'96 Genetic Eng Breast Cancer

Genetic Screening for Breast Cancer

Transcript of session held at the New York Mariott Marquis on Sunday, April 28, 1996, the session was part of the 7th International Conference on Judaism and Contemporary Medicine.
The session is moderated and introduced by Nobel Laureate Joshua Lederberg, Ph.D., and features presentations by Harvey Stern, M.D., and Rabbi Moshe Tendler, Ph.D.

DR. JOSHUA LEDERBERG (seen at right in a photograph taken at about the time he was awarded the 1958 Nobel Award for Physiology or Medicine jointly with Dr. George Beadle and Dr. Edward Tatum):

Our first speaker is Dr. Harvey Stern. I have some affinity and background with both of our speakers today. Like myself, Dr. Stern did his undergraduate work at Columbia College. He went on to do a Ph.D. at Columbia and then an M.D. at the Albert Einstein College of Medicine. He did a pediatrics residency at Childrens in Washington, D.C. And he is now at the Genetics and In Vitro Fertilization Institute in Fairfax, Virgina, where he's had much practical experience in using cutting edge reproductive technologies to relieve the distress of many desperate couples.

DR. HARVEY STERN: Thank you, Dr. Lederberg. It's indeed a pleasure to be here with you and I wish to thank the organizers for inviting me this morning to come talk about one of the more controversial issues concerning the application of genetic technology in the future.

This is certainly an exciting time to be in the field of medical genetics. As one can see from "Businessweek" and a number of other publications that you'll see, the capabilities and power of molecular biology has made an impact on the practice of medicine in a fashion which we have really not seen for many, many years. And I think it will continue to impact on how we approach our patients for probably at least the next 200 or 300 years, I hope.

Now with any new technology comes, of course, questions regarding the appropriate and ethical use of this technology. And certainly the power of molecular biology to help us understand not only who is affected with a particular disorder, but on a basic level to understand what the pathophysiology, what the basic problem is in a particular disease, has been greatly aided by our ability to look at genes and understand their function. However, with that ability comes the so-called double-edged sword where we now have the capability to understand things about ourselves and our propensity for disease, which raises a number of ethical and moral questions - for example, do we wish to know about such items? How is this information used in our society in a way that will benefit patients and not just insurance companies. So, again, with any development there is tremendous, tremendous controversy about how this will be used for the practice of medicine.

Now, what I'm going to discuss today is a new paradigm I think in the use of genetic testing. Most of us are familiar with the use of genetic screening for Tay-Sachs disease or Canavan disease or other disorders. And there, one does a test and gets an answer - yes, you are a carrier; yes, the child is affected; no, you're not a carrier. It's a very simple, straightforward answer.

The new paradigm that we'll be using is something called predictive testing. And predictive testing determines if a patient is at increased risk for a particular disease. It does not imply that that person either has the disease at this time or will ever develop it. And because of this, it is somewhat more difficult for patients and physicians and health care workers to understand the results of testing done for predictive values.

This is not a particularly new concept in medicine. And I think cholesterol testing is an example of a predictive test. An individual with an elevated blood level of cholesterol isn't necessarily going to have a heart attack or a stroke. They may get hit by a bus. They may develop cancer. However, it implies that they are at increased risk for this complication.

And the whole value of doing predictive testing is that some type of positive intervention can be done to modify that risk. And in the case of cholesterol, as we well know, modification of diet, exercise and so on can reduce that risk that is predicted by the test.

Now, we are going to be using this, though, in a different paradigm and, in fact, could be focused just a little bit towards other disorders. And one of the most exciting advancements is now the ability through molecular biology to approach the factors that are involved in the development of cancer and what predisposes us to cancer, particularly the most controversial recently of these areas involves breast cancer.

Now, just to put this in perspective, breast cancer is the most common malignancy among women. If one looks at that data from the American Cancer Society for 1996, it's estimated that there will be approximately 180,000 new cases of breast cancer diagnosed in this year. And there will be nearly 44,000 deaths from breast cancer. Overall, in the general population for all women, the risk of developing breast cancer in their lifetime is approximately 12 percent. So this is a very common disease also which separates it from some of the other genetic tests that are done for certainly much more rare conditions.

Now interest in the familiar or the genetic nature of breast cancer came from studying the number of families such as those shown on this slide, where there seem to be a very high number of individuals, of women in these families who had breast or ovarian cancer, and in whom this trait appeared to segregate in a typical Mendelian genetic fashion. And in here, this appears to segregate as a dominant gene with a decreased penetrance or decreased expression of the gene in males. And very quickly, people started to look at the effect of being part of one of these breast cancer families, as they've been called. And it was quickly shown that the risk is two- to three-fold higher for a woman who has an affected first degree relative with breast cancer for that person to develop breast cancer herself. And if you increase the number of affected relatives, the risk was even higher.

