Breast Cancer Risk Assessment and Genetic Testing

Slide 1:Breast Cancer Risk Assessment and Genetic Testing

Susan W. Caro, RNC, MSN, APNG Director, Family Cancer Risk Service Vanderbilt-Ingram Cancer Center

Slide 2:Objectives:

1. Appreciate the complex and emerging information about the impact of genetics on breast cancer risk. 2. Identify resources available for assessing genetic risk. 3. Articulate when risk counseling and assessment is recommended. 4. Know the TN resources for genetic risk assessment.

Slide 4:Why?

Hereditary cancer syndromes are being more clearly defined with increasingly clear recommendations for management. Clinical genetics tests for hereditary cancer syndromes are available and in some markets are being marketed directly to the consumer. Recognizing hereditary cancer syndromes provides the opportunity to identify those at significantly increased risk and offer options to identify cancers earlier or prevent cancer in these individuals. Potential for medico-legal implications of not recognizing hereditary cancer syndromes. Lynch HT, Paulson JD, Severen M, et al. Failure to Diagnose Hereditary Colorectal Cancer and Its Medicolegal Implications. Dis. Colon Rectum January 1999;42:31-35.

Slide 5:Hereditary Cancer Burden in Tennessee?

Breast Cancer 3,720 new diagnoses 920 deaths Colorectal Cancer 3,290 new diagnoses 1130 deaths If ~10% hereditary cancer � 372 new cases of hereditary breast cancer (392 CRC) this year. Could some of these have been foreseen, even prevented? *Excludes carcinoma in situ (CIS, non-invasive cancer) of any site except urinary bladder. Does not include basal and squamous cell skin cancers (of which there are 1.3 million per year). American Cancer Society, 2008

Slide 6:Prevention (medical)

In medicine, prevention is any activity which reduces the burden of mortality or morbidity from disease. This takes place at primary, secondary and tertiary prevention levels. Primary prevention avoids the development of a disease. Most population-based health promotion activities are primary preventive measures. Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms. Tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications. Wikipedia

Slide 7:All cancer is genetic, not all cancer is hereditary.

Slide 8:Breast Cancer Genes Found

BRCA1 (for BReast CAncer gene 1) was described in 1990 on chromosome 17, isolated in 1994 BRCA2 was isolated on chromosome 13 in late 1994 BRCA3?

Slide 9:The Development of Hereditary Cancer

1 damaged gene 1 normal gene 2 normal genes 2 damaged genes In hereditary cancer, one damaged gene is inherited. 1 damaged gene 1 normal gene 2 damaged genes � 2006 Myriad Genetic Laboratories, Inc. Myriad Genetics, Inc. S5: The Development of Hereditary Cancer A normal cell has two functional copies of each gene. Some genes (including p16) function as tumor suppressors, helping repair DNA damage and keeping the damaged cells from becoming cancerous. In a cell with two functional copies of a specific tumor suppressor gene, if only one copy of the gene is damaged, the cell will still function properly as the second �back up� copy of the gene is still functional. If the other copy of the gene is damaged within the same cell, the tumor suppressor function of the gene is taken away and the cell can become cancerous. This damage can occur through lifestyle, environmental exposures (carcinogens), and most commonly the normal aging process of cells. The chances of both copies of an important tumor suppressor gene being independently knocked out in the same cell are extremely small. Individuals with hereditary cancer have inherited one nonfunctional copy of a specific tumor suppressor gene in every cell of their body. Therefore these individuals require only one additional mutation to knock out the functional copy of the gene, making cancer development much easier. S5: The Development of Hereditary Cancer A normal cell has two functional copies of each gene. Some genes (including p16) function as tumor suppressors, helping repair DNA damage and keeping the damaged cells from becoming cancerous. In a cell with two functional copies of a specific tumor suppressor gene, if only one copy of the gene is damaged, the cell will still function properly as the second �back up� copy of the gene is still functional. If the other copy of the gene is damaged within the same cell, the tumor suppressor function of the gene is taken away and the cell can become cancerous. This damage can occur through lifestyle, environmental exposures (carcinogens), and most commonly the normal aging process of cells. The chances of both copies of an important tumor suppressor gene being independently knocked out in the same cell are extremely small. Individuals with hereditary cancer have inherited one nonfunctional copy of a specific tumor suppressor gene in every cell of their body. Therefore these individuals require only one additional mutation to knock out the functional copy of the gene, making cancer development much easier.

