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Insights Into Cancer – March 10, 2015

Breast Cancer: 2015

Presented by John Glaspy, MD

About the Lecture

Breast cancer continues to be the leading cancer in women with over 178,000 new cases detected yearly. The diagnosis is inevitably a life-altering, frightening experience for patients. New treatments are being developed at an unprecedented pace and navigating the maze of options available can be overwhelming and difficult for those affected by breast cancer. Women need information in order to be active participants in their care. Dr. Glaspy helps demystify the complexity by clarifying the best evidenced based approaches to systemic breast cancer management and shedding light on some important controversies. Clinical trials are a growing resource for women to obtain the latest novel treatments and he outlines some of the newest trials and recent trials. This information pertains to systemic chemotherapy,hormonal agents as well as some of the new trials evaluating targeted agents. The goal of this presentation is to help women and their families understand the latest information about this disease and best treatment options so they can stay informed and aware of changing strategies.

About the Speaker

John Glaspy, MD is board certified in internal medicine, hematology and oncology. He is a Professor of Medicine, Division of Hematology Oncology at the David Geffen School of Medicine at UCLA. He is the Associate Chief of the Division of Hematology-Oncology in the UCLA Department of Medicine and also the Vice-Chair for UCLA’s Jonsson Comprehensive Cancer Center Scientific Protocol Review Committee. He holds the Estelle, Abe, and Marjorie Sanders Endowed Chair in Cancer Research. During the course of his career, Dr. Glaspy has authored more than 300 articles, abstracts, and book chapters and conducted numerous studies in a variety of areas including breast cancer, stem-cell transplant diseases, diet, cancer-related anemia and fatigue, ovarian cancer and melanoma. He has received numerous awards and honors, including being named one of the “Best Doctors in America.” Dr. Glaspy has many important roles at UCLA that include seeing patients. He has specialties in a variety of cancers including women’s cancers, breast and ovarian, as well as in melanoma.

Lecture Summary

In order to understand breast or any cancer, it is sometimes helpful to rise above the specifics of the disease and ask the broader questions, “Why is there cancer?” and “Why have we not evolved to the point to be rid of cancer?” The research that we’ve done over many years has both increased our understanding of cancer and, at times, impeded research until we were better able to understand cancer and its processes, thereby shifting paradigms to reflect our new knowledge. It was not until the 1970’s and 1980’s that we realized that cancer is not a foreign body that invades us, but it is a hijacking of normal cell production processes. Two researchers trying to understand viruses in chickens led to our understanding of oncogenes; as a result, we now have a very different understanding of the cell biology and how normal cellular processes are hijacked and lead to the creation of cancer cells. One of our greatest discoveries is understanding the different cell processes ̶ how it replicates, divides and replaces itself. Our cells turn over at a very high rate. This is normal. When new cells are being created the body has a sophisticated mechanism for also identifying mistakes that are made in the DNA of the cells. Cells with these mistakes are often repaired by specific processes of the body or they have an automatic program for cell death known as apoptosis. Cells know when to grow like crazy to replace damaged cells and they have braking systems that tell them when enough cells are made and new ones are no longer needed. Normal cells have the capacity to engage new blood supplies. However, each of these normal processes in normal cells can be hijacked through mutations that lead to abnormal cells that no longer follow the rules of the original DNA and, instead, evolve into a process that creates cancer cells. With so many of our cells being reproduced mistakes are bound to be made. Many of these mistakes have little consequence, but cells that continue to divide and replicate with multiple mistakes can eventually lose the properties of a normal cell. These cells grow out of control, no longer behave like normal cells and can develop into cancer cells.

