FEBRUARY/MARCH 2012 VOL4, NO 1, SUPPLEMENT by Novellus Healthcare Communications, LLC

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FEBRUARY/MARCH 2012

VOL 4, NO 1, SUPPLEMENT

SUPPLEMENT

The Role of the Clinician in Preventing Cancer:

Hereditary Cancer Assessment as an Emerging Standard of Practice

ÂŠ2012 Novellus Healthcare Communications, LLC

CE INFORMATION

Faculty Lee P. Shulman, MD, FACOG, FACMG The Anna Ross Lapham Professor of Obstetrics and Gynecology and Chief, Division of Clinical Genetics; CoDirector, Northwestern Ovarian Cancer Early Detection and Prevention Program; Feinberg School of Medicine, Northwestern University, Chicago, IL Karen J. Spielbusch, CFNP Nurse Practitioner, New Mexico Gynecology Consultants, Albuquerque, NM Intended Audience Nurse practitioners, nurse-midwives, registered nurses, health educators, physicians, physicians assistants, pharmacists, and other clinicians who provide care to women. CE Approval Period: March 1, 2012 through March 1, 2013. Estimated Time to Complete This Activity: 1.5 hours Program Description/Identification of Need The material in this program is based on material from a symposium on October 13, 2011, at the 14th Annual NPWH Premier Women's Healthcare Conference, October 12-15, 2011, Austin, Texas. A physician and a nurse practitioner discussed Hereditary Breast and Ovarian Cancer (HBOC) and Lynch syndrome, hereditary cancer testing, how to incorporate testing into practice, and how to manage patients with identified inherited risk of cancer. Case studies were presented to walk the participants through the entire process of identifying risk to counseling, testing, and managing the identified mutation carrier. The educational need for this program was assessed through a comprehensive review of current literature and an assessment of educational gaps demonstrated by past conference attendees. Numerous studies named hereditary cancer syndromes as a critical area of need for primary care provider-targeted continuing medical education. New study data, ACOG committee opinions, discussions surrounding previous research, and ACOG practice bulletins continue to be released in the field of hereditary cancers. Clinicians who work in Ob/Gyn and women’s health practices are viewed by many women as the preventative arm of medicine. In fact, if only the early diagnosis or prevention of cancer is addressed, it is typical for women to be routinely screened for breast, cervical and colorectal cancers at their annual well-woman visit or referred for further screening tests. In addition to their role as prevention specialists they may also have long-term professional relationships that increase their opportunity to counsel, edu-

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cate, allay anxiety and provide the much needed interventions necessary if a woman is identified as a mutation carrier. Educational Objectives After completing this activity, the participant will be able to: • Identify the family history and other indicators for testing for Hereditary Breast and Ovarian Cancer (HBOC) and Lynch syndrome. • Explain the benefits of risk assessment followed by hereditary cancer testing of women at a specific threshold for risk of HBOC and Lynch syndrome. • Describe the medical management strategies for the BRCA1/2 and MLH1, MSH2, MSH6, PMS2, and EPCAM mutation carriers. Accreditation Statement This activity has been evaluated and approved by the Continuing Education Approval Program of the National Association of Nurse Practitioners in Women's Health (NPWH) for 1.5 contact hours of CE credit, which includes 0.15 contact hours of pharmacology content. Faculty Disclosures NPWH policy requires all faculty to disclose any affiliation or relationship with a commercial interest that may cause a potential, real, or apparent conflict of interest with the content of a CE program. NP'WH does not imply that the affiliation or relationship will affect the content of the CE program. Disclosure provides participants with information that may be important to their evaluation of an activity. Faculty are also asked to identify any unlabeled/unapproved uses of drugs or devices described in their presentation. Lee P. Shulman, MD, is a consultant for Bayer, Teva, GSK, Sequenom, Genzyme and Myriad Genetics Laboratories, Inc.; receives research support from Bayer; and has received honoraria from Bayer, Teva, GSK, Merck, Sequenom, and Genzyme. He is on the Speakers' Bureau for Bayer, Teva, Merck, GSK, and Sequenom. Karen J. Spielbusch, CFNP, is a consultant for Myriad Genetics Laboratories, Inc. Disclosure of Unlabeled Use NPWH policy requires authors to disclose to participants when they are presenting information about unlabeled use of a commercial product or device or an investigational use of a drug or device not yet approved for any use. Disclaimer Participants have an implied responsibility to use the newly

CE INFORMATION

acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Successful Completion of the Activity Successful completion of this activity requires the participant to: (a) read the learning objectives, disclosures, and disclaimers; (b) study the material in the learning activity; (c) complete the post-test online via one of the following methods: The Ob/Gyn Nurse (1) Log on to http://www.theobgynnurse.com (2) On the home page, scroll down to Continuing Education Activities and open The Role of the Clinician in Preventing Cancer: Hereditary Cancer Assessment as an Emerging Standard of Practice, CE Activity 11-06B. (3) Print out the post-test and evaluation, complete, and return the activity evaluation and post-test answers

only to address or fax number on the post-test/evaluation form. (4) Earn a score of 70% or higher on the post-test to receive CE credit NPWH (1) Log on to http://www.npwh.org (2) Click on CE Activities in the Professional Education dropdown at the top of the page (3) Open The Role of the Clinician in Preventing Cancer: Hereditary Cancer Assessment as an Emerging Standard of Practice post-test and evaluation form, CE Activity 11-06B. (4) Print out the post-test and evaluation, complete, and return the activity evaluation and post-test answers only to address or fax number on the post-test/evaluation form. (5) Earn a score of 70% or higher on the post-test to receive CE credit Commercial Support The symposium and this program have been made possible by an educational grant from Myriad Genetics Laboratories, Inc. The symposium was sponsored by The National Association of Nurse Practitioners in Women’s Health and the Global Education Group, Inc.

