From Our 2012 Archives
Avastin May Help Fight Early Breast Cancer
Studies May Reopen Discussions About Benefits of Avastin for Breast Cancer
By Brenda Goodman, MA
Reviewed by Louise Chang, MD
Jan. 25, 2012 -- Don't count out the drug Avastin as a breast cancer treatment just yet. But don't count it in, either.
In November, the FDA took the unusual step of nixing Avastin's approval for advanced breast cancer, saying that the serious risks of using the drug outweighed its small benefits for women with cancer that had spread beyond the breast.
Now new studies are under way looking at whether Avastin may work better if it's used earlier in the course of the disease as an initial therapy.
Two of those studies are reporting their first round of results this week in the New England Journal of Medicine.
They are not slam dunks for the drug, which prevents the growth of new blood vessels and is meant to starve fast-growing cancer cells by shutting off their blood supply.
Instead, both studies show that Avastin may slightly improve the odds that chemotherapy medications might shrink cancer from the breast before surgeons go in to remove it.
Using Chemotherapy Before Surgery
Often, chemotherapy drugs are given to patients after first having surgery to remove a tumor. The drugs are used to kill off any remaining cancer cells after surgery.
But doctors may also give chemotherapy to some patients prior to their operations.
That strategy can sometimes shrink tumors enough so that a woman is able to have only part of her breast removed instead of the whole thing. It can also help doctors refine their treatment plans. If the cancer doesn't respond well to the first drugs they try against it, they know to try a different plan of attack after surgery.
About 20% of women have their tumors disappear completely after a course of this pre-surgery chemotherapy.
Certainly, says Mary B. Daly, MD, PhD, chair of the department of clinical genetics at the Fox Chase Cancer Center in Philadelphia, disappearance of the cancer before surgery is a hopeful sign.
"Those women tend to do somewhat better, overall, than women for whom there's still tumor left," she says.
It is not yet known, however, whether that result -- something doctors call a complete pathological response -- will increase a woman's chances of survival.
Is Early Chemotherapy Better?
Indeed, Daly says studies that have compared women who've had chemotherapy before surgery to those who only had it after their procedures have found no survival advantage to the pre-surgery treatment.
"We've been burned before looking at early outcomes and assuming they will translate into late outcomes, only to find out that, in fact, it doesn't translate," says Daly, who reviewed the studies for WebMD but was not involved in the research.
"So the fact that at surgery, there was a little difference in the complete response rate ... doesn't necessarily mean that those women are going to live longer, and live longer free of their disease," she says.
Other experts agree.
"In the end, survival is really what matters," says Alberto J. Montero, MD, an oncologist and assistant professor of medicine at the University of Miami's Sylvester Comprehensive Cancer Center.
Montero wrote an editorial on the studies but was not involved in the research.
Researchers say the studies have continued to follow their patients, and they should be able to report on whether or not Avastin improves their chances of survival in the next few years.
Testing Avastin for Early-Stage Breast Cancers
While both studies showed some success when using Avastin, the types of breast cancer they worked on were different, making the sum result from the two studies a little murky.
For the first study, researchers in Germany assigned almost 2,000 women with newly diagnosed breast cancers to receive either six months of chemotherapy with the drugs epirubicin and cyclophosphamide followed by docetaxel alone or with Avastin.
About 15% of patients treated with epirubicin and cyclophosphamide followed by docetaxel saw their tumors disappear completely by the time of their surgery.
That number was slightly higher in the group that also got Avastin -- about 18%.
The second study, which was based in the U.S., tested whether Avastin improved complete response when added to the chemotherapy drug docetaxel alone or with either capecitabine or gemcitabine, followed by treatment with doxorubicin-cyclophosphamide, in 1,200 women.
As in the first study, more women saw their tumors disappear when Avastin was added to their pre-surgery chemotherapy -- about 35% had a complete response in the Avastin group compared to about 28% in the group that got chemotherapy alone.
That's where the similarities ended.
