GENETIC MANAGEMENT OF A FAMILY HISTORY OF BREAST AND / OR OVARIAN CANCER Full Title of Guideline: Author (include email and role): Division & Speciality: Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Summary of evidence base this guideline has been created from: GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF BREAST AND / OR OVARIAN CANCER Dr Abhijit Dixit Family Health Clinical Genetics Clinical Genetics department January 2019 Patients affected with or have a family history of breast and ovarian cancer. Please see guidelines for inclusion / exclusion criteria Previous version not on intranet Evidence 1 and 5 NICE -Familial breast cancer Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer Issued: June 2013 This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date or outside of the Trust. Page 1 of 15 1
GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF BREAST AND / OR OVARIAN CANCER Date: August 2015 Aim That individuals at an increased genetic risk of breast and / or ovarian cancer are offered evidence based care and information. Objectives 1. To target the use of resources consistently to ensure equity of service provision across our service. 2. To enable audit of the service. A small percentage of breast and ovarian cancer is due to the inheritance of a cancer susceptibility gene e.g. BRCA 1 and 2. Families who may be at increased risk to develop breast and / or ovarian cancer are identified on the basis of their family history of these two cancers. These guidelines include: A. Guidelines for referral of patients with a family history of breast / ovarian cancer from primary care to clinical genetics or a breast family history clinic. B. Guidelines for risk stratification of families with breast / ovarian cancer. C. Guidelines for the management of breast cancer risk. D. Guidelines for management of ovarian cancer risk. E. Guidelines for genetic testing of families with breast / ovarian cancer. Page 2 of 15 2
A. GUIDELINES FOR REFERRAL OF PATIENTS WITH A FAMILY HISTORY OF BREAST / OVARIAN CANCER FROM PRIMARY CARE: DIRECT REFERRAL TO CLINICAL GENETICS: Women with a non-mucinous ovarian cancer should be referred directly to Clinical Genetics REFERRAL TO BREAST FAMILY HISTORY CLINIC: Patients with the following family histories of cancer, all on the same side of the family, are at increased risk and should be referred: 3 relatives Three or more 1 st or 2 nd degree relatives with breast and / or ovarian cancer. 2 relatives One 1 st and one 1 st or 2 nd degree relative with breast cancer. One 1 st or 2 nd degree relative with breast cancer and one 1 st or 2 nd degree relative with ovarian cancer *. Two 1 st or 2 nd degree relatives with ovarian cancer*. One 1 st or 2 nd degree relative with breast cancer and one 1 st or 2 nd degree relative with either a sarcoma < 45, a glioma or a childhood adrenal cortical carcinoma*. 1 relative A 1 st degree relative with breast cancer under 40. A 1 st degree relative with bilateral breast cancer. A 1 st degree relative with male breast cancer. A 1 st degree relative with both breast and ovarian cancer. First degree relatives include parents, siblings and children. Second degree relatives include grandparents, aunts and uncles, nephews and nieces. * One should be a first degree relative unless the family history is on the paternal side of the family. Page 3 of 15 3
B. GUIDELINES FOR THE RISK STRATIFICATION OF FAMILIES WITH BREAST / OVARIAN CANCER The family history can be defined as being low, moderate or high risk. Low risk - less than 2 x lifetime risk of breast cancer Moderate risk - 2-3 x lifetime risk of breast cancer High risk - greater than 3 x lifetime risk of breast cancer Patients with the following family histories, on the same side of the family, fall into the moderate and high risk groups: MODERATE RISK 3 Relatives Three 1 st or 2 nd degree relatives with breast cancer at an average age of over 60*. One relative with ovarian cancer and two 1 st or 2 nd degree relatives with breast cancer where the average age for the breast cancer is over 60*. 2 relatives One 1 st degree relative and one 1 st or 2 nd degree relative with an average age of breast cancer over 50 and under 60*. One ovarian cancer and one 1 st or 2 nd degree relative with breast cancer over 50*. One 1 st or 2 nd degree relative with bilateral breast cancer and one 1 st or 2 nd degree relative with breast cancer over 60* 1 Relative A 1 st degree relative with breast cancer under 40. A 1 st degree relative with male breast cancer at any age. A 1 st degree relative with bilateral breast cancer, where the average age of diagnosis is over 50. First degree relatives include parents, siblings and children. Second degree relatives include grandparents, aunts and uncles, nephews and nieces. * One should be a first degree relative unless the family history is on the paternal side of the family. Page 4 of 15 4