And other factors that seemed to be prominent in these cancer families was that the presentation, the diagnosis, of breast cancer was made at an earlier age - as early as 30's or even high 20's, where the typical case of breast cancer is that of an older woman in the 60's, say. And also, the presentation appeared to be bilaterally more frequently. In other words, both breasts were affected at the time of diagnosis. So this was something that strongly suggested a genetic basis for the ideology of the cancer in these families.

And overall, it's been shown that about 5 to 10 percent - it's still a small number - but 5 to 10 percent of breast cancer in the United States and probably Europe is caused by these genetic factors or inherited factors.

Now, shortly thereafter, studying these families, a number of researchers showed that the tendency towards development of breast cancer was linked to a gene on chromosome 17. And in about half the families this was shown to be the case. The gene was rapidly isolated by tremendous effort by a number of groups. And the gene was named BRCA-1, and that's an acronym for breast cancer - BRCA. So this is the first gene that was isolated for breast cancer. And it was shown that in women who carried alterations in this gene that the risk of developing breast cancer, the lifetime risk, increased to approximately 85 percent versus the 12 percent that I had just mentioned.

In addition, it was also shown that in these families the risk of ovarian cancer,which is a very deadly and difficult to detect cancer, which normally occurs in less than a percent of the general population, was increased phenomenally to approximately 50 percent in these individuals.

I want to show you this data in graphical form because I think I'd like you to keep in mind the tremendous significance of this gene. And here on this screen in this first set of slides you've seen the cumulative risk of developing breast cancer in individuals with a mutation in the BRCA gene as compared to individuals in the general population, who are shown in white. And as you can see, there is a tremendous, tremendous impact on a woman's health in developing breast cancer.

And a similar story is seen in ovarian cancer, where the risk at- in the 60's increases from approximately .6 percent to up to about 44 percent. So that's a 50- to 60-fold increase. Please keep this in mind. This is a tremendous, tremendous risk for these patients. In addition to women, men, although they don't develop breast and obviously ovarian cancer, there does seem to be an increased risk for development of prostate and colon cancer in men who carry these mutations. So this does affect both sexes, although somewhat differently.

Now, to this date there have been four genes that have been associated with an inherited form of breast cancer, and these are shown in a slide. Today I'm just going to speak of the first gene there, the BRCA 1 gene, because it's the best understood and it's now the area where the most controversy has developed regarding testing for this mutation.

The BRCA gene belongs to a group of proteins called tumor suppressor genes. This is one of a number of ways that the abnormal uncontrolled growth of cells which we call cancer develops. And for those of you who may not have medical background and may not be used to this paradigm, I've brought along a cartoon. It turns out that we each inherit two copies of all our genes - one from our mother and one from our father. And in the same fashion, we both inherit tumor suppressor genes whose job it is to inhibit the growth, the uncontrolled growth, of cells. And normally, these two genes are sufficient to prevent the development of a tumor. Here it says colon cancer, but the same is true for any of the tumor suppressor genes. However, if a person inherits from their parents an abnormal gene - one of the genes is abnormal - then, as you can see, the second gene, although they may be able to stave off the onslaught of cancer for a while, has an increased risk of developing this just because the numbers have been cut in half.

And naturally, old age and effects of our environment - pollution, diet and so on - can affect, also affect the functioning of these genes. And probably these factors work together with the genetic predisposition in the development of cancer in these individuals. So basically, the loss of function of one of these tumor suppressor genes allows a second mutation to occur with a higher incidence in terms of development of a malignancy, as compared to an individual who has two normally functioning genes.

The BRCA gene as shown here is a rather large gene. And the reason I've shown this slide is to call your attention to the fact that there appear to be now numerous places in this gene where mutations can lead to an increased risk of breast cancer. And these are shown by the dots underneath the bar in the figure.

Now, the particular mutation that has caught everyone's attention and started the controversy is shown on the lefthand side. And this is a change, a genetic change called 185 Deletion AG, and basically is just a two-base pair deletion two of the building blocks of DNA are removed from this gene. And it seems to produce a total deficiency in the function of the BRCA tumor suppressor function of this gene.

Now very quickly, someone noticed an important characteristic about women who had this 185 Deletion A gene mutation - I'll just call it "185" for now - in that all the women who had this appeared to be Ashkenazi Jewish. And very quickly, studies went forward to look at this question because as opposed to all the 100 or 200 other mutations that have been identified in this gene, none were shown to cluster in a particular type of ethnic group that at least has been discovered so far. So this appeared to be an area where testing or at least looking into the prospect of testing in Jewish women appeared to make some sense.

The 185 mutation was then examined in the general population. And basically the way this was done, that laboratories who had maintained samples that were submitted for Tay-Sachs testing, so there was a captive population of Jewish DNA sitting around. And people went and looked for the incidence of this genetic alteration and found, really, I think to everyone's surprise, that 1 percent of the population carries this mutation. That is a phenomenal number for a cancer-producing gene.

