Sights set on first targeted therapy for triple-negative breast cancer
A new study is seeking new drugs to combat triple-negative breast cancer, an aggressive form of the disease that doesn’t rely on the hormones estrogen and progesterone or the protein HER2, which fuel the growth of most breast cancers.
The project’s goal? Find new drugs to combat the cancer, which doesn’t rely on the hormones estrogen and progesterone or the protein HER2, which fuel the growth of most breast cancers.
“Given this, the drugs that treat most breast cancers by blocking their ability to use those three things to survive don’t work on triple-negative breast cancer,” says Stacy Moulder, M.D., associate professor of Breast Medical Oncology and the trial’s principal investigator.
Instead, doctors are left to treat triple-negative patients with traditional chemotherapy drugs, surgery and radiation.
Typically, patients with a triple-negative breast tumor that’s larger than one centimeter and hasn’t spread to other parts of the body are given chemo before surgery. In nearly half of these patients, chemo works well. It kills all or nearly all of the cancer cells, and little to no cancer in the breast or lymph nodes is present at the time of surgery.
“This is associated with an extremely good prognosis,” Moulder says.
But the other half of patients who do not respond well to chemo face a high probability their cancer will come back within three years after treatment. When the disease returns, prognosis is poor.
“This is why triple-negative breast cancer is part of MD Anderson’s Moon Shots Program,” says Debu Tripathy, M.D., chair of Breast Medical Oncology and a collaborator on the trial. “We need drugs that work, and we need them now.”
Only a few years ago, researchers discovered that triple-negative breast cancer isn’t a “one-size-fits-all” disease. Instead, six distinct subtypes have been identified so far, “and more will likely be discovered in the future,” Moulder says. Within each subtype, tumors have different genetic defects. Therefore, “it stands to reason that each subtype should be treated differently,” says Jennifer Litton, M.D., associate professor of Breast Medical Oncology and a trial collaborator.
Much work remains before precision medicine becomes the standard of care for triple-negative breast cancer, according to associate professor of breast medical oncology Stacy Moulder. But experts from MD Anderson and beyond are working diligently to make it happen.
Yet the current standard of care is to use the same chemotherapy for all subtypes of the disease.
“This is a very complex group of cancers and they don’t all behave the same way,” Litton says. “To treat these patients we have to gain more knowledge of the molecular events that drive each subtype. Then and only then can we match the right drugs to the right patients.”
Drugs that specifically target a cancer’s genetic abnormality are called targeted therapy or precision medicine. Triple negative is the only form of breast cancer for which there is no targeted therapy, Litton says.
MD Anderson’s project is part of an effort to bring precision medicine to triple-negative breast cancer patients for the first time. Here’s how it works:
Patients who’ve been advised to start chemo before surgery (those whose tumors haven’t spread and are larger than one centimeter) first have their tumors biopsied. They then can immediately start the first of two sequential chemo regimens.
While patients are undergoing their first round of chemo, a chemo-sensitivity predictor test, developed by MD Anderson professor of Pathology W. Fraser Symmans, M.D., is run on their biopsied tumor samples to determine if their tumors will respond to chemo. If a tumor tests “chemo-sensitive,” the tumor is responding to the chemo. If a tumor tests “chemo insensitive,” the chemo is ineffective.
“You may wonder why patients in this trial are placed on chemo when we don’t yet know if their tumor is chemo sensitive,” Moulder says. “We start chemo immediately so we don’t waste time and allow the cancer to spread. If the chemo-sensitivity test determines that chemo won’t work for a particular patient, we haven’t done any damage and we can adjust their course of treatment.”
During this testing, the tumor’s molecular makeup is also revealed, and the patient’s triple-negative breast cancer subtype is identified.
After completing the first round of chemo, those patients whose tumors are found to be chemo-sensitive are prescribed a second round of standard chemo treatments before undergoing surgery. They need chemo only, not the toxicity of
more drugs. In the second round of treatment, patients with chemo-insensitive tumors are placed in clinical trials for targeted drugs that are predicted to work best on their individual tumor’s molecular makeup and subtype, in combination with standard chemo.
Two-thirds of patients enrolled in the study receive the treatment described above. The other third do not receive the results of the molecular testing. All patients are allowed to enter a clinical trial for the second part of their treatment, but only the first group will have the molecular testing results to guide their choice of clinical trial.