HIGH RISK 4 or more relatives Four or more close relatives with breast and / or ovarian cancer*. 3 Relatives Three 1 st or 2 nd degree relatives with an average age of breast cancer under 60*. One relative with ovarian cancer and two 1 st or 2 nd degree relatives with breast cancer where the average age for the breast cancer is under 60*. One male breast cancer at any age and 2 female breast cancers with an average age under 60 2 Relatives One 1 st and one 1 st or 2 nd degree relative with an average age of breast cancer under 50. One 1 st and one 1 st or 2 nd degree relative with ovarian cancer. One ovarian cancer and one 1 st or 2 nd degree relative with breast cancer under 50*. One 1 st or 2 nd degree relative with bilateral breast cancer and one 1 st or 2 nd degree relative with breast cancer under 60* or ovarian cancer at any age One male breast cancer at any age and a female breast cancer under 50 or an ovarian cancer at any age 1 Relative A 1 st degree relative with both breast cancer under 50 and ovarian cancer. A 1 st degree relative with bilateral breast cancer, both under 50. First degree relatives include parents, siblings and children. Second degree relatives include grandparents, aunts and uncles, nephews and nieces. * One should be a first degree relative unless the family history is on the paternal side of the family. Page 5 of 15 5
C. GUIDELINES FOR THE MANAGEMENT OF BREAST CANCER RISK The management of individuals with a family history of breast / ovarian cancer is determined by their risk calculated on the basis of their family history and genetic testing. Low risk Individuals at low risk do not require any other than that offered to the general under the National Breast Screening programme. Moderate risk Individuals at moderate risk may benefit from earlier and more frequent breast by. Current recommendations are that: 1) Women at moderate risk should be offered additional breast by. 2) should commence at 40 and performed yearly until the age of 50, then to consider annual 50-59 and then women are transferred to the National Breast Screening programme. High risk Individuals at high risk may also benefit from earlier and more frequent breast by and/or scan. They should also be offered referral to the Clinical Genetics department for genetic counselling including the possibility of genetic testing in the family. Table 1 summarises the surveillance recommendations for women with a AT mutation Table 2 summarises the surveillance recommendations for subgroups within the high-risk category for specific guidelines. Some women in the categories; a) <30% chance of a BRCA or TP53 mutation, and b) untested but >30% chance of a BRCA or TP53 mutation, will be eligible for indirect BRCA genetic testing. It is, therefore, important to calculate their personal risk of a BRCA mutation using Manchester score or BOADICEA. Table 1 Recommendations for women with AT mutations: Risk Ages Surveillance Protocol Frequenc y Notes A-T homozygotes 25+ No A-T heterozygotes 40-50 50+ 18 monthly Routine (3 yearly) Routine from 50 Page 6 of 15 6
Age Table 2 Moderate risk of breast cancer 1 High risk of breast cancer (but with a 30% or lower BRCA ortp5 3 carrier probability) 2 Untested but greater than 30% BRCA carrier probability 3 Known BRCA1 or BRCA2 mutation Untested but greater than 30% TP53 carrier probability 4 Known TP53 mutation f recommendations on surveillance for women with no personal history of breast cancer S u m m a r y o 20-29 30-39 Consider annual and consider annual and consider annual 40-49 mammograph y and annual and annual 50-59 Consider annual mammograph y unless dense breast pattern unless dense breast pattern programme unless dense breast pattern Consider annual 60-69 programme programme programme unless dense breast pattern unless dense breast pattern programme unless dense breast pattern Consider annual 70+ Page 7 of 15 7
programme programme programme programme programme 1 Lifetime risk of developing breast cancer is at least 17% but less than 30%. 2 Lifetime risk of developing breast cancer is at least 30%. High risk group includes rare conditions that carry an increased risk of breast cancer, such as Peutz-Jeghers syndrome, (STK11), Cowden (PTEN), familial diffuse gastric cancer (E-Cadherin). 3 Surveillance recommendations for this group reflect the fact that women who at first assessment had a 30% or greater BRCA carrier probability and reach 60 years of age without developing breast or ovarian cancer will now have a lower than 30% carrier probability and should no longer be offered surveillance. 4 Surveillance recommendations for this group reflect the fact that women who at first assessment had a 30% or greater TP53 carrier probability and reach 50 years of age without developing breast cancer or any other TP53- related malignancy will now have a lower than 30% carrier probability and should no longer be offered surveillance. Page 8 of 15 8
