Improving Outcomes and Accommodating Preferences in Earlier-Stage Breast Cancer
Kris Alden had her first mammogram when she was 28 years old. She had “lumpy breasts,” her doctors told her, so her late 20s through her 30s were filled with false alarms and mammograms. When she was 40 and another lump developed in her right breast, Alden didn’t rush to check it out. “It was Christmas. I have two kids. We were busy,” Alden recalls. “Every time I had found a lump prior to this, it was always the same. The doctors would tell me to watch it.”
By that spring, the lump was protruding from her right breast, so she saw her doctor, who ordered a mammogram, which led to a biopsy. Two weeks later, Alden was diagnosed with breast cancer.
At that time, in 2008, researchers were studying alternatives to the chemotherapy drug doxorubicin. This drug can have potentially toxic effects on the heart later in life. Alden was eligible for a clinical trial that would test the efficacy of less toxic chemotherapy drugs in lieu of doxorubicin.
The trial in which Alden participated is an example of the kinds of improvements that are ongoing in breast cancer treatment. In every operable stage of breast cancer, the newest treatment options and those in development allow physicians to fine-tune therapy, tailoring recommendations to specific patient populations and the genetics and wishes of individual patients.
“Looking back, breast cancer treatment had more of a one-size-fits-all approach,” says Keerthi Gogineni, a medical oncologist and hematologist in the Glenn Family Breast Center at Emory University’s Winship Cancer Institute. “We’re getting better at tailoring treatment, so that we don’t over- or under-do it.”
Stage 0: Ductal Carcinoma In Situ
Physicians might be overdoing treatment of ductal carcinoma in situ (DCIS). This is a non-invasive cancer isolated in the milk ducts that hasn’t spread to other breast tissue. The standard treatment is surgical removal of the lump or the breast — depending on how far the cancer has spread throughout the ducts; if lumpectomy is chosen, it is usually followed by radiation to reduce the risk that the cancer will come back, but radiation is not typically given after mastectomy for this disease type. In estrogen-positive DCIS — cancer that needs estrogen in order to grow — women might take medications to block or lower estrogen levels in the body for five years after surgery. But these treatments mostly affect the chance of breast cancer returning in the breast — the risk of spread to other organs, which is what causes death in breast cancer, is typically very low regardless of what treatment is used after surgery.
Researchers question whether every woman with DCIS needs such aggressive action against what is essentially considered pre-cancer. For some women, the cancer may never spread. “We’re trying to understand which women we can watch closely rather than subjecting them all to the full onslaught of surgery, radiation and hormone-blocking medication,” Gogineni says.
A study in the Journal of the American Medical Association Oncology found that, among more than 100,000 women with DCIS, African-American women and women who developed DCIS before the age of 35 had a higher risk of death. Estrogen-negative cancers slightly increased the risk of death. Other women may be able to consider scaling back treatment.
Women can ask their doctors whether genomic tests might help them make treatment decisions. The genomic test Oncotype DX analyzes the genes in early-stage, estrogen- positive breast cancer tissue to predict the chances the cancer will spread, and how much benefit chemotherapy might offer. Doctors are now using a modified version of this test in tissue that has been removed during surgery for some women with DCIS to predict the risk of localized recurrence, the chance that a new invasive cancer will develop in the same breast, and thereby estimate the amount by which radiation after surgery will lower that risk.
Women with hormone receptorpositive DCIS typically take tamoxifen for five years after surgery to reduce the risk of recurrence. But according to a recent study, a class of drug known as aromatase inhibitors could work better in some post-menopausal women. In the study, post-menopausal women under age 60 who took tamoxifen had a 12 percent chance of recurrence. Those who took the aromatase inhibitor anastrazole reduced that chance to 5 percent, although for women over 60, risk of recurrence was about 10 percent on either drug. In addition, anastrozole cut the risk of a new invasive breast cancer in the other breast in half, from 2.3 percent to 1.3 percent. Women may prefer anastrozole to tamoxifen because the side effects are different.
Tamoxifen blocks the activity of estrogen in breast cancer cells while it allows estrogen to act in some other parts of the body, such as the uterus. This can increase the risk of uterine cancer in women older than 50 by about 1 to 2 percent. It can also cause blood clots, with a risk of about 1 percent, mostly in the first two years the drug is taken.
Aromatase inhibitors — anastrozole, exemestane and letrozole — lower or stop remaining estrogen production throughout the body in women who have gone through menopause. These drugs won’t increase the risk for uterine cancer or blood clots, but they could raise the risk of bone issues. Bone fractures and osteoporosis occur in about 3 to 4 percent of patients taking these drugs, and arthritis, bone, back and joint pain in up to 29 percent.
