For patients facing a diagnosis of early stage breast cancer, the traditional course of treatment is typically surgery, followed by an often difficult course of chemotherapy to try to make sure the cancer doesn’t recur.
Doctors have long known that many of such patients who undergo chemotherapy don’t actually need it to prevent recurrence of the disease after surgery. But they haven’t known exactly which patients might safely skip the toxic treatment.
A European study published Wednesday in the New England Journal of Medicine sheds new light on the issue, concluding that many such patients might be able to avoid chemo, according to the Washington Post. The key factor: Nearly half of the patients considered at high risk for recurrence might actually be low risk based on genetic factors, researchers found.Genetic factors can mean low risk of #breastcancer recurrence Click To Tweet
The study involved almost 6,700 patients with localized breast cancer that hadn’t spread beyond three lymph nodes. Of those, about half were considered high risk based on clinical measures such as tumor size and patient age.
Typically, all would have considered chemotherapy as part of their treatment. But a 70-gene test called MammaPrint found that about 1,500 of that group were low risk based on genomic factors. They were considered “discordant”–high-risk patients based on clinical factors, but low risk based on gene-test results.
The 1,500 women then were randomly assigned to two groups, with one getting chemo and one not getting it. After five years, the survival rates of the groups were similar–just 1.5 percentage points higher for the women who’d received chemo. The survival rate for the non-chemo group was close to 95 percent. Given those findings, the researchers say, about 46 percent of women with breast cancer who are classified as high risk based on clinical factors might not need chemo.
Study co-author Laura J. van ’t Veer, a molecular biologist and leader of the breast oncology program at the Helen Diller Family Comprehensive Cancer Center at the University of California at San Francisco, did the research that led to the gene test while working for the Netherlands Cancer Institute.
Van ‘t Veer, who is an officer in the company now marketing the test, said MammaPrint “looks under the hood of the tumor and into the engine of the cancer to show whether the biology is truly aggressive and has capacity to invade surrounding tissue.”
She said the 1.5 percentage-point difference in survival rates between women who got chemo and the ones who didn’t was not statistically significant, especially considering the side effects of chemo, which can include fatigue, cognitive impairment and a prolonged disruption in schedule.
But Paul Kelly Marcom, a breast-cancer oncologist at Duke Cancer Institute, said that whether that survival-rate difference is significant is a personal decision by a woman and her doctor. He also noted that there are other genomic tests on the market and that physicians are in the early stages of learning how to use them.
“It’s not a quick or easy process,” he said, adding that he thinks physicians need more data before making big changes in clinical practice. Another test, called Oncotype DX, came on the U.S. market earlier and is more widely used. But it analyzes a smaller set of genes than MammaPrint and is used for only certain types of breast cancer. Both Oncotype DX and MammaPrint cost about $4,000. In many cases, Marcom said, insurance covers the tests.
An accompanying editorial in the journal said the trial showed “how a well-coordinated and highly collaborative multinational team of investigators can efficiently conduct a potentially practice-changing study.” It said the results “could allow some doctors and patients to choose to avoid chemotherapy if they have carefully considered their own tolerance for toxicity, risk, and uncertainty.”
Yet such decisions are “highly individualized.” The European study was called MINDACT for Microarray for Node-Negative Disease May Avoid Chemotherapy Trial. Some of the information was released in April at the American Association for Cancer Research annual conference.
Steve’s Take: The above NEJM study about the best way to treat early-stage breast cancer shows that “precision medicine” doesn’t always provide unambiguous answers about how to choose the best therapy. “Precision doesn’t mean certainty,” says David Hunter, a professor of cancer prevention at Harvard’s T.H. Chan School of Public Health.
As is true for many cancers, breast cancer responds best to treatment when it is caught early, before it has spread throughout the body. Dr. Fatima Cardoso, the study’s lead author and a breast cancer specialist at the Champalimaud Clinical Center in Lisbon, Portugal, says that creates a conundrum for doctors and patients alike. I’ll say it does.
Because it’s the only opportunity to cure the cancer, “when in doubt we tend to treat” women with early-stage breast cancer, she added, according to Shots (NPR). “So we know that we overtreat the patients with early breast cancer.” That means that women could end up undergoing chemotherapy even if it wouldn’t really improve their survival odds.
In this huge study, the genomic test, which studies 70 distinct features of a tumor, did a pretty good job of predicting who was at low risk for recurrence of breast cancer and could therefore avoid the pain, discomfort and risks of chemotherapy. (The test, priced at $4,200, is covered by some insurance in the United States.)
But the test results weren’t always definitive. About 95 percent of women who skipped chemotherapy as a result of the genetic test results were free of metastasis five years later, but those who had the additional treatment did about 1.5 percentage points better, give or take.
“It’s possible that the benefit is zero, and it’s possible that’s 2 percent or maybe even a little more, you can’t be sure,” says Dr. Clifford Hudis, chief executive officer of the American Society of Clinical Oncology.
He was not involved in the European study but co-wrote an editorial accompanying it. It would take another huge clinical trial to figure out whether chemotherapy does in fact add a small survival advantage.
But the study raises a bigger point here: The genomic test, as precise as it is, offers only probabilities, not absolute guidance. And that’s a lesson that applies to the whole new realm of precision medicine, which is billed as potentially transformative for medical care.
“The new tools will definitely be helpful, but they often will pose challenges about what the right decision is,” says Hunter, who wrote a perspective piece noting that people will need to develop a tolerance for uncertainty when using precision medicine tests.
Hunter hits the nail on the head with the simple quandary: “Is it worth all the trouble of chemotherapy for women who are found to be at low risk for recurrence in this genomic test? That’s a tough call, because it requires grasping the rather abstract idea of improving survival odds by maybe just 1 percentage point. As humans, we’re notoriously poor at assessing risk and making those calculations.”
Hunter concludes that doctors and patients need better tools to understand and communicate the subtleties that are inherent in precision medicine. Cardoso is already seeing this play out in her clinic. Women shown to be at low genetic risk on the MammaPrint test are usually opting not to have chemotherapy after their surgery.“But there always [are] some patients for whom 1 percent benefit is enough –and you need to respect the wishes of each individual patient.” She says the women clearly benefit from the new information, even though it doesn’t provide an absolute answer.
I did some digging and found an article, published almost 10 years ago to the month, explaining what the goals of this latest study were. The following are perspectives from some of the researchers there at the outset of the study.
“A large number of…women are receiving toxic chemotherapy unnecessarily, and we need a means of identifying them,” said Jo Anne Zujewski, senior investigator in the Clinical Investigations Branch of NCI’s Cancer Therapy Evaluation Program.”
The bottom line is that this clinical trial is “a test of a test,” explains Lea Ann Bernick, program manager of the Sutter Health Western Division Cancer Research Group.
“This is also a trial to improve standards of care…to better individualize what doctors are already telling patients to do based [on] their chance of recurrence,” she says. “Hopefully this study will give women…who fall into the gray or middle areas…another tool to use when making treatment decisions.”
So 10 years later and after all the time, effort, energy and costs invested in the study of some 6,700 patients with high-risk cancer recurrence, the conundrum remains: should I undergo chemo, or not? Zounds, what a choice!Steve's Take: Genetic tests do not definitely answer the question of whether or not to do #chemo Click To Tweet
(By the way, breast cancer in men is a rare disease. Less than 1% of all breast cancers occur in men. In 2016, about 2,600 men are expected to be diagnosed with the disease. For men, the lifetime risk of being diagnosed with breast cancer is about 1 in 1,000.)