D. GUIDELINES FOR THE MANAGEMENT OF OVARIAN CANCER RISK BRCA testing: BRCA1/2 testing should be offered to individuals who fulfil genetic testing criteria as outlined in section E. Management of ovarian risk: Ovarian risk should be discussed: In women with BRCA1 or BRCA2 mutations. In BRCA1/2 negative families, only discuss ovarian risk if the consultee has two or more first or second-degree relatives with ovarian cancer. At least one should be a first-degree relative of the consultee. At least two of the ovarian cancer cases should be first-degree relatives of each other. In BRCA1/2 negative families with breast cancer only, no discussion, surveillance or riskreducing surgery for ovarian cancer is required. There is no evidence of a significant increase in ovarian cancer risk in such families. Risk-reducing bilateral salpingo-oophorectomy Risk-reducing bilateral salpingo-oophorectomy can be considered after child-bearing is complete. Ovarian Ovarian is known to have both a high false positive rate and a high false negative rate and should not be recommended outside of a research study. Ovarian options currently differ in different regions and management of increased ovarian cancer risk remains the responsibility of the gynaecologist offering this service. All women who have taken part in UKFOCSS should be offered review at the end of the study by the gynaecologist coordinating their to discuss options. Page 9 of 15 9
E. GUIDELINES FOR GENETIC TESTING OF FAMILIES WITH BREAST / OVARIAN CANCER. Individuals with breast or ovarian cancer who fall into the high risk group can be offered genetic testing in order to try to identify a mutation in one of the BRCA genes. Individuals who undergo genetic testing must: 1) be referred to the Clinical Genetics department 2) receive genetic counselling about the implications of a positive result which would include discussion about, psychosocial well-being and the wider implications. 3) give informed, written consent for the test. 4) If the patient is terminally ill blood can be taken by the referring physician for DNA storage. Genetic counselling and discussion of testing can be performed at a later stage but the patient must identify a family member to whom the result can be given. Criteria for a diagnostic genetic test Please see table 3 for a full list of who should be offered a diagnostic genetic test. Criteria for a predictive genetic test Members of families where a mutation has been identified should be referred to a clinical geneticist to discuss predictive testing. 1) Individuals should be over 16 2) They should receive genetic counselling prior to the blood being taken which should include options, discussion of prophylactic surgery, psychosocial issues and the wider implications of the result. Other conditions to consider in families with breast cancer Consider the possibility of other conditions that increase the risk of breast cancer, particularly if BRCA testing is negative. 1) Think about Li-Fraumeni syndrome (TP53) in families with young-onset breast cancers, particularly if associated with sarcomas, adrenocortical tumours, or any other unusually young-onset cancers. Women with breast cancer <30 years should be offered TP53 testing. 2) Consider Cowden syndrome (PTEN) in families with breast cancer, thyroid cancer (particularly follicular) and endometrial carcinoma. Macrocephaly and mucocutaneous lesions can be important pointers on examination, so consider assessing for these at appointments. Overgrowth, seizures and learning difficulties can be seen in children with Cowden syndrome. Other thyroid lesions (adenomas, multinodular goitre) and breast fibrocystic disease are also part of the Cowden syndrome spectrum, as are lipomas and fibromas. Individuals eligible for the BOCS research study but not for clinical BRCA 1. A woman affected with breast cancer who has 2 relatives with ovarian or breast cancer (e.g. could be 3 women with late breast cancer) 2. A woman affected with bilateral breast cancer regardless of age at diagnosis. 3. Please note that women cannot be referred to clinical genetics purely for enrolment into the BOCS research study. Any unsuitable referrals will be returned to the referrer. Page 10 of 15 10
