Ephrat Levy-Lahad, MD

2009-2010 BCRF Projects:

1) The Israeli Breast Cancer Study
Preventive measures in general, and for breast cancer in particular are most effective in the persons at highest risk. The goal is to obtain genetic information to enable scientists to identify individuals at risk before they develop disease, at a time when prevention is most likely to be effective. With the advent of highly effective measures for breast (and ovarian) cancer prevention in carriers, it may be justified to offer BRCA1 and BRCA2 testing to all women in specific groups with common mutations, but first it is important to establish that cancer risk is indeed high in all BRCA1 and BRCA2 carriers, not only carriers who have had a personal and/or family history of breast or ovarian cancer. Dr. Levy-Lahad and her team have proposed to determine this cancer risk in the Ashkenazi population in Israel, by identifying BRCA1 and BRCA2 carriers through healthy males. If the scientists find that breast cancer risk in carriers identified through general screening is similar to current risk estimates from affected women, a general screening program could be warranted and could prevent breast cancer in hundreds of women in the US and Israel each year. If justified on a scientific basis, this program will serve as a model for genetic breast cancer prevention screening in general.

Dr. Levy-Lahad and her team completed their goal of recruiting 8,000 Ashkenazi Jewish men and have identified 175 families with BRCA1/BRCA2 mutations. The study is now in its second phase, in which they are counseling and testing women in these families, most of whom were not aware of their increased risk, and were not undergoing screening or utilizing prevention measures. The researchers' ongoing analyses show that carrier women are at high risk for breast cancer, even in BRCA1/BRCA2 families identified at random in the general population. Approximately half of families with BRCA1/BRCA2 mutations have little cancer history, and would not have been referred for genetic assessment of inherited cancer predisposition. The researchers are finalizing their analyses of the cancer risks, and if the risk estimates remain high, they believe these results will lead to consideration of BRCA1/BRCA2 screening in the general population.

In the coming year, they aim to explore the best ways to provide screening for BRCA1 and BRCA2 testing in all Ashkenazi Jewish women. In their previous study they found that even when BRCA1 and BRCA2 carriers were identified at random, not because they or their relatives had cancer, they still had very high risks of developing breast and ovarian cancer. About half of carriers did not have any family history of cancer, and would not have been picked up, had testing been done only in women with family history. Yet these carriers are just as much at risk and should be receiving appropriate preventive care, which is highly effective. Building on these results, the investigators now want to determine the best ways to provide BRCA1 and BRCA2 testing to all Ashkenazi women, so that screening will reach the maximal number of women in the most efficient manner and will lead to optimal knowledge and satisfaction among women screened. Crucial medical developments can be "lost in translation" if they are not implemented well, and in this study they will compare different implementation schemes. The study is performed in Ashkenazi Jews, because this population has a limited number of common BRCA1 and BRCA2 mutations, which are easy and inexpensive to test. In other populations, BRCA1 and BRCA2 testing is more complex, time consuming and costly. However, recent advances in genetics testing techniques will soon enable large scale, complex testing, so the researchers anticipate that in the near future the results of this study will be applicable to all women of all ancestries.

Mid-Year Progress Report:
Dr. Levy-Lahad reports that her team has completed their goal of recruiting 8,000 Ashkenazi Jewish men and has identified 175 families with BRCA1/BRCA2 mutations. They are completing the study's second phase, in which they are counseling and testing women in these families, most of whom were not aware of their increased risk, and were not undergoing screening or utilizing prevention measures. About 550 relatives of carriers, both women and men, have been tested during this second stage. Ongoing analyses show that carrier women are at high risk for breast cancer, even in BRCA1/BRCA2 families identified at random in the general population. Over half of families with BRCA1/BRCA2 mutations have little cancer history, and would not have been referred for genetic assessment of inherited cancer predisposition. The researchers are finalizing their analyses of the cancer risks, and since these risks appear to be high, they are currently planning a study to determine the best way to offer BRCA1/BRCA2 screening in the general population.