Slide 10:American Society of Clinical Oncology Guidelines for Genetic Testing

Personal or family history features suggestive of hereditary cancer risk Test can be adequately interpreted Test result will aid in diagnosis or influence medical management of the patient and/or family J Clin Oncol 2003;21:2397-406 Slide 19: Guidelines for Cancer Predisposition Testing For an individual whose personal and/or family history suggests the possibility of a hereditary melanoma syndrome, only a genetic test can confirm whether he/she carries a mutation in the p16 gene. The American Society of Clinical Oncology (ASCO) has recommended that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.1 These criteria can be applied to identify appropriate candidates for genetic testing for hereditary melanoma. Reference: 1. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397-406. Slide 19: Guidelines for Cancer Predisposition Testing For an individual whose personal and/or family history suggests the possibility of a hereditary melanoma syndrome, only a genetic test can confirm whether he/she carries a mutation in the p16 gene. The American Society of Clinical Oncology (ASCO) has recommended that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer.1 These criteria can be applied to identify appropriate candidates for genetic testing for hereditary melanoma. Reference: 1. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397-406.

Slide 11:Cancer Syndromes

Hereditary Breast Cancer Syndromes BRCA1, BRCA2, Cowden, CHEK2, Li-Fraumeni Hereditary Colorectal Cancer Syndromes HNPCC FAP Endocrine Syndromes � VHL, MEN1, MEN2, FMTC Other � Li Fraumeni, Peutz-Jeghers DNA Banking

Slide 12:Ask � out loud

Ask the question: Do you have a family history of cancer? Clarify - maternal AND paternal family history Ask the question again more specifically: Does anyone in your family have a history of breast, ovarian, colon cancer, colon polyps, or other cancers? Ask the question again at follow up visits, as family histories change over time. FCRS

Slide 13:Listen when your patients voice a concern:

In many health care encounters today, we are focused on the problem at hand and it is difficult to go beyond this. Not suggesting that every health care provider have an expert knowledge of the complex issues surrounding all of the hereditary cancer syndromes - rather that continual exposure to this information will prompt recognition and referral for more thorough evaluation of the family. A significant number of our patients seek consultation independently. Their health care providers do not always recognize the significance of family history.

Slide 14:Refer

Refer for comprehensive risk assessment and consideration of genetic testing. Genetic testing is only one aspect of this. There is a great deal to be learned from gathering and documenting the family history and the educational component of the counseling process. Many patients are concerned as a result of things they have read or been told about insurance discrimination. This is addressed in the counseling session (before any decision for genetic testing is made).

Slide 15:Family Cancer Risk Consultation

Should include: Education about cancer risk in families Cancer/genetic risk assessment Discussion of possible risks and benefits of genetic testing Psychological support, guidance about medical options, and referral for medical or surgical means of early detection or prevention of cancer Offit, 1998, p. 3

Slide 16:Comprehensive Risk Assessment / Consultation

Assess patient�s view of their risk, experience with cancer in the family Review what is known and not known about cancer risk Medical history, current surveillance activity Review family history and draw pedigree Document cancers in history (medical record and pathology review) Provide risk assessment - Risks associated with hereditary cancer syndromes under consideration, risks if no recognizable syndrome Education - Cancers, risks factors, surveillance, basic genetics, cancer genetics Testing? Benefits, limitations, risks, costs, insurance, process Recommendations for surveillance or possible preventive measures, discuss implications to others in family. Interpretation of test results, including psychological, social, and family implications of test results

Slide 17:Management Options / Counseling

Review options for increased screening or measures to decrease risk Discuss efficacy (or lack of efficacy/ or lack of data to support efficacy) of surveillance, prophylactic / risk reducing, or chemopreventive measures Increasing understanding of utility and consequences of surveillance and intervention options � a moving target.

