancer, and their data demonstrated that wild-type (i.e. unmutated) KRAS patients had better overall survival trend compared to KRAS mutants. “The median survival for KRAS mutants was observed to be 48 months…and 72 months in wild-type KRAS patients,” they reported in the study.

In addition, the study also revealed contrasts in treatment results for patients with different KRAS status. Specifically, metastatic colorectal cancer patients with absence of mutated KRAS were discovered to have a better survival result upon undergoing EGFR antibody therapy, compared to the KRAS mutants.

“We found that patients with wild-type KRAS who received EGFR-inhibitor targeted therapy such as cetuximab or panitumumab showed improved survival, as reflected by their median survival of 72 months,” their retrospective study noted.

Additionally, the study suggests that KRAS-mutated patients who were excluded from undergoing anti-VEGF targeted therapy – which inhibits growth of new blood vessels and thus limiting tumors from necessary oxygen and nutrients – would survived longer than those who did receive it.

“Our study showed a trend towards survival benefit in KRAS mutants who did not receive anti-VEGF targeted therapy (bevacizumab), with a median survival of 60 months when compared to KRAS mutants receiving the same treatment, whose median survival is 48 months,” they observed.

The researchers concluded that the absence of KRAS mutations play a big role in colorectal cancer patients’ likelihood of survival, and additionally could influence on the results of the targeted therapy that the patients choose to – or choose not to – undertake.

“Based on our study, metastasis CRC patients with wild-type KRAS status have better survival and this is more evident if they had undergone anti-EGFR targeted therapy. In contrast, KRAS mutants who skipped the anti-EGFR therapy tend to have a poor survival outcome,” the researchers said.

“In addition, our study suggests that KRAS mutant patients who did not receive bevacizumab have better survival in comparison to KRAS mutants who received anti-VEGF antibody therapy,” they added.

The case report is available on AMOR website at http://www.advmodoncolres.com.

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