Operable Stages 1-3
Depending on the size of the tumor, women with early stages of breast cancer may have surgery to remove the tumor without removing the whole breast. However, some women choose to have a mastectomy even when their physicians say it isn’t absolutely necessary. Women who want to avoid mastectomy, on the other hand, might have chemotherapy before surgery to first shrink the tumor as much as possible. Chemotherapy with the intent to improve the cure rate, either before or after surgery, may also be appropriate if breast cancer involves the lymph nodes, is triple-negative or is HER2-positive, Gogineni says. On the other hand, regardless of their size, breast tumors that are hormone receptor-positive and have not spread to lymph nodes may not need chemotherapy. The same may be true, she says, for some hormone receptor-positive breast cancers in patients who are postmenopausal, even if one to three lymph nodes are involved; this is being verified in a clinical trial.
Most women who have breast-conserving surgery, and some who have mastectomy, will need radiation after surgery.
After surgery, women with estrogen-positive cancer need to block estrogen in order to prevent recurrence. Pre-menopausal women typically take tamoxifen for five to ten years. In a recent study, however, pre-menopausal women tried a regimen usually reserved for those who have been through menopause. Essentially, the women were put into medically induced menopause in order to try the medication, the aromatase inhibitor exemestane.
In the trial, women in the control group received tamoxifen alone. Others were randomized to receive a medication to stop estrogen production in their ovaries, and then also took either tamoxifen or exemestane. Overall, suppression of the ovaries with either of the hormonal therapies proved no more effective than tamoxifen alone. However, in higher-risk patients (for example, those who required chemotherapy – typically women with node-positive breast cancer), the arm with ovarian suppression and exemestane appeared to be the best option, with lower rates of recurrence over the next five years.
Suppressing a premenopausal woman’s ovaries, however, brings more side effects than tamoxifen treatment alone. In fact, this sudden menopause can bring more intense symptoms than natural menopause. Breast cancer-related early menopause can also increase risk for heart disease and osteoporosis.
“There’s a tradeoff because of these additional side effects, but it’s an important additional option for women who are higher-risk,” Gogineni says.
HER2-positive breast cancers overproduce a protein called HER2. These tumors grow and spread quickly and have a high risk of recurrence. A targeted drug, Herceptin (trastuzumab), which inhibits the body’s overproduction of HER2, has radically improved survival in this subtype of breast cancer since it was approved by the U.S. Food and Drug Administration in 1998 for advanced breast cancer and in 2006 for early-stage disease.
In general, for women with very small (under 1 centimeter) and node-negative breast cancers, chemotherapy is often omitted, because their risk for recurrence is very small. However, in the case of HER2-positive tumors, the risk may be higher and may necessitate treatment with both chemotherapy and Herceptin. That was the case for Alden, whose cancer was HER2-positive. In addition to 20 rounds of chemotherapy, she was on Herceptin for a year. She took part in a clinical trial in which women received Herceptin and the chemotherapy drug paclitaxel, in lieu of chemotherapy with doxorubicin, to try to reduce the risk of heart damage that drug brings.
The side effects of standard chemotherapy plus Herceptin, including the risk of heart muscle weakening, has created a dilemma in balancing this against the small reduction in risk for these patients. However, new research from Dana-Farber Cancer Institute shows that women with stage 1 HER2-positive breast cancer may be able to get away with less chemotherapy than experts usually recommend. Women in this group typically receive as much as four to six months of chemotherapy that could include doxorubicin, cyclophosphamide, paclitaxel, carboplatin and/or docetaxel along with a year of Herceptin, Gogineni says. The recent study reduced the therapy to just 12 weeks of paclitaxel and Herceptin, followed by nine months of Herceptin alone. Shorter, lower-intensity chemotherapy can mean fewer side effects and getting back to a normal life sooner. Three years later, nearly 99 percent of the study participants were alive and cancer-free.
“We’ve always been conflicted about what to do when a woman had a very small HER2-positive breast cancer for which we otherwise would have not used chemotherapy,” Gogineni says. “I’m hopeful that these women can go through this less toxic therapy and still have excellent outcomes.”
The investigational tyrosine kinase inhibitor neratinib may also lower the risk of HER2-positive breast cancer recurrence in women who have already had standard therapy. In a recent phase 3 trial, women who took the neratinib pill once daily for a year — within a year of completing treatment with chemotherapy and Herceptin — had a lower risk of recurrence over the next two years compared to women who took placebo. Women with hormone receptor-positive tumors seemed to get the greatest benefit from the drug. But the benefit comes at the cost of what can be severe diarrhea.
“It’s a little early to see if this will improve overall survival,” Gogineni says. “These women already have very good outcomes, so you want to make sure that adding that extra medication offers them a real benefit, because there is a tradeoff in terms of side effects.” Studies are underway to see if diarrhea can be prevented in order to improve the benefit/risk ratio of this treatment.
Triple-negative tumors test negative for estrogen and progesterone receptors and for HER2 overexpression. This means that drugs designed to block those receptors won’t help women with this type of cancer. “These women have a higher risk of recurrence and higher mortality, so we’re always looking for ways to optimize treatment for them,” Gogineni says. Traditional chemotherapy given pre-operatively eliminates all evidence of invasive breast cancer (known as a pathological complete response) by the time of surgery in only one-third of women with triple-negative tumors; these patients have a better chance of a long-term cure.
