BRCA1 or BRCA2 – risk management (female)

Familial breast and ovarian cancer predisposition due to a germline pathogenic variant in the BRCA1 or BRCA2 gene is an autosomal dominant condition.

• Known or obligate female BRCA1 pathogenic variant carrier with no personal history of cancer
• Known or obligate female BRCA2 pathogenic variant carrier with no personal history of cancer
• Female at 50% risk of being a BRCA1 or BRCA2 pathogenic variant carrier (surgical management not recommended for this group*)

*predictive testing should be performed prior to any risk-reducing surgery being undertaken

Exclusion criteria

• Known male BRCA1 or BRCA2 pathogenic variant carrier with no personal history of cancer - see BRCA1 or BRCA2 – risk management (male)
• BRCA1 or BRCA2 pathogenic variant carrier with a personal history of cancer
• High-risk breast cancer family with uninformative BRCA result or no DNA testing available
• High-risk breast and ovarian cancer family with uninformative BRCA result or no DNA testing available
• Individuals with a BRCA1 or BRCA2 variant of uncertain significance
• Individuals with Fanconi anaemia due to biallelic BRCA1 or BRCA2 pathogenic variants are NOT covered by this protocol

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke, consider breastfeeding (if relevant), and avoid excessive sun exposure. Decisions about hormonal contraception and menopausal hormone therapy (MHT) should weigh a possible increase in breast cancer risk against the benefits. See Management of associated health issues below for additional information.

Cancer/tumour type	Recommendations
Breast	Surgical^
		Consider bilateral risk-reducing mastectomy The appropriateness and optimal timing should be individualised based on patient preference and risk trajectory (from CanRisk or iPrevent)
	Surveillance	Begin screening from age 25-30 yearsr Optimal timing should be individualised based on patient preference and risk trajectory (from CanRisk or iPrevent)
		Age	Strategy and frequency
		Under age 40 years	Annual MRI (US if MRI not possible)
		40-60 years	Annual MRI + MMG (MMG + US if MRI not possible)
		Over age 60 years	Annual MMG (consider MRI or US if over age 60 years with dense breast tissue)
		Pregnant	No MRI or MMG, consider US and CBE
	Risk-reducing medication	Consider medication to reduce risk of developing breast cancer for women not planning bilateral mastectomy within 3 years: Pre-menopausal women may consider tamoxifen Post-menopausal women may consider raloxifene, aromatase inhibitors or tamoxifen See COSA - Medications to lower the risk of breast cancer: clinician guide and offer COSA – Medications to lower the risk of breast cancer: patient guide
Ovarian/ fallopian tube	Surgical (BRCA1)^^	Recommend RRSO between the age of 35-40 yearsr with peritoneal lavage and SEE-FIM histological examination.^^^  Optimal timing should be individualised based on patient preference and risk trajectory (from CanRisk)
	Surgical (BRCA2)^^	Recommend RRSO between the age of 40-45 yearsr with peritoneal lavage and SEE-FIM histological examination.^^^  Optimal timing should be individualised based on patient preference and risk trajectory (from CanRisk)
	Surveillance	Do not offer serum CA125 and/or transvaginal ultrasound (TVU)
Uterine	Surgical  (BRCA1 and BRCA2)	Hysterectomy should not be recommended routinely Some carriers may choose to undergo hysterectomy with RRSO to enable use of oestrogen-only menopausal hormone therapy (MHT) to minimise breast cancer risk
Pancreatic	Surveillance	There is a lack of evidence of survival benefit from surveillance  Where possible surveillance should be carried out as part of a clinical trial^^^^ Consider annual surveillance with endoscopic US or contrast enhanced MRI/MRCP from age 50 years (or 5-10 years younger than the affected relative) in BRCA1 and BRCA2 carriers with at least one first- or second-degree relative with exocrine pancreatic cancerr Avoid smoking and obesity and minimise alcohol consumption

Abbreviations: CBE - clinical breast examination, MMG - mammogram (digital if available), MRI - magnetic resonance imaging, MRCP - magnetic resonance cholangiopancreatography, RRSO - risk-reducing salpingo-oophorectomy, US - ultrasound.
^{^} Note RRSO is not recommended to reduce risk of breast cancer due to lack of evidence of efficacy.^{r
^^} The pathogenic variant type, the patient’s preferences and the family history should be taken into consideration when deciding the timing of RRSO. It should be delayed until an age when ovarian cancer risk is increased above that of the general population.
^{^^^} Histological examination should be according to the SEE-FIM protocol to exclude occult malignancy.^{r
^^^^} Refer to Australian Pancreatic Cancer Genome Initiative for up-to-date screening trials. 

