Breast cancer (high risk with ovarian cancer family history) – risk management (female)

This protocol discusses management for unaffected women who have a high risk for developing breast cancer based on a validated risk assessment tool (e.g. CanRisk^r) and a verified family history of epithelial ovarian cancer. Unaffected women with a known pathogenic variant in a breast/ovarian cancer predisposition gene are discussed in separate protocols. 

To ensure appropriate risk management guidelines are followed, women with a high likelihood (≥10%) of a heritable pathogenic variant in BRCA1, BRCA2 or PALB2, based on a validated risk model (e.g. CanRisk), are advised to consider genetic testing.

• Women at greater than 30% lifetime risk of breast cancer (or greater than 8% risk between age 40 and 50 years) using a validated risk model such as CanRisk,^r IBIS^r or iPrevent^r who also have a verified family history of epithelial ovarian/fallopian/peritoneal cancer affecting a first- or second-degree blood relative

Exclusion criteria

• Families who have one woman with ovarian cancer and no additional family history of breast or ovarian cancer
• Individuals with a pathogenic variant in a breast/ovarian cancer predisposition gene
• An untested blood relative of an individual with a pathogenic variant in a breast/ovarian cancer predisposition gene
• Unaffected women with high personal risk (≥10%) of a BRCA1 or BRCA2 pathogenic variant using a validated risk model (e.g. CanRisk) who may consider genetic testing

Cancer/tumour type	Risk for this target group	General female population risk by age 85 years*
Breast	Greater than 30% lifetime risk (or greater than 8% decade risk between age 40-50 years)	13.1%
Ovarian	Risk varies according to ovarian tumour subtyper and family history and is not increased in all individuals	1.1%

*Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2017 data)

Management of early menopause

If risk-reducing bilateral salpingo-oophorectomy (RRBSO) is undertaken prior to menopause, MHT may be considered to minimise potential cardiovascular complications, sexual dysfunction and bone loss associated with premature menopause. The potential risks associated with MHT use should be discussed with the patient, including the potential for increased risk of breast cancer. Lowest risks have been seen in observational studies with use of oestrogen only preparations (for women who have had a hysterectomy) and short duration of therapy.^r For women who have not had a hysterectomy, Mirena and oral oestrogen may be a safer option than combined oral MHT.^r

Contraception

Combination oral contraceptive pill (OCP) use requires careful discussion about potential risks and benefits and alternative contraceptive strategies.  A small increased risk of breast cancer has been reported for current OCP users (RR 1.2) and for up to 10 years after cessation of OCP use, regardless of family history.^r The same result was found with newer formulations, including progesterone-containing implanted devices.^r Although there is evidence that the combined OCP can reduce ovarian cancer risk, it is significantly less effective than RRSO and is not recommended for cancer prevention. OCP cannot be used concurrently with breast cancer risk-reducing medications due to interactions.

Breast

Women in families with multiple cases of female breast +/- ovarian cancer are at increased risk of developing breast cancer. In the absence of a known germline pathogenic variant in a breast cancer predisposition gene, the exact levels of risk are difficult to determine. Risk models such as CanRisk, IBIS and iPrevent can calculate individual cancer risks.

Breast cancer risks can be low under age 40, even with family history, for women who do NOT carry a high-risk pathogenic variant. Potential harms of screening may outweigh benefits at this age, and an individual discussion is advised, based on the woman’s 10-year breast cancer risk assessment.

Surgical

Bilateral risk reducing mastectomy reduces absolute breast cancer risk to <2%.

