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Breast Cancer in 2012: Not Your (Grand)Mother’s Disease
Guest blog from Kelly Graham-Seyed, Susan G. Komen for the Cure Scientific Grants Manager
In the 1970’s, breast cancer was a disease that no one talked about, and doctors found very difficult to treat. The methodology used to identify estrogen receptor (ER) status was just being developed, and not commonly used. Fast forward 20 years, to the 1990s, and testing for the estrogen receptor was optimized and widely used in pathology labs to split breast tumors into ER+ and ER- types and help doctors to offer treatments that would be most effective in specific patients. In the late 1990s, recommendations from the American Society of Clinical Oncology to test for the HER2 receptor led to an additional division of breast cancer types. The early 2000s brought the analysis of breast tumor types to a genetic level, with the identification of 5 distinct subtypes of breast tumors based on the genes present in individual tumors’ genetic fingerprints. The year 2012 has further defined (and thus subdivided) breast tumor types, providing us with a better understanding of breast cancer, a roadmap to personalized medicine, and revealing more questions to answer in the years to come.
The Cancer Genome Atlas: A Major Breast Cancer StudyOne important study this past year came from The Cancer Genome Atlas Network (TCGA), a collaborative effort of more than 150 researchers from nearly 100 institutions, departments, and centers from around the globe. This project is the first comprehensive genetic analysis of breast cancer, combining information from six different technologies used to study the tumor genome. The study revealed four major types of breast cancer which can be further divided by alterations in the tumor’s genetic makeup. These alterations represent potential Achilles heels in the tumor’s biological processes, providing targets for new therapies. The data also showed similarities between basal-like breast cancers (which are mostly triple-negative) and high-grade ovarian cancers.
The significance of this project extends well beyond the science. First, it demonstrates the advantage of a collaborative research environment: science is not a “silo” and the breast cancer research community must rally around the cause to make major advances. Second, it shows that individual breast tumors are defined by much more than their ER and HER2 status, providing the rationale for making personalized medicine a reality. Lastly, the study demonstrates molecular commonalities in breast cancer and other types of cancer. The importance of this key finding means therapies already approved for treating other cancers may be available to implement in the breast cancer setting, making clinical trials more streamlined.
Genetic Studies of Breast Cancer
Other work that advanced our knowledge of breast cancer and its complexities in 2012 included a novel study from the Cancer Genome Project used methods similar to those used to determine the age and relationship between different species of animals to look back in time at the step-wise accumulation of genetic mutations in breast tumor samples. The take-home message from this study is that the mutations present in of the heterogeneous population of cells in a breast tumor occur when a tumor is starting to form and continues to evolve over time, resulting in unique genetic fingerprints for each breast tumor.
Another paper co-authored by Komen Scholar Judy Garber and Komen Grantee Kornelia Polyak and colleagues echoed these findings, suggesting that some BRCA1-associated breast tumors may not be initiated and driven by BRCA1 mutations, but may instead have other genetic mutations that drive the tumor’s growth, with BRCA1 mutations occurring later in the tumor’s life cycle.
Understanding Mammary Stem Cells
This year, researchers took a long, hard look at mammary stem cells (MASCs) that contribute to mammary gland development during key physiological changes (puberty and pregnancy). Scientists hypothesize that breast cancers arise when the biological processes in MASCs are deregulated. Komen Scholar Geoff Wahl studied fetal mammary gland development in mice and found striking similarities between the molecular pathways expressed in fetal MASCs and basal-like breast cancers, which may provide promising biomarkers for patient prognosis and targets for therapy development. Other studies focusing on adult breast stem cells unveiled a molecular mechanism for determining a mammary stem cell’s commitment to becoming a specific breast cell type. The genes that regulate these processes have been implicated in tumor development and metastasis, and may provide targets for future therapies and diagnostic tests.
New Approaches to Understanding Breast Cancer Treatment
Research efforts in 2012 have also advanced our understanding of breast cancer treatment. Many studies sought to understand the biology behind a tumor’s resistance to breast cancer therapy. Komen grantee Gary Johnson and his team at the University of North Carolina School of Medicine identified key signaling pathways involved in drug resistance, providing insight for developing more effective drug combinations to fight breast cancer, particularly in triple negative breast cancer, which is notoriously difficult to treat.
In other work, Komen Scholars Joan Brugge and Gordon Mills studied drug resistance in 3D breast cell cultures, which more closely resemble what occurs in the breast. They found that a combination of drugs that target cell survival pathways and cell proliferation pathways at the same time was more effective than treatment with a single drug.