When the German researchers took at closer look at their results, they were surprised to find that women whose cancers were not spurred by hormones -- so called triple-negative tumors -- were seeing larger-than-average benefits from Avastin.
Triple-negative tumors account for only about 10% to 20% of breast cancer, but they are among the toughest to treat. Studies have shown they are more likely to spread and recur than tumors that are sensitive to hormones.
Among women with triple-negative tumors, the rates of complete response were 27.9% for women on standard chemotherapy and 39.3% in those who also got Avastin.
In contrast, women with cancer that was sensitive to hormones had about the same results whether or not they got Avastin. "We didn't really expect that," says researcher Gunter von Minckwitz, MD, associate professor of gynecology at the University of Frankfurt and chair of the German Breast Group. "Almost all the effect comes from this triple-negative group."
He says there is some clinical data to suggest that tumors that don't respond to hormones may rely more heavily than other kinds of cancers on the development of new blood vessels for growth.
Avastin shuts down the ability of tumors to grow new vessels, thus starving the cancer of its food supply.
When researchers in the U.S. took a similarly close look at their data, they found the opposite.
Avastin's effects were more pronounced among women with breast cancer that was driven by either the hormones estrogen or progesterone. Among these women, 15% on traditional chemotherapy saw their tumors go away compared to 23% of the group that also got Avastin.
"It may indicate that [Avastin] has activity [in breast cancer], and that activity may be more profound in certain subsets of patients," says researcher Harry Bear, MD, a surgical oncologist at Virginia Commonwealth University School of Medicine in Richmond.
Both studies were supported in part by Roche, the company that makes Avastin. Other financing for the research came from government grants and the manufactures of the chemotherapy drugs that were tested.
Do the Benefits of Avastin Outweigh Its Risks?
In both studies, women who got Avastin had more side effects than those with standard chemotherapy. Those included fevers with low white blood cell counts, ulcers in the mouth and digestive tract, peeling of the skin on the hands and feet, infections, and high blood pressure.
While those problems are serious, researchers say going through some bad complications may be worth it if a woman can improve her chance of survival.
"In this setting, cure of the patient is the aim. Therefore, having bad side effects that will eventually go away may be worth it," says von Minckwitz.
Bear agrees, and says use of the drug in this way will hinge upon whether or not it actually improves a woman's chance of survival.
"If it improves survival, the risks will probably be worthwhile," Bear says.
But independent experts caution against making too much of the small differences Avastin seemed to make.
"I would not give Avastin to any patient in the [pre-surgery] setting based on these data," Aman U. Buzdar, MD, a medical oncologist and professor of medicine in the department of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
He points out that when both studies narrowed their definition of complete response to mean only invasive cancers that had disappeared from both the breast and the lymph nodes, their results were not statistically significant, meaning they could have occurred by chance. "These studies don't change anything in my mind, and it should not persuade patients that Avastin can change the biology of the disease," he says. "I think the FDA decision was very appropriate."
Buzdar says it may turn out that certain subsets of patients are helped by the drug, "but that still remains to be defined."
Daly agrees that the studies do little to show how the drug might best be used in breast cancer.
"This just leaves us more confused than ever," she says.
SOURCES: Bear, H. The New England Journal of Medicine, Jan. 25, 2012.Von Minckwitz, G. The New England Journal of Medicine, Jan. 25, 2012.Montero, A. The New England Journal of Medicine, Jan. 25, 2012.Mary B. Daly, MD, PhD, chair, department of clinical genetics, chair, cancer research, Fox Chase Cancer Center, Philadelphia.Alberto J. Montero, MD, oncologist and assistant professor of medicine, The Sylvester Comprehensive Cancer Center, University of Miami, Florida.Gunter von Minckwitz, MD, associate professor of gynecology, University of Frankfurt; chair, German Breast Group, Frankfurt, Germany.Harry Bear, MD, surgical oncologist, Virginia Commonwealth University School of Medicine, Richmond.Aman U. Buzdar, MD, medical oncologist and professor of medicine, department of breast medical oncology, University of Texas M.D. Anderson Cancer Center, Houston.