And, in fact, if you look at the incidents of breast cancer in Jewish women below the age of 50, probably between 16 and 25 percent is estimated to be due to this genetic alteration. And probably as high as 50 percent of ovarian cancer in Jewish women below age 50 is also a result of this gene.

And the figures below there show the cumulative incidence - what I call the penetrants of the 185 mutation in terms of the risk of developing cancer by the various ages shown on the slide. And as you can see, this is a very tremendous increased risk compared to the general population statistics.

Now, why does this mutation occur in the Jewish population? Well, it was looked at and it was shown as other mutations to be produced by what is called the Founder Effect. And presumably, hundreds of years ago, or even probably unknown, an individual- this mutation arose on an individual's chromosome and was passed around intact to members of a northern European Jewish community - because northern and eastern European - because of the close association of that population at the time and the lack of intermarriage. So this appears to be a gene that has been passed down through the Jewish population and has stated a high percentage rate in that group.

Now, one thing you may have noticed is that the implications of carrying this mutation in individuals were mostly elucidated in those families where breast cancer was already present. And people have raised the question as to what is the risk in the rest of this- in the rest of the population? Obviously is the entire 1 percent of Jewish women who carry this mutation. Are they at high risk for the development of breast cancer? And that we don't know.

Are there other modifying genes that may work in consort with the BRCA 1 mutation to increase the risk of breast cancer. And what is the chance that an individual in a family without other members with breast cancer will develop that disease in the future? And these are questions that are the subject of intensive study right now. All the answers are not quite in.

But when faced with the issue of whether to offer this testing to Jewish women, the clinicians and scientists at the Genetics and IVF Institute really evaluated the current information that we had, keeping in mind that this is a field in a state of flux. New Information is developed every day that will help us. But over the last few months, we really felt that there were several issues that had to be addressed. Number one, what was the significance of this mutation, which is the area that I've just discussed. Does the mutation have the same effect in families where there is breast caner as in families where breast cancer or ovarian cancer does not already occur? Do patients and physicians understand the interpretation of a positive and negative test? And this is a critical issue of education. Just as I gave you the example with cholesterol, a woman who carries the mutation may not develop breast cancer; her risk, though, is increased. And an individual who does not carry the mutation still may develop breast cancer, but her risk may be decreased compared to other Jewish women.

So, there's a lot of interpretation that must go on with this testing, as opposed to the "Yes, you're a carrier; No, you're not a carrier" that we've been used to in Tay Sachs paradigm.

And I think another issue that's very important to me is that if one is to offer testing, are the support services in place for further patient evaluation and treatment?

Well, one issue I've heard about this is that there are no options for women who have this mutation, so why should we do the testing? And I think that's kind of a silly argument. Obviously there are options. They may not be totally effective, but there are things that women can do. Lifestyle modification through diet, decreased intake of fats, smoking, exercise, decreased obesity and early childbearing clearly affect the incidents of breast cancer. Women can have increased modalities for surveillance for breast cancer; increased frequencies of mammography. And in those women in whom mammography may not be ideal, there are new modalities that are coming out that may be helpful, such as ultrasound or MRI mammography, which appears to be very promising, or the use of various cancer markers such as CA-125 for ovarian cancer.

All of these are not perfect. There is no foolproof way to evaluate this. However, I would agree that there are options now. And, of course, the most aggressive approach which has been taken by some women who have lived with cancer in their families and seen their mothers and sisters and aunts and cousin all come down with breast cancer, is a radical approach - that of prophylactic removal of the breasts and/or ovaries, which can significantly reduce the incidence of disease in these individuals.

What tactic any individual person will take really, I think, is a function of their own personality, their own input into this, plus I think their family background. In my experience, the women who have been the most aggressive have had multiple individuals in their family affected and have seen the ravages of this disease and the effects of chemo and radiation therapy on these loved ones.

Now, in answering the question as to whether this is pathological, I think if one looks at the basic biology of this, I think there are very few people who would question that this mutation is going to produce an increased incidence of cancer in these individuals. If one looks, the effect of the 185 mutation is to essentially truncate or cut off the production of the BRCA protein at a very early stage so that it is non-functional. And this method here which is shown, is called the protein truncation assay, is a method that can be used to detect this alteration. And you can see on the righthand picture of the slide there that there is a two- there are two proteins - one in green, which is the shortened one, and the normal size protein, which is present in normal individuals.

So from a biological standpoint in my mind and the minds of the other scientists at Genetics and IVF, there was very good evidence that this is not going to be a benign change. This is going to be a pathological mutation. The function of that tumor suppressor gene was destroyed.