Slide 18:How Much Breast and Ovarian Cancer Is Hereditary?

Sporadic Family clusters Hereditary Ovarian Cancer Breast Cancer 5%�10% 5%�10% 15%?20%

Slide 20:BRCA Mutations and Ashkenazi Jews

185delAG mutation noted in 1% of 850 samples of Ashkenazi Jewish individuals unselected for family history of cancer (studied stored samples from Tay-Sachs research) Carrier rate 3 X that expected in general population May account for 16% of breast and 39% of ovarian cancer in AJ women <50 2 other �founder mutations�

Slide 21:Male Breast Cancer and BRCA2

Studies of BRCA2 in population- and clinic-based series of male breast cancer patients from the United States and Europe have found carrier frequencies of BRCA2 mutations of 4% - 40% The percentage of male breast cancer cases that are associated with a BRCA2 mutation varies depending on the population. Figures from various studies (some small): 4% in U.S.; 21% in Sweden; 40% in Iceland. One study showed that among men with breast cancer and a first-degree relative (e.g., mother or sister) with breast cancer approximately 11% were carriers of a BRCA2 mutation. For male BRCA2 alteration carriers: Estimated cumulative risk of male breast cancer is ~6% by age 70 Age of onset not as early as female breast cancer in BRCA2 carriers BRCA1 may account for more cases of male breast cancer than initially estimated. (Couch et al. 1996, Thorlacius et al. 1996, Friedman et al. 1997, Csokay et al. 1999)

Slide 23:Risks of Breast Cancer with BRCA1 or BRCA2 Mutation

Easton DF, Ford D, Bishop T, and the Breast Cancer Linkage Consortium, 1995. Am J Hum Gen 56:265-271. Easton DF, et al., and the Breast Cancer Linkage Consortium, 1999. JNCI 91:1310-1319. Ford D, Easton DF, Stratton M, Narod S, et al., 1998, Am J Hum Genetics 62:676-689. Struewing JP, Harge P, Wacholder W, et al. NEJM, 1997. 336(20):1401-1408. Ford D, Easton DG, Bishop T, Narod S, 1994. Lancet 343:692-695.

Slide 24:Contralateral Breast Cancer Risk BRCA1/2 Mutation Carriers

Slide 25: The hope is that increased surveillance and/or interventions may identify cancers early or reduce the risk of cancers. Risk assessment may also identify those not at increased risk.

Recognition: the first step in management of familial cancer risk

Slide 26:Cancer Clusters

Cancer can happen in a family just by chance Cancer can cluster in families because of shared environmental exposures (diet, lifestyle, �environment�, work related exposures) Cancers may be due to inheritance of a single genetic alteration that poses very high risk of cancer Cancers may be due to inheritance of less penetrant genetic alterations

Slide 27:Sporadic/Familial/Hereditary

Sporadic cancers Age appropriate Common cancers Familial Cancer Occurring in or affecting more members of a family than would be expected by chance� Generally, two or more family members with the same type of cancer, age appropriate Hereditary Cancer -Multiple affected family members Several cases of the same type of cancer or cancers known to be part of an hereditary cancer syndrome (e.g. breast & ovarian, colon & endometrial, sarcoma & breast). Younger than expected ages of onset - such as breast < 40, colon < 50 Rare cancers in the family such as males with breast cancer Individuals with multiple primary cancers or multifocal or bilateral cancers Family history consistent with generation to generation transmission

Slide 28:Tools for risk assessment:

Breast cancer risk assessment models - Claus, Gail, BRCAPRO, Frank/Myriad models Models for other cancers from the literature Computer/Internet resources Gene tests, OMIM, NCI website Ongoing education