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THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

The Role of the Clinician in Preventing Cancer: Hereditary Cancer Assessment as an Emerging Standard of Practice Lee P. Shulman, MD, FACOG, FACMG, and Karen J. Spielbusch, CFNP

INTRODUCTION Hereditary cancer risk assessment is considered by many to be a specialized aspect of patient care. Many women's health practitioners, while understanding some of the more challenging and complex issues of cancer risk assessment, commonly believe that such hereditary cancer risk assessment falls outside of their clinical proficiencies or are reluctant to include them in their practice. This program provides a foundation for hereditary cancer risk assessment and shows that it can be incorporated into a primary care practice.

An Overview of Cancer Genetics The malignancies discussed in this program are solid tumors comprised of cells that have undergone malignant transformation either as result of inheriting mutated genes from either parent (heritable) or have been altered as result of molecular changes within an individual cell that predispose to cancer development that were subsequently passed on to “daughter cells” that eventually resulted in the malignant transformation of the specific tissue (somatic). Regardless of the actual mechanism, the normal cellular checks and balances are altered, resulting in the cells growing and developing in a disordered manner. In the 1960s, Knudson postulated that a two-step process was required for the malignant transformation of a tissue into a malignancy.1,2 The first step can either be inherited or somatic in nature with the second step being somatic. In addition, a specific timing between the first and second steps is likely needed for malignant transformation to occur. Accordingly, even when someone inherits a deleterious mutation, there need to be some second somatic alteration occurring within a set time-frame in order for cancer to develop. For example, a woman who inherits a BRCA1 mutation is not guaranteed to develop breast cancer. In fact, the likeli-

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hood that this woman will develop breast cancer is 85% chance, as another molecular or cellular event, which has thus far not been delineated, has to occur in order for cancer to arise. Many types of genes can be involved in cancer risk; they will not all be covered in this program. Oncogenes, which when mutated are activated, are associated with malignancies such as leukemia and lymphoma. Tumor-suppressing genes are inactivated when mutated, thus altering or stopping the production of proteins and other factors that inhibit tumorigenesis. Another potential mechanism of tumor development resulting from the mutation of a tumor suppressor gene may be an alteration in the life span of a cell. Planned cellular death, or apoptosis, is a process by which cellular development and function is closely regulated in order to regulate cell and tissue growth and development. An alteration in apoptosis can allow for cells to “live” longer and expose them to somatic molecular changes that can predispose the tissue to malignant transformation. BRCA genes (BRCA1 and BRCA2) and Lynch genes (e.g., MLH1, MLH2, MSH6, PMS2) are tumor-suppressing genes. When they are active, these genes suppress tumor growth (BRCA) or correct errors in DNA base

pairs (MLH, MSH, PMS) that inhibit the development of abnormal cells and their daughter cells. Mutation of these genes inhibits their regulatory function and markedly increases the likelihood of cancer development. Major Hereditary Cancer Syndromes in Women's Health The two genetic cancer syndromes that will most likely present among women in a women's health or primary care practice are Hereditary Breast and Ovarian Cancer (HBOC) and Lynch syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). HBOC is more common, and hereditary cancers can be found across racial and ethnic groups, although some ethnic groups may have a higher frequency of certain gene mutations than other groups. Female gender and age (peri/postmenopause) are major factors associated with the risk for developing breast cancer, with family history being the most important risk factor not associated with age or gender. For carriers of genetic mutations predisposing to cancer, a positive status will indicate the need for altered surveillance in order to increase the likelihood of earlier cancer detection. Preventative measures may also be recommended, such as risk-

THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

reducing surgery and reproductive decisionmaking. For non-carriers in families with the mutation, unnecessary interventions can be avoided by determining that individuals at risk for inheriting a parents’ mutation have not inherited the said mutation. Characteristics of cancer predisposition syndromes resulting from mutated tumor suppressor genes include: earlier age at onset than in the general population, higher rate of bilaterality, associated tumors. However, there are no differences in pathology, metastatic pattern, prognosis or survival characteristics based on genetic characterization. Women with stage 1 breast cancer who are BRCA1-positive will not necessarily or not typically do better or worse than women with stage 1 breast cancer who are BRCA1-negative. However, other genetic markers can indicate prognosis, such as HER2/neu and estrogen receptor positivity in breast cancer, but they are usually markers of somatic genetic changes rather than germ line (germinal) gene alterations such as BRCA1/2 mutations. BRCA1, BRCA2 and Lynch-associated mutations convey a well described increased risk for the development of breast and ovarian cancer. However, the vast majority of women with breast cancer will be mutation negative and even a highrisk population has a relatively low frequency of individuals with BRCA1/2 mutations. For example, among women aged 35 years and under with breast cancer, only approximately 10 percent of this cohort will be BRCA1- or BRCA2-positive.3,4 Therefore, BRCA screening should not be considered as a screening modality for the general population. Breast and Ovarian Cancer Epidemiology Table 1 presents the demographics of breast and ovarian cancer, comparing the incidence of new cases and deaths between 2006 and 2010.5,6 Overall, breast and ovarian cancers consistently cause 15% and 5% of cancer deaths, respectively. Deaths due to ovarian cancer occur at a relatively high rate compared to new cancer diagnoses, most likely due to detection at later stages of the disease.

