Deborah L. Toppmeyer, MD, RWJMS associate professor of medicine; director, LIFE Center for Breast Cancer Awareness; and director, New Jersey Comprehensive Breast Cancer Program at CINJ
Can Drugs Prevent
Breast Cancer?
by Eve Jacobs
|
Ask a roomful of female baby boomers which disease they fear most and nine out of 10 will likely say breast cancer. Potentially disfiguring and historically deadly, too many in the 40- to 60-age group have witnessed a mother, an aunt, a cousin or close friend succumb to its ravages, or to the toxic side effects of the chemotherapy aimed at stemming its tide.
ince age is the greatest risk factor for breast cancer — 75 percent of those diagnosed are 50 or older — and the statistics tell us that one in nine American women will develop this disease in her lifetime, it seems critical for boomers to be on top of the latest findings and recommendations. Also, “since American women are choosing to have children later in life, we put ourselves at even higher risk,” says breast cancer specialist, boomer and mother-of-two Deborah Toppmeyer.
But the news is certainly not all bad. Toppmeyer wants boomers to know that breast cancer is no longer the disease that our mothers knew. Its “prognosis” has undergone a sea change in the last two decades, resulting in decreasing mortality rates since 1975.
The primary reason is better screening—and the fact that this age group of women has gotten the message that mammography is highly effective in catching breast problems early, before they become killers. “Our ability to find a cancer when it’s small and localized has been the driving force in reducing mortality,” she says.
Also, over the last 10 years, “our understanding of the molecular characteristics of the disease has grown and, consequently, our ability to treat it successfully,” says the director of The Cancer Institute of New Jersey’s breast cancer program. “We now understand that breast cancer is not one disease, but many, and individualizing patients’ therapies yields far better outcomes.” This knowledge of the unique molecular characteristics of breast cancer has led to the development of “targeted therapies” that have changed the natural history of the disease.
From left to right: Deborah Toppmeyer, MD, medical oncologist; Ann Augustyn, MS, certified genetic counselor; Jana Pruski-Clark, MPH, MS, genetic counselor; and Kimberly Ranieri, MS, genetic counseling program coordinator, certified genetic counselor.
“Targeted therapy” is precisely what it sounds like. The treatment is directed at a specific abnormality found on some breast cancer cells and aims to slow or stop these cells from growing without harming healthy cells in the process. Right now, several “targets” are being studied and a number of these therapies are in clinical trials.
The one-size-fits-all treatment of our mothers exists no longer. “We are getting a better grasp on the heterogeneity of breast tumors based on their genetic profile,” states Toppmeyer.
One of the oldest targeted therapies is the hormonal manipulation of breast cancer. Years ago, the only treatment other than surgery to the breast and surrounding tissue was removal of the ovaries, thereby halting the exposure of the hormone responsive breast cancer cells to estrogen. Newer hormonal therapies include the antiestrogens or selective estrogen receptor modulators (SERMS) and aromatase inhibitors.
Among the first and best known of the antiestrogens is tamoxifen (Nolvadex)—a pill for women that targets the estrogen receptor of hormone positive breast cancers. It has been used for more than 30 years to treat women with advanced disease, and also as an adjuvant (given in addition to the primary treatment) systemic therapy for early stage disease. Clinical studies have shown that five years of tamoxifen reduce the risk of breast cancer recurrence by 50 percent and mortality by 28 percent. Tamoxifen has more recently been approved as a preventative agent for women at high risk for breast cancer. This antiestrogen was found to reduce invasive breast cancer by 49 percent and noninvasive breast tumors by 50 percent in this group.
Recently, another SERM, raloxifene (AVISTA), previously approved for treating osteoporosis, was given the green light as a breast cancer preventative in postmenopausal women at increased risk of the disease. The STAR trial (study of tamoxifen and raloxifene) determined that raloxifene is as effective as tamoxifen for this group — with fewer potentially serious side effects including uterine cancer and blood clots.