Slide 29:Models used to calculate breast cancer risks

Claus Model - Age specific risk estimates for breast cancer, considers maternal and paternal history, age at onset, first and second degree relatives (excludes some relatives). Gail Model - Estimates the chance that a woman of specific age would develop breast cancer, includes age at menarche, childbirth, # of prior biopsies, and first degree relatives. Excludes paternal relatives, non-first degree relatives. Adapted to consider atypical hyperplasias. Tyrer-Cusick Model � (2004) Uses personal risk factors for breast cancer, and likelihood of BRCA gene mutation and a low penetrance gene to assess breast cancer risk. Claus EB, Risch N, Thompson WD, 1990;1991;1994; Gail MH, Brinton LA, Byar EP, et al, 1989; Tyrer J, Duffy SW, Cuzick J. Stat Med 2004; 23: 1111-1130 FCRS

Slide 30:Models used to calculate likelihood of BRCA1 or BRCA2 mutation:

BRCAPRO - computer model, uses pedigree to calculate risk based on several different models. Frank or Myriad Model/Tables - use family history and personal history to estimate risk of mutation in BRCA1 or BRCA2. BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) � University of Cambridge computer model to assess risk of BRCA1/2 mutation. Euhus D, Berry D, Parmigiani G, Iverson E, 1998; Frank TS, Manley SA, Olopade OI, et al, 1997, 1998. Antoniou AC, Hardy R, Walker L, Evans DG, Shenton A, Eeles R, Shanley S, Pichert G, Izatt L, Rose S, Douglas F, Eccles D, Morrison PJ, Scott J, Zimmern RL, Easton DF, Pharoah PD. J Med Genet. 2008 Jul;45(7):425-31. Epub 2008 Apr 15.

Slide 31:Characteristics of those families appropriate for consideration for BRCA1 or BRCA2 testing (including patient�s personal history)

several breast cancers or breast and ovarian cancer two or more ovarian cancers in one family presence of bilateral cancers of the breast or ovary cancers diagnosed at younger than expected ages multiple affected relatives, demonstrating an autosomal dominant pattern of inheritance presence of individuals diagnosed with more than one cancer, e.g. breast and ovarian breast and/or ovarian cancer and Ashkenazi (Eastern European) Jewish heritage male breast cancer

Slide 32:Cindy�s Story

Cindy 34 yo + BRCA2 mutation Renee 65 yo Ov dx 46 Br dx 52 John 66 yo Caroline 2 yo John Jr. 6 yo Rick Colon dx 31 D. 33 James 5 yo Katherine 3 yo Jason 31 yo Jane 28 yo Bessie D.91 Br Dx 91 Kate 61 yo X 3 No CA Alice D. 50 ? stomach Janice 61 yo ? Susan 30 yo FCRS

Slide 33:Cindy�s Risk Assessment

Gail Model Race - Caucasian Age - 34 Age Menarche - 13 Age 1st live birth - 28 # Mother, Sister, Daughter with Breast Cancer - 1 # previous biopsy - 0 5 year risk = 0.5% lifetime risk = 19.2% Claus Model Using Table of One First Degree Relative Predicted cumulative probability of breast cancer by age: 39 = .8% 49 = 2.3% 59 = 4.9% 69 = 8.2% 79 = 11% Benichou J, Gail M, Mulvihill J. 1996. JCO 14:103-10 Claus EB, Risch N, Thompson WD, 1994. CANCER 73:643-51. FCRS

Slide 34:Hereditary Breast/Ovarian Cancer Syndrome

2 L br ca 42 R br ca 55 Oophorectomy (BSO) 53 + BRCA2 3 5 FCRS 3 75 3 70-80 No cancer 30-50 No cancer +BRCA2 Bil mastectomy Bil Salingo-oophorectomy 36 5 d. 94 ht dz Br ca 44 Ov ca 52 d. 79 d. Br ca 42

Slide 35: - Risk Perception - Everyone�s is Unique

Individual�s view of �high risk�, �common�, �rare�, �unlikely� is colored by their experience and psychological make-up. Half-full vs. half-empty Experience with statistics (�I will be the <1% who develops �.�) Personal experience with cancer or cancer scares, caring for others with cancer (especially if repeatedly or recently) Relationships and age influence reaction - parent�s cancer and child or adolescent vs. adult, siblings with cancer, friends with cancer. Page DL, Caro SW, Dupont SD, 1998.