Table 1. Breast and Ovarian Cancer Epidemiology 5,6 Breast Cancer

2010

2006

New Cases

207,090 26% of all cancers

212,920 31% of all cancers

Deaths

39,840

40,970

15% of all cancer deaths

1975 to 2007 improved survival: 75% to 89% Ovarian Cancer

2010

2006

New Cases

21,880

3% of all cancers

20,180

3% of all cancers

Deaths

13,850

5% of all cancer deaths

15,310

5% of all cancer deaths

2002 to 2010: death rates decreased by 1.4%; 2005 to 2010: no change in 5-year survival

BRCA1 and BRCA2 Genes BRCA1 and BRCA2 genes are inherited in an autosomal dominant fashion and are equally likely to be transmitted from either parent. The BRCA genes are two distinct tumor-suppressing genes on different chro-

BRCA1 and BRCA2 genes are inherited in an autosomal dominant fashion and are equally likely to be transmitted from either parent. mosomes, and each has a distinct role in cell cycle regulation. A mutation of BRCA1 confers an up to 80% lifetime risk of breast cancer: 20% of BRCA1-positive breast cancers develop by age 40, 51% by age 50, and 73% by age 70.7 Again, fewer than 10% of women under the age of 35 with breast cancer are mutation carriers.3,4 Women with a BRCA1/2 mutation also have a 15-60% lifetime risk of developing ovarian cancer.7 Certain populations have historically been geographically or socially isolated and have thus increased the frequency of certain genes in their communities. In this regard, certain mutations in the BRCA1/2 genes are at a considerably increased risk in the Ashkenazi Jewish (social isolation) and Icelandic (geographical isolation)

communities. Such mutations are known as “founder mutations.” There are three mutations that are highly prevalent among Eastern European (Ashkenazi) Jews or among people of such ancestry. Two are found on the BRCA1 gene and one is found on the BRCA2 gene.8 The BRCA1 185delAG type is a common mutation in Ashkenazi Jews, among who it occurs with a frequency of 1%, as compared to 0.1% in the general population.9,10 The BRCA1 5382insC mutation occurs with a 0.1% carrier frequency in this same group.11 The BRCA 2617delT mutation confers a lifetime breast cancer risk of about 75% and a lifetime ovarian cancer risk of about 1015%11 and also confers a lifetime male breast cancer risk of 6%, which is 100-fold greater than in the general population.11 This mutation also occurs in approximately 1^% of all Ashkenazi Jews, compared to approximately 0.1% of non-Ashkenazi individuals. In Iceland, a founder mutation on BRCA2 (999delG) is associated with approximately 7% of ovarian cancers.12,13 Ovarian Cancer The epidemiology of ovarian cancer is summarized in Table 2. The baseline population risk is 1.5%14 and rises to about 5%15,16 and 7%15 in women with 1 or 2 first degree relatives (mother, sister, child) who have had the cancer. Women with HBOC have an up to 40-60%% lifetime risk of developing ovarian cancer and those with known BRCA mutations can have a lifetime risk of anywhere between 10 and 60%.14,17

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Table 2. Ovarian Cancer Risk Family History of Ovarian Cancer

Approximate Lifetime Risk

None

1.5%14

1 first-degree relative

5%15,16

2 first-degree relatives

7% - varies with age of patient and age of relatives at diagnosis15

Lynch syndrome - Hereditary Nonpolyposis Colon Cancer (HNPCC)

10%14

Hereditary Breast and Ovarian Cancer (HBOC) syndrome

40%17

Known BRCA1 or BRCA2 mutation

10-50%14,17

Table 3. "Red Flags" Hereditary Breast and Ovarian Cancer (HBOC)21,22 Lynch Syndrome (HNPCC)18-20,23-25 • Breast cancer diagnosed at <50 years of age • Ovarian cancer at ANY age • 2 or more breast cancers in one individual • Breast and ovarian cancer in one individual • Ashkenazi (Eastern European) Jews with an HBOC associated cancer • Male breast cancer at ANY age • Previously identified BRCA mutation

Lynch Syndrome - Hereditary NonPolyposis Colorectal Cancer (HNPCC) Women with breast cancer can be considered to have HBOC given the appropriate family history or genetic testing outcome. However, ovarian cancer can be considered to be a component of HBOC as well as Lynch syndrome. Lynch syndrome is characterized by an increased risk for colon, endometrial, and ovarian cancers, as well as other solid tumors.18 Because of the increased risk for colon cancer, colonoscopy is an important component of the screening of individuals with Lynch syndrome, as is regular evaluation of the endometrium in affected women.19 Only those individuals with profound family histories are offered genetic testing according to Bethesda Guidelines.20 Other individuals with less severe family histories, but who have suspicious endometrial or colonic lesions, are evaluated for germinal genetic mutations. This is done by evaluating the tissue using immunohisto-