Newer hormonal therapies that have also impacted the treatment of hormone sensitive breast cancer are the aromatase inhibitors (AIs). Effective in post-menopausal women, they work by blocking an enzyme, aromatase, which is critical for estrogen production in this group. The approved AIs include Arimidex (anastrazole), Femara (letrozole), and Aromasin (exemestane).
Newer targeted therapies that have been well studied are now assuming a prominent role in breast cancer treatment.
Herceptin® — a monoclonal antibody — is one of the newest treatments in Toppmeyer’s arsenal. According to the National Cancer Institute, results from two large trials showed “that those patients with early-stage breast cancer who received Herceptin® (trastuzumab) in combination with chemotherapy had a significant decrease in risk for breast cancer recurrence and an improvement in overall survival compared with patients who received the same chemotherapy without trastuzumab.”
HER-2 positive tumors “over-express” or make too much of the protein HER-2, found on the surface of cancer cells. The therapy slows or stops the growth of these cells by attaching to the protein and blocking its action, but is only effective in treating the 25 to 30 percent of breast cancers that over-express this protein. These tumors also tend to be faster-growing and recur more frequently than those that do not overproduce HER-2.
Because many primary breast tumors rely on the formation of new blood vessels for their growth and spread, some of the newest targeted therapies aim to block angiogenesis — the formation of blood vessels. Among the anti-angiogenics currently being studied is bevacizumab (Avastin), a monoclonal antibody targeting vascular endothelial growth factor-A, necessary to tumor angiogenesis. Avastin™ can stop some breast cancers from developing new blood vessels, thus cutting the cancer’s oxygen and nutrient supply, and causing shrinkage of the tumor or halting its growth.
In April 2005, preliminary results from a large, randomized clinical trial were released, showing that patients with previously untreated, recurrent or metastatic breast cancer who received Avastin™ in combination with standard chemotherapy had a longer time period before their cancer progressed than patients who received the same chemotherapy without Avastin. Toppmeyer thinks the drug shows promise for early disease and says that large ongoing clinical trials will address this question. Avastin has already been approved by the FDA for the treatment of metastatic colorectal cancer in combination with a specific chemotherapy regimen.
In conclusion, Toppmeyer says that all of these advances add up to meaningful benefits for the patient. “What I can tell my patients is that less is now more — less surgery so less pain, disfigurement and potential for infection, less medicine so less toxicity and misery caused by the treatment, and less radiation, inarguably an excellent change. The result is improved quality of life and extended survival.”
She speaks to the social conscience of her fellow boomers when she reminds us that drugs such as Herceptin and Avastin would not be approved if patients did not participate in clinical trials. The breast cancer specialist says CINJ patients are more willing than most to step into that pioneering role — 15 to 20 percent of them sign up for clinical trials as compared with 2 percent nationally. Although some patients fear that they are being used as “guinea pigs,” the breast cancer specialist calls them “true pioneers. By participating in well-designed clinical trials, they have changed the landscape of breast cancer treatment.”
She concludes by saying: “Our mission is to pursue cutting edge research that will
ultimately translate into better quality of life, survival, cure and prevention so that no woman in the future will ever again need to deal with the devastation of a breast cancer diagnosis.”
Factors That May Increase a Boomer’s Chance for Breast Cancer
- Early age of menstruation
- Late age of menopause
- No children or children later in life
- No breastfeeding
- Overweight and obesity
- Genetics
Regarding the Family Tree
There are no easy answers to the question: Who will get breast or ovarian cancer? If the medical significance of your family tree were that simple to decipher, you wouldn’t need the expertise of a cancer genetic counselor like Kim Ranieri. Although only 5 to 10 percent of all breast cancers are thought to be hereditary, for families with the BRCA1 or BRCA2 gene mutation, the potential impact can be enormous.
Baby boomers may wonder if a genetic risk assessment would be of value to them — or primarily of value to their children and subsequent generations. According to the genetics specialist, it can have significance for all women in the
family, and also for the men.
