Breast Cancer Treatment in the 21st Century
Olga Olevsky, MD, Clinical Instructor, Dept of Hematology/Oncology, David Geffen School of Medicine at UCLA, medical oncologist and researcher
This is a summary of a lecture presented on July 14, 2009.
Understanding breast cancer requires understanding the normal anatomy of the breast. The breast is a milk producing organ that sits on the muscle of the chest wall and is made of ducts, lobules and fatty tissues. Milk is made in the lobules and flows via the ducts to the nipple. The breast is controlled by estrogen, a hormone that circulates throughout the blood. Estrogen attaches to the estrogen receptors on breast cells and signals for the breast cell to grow and produce milk when a woman ovulates. If there is no pregnancy during that monthly cycle the growth pathway receives a signal to stop producing milk and the breast returns to its normal size. The next month the process starts again. In breast cancer, the normal pathway is subverted. A cluster of cells grows out of control, does not respond to normal signals and crowds out normal cells. This aberration can happen in response to estrogen or in response to other growth factors.
Pre-cancer and Invasive Cancer
Ductal carcinoma in situ (DCIS) is the earliest form of pre-cancer in the breast. In DCIS the cells that become abnormal are still localized inside the breast duct and have not spread to other parts of the breast. DCIS is often referred to as stage zero breast cancer. Lobular carcinoma in situ (LCIS) is when there are abnormal cells in the lobules, where the milk is made, and the cells have not invaded or spread to other parts of the breast.
Invasive breast cancer occurs when these abnormal cells leave the duct or lobule, multiply and invade the surrounding breast tissue. This type of cancer can also travel via the blood stream and lymph system, and settle in other organs, such as the lung, bone, brain or liver. These distant locations, once detected, are called metastases. In early stage breast cancer there are many treatments that are used to prevent metastases. There are also multiple therapies available to treat metastases, but to cure (ridding the body of all breast cancer cells) is no longer an option.
The treatments for breast cancer are surgery, radiation and systemic therapy which include hormonal therapy, chemotherapy and targeted/biologic therapies.
In breast conserving surgeries only the malignant area is removed along with a margin of healthy tissue surrounding the tumor. This type of surgery is referred to as lumpectomy, wide excision, segmentectomy and partial mastectomy. In a mastectomy the entire breast is removed and is often followed by immediate or delayed reconstruction, although this is a personal choice. A mastectomy is performed if a tumor is large, multiple areas of the breast are affected, the location of the tumor makes it necessary, or if there is a genetic, or familial, predisposition to developing breast cancer.
Although many people assume breast cancer is a hereditary condition, familial cancer accounts for only 5-10% of all breast cancer diagnoses. A substantial number of familial cases are related to mutations of the BRCA1/BRCA2 genes, which can be determined by doing a special type of blood test that looks at gene sequencing. If a mutation is present, a woman has a 50-85% chance of developing breast cancer by the age of 70. There is also a 40% chance of developing ovarian cancer. Many women consider having bilateral (both sides) mastectomies to remove their breast tissue and, thus, reduce the likelihood of developing breast cancer. Women also opt for removal of their ovaries (oophorectomy) for the same reason. These are personal choices that need to be discussed with a knowledgeable physician; individual circumstances as well as timing must be taken into consideration. These interventions might be initiated after a woman has had children and feels that her family is complete.