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• Colorectal/endometrial cancer <50 • Multiple Lynch-related cancers in an individual/family • Previously identified mutation

chemistry for the absence of certain proteins that are indicative of gene mutations in one of the mismatch repair (MMR) genes associated with Lynch syndrome.19 Guidelines for Hereditary Cancer Testing Table 3 lists key “red flags” to help identify which patients may have HBOC or Lynch syndrome. These women should be referred for counseling and consideration

The rationale for hereditary cancer risk assessment is to determine optimal patient screening modalities. of genetic testing. It is important to recognize that women whose fathers have a family history of breast, ovarian or colon cancer as well as having fathers with breast or colon cancer are potentially at the same

increased risk as if the woman’s mother or her family were similarly affected. In some practices, women of Ashkenazi Jewish descent are automatically tested because of this ethnic group's higher incidence of HBOC mutations; however, such testing is not recommended unless there is some family history of breast or ovarian cancer, as even in this high-risk community, the overall frequency of BRCA mutations is less than 5%. For Lynch syndrome, investigation is indicated in women under the age of 50 who have had colorectal or endometrial cancer, women with a number of family members who have had Lynch-related cancers, and women with a previously identified Lynch syndrome mutation. Effectively Implementing Risk Assessment in Your Practice The American College of Obstetricians and Gynecologists (ACOG) has published a number of opinions and recommendations on reviewing a patient’s family history and that it is crucial in determining the risk of inherited medical conditions and diseases.21,26,27 They recommend regular review of family history information, additional evaluation of patients as needed, and the inclusion of cancer risk assessment as a part of routine practice. Women's healthcare providers and primary care practitioners are thus tasked with incorporating such assessments into the routine care of their patients. The rationale for hereditary cancer risk assessment is to determine optimal patient screening modalities, including the need for increased surveillance or the possibility of chemoprevention or prophylactic measures to reduce the occurrence of cancer. Given the many tasks that need to be accomplished during an office visit, how does one include hereditary cancer risk assessment into the annual visit? Should patients be referred for genetic counseling? Unfortunately, many patients referred for genetic counseling fail to make an appointment and others are lost to followup by their primary care provider. Patients are most comfortable with their own care providers, and primary care providers and

THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

nurse practitioners can provide cancer risk assessment for most of their patients. A genetic counselor is a valuable resource who needs to be involved in complex cases when there is a shortage of trained genetic professionals in a particular community; the baseline assessment and even testing can be undertaken by many primary care providers. Patient and Family Information Personal history is only one piece of the process that helps determine hereditary cancer risk. Because hereditary cancer syndromes are autosomal dominant, both parents’ family histories are important. Family history should include at least the previous two generations, and try to obtain information from even more distant relatives, as hereditary cancers can skip a generation. Of clinical import is not just the number of relatives that have had a specific cancer, but the age at which they were diagnosed. Furthermore, relative risks are higher in families with affected first-degree relatives.28 Early onset of breast cancer, colon cancer, or uterine cancer is a red flag for an increased likelihood of hereditary cancers. In addition, multiorgan cancers also indicate an increased risk for a heritable cancer syndrome. A relative having both breast and ovarian cancer at any age is thus highly suspicious for HBOC. From the perspective of the office visit, a standard questionnaire can be very effective in obtaining important family history information that will help to determine cancer risk. (See Appendix 1.) The questionnaire is completed by new patients and by all patients each time they come for their annual exam. A routine series of questions takes only a couple of minutes to answer, starting with yes or no questions, such as: Have you ever had breast cancer? Ovarian cancer? Uterine cancer? Colon cancer? Has anybody in your family had a history of breast cancer (male or female), ovarian cancer, uterine cancer; and if so, at what age were they diagnosed? The answers to these questions will quickly provide an indication of whether the patient is at an increased risk of developing hereditary cancer. If any of the responses are

“yes,” the details need to be confirmed and the list of “red flags” (Table 3) reviewed. Propensity for hereditary cancer and the need for further counseling and possibly testing is then addressed and discussed, explaining that some management decisions may depend on further evaluation. Patients are informed that based on the results of their further evaluation, they may be referred to a specialist, who will then discuss their specific management options. The additional time needed for this is only a few minutes. Interpreting Test Results Interpretation of genetic test results can be challenging and may require input from genetics or cancer specialists. A positive test informs the healthcare provider and patient that the risk for developing the specific genetic-related cancers has increased and that a change in surveillance for these malignancies is now warranted. If testing results are negative, it means that the

Women identified with a cancer risk, are not told that they will develop cancer, but rather, that their risk of developing cancer is higher than that of the general population. patient has not inherited the recognized gene or genes that predispose to an increased risk for cancer development. If the testing is being performed because of a relative with a known gene mutation, then a negative result may presage a risk assessment similar to the general population. However, if testing is being performed to assess risk in a person or family without a known mutation, then a negative result may not result in a lower risk for cancer development. A further complication in the assessment of results is found in cases characterized by a genetic variant of undetermined significance (VUS), a finding of a genetic alteration that has not been associ-