Okay. In terms of how the testing would be applied, in terms of understand and education, obviously I've listed here four circumstances in which this mutation- testing for this mutation could be applied. In families where the mutation has already been identified - and I think most people would agree that in this situation tremendous information is generated by doing the testing. One can tell which women are at risk and eliminate those that are not at risk in these families.

Also in examples number two and three there, were there are individuals with breast cancer in the family, multiple members or even a single member, these people are at increased risk for carrying the 185 mutation. And then they would move up to the first category. So I think for these two groups, too, there is definite benefit in the testing, obviously the interpretation of a result in these families could be somewhat different, but there definitely is benefit.

The most controversial area is the fourth one, where just a woman who is concerned about her own health risk has the test. What does it mean? Well, harm could be done if the woman walks away thinking, "Well, I'm not at risk." Because she is. There are many ways to develop breast cancer. This may reduce her risk slightly, but she is still at risk. And again, in a positive result, she's not necessarily going to die or develop breast cancer, but it gives her, empowers her to take charge of her own life, of her own health care and to develop a strategy with her physician which is best for her in terms of how to monitor the potential progress of this disease.

In my mind now, it is not a question anymore of whether the testing should be done. I think enough people agree now that in circumstances this testing shall and will be done. To my mind, the emphasis now should be placed on how it's done; is it done correctly; is it done with the right people involved on a multi-disciplinary team, like one shown here, where all aspects of the patient's care can be developed, such as a specialist in imaging, a specialist in plastic surgical repair - a breast surgeon, an oncologist. And not to forget a psychiatrist or psychologist or social worker because the implications in the psychological sense are tremendous for these women. The women who are affected, obviously depression is a tremendous problem. For survivors whose sisters or mothers were affected but they themselves don't carry the gene, survivor guilt - "Why me? Why did I survive and my sister or mother didn't?" These are all issues that this type of testing is going to bring up. And these things will need to be addressed in any comprehensive center of excellence.

At Genetics and IVF, I've set up all these parameters so that I think right now the counseling and the other follow-up and evaluation components of this testing are in place. And my hope is that other centers will follow this.

Now, an issue that I think is even more fundamental in this situation is that if a woman and her doctor want to obtain this information regarding her own health risk and the patient understands the risks of the tests, the limitations, the interpretations, is it not her right to have this medical information? There has been a call to ban this type of testing, saying it's going to cause more harm than good, that it's not useful and that it should be regulated by the federal government - something that gives me the chills, personally.

Again, I think the patient response to this from breast cancer families or women with breast cancer have been tremendous and pretty much totally supportive. And I think if you read this section here from an editorial from "The New York Times," I think it expresses the sentiment of most women. "Basically, if I didn't want to give- if I didn't want to know the results of my test, I would not have given my blood. Who are they to tell me that the results will do me more harm than good?"

This is a woman who wants to take charge of her life. She understands this. For people who don't want the testing, that is their option, that is their privilege. However, the issue is whether a total ban on this testing is either rational - because it can save lives. Okay? A hundred and eighty-thousand cases of breast cancer a year. If 10 percent of those or 5 percent, 9,000, are due to this familial gene, how many women's lives could have been impacted in a positive way by doing this test? How many lives could be saved? And knowing that in mind, how long can we wait to give this testing, make it available to the public, to Jewish women right now? It is a good test. It provides them information.

As this picture says, the future is now. We are entering into a new area of our ability to use genetics to improve our health care. And I think although we should, as Tony Holtzman says, "Proceed with caution," I think the risk is that if we proceed too cautiously and wait, as some people have suggested, five-10 more years until all the information about this BRCA mutation is really known by prospective epidemiologic studies, are we doing a service to our patients? Are we doing a service to women? In my mind, and as someone who has dealt with genetic disease in the Jewish population for 10 years, I think this is a silly argument. I think that women are smart enough to understand that we don't know everything; that the test is not perfect yet; that there may be better information in two years. But for those people who wish to have this information now, I think it is our moral obligation to supply this information to them in a setting where they can receive proper medical care, proper counseling and proper follow-up.

DR. LEDERBERG: Thank you very much, Dr. Stern. We'll reserve the questions until the speaker has concluded and we'll do them together.

We'll hear now from Rabbi Tendler. Dr. Tendler has a Ph.D. from Columbia and is on the faculty of Yeshiva University and its affiliate, the Rabbi El Kanan Seminary - and I'll add my personal note - where my father attended 75 years ago. He has written extensively on biomedical ethics. Rabbi Tendler....

DR. MOSHE TENDLER: I think the speaker you just heard just about covered the entire field, presenting the biological, biomedical information and drawing your attention to some of the ethical issues involved. I'd like to broaden both a little bit, especially from the vantage point of biblical ethics from the Judeo-Biblical tradition.