Lymph nodes are organs of the immune system responsible for fighting foreign invaders within the body. When a person has a sore throat the lymph nodes in the neck get inflamed. The same thing happens in the breast, but with the breast area the lymph nodes in the armpit (axilla) get inflamed. When cancer cells migrate or travel outside the breast, the lymph nodes can trap the cancer cells. There is often a first lymph node that receives drainage from the tumor area and thus is most likely to be affected. In the past, the lymph nodes in the armpit were removed and examined for the presence of cancer cells which, if found, would indicate an increased potential for the disease to spread and have implications for additional treatment. Surgeons often took many lymph nodes from each patient which was a more invasive surgery for the woman. One of the problems with this surgery is that it then created a significant side effect, lymphedema, wherein lymph fluid can get trapped in the extremities such as the arm because the lymph node system and pathways are disrupted by the surgery. Approximately 90% of the time the axillary nodes will drain the breast. The other 10% of the time the drainage is into the supraclavicular and internal mammary area. About 10-15 years ago, a new procedure was implemented based on the idea that fewer lymph nodes could be removed if the first one or two could be identified that receives drainage from the breast tumor. These first lymph nodes are called “sentinel lymph nodes.” The sentinel lymph node technique is done before and during the surgery. The area around the tumor is injected with a tracer blue dye or a small amount of radioactive isotope a short time prior to the surgery. In surgery a lymph node is identified with the highest amount of the radioactivity or the highest amount of blue dye. That node is then removed and sent to the pathologist. If no tumor is identified, there is a 95+% chance that no other nodes are involved. This has become the standard procedure and represents a perfect example of how understanding physiology can be used to get the maximum amount of information with the fewest number of problems. This technique has revolutionized breast surgery.
Radiation therapy significantly reduces the chances of the tumor returning to the breast or armpit (axillary) areas. Radiation therapy is used after surgery to make sure that no loose cancer cells are left in the breast. It is always used after a lumpectomy and the radiation is directed to the entire breast. Sometimes an extra boost is given to the specific area where the tumor was surgically removed, which is called the “tumor bed.” Sometimes radiation is used after a mastectomy; this depends on the status of the clear tissue around the surgical site. If the tumor is close to the chest wall for example, then this is often an indication for radiation after a mastectomy. When the lymph nodes are positive for breast cancer, the areas around the lymph nodes have to be radiated after a mastectomy. Radiation is a way of controlling local disease, meaning disease in and around the breast/chest wall. It does not prevent recurrence in other parts of the body.
The role of a medical oncologist is to address the possibility of a recurrence. Recurrence means that the same tumor shows up in an organ other than the breast at some point in the future. After surgery, when there is no visible disease left in the breast, the goal is to prevent a systemic recurrence. Medical oncologists also deal with systemic recurrences that can happen at a later point in time. Many people wonder how breast cancer can develop in a different organ at some point down the line. It means that the cells travelled there when the original tumor was still in place and that the cells were dormant or did not become apparent until years later when they have grown into a tumor mass big enough to be found on scans or cause symptoms.
Adjuvant Systemic Therapy
The value of systemic therapy after surgery, when there is no visible disease left, is to try to eradicate the microscopic cells that could have escaped into the bloodstream. Systemic therapy means that the entire body has to be treated. Systemic therapy is either oral or intravenous so that it is absorbed into the bloodstream. There are two types of systemic therapies: (1) targeted therapy, which is directed specifically at the pathways responsible for driving the growth of cancer cells; and (2) chemotherapy, which directed at rapidly dividing cells but affects healthy cells as well as tumor cells.
Not everyone gets adjuvant systemic therapy. Patients who have more lymph node involvement, larger tumors, and higher staging all have a greater possibility of recurrence. Most of the time chemotherapy is used in individuals with large tumors or who have lymph node involvement.
In recent years there have been two tests developed to help select which patients are more likely to benefit from chemotherapy. Both are FDA approved and used with individuals who have hormone sensitive breast cancer, which means that the tumors have hormone receptors for estrogen and/or progesterone on the surface of the cells. One test is called Oncotype DX® and the other is called Mammaprint®. Both of these tests provide more detailed genetic information and are used to predict, based on a molecular profile, if the tumor is likely to recur. The Oncotype DX® is based on an analysis of 21 genes and assumes that the patients will receive hormonal therapy. Patients are sorted based on the molecular profile of the tumor, and a prediction is made about the probability of the tumor recurring over the next 10 years. Once the genetic analysis of the patient’s tumor is performed, the test estimates a recurrence for a particular individual and assigns them into a low, intermediate, or high risk recurrence category. Mammaprint® is a test that is based on an analysis of 70 genes; this test, however, must be decided on at the time of surgery as it requires fresh tissue samples, not ones that have already been processed by the pathologist. It is more sensitive and classifies patients more accurately into the high and low risk or recurrence groups over the next 10 years. This test has not been as widely used because of the timing needed for the sampling of tissue. Both of these tests are gaining use, both are good examples of how cancer treatment is become more individualized, and both highlight the importance of understanding the biological characteristics of the tumor.
