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Dr. Patricia Ganz, Professor of Medicine, UCLA: The Promise and Pitfalls of Cancer-Related Genetic Counseling and Testing: I am going to give an overview to explain why we brought up cancer-related genetic testing and counseling as an issue. We have had clinical genetic testing for the BRCA-1 and -2 breast cancer genes for about 10 years. As we end this decade, we feel we have passed an important milestone, and we should think about what has happened over this time. In addition, legislation against genetic discrimination has been on the agenda in Congress for probably 10 or 11 years and has finally been approved in the House of Representatives with hope of passage this year. So I think there are a number of issues that make it timely for us to begin a discussion.

In setting the stage for today’s speakers, I will be somewhat anecdotal and provide examples that I hope illustrate why we are here today. As a historical overview and dynamic case study of how we got to our present situation, I will start with what I think has been the successful integration of genetic testing and counseling in the management of breast cancer. I will try to fit clinical cancer genetics into the prevention paradigm, discuss some access and direct-to-consumer marketing issues, and sum up with some of the challenges that I see, hoping that our speakers today will cover them in greater detail.

I started my medical school surgical rotation in 1971 which brought me to part of the breast service and a surgeon at the county hospital who was participating in a National Surgical Adjuvant Breast and Bowel Project



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2 Prepared Presentations and Discussion Dr. Patricia Ganz, Professor of Medicine, UCLA: The Promise and Pitfalls of Cancer-Related Genetic Counseling and Testing: I am going to give an overview to explain why we brought up cancer-related genetic testing and counseling as an issue. We have had clinical genetic testing for the BRCA-1 and -2 breast cancer genes for about 10 years. As we end this decade, we feel we have passed an important milestone, and we should think about what has happened over this time. In addition, legislation against genetic discrimination has been on the agenda in Congress for probably 10 or 11 years and has finally been approved in the House of Representa- tives with hope of passage this year. So I think there are a number of issues that make it timely for us to begin a discussion. In setting the stage for today’s speakers, I will be somewhat anecdotal and provide examples that I hope illustrate why we are here today. As a historical overview and dynamic case study of how we got to our present situation, I will start with what I think has been the successful integration of genetic testing and counseling in the management of breast cancer. I will try to fit clinical cancer genetics into the prevention paradigm, discuss some access and direct-to-consumer marketing issues, and sum up with some of the challenges that I see, hoping that our speakers today will cover them in greater detail. I started my medical school surgical rotation in 1971 which brought me to part of the breast service and a surgeon at the county hospital who was participating in a National Surgical Adjuvant Breast and Bowel Project 

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 CANCER-RELATED GENETIC TESTING AND COUNSELING (NSABP B-04) clinical trial that was comparing radical mastectomy to modified radical mastectomy. To my surprise, a woman at that time had to consent to either a radical or modified radical mastectomy before she even knew she had cancer. A frozen section diagnosis of her breast mass was made while she was on the operating table, and if she had cancer she would either have the standard radical procedure or the modified radical mastectomy. She awoke from anesthesia not knowing if she had breast cancer and whether she had the very radical or less radical procedure. This trial was important in showing that radical mastectomy was no better than modified radical mastectomy, and fortunately we have advanced in the local treatment of breast cancer since that time. Today, most breast cancers are discovered through mammography, and more than 50 percent of them are stage I small tumors. In the early 1980s, advocates suggested that a two-step procedure was needed to provide a diagnosis and an opportunity to consider treatment options before surgery. As a result we now do small incisional biopsies or lumpectomies, sentinel node biopsies, and breast irradiation in many instances. We also have trials going on to examine whole versus partial breast radiation for women with lumpectomies, because long-term survivors may develop a second cancer in the same breast, and if they have already experienced all the radiation they can tolerate in that breast, mastectomy will be their only treatment option at that point. Clinical genetic testing for breast cancer genes is often done prior to surgical decision making. If a woman is going to need hormonal therapy or chemotherapy before her definitive surgery, genetic testing may weigh very heavily in whether she decides to have a mastectomy on the tumor side or even bilateral mastectomy as part of the initial treatment planning. Because endocrine therapy may be given for up to 10 years for primary or secondary prevention, genetic information may have substantial implica- tions. We recognized that breast cancer is a systemic disease, and through clinical trials and evolving practice, we have achieved important decreases in incidence and improvements in survival. We have eliminated the one-step surgical approach and turned to minimally invasive biopsies, lumpectomies, and radiation, with mounting evidence for as good or better results with less radical options. The bottom line here is increasing patient involvement in surgical decision making and also now genetic decision making, although what I am describing in terms of the incorporation of genetic testing and decision making as part of treatment management may only be occurring at tertiary