I may just make a side comment before I begin. The statistics on breast cancer in females should be, I think, matched up against the incidence of lung cancer in females who were kind enough to run an experiment for us in the last 25 years to prove that smoking causes lung cancer. For last year, more women died of lung cancer than of breast cancer. That's a special mitzvah to call attention to the people here to a "halayek" - a ritual religious obligation to begin to treat smoking the same as eating at McDonald's. In halayek, there is no distinction between the two.

The BRCA 1 mutation didn't allow for any screening discussion because there are over 60 mutations of this gene. And any testing program must focus on a specific mutation in order to find it. It became feasible only when it was discovered that Ashkenazi women, one of these mutations is available for screening because of its high incidence. As mentioned, 1 percent of Ashkanazi women have this particular mutation, which means approximately 5.5 million women worldwide and, half of them living in the United States of America, can be screened for this gene. The question is should you and what are the pitfalls?

In Washington, D.C., now, there is a testing program going on; a pilot program. They felt the Washington, D.C. community is a community that can be reached - high in educational level. The Jewish community is relatively concentrated in a small area. And they are now running that pilot screening program. I think it began only a month or two ago and I'm sure that the results of that program will determine whether screening is provided for the entire United States.

I'd like to lay a psychological foundation for this discussion and partly for the discussion that I will be having after this on alternative medicine. If I can have the first slide.

Let's call your attention to the problem. You can't see the text. I didn't want to present the text to you, just the headline. "Science" - January '96 - I think it was January 10th, 1996. We got Motsalis [sp?]. That's a second cancer susceptibility gene that's been found which now complicates the picture even further insofar as looking for certitude. For that's why anyone would go into a testing program. I would like to know if, indeed, this danger awaits me; maybe I can do something about it. But it gets more and more complicated. We find another susceptibility gene and all we can say is, well, we'll screen you for this one, but I can't tell you about the second one. And the second one is also a highly significant cause of genetic cancer, of breast cancer. It is not involved in ovarian cancer, only the BRCA 1 also has the high incidence of ovarian cancer.

The Yeshiva just now, as the lecturing was presenting, thought it wise to put this as the first layer of cement in a foundation that allows for no modification. Torah in science shares certain axioms. The first is causality. There is cause in this world. Things just don't happen. And second, there's rationality, which means that the human mind can understand this causality. For to have causality and them claim, "I'm sorry, but I don't understand it," then you're back into the Dark Ages of superstition. Then you may just as well dance around a cauldron and throw in frog skins in order to cure disease.

But maybe the most important point is that causality isn't only in the broad strokes of nature. For that, man understood from time immoral. He knew about the changing seasons. He knew about the phases of the moon. We knew that things happen, repeat themselves over and over again. But then when it came to you, to your health, to the microcosms, their rationality failed. And to this day, that rationality has not succeeded in penetrating, as we'll see later in the next session, the great respect that the laity has for various kinds of alternative medicine despite the lack of rationality, especially disturbing in this so-called scientific age.

We come from a ethical system that claims unto itself scientific validity. If science is a study of knowledge that can be reproduced, knowledge that can be replicated or refuted by experimentation, then our system of ethics has been around for 3,500 years in every form of society, in every part of the world and not found to be wanting.

Information that comes in about a BRCA 1 or 2 gene, the question of whether you should screen or not is a question that also must be answered by the Rabbi. What are the ethical implications for the observant Jew? Prayer, making peace with God - that's a daily responsibility of man. When you're sick, you go to a doctor. Faith healing has been rejected by God, by telling you "Thank you very much for your faith, but I set up a world by natural law and I expect you to respect my natural law as much as you respect the articles of your faith. For the natural law is also the will of God." And consequently, the duty to make use of the best medical information we have, the responsibility to seek the finest physician, the responsibility to e aware of what's happening in the field is no less a mitzvah than the responsibility to put on "fillen [sp?],'' observe the sabbath, eat Kosher, etc. That puts a special burden on the observant Jew. Or to put it differently, an observant Jew must be observant of what's happening in the world.

This information about the gene for cancer, be it breast or liver or Alzheimer's, all puts a religious burden on us. We do not share that responsibility with other faith communities. Second, is the obligation to others, as well as to ourselves, where we say a personal obligation is first to oneself and then to others. This information, if indeed the best medical knowledge says that we should screen our women for these two genes - the 1 and the 2 BRCA - then it becomes the responsibility of the Jewish community to do so. Then this test program that's going on in Washington belongs in Crown Heights and in Munsey and in Boro Park because of the high concentration of Jewish women there. And it becomes the financial obligation of the Jewish community to fund it to make sure that it goes on.

