Targeted therapies are extending the life of some patients with advanced colorectal cancers. Unlike chemotherapy, which kills all fast-growing cells, targeted therapies are a bit more nuanced.
“Targeted therapies are outside the scope of chemotherapy,” says Dr. John Strickler, a medical oncologist at Duke Health in Durham, North Carolina. “They are drugs that target some aspect of the tumor; for example, the vascular structure [blood vessels that supply nutrients to the tumor], or receptors involved in a tumor’s growth and spread, or a specific mutation. There are many tumor types where targeted therapies have become the standard of care.”
For colorectal cancer, there are currently two main targets, says Dr. Muhammad Beg, a medical oncologist at UT Southwestern Medical Center’s Simmons Cancer Center. Vascular endothelial growth factor drugs (bevacizumab, ramucirumab and Ziv-aflibercept) are among the oldest targeted therapies. They block the growth of new blood vessels to the cancer. Epidermal growth factor receptor drugs (cetuximab and panitumumab) target a specific protein, EGFR, on the tumor. Both are given in conjunction with chemotherapy in patients whose CRC has spread.
[See: 6 Options for People Who Don’t Want a Colonoscopy.]
The key to targeted therapies is determining which tumors have a target that might respond to one of the available therapies. So oncologists test every patient’s tumor for known genetic mutations. In colorectal cancer, one of these genes is called KRAS wild type. Despite the confusing name, KRAS wild type is the normal version of this particular gene, which regulates cell division. RAS, a family of proteins of which KRAS is the most common form, is a key target for anti-cancer treatments. About 30 percent of cancers have tumor-forming (oncogenic) mutations in RAS.
Researchers have found that whether colorectal cancer patients have the normal or mutated KRAS wild-type gene (or NRAS wild type, a less common version) has treatment implications. About 30 to 50 percent of CRC tumors have the mutated KRAS gene. Mutated KRAS does not respond well to EGFR targeted therapies. Patients with normal KRAS, on the other hand, may benefit from EGFR or VGFR therapies.
That said, not all KRAS wild-type CRCs respond to EGFR therapies, either. Some colorectal cancer tumors (perhaps 5 to 10 percent) have another mutated gene, BRAF, which may affect the response to targeted therapies. Like KRAS wild type, BRAF also regulates cell growth. It may be that mutated BRAF makes CRC tumors resistant to EGFR therapies, experts say.
“The RAS story is pretty mature,” Beg says. It’s an example of using genomic information to make decisions about cancer treatments. “We’re getting smarter at [identifying] who are good candidates [for targeted therapies].” Oncologists are testing all colorectal cancer tumors now for KRAS, NRAS and BRAF mutations.
Like other cancer treatments, targeted therapies have side effects. Beg says most EGFR side effects are skin-related. “For example, patients will develop a rash on their face, back or trunk,” he says. “It can get quite significant.” Bleeding, clots (which can lead to heart attack or stroke) and high blood pressure can be side effects of VEGF inhibitors.
CRC tumor sidedness — whether the tumor develops on the right or left side of the body — is also a consideration in making decisions about targeted therapies. Sidedness is related to whether patients receive VGFR or EGFR therapies. Right-sided tumors predict EGFR resistance, Beg says.
[See: 8 Questions to Ask Your Doctor About Colon Cancer.]
What’s New in Targeted Therapies
Beg says there hasn’t been a lot of innovation in colorectal cancer target therapies in recent years. However, he adds, that’s changing.
In May 2017, the U.S. Food and Drug Administration approved the drug pembrolizumab for metastatic colon cancers that are not candidates for surgery, have progressed following chemotherapy and have high microsatellite instability. MSI-high tumors are hyper-mutated tumors, Strickler says.
Pembrolizumab is an immunotherapy drug that targets PD-1, a protein that cancer uses to defend itself and hide from the immune system. The drug blocks this ability in tumors. “It’s an option for about 4 percent of patients with metastatic CRC,” Strickler says.
The downside to targeted therapies — in addition to side effects and limited patient populations — is resistance. After a while, the drugs simply stop working. Patients gain about two or three months of survival from each targeted therapy, Beg says, but by sequencing — offering one drug after another — median overall survival for advanced colorectal cancer has improved from six to nine months in the 1990s to 30 months now. Prolonging patients’ lives by sequencing targeted therapies also buys time, as researchers continue to develop new therapies.
[See: What Causes Cancer? 5 Unlikely Claims Explained.]
Strickler says oncologists are beginning to treat CRC as many diseases, not just one. “We are segmenting patients into finer and finer groups,” Strickler says. “The science used to treat cancer is becoming more complex. It’s not one-size-fits-all. There are many different types of [colorectal cancer], and we treat them with different types of therapies.”
More from U.S. News
8 Questions to Ask Your Doctor About Colon Cancer
6 Options for People Who Don’t Want a Colonoscopy
10 Weird Things That Can Make You Poop
Understanding Targeted Therapies for Colorectal Cancer originally appeared on usnews.com