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 PREPARED PRESENTATIONS AND DISCUSSION centers—not yet the norm, but the way things are developing. We have important improvements in survival as a result of our progress: 90 percent 5-year survival rate for early stage patients, more than two million breast cancer survivors alive today, and continued improvements expected. These data have important implications: if we expect women to live a long time, having as much information about their potential risks for a second cancer either in the breast or the ovaries or some other organ is critical to decision making and treatment planning. Important discoveries in the 1990s improved our understanding of risk factors for breast cancer. Two genes, BRCA-1 and -2, thought to be respon- sible for 5 to 10 percent of breast cancers, were discovered on chromosomes 17 and 13, respectively. They could be responsible for as many as 20,000 of the 200,000 breast cancers diagnosed each year in the United States; these 20,000 women might benefit from genetic information to assist decision making at diagnosis. Certainly after diagnosis in terms of the prevalent cases, there are many women who may be carrying genetic predisposition genes that would affect their future health as well as that of the families, so the potential ramifications of genetic information are important. What happened at UCLA as an exemplar of progress at the end of the twentieth century? We were involved in the first breast cancer preven- tion trial, and shortly after that I established a high-risk program within our Revlon/UCLA breast center. It became clear to me that other centers around the country that were doing the leading-edge work in terms of the alpha and beta testing for genetic testing were beginning to see these high- risk populations and that this would be an important clinical service as well as an avenue to do clinical translational research. When clinical testing became available in 1997 for the BRCA-1 and -2 genes, we had a decision to make: were we going to put this into the clinical testing arena with all of the other genetic testing that was done with prenatal and other conditions, or were we going to somehow treat this differently? Because of concerns about the potential for genetic discrimination, the time needed to counsel women or others, we believed it best to proceed through a research protocol, not only to provide these services to people in a situation where they could be protected against potential legal or discriminatory practices, but also to collect research data on outcomes. We started this as the UCLA Family Cancer Registry and Genetic Evaluation Program, a shared resource at the cancer center. We opened this up to anyone who had a cancer history, so it wasn’t just breast and ovarian cancer. Patients who enter this program are not necessarily seen just once,

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 CANCER-RELATED GENETIC TESTING AND COUNSELING but may be seen repeatedly and benefit as new science provides new infor- mation on their condition and leads to new decision making. A woman came to us in 1996 for high-risk surveillance in the course of clinical assessment and evaluation. Her sister had bilateral breast cancer diagnosed at age 35, and her mother had breast cancer diagnosed at age 45 and died at age 48 with metastases. Annual screening mammography and clinical breast exams three to four times a year were recommended. In 1999 she joined the family registry. In November of 2000, her mam- mogram was negative, but early in 2001, at age 41, she was diagnosed with breast cancer. As she was going through her surgical decision making, she considered whether she should have bilateral mastectomies. Because of her strong family history, we did genetic testing, and she had no evidence of a deleterious breast cancer gene mutation. We also pursued this further by testing for the tumor suppressor gene, PTEN, because of her very strong family history. When this turned out to be negative, she decided just to have a lumpectomy and radiation therapy because no genetic predisposition could be found in spite of three first-degree relatives with breast cancer, one of them bilateral. Subsequently, we learned of new mutations (large deletions) in BRCA-1 that were associated with the risk of breast cancer in similar families, and on retesting she was found to have one of these very large deletions that was the cause of what was going on in her family. She then elected to have bilateral prophylactic mastectomies and also bilateral oophorectomies because of the very strong risk of both of these diseases. The 2002 update of her pedigree at this point in time is displayed in Figure 2-1 with a summary of the relevant events. The patient is indicated in this pedigree by the large arrow. We fortunately have had the ability to perform long-term tracking of the people in our registry. We send them an annual questionnaire. I have had very good genetic counselors who work with me and who remember these cases. We probably have many more of them in our registry with family histories and unknown mutations. This is the luxury of having a research registry, but the average patient who has his or her blood drawn by a medical oncologist or even a clinical genetics counselor may not have such a luxury. The patient may not be well enough informed to follow through in this evolving field, where new information is coming continually. This is going to be a long-term problem. Ellen Stovall, CEO, National Coalition for Cancer Survivorship: Are you still following this woman, and if so, how is she doing?

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 PREPARED PRESENTATIONS AND DISCUSSION Irish ancestry D. 54 Br Ca Australian/ Swiss/ dx 50’s Italian 70’s D. 62 Rt Br Ca 4/2001 – tested negative D. 48 mets Melanoma dx for BRCA1/2 Melanoma dx@45 70’s 9/2002 – deletion BRCA1 dx @61 Identified 11/2002 Bilat MRM and BSO 4 3 41 42 Melanoma Bilateral Br Ca dx 35 Tx = BRM found 2nd primary on surgery Unaffected 12 11 2/2001 – tested negative for Polyps BRCA1/2 Affected with cancer “juvenile polyposis” FIGURE 2-1 Pedigree of a high-risk patient. Dr. Ganz: Yes, we are. She is doing very well, and she is a very outspoken advocate for this kind of testing and follow-up. I have shown you a nice example of how this can work and work well. But I don’t think this is the routine around the country. I think my col- leagues today who are going to be discussing this will tell us about what is going on in the real world. If you think about where clinical cancer genetics belongs, it is in the prevention paradigm: either primary or secondary prevention. In somebody who doesn’t have cancer yet, we want to prevent cancer in the future. If somebody, genetically predisposed or not, has already had cancer and is, therefore, at highest risk for a second cancer, we want to intervene there too. Survivors account for about 15 percent of all new cancer diagnoses that occur every year. It takes a very long period of time for breast cancer to develop from the very first cell that is malignant to one that we can detect—dissemination occurs in the interval between the first cancer cells and cancer detection. We know that hereditary cancers account for about 5 to 10 percent of all cancers. If we can find people with the first hereditary mutation who then are going to acquire other mutations that will lead to cancer, we have a real opportunity to intervene.