Two recent trials studied whether platinum-containing chemotherapy drugs — typically reserved for stage 4 breast cancer and also sometimes used in earlier-stage HER2-positive cancers — could better shrink triple-negative tumors than traditional options. Study participants who got the platinum-based drug carboplatin prior to surgery were more likely to have a pathological complete response at the time of surgery than the women who got standard chemotherapy drugs. This type of medication, however, tends to bring more side effects, including low counts of white blood cells that help fight off infection and platelets that help the blood clot.
“These drugs can affect the kidneys and cause numbness or tingling in the hands or feet that could affect function,” Gogineni adds. “The more drugs you add, the more potential for toxicity.”
While the studies show that platinum drugs can help conserve the breast, it’s too soon to tell whether they will increase overall long-term survival.
A new national clinical trial (NCT02445391) will test the benefits of neoadjuvant platinum therapy in women with triple-negative tumors who have undergone standard chemotherapy but still have evidence of disease prior to surgery. Another trial (NCT02488967) will explore whether the addition of a platinum-containing drug in combination with standard chemotherapy after surgery will prolong survival.
A different trial will test targeted drugs in women with triple-negative breast cancer. In the trial, known as BRE12-158, patients will receive standard treatment, including chemotherapy, prior to surgery. If they still have evidence of cancer in the breast at the time of surgery, the tissue that is removed will be sent for gene sequencing. If researchers find any genes that help the cancer grow that could be shut down by existing drugs, regardless of which cancers the drugs are approved to treat, the women will receive those drugs.
Even when there is no evidence of cancer after surgery, there may be microscopic seed cells that blood tests and scans cannot detect, which may cause a recurrence later.
“Researchers are trying to develop tests that quantify and characterize cancer cells/DNA in the bloodstream. Typically these are referred to as circulating tumor cells or cell free DNA. The hope is that, eventually, this enables us to better predict who is going to develop a recurrence and, if and when a relapse happens, to characterize that tumor in a way that we can treat it with targeted therapy,” Gogineni says.
Physicians often recommend that women with breast cancer who have a BRCA gene mutation have a mastectomy rather than a lumpectomy because of their high risk of a second breast cancer. But until recently, BRCA status has not impacted doctors’ recommendations for systemic therapy — that is the medications, including chemotherapy, that women take before or after breast surgery.
In recent years, studies have shown that women who carry these gene mutations may be particularly responsive to platinum chemotherapy and also to a newer class of drugs called poly (ADP-Ribose) polymerase (PARP) inhibitors. PARP inhibitors block an enzyme that repairs DNA. But blocking it in certain cancers can kill the cancer cells.
The first PARP inhibitor to be approved by the FDA is Lynparza (olaparib), which is indicated for BRCA-positive ovarian cancer after progression on three chemotherapy regimens. But studies have indicated that the drug could be helpful for patients with BRCA-positive breast cancer, as well, and other PARP inhibitors are also being studied in the metastatic setting. In addition, a large trial (OlympiA) is comparing Lynparza to placebo following standard chemotherapy for early-stage, BRCA mutation-related breast cancer.
Deciding What's Best For You
Any serious diagnosis naturally brings with it anxiety, fear and anger. These emotions can make it difficult to absorb all the information and treatment options doctors offer. “When you’re first diagnosed, you’re in a cancer bubble where you can’t comprehend anything,” Alden says.
It’s OK for women to take the time they need to process the news of their diagnosis before thinking about a treatment plan. “Breast cancer, for the most part, is not an emergency,” says Karen Sepucha, director of the Health Decision Sciences Center at Massachusetts General Hospital. “You often have up to several weeks to get some second opinions, to review the information, to ask questions and make sure that you have time to get past that initial shock and be able to participate.”
Women can work together with their doctors to choose a course of action that not only fits the type of cancer they have but also the type of person they are. “The whole idea of personalized medicine is personalizing it to the genetics of the tumor, and in shared decision making we’re talking about personalizing treatment to the patient as a person,” Sepucha says.
Doctors and patients each have individual expertise when it comes to choosing the best treatment options. “The doctor’s going to bring the science. You’re the expert on who you are and what you care about. Your responsibility as a patient is to help make that known so the doctor can tailor the recommendations to your goals and preferences,” Sepucha says.
When doctors ask patients their goals of treatment, patients often simply say, “I want to live.” But patients need to take that a step further and tell their doctors what makes life worth living. For Alden, peace of mind makes life worth living. As soon as she learned she had breast cancer, Alden knew she wanted a double mastectomy. “If I were to keep my lumpy breasts, every time I found a lump, I would go off the deep end,” she says. Alden’s doctors told her a double mastectomy wasn’t medically necessary, so she explained why it was important to her.
“We think breasts are what defines us as women, but to me, they were what was killing me. I needed them gone,” she recalls. “They completely understood and backed me 100 percent.”
Seven years after she was diagnosed with breast cancer, Alden now has no evidence of disease. And she (almost) never looks back. “Every once in a while, I try to remember what it was like before, and then I think, ‘Don’t go back there. You’re so happy with who you are now.’”