What Does Resistance to Targeted Therapy Mean?
Targeted therapies for cancer are medicines designed to precisely target the protein that’s making your cancer grow. In the case of epidermal growth factor receptor (EGFR)-positive lung cancer, these medicines are designed to block the mutant EGFR protein receptor on the surface of your lung cancer cells to slow or stop the cancer.
Resistance to targeted therapy means that your cancer doesn’t respond at all or as much to an EGFR inhibitor medicine as expected. As a result, your tumor will keep getting bigger or may spread despite treatment. Treatment resistance can happen in different ways and for different reasons.
Primary resistance
Primary resistance means that your cancer is resistant from the very beginning of treatment. It means that something else about your EGFR-mutant cancer allowed it to persist despite treatment with medicines designed to block the EGFR.
Acquired resistance
Acquired resistance means your cancer responded at first but stopped responding later. Your cancer has gotten a new ability to resist the targeted therapy. When this happens, you’ll have disease progression.
“Unfortunately, despite how well the pills work up front, at some point, the tumor will outsmart the pill and grow or go someplace new, and that’s what we call progressive disease,” explains Christine Bestvina, MD, a lung cancer specialist at the University of Chicago Medicine in Chicago. “How that tumor outsmarts that pill is what we call resistance.”
Acquired resistance can happen fast or very slowly over the course of years. On average, treatment resistance to an EGFR inhibitor taken alone starts to happen within a year. Combination treatments may help delay resistance. Rest assured, resistance is something your oncologist and care team understand and can help you prepare for even before it happens. You’re not alone in this.
Why Do People With EGFR Lung Cancer Develop Resistance to Treatment?
First, remember that cancer is complex. Your cancer isn’t exactly like anyone else’s cancer. If you were to peer inside each of the cells inside your cancer, you’d find differences there, too.
In fact, it isn’t you who has developed resistance to treatment, but it’s the cancer. The reason it happens comes down to basic principles of evolution and survival of the fittest. In fact, it happens because the targeted therapy you’re taking works so well against the most common forms of EGFR-mutant cancers.
The medicine you’re taking kills off cells that are sensitive to it. But, any cells in the mix that are resistant can get left behind. Those cells may keep dividing and growing where they are. Or, they may spread to new places. Cells that were sensitive to start with might develop changes that allow future generations of cells to become resistant as well.
How Did My Doctor Decide I Have Developed Resistance?
Misako Nagasaka, MD, an oncologist specializing in lung cancer at the University of California Irvine Chao Family Comprehensive Cancer Center in Orange, California, says most often resistance is detected based on progression observed in regular scans. Standard treatment for EGFR-mutant lung cancer includes scans every three to six months. Ask your oncologist how often you should have scans.
“Let’s say [for example] that the cancer started out with a 5-centimeter tumor, and then let’s say that it responded to treatment and it went down to 2 centimeters,” Nagasaka says. “Sometimes, these treatments stop working, and it starts to regrow, or you could develop a new metastasis, a new spot in the body.”
Bestvina says the primary way oncologists look for resistance and progression in lung cancer today includes CT scans of different areas, including your:
- Chest
- Abdomen
- Pelvis
Your oncologist may also order an MRI of your brain.
“Knowing what’s happening in a patient’s brain is extremely important, particularly for patients with EGFR mutations,” Bestvina says.
Your doctor may order blood tests to look for increases in certain markers that tend to rise with NSCLC. Doctors can also look for cancer DNA in your bloodstream. In the future, Bestvina says, doctors may more often use cell-free, circulating tumor DNA (ctDNA) to detect progression even before it can be seen in a scan.
“The hope is that we will be able to identify early progression before patients feel different and before their CT scans show it,” Bestvina says.
Identifying the Resistance Type
When there are signs your cancer is progressing, your doctor can order more tests to understand what type of resistance you have. Your tests may include biopsies of the cancer in your lungs or of cancer in any new spots that can be biopsied safely. Genomic tests of your biopsied tissue can look for particular mutations in your cancer tissue that may explain the resistance or identify new treatment targets.
Liquid biopsy, or ctDNA testing, is another way to look for cancer DNA in your bloodstream and any changes in your cancer’s molecular profile. Talk to your doctor about what sort of testing you’d prefer and what they recommend.
“In my clinic, I always encourage patients to get at least a liquid biopsy, which is blood-based molecular testing, to see what has changed, what resistance mechanisms we can capture in the blood,” Nagasaka says. “Sometimes that’s helpful, sometimes it’s not helpful. When it’s not helpful and when there is an area that we can safely go after, meaning a biopsy, I also try to encourage patients to get one.”
Nagasaka says it’s always worth testing because resistance can be unpredictable. The only way to know what’s driving cancer progression is to look deeper at the tissue and its underlying molecular or genetic makeup.
“I see 40 to 50 lung cancer patients every week…and I have seen crazy things happen,” she says. “For example, we have seen histology change. So, you thought you were treating adenocarcinoma, but then at the time of resistance, you do a biopsy, and it shows small-cell [lung cancer], or squamous cell, or some type of other change in the histology.”