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 CANCER-RELATED GENETIC TESTING AND COUNSELING How do we find who is at risk for breast, colon, or prostate cancer, or melanoma and other diseases where we either have those genes identified or will in the future, when there are so few individuals? I think this is the real challenge that we face from the prevention and population perspective. Characteristically, in families with sporadic breast cancer, none of the cancer is diagnosed prior to age 60, there is no ovarian cancer, and no clear pat- tern on one side of the family or the other. Characteristically, in hereditary breast cancer, onset of cancer is under age 50, ovarian cancer (though not always present) occurs at any age, breast and ovarian cancer occurs in the same individual, there is male breast cancer, and there is Ashkenazi ancestry. We know that one in 40 to one in 50 individuals of Ashkenazi heritage are likely to carry one of the three founder mutations for breast cancer. The American Society of Clinical Oncology’s (ASCO’s) most recent guidelines for breast cancer care and surveillance recommend that any younger woman of Ashkenazi Jewish heritage with breast cancer, even if there is no family history, should have genetic testing. So the key is the family history on both sides of the family, maternal and paternal, to accurately assess risk and make decisions about whether it is appropriate to do testing and genetic counseling. From the speakers today, we will hear who in the workforce should be doing that genetic counsel- ing, whether we have enough people in the workforce, and whether we can rely on primary care physicians to take the appropriate family histories. Genetic testing just gives you information; it doesn’t tell you what to do. We need the expertise of someone who knows about the genetics and the risks for various cancers and what the preventive strategies might be. We should suspect hereditary cancer when there are two or more relatives on the same side of the family, an early age at diagnosis, multiple primary tumors, bilateral or rare cancers, a constellation of tumors consistent with a specific cancer syndrome (e.g., breast and ovarian cancer, colon and uterine cancer, colorectal cancer associated with polyposis), autosomal dominant transmis- sion, and the Ashkenazi heritage in particular. Increasingly there are reports of multiple cancers associated with hereditary predisposition genes. Genetic testing of incident cases of ovarian cancer in the population identified high rates of BRCA-1 and -2 expression, and complete pedigrees found that the women who were gene carriers had many other family relatives with a constellation of other com- mon solid tumors—a different way of case finding. This finding needs to be corroborated, but we know already about the breast-ovarian association or the association between BRCA-2 and pancreatic and possibly prostate

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 PREPARED PRESENTATIONS AND DISCUSSION cancer and melanoma, or BRCA-1 and possibly testicular and some gastro- intestinal (GI) cancers. Dr. Harold Moses, Director Emeritus, Vanderbilt-Ingram Cancer Center: What proportion of pancreatic cancer patients have BRCA-2? Dr. Ganz: It is about 5 to 10 percent, so it accounts for a lot of the familial pancreatic cancers. We have now a funded screening study to go back to our registry and identify BRCA-2 carriers with pancreatic cancer in the family. I think this is the tip of the iceberg in what we understand. I think as clini- cal genetic testing becomes more widespread for cancer predisposition and people recognize this, we are going to become more aware of other sites. Because most of us do not routinely take a thorough family history of our cancer patients, we don’t consider or discover family connections. But I think as research evolves we are going to see predispositions in other organs. You have heard already about the success in tertiary centers of the inte- gration of breast and ovarian cancer, genetic testing, and screening. This has likely occurred because we have had people who have been interested from the research standpoint, but also there is a high level of consumer aware- ness and a lot of available breast cancer information, and physicians who are treating these patients are aware that this is an issue particularly in the young patients who present to them. We have a diametrically different experience with colorectal cancer patients. It has been very difficult to get the attention of gastroenterologists. There are many published papers describing that people who have family histories of colorectal cancer are not coming in for genetic testing. Clearly, a colon full of adenomatous polyps in familial adenomatous polyposis (FAP) is a signal, and those patients will be referred for testing. However, in attenuated FAP, there may not be as many polyps in the colon, so it requires an astute gastroenterologist to take a history and refer. There are new mutations, spontaneous mutations where the family history may not be as strong. There has not been as much patient demand from the colorectal cancer community. We are talking about a community that perhaps is not as active as the breast cancer community in advocacy. There is also the thought that the family members will be screened with colonoscopy. If your mother has colon cancer at age 40, it is agreed that her children need to be screened, but half of them might be screened intensively unnecessarily because they don’t carry a mutation. Similarly, her children would begin screening at a

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0 CANCER-RELATED GENETIC TESTING AND COUNSELING younger age, but half of them might not need that. It would be desirable to avoid overscreening in terms of cost and psychological morbidity, so valuable decision making could be facilitated if genetic testing was done. This lack of patient and doctor awareness and utilization, and even less fre- quent follow through after referral, bespeaks a different culture, although I think that this is beginning to change and that gastroenterologists and GI oncologists now have begun to see the importance of testing to some extent because there are associated cancers. Mutations involved in the development of hereditary colorectal cancer include FAP and hereditary nonpolyposis colorectal cancer (HNPCC). Testing is more complicated for this cancer, and it is much more difficult for medical oncologists or general physicians to do in their practices, whereas the BRCA-1 and -2 mutation testing and preventive strategy are much more straightforward. The very high risks of lifetime development of colorectal cancer, 78 percent, or endometrial cancer, 43 percent, and other cancers in HNPCC mutation carriers suggest preventive interventions, such as pro- phylactic hysterectomy in female carriers or upper endoscopic examinations to screen for stomach cancer (19 percent) (Aarnio et al., 1995). With HNPCC we see a wide variety of cancers, and I think we are prob- ably going to see more of that with the breast cancer genes as well, because these mutations are in every cell of the body, so the potential to develop a malignancy is widespread. As in breast cancer, surveillance is valuable in HNPCC families too, reducing the incidence of cancer from 11.9 percent to 4.5 percent in one study (Jarvinen et al., 1995). Breast and colorectal cancer are two major diseases that are very common in the population. We know that 5 to 10 percent of the individuals who are getting these diagnoses were predisposed. Could we have prevented the disease, could we have made it possible for these individuals to never have developed cancer? That is why I see this as an important prevention paradigm. Now, in addition to the barriers that I have discussed, are there others that might limit our access to quality genetic testing and counseling? There are some important structural problems as my colleagues who are speaking today will report in more detail. Physicians do a poor job of taking a family history. The surgeon general and the CDC have had campaigns on this, and there is increasing awareness. And family histories need to be refreshed over time to include disease events (such as cancer) occurring after the original history was taken. There are a limited number of trained genetic counselors, and I think we are going to hear about that. I don’t know what the exact number is, but

