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This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.
What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.
In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.
Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.
“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).
Israeli study
The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.
To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.
They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)
The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”
So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:
“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”
But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.
“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.
“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.
‘A fresh look’
Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.
“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.
He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.
But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.
“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”
Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).
“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”
Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.
“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.
Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.
“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.
‘A public health nightmare’
Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.
“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”
He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.
In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.
For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”
Dr. King declared no conflicts of interest relevant to the research.
This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.
What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.
In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.
Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.
“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).
Israeli study
The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.
To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.
They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)
The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”
So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:
“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”
But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.
“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.
“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.
‘A fresh look’
Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.
“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.
He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.
But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.
“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”
Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).
“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”
Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.
“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.
Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.
“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.
‘A public health nightmare’
Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.
“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”
He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.
In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.
For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”
Dr. King declared no conflicts of interest relevant to the research.
This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.
What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.
In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.
Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.
“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).
Israeli study
The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.
To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.
They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)
The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”
So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:
“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”
But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.
“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.
“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.
‘A fresh look’
Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.
“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.
He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.
But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.
“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”
Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).
“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”
Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.
“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.
Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.
“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.
‘A public health nightmare’
Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.
“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”
He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.
In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.
For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”
Dr. King declared no conflicts of interest relevant to the research.