Who seeks out the expertise of a cancer genetic counselor? According to Ranieri, it’s someone worried about the chance of getting a particular cancer based on their family history. At The Cancer Institute of New Jersey’s LIFE Center, men and women are usually referred because of a personal or family history of breast, ovarian or colon cancer. In the case of breast cancer, the patient is most often a woman in her 40s (although patients can be of any age) with a family history. In some cases, she already has had a breast cancer diagnosis or a close family member with one.
If you decide to seek the services of a genetic counselor, what would you do? First, you and your physician discuss whether this kind of counseling might be of value to you. Then, after making an appointment with a genetic counselor, you fill out a six-to-eight page questionnaire detailing both your mother’s and father’s family medical histories and return the form prior to your first meeting. A counselor draws up a family tree based on the information you’ve provided.
At the first appointment, you and the counselor discuss the family tree and also your
medical and hormonal history. The counselor may be able to help you recall or access additional family medical information — such as the ages of cancer diagnoses, which can be critical, or other family members who have had cancer — to better fill in the history.
Red flags for hereditary breast and ovarian cancer include:
- Several individuals on the same side of the family with breast cancer and/or ovarian cancer;
- Breast cancer diagnosed before age 50 (the average age for nonhereditary breast cancer is 60 to 65) on either side of the family;
- Ovarian cancer at any age. (Ovarian cancer is less common than breast cancer, so although younger ovarian cancer is more significant, the disease is a red flag at any age in the context of a significant family history.)
- A family member who has been
diagnosed with both breast and ovarian cancers; - A family member with breast cancer in both breasts;
- Being an Ashkenazi Jew.
Ranieri says that having a mother, sister or daughter with breast cancer doubles a woman’s risk for the disease. But despite multiple risk factors, an individual may never get breast cancer.
Also, “having someone in your family with breast cancer doesn’t mean it’s hereditary. Many women have a relative with breast cancer in their family tree,” she continues.
Constructing a family tree is sometimes very difficult, she states. “Someone may be of Ashkenazi Jewish ancestry and have lost many young relatives in the Holocaust. Other patients are adopted and have no access to family records. Or family members fight sometimes and lose touch with each other.”
The counselor says that holes in the family history should not stop someone from coming in. “We use what each person can provide and make recommendations.”
The other important piece of the package is a hormonal history. Longer estrogen exposure generally elevates breast cancer risk. Factors that raise hormonal risk include: a first period before age 12; having no children or bearing a first child after age 30; and going through menopause after age 55. Multiple breast biopsies, even without a malignancy, also drive up risk.
Following discussion of the family tree, and medical and hormonal histories, Ranieri advises the client whether or not genetic testing will provide her with useful information. “I may be able to tell a worried woman that she is at low risk and explain why she doesn’t need testing,” she says, “or the client may be at high risk but
genetic testing may not be called for.”
When genetic testing is recommended, Ranieri says she talks with the patient for more than an hour. The test involves a simple blood draw, but its ramifications can be major. “We talk about what the test can mean for that individual and for her children and siblings.
“We also discuss where this may end up five steps down the road,” she continues. “If someone tests positive for a mutation in the BRCA1 or BRCA2 gene, her risk for breast cancer could be as high as 87 percent, but we can’t tell her when it might happen or even if — it’s not 100 percent.”
BRCA1 and 2 are tumor suppressor genes — in other words, they stop tumor growth. “The mutation means that you don’t have the internal police system. You’re less able to stop cells from growing out of control,” Ranieri states.
The genetic counselor explains that because BRCA1 and 2 are autosomal dominant genes, the chance of passing on the mutated gene to a child is 50 percent. The gene mutations don’t skip a generation and both boys and girls can inherit them. The BRCA1 and 2 mutations not only increase the risk for female breast and ovarian cancers, but for male breast cancer, prostate and pancreatic cancers, and several lesser known malignancies, although the risk is not nearly as high.
A BRCA 1 or 2 mutation can raise the risk of getting female breast cancer up to 87 percent (compared with 13.2 percent in the general population); male breast cancer up to 6 percent (from 1 percent); prostate cancer up to 20 to 25 percent (compared to 15 percent); and ovarian cancer up to 47 percent (compared with 1.7 percent).