ated with either a benign or deleterious genomic state. Testing Concerns A big concern for patients and providers is the cost and impact of genetic testing. Actual coverage for genetic testing guidelines for hereditary cancers varies throughout the United States and many patients may find themselves having to pay several hundred to several thousands of dollars for genetic testing. Contacting insurance providers prior to undergoing testing is an important part of the process by which individuals choose to undergo or forego such testing. As for Medicare, it only covers genetic testing if the patient is already affected, not if they have a higher risk due to a family member(s) with cancer. Another concern is that such testing, or even the consideration of such testing, may serve to identify them at high risk for developing cancer and thus lead to discrimination in a variety of situations including insurability and employment. However, the Genetic Information Nondiscrimination Act of 2008 (GINA) prohibits the use of such information by healthcare insurers and others.29 Management of the Woman with Identified Cancer Risk Women identified with a cancer risk, whether due to a gene mutation or a considerable family history, are not told that they will develop cancer, but rather, that their risk of developing cancer is higher than that of the general population. Keep in mind that cancer risk assessments are mathematical models and are therefore not perfect. In addition, negative genetic test results do not guarantee protection from cancer. Breast Cancer Key risk factors for breast cancer are: 28,31,32 • Age • Family history of breast cancer • Diet and lifestyle (obesity, excessive alcohol consumption) • Increased estrogen exposure – Early menarche – Late menopause

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THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

Table 4. Potential for HBOC 21,22 Patients with 5-10% Chance of Being in an HBOC Family • Breast cancer at ≤40 years of age • Bilateral breast cancer (esp. if 1st occurred before age 50) • Breast cancer at ≤50 years of age and close relative with breast cancer at ≤50 years of age • Jewish women with breast cancer at ≤50 years of age − 2 or more close relatives falling into any of these categories Patients with >25% Chance of Being in an HBOC Family • Personal history of both breast and ovarian cancer • Have ovarian cancer AND close relative with ovarian cancer (any age) or breast cancer (<50 years of age) • Jewish women with ovarian cancer (any age) or breast cancer (≤40 years of age) • Have breast cancer (<50 years of age) and close relative with ovarian cancer (any age) or male with breast cancer • 1° or 2° relative with known BRCA1 or BRCA2 mutation

Table 5. 2007 American Cancer Society Guidelines for MRI Breast Screening33 • Women at high risk (>20% lifetime risk) − MRI plus mammogram every year • Women at moderately increased risk (15-20%) − Consult with their doctor about benefits and limitations of adding MRI to yearly mammograms • Women with lifetime risk <15% − Yearly MRI screening is not recommended

– Postmenopausal hormone therapy >5 years – Postmenopausal estrogen therapy >15 years These are valid whether or not the patient has a deleterious genetic mutation. Overall, women in the United States have a lifetime probability of about 12% for developing breast cancer.30 Breast cancers resulting from deleterious gene mutations are estimated to account for approximately 5% of cases.28 Table 4 summarizes two levels of potential for HBOC-related breast cancer. The obvious implication of hereditary cancer risk assessment and genetic testing is to have an improved ability to accurately assess risk and reduce morbidity and mortality. Such guidelines are helpful in identifying women who would best be served by counseling or a more detailed evaluation. What action should be taken with a woman at high risk of developing breast

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cancer? The American Cancer Society issued guidelines in 2007 for MRI breast screening, as summarized in Table 5.33 In some practices, the MRI and mammograms are staggered by six months with interspersed breast exams. This allows for

As already mentioned, there are no clinically proven effective screening modalities for ovarian cancer. some assessment of the high-risk woman on a quarterly basis. Whether this approach of different assessments at different times results in better outcomes than a more convenient, consolidated schedule is currently unknown. With regards to conservative prophylac-

tic options, tamoxifen is recommended for consideration by women with a 5-year risk of developing breast cancer over 1.6%.34,35 In this population, the greatest benefit is seen among premenopausal women, in women without a uterus, and in women with a 5-year risk of over 5%. Prophylactic total mastectomy is an option that has been shown to reduce the risk of breast cancer in BRCA mutation-positive women by 90%.36 This is obviously neither a conservative nor benign option and is, unfortunately, not 100% effective in preventing breast cancer. Ovarian Cancer While the risk of developing breast cancer in the general population is about 12%,37 the lifetime risk of developing ovarian cancer is only about 1.5%.38 Despite this comparatively lower risk, ovarian cancer is the fifth most common cause of cancer death among women in the United States.14 It is a cancer that is usually detected at a later stage, when the prognosis is poor because surgical and medical interventions are not effective in treating the disease.14,39 The comprehensive 5-year survival rate, about 45%, has not changed for some time, which is considerably skewed as the 5-year survival rate for Stage III-IV cancers is only 12% compared to over 90% for Stage 1 lesions.6,40 A number of strategies can be undertaken to reduce the risk of ovarian cancer. These are shown in Table 6. In general, the premise centers around the inhibition of ovulation. Oral contraceptive use has also been found to reduce the risk of ovarian cancer (see Table 6), and this includes both older formulations and newer combination contraceptives.41 Of note is that oral contraceptives have not been found to increase the risk of breast cancer in patients with BRCA mutations.42 For women with deleterious genetic mutations, premenopausal salpingooophorectomy can be offered upon completion of childbearing,21 which confers an 8595% risk reduction.14 Unfortunately, the possibility still exists for developing pelvic or abdominal epithelial cancer. As already mentioned, there are no clinically proven effective screening modalities for ovarian cancer. Goff and colleagues

THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

studied symptom presentations, their frequency, severity and duration in the attempt to determine whether specific symptoms could help identify women at risk and with an earlier and more treatable form of the disease.39 In their case-controlled study they evaluated symptoms that were considered positive indicators if they occurred more than 12 times a month and were present for less than 1 year. These were pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full. Unfortunately, these symptoms are non-specific and may occur in healthy women as well as in women with advanced stage disease. In an attempt to identify ovarian cancer at an early stage, van Nagell and colleagues studied the efficacy of annual transvaginal sonography.45