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 PREPARED PRESENTATIONS AND DISCUSSION it is about 500 to 600 in the cancer genetic interest group of the National Society of Genetic Counselors, according to Dr. Weitzel. This kind of counseling is complex and takes time. Even with the more straightforward tests such as BRCA-1 and -2, there are variants of uncertain significance. This means these variants are polymorphisms that might lead to a delete- rious mutation and a risk of getting cancer or later might be determined nonharmful—it is uncertain. It is a tracking issue. When tests are ordered by an oncologist or another physician and a variant of unknown significance is found, the patient may be told that the physician cannot interpret the result. These patients may wind up coming to us, and we have to try to explain it to them. So we need to prepare the patient before we even do the test that this could happen—that we might have an inconclusive finding. For colon cancer tests, it may be much more complicated to strategize. The truth is, we have a limited number of clinical tests available, so this is not something we would be asking all doctors to do in their offices, because it is quite complex. Direct-to-consumer marketing exists over the Internet. Genetic coun- selors being in short supply, a patient or consumer can get specific educa- tional information from websites without risking genetic information in his or her medical record. Counseling sessions can occur over the phone with a counselor from a particular company. Arrangements to draw blood and send it to the standard laboratory can be made, and results returned to the patient or consumer. This has the advantage of being available, convenient, and private. But in terms of quality control, are we dealing with the worried well person here, who is deciding to have these tests on his or her own, or is it providing a service to people who may not have access? Other ways of delivering the service have been funded by the National Human Genome Research Institute’s Ethical, Legal, and Social Implications (ELSI) program using conferencing by telephone, counseling and other tests, video confer- encing, group counseling, and other strategies. Limited health insurance coverage for counseling and testing is another barrier. I have not experienced this in my urban area, but I hear about it at other places such as the M.D. Anderson Cancer Center. Patients are referred and then they find out that either they don’t have insurance coverage for the genetic test or the copayment is 50 percent— it could be for both the coun- seling and the testing—for a test that costs over $3,000. Unless patients truly understand that this is important to their care, they may choose not to have the test. We will have other people talking about health insurance and employment discrimination, issues that are of concern for everyone.

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 CANCER-RELATED GENETIC TESTING AND COUNSELING Concern about employment discrimination is one of the reasons that at UCLA we had separated our testing into research protocols. Nevertheless, we are now moving into the clinical arena as many of our patients end up having preventive surgery, and information about their genetic tests gets into the record as part of that clinical intervention, or in the case of women with breast cancer who are going to need magnetic resonance imaging (MRI) screening, genetic information is needed in the record to justify the special imaging. I think there is a trend, and the recent genetic discrimina- tion legislation will address this. One of the other hidden messages is that there is inadequate reimburse- ment for health-care providers to perform counseling and testing. Even though there is reimbursement for an initial consultation visit, many addi- tional hours can be spent discussing and supporting these patients as they go through their decision making. It is very complex and labor intensive for counselors and physicians. Even though it is just a blood test sent to the laboratory, we have to identify the potentially at-risk population, do pretest counseling, obtain informed consent for the test, decide on the right tests to do, disclose and explain the results (separately after 3 to 4 weeks waiting for the laboratory report), and then make sure that the patients know what to do with the test information and what their options are. This process relies on shared decision making and a very intense interaction with the patient or healthy person. We can experience with patients a range of emotional responses, partic- ularly if they are not prepared for a positive result. If the doctor has warned there is a high likelihood and the patient finds out that they are indeed positive, that is fine, but if counseling has implied that testing is being done just to be safe, and the patient does not expect the abnormal result, it can be very difficult. We have found that patients with cancer already, the breast cancer patients in particular, who might be expected to value an explanation for their disease, are sometimes more distressed because they know what cancer means, and they now have to think about it again, make decisions about preventive treatment, and consider informing other family members, those who are at risk. Very often when that information suddenly and unexpectedly involves the man’s side of the family, where there has been no expression of the disease, it can be very challenging. There is a website for women who have had breast cancer in their family called FORCE (Facing Our Risk of Cancer Empowered); it is like many other patient advocacy awareness and educational resources that are available. I thought it was interesting that they referred to themselves as “pre-vivors.”

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 PREPARED PRESENTATIONS AND DISCUSSION Cancer pre-vivors are individuals who are survivors of a predisposition to cancer but have not developed the disease; they are those who are living at risk. I don’t know that we should be making patients out of healthy people, but it is an interesting example of some of the current thinking. I am very excited about the speakers we have here today, because we are focusing on forum initiatives to identify and define the challenges of delivering quality care to those who have cancer, are survivors (and many of those will have had a hereditary predisposition to cancer), and then the large number of pre-vivors who will benefit from high-quality and afford- able genetic counseling and testing without the fear of discrimination. Dr. Margaret Spitz, Chair, Epidemiology, M.D. Anderson Cancer Center: That was a wonderful overview, Dr. Ganz. Could you briefly say what your thoughts are about the American Cancer Society (ACS) recom- mendations for breast MRI in high-risk women? Dr. Ganz: I got a preview of the recommendations last week, so I have been going back and forth e-mailing my genetic counselors all this week. The ACS in its enthusiasm for screening can often push to the edge of the evidence. This doesn’t mean it is either right or wrong. I was talking to a breast surgeon the other day, and he was saying maybe 20 percent of his patients with breast cancer now get an MRI in their diagnostic workup. He sees perhaps 350 new cases a year. So now if he needs to have an MRI on the contralateral breast in every woman he diagnoses, he fears that there will not be sufficient MRI services available. Women who have had one breast cancer already are clearly at high risk for another. There is also a concern about the quality of MRI services. A very good tertiary center with experienced imagers such as ours will not accept the films from an outside community. The quality is often poor, and there is an issue with liability in terms of interpretation. So I am not sure that we have the infrastructure to do all these MRIs. Also, we did a rough calculation, and the 20 percent lifetime risk (that would be somebody with one first- degree relative of any age and say a biopsy) adds up to a lot of people to be screened. We definitely have been screening our carriers with MRI, and we have patients already asking for MRI. Perhaps Dr. Niederhuber from the NCI will weigh in on this at some point, but I think it is an issue. Dr. John Niederhuber, Director, National Cancer Institute: In my expe- rience as a surgeon, MRI has been very helpful to me many times in trying