Because the third verse, the one that you're all familiar with - "Lo sammo lo dam briaha [sp?] - "They should not stand idly by while your fellow man is wallowing in his blood, literally" - that puts a financial obligation. You're not a doctor, you can't help. You're not a scientist, you don't understand much. But you can take money out of your pocket and hire a doctor and hire a scientist. And that's your obligation to do so. That also is the ethical basis of universal health care - why it's the duty of a Jew to make sure that health care is available to everybody.

Here, too, I just need the headline. The public understanding of science, I find that as a long-term teacher one of the most difficult areas in public health. You can make something available. You can make sure the papers carry the information. The ability to penetrate a genetic problem or penetrance is also an educational problem - how do you penetrate the mind of a public so that they understand what is their obligation, what they are supposed to do? That I believe will become as science masters nature more and more, as we peel off the veils of nature, we are not making the same progress in having the public understand the consequence of scientific research even when it's already in the applied stage. And this I cite also as an obligation of a Jewish community, for it's our responsibility to take care of ourselves, to take care of each other. And if I cannot have you understand what you're supposed to do, even making it available will not accomplish the task.

I'm sorry, this is one I did want you to see - a little piece of it. I just can read that little part that I marked off there. "Testing for cancer risks." This was an editorial in "The New York Times" approximately 11 months ago in March of last year, when the first discussion of the BRCA 1 gene hit the newspapers, discussion about testing, and they just threw in their caveat.

"We know that it's premature. We know there is much more to learn. But get the darn thing going. Period." A decision by an editorial board - go ahead with the testing program. No discussion of the consequence of a testing program; the ethical, moral implications thereof.

The consequence of knowing. So you test, then what? We've been wary of eugenics since the Hitlerian era. Hitler used eugenics to destroy our people - bad eugenics, false eugenics, but eugenics never the less. We're now doing with our testing programs, we are confirming indeed, you have bad genes. What follows there from could very well be pleading with you, don't you pollute the gene pool. Don't have children. Followed by legislation to make sure you don't have children, which is the horror of eugenics when it becomes legislated, as indeed history has shown it does so.

Once we enter into a screening program, the next question will be so what does public policy say about 1 percent of an Ashkenazi woman population that carries this bad gene, about the Jewish people, their responsibility to world society to not to have children so that that gene dies out.

Second, discrimination and confidentiality. People who are active in the AIDS community, in the gay community, the community of those who are highly susceptible to that disease, have been extremely wary about testing for fear of violation of confidentiality. We have other problems. There's confidentiality, which I believe is a bogeyman. I don't know if that's such a terrible thing. I think that there is a adequate evidence from our work in venereal disease to show that even government screening programs can be trusted to maintain confidentiality. I try to review the literature. I haven't found anything that even suggests that there's been a break in confidentiality concerning the testing for gonorrhea or for syphilis. And that involves far more people than any other testing program.

But I believe the problem of discrimination is especially acute within the Jewish community. In social interaction, there is stigmatization. I think our community is far more susceptible to that kind of discrimination. We deal with families, not only with boy and girl. We are trained not only for "yihutz [sp?]" purposes, just in order to establish a relationship with renowned families, but the whole orientation concerns the previous generation and the subsequent generations. And if someone would have the gene tested and know that she is a carrier for the BRCA 1 gene, simple integrity at some point would require her to tell her husband, to tell her fiance that she carries that gene. And then I will tell my son that there are other girls around. It's like subway trains - you miss one, you take the next one. It's no big deal. What do you want to get stuck with this one? Look what trouble you can get into.

You see, our children talk to us about getting married. In other social groups, in other faith communities, the parents get a call - "Congratulate me, I was just married." That doesn't happen by us. And therefore, discrimination is a real concern - discrimination and stigmatization.

What do you do about it, though? I have to now weigh what is good for the woman, what is good for her now, what is good for health, what is good for her happiness; an extremely complex problem that requires much, much thought yet. And then I think this already is a serious problem already in other screening - namely, the involvement of the insurance companies in discriminating against people with certain genotypes and, therefore, the consequential problem for employment.

And then, a problem which speaks also to the economic status of health care in America - the availability of counselors who can handle the information and help the people cope with a new set of facts in their lives. We know what kind of damage was done when adolescents were screened for Tay Sachs and were told you're a carrier. And so what? So you'll make sure that before you get married, you'll check that fiance is not a carrier. We have an organization set up for that - Dole Y'Shuram [sp?], that takes care of that with a lot of care for confidentiality.

Yet, the idea of carrying in my pocket, "I'm a defective human being because I have a bad gene" proved to be a psychological trauma that caused much, much damage. And, therefore, we hesitate when to start our screening program for Tay Sachs. We do it when you're on the market, when you're ready, uh-tut-tut. You wait a little too long, you're already emotionally committed. It's too late to test. A little before, it's unnecessary. Also, a problem which that one we managed to find a happy medium; when to do it. After the first date - if the first date goes well, you make sure that you both submit blood samples.