Lynch syndrome also predisposes to ovarian cancer...but not an increased likelihood of breast cancer. Their research showed some success in detecting ovarian cancers, but there were also missed cases: the positive predictive value (PPV) of an abnormal ultrasound was found to be only 14%. Biomarkers for ovarian cancer are a problematic issue. One such marker, CA125, can be elevated in a number of benign gynecologic conditions such as endometriosis, pelvic inflammatory disease, and even during ovulation. HE4, especially in combination with CA-125, has been found to have an improved ability in differentiating benign from malignant tumors in women who already have a pelvic mass.46 Despite these small advancements, there is no evidence to support increased surveillance that will detect early-stage lesions and improve morbidity and mortality rates associated with ovarian cancer.47 Lynch syndrome also predisposes to ovarian cancer, where family history can be associated with endometrial, colon, or ovarian cancers but not an increased likelihood of

Table 6. Ovarian Cancer Risk Reduction14 Modalities

Notes

• Birth control pills (oral contraceptives) • First full-term pregnancy before age 25; number of pregnancies • Breastfeeding • Bilateral tubal ligation/ hysterectomy – RR 0.33/0.67 • Prophylactic oophorectomy − Risk of primary peritoneal cancer remains

• Oral contraceptive use reduces the risk of developing ovarian cancer41,43 − 5 years of use: 35% reduction − 10 years of use: 45% reduction − 15 years of use: 65% reduction • Women with BRCA1 and BRCA2 mutations who had used oral contraceptives for 6 years or more had a 50-60% lower risk of ovarian cancer44 • No increase in incidence of breast cancer found in women with BRCA1 or BRCA2 mutations taking low-dose oral contraceptives42

breast cancer. More frequent colonoscopy and endometrial surveillance beginning during the reproductive years is recommended to evaluate women carrying deleterious Lynch-associated gene mutations.20 Endometrial Cancer Lynch syndrome accounts for 2-5% of all colorectal and endometrial cancers.48 The American Cancer Society recommends that women with Lynch syndrome, or those who are likely to carry a mutation and those who have a strong family history of colon cancer, be offered a yearly endometrial biopsy to test for endometrial cancer.49 Prevention strategies to reduce the risk of endometrial cancer in women at increased risk include the use of hormonal contraceptives, intrauterine contraceptive devices, weight reduction and lifestyle modification, pregnancy and breastfeeding, and, after completion of childbearing, hysterectomy. While the use of hormonal contraceptives is again at the center of conservative prevention strategies, it is not the inhibition of ovulation that is the foundation of risk reduction for endometrial cancer, but rather the progestigenic prevention of endometrial proliferation, which is also accomplished by intrauterine contraceptives.49 Case Examples The following two simplified cases help

to illustrate situations which may arise in practice and provide issues to consider regarding hereditary cancer risk assessment and follow-up of healthy women. Case 1 42-year-old unaffected woman • paternal grandmother with breast cancer at age 49 • paternal aunt with ovarian cancer at age 56 Would you recommend genetic testing for this patient? This patient has two red flags: family history of ovarian cancer at any age and family history of breast cancer under age 50. She is a candidate for genetic testing. How would you manage this patient’s risk? This will depend on whether the genetic testing comes back positive or negative. Most such women are going to be negative, which may not reduce her risk for developing breast cancer. With negative genetic testing results, this woman's breast cancer and ovarian cancer risks are still somewhat elevated as result of her family history. Using the Tyrer-Cuzick Model (available at http:// www.ems-trials.org/riskevaluator/), her risk of breast cancer is 14.4%, which is higher than that of the general population. According to the American Cancer Society (ACS) guidelines, her increased risk is not at a level high enough to war-

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THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

rant annual breast MRI screening.50 However, she should be undergoing annual mammographic examinations, as the ACS recommends the commencement of mammographic screening of women with a family history of breast cancer at an age commensurate with 10 years earlier than the youngest age at which their relative(s) were diagnosed.50 As such, she should have begun mammographic examinations at the age of 39.

The role of the primary care provider is critical for [women at risk]...the overall process may be far better accepted by [the woman] regardless of outcomes because of that strong and familiar clinician-patient relationship. With positive genetic testing results (BRCA1/2), this woman could have an up to 87% lifetime risk of breast cancer and up to 44% of ovarian cancer. Management considerations would then include annual mammograms and breast MRI, consideration of chemoprevention, and possibly riskreducing surgery. The role of the primary care provider is critical for these women, as the provider that has the closest clinical relationship with this patient, is best suited to provide medical and emotional support as she goes through the counseling, screening and diagnostic processes. Indeed, if that primary care provider was the health care professional that provided the initial cancer risk assessment and counseling, the overall process may be far better accepted by the woman and her family regardless of outcomes because of that strong and familiar clinician-patient relationship. Case 2 Healthy 40-year-old woman • father died of colon cancer at age 48