We now know that breast cancer is not a homogeneous disease, and can no longer be treated with a one size fits all approach. There are different categories of breast cancer , each requiring a tailored treatment. Breast cells that develop into cancer use different pathways, and by identifying these pathways, scientists can target therapeutic interventions at the specific factors that drive the pathways.
Cancers with Hormone Receptors
Cancers that have estrogen/progesterone receptors on the cells are fueled by estrogen in the body, which helps them to grow out of control. Estrogen is produced in great amounts in the ovaries in pre-menopausal women. However, it is still produced in smaller amounts in post-menopausal women in bone, liver and muscle tissues and this small amount is still enough to stimulate breast cancer growth. The hormone receptors on the outside of the cell allow the hormones to bind to the cell, which then tells the cell to grow. Tamoxifen, a hormone used to treat breast cancer, looks like estrogen but prevents estrogen from binding to the cell by blocking the receptor. Estrogen is still present in the blood but its effect is blocked by the tamoxifen. The strategy for using tamoxifen was determined 30 years ago. It works in both pre- and post-menopausal women and reduces the risk of recurrence of breast cancer by about 50% in individuals who have the receptor present on the cancer cell.
Another targeted treatment discovered more recently is a group of drugs called aromatase inhibitors which block estrogen production in post-menopausal women. They block an enzyme that converts estrogen precursors to estrogen. There are two that work similarly Arimedex® (anastrazole) and Femara® (letrazole). There is a third that is slightly different but accomplishes the same task called Aromasin® (examestane). All three inhibit aromatase, block estrogen production, and decrease estrogen levels. Several large multicenter, multicountry trials compared tamoxifen to aromatase inhibitors as adjuvant therapy in post-menopausal women. Every study reported an improvement in relapse free survival in the range of 20-40% on top of the benefit acquired with tamoxifen. This strategy can only be used in post-menopausal women who make very small amounts of estrogen. In pre-menopausal women, the ovaries do not use aromatase to make estrogen although they do have the aromatase enzyme but it accounts for only about 10% of estrogen production. Blocking aromatase would not change estrogen levels or alter risk of recurrence in premenopausal women.
For pre-menopausal women, estrogen can also be blocked by a monthly injection to temporarily shut down the ovaries; women who are finished with childbearing can opt to remove their ovaries. An aromatase inhibitor can be used to fully shut down estrogen production in other organs after these procedures. We do not know if this strategy is better than tamoxifen alone. For now tamoxifen is the standard of care in premenopausal women.
The common side effects for anti-estrogen therapies are the same as the symptoms of menopause: hot flashes, irritability/depression, and vaginal dryness. Tamoxifen has a 1% risk of the following side effects in the five years of recommended treatment: stroke, blood clots, and uterine cancers, which are easily detected in the early stages because they cause bleeding. Aromatase inhibitors increase the risk of osteoporosis and bone fractures. Women on aromatase inhibitors need to be aware of the potential for bone loss, should have bone density scans, and may need to be on bone strengthening medications while taking this treatment. Biphosphonates such as Fosamax® (oral weekly), Boniva® (oral monthly), and Zometa® (intravenous) can be used to interfere or prevent bone damage. They interfere with the formation of osteoclasts which break down old bone and form a barrier between the bone and osteoclasts. Bones usually remain stable while on aromatase inhibitors. A recent Austrian study published in February in the New England Journal of Medicine reported that Zometa®, when added to adjuvant hormonal therapy in premenopausal breast cancer patients, caused a reduction in breast cancer recurrence. This is exciting, but clinicians are waiting for confirmatory results, and there is no information on women who received chemotherapy.
We are still not completely sure how long to keep women on hormonal therapy. Most women are put on anti-estrogen therapy for five years. A very large North American study (MA17) evaluated women after 5 years on tamoxifen. Women were assigned to no additional therapy or to letrazole (Femara®) for another 5 years. The risk of late relapse was reduced by 40% and the trial was so positive that it was stopped after 2.5 years. Women taking the placebo were offered active therapy. Even women with a 2.5 year break in therapy had a 40% reduction in further risk of late relapses.
