Publications
Insight, Summer 2007
In the latest issue of Insight, learn about new targeted (biologic) therapies for early-stage and advanced breast cancer and strategies for coping with treatment-related insomnia and fatigue. In the profile Darlene Cooke discusses her participation in a phase I clinical trial for metastatic breast cancer and how exercise and volunteerism enhance her quality of life.
Table of Contents
Understanding Targeted Therapies for Breast Cancer
Researchers are beginning to understand the complex process involved when a healthy cell turns cancerous. This has paved the way for the emergence of targeted therapies, which hone in on the specific biological pathways that enable cancer cells to grow and thrive.
Biologic therapies work better than chemotherapy and radiation at targeting cancer cells over normal cells. Also, unlike traditional therapies, they can selectively attack specific populations of cancer cells. Today targeted therapies are used in combination with traditional treatments, but one day may replace them, reducing impact on healthy cells and improving quality of life.
"Targeted therapies are transforming the care of women with early-stage breast cancer," says Generosa Grana, MD, director of the breast cancer program at the Cancer Institute of New Jersey at Cooper and a member of LBBC’s medical advisory board. "We want to cure these women and keep the cancer from ever coming back. These therapies offer hope for a long-term solution. They’re also helping women with advanced disease live longer, often with a better quality of life."
Targets in Breast Cancer
Estrogen
The estrogen receptor was the first target identified for breast cancer treatment. About 75 percent of breast cancers are estrogen- (ER) or progesterone-receptor (PR) positive, meaning their growth is fueled by hormones.
Therapies that target the estrogen pathway both treat cancer and prevent recurrence. The oldest and best-known example is tamoxifen, which binds to the estrogen receptor in cancer cells, blocking the effect of the real hormone. For years, tamoxifen has been prescribed for all women with hormone-receptor positive disease.
Recently, the U.S. Food and Drug Administration approved a new type of estrogen-targeting therapy after clinical trials showed that aromatase inhibitors were a better choice than tamoxifen for post-menopausal women. Instead of blocking the effect of estrogen, aromatase inhibitors—including exemestane (brand name: Aromasin), anastrozole (brand name: Arimidex), and letrozole (brand name: Femara) —reduce its production by the adrenal glands and fat tissue, the main sources of the hormone after menopause. Each is taken by pill once a day for up to five years, although women with advanced disease can take it as long as it works well.
Another option for post-menopausal women is fulvestrant (brand name: Faslodex), which works by attaching to and destroying the receptors on the cell surface that respond to estrogen. It is given as a once-a-month injection.
HER proteins
About 25 percent of breast cancers make too much of a protein known as HER2 (human epidermal growth factor receptor), which triggers rapid cell division and growth. HER-positive cancers tend to be more aggressive than HER-negative cancers, but targeting the protein has opened up new treatment possibilities.
When it was approved by the FDA for HER2-positive, metastatic breast cancer in 1998, trastuzumab (brand name: Herceptin) was lauded as a major treatment advance. Trastuzumab works by binding to the HER2 receptor on the cell surface and blocking its function within the cell. Subsequent clinical trials showed its usefulness in treating earlier stage HER2-positive cancers, and in 2006, trastuzumab received FDA approval for use as part of a regimen for early breast cancer that includes the chemotherapy medicines doxorubicin (brand name: Adriamycin), cyclophosphamide (brand name: Cytoxan) and paclitaxel (brand name: Taxol).
"What it gives in early-stage cancers is a 50 percent reduction in risk of recurrence, and a 35 percent reduction in mortality," says Dr. Grana. "There is a possibility of damage to the heart, so cardiac risk has to be considered."
When Rosalie Gerber, 43, of East Lyme, CT, was diagnosed in 2003, her doctor suggested she take part in a large national clinical trial of trastuzumab.
"At a time when all the news I was receiving was bad—my cancer has spread into the lymph nodes, and it was the more aggressive HER2 positive type—the clinical trial felt like my one glimmer of hope," she recalls. "I was even more hopeful when I found out I was in the group of women who would receive Herceptin in addition to traditional therapy."
Rosalie completed the 52-week trial in 2004, and by 2005, the news about trastuzumab appeared to be good.
"Once the oncology conferences and journals were reporting that Herceptin lessened the chance of recurrence, I felt so much joy and possibility," she says. "I did not experience heart damage or any major side effects, besides the inconvenience of going in for weekly treatments. It was absolutely worth it."
