Author Interviews, Breast Cancer, Brigham & Women's - Harvard, Chemotherapy, Nature / 25.08.2016
Breast Cancer Cells Can Switch HER2 On and Off, Requiring Combination Treatment
MedicalResearch.com Interview with:
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Dr. Shyamala Maheswaran[/caption]
Shyamala Maheswaran, PhD
Associate Professor of Surgery
Harvard Medical School
Assistant Molecular Biologist
Center for Cancer Research
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: About 85% hormone receptor positive HER2 negative metastatic breast cancer patients show that cancer cells acquire HER2 expression during disease progression. These HER2 positive cells coexist with HER2 negative cancer cells, and these two populations are able to spontaneously oscillate between these two states; in culture and in cancers established in mice. Both HER2 positive and HER2 negative cells form tumors when injected into mice, but HER2 positive cancer cells form tumors more rapidly than HER2 negative tumors. At a molecular level, several growth factor pathways are activated in HER2 positive cancer cells, while activation of the Notch pathway, an embryonic signaling event, is observed in HER2 negative cells. Thus the HER2 positive and HER2 negative cancer cells exhibit differential sensitive to drugs: the HER2 positive cells, which are more proliferative and non-responsive to HER2-targeting agents, are responsive to chemotherapy drugs whereas the HER2 negative tumor cells are sensitive to Notch inhibitors. A combination of chemotherapeutic drugs and notch inhibitors effectively eliminate tumors formed by a mixture of these two population of cancer cells compared to either drug alone. These findings highlight the importance of tumor heterogeneity in cancer progression and drug responses and suggest that targeting all the different populations within cancers is necessary to effectively manage cancer progression.
Dr. Shyamala Maheswaran[/caption]
Shyamala Maheswaran, PhD
Associate Professor of Surgery
Harvard Medical School
Assistant Molecular Biologist
Center for Cancer Research
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: About 85% hormone receptor positive HER2 negative metastatic breast cancer patients show that cancer cells acquire HER2 expression during disease progression. These HER2 positive cells coexist with HER2 negative cancer cells, and these two populations are able to spontaneously oscillate between these two states; in culture and in cancers established in mice. Both HER2 positive and HER2 negative cells form tumors when injected into mice, but HER2 positive cancer cells form tumors more rapidly than HER2 negative tumors. At a molecular level, several growth factor pathways are activated in HER2 positive cancer cells, while activation of the Notch pathway, an embryonic signaling event, is observed in HER2 negative cells. Thus the HER2 positive and HER2 negative cancer cells exhibit differential sensitive to drugs: the HER2 positive cells, which are more proliferative and non-responsive to HER2-targeting agents, are responsive to chemotherapy drugs whereas the HER2 negative tumor cells are sensitive to Notch inhibitors. A combination of chemotherapeutic drugs and notch inhibitors effectively eliminate tumors formed by a mixture of these two population of cancer cells compared to either drug alone. These findings highlight the importance of tumor heterogeneity in cancer progression and drug responses and suggest that targeting all the different populations within cancers is necessary to effectively manage cancer progression.
Dr. Petkov[/caption]
Valentina Petkov, MD, MPH
Health Scientist/Program Officer
NIH/NCI/DCCPS/Surveillance Research Program
MedicalResearch.com: What is the background for this study?
Dr. Petkov: The number of breast cancer diagnoses is increasing in older patients because of increasing life expectancy and changing population demographics. Despite high incidence, little is known about breast cancer biology and outcomes in patients older than 70, which are often under-represented in clinical trials. The 21-gene Oncotype DX Breast Recurrence Score assay has been used in clinical practice to predict distant recurrence risk and chemotherapy benefit in lymph node negative, hormonal receptor positive (estrogen and/or progesterone receptor positive) invasive breast cancer since 2004. The goal of our study was to evaluate the role of the 21 gene assay in older patients at population level.