Surveillance

Mammography has been shown to reduce mortality for women at population risk of developing breast cancer. Annual mammography in an observational study of women aged 40-49 with a family history of risk of breast cancer (3% absolute risk during this time period) detected breast cancers at lower stages (smaller, fewer positive lymph nodes and lower grade) than in women who are not involved in a screening program.^r

The sensitivity of mammography has been reported to be lower (50%) for women with high breast density, and limited evidence supports adding breast MRI, breast ultrasound or tomosynthesis to increase sensitivity. A systematic review of mammography with digital breast tomosynthesis use for breast cancer screening found lower false positive rates, recall rates and increased cancer detection when compared to standard 2D mammography, adding support for its use in screening.^rr

Screening with use of MRI in addition to mammography has been shown to have a significant increase in sensitivity for women with a high risk of breast cancer based on family history (55% with mammography alone increasing to 98% with the addition of MRI). Cancers detected have also been earlier stage, required less adjuvant therapy and had a lower rate of metastatic disease.^r However, false positive findings increased and specificity decreased with use of MRI.^r

Risk-reducing medication

Five years of treatment with selective oestrogen receptor modulators (SERM), such as tamoxifen and raloxifene, or aromatase inhibitors (AIs), such as anastrozole or exemestane, have been shown to reduce the risk of oestrogen receptor-positive breast cancer in women identified to be at increased risk. A meta-analysis showed that tamoxifen reduced breast cancer incidence by 32% compared with placebo in women at increased risk. Tamoxifen was more effective at reducing breast cancer risk than raloxifene but had greater toxicity. AIs (for post-menopausal women only) reduced breast cancer risk by 53% compared with placebo.^r After cessation of therapy, persistent breast cancer risk reduction has been shown for tamoxifen and anastrazole.^rr None of the medications have proven mortality benefit.

Ovarian^r

Ovarian cancer risk estimates vary according to several factors including the number of relatives with ovarian cancer, their age(s) at diagnosis, the tumour subtype of their cancers and the degree of relationship between those affected and the consultand. Different types of ovarian cancer have different risks for relatives (when BRCA pathogenic variants are excluded). There is a lower risk of ovarian cancer for women with a family history of clear cell or mucinous ovarian cancer and higher risks for family history of high grade serous or endometrioid histology. Serous histology increases the risk two- to four-fold for relatives, with higher risks for young onset (age <50 years). Families with high grade serous or endometrioid ovarian/fallopian tube/primary peritoneal cancer are more likely to have BRCA pathogenic variants, and testing is now advised for most women with ovarian type cancer with high grade non-mucinous pathology especially if there is additional family history of breast and ovarian cancer. Residual risk is also dependent on current age.

Ovarian cancer risk is lower in families where BRCA pathogenic variants have been excluded. The CanRisk Web Tool (which uses BOADICEA version 5) uses an ovarian cancer risk assessment model that includes the effects of pathogenic variants in BRCA1, BRCA2, RAD51D, RAD51C and BRIP1, polygenic risk scores, residual family history and personal lifestyle/hormonal/reproductive risk factors. However, this tool has not been independently validated for ovarian cancer risk. 

Decisions about RRBSO should be individualised based on the empiric residual lifetime risk, current health status, cancer anxiety and personal preference. Women with one first degree relative with high grade serous or endometrioid ovarian cancer have an estimated lifetime ovarian cancer risk of 2-5%.^r Women with two first degree relatives with high grade serous or endometrioid ovarian cancer have a predicted lifetime ovarian cancer risk of 8% provided a BRCA1 or BRCA2 pathogenic variant has been excluded in a relevant family member.^r In some families with a strong history of both breast and ovarian cancer, the ovarian cancer risk may be as high as BRCA pathogenic variant carriers.

Surgical

RRBSO for ovarian cancer risk

There is no effective ovarian cancer screening program, so management relies on risk-reducing removal of the ovaries and fallopian tubes (RRBSO). Individual discussion is required regarding acceptable levels of ovarian cancer lifetime risk. If a woman does not have a known BRCA, PALB2, RAD51 or BRIP1 pathogenic variant, then her lifetime risk is likely to be below 5%, unless she has two close relatives with ovarian cancer.