But what do you do over here? When do you start testing? Next slide. All right, next one. At what point will we begin testing? At children or adolescence? Or, I'm just leading up to the next one- or do we check now when the woman is pregnant? For we can - move to the next one, please - we can now do fetal sorting. When a woman is eight-nine weeks pregnant, we can take a few cc of blood and find a fetal cell in her blood and we'll tell her that your female fetus you're carrying also carries the BRCA 1 gene, so get rid of that one and start again. And suddenly counseling also becomes value laden. And for our people, most significantly, we don't abort - not unless there is maternal life at stake.

Yet, this information, once fetal sorting becomes routine, as it will be imminently, then who will withhold that information from people? And then we end up with what's known as the perfect child syndrome. And this double-edged helix shows the scientist sifting until he finds a good one.

There are a lot of genes to screen for. You're opening up an avenue of testing and counseling parents which will impact on the basic value system of Tovah Judaism.

A day or two ago, there appeared in "The New England Journal of Medicine" a key clinical evidence of an Alzheimer's gene. And I'd like to suggest that the points that they made as to should you test for the Alzheimer gene or not are completely transferrable to our discussion for the breast cancer gene. I hope I got that large enough for you people to read it.

What they suggest as clinical issues to take into account is, one, whether the genotype information is to be disclosed to participants, where the impact of that genetic information can be- what that impact should be on the participants, especially on family members.

We have autonomy in America today. We're not doing well with it, but we have autonomy. If someone in the family decides she's in that group who wants to know and, consequently, she goes in for a test and finds out that she has that gene, it puts a special burden on the other females in the family; a burden they don't want. They may be so constructed in their ethical, spiritual life that they do not want to know. And that is also part of autonomy - the right to refuse testing. I now have to sit and decide as a rabbi, must I compel them to be tested because now it's something they need for their health? Or, after all, it is not 100 percent. The incident is only 1 percent. And in a family that has one, possibly the incidence may go up to 50 percent or 80 percent. But the consequence of knowing may be so traumatic for that individual that her personality does far better- doesn't want to know. Yet, we suddenly put a burden on her by informing her that your sister was tested or your aunt was tested and now you have to decide whether you want to be tested or not. Is that not an invasion of her right of privacy? Or do we keep that information from her?

The problem of ensuring confidentiality of test results; the question of source of payment for all this; the problem of proper assessment, proper counseling, et cetera, et cetera, this they assign to their problems with the new Alzheimer gene is transferrable to every new gene that we'll discover, especially to this breast cancer gene.

I just threw this in just to let you know we've got another gene coming up. We now have a gene for liver cancer. The box is open. Anybody who has success in finding one gene has the reagency, has the ability to find other genes as well. And as you know, there's a strong belief that in the community that many of our diseases, if not most of them, have a genetic basis.

Where do you stop? And where do you make for yourself a place for your faith in God, knowing very well that I don't need a cancer gene to finish me. All I have to do is cross the street at the wrong time or walk under a building when the wind blows off a piece of the roof. I realize how frail man's existence is and how much we depend upon God's personal protection. Is there a place for genetic testing when a man wants to say, a woman wants to say I will go - "Tolem Tia Mashema Lakeka [sp?]" - I will walk with simple faith and take my chances.

DR. LEDERBERG: I must say that what we have just heard from our two speakers is the most sensitive, well-informed and compassionate and broadminded discussion of a contorted set of issues that has ever been pleasure and experience to hear. And I want to express my own gratitude to both of them for that.

Nothing comes for free. A desire of an individual woman to know more about herself, to better improve her own chances of survival, to relieve her own anxiety or to take further steps is in the balance against a very complex set of social and ethical choices about the entire process in which that's embedded. And I think this was beautifully articulated by our two speakers. And I want to thank them also, as well, for the very spirit in which they conducted this debate.

We have about five minutes for questions and discussion. I'll ask both of our speakers to please come to the podium and be available for the darts and arrows. Take your chair with you, if you like. And questioners, please indicate to whom your questions are addressed. And you have only two choices - one or the other speaker.

1ST QUESTIONER: A couple of months ago I attended a conference that went over the same topics and there was one institution that was offering testing for the breast cancer gene and came across a situation where there were identical twins. One of the twins chose to be tested; the other one absolutely did not want to be tested. The decision was to test neither of them. My question is, Dr. Tendler, if you were presented with this how would you deal with it?

1ST QUESTIONER: The people doing the testing decided that it would be best not to test either.

DR. STERN: Well, that raises a whole new set of issues about what's their discretion about making- yes, go ahead.

DR. TENDLER: You're raising the issue, who decides. I mentioned that we are now living under the big "A" -- the "A" of autonomy. The idea that someone can be refused an existing test just doesn't sit well with the American community or the American legal community today. I would hate to be the head of that organization or on the board of directors if this one who wanted to be tested turns out years later to have that disease, that oncological entity. I would rather be the lawyer for him than for the organization there.