Some women experience fever, nausea and, in a small percentage of cases, damage to the heart’s ability to pump effectively. All women must be monitored for this effect.
Because Rosalie’s cancer was ER positive, she continues to take tamoxifen and goserelin (brand name: Zoladex), another kind of anti-estrogen treatment that suppresses the ovaries’ hormone production in pre-menopausal women.
"People tend to think of breast cancer as one disease, but I’ve learned that it’s not," she says. "It is very individual, with different women needing different approaches."
Research on HER-targeted treatments has not stopped with trastuzumab. A newer targeted therapy called lapatinib (brand name: Tykerb) blocks the effect of HER2 and a related protein, HER1, by interfering with the pathway inside the cell instead of at its surface.
Although still under investigation, lapatinib appears to offer several benefits over trastuzumab: it is taken in a more convenient pill form, instead of intravenously, and it appears to pose less cardiac risk. Side effects can include diarrhea, redness and tingling in the hands and feet, rash, stomach upset, vomiting and fatigue.
Earlier this year, lapatinib received FDA approval to be given in combination with capecitabine (brand name: Xeloda) to treat advanced, HER2-positive breast cancer that has stopped responding to other trastuzumab-chemotherapy combinations.
This is what happened to Olga Iboura Ogoussan, 35, who was diagnosed with stage 3 breast cancer in 2001, soon after moving to South Carolina from Africa to pursue a graduate degree in public health. Although her cancer was HER2-positive, at that time trastuzumab was approved only for metastatic disease.
When the cancer spread to her lungs in 2004, Olga started taking trastuzumab in combination with chemotherapy. This past spring, new activity in her lungs prompted her doctor to recommend a switch to lapatinib, which she started in May.
"The plan now is to stay on it as long as it works," Olga says. "I like that I can take it as a pill and not have to go to the hospital every week. I get tired from time to time, but for now my main side effect is a skin rash on my face."
Olga is getting ready to defend her dissertation, which focuses on the experience of women with stage 4 breast cancer.
"More of us are living longer with this disease," she says. "Over the past few years, I’ve been able to be as active as possible and continue my doctoral program in public health. I will not give up what I am doing as long as I am functioning well."
VEGF (Vascular Endothelial Growth Factor)
To get the oxygen and nutrients they need to grow and spread, tumors create new blood vessels through a process called angiogenesis.
Bevacizumab (brand name: Avastin) is a medicine that targets the VEGF protein, which plays a key role in angiogenesis. The FDA already has approved bevacizumab for advanced cancers of the colon, rectum and lung. It is now in clinical trials for advanced breast cancer.
"The real promise of Avastin, especially if it someday proves effective in early-stage breast cancer, is that it might give us something beyond chemotherapy to offer women with HER2-negative cancer, who can’t benefit from Herceptin or lapatinib," says Dr. Grana.
Pamela Lipton, 47, of Newton, MA, took bevacizumab and paclitaxel two years ago for stage 4 breast cancer. Pamela initially was diagnosed with stage 1 cancer, but a subsequent CT scan showed the cancer had spread to her liver.
"This was May 2005, when Avastin was getting lots of attention," she recalls. "I remember my friend calling me from the American Society of Clinical Oncology meeting and telling me, ‘Well, you picked a good time to get metastatic breast cancer.’ I don’t know if I agree with that, but he did urge my doctor to try it."
Throughout the summer, Pamela took paclitaxel every week and bevacizumab every other week, following it up with additional chemotherapy in the fall. In January 2006, she started on the aromatase inhibitor anastrozole, since her cancer is hormone receptor positive. It tested negative for HER2.
"I feel like I have been given a fighting chance by having both the traditional and targeted therapies," Pamela says. "Five years ago, these treatments simply would not have been there."
Early clinical trial results suggest that bevacizumab may slow the progression of advanced breast cancer better than paclitaxel alone. Bevacizumab can cause side effects such as high blood pressure and nosebleeds, and some studies suggest a slightly higher risk of stroke and other clotting and bleeding problems.
Other anti-angiogenic therapies that may have applications in breast cancer are sunitinib malate (brand name: Sutent), axitinib and sorafenib (brand name: Nexavar).
What This Means for You
"We are in an era when breast cancer care is dictated by estrogen-receptor or HER2 status," Dr. Grana says. "The discussions are getting much more complex and the treatments more individualized. Women need to ask about these in addition to everything else that goes into making treatment decisions, such as tumor size, stage and grade. Then they need to work with their doctors to consider other factors, such as age and lifestyle and other health issues, to make the final treatment plan."