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• sister was diagnosed with endometrial cancer at age 42, and is not in communication with the patient Would you recommend genetic testing for this patient? Unfortunately, there is no access to the affected family members to have them tested or to learn whether they were tested and what the results were, so this woman may be a good candidate for genetic testing. How would you manage this patient’s risk? If her genetic testing results are positive for Lynch syndrome, then she has an up to 80% lifetime risk of colon cancer (6580%) and will need to be screened with colonoscopy every 12 to 18 months. Her risk of endometrial cancer will also be elevated (27-71%), so she should be offered an annual endometrial biopsy or transvaginal ultrasound examination to evaluate her endometrium.49 As her risk of ovarian cancer is increased (9-12%), she should be offered an annual pelvic examination and ultrasound evaluation, and should be strongly encouraged to initiate oral contraceptives if they are not contraindicated, she is premenopausal, and she does not wish to conceive. In the case of negative mutation test results, she may still have an increased risk of colon cancer and should be screened every 3-5 years. Her risk of endometrial and other cancers are the same as for the general population and normal monitoring would be required, e.g., endometrial biopsy if she has abnormal spotting.

SUMMARY • Genetic factors clearly influence the development of gynecologic malignancies (except for cervical cancer). • Most gynecologic malignancies occur in women with little or no family history of the malignancy. • Obtaining and reviewing family history remains a vital component of women’s health care. • If there is a family history of gynecologic cancers, then detection of gene mutations that increase the likelihood of cancer development may improve clinical outcomes.

• Women at increased risk for cancer predisposition syndromes (based on family history) should be offered genetic testing within the context of counseling. • Primary care providers can provide the assessment, counseling and testing for many of their patients. While referral to genetic specialists may be needed in some cases, the initial family history, counseling and testing can be easily performed by the patient’s primary care provider, a clinician who has developed a strong relationship that can facilitate optimal evaluation and care. Because of the death of geneticists and genetic counselors, it is the primary care or woman's healthcare practitioner who may have the biggest impact on performing cancer risk assessment.❖ References 1. Knudson A. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA.1971;68(4): 820-823. 2. Knudson A. Antioncogenes and human cancer. Proc Natl Acad Sci USA.1993;90:10914-10921. 3. Peto J, Collins N, Barfoot R, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst.1999;91(11):943-949. 4. Malone KE, Daling JR, Neal C, et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer.2000;88 (6):1393-1402. 5. American Cancer Society. Cancer Facts &Figures 2006. Atlanta: American Cancer Society; 2006. 6. American Cancer Society. CancerFacts& Figures2010. Atlanta: American Cancer Society; 2010. 7. Brose MS RT, Calzone KA, Stopfer JE, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst.2002;94(18): 1365-1372. 8. Metcalfe K LH, Ghadirian P, Tung N, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22 (12):2328-2335. 9. Struewing JP AD, Peretz T, Avishai N, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet. 1995;11(2):198-200. 10. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New Engl J Med. 1997; 336(20):1401-1408. 11. Roa BB BA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA 1 and BRCA2. Nature Genetics.1996;14:185-187. 12. Johannesdottir G, Gudmundsson J, Bergthorsson JT, et al. High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res.1996; 56(16):3663-3665. 13. Mikaelsdottir EK, Valgeirsdottir S, Eyfjord JE, et al. The Icelandic founder mutation BRCA2 999del5: analysis of expression. Breast Cancer Res. 2004;6(4):R284-290. 14. American Cancer Society.Ovarian Cancer. 2011. http://www.cancer.org/acs/groups/cid/documents/webcontent/003130-pdf.pdf.Accessed November 14, 2011. 15. Stratton JF, Pharoah P, Smith SK, et al. A systematic review and meta-analysis of family history and risk of ovarian cancer. Br J Obstet Gynaecol.1998;105(5):493-499.

THE ROLE OF THE CLINICIAN IN PREVENTING CANCER

16. Schildkraut JM, Risch N, Thompson WD. Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship. Am J Hum Genet. 1989;45(4):521-529. 17. Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. 18. Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76(1):1-18. 19. Shulman L. Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA 1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome. Clinical Obstet Gynecol Clin N Am. 2010;37:109-133. 20. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261-268. 21. American College of Obstetricians and Gynecologists; ACOG Committee on Practice Bulletins--Gynecology; ACOG Committee on Genetics; Society of Gynecologic Oncologists.ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2009;113(4):957-966. 22. Lancaster JM, Powell CB, Kauff ND, et al. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2007;107(2):159-162. 23. Vasen HFA, Wijnen JTh, Menko FH, et al. Cancer Risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110(1020-1027). 24. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81:214-218. 25. Plaschke J, Engel C, Kruger S, et al. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol. 2004;22(22):4486-4494. 26. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 478: Family history as a risk assessment tool. Obstet Gynecol. 2011;117 (3):747-750. 27. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG Committee