Those at increased risk have many “really good” options for increasing their chances to remain healthy, says Ranieri, including more frequent exams, possibly three or four times yearly, chemoprevention and preventive surgery. The counselor explains that Tamoxifen for breast cancer can cut the risk by as much as 50 percent (although it’s not known how long the effects last); breast MRIs can be added as routine screening in addition to mammograms; transvaginal ultrasound and the CA125 blood test can be used to screen for ovarian cancer (although these have serious limitations); oral contraceptives can be prescribed to cut the risk for ovarian cancer; and prophylactic surgery may be recommended.
She says that removing the ovaries after childbearing reduces the risk of ovarian cancer by 80 percent and breast cancer by 40 to 50 percent. “This is our strongest recommendation, when a woman is done with childbearing.
“Prophylactic mastectomy is also an option available to women with a BRCA1 or BRCA2 mutation,” she continues. “However, since screening for breast cancer helps detect problems early, preventative mastectomy is not necessarily recommended for all patients.”
When seeking genetic counseling, sometimes a mother and daughter come in together, or maybe it’s a grandmother and granddaughter, or it could be a teenager whose mother has died of breast cancer, but Ranieri says “we usually do not test children. Hereditary breast and ovarian cancer is an adult onset condition.”
In conclusion, the counselor explains that when a client thinks she would like to go forward with testing, a detailed conversation needs to ensue on how she will react if she comes up positive. “If someone tests positive, that means her siblings — and her children — automatically have a 50-50 chance of having the same mutation. Testing can forever change the family dynamic if that is information the sister or child does not want, so it’s very important to involve family members in the discussion.”
Facing My Fear: A Genetic Journey by Susan Glick
I am staring at a piece of paper that says depending on the quality of my DNA, I could have a 50 percent chance of ovarian cancer and an 85 percent chance of breast cancer before age 70. I am 45, Ashkenazi Jewish, with a 6-year-old daughter and an 11-year-old son. How did I get here? Why did I start the process that placed these startling figures in my hand, head and heart? An exploration into the statistical jungle of genetic testing has brought me face to face with terrifying facts that pertain to me.
This journey through genetic testing actually started with my mother, who died in 1984 of a virulent, high-grade cancer strongly suspected to be ovarian. At 25, I was the primary caretaker during much of her illness. She died 12 months after diagnosis at the age of 52. Her battle against cancer was difficult at best and a future I did not relish to repeat. So, at the urging of my gynecologist, I scheduled an appointment for genetic testing for the BRCA1 and BRCA2 gene mutations most commonly found in the Ashkenazi Jewish population. (For more information, see “Regarding the Family Tree.”)
Left to right: author susan glick with old family photos of her mother as a child, as a young woman, and with her grandmother.
A week before my genetic counseling, I received scary and timely news: at age 49, my sister has been diagnosed with breast cancer. This confluence of events drives more purpose and energy into my desire to understand my cancer risks. My sister has now become the “index female,” a living family member who has cancer. According to the profiles used to assess hereditary susceptibility, my risk has risen concomitantly.
Kayon Williams, MS, a genetic counselor from the NJMS Center for Human and Molecular Genetics, is wonderful. In our first session, she diagrams my family history, explains cancer risks as well as the benefits and limitations of my having this genetic testing. The diagram shows I have a strong risk for cancer in my family. In addition to my mom’s death and my sister’s diagnosis, my maternal grandmother had breast cancer in her late 70s and my mother’s brother, her only sibling, died from non-Hodgkin’s lymphoma in his early 60s. On the other side of my family, my father died of lung cancer by 60. His aunt had breast cancer, so did her daughter, and the daughter of another uncle. Without my family history, the risk of ovarian cancer is approximately 1.2 percent and the risk for breast cancer is between 10 and 12 percent. My blood sample was sent to the single national laboratory that holds the patent to sequence the BRCA1/2 genes. Getting results will take close to four weeks.