Dr. Grana notes some variation may exist among centers that test for the estrogen receptor and HER2 gene, so it is important to make sure the test is done by a high-volume, high-quality lab.
She also points to a newer test, the Oncotype DX assay, which may be helpful for women with ER-positive, lymph node-negative cancer who are trying to decide whether to use an anti-estrogen treatment alone or combine it with chemotherapy. The test, which predicts the likelihood of recurrence by looking at the expression of certain genes in a tumor sample, may help some women feel more confident foregoing chemotherapy.
"The bottom line is that the decisions are not made based on any one factor in isolation, but on the entire picture of the individual woman," Dr. Grana says.
Now that cellular pathways are being used as targets for breast cancer treatment, researchers want to find out whether any of these pathways are interconnected.
"A key question is whether it is better to target more than one pathway, or different points along the same pathway," says Dr. Grana. "It probably will prove to be the case that it is not one target but multiple targets that give the most benefit." She cites the examples of two upcoming clinical trials that will assess the effectiveness of combining trastuzumab with lapatinib or with bevacizumab.
Researchers are also searching for new targets, since many women have tumors that are HER2-negative and ER/PR negative—or "triple-negative." Recent studies suggest that African-American and Latina women are more likely to fall into this group. Triple-negative cancers cannot benefit from trastumuzab and estrogen-targeting treatments.
Clinical trials of various combinations of targeted and traditional therapies for breast cancer are ongoing, so check with your healthcare team if you think you might be a candidate.
Counting Sheep: Coping with Insomnia and Fatigue
Right after her breast cancer diagnosis, Eileen Aurience, 55, noticed a change in her sleeping habits. Normally a sound sleeper, she found herself awakening several times a night with nausea, thirst or restlessness. The worst part: the disquiet of her mind.
"I was thinking about cancer, feeling sick," she says. "I couldn’t turn my mind off to rest. It kept ticking away."
Eileen, who coordinates transportation for special needs children in suburban Chicago, asked for help when fatigue began to impede her functioning. Her doctor prescribed zolpidem tartrate (brand name: Ambien). The medicine offered a short-term solution that helped her sleep better and think more clearly.
"When you don’t have enough rest, you see things differently," she says. "With more rest, I felt like I could face overwhelming things being thrown at me."
Eileen’s story is familiar to thousands of women who report a non-refreshing sleep and a level of fatigue they never experienced before cancer. Sleep disturbances are among the least understood symptoms that may accompany cancer and its treatment. An Internet search yields many treatment options. Yet health professionals have not agreed on a standard of care because of lack of research on sleep disturbances in people with cancer. Still, experts point to several methods that may help you improve the quality of your sleep and reduce daytime fatigue.
Looking for a Lullaby
Treatment can prompt a number of sleep disturbances, or changes in nighttime sleep that influence daytime functioning.
The most common sleep disturbance, insomnia, is described by mental health professionals as difficulty starting or staying asleep or getting restful sleep for at least one month that prompts significant distress or impacts ability to function. People with insomnia may wake up too early or feel tired during the day, despite spending enough quiet time in bed. Insomnia can result in feelings of fatigue.
Fatigue is defined by the National Comprehensive Cancer Network as a distressing, persistent sense of tiredness or exhaustion related to cancer or treatment not proportionate to recent activity and interfering with normal functioning.
Up to 90 percent of women in chemotherapy and between 40 and 70 percent of women who have lumpectomy and radiation treatment report insomnia and fatigue, estimates Ann M. Berger, PhD, RN, AOCN, FAAN, a sleep expert and advanced practice nurse at the University of Nebraska Medical Center. Those statistics do not include the one-third of longer-term survivors who report chronic insomnia and fatigue, which lasts for more than six months after completing treatment.
Why Can’t I Sleep?
Chemotherapy-related anemia is a major cause of fatigue that can interfere with sleep. The treatments that work so effectively at killing your cancer can deprive your body of the healthy red blood cells it needs to give you energy.
All women over age 50 are at higher risk for difficulties with the thyroid gland, which releases hormones that control alertness. Radiation therapy to the chest wall may exacerbate existing problems.
Cancer itself may impact your energy level. Your body may not process nutrients as efficiently or may be expending its energy fighting disease. People with additional health problems with the heart, lungs or kidneys are at higher risk.
Medicines that contribute to fatigue include opioids, antidepressants, neuroleptics, beta blockers, benzodiazepines and antihistamines. The more medicines taken, the more likely they may interact and prompt fatigue.