HER 2 Pathway
The HER-2 pathway is another important mechanism by which breast cancer is regulated for some women. This pathway drives the cells to proliferate but it is not under estrogen control. This pathway may also be important in the development of the breast. Normal breast cells have HER-2 protein (receptor) on their surfaces but some women have too many receptors on their cells. Having too many receptors on the cell causes out-of-control growth of cancer cells as well as the formation of aggressive tumors. The fundamental alteration that causes HER-2 positive tumors is gene amplification which results in high levels of protein production. The abnormality in this pathway was discovered by Dennis Slamon, MD, at UCLA in the late 80s. His lab also discovered that the HER-2 pathway was altered in 25% of the patients and that those patients had both more aggressive disease and decreased survival. Dr. Slamon and his colleagues developed a biologic substance Herceptin® that targeted the HER-2 receptor and prevented breast cancer cell growth. In Dr. Slamon’ words, “…We can think of HER-2 receptor as an old fashioned TV antenna that sits on top of the house. The antenna would receive the signal from the outside, and transmit it to the inside, to the TV, thus making the TV receive the signal. In the case of HER-2 receptor, this receptor sits on the surface of the cell like an antenna, and receives growth signals from the outside, transmits it to the cell, and tells the cell to grow. HER-2 is a protein, Herceptin® is an antibody against that protein, that acts like a blanket that covers the antenna and stops it from receiving the correct signals from the outside and stops the signaling process and growth.” Herceptin® is not chemotherapy and does not cause hair loss. It can weaken the heart muscle, but this can also be caused by chemotherapy such as Adriamycin.
This treatment was the first therapy that significantly prolonged overall survival in metastatic breast cancer. The recurrence rate in women with early breast cancer that received that agent, dropped by 50% compared to the women that did not get it. The efficacy of Herceptin® counteracted the aggressiveness of the tumors, essentially making the recurrence risk similar to HER-2 negative tumors. The degree of benefit in early breast cancer has been considered the largest since the introduction of tamoxifen in hormone positive disease.
Within the last year another agent was approved by the FDA for patients with HER-2 positive disease. Lapatinib (Tykerb®) is used together with chemotherapy in women that are no longer responding to Herceptin®. It is only approved for patients with metastatic disease. It is a small molecule that attaches to the HER-2 protein on the inside of a cell and then blocks the downstream cascade of events in the HER-2 pathway.
Triple Negative Breast Cancer
Some breast cancers have no hormone receptors and are not HER-2 positive. These tumors are referred to as triple negative breast cancers. They tend to be more aggressive tumors, and have a high proliferation rate, that is they are dividing rapidly. Triple negative tumors are the most sensitive to chemotherapy because chemotherapy acts on rapidly dividing cells. There are several different chemotherapies used with these tumors. Women with triple negative disease do not get hormone therapies (tamoxifen or the aromatase inhibitors) and do not get treated with Herceptin®. While these tumors tend to be more aggressive, when they respond to chemotherapy the response is often enduring. If the tumor does not come back in a short time, it often does not come back at all.
Other Targeted Treatments Approved
Tumors require blood vessels for growth. Tumors secrete a special protein called VEGF (vascular epithelial growth factor) that stimulate blood vessel growth. Blood vessels deliver nutrients to the tumor and serve as highways through which tumor cells can spread. Recently an antibody was developed that blocks the circulating vascular growth factor thus interrupting the development of new blood vessels and starving the tumor of nutrients. Bevacizumab (Avastin®) targets this pathway. In several large studies the addition of bevacizumab (Avastin®) to chemotherapy regimens significantly increased the response and progression free survival in breast cancer. This drug also has been found to normalize the blood vessel growth which otherwise tends to be very erratic, and may actually increase the effectiveness of chemotherapy to the tumors.
The nature of medical oncology is changing quickly and oncologists are moving away from a “one size fits all” treatment plan. Cancer treatment is becoming more personalized as knowledge and understanding of the biology of the cancer is used to maximize treatments. In the process, the side effect profiles are changing with the goal of minimizing harm by using targeted approaches.