We used Surveillance Epidemiology and End Results (SEER) data. We included in the analysis 40,134 patients who were diagnosed with invasive breast cancer between 2004 and 2011, had negative nodes and their tumors were hormonal receptor positive and HER2 negative. Breast Cancer Specific Mortality (BCSM) was assessed at 5 years after diagnosis in patients with low risk (Recurrence Score <18), intermediate risk (Recurrence Score 18-30) and high risk (Recurrence Score >30).
Dr. Sibaji Sarkar[/caption]
Sibaji Sarkar Ph.D
Instructor of medicine
Boston University School of Medicine
Boston
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Sarkar: Although breast and ovarian cancers have different clinical presentations, there are certain molecular events that are conserved between the two types of cancers. For example, mutation in a few genes, such as BRCA1, BRCA2, is an indicator of possible development of both breast and ovarian cancers. ARHI, a pro-apoptotic imprinted gene is epigenetically silenced in both breast and ovarian cancers. A similar pattern was observed in microRNA as well. There are also several genes which are differentially expressed in these two types of cancers but few of these striking resemblances led us to investigate whether they have a common origin. In this paper, we compared genetic and epigenetic events in both breast and ovarian cancers and we hypothesize that they may have similar origin (mechanism of formation of cancer progenitor cells), which should be regulated by epigenetic mechanism.
Dr. Uras[/caption]
Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl
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Dr. Sexl[/caption]
Institute of Pharmacology and Toxicology
University of Veterinary Medicine
Vienna
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Patients suffering from AML have poor prognosis and high mortality rate despite considerable advances in chemotherapy and hematopoietic stem cell transplantations. Up to 30% of patients with AML harbor an activating mutation in the FLT3 receptor tyrosine kinase (FLT3-ITD). Such mutations are associated with a high predisposition to relapse after remission. In a simplified way we can say that these tumor cells depend on FLT3: Is FLT3 blocked, cells die. Hence, FLT3 inhibitors are being developed as targeted therapy for FLT3-mutant AML; however, clinical responses are short-lived and their use is complicated by rapid development of resistance. This emphasizes the need for additional therapeutic targets.
Our study represents a novel therapeutic window to specifically target and kill AML cells with FLT3-ITD mutations. We found that the tumor-promoting enzyme CDK6 but not its close relative CDK4 directly regulates and initiates the production/transcription of FLT3 and thus lead to disease. The FDA-approved kinase inhibitor Palbociclib not only blocks the activity of CDK6 but in turn impairs FLT3 expression: Mutant AML cells die immediately. The treatment does not affect cells without the mutation.
The power of CDK6 inhibition in AML cells goes beyond FLT3: Palbociclib also stops production of the PIM1 kinase and thus overcomes the potential activation of survival pathways counteracting the effects of FLT3 inhibition.
Dr. Kapp[/caption]
Julie M. Kapp, MPH, PhD
Associate Professor
2014 Baldrige Executive Fellow
University of Missouri School of Medicine
Department of Health Management and Informatics
Columbia, MO 65212
MedicalResearch.com: What is the background for this study?
Dr. Kapp: For the past several decades the U.S. has had the highest obesity rate compared to high-income peer countries, and for many years people in the U.S. have had a shorter life expectancy. For female life expectancy at birth, the U.S. ranked second to last. At the same time, the U.S. has the third highest rate of mammography screening among peer countries, and the pink ribbon is one of the most widely recognized symbols in the U.S. While the death rate in females for coronary heart disease is significantly higher than that for breast cancer, at 1 in 7.2 deaths compared to 1 in 30, respectively, women have higher levels of worry for getting breast cancer.
Dr. Maryam Farvid[/caption]
MedicalResearch.com Interview with:
Maryam Farvid, Ph.D.
