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BCRF Grantee Since

2001

Donor Recognition

The Roz and Les Goldstein Award

Ephrat Levy-Lahad, MD

Director, Medical Genetics Institute
Shaare Zedek Medical Center
Jerusalem, Israel
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Current Research

Project 1: Co-Investigators: Mary-Claire King, PhD, University of Washington, Seattle, WA and Moien Kanaan, PhD, Bethlehem University, Palestinian Authority

The general aim of this project is to determine the genetic basis of inherited predisposition to breast cancer in the Palestinian Arab population, within the context of establishing the necessary infrastructure to provide cancer genetics services. While the incidence of breast cancer in Arab women is approximately one third that of Israeli Jews, it occurs more often in younger women, has poorer prognostic characteristics, and often clusters within extended families. This suggests that an inherited component is likely in many cases. In addition to the clinical implications of this project to these underserved women and their families, because this population has not been studied extensively, the researchers have already identified novel mutations in known genes, and expect to determine new inherited cancer genes which will be relevant to women of all ancestries world-wide.

This international research team originally aimed to assess the mutational spectrum, prevalence, and risk associated with BRCA1 and BRCA2 mutations among Palestinian and Arab-Israeli women. With the emergence of new sequencing technologies, they have expanded this goal to a global genomic analysis of the genetics of breast cancer in this population, including BRCA1 and BRCA2, as well as assessing the contribution of additional genes as they become known and aiming to identify novel breast cancer genes.

The researchers have enrolled over 1,700 Ashkenazi Jewish individuals (80% women) in a screening program for the three BRCA1 and BRCA2 mutations common in this population. They identified 32 carriers of BRCA1 or BRCA2 mutations. Forty percent of these carriers did not have significant family history, and would not have been identified without a universal screening program. Only one-third of the carriers' first degree relatives have been tested so far. Although and another 17 carriers were identified among relatives of carriers, this low rate of relatives' referral underscores the fact that general screening may circumvent familial barriers to sharing genetic information among relatives.

About 60% of people offered testing decided to participate. Women were more interested in being tested than men, and younger women (<70 yrs) more than older women. Having children or daughters did not affect participation in screening, suggesting that women have genetic testing to promote their own health. To facilitate large-scale screening, participants were only given written material before being tested, rather than receiving full genetic counseling with a genetic counselor. At one week post testing and 6 months after receiving test results, over 90% of people were highly satisfied with having participated. Knowledge score was 7/10 at both time points, and only 1-2% reported stress related to testing. These results suggest that universal, large scale genetic screening to prevent breast and ovarian cancer is feasible without significantly compromising satisfaction, knowledge and test-related stress. However, the investigators will also compare this directly to traditional genetic counseling.

Project 2: Dr. Levy-Lahad’s general aim is to conduct a trial of population screening for BRCA1/ BRCA2 mutations. Ashkenazi Jews in various health care settings are offered BRCA1/BRCA2 testing in order to identify carrier women at risk for breast and ovarian cancer. Carriers are offered appropriate surveillance and prevention measures and asked to refer their at-risk relatives. The study aims to identify the optimal screening strategy by comparing various screening options, e.g. by different health professionals, in different health care settings and by mode of recruiting (persons passively recruited by responding to information posters and brochures, or actively recruited by a health professional). The Shaare Zedek team has added another aim, which is to compare minimal pre-test information with traditional genetic couseling.

To date, Dr. Levy-Lahad's team has enrolled over 1,700 Ashkenazi Jewish individuals (80% of whom are women) in a screening program for the three BRCA1 and BRCA2 mutations common in this population. They identified 32 carriers of BRCA1 or BRCA2 mutations. Forty percent of these carriers did not have significant family history and would not have been identified without a universal screening program. Only one third of the carriers' first degree relatives have been tested so far. Although and another 17 carriers were identified amongrealtives of carriers, this low rate of relatives' referral underscores the fact that general screening may circumvent familial barriers to sharing genetic information among relatives. About 60% of people offered testing decided to participate. Women were more interested in being tested than men, and younger women (<70 yrs) more than older women. Having children or daughters did not affect participation in screening, suggesting that women have genetic testing to promote their own health. To facilitate large-scale screening, participants were only given written material before being tested, rather than receiving full genetic counseling with a genetic counselor. At one week post testing and six months after receiving test results, over 90% of people were highly satisfied with having participated. Knowledge score was 7/10 at both time points, and only 1-2% reported stress related to testing. These results suggest that universal, large scale genetic screening to prevent breast and ovarian cancer is feasible without significantly compromising satisfaction, knowledge and test-related stress. However, Dr. Levy-Lahad's team will also compare this directly to traditional genetic counseling.