RRBSO reduces the risk of ovarian cancer to below an absolute level of 5% in BRCA carriers and is expected to do likewise in breast-ovarian non-BRCA families. RRBSO is predicted to increase survival in women at high ovarian cancer risk but optimal management of early menopause, which may include referral to menopause clinics, is important in providing the best long-term health outcomes for women. Discussion with a clinician with relevant expertise is advised when making decisions about the role (if any) of RRBSO for an individual woman.

[%id%]

[%title%]

Read abstract

[%abstract%]

Bibliography

Domchek, S. M., T. M. Friebel, C. F. Singer, et al. 2010. "Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality." JAMA 304(9):967-975

Read abstract

CONTEXT: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE: To estimate risk and mortality reduction stratified by mutation and prior cancer status. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. MAIN OUTCOMES MEASURES: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. RESULTS: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). CONCLUSIONS: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

FH01 collaborative teams. 2010. "Mammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective, single-arm, FH01 study." Lancet Oncol 11(12):1127-1134

Read abstract

BACKGROUND: Evidence supports a reduction in mortality from breast cancer with mammographic screening in the general population of women aged 40-49 years, but the effect of family history is not clear. We aimed to establish whether screening affects the disease stage and projected mortality of women younger than 50 years who have a clinically significant family history of breast cancer. METHODS: In the single-arm FH01 study, women at intermediate familial risk who were younger than 50 years were enrolled from 76 centres in the UK, and received yearly mammography. Women with BRCA mutations were not explicitly excluded, but would be rare in this group. To compare the FH01 cohort with women not receiving screening, two external comparison groups were used: the control group of the UK Age Trial (106,971 women aged 40-42 years at recruitment, from the general population [ie, average risk], followed up for 10 years), and a Dutch study of women with a family history of breast cancer (cancer cases aged 25-77 years, diagnosed 1980-2004). Study endpoints were size, node status, and histological grade of invasive tumours, and estimated mortality calculated from the Nottingham prognostic index (NPI) score, and adjusted for differences in underlying risk between the FH01 cohort and the control group of the UK Age Trial. This study is registered with the National Research Register, number N0484114809. FINDINGS: 6710 women were enrolled between Jan 16, 2003, and Feb 28, 2007, and received yearly mammography for a mean of 4 years (SD 2) up until Nov 30, 2009; surveillance and reporting of cancers is still underway. 136 women were diagnosed with breast cancer: 105 (77%) at screening, 28 (21%) symptomatically in the interval between screening events, and three (2%) symptomatically after failing to attend their latest mammogram. Invasive tumours in the FH01 study were significantly smaller (p=0·0094), less likely to be node positive (p=0·0083), and of more favourable grade (p=0·0072) than were those in the control group of the UK Age Trial, and were significantly less likely to be node positive than were tumours in the Dutch study (p=0·012). Mean NPI score was significantly lower in the FH01 cohort than in the control group of the UK Age Trial (p=0·00079) or the Dutch study (p<0·0001). After adjustment for underlying risk, predicted 10-year mortality was significantly lower in the FH01 cohort (1·10%) than in the control group of the UK Age Trial (1·38%), with relative risk of 0·80 (95% CI 0·66-0·96; p=0·022). INTERPRETATION: Yearly mammography in women with a medium familial risk of breast cancer is likely to be effective in prevention of deaths from breast cancer.

Goss, P. E., J. N. Ingle, J. E. Ales-Martinez, et al. 2011. "Exemestane for breast-cancer prevention in postmenopausal women." N Engl J Med 364(25):2381-2391

Read abstract

BACKGROUND: Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. METHODS: In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. RESULTS: A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P=0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P=0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P=0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed. CONCLUSIONS: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174

Randall, D., S. Morrell, R. Taylor, et al. 2009. "Annual or biennial mammography screening for women at a higher risk with a family history of breast cancer: prognostic indicators of screen-detected cancers in New South Wales, Australia." Cancer Causes Control 20(5):559-566