2) Co-Investigators: Mary-Claire King, PhD, University of Washington, Seattle, WA; and Moein Kanaan, PhD, Bethlehem University, Palestinian Authority

Drs. Levy-Lahad, King and Kanaan have created an infrastructure for Cancer Genetics counseling and testing for Arab women in the Palestinian Authority and Israel. Following a training course developed by the investigators and hosted at Shaare Zedek Medical Center (SZMC) in Jerusalem, Palestinian genetic counselors now provide counseling at Augusta Victoria Hospital in East Jerusalem, the major referral hospital for Palestinian cancer patients, ArabCare Hospital in Ramallah and Bethlehem University (BU). Laboratory infrastructure for sequencing and full BRCA1 and BRCA2 analysis has been established at the Hereditary Research Lab in Bethlehem University.

In the Palestinian Authority and Israel combined, they have enrolled over 250 Arab women with breast cancer. More than 20% of these women have family history suggestive of an inherited predisposition to breast cancer, and genetic analysis of BRCA1 and BRCA2 mutations is now underway at both BU and SZMC. In women with personal and family history of breast or ovarian cancer, full analysis of BRCA1 and BRCA2 is performed. Other study participants are tested for mutations previously found in Arab families.

Current results suggest that when specific BRCA1 and BRCA2 mutations occur within families, they are not recurrent or common in the general Arab population. Continued analyses will allow the researchers to identify the spectrum of mutations characteristic of the Arab population. They are planning to extend the study by searching for novel breast cancer genes using novel genomic technologies. Breast cancer genetic services established for the Palestinian population will ultimately increase their understanding of the causes of breast cancer in general and is already enabling early detection and prevention in this population.

Mid-Year Progress Report:
In the Palestinian Authority and Israel combined, the researchers have enrolled over 400 Arab women with breast cancer. More than 20% of these women have family history suggestive of an inherited predisposition to breast cancer, and genetic analysis of BRCA1 and BRCA2 mutations is continuing at both BU and SZMC. The researchers have identified a novel BRCA2 mutation occurring in a number of Palestinian families, probably originating from a common ancestor. Although this mutation is not common the general Palestinian population, it may occur in ~1% of breast cancer patients. They are beginning to search for novel breast cancer genes using advanced genomic technologies. Breast cancer genetic services established for the Palestinian population will ultimately increase our understanding of the causes of breast cancer in general and are already enabling early detection and prevention in this population.

Bio:
Ephrat Levy-Lahad, MD, is Professor of Internal Medicine at Hebrew University and, since 1996, Director of the Medical Genetics Institute at Shaare Zedek Medical Center in Jerusalem. Dr. Levy-Lahad is one of the world's foremost authorities on inherited breast cancer among Jewish women. She directs the Israel Breast Cancer Study (IBCS), the sister project of the New York Breast Cancer Study (NYBCS), which is directed by Mary-Claire King and Joan Marks; both projects are sponsored by The Breast Cancer Research Foundation.

The IBCS asks the question: Should genetic testing of BRCA1 and BRCA2 be offered, on a voluntary basis and without cost, to all Ashkenazi Jewish women in Israel? Does clinical evidence support this option? In addition to her work on inherited breast cancer among Jewish women, Dr. Levy-Lahad initiated, in partnership with Dr. Moien Kanaan of Bethlehem University and fully supported by BCRF, a highly successful effort to bring cancer genetics services to underserved Arab Israeli and Palestinian women.

Dr. Levy-Lahad received her MD degree from the Hebrew University-Hadassah Medical School in Jerusalem, Israel. She then completed a residency in Internal Medicine at Shaare Zedek Medical Center in Jerusalem, and a three-year fellowship in Medical Genetics at the University of Washington in Seattle. Since 1996, when she returned to Israel, she has been Director of the Medical Genetics Institute and senior physician in the Department of Medicine at Shaare Zedek Medical Center. Dr. Levy-Lahad holds a faculty appointment as Associate Professor in Medicine and Genetics at the Hebrew University-Hadassah Medical School in Jerusalem.

Dr. Levy-Lahad also serves on the International Bioethics Committee of UNESCO and chaired that committee's development of guidelines for stem cell research. She was recently named one of "Israel's Best Doctors."