Common types
Common resistance mechanisms or “resistance types” may show up as single letter “typos” or insertions or deletions of short sequences in the cancer’s EGFR genes that look different from the EGFR mutation your cancer carried before treatment. The most common resistance mutation is known as a T790M. This mutation comes up at resistance more than half the time.
Other targets
Tests can also look for other genetic changes or drivers of your cancer that may expand your treatment options, including:
- MET
- HER2
- BRAF
- ALK
- RET
- KRAS
- ROS1
What Does This Mean for Me?
The first thing this means is that it’s time to take a deep breath. Treatment resistance is a well-known problem. While it’s overwhelming and another challenge to overcome, it isn’t unexpected. Remember that it didn’t happen because of anything you did or didn’t do either.
“Resistance is a challenge and happens essentially in everybody at some point,” says Pasi Jänne, MD, a medical oncologist at Dana-Farber Cancer Center in Boston, Massachusetts.
Researchers and doctors have developed many more specific treatments to fight various forms of cancer, including EGFR-positive lung cancer, than ever before. This means you can expect to live longer and better today, with more treatment options, than ever before. When one treatment stops working, you’ll have new options to consider.
How Does This Change Your Treatment Options?
Your treatment options will depend on many factors.
“Resistance is not a one-size-fits-all thing,” Jänne says. There are a lot of pieces of information that go into making that ultimate decision.
Other targeted options or combinations
Your treatment options will depend on what type of resistance your cancer has developed. For example, targeted therapies have been developed to block the most common resistance mutation (EGFR T790M). If your cancer has other driver mutations and treatment targets, this may open up new treatment options.
You may consider a new treatment combination, such as the addition of chemotherapy or another EGFR inhibitor. If your cancer has a change in another gene called MET, you may benefit from adding a bispecific antibody that targets EGFR and MET. Sometimes, these are taken along with chemotherapy. Antibody-drug conjugates, which direct chemotherapeutic medicines straight to the cancer, are yet another option.
Local consolidated therapy
Nagasaka says that when the progression is small or limited to a few spots, radiation or surgery may be enough to control them while you remain on your original targeted therapy.
“The idea is that whatever treatment the patient is currently on is doing most of the job; however, there’s this one or two or a few spots that are just not responding,” she says. “When it’s not cancer exploding all over the place and it’s just a few spots, that’s easy to take care of with radiation or surgery.”
Clinical trials
Clinical trials are a good option to consider at every step of the way, including when your cancer has become resistant.
“I think anytime there needs to be a therapeutic decision, it’s always good for patients to understand what is the established standard in this situation and what is a potential clinical trial if available,” Jänne says.
Ask your doctor about any trials that are underway near you and whether you might be a good candidate to enroll. For example, Nagasaka noted, C797S is a known resistance mutation that often arises following treatment with third-generation EGFR inhibitors. Multiple clinical trials are currently underway testing new inhibitors designed to specifically target C797S.
“If you are able to detect that kind of resistance, you can basically transition patients over to clinical trials very smoothly,” she says.
Treatment expectations going forward
No one can predict the future. But you can expect to have many treatment options, with more becoming available all the time. You can expect the outlook for EGFR-mutant lung cancer to continue improving.
“The field is so rapidly evolving that I feel like at this time, we honestly can’t even give patients good prognosis estimates because of how many new drugs are coming available in this space,” Bestvina says. “In the next year or two, we anticipate [approvals], and the goal is that these patients are going to be living much longer and much better. Just know that the science is rapidly evolving.”
What You Can Do Right Now
If your cancer has become resistant to one treatment, it isn’t the end of the road. It means it’s time to ask your questions, think through your options and goals, and work with your care team to decide what’s next. Cancer can leave you feeling like you’ve lost control. But focusing on things that you can control can help. Some ideas include:
- Get informed, and find support through organizations such as the EGFR Resisters (https://egfrcancer.org/).
- Get a second opinion. Given many options, Bestvina says it “can only be helpful to have a second set of eyes on your case and a second set of thoughts about the best way to approach it.”
- Explore other options that may be available via clinical trials.
- Look for reasons, big and small, to remain hopeful while prioritizing the things in life that make you happy or fulfilled.
Mentally prepare yourself
It’s never too soon to start talking with your oncology care team about the possibility of treatment resistance now or in the future, what you can expect from your current treatment, and what your options might be later, Nagasaka says.
“I think it’s helpful for patients to have a basic understanding of treatment resistance,” she says. “We, of course, don’t want them to develop treatment resistance. We want patients to do really well on whatever treatment they are on, but giving them a heads up is important because it mentally and emotionally prepares patients and caregivers about the possibility that at some point, there might be more biopsies. The tumor might get resistant to treatment. They might need to switch treatment, and I think knowing that possibility, having that heads up, is helpful.”