It was after this session with Williams that I found myself back at my office, staring at the summary sheet of cancer risks for BRCA1/2 carriers. The implications were stunning; I had never seen figures like this before. As a carrier, the risk for breast cancer with any of the three changes is estimated at 50 to 85 percent and the risk of ovarian cancer between 10 and 50 percent. While effective screening techniques have been developed for breast cancer, testing for ovarian cancer has not advanced. The mortality rate for ovarian cancer is approximately 70 percent and can be as high as 80 percent, depending on the stage of cancer at the time of diagnosis. If I test positive, I could receive a strong recommendation for a prophylactic salpingo-oophorectomy, removal of the ovaries and fallopian tubes, which induces surgical menopause. While waiting for results, I explore my family history further by contacting a cousin with recurrent breast cancer who underwent a salpingo-oophorectomy. I also read voraciously every article from PubMed and other reliable Internet resources on ovarian and breast cancers, oophorectomies, surgical meno-pause and risk reduction. I have worked in healthcare administration for nearly 18 years; scientific words and medical terminology don’t scare me. I am determined to face facts head on and make the most informed decision possible.
To prepare for potential surgery, I also schedule a full gynecological exam, mammography and transvaginal ultrasound under the guidance of my gynecologist.
Three weeks later, my results come back negative. The relief isn’t complete, however, and in a follow-up session with Williams, we discuss the implications of being negative. My result is considered an “uninformative” negative, since I don’t have cancer and there is no known genetic mutation in my family. I learn that if my sister had tested positive for one of the three BRCA1/2 mutations, my results would have given us more information. Without a positive result in my family to confirm that the testing worked, my negative result provided little information. With an uninformative negative, my risks now fall somewhere between a BRCA1/2 carrier and the general population — a wide middle ground.
Furthermore, one recent study found that up to 12 percent of patients determined to be negative through the proprietary lab procedures in the U.S., actually tested positive later for a BRCA1/2 mutation when alternative test methods were offered. In fact, simply being the daughter of a woman with ovarian cancer raises my risk to 7.5 percent, nearly 7 times higher than for women in the general population. Meanwhile, the National Comprehensive Cancer Network, a resource for healthcare providers, recommends that I be offered “research and individualized recommendations according to personal and family history.” My negative results feel like a happy detour around the studied cancer risks of carrying BRCA1/2, but haven’t helped me arrive at a decision regarding prophylactic surgery.
To make the best decision, I seek opinions from another genetic counselor, my gynecologist and, finally, a gynecological oncologist who will do the ovarian surgery if I am willing. From four healthcare professionals come four similar recommendations: they agree about the surgery. The downside of early surgical menopause, along with the minor possible side effects of laparoscopic surgery, are not enough to outweigh the significant risk reduction I’ll receive from a salpingo-oophorectomy. Various studies all point to risk reductions as high as 96 percent for ovarian cancer and 50 percent for breast cancer for pre-menopausal women.
None of the four healthcare providers consulted attempted to dissuade me from elective surgery. Each answered in similar words: my family history shows salient risks and while my tests results were uninformative negative, we just don’t know enough yet. In fact, they are confident that undiscovered genetic mutations may exist even in my case.
I decide to have the surgery. My gynecological oncologist understands my situation and promises to obtain a full pathological analysis. Three percent of women who have this prophylactic surgery are found to harbor some cancerous cells, usually at or before stage one and I want to know everything. We also discuss how I’ll manage potential discomforts and deleterious outcomes of surgically induced menopause.
This decision is not for everyone. But, I’ve spent my life looking over my shoulder at the risk of cancer, always wondering when my diagnosis would come, and would it be ovarian. Every decision has been predicated on the assumption of a shortened life like my parents. Watching my mother fight and ultimately lose to one of the most feared cancers was a watershed event for me. Now, as I head toward surgery, I know I am doing all I can to stay around a little longer, for me, my family, and especially my children.
P.S. The surgery went well. Within the first seven days menopause started and I decided to use medication to ease the transition. My mental outlook also transitioned: I am still very aware of my mortality but I don’t live with dread and actually look happily towards my future.
The author, Susan Glick, is a manager in UMDNJ ’s Department of University Affairs.