In order to further understand cancer cells, it is helpful to know some “Darwinian Basics.” There are two primary principles. First, all living things evolve to optimize their reproduction and the survival of their offspring. For those who do not accept “Darwinian theory,” we could say that all living things were designed to optimize their reproduction and the survival of their offspring. The second principle is that an internal “budget’ governs all living things, and this budget is composed of energy. This energy is allocated to serve the two primary principles just presented. Energy for all living things is allocated into these categories:

  • Replacement of turning over cells – we replace our GI tract repeatedly and our blood cells throughout the day; our bodies are constantly in a state of replacing and turning over cells.
  • Maintenance of temperature and homeostasis – our bodies produce potassium and sodium because they leak out of cells and are needed to maintain normal cell functioning.
  • Finding food – this task is easier to accomplish in the modern age and, thus, less energy is expended on this than our ancestors did when they hunted and gathered.
  • Reproduction – sexuality, childbearing and childrearing require a lot of energy because humans are dependent on their parents for a long time.
  • Escaping predators – this is not as important as it once was.
  • Repairing damage – this is the key biochemical process which essentially retards aging and prevents cancer. In this day and age, we save our budget in some areas (like finding food and escaping predators) but we put a lot of energy into maintaining well-being and, as a result, we live for a longer time than our ancestors.

Our design and, thus, how we allocate energy is based, evolutionarily-speaking, on the probability of how long it might be before a violent death because of the first principle I presented—that all living things are meant to optimize their reproduction and the survival of their offspring. If you contrast mice and humans, mice mature and reproduce within two months of being born because they have a high likelihood of being killed by a predator—such as a flying eagle that uses them as food. We, on the other hand, cannot reproduce for years. In contrast, the tortoise puts a lot of energy into repairing ongoing cell damage as they tend to live for more years than humans. Much of this thinking has evolved from a brilliant neurophysiologist, Jared Diamond, who wrote the book, The Third Chimpanzee.

As humans, we spread energy across all of the dimensions. If we put our entire budget of energy into just repairing cells, we would be like the fastest battleship ever built that put its entire budget into speed but sacrificed its armor. As a result, when it gets hit it sinks immediately and turns out to be the biggest battleship design disaster in history.

Cancer and Breast Cancer
How does this relate to cancer? Cancer is largely a disease of damaged DNA and the proteins that regulate DNA. When we put our energy into repairing DNA damage, we make mistakes; as we age we make more mistakes. Mistakes accumulate, and as more mistakes are made many of these get passed on. As a result, we have accumulating mistakes in the normal cell process of repair. Unrepaired DNA damage leads to mutations. Mutations can come from environmental factors, but also from factors internal to the body. It takes a lot of mutated cells to go from normal processes to developing cancer. Cancer is essentially the mutations that accumulateàfirst developing into slightly irregular cells, often called dysplasiaàif they progress, they become carcinoma in situ and, if the inhibiting factors are hijacked, àthey invade the cell and organ walls. Cancerous tumors need a good blood supply, and those normal processes that allow for the development of blood vessels are hijacked to create direct blood supplies to the cancer cells which, in turn, feeds them. Finally, as these cells become more mutated they lose their ability to stay in one place and they use the blood cells like a highway to travel through the body and set up in other parts of the body. These new growths are called metastases.

It is not by chance that the highest incidence cancers for men and women are prostate and breast cancer. These are hormonally regulated organs, in part because a lot of our “energy budget” is invested in making certain that we can reproduce. These cancers are the price we pay for sexual reproduction. While prostate and breast cancer account for 28% and 29% of all cancers in the US, they only account for about 10% and 14% of all cancer deaths.

Cancers do not occur uniformly across all countries, and there is wide variation in the incidence of breast cancer across different countries. This variation raises the question of whether there is something genetically or environmentally different in people from different countries. Epidemiological studies look at population differences. Studies tracing Japanese women have uncovered some of the potential answers. Japanese women who had lived their entire lives in Japan had very low rates of breast cancer. However, researchers found that if these women migrated to other places, such as Hawaii and then mainland United States, within one generation their rate of breast cancer begins to rise. The steepest jump in the frequency of developing breast cancer occurs when these Japanese women migrate to the mainland United States. This happens too quickly to believe that a genetic change per se has taken place; rather we believe that changes in lifestyle, such as diet, may account for this rapid increase in their rate of breast cancer.