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0 CANCER-RELATED GENETIC TESTING AND COUNSELING They may still be out there in multigenic forms, in the slot machine version, where we get lemons on three different genes, highly penetrant. But I think part of why there has been less genetic discrimination is that the science has not provided enough opportunities in terms of highly pen- etrant, high-probability expensive diseases, particularly expensive diseases that are likely to manifest within a time window that is short enough for an insurer to care. The third reason is that there has been legal intervention. The HIPAA, the Kassebaum-Kennedy bill of 1996, took employer-provided insurance off the map, and that is a huge percentage of insurance. The 30 percent of Americans who get their health care from Medicare or Medicaid are not subject to medical underwriting. The 15 percent of Americans who do not have health coverage are bereft of health coverage more because of income level than any sort of medical underwriting. So the number of people even subject potentially to medical underwriting in the United States is probably down around the 5 to 8 percent of the population that buys individually underwritten coverage. So, the factors include the structure of the health-care system, the lack of a significant number of strong genetic predictors of disease, some legal interventions at the federal level such as HIPAA, and also at the federal level, some Clinton administration language inserted into an enforcement guidebook of the Equal Employment Opportunity Commission giving an expansive definition of employment discrimination under the Americans with Disabilities Act with respect to discrimination. Then, there have been a plethora of state laws. Roughly 45 states have laws limiting or banning the use of genetic information in health insurance underwriting. Roughly 30 to 35 have laws banning the use of genetic information in employment. So, a number of states have stepped in, even where the federal government has not. In addition to those factors, if any addition is needed, I think, frankly, the insurance industry has been walking on eggshells about this. They have not been eager to embrace genetic underwriting because they see it is a political loser—the last thing the insurance industry needs is another real political loser. So, to some extent, I think there has been some intentional forbearance for political reasons by the industry from adopting a broad and forthright approach to genetic discrimination, aided of course by the fact that it can only work in the individually underwritten market, and then only in the small number of states that have not otherwise banned it.

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0 PREPARED PRESENTATIONS AND DISCUSSION Dr. Khleif: What is a broad approach? Mr. Greely: A company could say, we want everybody to answer questions about whether they have gotten genetic testing; we want people to get genetic tests, and we will not cover you if we think you are at high risk. Dr. Khleif: As opposed to what, right now? Mr. Greely: As far as we can tell right now, in the few states that still allow medical underwriting with genetic information in the individual market, a few companies are using it, but not very many even there. There is no evidence of it in other health insurance markets. Nor is there any signifi- cant evidence, apart from Burlington Northern, and a very odd case out of Lawrence Livermore Laboratory that I never really understood, of employ- ment discrimination. So there is really not much evidence this is happening. But there is a fair amount of evidence that people are afraid of it. I think all the genetic counselors around the room, or all the people involved in provision of clinical genetic services, have mentioned in their talks this issue of genetic discrimination as a factor that patients care about. They are worried about losing their insurance or their employment even though there does not seem to be any basis for that fear. Dr. Greene: The clinical genetics provider community told them to be worried. Mr. Greely: Because your lawyers advised you to tell them to be worried about that, in large part. Dr. Greene: And with this becoming the de facto standard of care when counseling for highly penetrant cancer susceptibility, you cannot have a discussion with a patient without warning them that they could be discrimi- nated against in each of these different settings. Mr. Greely: Which I think began in part because at the time guidelines were being set up in the early 1990s, people expected it, not unreasonably, to turn out to be a bigger problem than it was. Dr. Weitzel: We were saddled with the Huntington’s model.

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0 CANCER-RELATED GENETIC TESTING AND COUNSELING Dr. Khleif: If you don’t disclose on an application that you have a genetic abnormality, could that not be taken against you if you develop the condition? Mr. Greely: As a good lawyer, the first two words in answering any question are, it depends. With respect to group coverage through an employer, which I assume you probably have, there is an application process that covers you without regard to your health risk. For individual coverage, you can be asked questions, and if you do not answer those questions, they may deny you. And if you answer those questions in a way they do not like, they may deny you. In some 40 states, they cannot ask and act on questions about your genetic information. They can ask if you have had colon cancer, and they can deny you if the answer is yes, but they cannot ask in the vast major- ity of states if you are at genetic risk for colon cancer. They can ask if you have other conditions that might affect your health. If you say yes, I am a genetic risk for colon cancer, they are not allowed to take that into account in underwriting in those 40-odd states. Every state law is somewhat dif- ferent; some of them cover individual markets, some of them cover group markets, and some of them cover both. They all have different definitions. But by and large, the states have been pretty strict about this. But there is a lot of fear. The survey evidence on fear is mixed. The anecdotal evidence is quite strong. All the surveys find some evidence of fear. People rank it differ- ently in terms of how important it is to their decisions not to get tested. Dr. Bach: Just a clarification. That is relevant to health insurance; is that also relevant to life insurance? Mr. Greely: No, and I will come back to the other insurances. But the ones I think we care most about are health insurance and employment; these are the two areas of genetic discrimination that cause the most concern in the United States. Depending on the survey evidence, somewhere between a third to a half of people will list fear of genetic discrimination as one reason they did not pursue genetic testing. I am not sure how much credence to give responses like that, in part because I think that for a lot of people, who may have reasons for being nervous about genetic testing, saying I am worried about discrimination is an easy and socially approved answer. Saying I am worried about what my wife will think, or I am worried about the conversation I will have to have with my mother, or I am worried about the possibility of learning that I