Breast cancer

Surgical

Bilateral risk-reducing mastectomy reduces cancer risk by at least 90%^r in BRCA1 and BRCA2 pathogenic variant carriers (depending on the operation performed). Statistically significant survival benefit associated with bilateral risk-reducing mastectomy compared with surveillance is yet to be demonstrated.

Although early studies suggested pre-menopausal RRSO reduced breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers, they were subject to several biases that tended to overestimate benefit. Contemporary studies, designed to minimise bias, have yielded contradictory findings but overall there is no clear and consistent evidence for a role of RRSO in reducing breast cancer risk and it should not be used specifically for that purpose.^r

Surveillance

The estimated breast cancer risk under age 30 years for BRCA1 and BRCA2 carriers is 4% (95% CI 2-7 and 2-9, respectively).^r Personal lifestyle and family history factors, such as the presence of young onset cancer, may affect the risk trajectory and can be personalised using the validated risk prediction tools specified (e.g. CanRisk or iPrevent). A decision to commence breast screening at the younger end of the 25-30 year age range may therefore be considered when an individual’s estimated risk is greater than 4% by age 30 years or based on patient perception and preferences regarding risk.

Magnetic resonance imaging (MRI) is the preferred screening technique due to its high sensitivity compared with mammogram (MMG) or ultrasound (US). The addition of MMG is limited and does not lead to a significant increase in sensitivity compared with MRI alone.^r There is no added value of US or clinical breast exam in women undergoing MRI for screening.^r MRI detects tumours which are smaller and more likely to be node-negative than MMG. MRI has a recall rate (requiring further investigation and/or biopsy) of 15% for initial screening, which decreases with subsequent rounds of screening to <10%.

MMG screening is not recommended before age 40 years in BRCA1 and BRCA2 pathogenic variant carriers. The sensitivity of MRI is not influenced by age or breast density, being similar in women aged over 50 years to those aged under 50 years.

The rate of cancers occurring between annual screening (interval cancers) is higher in BRCA1 pathogenic variant carriers than other high risk populations.

Risk-reducing medication

Tamoxifen, raloxifene, anastrozole and exemestane have been shown to reduce the relative risk of breast cancer in high risk women by 30%-60%. Five years of daily tamoxifen (20mg) or anastrozole (1mg) reduces risk for at least 20 and 10 years, respectively. Lower dose, shorter-duration tamoxifen (e.g. 5mg daily for 3 years) is an option if the 20mg dose is not tolerated.^r

To date studies have not included enough BRCA1 or BRCA2 pathogenic variant carriers to determine efficacy for primary prevention in this population. Tamoxifen use is associated with a reduction in contralateral breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers with breast cancer.^r Risk-reducing medications can be offered to BRCA1 and BRCA2 pathogenic variant carriers who postpone or do not undergo bilateral mastectomy. As with all interventions, discussion of risks and benefits should occur. See COSA - Medications to lower the risk of breast cancer: clinician guide

Ovarian and fallopian tube cancer

Surgical

The estimated ovarian cancer risk for BRCA1 carriers under age 40 years is 2% (95% CI 1-3) and for BRCA2 carriers under age 50 years is 0% (95% CI 0-2).^r Personal lifestyle and family history factors, such as the presence of young onset cancer, may affect the risk trajectory and can be personalised using the validated risk prediction tools specified (e.g. CanRisk). A decision to perform RRSO at the younger end of the age range may therefore be considered when an individual’s estimated risk is at the upper end of the confidence interval or based on patient perception and preferences regarding risk.

Bilateral risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian and fallopian tube cancer in BRCA1 and BRCA2 pathogenic variant carriers. Careful examination of the resected tubes and ovaries using the SEE-FIM protocol is essential.^r Those with serous tubal intraepithelial carcinoma (STIC) found in their RRSO specimen are at very high risk for subsequent peritoneal cancer (27.5% at 10 years post RRSO) whereas those with no STIC at RRSO have a low risk (10 year risk <1%).^r

The effectiveness and safety of risk-reducing bilateral salpingectomy followed by delayed bilateral oophorectomy has not been established. It is not recommended for ovarian cancer risk management unless part of a clinical trial.

The decision to perform hysterectomy at the time of RRSO should be individualised. The absolute risk of uterine cancers in BRCA1 and BRCA2 carriers is relatively low.^r Hysterectomy may simplify subsequent menopausal hormone therapy, or the use of tamoxifen for breast cancer risk or as adjuvant treatment of breast cancer, but may not be justified for endometrial cancer prevention alone.

Surveillance

For asymptomatic women annual transvaginal ultrasound (TVU) and serum CA125 levels have poor sensitivity and specificity for ovarian cancer. They do not reliably detect ovarian cancers at an early stage, nor do they affect outcomes. This is true of women in the general population and women at high risk of hereditary ovarian cancer. Effective ovarian cancer risk management relies on RRSO.