Read abstract

OBJECTIVE: This study examined whether offering annual mammography screening for women with the risk factor of a family history of breast cancer resulted in more favorable prognostic indicators of diagnosed cancers than the usual approach of biennial screening. METHODS: The study involved women aged 50-69 years with a family history of breast cancer, defined as having > or = 1 first-degree relative diagnosed with breast cancer, who were diagnosed with a screen-detected invasive breast cancer between 1998 and 2004 in BreastScreen New South Wales (n = 590). The women were grouped according to whether they screened in an area offering annual screening to women with a family history, or were offered the standard biennial screening. The odds of having favorable tumor size, grade, and nodal status prognosis were compared between these screening groups using logistic regression. A comparison group of women without a family history, all offered biennial screening, was also evaluated based on the same area groupings to examine whether any differences were due to the area, rather than the screening interval policy. RESULTS: Women with a family history who were offered annual screening at BreastScreen NSW were significantly more likely than those who were offered biennial screening to be diagnosed with a tumor < or = 20 mm in size (adjusted odds ratio (AOR) = 1.91, 95% CI: 1.21-3.02), and to have a node-negative tumor (AOR = 1.61, 95% CI: 1.03-2.50). There were also significantly higher odds of being diagnosed with tumors < or = 15 mm (p < 0.001) and < or = 10 mm in size (p = 0.011) in women offered annual screening. There was no significant difference in the odds of a Grade 1 tumor being detected (AOR = 1.26, 95% CI: 0.87-1.81), although the direction of the effect was consistent with that seen for size and nodal status. No significant differences were found in the comparison group of women without a family history. CONCLUSIONS: Offering annual screening for women aged 50-69 years with a family history of breast cancer significantly increased the odds of being diagnosed with a smaller, node-negative tumors. Further investigation is required to assess whether the improved prognostic indicators translate into significantly better mortality outcomes for women with a family history offered annually screening.

Rosenthal, A. N., L. Fraser, R. Manchanda, et al. 2013. "Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule." J Clin Oncol 31(1):49-57

Read abstract

PURPOSE: To establish the performance characteristics of annual transvaginal ultrasound and serum CA125 screening for women at high risk of ovarian/fallopian tube cancer (OC/FTC) and to investigate the impact of delayed screening interval and surgical intervention. PATIENTS AND METHODS: Between May 6, 2002, and January 5, 2008, 3,563 women at an estimated >/= 10% lifetime risk of OC/FTC were recruited and screened by 37 centers in the United Kingdom. Participants were observed prospectively by centers, questionnaire, and national cancer registries. RESULTS: Sensitivity for detection of incident OC/FTC at 1 year after last annual screen was 81.3% (95% CI, 54.3% to 96.0%) if occult cancers were classified as false negatives and 87.5% (95% CI, 61.7% to 98.5%) if they were classified as true positives. Positive and negative predictive values of incident screening were 25.5% (95% CI, 14.3 to 40.0) and 99.9% (95% CI, 99.8 to 100) respectively. Four (30.8%) of 13 incident screen-detected OC/FTCs were stage I or II. Compared with women screened in the year before diagnosis, those not screened in the year before diagnosis were more likely to have >/= stage IIIc disease (85.7% v 26.1%; P = .009). Screening interval was delayed by a median of 88 days before detection of incident OC/FTC. Median interval from detection screen to surgical intervention was 79 days in prevalent and incident OC/FTC. CONCLUSION: These results in the high-risk population highlight the need for strict adherence to screening schedule. Screening more frequently than annually with prompt surgical intervention seems to offer a better chance of early-stage detection

Sherman, M. E., M. Piedmonte, P. L. Mai, et al. 2014. "Pathologic Findings at Risk-Reducing Salpingo-Oophorectomy: Primary Results From Gynecologic Oncology Group Trial GOG-0199." J Clin Oncol 32(29):3275-3283