Komen grantee Trey Westbrook and his team at Baylor have been using a technology, called functional genomics, to study genes that play a role in cancer. Using this technology, Dr. Westbrook identified a gene that is related to the propensity for a tumor to metastasize, which may provide doctors with a new drug target to prevent metastases.
A Look Towards the Future
The new technologies and research advances of 2012 have enhanced our understanding of the complex biology of breast cancer and provided the foundation for testing possible new therapies. In years to come, researchers will build upon these advances to move us closer to a world without breast cancer. When we achieve that vision, we will have today’s (and yesterday’s) scientists to thank for sending us in the right direction with their research and perseverance.
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Voices of Impact – Prof. Yosef Yarden
Established by Susan G. Komen for the Cure® in 1992, the Brinker Award for Scientific Distinction is a marquee award that honors leading scientists for their significant achievements and contributions in basic and translational science and clinical practice that have advanced the fight to save lives and realize our vision of a world without breast cancer. This year’s awardees are Dr. Hyman Muss, an American clinician-scientist and Prof. Yosef Yarden, an Israeli researcher whose work has led to more personalized treatments for breast cancer. Dr. Muss and Prof. Yarden received their awards at the 2012 San Antonio Breast Cancer Symposium on December 5, 2012.
YOSEF YARDEN, Ph.D., Rehovot, Israel
Professor of Molecular Biology at the Weizmann Institute of Science; Head of the Marvin Tanner Laboratory for Research on Cancer; Incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology; Research Professor, Israel Cancer Research Fund“I was driven by curiosity—what causes cells to grow and how do these processes go awry in cancer? —and the challenge of answering these questions through research.”
Cancer biology is like a very complicated puzzle, and scientific discoveries are like the puzzle pieces that fit together to help us see the full picture, to help us understand the biological drivers of cancer and how we can target them with cancer drugs. I am especially proud that my basic research has helped put together some pieces of the breast cancer puzzle and build the foundation for several widely used breast cancer drugs that target key molecules driving breast cancer.
But when I first joined the field, my initial motivation was scientific. I was driven by curiosity—what causes cells to grow and how do these processes go awry in cancer? —and the challenge of answering these questions through research. At this time, we did not know that epidermal growth factor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) are related to so many types of tumors. The term “HER2-positive” breast cancer did not exist.
As an undergraduate student at the Hebrew University in Jerusalem, my enthusiasm was ignited by the ability of small biologically active molecules, called growth factors, to cause certain cells to respond (for example, by growing and dividing) while not affecting neighboring cells. I was fascinated by studies reported by Stanley Cohen, who found that a specific receptor, or protein on the cell surface, could bind to epidermal growth factor (EGF) and trigger a cell to respond. Hence, my doctoral project at the Weizmann Institute focused on the receptor for EGF (called EGFR). This work led to two important discoveries: the one that received media coverage found that a large portion of the genetic code for EGFR was included in a virus, which causes cancer in birds. Unexpectedly, the other finding revealed that EGFR is inactive unless it forms a pair with another EGFR molecule.
By the time I was polishing my thesis, a protein in the same family as EGFR was independently discovered by Axel Ullrich (who called it HER2) and Robert Weinberg (who called it Neu). Later studies by Dennis Slamon and others reported exaggerated levels of HER2/Neu in breast tumors. The puzzle begins to take shape.
I went on to train in Ullrich’s and Weinberg’s laboratories (1985-1989). While there and later in my own laboratory in Rehovot, we extensively compared EGFR and HER2/Neu. These studies, some of which were generously supported by Susan G. Komen for the Cure, discovered the Neuregulin family of EGF-like factors and led to the realization that HER2/Neu regulates a network of receptors. In other words, by forming pairs with EGFR and other family members, HER2/Neu enhances and prolongs biochemical signals initiated by growth factors in the neuregulin family and EGF. Hence, blocking HER2/Neu in breast cancer with targeted drugs can block the action of multiple growth factors and receptors, thereby inhibiting tumor growth.
Decades of research have helped us to understand the biology of breast cancer and apply that knowledge to develop better ways to treat breast cancer, based on the proteins driving the growth and spread of tumor cells. But the puzzle is not complete. Our current studies are unveiling a plethora of molecular mechanisms that permit HER2/Neu to evade processes inside the cell, like intracellular breakdown of HER2/neu, that regulate its activity. Understanding how HER2/neu is regulated will help us to develop new ways to enhance the therapeutic impact of anti-HER2/neu drugs.
I’m honored to be recognized for my contributions to this understanding of breast cancer biology with the Brinker Award for Scientific Distinction, but clearly, no single researcher or scientist holds all of the answers, and I am grateful for the community of global researchers working together to unlock the pieces of cancer’s puzzles. By funding research in the U.S. and internationally, I see Susan G. Komen for the Cure as a convener of the global research community – a vital step toward Komen’s noble goal of ending suffering from breast cancer forever.