Breast cancer accounts for approximately 21% of all cancer diagnosed in women world-wide (1,000,000 cases per year). There is a six-fold difference in high versus low incidence countries. The rates in some low-risk areas–such as Japan, Singapore, and Korea–have doubled and tripled in the past 40 years. While low and middle-income countries have an incident rate of 45% of breast cancer, approximately 55% of deaths occur in these same countries. While there is a small percentage of breast cancer associated with an inherited predisposition, there also is strong evidence that dietary fat, dietary poly-unsaturated fatty acids, dietary estrogens, and radiation exposure are all environmental influences that increase breast cancer. It appears that polyunsaturated fatty acids–that are high in Omega 6 and are found in corn oil–make the breast tissues more susceptible to the development of cancer. On the other hand, the fish oils eaten by women in Japan, as part of their regular diet, are high in Omega 3s and may actually provide some protection to breast tissues.

We know that breast cancer risk is related to increases in menstrual cycling, which is likely exposure to hormones. Women who begin menstruating at an earlier age, who have a later age of menopause, or women who do not have children have slightly higher rates of breast cancer. Additionally, the older a woman is at the age of her first live birth also increases the risk slightly. On the other hand, increased number of births decreases the risk of breast cancer. Other factors that increase risk include having a first-degree relative with breast cancer, higher density breasts, postmenopausal obesity and alcohol use.

The discovery of the BRCA1 and BRCA2 genes also increases a woman’s risk of developing breast cancer, as well as some other cancers, such as ovarian cancer. BRCA1 and BRCA2 are involved in the repair of DNA. While this is a complex model, it has provided researchers with clues to understanding breast cancer. Essentially, the same mechanism that helps women develop breasts is involved in the process by which women also develop breast cancer, i.e., hormones play a major role.

The Women’s Health Initiative trial uncovered a number of important findings for women. First, they debunked the myth that estrogen protected women’s cognition or their hearts. Secondly, they found out that estrogen, when combined with progesterone, increased the rate of breast cancer. These findings had a major impact on women’s health; prior to these findings there were 15 million women using hormone replacement therapy in the United States while after these results were published this number quickly dropped to less than 9 million.

In the current synthesis of the data to date, estrogen serves to proliferate breast cancer and to play a role in errors /mutations of DNA. Factors such as dietary fat, less exercise, hormone replacement therapy, alcohol and no children increase estrogen levels which increase the risk of proliferation. Omega 6’s from polyunsaturated fatty acids make breasts more sensitive to these risk factors while Omega 3’s may quiet the breast.

Women at risk for breast cancer have been studied in trials evaluating the benefit of tamoxifen, exemestane (an aromatase inhibitor) and raloxifene. Tamoxifen and Exemestane are good drugs for both preventing invasive and non-invasive breast cancers. Tamoxifen does a similar job to raloxifene in invasive breast cancer but is a little inferior in non-invasive breast cancer. Individuals who take tamoxifen have a slightly increased chance of developing deep vein blood clots and endometrial cancers.

Treatment of Breast Cancer
Oncologists make treatment decisions based on each patient’s risk factors. Surgical procedures are used for local control of the breast. Mastectomy and lumpectomy with radiation are equivalent surgical procedures when lumpectomy is possible. Radiation therapy is used to improve lumpectomy in lymph node-negative women. In women whose lymph nodes test positive for breast cancer, having radiation improves survival. Adjuvant systemic therapy is also used to improve overall survival. Hormonal therapy is appropriate when the breast cancer is positive for estrogen receptors, and the HER2 is normal. Chemotherapy is used along with other targeted treatments depending on the status of HER2 status, estrogen and progesterone receptor status, the size of the tumor, lymph nodes, and grade. There are tools to help assess the risk of relapse, and it is our job as oncologists to evaluate and recommend the best treatment for each patient.