Read abstract

PURPOSE: Risk-reducing salpingo-oophorectomy (RRSO) lowers mortality from ovarian/tubal and breast cancers among BRCA1/2 mutation carriers. Uncertainties persist regarding potential benefits of RRSO among high-risk noncarriers, optimal surgical age, and anatomic origin of clinically occult cancers detected at surgery. To address these topics, we analyzed surgical treatment arm results from Gynecologic Oncology Group Protocol-0199 (GOG-0199), the National Ovarian Cancer Prevention and Early Detection Study. PARTICIPANTS AND METHODS: This analysis included asymptomatic high-risk women age >/= 30 years who elected RRSO at enrollment. Women provided risk factor data and underwent preoperative cancer antigen 125 (CA-125) serum testing and transvaginal ultrasound (TVU). RRSO specimens were processed according to a standardized tissue processing protocol and underwent central pathology panel review. Research-based BRCA1/2 mutation testing was performed when a participant's mutation status was unknown at enrollment. Relationships between participant characteristics and diagnostic findings were assessed using univariable statistics and multivariable logistic regression. RESULTS: Invasive or intraepithelial ovarian/tubal/peritoneal neoplasms were detected in 25 (2.6%) of 966 RRSOs (BRCA1 mutation carriers, 4.6%; BRCA2 carriers, 3.5%; and noncarriers, 0.5%; P < .001). In multivariable models, positive BRCA1/2 mutation status (P = .0056), postmenopausal status (P = .0023), and abnormal CA-125 levels and/or TVU examinations (P < .001) were associated with detection of clinically occult neoplasms at RRSO. For 387 women with negative BRCA1/2 mutation testing and normal CA-125 levels, findings at RRSO were benign. CONCLUSION: Clinically occult cancer was detected among 2.6% of high-risk women undergoing RRSO. BRCA1/2 mutation, postmenopausal status, and abnormal preoperative CA-125 and/or TVU were associated with cancer detection at RRSO. These data can inform management decisions among women at high risk of ovarian/tubal cancer

Vogel, V. G., J. P. Costantino, D. L. Wickerham, et al. 2010. "Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer." Cancer Prev Res (Phila) 3(6):696-706.

Read abstract

The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.

Version 7

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.7.

Version 6

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: Template sentence updated. Cancer/tumour risk management guidelines: Template sentence updated. Lifestyle factors sentence moved above table. Management of associated health problems: Accordion title changed to "Management of associated health issues". Subheading title changed from "Menopausal hormone therapy (MHT) and cancer risk"  to "Management of early menopause". Version number increased to V.6.

Version 5

Date	Summary of changes
10/08/2021	Protocol discussed at March 2021 cancer genetics reference committee meeting. Discussions continued electronically via MS Teams. Protocol approved for publishing with the following changes made:   Summary First two paragraphs rewritten 'BOADICEA' changed to 'CanRisk' (and throughout the document) as an example of a validated risk assessment tool Target group Second bullet point removed Exclusion criteria - fourth bullet: 'Unaffected' added to start of sentence Lifetime risk of cancer Ovarian: 'pathology' changed to 'ovarian tumour subtype' Cancer risk management guidelines Breast - Surveillance - <40 years: '...determine commencement age for screening based on personalised risk by age' changed to 'Age for screening commencement may be individualised if the10-year risk is 3% or greater' 'Recommend annual breast MRI +/- mammography if screening advised' changed to 'Annual breast MRI if screening advised ' Breast - Surveillance - 40-50 years: age changed from '>40 years' to '40-50 years' strategy and frequency reworded Breast - Surveillance - Over age 50 years: new row added in to table Breast - Risk-reducing medication: section reworded to align with ID 1424 Ovarian - Surgical: second bullet reworded Management of associated health problems Management of early menopause 'Hormone replacement therapy (HRT)' changed to 'Menopausal hormone therapy (MHT)' 'For women who have not had a hysterectomy, Mirena and oral oestrogen may be a safer option than combined oral MHT.' added to end of paragraph and new reference added Contraception and fertility: section reworded Evidence for risk management guidelines Breast - Surveillance: section revised Breast - Risk reducing medication: paragraph reworded to align with ID 1424 Ovarian: section revised Ovarian - Surgical: second paragraph removed Version number increased to V.5. Review in 2 years
04/11/2021	The following change was made to the document and approved by the Chairs: Summary section: PALB2 added to second sentence.
02/03/2022	The following changes were made to the document: Minor wording changes made in Target population, Lifetime risk of cancer/tumour, Cancer/tumour risk management guidelines and Management of associated health problems. Lifetime risk of cancer/tumour - general population risk updated with AIHW 2017 data.