The side effects of anti-estrogen therapies can contribute to fatigue. Dee Frame Hourigan, 53, of Tucson, AZ, says chemotherapy-induced menopause and tamoxifen prompted sleeplessness "almost immediately."
"If I sat at home, I was sure to fall into a slump," she says. "So I continued working, which was difficult because I was tired all the time. I would wake up with night sweats and not be able to fall back asleep easily. Once I fell back asleep, it was almost time for me to get up and begin my day."
The emotional toll of breast cancer also contributes to fatigue: "You’re living in a state of being scared all the time, and worried, and stressed—and not knowing how to handle what is going on with your body and in your mind," Dee explains.
Dee used work to cope, but many women have concerns about managing their fears. Some women find comfort in continuing to do what they can. Dr. Berger says people who take on a "sick role" or have a history of anxiety or depression may be more vulnerable to sleep disturbances than those who continue to perform their usual tasks.
"We tell people to delegate, but some people give away too many of their roles," Dr. Berger says. "Breast cancer treatment goes on for a long time. If you start in this cycle of becoming less active, you’re more likely to report more fatigue and lower functioning."
Sleep and Metastasis
Fatigue can present a significant challenge for women living with advanced breast cancer.
During periods when the disease is active, cancer cells "send out signals to tell [the body] that something isn’t right," says Dr. Berger. "Those signals are often felt by the person as fatigue." Medication to control pain and the emotional exhaustion of constant treatment also impact sleep.
Lori Buck, 37, of Dallas Center, IA, gave up nursing and housekeeping after her diagnosis with stage 4 cancer. She says she needs at least 12 hours of sleep to function well.
"Later in the evenings I can’t find the words to say the things I want to say," says Lori. "Sometimes I feel like I’ve had a few six packs of beer, just because I haven’t gotten enough sleep."
Lori has found relief by focusing her waking hours on her children: "I enjoy things more than I used to. I used to do laundry and dishes while they were playing—now I just spend time with them."
Seeking Mr. Sandman
Opinions abound on how to treat fatigue, but only exercise has rigorous scientific backing.
Federal government and Oncology Nursing Society guidelines recommend brisk walking for 20 to 30 minutes at least four days a week. If you find it hard to motivate yourself, try walking with a friend or pet or running errands along the way. Because fatigue may be symptomatic of other health problems, talk with your healthcare team before starting any exercise routine or intervention.
Women also treat fatigue with a variety of non-established methods, in which some find success. For example, Joanne Locke, 59, of Ellicott City, MD, tried acupuncture and Tai Chi.
"It’s hard to say whether they helped me with fatigue, but they were wonderful for my head," she says. "The Tai Chi especially helped me with everything else, so it may have helped me sleep better."
Other options include strength and resistance training, yoga, dancing and swimming. The key is to find the activity that will help you to "continue to be as active as possible during and after treatment to attempt to keep fatigue low and sleep well," says Dr. Berger.
Small studies also have shown promoting good "sleep hygiene" to be helpful. Keep regular bed and wake times seven days a week, no matter how good or poor your nighttime sleep. Avoid napping, especially within four hours of bedtime. If you need a nap, sleep no more than 45 minutes.
Use your bed only for sleeping and intimacy. If you find yourself awake at night for more than 20 minutes, leave your bed and go sit in a comfortable chair in a dark room with a book or quiet music. When you start feeling drowsy again, return to bed.
Conserve energy during the day. Pam Scroggins, 40, of Charlotte, NC, works two jobs. After her diagnosis, she improved her diet, cut back on socializing and started clustering her activities to make more efficient use of her time.
"Just like we plan our meals to have a better diet, we need to plan our rest," Pam says. "It’s a choice not to stay up late or go out in the middle of the week. I’m more frugal with my time now. Rest is right up there with breathing."
Pam also uses medicine to help her sleep. Medications that help with sleep include hypnotics like zolpidem tartrate and alprazolam (brand name: Xanax) and antihistamines. They are designed for short-term use and can sometimes prompt a "sleep hangover" the next morning. However, medicine helps some women rest enough to explore alternatives.
Psychostimulants may also help people feel more alert while awake; these include modafinil (brand name: Provigil) and methylphenidate (brand name: Ritalin). Most psychostimulants have been studied only among women with advanced breast cancer.
Many herbal remedies and natural products are thought to impact fatigue, but they have not been tested for possible interactions, so women receiving chemotherapy should avoid them. One exception is melatonin, a product derived from a natural body chemical. Whatever option you explore, discuss it with your healthcare team.