Visiting Scientist
Department of Global Health and Population
Harvard T.H. Chan School of Public Health
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Farvid: Breast cancer is one of the most frequently diagnosed cancers and is the second leading cause of cancer deaths among women in the United States. While we know many breast cancer risk factors, few of them are easily modified. Further, evidence suggests that exposure to carcinogens and anti-carcinogens in early life may play an important role. According to this study, what women eat as teens or young adults could affect their breast cancer risk in the future. Teenage girls who eat a lot of fruits may have a lower risk of breast cancer later in life. The risk of breast cancer among women who reported the highest amount of 
Jayant S Vaidya MBBS MS DNB FRCS PhD
Professor of Surgery and Oncology,
Scientific Director, Clinical Trials Group,
Division of Surgery and Interventional Science,
University College London
Whittington Health - Clinical Lead for Breast Cancer
Royal Free Hospital
University College London Hospital
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Vaidya: TARGIT-A randomised clinical trial (
Dr. Reina Haque[/caption]
Reina Haque, PhD MPH
Research scientist
Kaiser Permanente Southern California Department of Research & Evaluation
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Haque: The study fills an important knowledge gap about the long-term association of aromatase inhibitors on cardiovascular disease risk in breast cancer survivors.
This was a retrospective cohort study that included a cohort of 13,273 postmenopausal breast cancer survivors who were diagnosed with breast cancer, either estrogen or progesterone receptor positive, from 1991 to 2010. The patients were followed through 2011, or a maximum of 21 years. The study participants were divided into four groups based on the drugs they received: 31.7 percent were treated only with tamoxifen; 28.6 percent only with aromatase inhibitors; 20.2 percent used both; and 19.4 percent did not use any of these drugs. These oral drugs are used to combat breast cancer recurrence, but may have long-term side effects on other organs.
The study determined that the risk of cardiac ischemia (which can lead to a heart attack) and stroke were not elevated in patients who only took aromatase inhibitors compared to those who only took tamoxifen. These results provide reassurance that aromatase inhibitors may not increase risk of the potentially fatal cardiovascular outcomes compared to tamoxifen.
Dr. Stamatia Destounis[/caption]
Stamatia Destounis, MD, FSBI, FACR
Elizabeth Wende Breast Care, LLC,
Clinical Professor of Imaging Sciences
University of Rochester
School of Medicine and Dentistry
Rochester NY 14620
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Destounis: Identification of women who have an increased risk of breast cancer is important, as they are often eligible for additional screening methods, such as breast MRI. One criterion for eligibility for screening breast MRI is >20% lifetime risk of breast cancer, as determined by risk assessment models through genetic counseling.
At my facility, we have incorporated a genetics program. Through the program we are flagging and identifying a large volume of patients who are potentially eligible for additional services. This study was conducted to determine the value of screening MRI in the patient subgroup who have undergone genetic counseling at my facility. In this group we found 50% of patients who were referred for counseling were also recommended to have screening MRI. However, only 21.3% of those recommended actually pursued the exam. Of those patients who did have a screening MRI, 4 were diagnosed with breast cancer, all of which were invasive and node negative. We ultimately had a 10% biopsy rate and 50% cancer detection rate in this subgroup.
Dr. Elizabeth Rafferty[/caption]
Elizabeth A. Rafferty, MD
Department of Radiology,
Massachusetts General Hospital, Boston
Now with L&M Radiology, West Acton,
Massachusetts
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Rafferty: Breast tomosynthesis has been approved for mammographic screening in the United States for just over 5 years, and many single center studies have demonstrated its improved performance for screening outcomes over digital mammography alone. Our previously published multi-center analysis, (JAMA 2014;311(24), the largest study on this topic to date, demonstrated significantly improved cancer detection and reduced recall rates for women undergoing tomosynthesis compared with digital mammography alone. In the current issue of JAMA we evaluate the differential screening performance after implementation of breast tomosynthesis as a function of breast density.
While tomosynthesis continues to be increasingly available, questions remained about which women should be imaged with this technique. In particular, does this technology offer additional benefit for all women, or only for women with dense breasts. The size of the database compiled by the centers participating in this study allowed us to evaluate this important question.
The most critical finding of our study was that the use of tomosynthesis for breast cancer screening significantly improved invasive cancer detection rates while simultaneously significantly reducing recall rates both for women with dense and non-dense breast tissue. Having said that, the magnitude of the benefit was largest for women with heterogeneously dense breast tissue; for this population, tomosynthesis increased the detection of invasive cancers by 50% while simultaneously reducing the recall rate by 14%.