Version 4

Date	Summary of changes
17/12/2019	Protocol reviewed at May 2019 reference committee meeting. Discussions continued via email. Protocol published with the following changes made: Summary: "Women with a high likelihood (≥10%) of a heritable mutation in BRCA1 or BRCA2 based on a validated risk model (BOADICEA) are advised to have genetic testing to guide their risk management." added to end of first paragraph Target group: criteria reviewed. Links to validated risk assessment models (iPrevent, IBIS and BOADICEA) added Life time risk of cancer: general population data updated  Cancer risk management guidelines:  ​Breast - Surgical: "followed by self surveillance of the breast area" removed Breast - Surveillance: Age to begin separated into <40 years and >40 years. Surveillance strategy recommendations reviewed and updated Breast - Risk reducing medication: "Provide information on risk reducing medication" changed to "Discuss risk reducing medication. iPrevent provides tailored information about absolute risks and benefits." Ovarian - Surgical: "SEE-FIM protocol at RRBSO" added Footnote: "minimise exogenous estrogen and progesterone exposure." added Management of associated health problems: reviewed and updated. New references added Evidence for cancer risk management guidelines Breast - Surgical: Pre-menopausal RRBSO for breast cancer risk removed Breast - Surveillance: reviewed and updated. New references added Breast - Risk reducing medication: reviewed and updated. New references added Ovarian - RRBSO for ovarian cancer risk: reviewed and updated Protocol template changes applied "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up Protocol version number increased to V.4. Review in 1 year
19/08/2020	Minor wording change in the Evidence for risk management guidelines section: "Other high risk genes (PALB2, ATM 7271T>G) ...have not been associated with an increased risk of ovarian cancer" changed to say "Other high risk genes (ATM 7271T>G)... have not been associated with an increased risk of ovarian cancer."
18/12/2020	The following sections of the document were updated to align with the revised eviQ cancer genetics risk management template: Lifetime risk of cancer table: Heading changed to "Lifetime risk of cancer/tumour" Risk for general population updated to AIHW 2016 data Cancer risk management guidelines: Heading changed to "Cancer/tumour risk management guidelines" Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk."  Surveillance: "Age to begin" changed to "Age"  Website resources: added link to "COSA - Medications to lower the risk of breast cancer: clinician guide" and "COSA - Medications to lower the chance of breast cancer: information for women"

Version 3

Date	Summary of changes
04/08/2016	Discussed at reference committee meetings between 2014-2015, discussions continued over email and protocol published.
12/08/2016	Cancer risk management recommendations table - age to start screening wording updated.
28/09/2016	'Unaffected' removed from title.
31/05/2017	Transferred to new eviQ website. Version number changed to V.2.
29/01/2019	Link changed from Cancer Australia Risk-reducing medication resource to COSA medication to lower the risk of breast cancer: clinician guide as per consensus at November 2018 RCM. Version kept at V.2.
28/08/2019	Protocol title changed from 'Risk management for a female with a high breast cancer risk (ovarian cancer)' to 'Breast cancer (high risk with ovarian cancer family history) – risk management (female)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.3.