"Don’t believe everyone should anticipate insomnia and fatigue," Joanne says. "But if you do feel it, you need to find a coping mechanism, whether it’s a medicine, your support group, or things that work for other people. Don’t suffer in silence. You have enough to put up with; this is the time to be good to yourself."
Active for Life: Exercise Helps Woman Manage Advanced Breast Cancer
It was like any other day. Darlene Cooke, 58, was jogging in her Haverford, PA, neighborhood. Always an active person, Darlene engaged in sports as part of her routine. Exercise helped relieve the stress from frequent travel at her job for a medical publishing company. It was 2003, and it had been 20 years since her treatment for breast cancer. Then, suddenly, a car hit her.
Darlene entered the hospital and was treated for broken ribs. When the fluid in her pleura, the thin membrane that lines the inside of the chest cavity and covers the lungs, failed to clear up as expected, Darlene’s surgeon referred her to a specialist. An oncologist made the final diagnosis: stage 4 breast cancer in the pleura and upper right leg bone.
Darlene was flabbergasted.
"I knew in the back in my mind that my breast cancer had had lymph node involvement and it could come back, but it had been so long [that] I was taken aback," Darlene remembers.
But after she got used to the idea, Darlene felt the second diagnosis wasn’t as devastating as the first.
"There is so much information out there now," Darlene says. "It’s talked about a lot more and you know women are surviving. So my thoughts turned to, ‘what can I do about it?’"
Darlene started on aromatase inhibitors, but they eventually stopped working. In 2007, Darlene’s doctor suggested participating in a Phase I clinical trial of an experimental gene therapy for people with cancer in the pleura. The therapy involves injecting an adenovirus into the body to activate the immune system to fight the cancer, explains lead investigator Daniel Sterman, MD, of the Hospital of the University of Pennsylvania. Darlene began the therapy before Memorial Day 2007—the first person with breast cancer to participate. She received two doses of the adenovirus and will be reevaluated after 75 days.
Darlene thinks it’s important to participate in clinical trials because "if it works, it’s an incredible breakthrough," and it could eventually lead to better treatments. However, she encourages women to "get information, talk to the doctor, ask every possible question, be totally informed, then make a decision. Know what you’re getting into."
Despite the side effects of treatment, Darlene continues her active lifestyle. Although she no longer runs, she tries to walk three miles five times a week and frequently hikes, kayaks and sails with her husband, John.
"At this point in my life, it would be very hard to stop exercising—it’s an integral part of my life," Darlene says. "And everything you read says exercise is good for you."
The support of her husband, sister, stepdaughters, friends, and six grandchildren has also been a source of strength.
"This experience has intensified my relationships and made me realize how important family and friends are," she says. "I was a pretty Type-A personality, but now I have slowed down, and not in a bad way. I’ve been reprioritizing things and realizing it’s okay to relax, enjoy life and take it easy."
She says it’s also important to talk about cancer to those you care about. "People don’t know what to say, so it helps to tell them what you need," Darlene says.
Giving back has also helped Darlene cope. When she was first diagnosed in 1982 at age 37, she didn’t know anyone else who had breast cancer, so she turned to the American Cancer Society’s Reach to Recovery program. A volunteer gave her the opportunity to express feelings, talk about fears and ask questions.
"Talking to someone who had breast cancer was helpful," Darlene says. "I thought of it as a death sentence, but I saw that she was alive, and it made me feel better."
Inspired by her experience, Darlene became a Reach to Recovery volunteer a year after her diagnosis. She served for many years as a volunteer and a board member.
"I wanted to help other women because it made such a difference for me," she says.
Three years after her diagnosis of metastatic disease, Darlene became an LBBC Survivors’ Helpline volunteer. Today, she talks to women who are going through similar circumstances and offers guidance, information and hope.
"Some of the time the caller has a purpose or specific question, but most of the time they just want to talk. I try to answer questions and provide support," Darlene says. "I have talked to women who have had their breast cancer come back, and I tell them I have been around for 25 years since my first diagnosis and four years since my second diagnosis, and I’m still here! Quality of life is important, and I try to help women think about it in those terms."
The most important thing to remember is that there is life after advanced breast cancer, she says.
"We are at [the] cutting edge with treatments right now, and all the [treatments] are so new. The good news is there are many things to try," Darlene says. "There is a lot of hope out there, but it is an up and down roller coaster ride—you have to try and stay above it."
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