Breast Cancer Treatment: Past, Present, and Future
About the Lecture
In a given year, over 200,000 women in the US are diagnosed with breast cancer, and over 40,000 women die of their disease. These numbers are large, but we can take comfort in knowing that death rates from breast cancer have been declining over the past several decades, largely due to the evolving ability to treat breast cancers differently, based on their individual characteristics. Breast cancer is not one disease, but rather several different diseases. An effective treatment plan must be personalized, to both the individual and to her specific type of breast cancer. Rena Callahan, MD will review breast cancer treatment then, now, and in the future in a way that is easy to understand so that patients and their families are armed with information to ensure they have the most current and effective treatment plan.
Rena Callahan, MD is an Assistant Clinical Professor in the Department of Medicine, Division of Hematology/Oncology at the David Geffen School of Medicine UCLA. She attended Yale University for undergraduate study, and later attended the University of Pennsylvania, School of Medicine where she graduated with high honors, Alpha Omega Alpha. She completed her Internal Medicine and Hematology/Oncology training at UCLA. She is now a member of the UCLA Hematology Oncology faculty and is active in the breast cancer research program. Her time is spent seeing patients on and off clinical trials. Dr. Callahan’s other interests include integrating complementary therapies with Western evidence-based medicine.
This event is supported in part by a grant from Pfizer.
This is a summary of a lecture presented on September 9, 2014.
Treatment for breast cancer has evolved over time. Breast cancer was originally treated as a local disease, and the primary treatment was radical surgery. Over time, radical surgery evolved into more breast-conserving surgery known as lumpectomy. Radiation was used to control the local/regional disease. Breast-conserving surgery with radiation is still a very important treatment for local or regional disease; however, this treatment does not address potential micrometastases that may have traveled outside of the locoregional area and require systemic treatment. Treating breast cancer is not just about treating the tumor- it is also about treating the whole body. We have learned that tumors in the breast do not kill women; it is the tumors in the body that lead to mortality.
Every patient with breast cancer must have their tumor “staged.” Staging is based on (1) the size of the original tumor, (2) whether or not there are lymph nodes that are found to have the disease in them, and, (3) if the disease has spread to other organs. Chemotherapy used to be given to all women with early stage disease who had positive lymph nodes. While the stage does correlate with outcome, it does not necessarily reflect what is going on in the underlying biology of the tumor. In 2001, a very important large-scale landmark study was published that evaluated many different breast cancer samples based on the genes that were turned on and off on a large array of genes. They found five major types of breast cancer clusters: Basal-like, Her2/neu+, Luminal Subtype A, Luminal Subtype B, and Luminal Subtype C. They also found different survival types associated with these different molecularly similar clusters.
Clinical care of breast cancer is not yet able to use gene expression array as a way of identifying these subtypes; at this point in time it is only used in research. However, it has given us a new way of looking at breast cancer. Instead of gene arrays, we use surrogate markers, proliferation and grade to determine your treatment choices. The Luminal A and Luminal B groups are usually estrogen/progesterone positive. The Luminal A group tends to have a low Ki67 rate which means that there are a lower percentage of abnormal cells dividing at one time, and their grade of the tumor is usually low. These have been identified as indolent, best treated with endocrine therapy and not chemotherapy because these tumors are often resistant to chemotherapy. The Luminal B group tends to have a high Ki67 rate that is also high grade. These tumors usually do best with chemotherapy and endocrine therapy. The HER2 enriched molecular type is usually HER2+, has a high Ki67 rate and is also high grade. These tend to be highly aggressive tumors that need a combination of chemotherapy and trastuzumab or also known as Herceptin. The Basal-like molecular type tends to be estrogen and progesterone receptor negative, and HER2 negative as well, thus referred to as “triple-negative” breast cancers. They tend to have high Ki67 rates, are high grade and are very aggressive tumors that need chemotherapy.
The landscape of breast cancer is changing, and “one-size” no longer fits all. The evolution of treatment approaches to early breast cancer suggests that the biology or the molecular structure may trump size.
The goal is to develop more targeted therapies that go after a specific driving force within the cancer cell by identifying what genes or proteins are driving the malignant behavior. It also requires the ability to assess for the presence of the target in the tumor or microenvironment. Ultimately, the goal is to get to less toxic and more effective treatments.