But I think the proper ethical response to that is of course the one who wants to be tested should be tested. And you should get from him a word of honor you won't tell it to anybody else. His brother doesn't want to know; you shouldn't foist- invasion of privacy is withholding information. Invasion of privacy is providing information when it's not wanted. And if the fellow violates it because he's his twin and he doesn't like him anyway and he wants to annoy him, there's nothing we can do about it.

1ST QUESTIONER: Do you have a comment on that situation? What would you do? You're in that spot.

DR. STERN: Yeah, this issue has come up regarding- it wouldn't even have to be an identical twin. Individuals where an affected patient may have a number of brothers and sisters who are at risk and who may or may not want to know this information. And these are very difficult decisions. And the question is which is- you know, who has the primacy - the person who doesn't want to know or the person who does?

There is no great answer. My personal decision would be to test the individual who wishes to know. I think it would be extremely difficult to hide the fact, especially since the person's actions probably will give away the result of the testing. But I think in my- from my presentation, I'm a firm believer in the right of the women to know, if they wish.

DR. TENDLER: I think we should differentiate between tuberculosis, breast cancer, Alzheimer's. There is information that we have now for which or about which we are incapacitated; nothing to do about it. If someone has a Huntington's gene, all he has to do is wait until he dies. We have nothing to tell him to do. And, therefore, that knowledge is devastating. That knowledge means he dies, depending on his personality, most likely dies right away and doesn't have to wait until he's 50 or 55. I don't mean commit suicide, I mean for all intents and purposes, as far as planning for the future, as far as a contentment of life, etc.

Breast, there's something to do about - more frequent screening. I don't know mammography - most likely that causes more cancer than will the gene if they keep on doing mammography every three months, as some people suggest. You have this excess exposure to radiation. But there's self-testing. And right now, of course, the breast cancer gene has in it, I think, a tremendous potential for the good because they've discovered that this gene produces a protein that leaves the cell and modifies the activity of normalizing the cell, so it's possible now to hunt up something which will mimic the action of the protein or to do a little bit of genetic transfer; actually get some new good genes to produce the good protein that controls the cells to normal growth in the absence of the controlling influence from the messed up protein molecule that's coming out from the mutated gene.

So that when there is something to do, then I would lean very heavily on finding out and let's do something about it. But I think the real problem is when you have a gene you're checking for, for which there is nothing to do - just the knowledge itself. Knowledge without the ability to cope with than knowledge in a practical way becomes, I think, knowledge that is a tyranny of knowledge that can only hurt the individual.

DR. LEDERBERG: I'm going to make a very brief intervention myself. I was provoked by Dr. Tendler's remarks. I was so exorcised about the issues of eugenics that he talked a little while ago that I introduced a counter program and I called euphenics. My belief and hope- firm belief was that genetic analysis is not going to stop at testing, it's not going to stop at diagnosis. And just as was implied here, that a still deeper examination of the effects of these genes will result in direct remedies, not merely diagnosis, not merely of the people that might be affected by it that is affecting the phenotype, hence euphenics, as against efforts to go after the genotype, the eugenic program.

I'm quite confident we will see that. We will see that with Alzheimer's. We'll see that with breast cancer just along the lines we just indicated. So there is that ray of hope for the future. And it's a way of bypassing some of the very serious dilemmas where it's very difficult to know what the best solution is in the sphere that you've indicated.

DR. STERN: I mean, I certainly would agree with you on that. And I think that's why I stressed the importance of a person skilled in those areas as being part of the team. The guilt produced by passing the gene on to one's child; the guilt of having the gene; the depression of having the gene; the guilt of being a survivor or being not affected while one's sibling or parents or other relatives are affected and could potentially die from this, again produces a tremendous psychological burden on patients who are undergoing this testing. And I certainly agree with you that support services should be available and a psychologist-psychiatrist should be an integral part of the team.

Because we're not, as I said, we're not dealing with a yes-no, you have it-you don't situation. There's a tremendous amount of uncertainty involved in this. And I think people that can have the effect of producing increased anxiety, even in people who test negative for the gene mutation.

DR. LEDERBERG: I want to close on a comforting note. Quite literally, none of us is perfect. The genes for which we have diagnostic testing only begin to scratch the surface. There are quite reliable estimates that every human being is carrying between two and four lethal or semi-lethal disease-oriented genes in their own genotype. It's part of our evolutionary heritage. We could not have evolved to our present circumstance without having had an inevitable additional package of these deleterious genetic factors.

So you really don't need to worry that you are bereft of the possibility of transmitting genes for good and evil to the next generation. That's built in to the human condition.

We could have extended this discussion many hours. It was a fascinating one. I thank you for your attention and I thank above all, our speakers.