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0 PREPARED PRESENTATIONS AND DISCUSSION am going to die sooner than I thought, those may be harder responses to a survey question than simply to say, yes, I am worried about health insurance discrimination. Whatever it is, counselors report that there is a significant number of people who are concerned. There is significant concern in the community both that people who should for medical reasons be getting predictive testing are not, and people who you would like to have testing done in research are avoiding it for fear that even with promises of certificates of confidentiality from NIH, there is still the possibility of genetic discrimination. I have written both in the Pennsylania Law Reiew in 2001 and then in a perspective in the New England Journal of Medicine in September of 2005, that one nice way to deal with the fear is to pass clear broad federal legislation applying to all 50 states that would allow counselors to tell patients they are protected under federal law that provides fairly broad pro- tection. We are I think on the verge of having that happen. The GINA was first introduced by Representative Louise Slaughter in 1995 in the 104th Congress. After languishing in subsequent congresses, now in the 110th, the bill is being taken seriously. It has been approved by the Senate Com- mittee on Health, Education, Labor, and Pensions. It has been approved by the three different House committees that have jurisdiction over it, the Education and Labor Committee, the Energy and Commerce Committee, and the Ways and Means Committee. The last one of those approved it just earlier this week. The three House committees all put in somewhat different amendments, so there is going to be a tricky period of reconciling those amendments inside the House (where the bill passed April 25, 2007), let alone in reconciling them with the Senate bill, which was completely unamended. But that is the legislative norm. When you get to the hearing stage, which this bill had never gotten to before, you get those kinds of detailed markups and amendments. The GINA would ban genetic discrimination, or discrimination based on genetic information, broadly in health insurance and employment throughout the United States. Its health insurance provisions go to group insurance, individually underwritten insurance, and medigap insurance. It does not affect life, long-term care, or disability insurance, but it covers employers’ self-insured plans as well as another major component, HMOs and managed care plans, as well as indemnity plans. The employment provisions govern all employers. It even governs Con- gress, the executive branch, and the judicial branch, which Congress does not always do. So it has very broad coverage. It bans in both insurance and

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0 CANCER-RELATED GENETIC TESTING AND COUNSELING employment the use of genetic information in making decisions, broadly. Genetic information is defined as the results of individual or family genetic tests or family medical history. Personal medical history is not covered, family medical history is. Genetic tests are defined as tests of DNA, RNA, proteins, or metabolites that provide information about a gene, a genetic variation, or mutation, or chromosomal abnormality. Expressly exempted from genetic tests is anything that provides information about sex or age. I have no idea what they are thinking about in terms of the genetics of how old you are. The act also says that for metabolites and proteins, it does not include a variety of tests that nongenetics people would do. I think that is the cholesterol exception, cholesterol and sugar. So they do not want to say, every time you get a cholesterol test it is a genetic test, although of course it is in a sense. If you have a normal cholesterol, it shows you do not have familial hypercholesterolemia. If you have an LDL level of 800, it shows you do have familial hypercholesterolemia, a genetic disease. Otherwise the law is awfully broad. An important aspect of GINA, which drives employers crazy, is that it does not preempt state laws. So for those of us in California, our employers and insurers will have to deal both with the federal law, and because California law in some respects is more stringent—and the courts will have a good time figuring out what stringent means in some of these cases—California law will also apply. In a state with a less stringent law, the federal law would apply. So the federal law is the minimum standard; states can be more strict if they choose. The GINA would be enforced by administrative penalties through vari- ous cabinet secretaries, notably DHHS, among others, and also enforced on its employment side, not the insurance side, by the same sort of litigation remedies, that is, lawsuits, that apply under the Civil Rights Act of 1964, with the same limitations on damages, punitive damages, and otherwise, something that provokes opposition on grounds that it will lead to more lawsuits. So that is the Genetic Information Nondiscrimination Act of 2007, which I believe is going to become law. Last year the Senate passed an equivalent act 98-0. The White House specifically endorsed last year’s bill, not just the concept, which President Bush had endorsed from the time he took office. They have specifically endorsed this year’s bill. There is an antiabortion amendment that is going to get some play on whether or not ex vivo embryos count as people for purposes of the dis- crimination bill. There is going to be some maneuvering, but it really looks