Estrogen/Progesterone Receptor (ER/PR) Positive Breast Cancer
60-75% of all breast cancers are hormone sensitive (ER+/PR+). The anti-estrogen treatment, e.g., tamoxifen, was the first targeted therapy for breast cancer. Hormones are a driving force of hormone receptor-positive breast cancer. Hormonally-targeted therapy saves lives and helps prevent metastases Tamoxifen is a targeted systemic treatment that blocks the estrogen receptor that has been around since the 1980s. It is given after the patient’s primary treatment to prevent the chance of recurrence. The data for tamoxifen are strong; in a meta-analysis of 10,000 patients comparing a placebo compound to tamoxifen for five years, the patients who received tamoxifen did better in both rates of recurrence and mortality. This finding held true even after they had stopped the drug for ten years or more. In the recently published “ATLAS” study (2012), researchers determined that younger women benefited by taking tamoxifen for ten instead of five years. There was a 25% reduction in breast cancer recurrence and a 29% reduction in mortality. This study does not take into consideration the introduction of the aromatase inhibitors.
Another targeted systemic treatment are Aromatase inhibitors (AIs), which were developed to interfere with the peripheral production of estradiol in post-menopausal women with breast cancer who have hormone-sensitive tumors. Researchers began testing AIs in the 1990s. There are three drugs that fall into this classification: anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin). AIs are only appropriate for post-menopausal women; they do not work in women with functioning ovaries with ER+ and/or PR+ tumors. Multiple randomized phase III clinical trials were performed, and all show a 2-6% reduction in the risk of breast cancer recurrence compared to tamoxifen. The current standard is five years of therapy, and they are awaiting results comparing ten years.
Currently, the standard of care is tamoxifen for premenopausal women and AIs for post-menopausal women with early-stage breast cancer. However, the future may involve using AIs with a drug to suppress the ovaries in pre-menopausal women. By shutting off the ovaries, women will be able to take the AIs earlier. There is currently a trial going on that evaluates this therapy involving ovarian suppression. After five years, there are data that suggests that this process using exemestane plus ovarian suppression improved disease-free survival, however, at five years there was no difference in overall survival. The question remains whether this will change over more time. In a subset analysis of this data, 25% of women had suboptimal estradiol suppression at any given point in time. We also noted that patients who received AIs compared to tamoxifen had a slightly higher rate of quitting the drug (16% compared to 11%).
As oncologists, one of our biggest questions is who should receive adjuvant chemotherapy in addition to endocrine therapy? There is a web-based model called Adjuvant! Online, www.adjuvantonline.com that incorporates US SEER data, Early Breast Cancer Trialists Collaborative Group (EBCTCG), and the Oxford Overview data. It estimates the ten-year risk of relapse and mortality. It estimates the benefit of chemotherapy and/or endocrine therapy. It takes into consideration, age, comorbidities, estrogen receptor status, size, grade, and nodes. One of its shortcomings is that no Her2 or progesterone data is entered, and it may not be appropriate for very young women because the data sets that were used were not made up of young women.
Another approach is to use a commercial available genomic test. The MammaPrint test looks at 70 genes that have the highest relationship to breast cancer to see how active they are and then calculates a recurrence score that is either low risk or high risk. When it first came out it had to be ordered by the surgeon as it could only be done on fresh tissues that had not been preserved in the usual manner. The more commonly used test is the Oncotype DX test that analyzes the activity of a group of 21 breast cancer-related genes that can affect how your specific cancer is likely to behave and respond to treatment. It sorts ER+ breast cancer patients into low, intermediate or high-risk groups. Patients in the high-risk group benefit from chemotherapy although the patients in the low and intermediate groups did not show such a benefit. There is some question about the intermediate group; for those patients that have other aggressive signs, it may be worth a detailed discussion with your oncologist.
for post-menotandard of care is tamoxifen for premenopausal women and AI’ for breast cancer. lity to assess for the presence
Metastatic recurrences after adjuvant treatment become resistant to endocrine therapy. Fulvestrant is a selective estrogen receptor downregulator (SERD) that degrades the estrogen receptor and the tumors. It is approved in the US for metastatic ER+ breast cancer with progression on endocrine therapy. It is an intramuscular injection that is given two times per month for the 1st month, and then once every 4 weeks thereafter.
Everolimus is another targeted drug that can be used ER+ metastatic disease. Everolimus blocks the mTOR pathway that hormone-sensitive breast cancers sometimes use when they become resistant to anti-estrogen therapy. In the recently published “BOLERO-2” phase III study, 724 patients with post-menopausal ER +, HER2 negative metastatic breast cancer were randomly assigned to receive an aromatase inhibitor (exemestane) alone or with everolimus. Patients who received everolimus lived significantly longer without their disease getting worse compared to patients who did not receive everolimus. It is now being tested in early stage breast cancer.