Slide 36:Testing Process

Counsel/Education Gather pedigree and documentation Test affected individual for mutation If family + for mutation, then can test unaffected individuals If + mutation in family, - mutation in individual, individual risk is close to population risk If no identified mutation in family, risk is estimated based on history and empiric data

Slide 37:Outcome of process

Clarify risks of cancer Identify individuals who may not be aware of increased risk Identify individuals who may not be at increased risk Identify those appropriate for increased cancer surveillance, or measures to decrease risk (prophylactic surgery, chemoprevention), or those appropriate for research on surveillance or chemoprevention

Slide 38:Options for Women at Risk

Increased Surveillance Risk-reducing Surgery Medical Intervention FCRS

Slide 39:Increased Surveillance

Breast Cancer Clinical examination every 6 months Mammogram yearly beginning age 25-35 MRI (ACS 2007) Monthly BSE Prompt evaluation of abnormal findings Ovarian Cancer Ca-125 Pelvic color-doppler ultrasound every 6-12 months Pelvic examination every 6-12 months

Slide 40:ACS Recommendations for Breast MRI Screening as an Adjunct to Mammography 2007

Recommend Annual MRI Screening (Based on Evidence*)�� BRCA mutation��� First-degree relative of BRCA carrier, but untested��� Lifetime risk 20�25% or greater, as defined by BRCAPRO or other models that are largely dependent on family history Recommend Annual MRI Screening (Based on Expert Consensus Opinion )��� Radiation to chest between age 10 and 30 years�� �Li-Fraumeni syndrome and first-degree relatives��� Cowden and Bannayan-Riley-Ruvalcaba syndromes and first-degree relatives Insufficient Evidence to Recommend for or Against MRI Screening ��� Lifetime risk 15�20%, as defined by BRCAPRO or other models that are largely dependent on family history��� Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)��� Atypical ductal hyperplasia (ADH)�� Heterogeneously or extremely dense breast on mammography��� Women with a personal history of breast cancer, including ductal carcinoma in situ (DCIS) Recommend Against MRI Screening (Based on Expert Consensus Opinion)��� Women at <15% lifetime risk * Evidence from nonrandomized screening trials and observational studies. Based on evidence of lifetime risk for breast cancer. Payment should not be a barrier. Screening decisions should be made on a case-by-case basis, as there may be particular factors to support MRI. More data on these groups is expected to be published soon. CA Cancer J Clin 2007; 57:75-89

Slide 41:Risk-Reducing Surgery

Mastectomy Total mastectomy vs.. subcutaneous mastectomy? Not 100% effective, true risk reduction unclear, >90%. Hugely personal decisions. Oophorectomy Unfortunately not 100% effective in eliminating ovarian cancer risk, as intraabdominal carcinomatosis has occurred (2-4%) Questions - hysterectomy? HRT?, do we screen after BSO Bilateral oophorectomy reduced risk of breast cancer in BRCA1 mutation carriers. (RR=0.53). HRT did not negate reduction in risk. Rebbeck TR, Levin AM, Eisen A, et al. JNCI 91(17):1475, Stuewing JP, Watson P, Easton DF, et al JNCI Monographs 1995. 17:330; Eisen A, Rebbeck TR, Wood WC,Weber BL. JCO 18(9)�1980; May 2000. Hartmann LC, Daniel JS, Woods JE, et al. NEJM 340(2):77-84, Jan 14, 1999;

Slide 42:Medical Interventions

Breast Cancer Risk reducing medications should be discussed based on current understanding. Ovarian Cancer Oral contraceptives have been shown to decrease the risk of ovarian cancer in the general population. In women with mutations in BRCA1 or BRCA2 that risk reduction was also documented, with 60% reduction (RR=0.4) with use of 6 years or more. Narod SA, Risch H, Moslehi R, et al. NEJM 1998, Aug 13;339(7):469-71. Fisher B, Costantino JP, Wickerman DL, et al. JNCI, 1998; 90(18):1371-1388.