A 4. A man affected with breast cancer (i.e. Manchester score <14). 5. Table 3: Guidelines for BRCA1 and BRCA2 diagnostic genetic testing Woman with breast cancer who 1. has a breast cancer diagnosed under the age of 30 2. has bilateral breast cancer and both cancers diagnosed <50 yr 3. has triple negative breast cancer diagnosed <50 yr 4. has non-mucinous epithelial ovarian cancer 5. has bilateral breast cancer and a relative with breast cancer <60 yr 6. has a relative with breast cancer and both diagnosed <45 yr 7. has relatives with breast/ovarian cancer and Manchester score 15 B Woman with ovarian cancer who 1. has non-mucinous epithelial ovarian cancer (e.g serous or endometrioid) C Man with breast cancer who 1. has a relative with a non-mucinous ovarian cancer or male breast cancer 2. has relatives with breast cancer and Manchester score 15 D Individual unaffected with cancer who 1. has at least one first degree relative with breast/ovarian cancer and familial Manchester score 20 2. has first degree relative with ovarian cancer and familial Manchester score 17 Key Relative = first degree or second degree relative only, except when calculating Manchester score* Triple negative breast cancer = breast tumour negative for oestrogen receptor (ER)*, progesterone receptor (PR) and HER2 expression $ Ovarian cancer scoring: A serous peritoneal primary tumour or fallopian tube cancers should be considered as if an ovarian cancer Manchester Score Cancer, age at diagnosis Score Breast Cancer, <30 11 Breast Cancer, 30-39 8 Breast Cancer, 40-49 6 Breast Cancer, 50-59 4 Breast Cancer, >59 2 Breast Cancer, <60 13 Breast Cancer, >59 10 Ovarian Cancer,<60 13 Ovarian Cancer, >59 10 Pancreatic Cancer 1 Prostate Cancer, <60 2 Prostate Cancer, >59 1 Page 11 of 15 11
See accompanying FAQs for common queries. Pathology adjustments to Manchester Score are no longer required. Women with triple negative breast cancer diagnosed <50 years are eligible for BRCA testing (see A2 above). Ovarian cancer histology Diagram 1: Origins of the three main types of ovarian cancer i Any patient with a non mucinous, non germ cell, non sex cord, non-borderline ovarian tumors should be offered BRCA1/2 testing and counted as an ovarian cancer when assessing whether to offer BRCA1/2 testing. A serous peritoneal primary tumour or fallopian tube cancers should be considered as if an ovarian cancer. Serous and endometrioid ovarian tumours are strongly associated with BRCA mutations. Mucinous and borderline cancers are not associated with BRCA mutations and should not be considered when assessing risk of BRCA mutation in families. Consider possibility of Lynch syndrome if history of bowel or endometrial cancer in family. Other ovarian cancer types such as sex-cord or germ cell have not been strongly associated with a BRCA1/2 mutations. Other types of epithelial-stroma ovarian cancers except mucinous or borderline cancer should be counted as an ovarian cancer when assessing whether to offer BRCA1/2 testing Page 12 of 15 12
From: Update on the Manchester Scoring System for BRCA1 and BRCA2 testing. DGR Evans et al. J Med Genet 2005; 42: e39 Page 13 of 15 13
Ashkenazi Jewish ancestry: Approximately 2% of general Ashkenazi (4 Ashkenazi grandparents), and 10% of Ashkenazi women with breast cancer carry BRCA1 or BRCA2 founder mutations. Breast cancer penetrance is lower with the common mutations: BRCA1-56% by 70, BRCA2-25% by 70 Author: Dr A Dixit August 2015 Review Date: Dr A Dixit January 2019 References NICE Guideline Familial Breast Cancer: The classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. Issued October 2007 NICE Guideline CG164- Familial breast cancer: Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. Issued June 2013 Page 14 of 15 14
Eccles DM et al. Guidelines for a genetic risk based approach to advising women with a family history of cancer. J Med Genet 2000; 37:203-9 Report of Consensus meeting on the management of women with a family history of breast cancer. Public Health Genetics 1998 Evans DGR et al. A new scoring system for the chances of identifying a BRCA 1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 2004; 41:474-480 Evans DGR et al. Update on the Manchester Scoring System for BRCA1 and BRCA2 testing. J Med Genet 2005; 42: e39 Evans DGR et al. Additional pathology and biomarker information significantly improves the performance of the Manchester scoring system for BRCA1 and BRCA2 system. J Med Genet 2009; 46: 811-817 Kwon JS et al. Expanding the Criteria for BRCA Mutation Testing in Breast Cancer Survivors J Clin Oncol 2010; 28: 4214-20 Lakhani SR et al. The Pathology of Familial Breast Cancer: Predictive Value of Immunohistochemical Markers, Estrogen Receptor, Progesterone Receptor, HER-2, and p53 in Patients with Mutations in BRCA1 and BRCA2. J. Clin. Oncol. 2002 20:2310-2318 Version 3 i Page 15 of 15 15