“This helps us determine if our new approach of adding a targeted drug based upon the molecular testing results will benefit patients,” Moulder says.
No placebos are used in these trials. Some of the drugs tested already are approved to treat other cancers. Others are new and haven’t yet gained Food and Drug Administration approval. If they perform well and increase the number of
patients with minimal or no cancer at the time of surgery, the drugs will enter the path to FDA approval.
“This is personalized medicine at its finest,” Moulder says. “The practice of tailoring drugs and therapies to individuals based on their genes or their cancer’s genes is the way of the future.”
An added benefit, she says, is that genetic testing may identify some tumor abnormalities that until now have been unknown.
“I’m sure there are many more triple-negative subtypes that we don’t yet know about,” she says. “I’m guessing in the next decade we’ll identify 20 or 30 more. The challenge will be to find drugs that work best for each one.”
Developing a cancer-fighting drug can cost more than a billion dollars and the journey from research lab to patient can take more than a decade. Even then, only one of five drugs is ever approved for human use.
MD Anderson’s trial streamlines the process by testing multiple drugs from different manufacturers simultaneously. This approach is called a “platform” design because it works much like multiple delivery trucks simultaneously depositing their goods for inspection on a warehouse loading dock. In the trial, multiple drugs are inspected simultaneously. Those that are ineffective are removed from the trial, and new drugs are added as the trial progresses.
In conventional breast cancer trials, sample sizes as large as 5,000-10,000 patients are required to ensure statistical accuracy. But because the platform trial is using molecular testing to match people with drugs, the number of patients needed is much less. As few as 14 and no more than 37 patients need to be treated on the targeted therapy clinical trial before a pharmaceutical company learns if a drug shows promise.
It’s a win-win for everyone, Moulder says.
“Because there are multiple drugs within the study, patients have a good opportunity of getting an investigational drug that, by virtue of being in the study, appears promising,” she says. “And ineffective drugs are eliminated sooner.”
Much work remains before precision medicine becomes the standard of care for triple-negative breast cancer, Moulder says. But experts from MD Anderson and beyond are working diligently to make it happen.
This trial alone involves faculty members specializing in surgery, oncology, pathology, radiation, diagnostic imaging and basic science research. By harvesting cancer cells that remain after treatment, they’re studying disease resistance using leading-edge laboratory science, an effort led by Helen Piwnica-Worms, Ph.D., vice provost
of science and professor of Cancer Biology. Other translational research scientists, including Beth Mittendorf, M.D., Ph.D., associate professor of Surgical Oncology, and Naoto Ueno, M.D., Ph.D., professor of Breast Medical Oncology, will determine the effects of targeted therapy on the body’s immune response and use preclinical models to find the best combination of drug treatments to move forward into clinical trials. Additional imaging projects are being led by Diagnostic Radiology faculty Wei Yang, M.B.B.S., Mia Rauch, M.D., Ph.D., Beatriz Adrada, M.D., and Rosalind Candelaria, M.D., to improve researchers’ ability to evaluate tumors’ response and sensitivity to chemotherapy. Their goal is to use what’s learned to design more clinical trials, with each one getting closer to identifying the best drugs for each disease subtype.
“Right now, the idea of using a test to predict a patient’s response to chemotherapy and to identify the molecular features of the patient’s tumor, then matching drugs to those features, is all very new,” Moulder says. “This study is designed to confirm that this approach works. And if it does, it’ll be a game changer for women with triple-negative breast cancer.”
As part of the triple-negative breast and high-grade serous Ovarian Cancers Moon Shot, all such patients are offered genetic screening for mutations in the BRCA 1 and 2 genes, which elevate a person’s risk for either cancer. If the patient has these inherited mutations, that raises the possibility that sisters, daughters and other relatives might have the same risk-increasing mutations.
Triple-negative breast cancer...
Account for 15% of all breast cancers
Occur more frequently in women under age 50
Tend to be more aggressive than other types of breast cancer
Are more likely to recur after treatment
Disproportionately strike women of African, Latina or Caribbean descent, and those with BRCA1 and BRCA2 mutations
Have poorer survival rates than most other breast cancers for the first five years after diagnosis
Have as good as, and sometimes better, survival rates than most other breast cancers after the five-year survival mark