We are in the middle of a major paradigm shift in how we classify cancers, particularly breast cancers. In the past, tumors were classified by how they looked under the microscope and their organ of origin. Rudolf Ludwig Karl Virchow (1821-1902) developed this classification system for cancer in 1863. Since that time, medical students have memorized what has been an enduring paradigm that is only now changing. In our old paradigm, 70-80% of all tumors were defined as infiltrating ductal carcinoma, a definition which provided little understanding about the wide variability of outcomes for patients with this diagnosis and offered no information about treatment. Today, tumors are classified based on their molecular structure. Each cancer cell has a distinctive pattern in which some genes are turned on while others are turned off. These distinct gene array patterns have been identified and, as of right now, we have defined five different subtypes of breast tumors. They are: basal-like, Her2/neu+, Luminal Subtype A, Luminal Subtype B, and Luminal Subtype C. This shift in classifying breast cancers had led to a major change in breast cancer treatment. In the past, tumors were treated with chemotherapy that killed all rapidly dividing cells. Now, research dictates that tumors are treated with therapy that is rationally targeted toward the molecular defect in tumor cells, leaving normal cells alone. This targeted treatment means that we must determine the underlying biological reasons for the cells’ malignancy to allow for subcategorization of tumors based on molecular abnormality. We must know more about the details of how cancerous cells are different from each other to create less toxic and more effective treatments.

Endocrine Therapy
The first kind of targeted therapy used in breast cancer treatment was anti-hormonal therapy. It was first recognized in 1880 by the Scottish surgeon, George Beatson. He learned from Scottish farmers that the removing a cow’s ovaries altered her ability to lactate. He removed ovaries from three women with breast cancer and noted that their breast tumors shrank dramatically; however, when this treatment was repeated on a larger scale in London, only two-thirds of the patients responded. Doisy discovered estrogen in 1920, and Elwood Jensen discovered the Estrogen receptor in 1968. In hormonally driven cancers, normal receptors on the cell of the breast are hijacked, and they begin behaving abnormally. Researchers found that when tamoxifen was given to patients with hormonally driven cancers, the drug acted like an estrogen by blocking the estrogen receptor, but it did not make the breast cancer grow.

Tamoxifen is a selective estrogen receptor modulator that was discovered in 1962. It blocks the effects of estrogen by competing with estrogen for the receptor binding. It has anti-estrogenic effects in the breast and pro-estrogenic effects in the bone and the uterus. It is used in both pre- and post-menopausal women. The standard of care in premenopausal women has been to take it for five years in women who still make estrogen in their ovaries. Using tamoxifen in women after their primary treatment stops microscopic disease from growing and reduces both recurrence and mortality. There was recently a study indicating that ten years of tamoxifen may be better than five years.

Another targeted systemic treatment are aromatase inhibitors (AIs), which were developed to interfere with the peripheral production of estradiol in women with breast cancer who are post-menopausal and 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). They are only appropriate for post-menopausal women with ER+ and/or PR+ tumors. We have evaluated many randomized phase III clinical trials, 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.

Hormones are a driving force of hormone receptor-positive breast cancer. Hormonally-targeted therapy saves lives and helps prevent metastases. Once a woman with hormone receptors has metastatic breast cancer the tumors are developing resistance to estrogen therapies. Women are usually switched from one drug to another, but as they move through these drugs, the effectiveness declines because the tumors are developing a resistance to the drugs. Several pathways may be activating estrogen receptors without estrogen. This includes the mTOR pathway which may function as a second messenger. There are new targeted approaches for early breast cancer that is hormonally sensitive as there are new targets being studied in patients with metastatic disease. Often, research studies are done in resistant disease and then tried in early disease. One of these targeted drugs, everolimus, was tested in cell lines and phase I/II studies and shows promise in ER+ disease. Everolimus blocks the mTOR pathway that hormone-sensitive breast cancers sometimes use when they become resistant to anti-estrogen therapy. In the phase III “BOLERO-2” study, 724 patients with post-menopausal ER +/ HER2- metastatic breast cancer were randomly assigned to receive an AI (exemestane) alone or with everolimus. Patients who received everolimus lived significantly longer without their disease getting worse than patients who did not receive everolimus. It is now being tested in early stage breast cancer. Another drug, called palbociclib, recently received approval from the FDA for use in ER+ metastatic breast cancer after it showed excellent results in a Phase II trial. Palbociclib alters the cell cycle in a somewhat complicated way, and it was also given with letrozole. It was originally being tested for triple negative breast cancer, but the estrogen positive breast cancers responded more favorably.