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Voices of Impact – Dr. Hyman Muss
Established by Susan G. Komen for the Cure® in 1992, the Brinker Award for Scientific Distinction is a marquee award that honors leading scientists for their significant achievements and contributions in basic and translational science and clinical practice that have advanced the fight to save lives and realize our vision of a world without breast cancer. This year’s awardees are Dr. Hyman Muss, an American clinician-scientist and Prof. Yosef Yarden, an Israeli researcher whose work has led to more personalized treatments for breast cancer. Dr. Muss and Prof. Yarden received their awards at the 2012 San Antonio Breast Cancer Symposium on December 5, 2012.
Dr. Hyman B. Muss, MD, Chapel Hill, NC – Clinician-Scientist
Professor of Medicine and Director, Geriatric Oncology Program, UNC Lineberger Comprehensive Cancer Center; Co-chair, Alliance CALGB Committee on Cancer in the Elderly“Many are surprised to learn that the average age of women diagnosed with breast cancer is 61. It is far more prevalent in 70-year-old women than in 40-year-old women.”
“It is essential that we give these patients the medical treatments that are right for them, as we address the special issues of aging patients.”
My lifelong interest in breast cancer treatment for older women began 30 years ago when I was working as a medical oncologist in breast cancer at Wake Forest University. The chief of medicine was William Hazzard, one of the great gerontologists, and he asked me in the early 1980s to work on a project with one of the medical residents involving metastatic breast cancer in older women.
We found then that the older women with metastatic breast cancer had similar outcomes as younger women, suggesting that older women should not be excluded from clinical trials based on age alone. This was novel for the time. Our findings were published by the Journal of the American Medical Association and the next thing I knew, people from around the country were asking me about older people and breast cancer. I got more interested, I learned more, I devoted myself to this field, and I’ve never looked back.
One of the great ironies of cancer care is that we as a society tend to think of cancer as a disease in younger people. Many are surprised to learn that the average age of women diagnosed with breast cancer is 61. It is far more prevalent in 70-year-old women than in 40-year-old women. Yet, fewer older people are offered the option to participate in clinical trials, and many are not offered the state-of-the-art treatment that may be offered to younger women.
We know that some of these issues are the result of age bias, and so we’ve been working very hard to educate oncologists and the community about cancer treatment in older people. Komen has been a great supporter of the American Society of Clinical Oncology, and through ASCO, we’ve begun education modules about cancer treatment in older patients. It is essential that we give these patients the medical treatments that are right for them, as we address the special issues of aging patients.
As part of this work, we’re also educating Fellows on the basic principles of geriatrics, and trying to educate about the importance of moving older cancer patients into clinical trials so that we can understand and better treat people in this age group. At the same time, we’re working very hard on molecular models of aging, that is, changes that occur as we age that might make us less resilient and able to tolerate treatments.
In all these ways, we’re working to move to a personalized medicine model that ensures the highest and best treatments for the population most vulnerable to cancer: older patients.
Those of us who have worked in geriatric oncology truly love what we do. We have to, because it’s not as popular as other medical specialties, and I truly worry about a shortage of doctors able to care for a growing group of seniors in our country.
I’m honored to be chosen for the Brinker Award for Scientific Distinction, but the truth is, I’ve been very fortunate to do work that I love. In my case, it’s made better by a wonderful family and my 42-year marriage to the love of my life, Loretta, who as a retired nurse has helped establish a patient and family advisory board for cancer patients at the University of North Carolina Cancer Hospital.
It’s a great life, and my thanks to Komen for recognizing the special work of all people working to end cancer, forever.
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2012 San Antonio Breast Cancer Symposium – Clinical Trials
Members of Komen’s Research, Evaluation and Scientific Teams were out in force at the recent San Antonio Breast Cancer Symposium, including Komen’s Scientific Grants Manager Krissa Smith, who reports on a session about the importance of clinical trials.
As the San Antonio Breast Cancer Symposium wrapped up last week, we had the opportunity to hear from the world’s leading clinicians and basic researchers on the progress of their efforts to improve current treatments for breast cancer. This included a review of results of recent clinical trials into newly developed drugs or combinations of already approved therapies – all in an effort to move the needle toward personalized treatment for women and men facing breast cancer.
We were pleased to see so many Komen-funded researchers and members of our scientific team presenting at this major international conference, and especially excited about what we are learning in terms of personalizing breast cancer treatment.
The conference wrapped Friday with a general session on clinical trials targeting HER2, moderated by Komen’s Chief Scientific Advisor, Dr. George Sledge.