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 PREPARED PRESENTATIONS AND DISCUSSION like it is going to go through this time, which means genetic discrimination should diminish from very small to very, very much smaller. But it also means that counselors and others should be able to tell patients, there is a federal law that is broad and quite clearly protects you against employment discrimination and health insurance discrimination. We cannot promise you that the law will always be obeyed, but there are good penalties to encourage that. So I think to some extent, that should provide a useful solu- tion for many of the concerns. But there are some future issues here. There are three other forms of insurance—disability insurance, life insurance, and, importantly, long-term care insurance. Neither this bill nor state law, say anything about any of those. The only state laws I know of that talk about life insurance say that you cannot discriminate based on genetic information on life insurance unless it is actuarially justified, which is not terribly consoling to people with a Huntington’s disease allele. Frankly, I do not think that is likely to change much in the United States because we tend to view those forms of insurance more as luxuries and less as the kind of necessity that health insurance has become. Life insurance, par- ticularly high-margin life insurance, is not something that is that common. A lot of people get their life insurance through employers, who again are not allowed to risk rate, to medically underwrite. If you want to go out and buy 5-year term insurance for a 10 million dollar payoff, you are going to get medically underwritten, and I think that is likely to continue. Disability insurance is a little less certain. There is some federal- and state-mandated disability insurance that will be very attractive to lots of people with these kinds of genetic risks. I think there may be more pres- sure to make changes there, but most people do not know about it and do not live with disability insurance to the same extent they do with health insurance. Without health insurance, we all know you can quickly become bankrupt. Disability insurance is less of a concern. I think the sleeper here, although not so much for the cancer com- munity, is long-term care insurance, since the disaster about to confront the American health-care financial system is paying for long-term care. One proposed solution to that is to shift more into long-term care insur- ance. There is some genetic testing that long-term care insurers and those contemplating buying long-term care insurance would really be interested in, and that is the Alzheimer’s test, particularly the ApoE4 allele test. This could be a good predictive test for something that would require long-term care and would represent the kind of adverse selection that insurers like to

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 CANCER-RELATED GENETIC TESTING AND COUNSELING complain about. That is plausible in the context of long-term care insur- ance, which is an expensive investment that very few people are making. The increasing integration of genetic information in medical practice may pose trickier discrimination issues. The results of genetic tests may define allowable benefits; for example, insurers might decide not to pay for prophylactic bilateral mastectomy in the absence of a positive BRCA test. As far as I can tell, that situation is not covered by the new federal law. It does not prohibit an insurer from conditioning certain benefits on taking a gene test. It prohibits them from demanding a gene test, but does that include conditioning coverage of an intervention absent a good genetic reason documented by a positive test? From the legislative language, it is not clear to me that that is what Congress means. All this assumes that genetic testing will be of value to clinicians and integration will continue, and that will be the case only if clinical decisions are directed by the results of genetic tests. Fitting testing in that context into a nondiscrimination framework may be tricky. I think it can be done, but there will be some problems along the way. To put all this in a broader context: genetic discrimination against people who have a predictable high risk as a result of their genetic varia- tions for serious disease is certainly not trivial. The problem is not genetic discrimination in insurance, but the 15 percent of our population, the 45 or 46 million Americans who do not have any coverage at all, the 60 or 65 million Americans who will spend some of 2007 with no coverage, and the additional 20 or 30 million Americans who are seriously underinsured. That is a function not of genetics or the laws of nature, it is a function of the fact that we live in the only rich country that doesn’t have a civilized health-care financing system. Interestingly, the British worry about genetic discrimination, not for health insurance because of the National Health Service, but for life insurance. They have a mortgage and banking system that makes loans heavily contingent on getting credit or life insurance which is medically underwritten. So you cannot buy a house unless you get life insurance to pay off the bank if you die before the end of the mortgage. Genetic dis- crimination is an issue based on the kind of society you live in. For them it is life insurance, for us it is health insurance. Our problem is that we do not cover everybody, and our system is likely to collapse within the next 10 years because costs keep going up too quickly. So this complicates all of our considerations, everything from how to reimburse genetic counseling to how many new oncologists will be

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 PREPARED PRESENTATIONS AND DISCUSSION needed, because it is likely we are going to have a substantially, but at present unknowably, different health-care financing system within the next 10 years. So that is an important uncertainty to keep in mind that will affect everything about genetic testing for cancer, and, of course, everything about the health-care system entirely. In the broad context of cancer, genetic testing for assessment of cancer risk is currently an interesting but relatively small issue, which is not to minimize the important efforts of the researchers working on it and all the women and men struggling with high risk. If we examine the known genetic variations that are highly correlated with cancer; BRCA-1 and -2, HNPCC, FAP, and many smaller syndromes, and we add all the people up who are likely to be diagnosed with cancer from one of those currently known genetic sources in a year, I doubt that we get to 50,000. There are 1.4 million Americans diagnosed with cancer every year. Roughly 50,000 of them are diagnosed with cancer that is probably the result of what we currently know to be cancer-related genetic variation. Probably less than one percent, perhaps 0.5 percent, of our popula- tion carries genes that we know heavily influence cancer risk. That is 1.5 to 3 million people, and those are not trivial lives in any way. But in the greater world of cancer, that is not a huge number. Twenty percent of our population is walking around with a well-known high cancer risk because they smoke. That is many, many fold the genetic risks we know about. There may be more strong genetic cancer risks out there. We have not found them yet, and they are not going to be easy to find, or we would have found them already. They will probably be multigenic, several different alleles in several different genes, probably combined with some environmental triggers as well. It is hard to know how that is going to sort out, but right now, I would say within the overall scheme of the cancer world, this is an interesting component for research purposes. Identifying the genes tells you something about the natural history and the etiology of the disease that may be useful for the sporadic cases as well. It will be helpful to some, but at present seems unlikely to be a huge driver. I think we will see more significance in cancer treatment and diagnosis using the genomes not that people are born with, but those of their tumors, to both diagnose cancer by looking for malignant cells or cell surface markers, and then by making decisions about treatment and prognosis based on tumor genetic analysis. My guess is, that will have a bigger effect on cancer in America, at least in a direct way.