Another treatment on the horizon for endocrine resistant metastatic breast cancer is a targeted therapy called palbociclib that targets the CDK4/6 which is overactive in many ER+ breast cancer cells. Palbociclib is a CDK 4/6 inhibitor which helps to regain control of the cells cycle and blocks tumor cell proliferation. It is a pill that can be taken at home daily. In the “Paloma-1” Phase II study, 165 postmenopausal women with ER+ and HER2 negative locally advanced or metastatic breast cancer with no prior treatment received letrozole or letrozole plus palbociclib. This trial was conducted at UCLA by Richard Finn, MD and Dennis Slamon, MD. They found a marked improvement in the combined intervention: the progression-free survival was twice as long, 20.2 months vs. 10 months. In August of 2014, Pfizer filed a new drug application based on the Paloma 1 results.
HER-2 Amplified Breast Cancer
Approximately 25% of breast cancers overexpress HER2, which drives cancer cells to grow. Three large-scale studies have shown that the HER2-targeted treatment, trastuzumab (Herceptin) improves both disease-free survival and overall survival in women with early stage HER2-positive breast cancer. This regimen is used in combination with chemotherapy as an adjuvant treatment, and it has dramatically changed the overall survival for patients with this type of disease. A number of additional questions have been raised, including whether it is better to use this regimen concurrently with chemotherapy or sequentially (after chemotherapy). The N9831 study showed that concurrent works better than sequentially. One year has been shown to be the best compared to six months or two years and is currently the standard of care.
There are additional targets that are being investigated for HER2+ disease that are once again being investigated in the metastatic group of patients. The “Cleopatra” trial focused on patients who, over time, develop a resistance to Herceptin and chemotherapy. In this trial, the combination pertuzumab, trastuzumab, and docetaxel was compared with trastuzumab, a placebo, and docetaxel. Researchers found that patients with previously untreated HER2+ metastatic breast cancer who received all three drugs had progression-free survival and overall better survival. As of 2012 this has become a new standard of care for HER2+ stage IV disease.
There are other treatments being used or evaluated in stage IV disease that may soon be used in the care of patients with early stage disease. Some of these include lapatinib and TDM-1. In the “Emilia” study, T-DM1 (trastuzumab with emtansine) was compared to Xeloda plus lapatinib. We found the T-DM1 did not need to be combined with a chemotherapy agent and, thus, had fewer side effects. Overall survival was also better in the T-DM1 group. This drug was approved in February of 2013 as Kadcyla (ado-trastuzumab emtansine). There are additional drugs under review: Everolimus is an mTOR inhibitor and seems to show some effect in HER2 positive breast cancer; neratinib is a small molecule, and a peptide vaccine is also being investigated.
We are making many advances and what is currently available for the targeted treatment of widespread disease may, in the future, be used in the treatment of early stage breast cancer. These advances will help personalize treatment as well as reduce the likelihood of this disease returning.
Triple Negative Breast Cancer
Triple negative breast cancer refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and HER2. It is defined not by what it is, but rather by what it is not. Triple negative breast cancers have been less studied, and more research is needed for this aggressive tumor type. Triple negative breast cancers occur in about 15% of all breast cancer, and they comprise a very heterogeneous group of cancers that require a more aggressive treatment. They have a high risk of recurrence, are high grade, affect younger women, and disproportionately affect African Americans. It also has some overlap with individuals who test positive for the BRCA genes. About 75% of the triple negative breast cancers are basal-like while 25% are not basal-like.
The standard of care for early stage triple negative disease is chemotherapy. Stage IV disease can be stabilized with chemotherapy.
There are currently no specifically approved drugs for triple negative breast cancer. There are some research studies looking at PARP inhibitors that target that part of DNA that repairs damaged cells, particularly in the BRCA gene mutations. Researchers are investigating giving a platinum chemotherapy (prior to surgery. LC 161, a drug that promotes cancer cell death, is also under review for triple negative tumors. Other targeted agents are also being studied.
An efficient trial model for this population is to use the therapy prior to surgery. There is no difference in survival comparing patients who have had chemo before or after surgery. Chemo may shrink a large tumor which increases the chances that a patient can have breast-conserving surgery rather than a mastectomy. Chemo can also assess whether the patient will respond to therapy, which is particularly helpful as a research tool.
We are making many advances because of the many clinical trials that have been and are being conducted. Clinical trials are not just for patients with advanced disease. There are many new trials opening up and being brought to UCLA for patients with early stage disease as well. Systemic treatment is still necessary and a very important area for personalized care of breast cancer.
The future will likely involve evaluating tumors based on their gene expression. Enrollment in clinical trials is essential to developing rational therapeutics to increase efficacy and minimize toxicity. Neo-adjuvant treatment has to be based on knowledge and understanding of tumor biology not just size of the disease. Finally, we need to debunk the myth that participating in trials is using people as “guinea pigs.” Clinical trials may be the best medicine. Ask about clinical trials even with early stage disease and or look for trials yourself at http://www.clinicaltrials.gov/.