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Opinion No. 483: Primary and preventive care: periodic assessments. Obstet Gynecol. 2011;117(4): 1008-1015. Henderson IC. Breast Cancer. In: Gerald P. Murphy WL, Jr, Ratmond E. Lenhard, Jr, ed. American Cancer Society Textbook of Clinical Oncology. 2nd edition ed. Atlanta: American Cancer Society; 1995:198-219. U.S. Department of Health & Human Services. Genetic Information. Genetic Information Nondiscrimination Act (GINA) 2008; http://www.hhs.gov/ocr/privacy/ hipaa/understanding/special/genetic/.Accessed November 14, 2011. National Cancer Institute. FactSheet. Probability of breast cancer in american women, September 17, 2010; www.cancer.gov/cancertopics/factsheet/detection/Fs5_ 6.pdf. Accessed November 14, 2011. Harris J, Morrow M, Norton L. Malignant Tumors of the Breast. In: Vincent T. DeVita Jr, Samuel Hellman, Steven A. Rosenberg, eds. Cancer: Principles & Practice of Oncology. 5th edition. Philadelphia: Lippincott-Raven Publishers; 1997:1557-1616. Trichopoulos D, LipworthL, Petridou E, Adami H-O. Epidemiology of Cancer. In: Vincent T. DeVita Jr, Samuel Hellman, Steven A Rosenberg, eds. Cancer: Principles & Practice of Oncology. 5th edition. Philadelphia: Lippincott-Raven Publishers; 1997:231-257. Saslow D, BoetesC, Burke W, et al. for the American Cancer Society Breast Cancer Advisory Group. American Cancer Society Guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89. Chlebowski RT, Col N, Winer EP, et al. for the American Society of Clinical Oncology Breast Cancer Technology Assessment Working Group. American Society of Clinical Oncology Technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol. 2002;20(15):3328-3343. Cuzick J, Forbes J, Edwards R, et al.; IBIS investigators. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360 (9336):817-824. Meijers-Heijboer H, van Geel B, van Putten WLJ, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. New Engl J Med. 2001;345 (3):159-164. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/ 1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.http:// seer.cancer.gov/statfacts/html/breast.html. Accessed

November 14, 2011. 38. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/ 1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.http://seer. cancer.gov/statfacts/html/ovary.html. Accessed November 14, 2011. 39. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index. Cancer. 2007;109 (2):221-227. 40. American Cancer Society. Cancer Facts & Figures 2005. Atlanta: American Cancer Society; 2005. 41. Hannaford PC, Sivasubramanian S, Elliott AM, et al. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study. Br Med J. 2007;335(7621):651658. 42. Milne RL, Knight JA, John EM, et al. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2005;14(2):350-356. 43. Collaborative Group on EpidemiologicalStudies of OvarianCancer, Beral V, Doll R, Hermon C, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008;371 (9609):303-314. 44. Narod SA, Risch H, Moslehi R, et al., for The Hereditary Ovarian Cancer Clinical Study Group. Oral contraceptives and the risk of hereditary ovarian cancer. New Engl J Med. 1998;339:424-428. 45. van Nagell JR, DePriest PD, Ueland FR, et al. Ovarian cancer screening with annual transvaginal sonography. Cancer. 2007;109(9):1887-1896. 46. Moore RG, Brown AK, Miller MC, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. 2008;108(2):402-408. 47. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995;273(6):491-497. 48. Singh H, Schiesser R, Anand G, et al. Underdiagnosis of Lynch syndrome involves more than family history criteria. Clin Gastroenterol Hepatol. 2010;8(6):523-529. 49. American Cancer Society. Uterine Cancer. 2011. http:// www.cancer.org/acs/groups/cid/documents/webcontent/ 003097-pdf.pdf.Accessed November 16, 2011. 50. American Cancer Society. Breast Cancer: Early Detection. 2011. http://www.cancer.org/acs/groups/cid/ documents/webcontent/003165-pdf.pdf.Accessed November 16, 2011.

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APPENDIX 1

Family History Questionnaire Patient Name:

Provider:

Date of Birth:

Date Completed:

Instructions: Please circle Y or N as they apply to YOU and your family (mother AND father's side). Beside each statement, please list the family member’s relationship to you (e.g.: self, paternal uncle, maternal aunt, paternal grandmother) and their age at diagnosis. Each statement should be answered individually, so you may list the same cancer diagnosis more than once. This is a screening tool for the common features of hereditary cancer syndromes. If you circle Y to any statements below, you MAY be appropriate for genetic testing. Ask your healthcare provider for additional information. BREAST/OVARIAN CANCERS PERSONAL HISTORY Y N

Have you had breast cancer

Y N

Have you had cancer in both breasts

Y N

Multiple cancers in SAME breast

Y N

Have you had ovarian cancer

RELATIONSHIP / AGE AT DIAGNOSIS

FAMILY HISTORY Has anyone in your family ever had: Y N

Breast Cancer

Y N

Ovarian Cancer

Y N

Males with breast cancer in your family

Y N

Are you of Ashkenazi Jewish ancestry

MATERNAL OR PATERNAL

COLON/UTERINE CANCERS PERSONAL HISTORY Have you ever had:

RELATIONSHIP / AGE AT DIAGNOSIS

Y N

Uterine Cancer

Y N

Colorectal Cancer

Y N

Ovarian Cancer

Y N

Stomach, Kidney/Urinary Tract, or Brain Cancer

Y N

Small Bowel Cancer

FAMILY HISTORY Has anyone in your family ever had:

MATERNAL OR PATERNAL

Y N

Uterine Cancer

Y N

Colorectal Cancer

Y N

Ovarian Cancer

Y N

Stomach, Kidney/Urinary Tract, or Brain Cancer

Y N

Small Bowel Cancer

COLON POLYP HISTORY MATERNAL OR PATERNAL Y N

10 or more colon polyps in a lifetime

Candidate for further risk assessment and/or genetic testing

Patient offered genetic testing

Information given to patient to review

Accepted

Follow up appointment scheduled Date: __________________

Not a candidate for testing

BRCA testing

Lynch syndrome

Patient Signature

Date

Provider Signature

® Declined

Date

NOTES

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