Mid-Year Summary

Project 1: In the Middle East, genetic analysis and medical follow-up services for breast and ovarian cancer risk among Jewish women are among the best in the world. But comparable services were not available women of other ancestries in the region. In 2007, BCRF sponsored the creation of the Middle East Breast Cancer Study (MEBCS), the goal of which is to provide genetic analysis and genetic counseling follow-up services, of the same excellent standard, to women of other ancestries in the region, and has sponsored the MEBCS continuously ever since. MEBCS is directed jointly by Ephrat Levy-Lahad, MD, of Shaare Zedek Hospital and Hebrew University, Jerusalem, Israel; Moien Kanaan, PhD, of Bethlehem University, Bethlehem, Palestinian Authority; and Mary-Claire King, PhD, of the University of Washington, Seattle, USA. The MEBCS is a sister project of the New York Breast Cancer Study (NYBCS), directed by Dr. King, and the Israel Breast Cancer Study (IBCS), directed by Dr. Levy-Lahad, both of which are also sponsored by BCRF.

As of this year, the MEBCS has enrolled 799 breast cancer patients of Palestinian and Arab-Israeli origins. Thus far the researchers have carried out genomic analysis for 268 of these patients: 147 patients with family history of breast or ovarian cancer, in addition to their own breast cancer, and 121 patients diagnosed with invasive breast cancer at or before age 40. Genomic analysis of DNA of these patients, as for NYBCS and IBCS patients, comprises sequencing BRCA1 and BRCA2 and more than 30 other known and candidate breast cancer genes. Sequencing is performed using BROCA, the multi-gene targeting and next-generation sequencing approach developed, validated, published, and operationalized in the clinical setting by Dr. King’s lab.

Of the familial and young-onset breast cancer patients, 12% had inherited a damaging mutation in BRCA1, BRCA2, or one of the other breast cancer genes. Eleven different genes carried mutations in patients from this population. Among breast cancer patients with family history of breast or ovarian cancer, 16% carried a damaging mutation in a breast cancer gene; among young-onset breast cancer patients, 7% carried such a mutation. About half of the mutations were in BRCA1 or BRCA2 and about half of the mutations were in other genes involved in repair of damaged DNA. The researchers are now screening these mutations in the total cohort of >800 patients in order to determine the frequency of each. They are also studying how each mutation affects the function of its gene. In the next months, they will also extend BROCA analysis to 70 additional patients from the MEBCS, 44 with familial breast cancer and 26 with young-onset breast cancer.

A striking observation of the study this year is how many patients from very severely affected MEBCS families have no clearly damaging mutation in any of the known breast cancer genes. The researchers speculate that breast cancer in these families is due either to mutations in as-yet-unidentified regulatory regions of known breast cancer genes that are far from the genes themselves (i.e. a long distance genomic trouble-maker effect), or to an as-yet-unknown gene. The observation fits ytheir hypothesis that breast cancer in the Palestinian population has many different genetic causes, and therefore that studying this population will enable discovery of new genes underlying breast cancer in women from all parts of the world

 

Project 2: This study is offering carrier screening for BRCA1 and BRCA2 mutations to Ashkenazi Jewish individuals who have not been previously diagnosed with cancer. Testing is offered to all comers, not based on family history of cancer. Over 40% of carriers identified did not have significant family history, and would not have been identified without a universal screening program. Over time, carrier identified refer their relatives – compared to only one- third of the carriers' first degree relatives who were tested in the previous update, currently approximately half of female relatives have had testing . This low rate of relatives' referral underscores the fact that general screening may circumvent familial barriers to sharing genetic information among relatives.

To facilitate large-scale screening, participants were only given written material before being tested, rather than receiving full genetic counseling with a genetic counselor. At 1-week post testing and 6 months after receiving test results, over 90% of people were highly satisfied with having participated. Knowledge score was 7/10 at both time points, and only 1-2% reported stress related to testing. The research team has now started comparing this to traditional pre-test genetic counseling. Compared to the screening program, people who had pretest counseling reported even greater satisfaction (96% vs. 91%)and had greater knowledge scores (8/10 vs. 7/10) but test-related stress was also more frequent in this group, albeit uncommon (4%). This suggests that even though pre-test counseling is superior in some respects, the absolute advantage over a screening program is small, so, universal, large scale genetic screening to prevent breast and ovarian cancer is feasible without significantly compromising satisfaction, knowledge and test-related stress.

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 medical 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.

In April 2012, Dr. Levy-Lahad was appointed co-chair of Israel's National Bioethics Council. She also currently 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."

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