Slide 43:Misconceptions about genetic testing:

Testing is not covered by insurance. In most instances insurance covers the cost of testing like any other medical expense. Testing is complicated. True and false � choosing the appropriate test is not always simple, there are significant opportunities for misinterpretation. Seek consultation with a health care provider (nurse practitioner, genetic counselor, MD) specializing in hereditary cancer. Testing will cause you to lose your insurance. Concerns exist about genetic discrimination, but after nearly 15 years of clinical testing, no significant problems have been seen. Members of group health insurance plans have protection under Federal Law (HIPPA, 1996). GINA signed into law May 2008, extends protections from discrimination based on genetic information to those with private health insurance

Slide 44:�Walking with the Ghosts of My Grandmothers� a painting by Hollis Sigleron the cover ofthe journal ScienceOctober, 1994

Slide 45:Hereditary Diffuse Gastric Cancer Syndrome

Autosomal dominant inheritance Germline mutations in CDH1/E-Cadherin Gene (described in hereditary gastric families in 1998) Initially found in Maori families, since described in families from many ethnic groups. Penetrance thought to be 70%, Also increased risk of colon cancer and breast cancer

Slide 49:Li-Fraumeni Syndrome

Initially described by Frederick Li and Joseph Fraumeni (1969) as syndrome associated with sarcomas and other diverse tumors. Associated cancer include soft-tissue sarcoma, osteosarcoma, early-onset breast cancer, brain tumors, adrenocortical carcinoma, and leukemias, primarily acute leukemia. (Was also called SBLA for Sarcoma, Breast/Brain, Leukemia, and Adrenal) Inherited in an autosomal dominant manner. Other reports have associated other cancers - including melanoma, cancers of the stomach, pancreas, colon, and esophagus, and gonadal germ cell tumors. Gene mutations TP53 (1990) on 17p13, possibly others

Slide 50:DNA BANKING

If genetic testing is not possible or not informative, DNA banking is a relatively inexpensive and simple procedure that can save a sample of the affected person�s DNA for future testing.

Slide 51:Resources to find cancer genetics professionals in your area:

http://www.cancer.gov/search/genetics_services/ genetests.org http://www.nsgc.org/resourcelink.cfm

Slide 52:Disparities�.

Slide 53:Family Cancer Risk Service of the Vanderbilt-Ingram Cancer Center is made possible by support from:

From Generation to Generation � 1998 Jay M. Rotberg, artist and sculptor Vanderbilt-Ingram Cancer Center Tennessee Breast Cancer Coalition Susan G. Komen Foundation, Greater Nashville Affiliate (past) Our physician consultants: Mark Kelley, Ingrid Meszoely, Marta Crispens, John Phay, Paul Wise And the individuals and families who seek counsel

Slide 54:Family Cancer Risk Service of the Vanderbilt-Ingram Cancer Center

From Generation to Generation � 1998 Jay M. Rotberg, artist and sculptor Susan Caro, RNC, MSN, APNG Director Kate McReynolds, MSc, RN Telephone: (615) 343-0738 or TOLL FREE: 1-877-688-7555

Slide 55:Selected Hereditary Cancer Syndromes

OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York.

Slide 56:Selected Hereditary Cancer Syndromes (cont�d)

OMIM, Elsas LJ, Trepanier A. Cancer Genetics in Primary Care. Postgraduate Medicine 107(4):191-208, April 2000., Offit K. Clinical Cancer Genetics, Wiley-Liss, 1998, New York

Slide 57:Stigmata of Selected Syndromes Associated with Susceptibility to Cancer

Syndrome Major Cancer Risks Selected physical findings Offit, K. Clinical Cancer Genetics, Risk Counseling & Management, Wiley-Liss, New York, 1998.

Slide 58:RED FLAGS � Think about hereditary susceptibility when you see:

Breast Cancer at age less than 50 Ashkenazi Jewish heritage and breast or ovarian More than one ovarian cancer in a family, or breast and ovarian cancer Men with breast cancer More than one pancreatic cancer in a family Colorectal cancer less than 50 years of age Polyposis Pheochromocytoma Medullary thyroid cancer