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 CANCER-RELATED GENETIC TESTING AND COUNSELING Mr. Kean: People move from health insurance plan to plan as they change employers, and a lot of those require some sort of certification regarding preexisting conditions. Are those preexisting definitions included in the discrimination law, either with regard to employment or health insurance? Mr. Greely: They are covered with respect to employment in the 1996 HIPAA legislation. With respect to employer-provided coverage, genetic risks cannot be preexisting conditions. The HIPAA also limited the total period of time for a preexisting condition exclusion to 18 months. But with employer-provided coverage, genetic risks do not count for that and cannot be used. I do not recall whether the provisions of GINA cover preexisting conditions in the individual market or not. Just as another example of the complexities you run into, Kaiser Permanente is planning a study of the genetics of 500,000 Kaiser members in northern California. They already have the clinical information on them, and they are going to add genotypes. They need to get an amendment to GINA to do it, because GINA prohibits an HMO from requesting that its members take family genetic tests. Ms. Javitt: Even if GINA passes, there is still the exclusion of disability and health insurance benefits for military service members if they have a condi- tion that is found to be of genetic origin. My question is, if insurers have basically not been using genetic information to underwrite, why have they opposed GINA for 12 years? Mr. Greely: I think the answer is complicated. First, the large group insurers, as far as I can tell, did not fight that hard. It was the 800 or so small insurers that usually provide individual coverage in a handful of states who did not want any restrictions on their medical underwriting abilities in the individual market. Even their opposition has cooled significantly as more states have banned it. The real opposition here came from the National Federation of Independent Businesses, the Chamber of Commerce, and other organizations who are worried about the employment law side of it, because they do not want any new federal law that allows employers to be sued by employees for anything. Dr. Khleif: I have a question that is relevant to the United States and also relevant to the international situation. The FDA reviews studies that are being conducted by domestic and foreign investigators. Some of the foreign

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 PREPARED PRESENTATIONS AND DISCUSSION countries do not even have laws about genetic testing and discrimination. So from a bioethical perspective, what are the things that need to be taken into consideration regarding those issues? What we look for is whether the person is going to be counseled properly or not. But we do not examine the protections in that particular region of the world for the individually identifiable information that is needed for the scientific goals of the study. Mr. Greely: That is an interesting question, and not one that I have really given thought to. I would think that if you wanted to take a step beyond proper informed consent and protection against research risks, you would look at the structure of the health insurance system. In the developed world, that is not going to be a problem, because there is universal coverage. In low-income countries, it is not going to be a problem because almost all the population is not going to have coverage anyway. In middle-income countries or in the case of rich or middle-class people in the poor world, you might inquire what the structure of the health-care financing sys- tem is in that country and whether there are protections against genetic discrimination. Dr. Khleif: I wonder if there are some guidelines being developed for genetic testing and discrimination. This is an issue that is going to be more and more significant. Mr. Greely: I agree. I think that is interesting and might be a worth pur- suing. It is not going to be so much a problem with Europe or China or Korea, but I have no idea what the health-care financing system’s position on genetic discrimination is in India or Thailand or Brazil. Dr. Greene: I wonder about the numbers you suggested for carriers with high-penetrance mutations in the general population. I cannot say that I know off the top of my head what the correct number is, but when you con- sider BRCA-1 and -2, for example, people argue about what the prevalence of deleterious mutations is in the general population; one in 500 seems like a reasonable place to start. Mr. Greely: That is actually what I did. I started with BRCA-1 and -2 at 0.2 percent. I added HNPCC and FAP, probably another 0.2 percent or so. After that, the pickings get slim. There is a little bit of melanoma. There are things such as Li-Fraumeni, a very small number of people. So I think

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 CANCER-RELATED GENETIC TESTING AND COUNSELING the wiggle room between 0.5 and 1.0 percent is probably fair from what we know today. I agree that it may not be fair for what we will know in 10 years. It would have been nice if I had gone through and found all the latest numbers on all the syndromes, but from work I have done in the past, those numbers are not very solid, anyway. Dr. Weitzel: Part of the problem is that because of all the phenocopies, we are looking at only 20 percent of the people we select to test being true positives. We cannot select better than that because breast cancer pheno- copies are everywhere. It does not diminish the need for genetic testing, because with testing we identify those few that do have very high risk. Proportionately, they have a much higher impact on the health system, because if they go on without screening, they will develop disease at very highly penetrant rates. Mr. Greely: I do not disagree with that. If you take as a high estimate 10 percent of breast cancer diagnoses in women with a BRCA-1 or BRCA-2 mutation, that is about 21,000 women a year. If you do 1 percent with colon cancer, it is about 1,500 a year out of 148, 000 new cases. Those are the two most important ones among the cancer risk syndromes, and you are up to 23,000 people out of 1.4 million total new cancer diagnoses. So it is not to say they are not important, but they are not a huge percentage of the cancer burden as far as we know. Dr. Greene: We may end up testing 20 percent of those new cases in order to find the 5 percent, let’s say, that are true positive. So the application of the science allows one to identify the patients for whom genetic testing will convey the greatest benefit. Mr. Greely: Although, I think we are headed to a situation where with new technology and the expiration of the Myriad patent in 2013, we test just about everybody at low cost within the next 10 to 15 years. So, we will have population-wide numbers as well and be able to do disease prediction, and only test people who are at high risk. Dr. Harold Moses, Director Emeritus, Vanderbilt-Ingram Cancer Center and Chair, National Cancer Policy Forum: I would like to thank all the speakers. It has been very informative. I would like to thank all the people who asked questions and added to the discussion and to what I think has been a very productive workshop.