One of the great breakthroughs in breast cancer research was the identification of the HER2 receptor found on some breast cancer cells and the later development of the drug trastuzumab that targets HER2, also known as Herceptin. HER2 is now used as a marker that clinicians utilize to classify breast cancer subtypes and, using trastuzumab, to treat specific cancer subtypes.
Researchers have developed a second antibody – called pertuzumab — that combined with trastuzumab is used to target HER2. Komen Scholar Jose Baselga presented the results of the CLEOPATRA trial that evaluated the combined treatment of trastuzumab plus pertuzumab, published in the New England Journal of Medicine. The study concluded that by adding pertuzumab to the treatment, patient survival was significantly improved. Researchers also found that mutations in a gene called PI3KCA indicated a worse prognosis for breast cancer patients in this trial. However, anti-HER2 treatment was beneficial for patients with or without the PI3KCA mutation and the results of this trial indicate that this new treatment combination would be beneficial for HER2+ breast cancer patients.
Other clinical trials presented in this session evaluated the duration of trastuzumab treatment. Komen Scholar Alumnus Aron Goldhirsch was involved in the HERA trial presented later Friday morning that investigated if treating patients for longer than one year with trastuzumab – the current standard – affected patient survival, or if two years would be more effective. The conclusion from this trial is that there is no significant increase in overall survival for patients who received two years of treatment, even after eight years of follow-up, and confirms one year as the standard of care.
Because there may be some cardiac side effects, a second trial (PHARE) evaluated whether trastuzumab could be given for only six months with the same benefits. This trial indicated that patients who received six months of treatment had a similar survival compared to patients treated for a year. While further work needs to be done, these results are encouraging because they indicate that trastuzumab treatment duration could actually be reduced.
These reports were encouraging to us at Komen because they allow doctors and researchers to home in on ways to personalize treatments for women and men with breast cancer – a far cry from the “one size fits all” treatment approach that existed for breast cancer patients when we started our work at Komen in 1982. Our research portfolio over 30 years has grown to more than $750 million – second only to the U.S. government. And our focus now is on results that can be taken from the lab to the bedside, to consumers and patients, in the shortest period of time.
Thanks to all of our supporters who have helped us fund the most respected breast cancer researchers in the world.
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2012 3-Day Series Wrap Up – THANK YOU!
It’s been a few weeks, but the 2012 Susan G. Komen 3-Day™ Series closed with a bang in San Diego, California on November 18, 2012. The millions of steps taken will forever make an impact in the fight to end breast cancer. This year, more than 22,000 women and men joined the fight and raised tens of millions of dollars for Susan G. Komen for the Cure.From the east to west coast and cities in between, thousands of people gathered to walk, support and volunteer for the Komen 3-Day. As any participant will tell you, the 3-Day is a family and community. The people who choose to raise $2,300 and more are dedicated and passionate about giving everyone the lifetime they deserve. Where else could you find a group of people more enthusiastic about sleeping in a sea of pink tents?
Every member of the 3-Day family has an inspiring story to share. Many participate in multiple events, come out to support walkers year after year or volunteer their time to help make the 3-Day run smoothly. Among the 3-Day staples are the Pink Fireman, Peanut Butta the cuddly teddy bear and, of course, our ever handsome 60-Mile Men who bare all to raise money for the cause.For many, participating in the Susan G. Komen 3-Day is more than completing 60 miles; it’s about giving hope to those who’ve been affected by breast cancer. When First Sergeant Laurie Cherry found out her deployment for active duty meant missing her first Arizona 3-Day, she knew she couldn’t walk away from her commitment to either organization. Instead, Laurie decided to continue her training and fundraising overseas and she completed the 60 miles from abroad the same weekend of the Arizona 3-Day.
You don’t even have to walk 60 miles to be embraced by the 3-Day family. Kris and Ken Kaukker, two route safety volunteers lovingly known as the Tutu Brothers were showered with 3-Day love when their bikes went missing at the Washington, D.C. event. Just moments after Kris updated his Facebook page with the news, 3-Day walkers, “walker stalkers” and crew from across the nation sprang into action to help the duo get back on their wheels.The joy, tears, miles and community built in three short days not only makes a powerful impression on our participants, but also makes a lasting impact in the fight against breast cancer. At Susan G. Komen, we’d like to give a sincere and heartfelt thank you to every walker, crew member, volunteer and supporter of this year’s 2012 Susan G. Komen 3-Day Series.
If you want to experience the journey of a lifetime and become part of the Susan G. Komen 3-Day family, visit The3Day.org to get more information or register for the 2013 event series.