Her2 Driven Breast Cancers
Everyone has Her2 receptors and in most breast cancer cells it is expressed in a normal way; however, some breast cancers instead of having 20,000-50,000 receptors have up to 2,000,000 Her2 receptors. These receptors sit on the cell like antennae and send signals to the cell to keep dividing and to not die. Approximately 20% of all breast cancers overexpress HER2 which propels the 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+ breast cancer. Herceptin is used in combination with chemotherapy as an adjuvant treatment and it has dramatically changed the overall survival of this type of disease. A number of additional questions have been asked, including whether trastuzumab is better when given 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 two years or 6 months and is currently the standard of care. It has changed the survival of this group of women from having the deadliest form of breast cancer to being the most treatable.

There are additional targets that are being investigated for HER2+ disease that are once again being investigated among patients with metastatic disease. Pertuzumab, trastuzumab, and docetaxel were compared against trastuzumab, a placebo, and docetaxel. Progression-free survival and overall survival is better in this initial study for patients with previously untreated HER2+ metastatic breast cancer who received all three drugs. Since 2012, this has become the standard of care for HER2+ stage IV disease.

Our major clinical concern is that patients with this disease can develop a resistance to trastuzumab, both primary and secondary. We are working to find a way to delay and overcome resistance to trastuzumab and future Her2 targeted treatments. The HER family has 4 receptors, and we are turning increasing attention to Her3.

After the Phase III CLEOPATRA study for first-line use in HER2+ breast cancer, the government approved the use of Pertuzumab. It was shown to increase overall survival among patients with HER2+ metastatic disease. By giving it in the neo-adjuvant setting, they were able to determine that it was reducing HER2+ breast cancer and so became approved more quickly and with a smaller number of patients. T-DM1 (trastuzumab emtansine) is a drug conjugant which means that chemotherapy is hitched to the trastuzumab and is delivered in a high dose only to the tumor cells. The benefit is that women do not lose their hair. By knowing the mechanism of how HER2+ breast cancer works, more creative and less toxic treatments have been devised that improve the quantity and quality of life. In the Phase 3 “EMILIA” trial, TDM-1 was used and was compared to lapatinib and capecitabine; progression-free survival was improved. TDM-1 works in breast cancer cells that are resistant to trastuzumab.

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. Triple negative breast cancer is defined by what it is not, rather than by what it is, which reflects our relative lack of understanding of this type of breast cancer. It is more common with BRCA mutations and in African Americans. We used to believe that the differences in survival for African American women was due to disparities in health care and while there still may be disparities in health care, they also are more likely to develop this aggressive form of breast cancer. Triple negative breast cancers comprise a very heterogeneous group of cancers and require more aggressive treatment. Triple negative breast cancers have been less studied, and we need more research on this aggressive tumor type. The standard of care for early-stage disease is chemotherapy.

There are some promising areas that include PARP inhibitors and immune checkpoint inhibitors. However, triple negative breast cancer can evade the normal immune system checkpoints; even when the immune system identifies that something has gone awry, the system asks for a password and the triple negative breast cancer cells are able to supply it because they are, in fact, part of the self.

Single strand DNA repairs are repaired by PARP. In triple-negative breast cancer, it may be important to break the ability of the cell to repair the cell and create a double strand break in the DNA thereby forcing the cell to die. The initial trial with PARP inhibitors did not demonstrate a positive effect, but it is possible the actual PARP inhibitor was not the correct one rather than the model being ineffective for this subset of patients with triple-negative breast cancer.

Right now, triple-negative breast cancer is treated very aggressively with chemotherapy in hopes of destroying all of the cells and allowing the woman to lead a cancer free life. There is much research to do still in triple negative breast cancer; early detection and aggressive treatment are the best approaches until new targets and understandings are developed for this disease.

Overall, there is much more change and research into the different forms of breast cancer to come in the near future.

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