Risk-reducing medication

Although there is evidence the combined oral contraceptive pill can reduce the ovarian cancer risk, it is significantly less effective than RRSO and it is not recommended for cancer prevention.

Pancreatic cancer

Surveillance

Some studies suggest offering surveillance from age 50 years in BRCA1 or BRCA2 germline pathogenic variant carriers with a first- or second-degree relative with pancreatic cancer. Studies suggest surveillance can achieve ‘downstaging’ at diagnosis, although advanced interval cancers are common, and there is no evidence for improved survival. However, in one recently published screening study of patients at high risk of developing pancreatic cancer, most screen-detected pancreatic cancers were stage I with favourable long-term outcomes.^r

If surveillance is offered it should be undertaken in an experienced high-volume centre after detailed discussion regarding limitations of screening including cost, high incidence of benign or indeterminate pancreatic abnormalities and uncertainties about the benefit. Most small cystic lesions found on screening will not warrant biopsy, surgical resection, or any other intervention.

Research studies

Research is taking place in all aspects of hereditary breast and ovarian cancer. Families may be invited to participate in research trials. Speak to your doctor for more information.

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Bibliography

Antoniou, A., P. D. Pharoah, S. Narod, et al. 2003. "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 72(5):1117-1130.

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Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

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

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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.

Heemskerk-Gerritsen, B. A., M. B. Menke-Pluijmers, A. Jager, et al. 2013. "Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis." Ann Oncol 24(8):2029-2035.

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BACKGROUND: To prospectively assess the efficacy of bilateral risk-reducing mastectomy (BRRM) when compared with surveillance on breast cancer (BC) risk and mortality in healthy BRCA1 and BRCA2 mutation carriers. PATIENTS AND METHODS: Five hundred and seventy healthy female mutation carriers (405 BRCA1, 165 BRCA2) were selected from the institutional Family Cancer Clinic database. Eventually, 156 BRCA1 and 56 BRCA2 mutation carriers underwent BRRM. The effect of BRRM versus surveillance was estimated using Cox models. RESULTS: During 2037 person-years of observation (PYO), 57 BC cases occurred in the surveillance group versus zero cases during 1379 PYO in the BRRM group (incidence rates, 28 and 0 per 1000 PYO, respectively). In the surveillance group, four women died of BC, while one woman in the BRRM group presented with metastatic BC 3.5 years after BRRM (no primary BC), and died afterward, yielding a HR of 0.29 (95% CI 0.02-2.61) for BC-specific mortality. CONCLUSIONS: In healthy BRCA1/2 mutation carriers, BRRM when compared with surveillance reduces BC risk substantially, while longer follow-up is warranted to confirm survival benefits.

Kriege, M., C. T. Brekelmans, C. Boetes, et al. 2006. "Differences between first and subsequent rounds of the MRISC breast cancer screening program for women with a familial or genetic predisposition." Cancer 106(11):2318-2326.

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BACKGROUND: Within the Dutch MRI Screening (MRISC) study, a Dutch multicenter screening study for hereditary breast cancer, the authors investigated whether previously reported increased diagnostic accuracy of magnetic resonance imaging (MRI) compared with mammography would be maintained during subsequent screening rounds. METHODS: From November 1999 to October 2003, 1909 eligible women were included in the study. Screening parameters and tumor characteristics of different rounds were calculated and compared. The authors defined 3 different types of imaging screening rounds: first round in women never screened by imaging before, first round in women screened by imaging (mainly mammography) before, and subsequent rounds. RESULTS: The difference in sensitivity for invasive cancers between mammography and MRI was largest in the first round of women previously screened with mammography (20.0 vs. 93.3%; P=.003), but also in subsequent rounds, there was a significant difference in favor of MRI (29.4 vs. 76.5%; P=.02). The difference in false-positive rate between mammography and MRI was also largest in the first round of women previously screened with mammography (5.5 vs. 14.0%; P <.001), and it remained significant in subsequent rounds (4.6 vs. 8.2%; P <.001). Screen-detected tumors were smaller and more often lymph node negative than symptomatic tumors in age-matched control patients, but no major differences in tumor stage were found between tumors detected at subsequent rounds compared with those in the first round. CONCLUSIONS: In subsequent rounds, a significantly higher sensitivity and better discriminating capacity of MRI compared with mammography was maintained, and a favorable tumor stage compared with age-matched symptomatic controls. As results of these subsequent screening rounds were most predictive for long-term effects, the authors expect that this screening program will contribute to a decrease of breast cancer mortality in these high-risk women.

Phi, X. A., N. Houssami, I. M. Obdeijn, et al. 2015. "Magnetic resonance imaging improves breast screening sensitivity in BRCA mutation carriers age >/= 50 years: evidence from an individual patient data meta-analysis." J Clin Oncol 33(4):349-356.

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PURPOSE: There is no consensus on whether magnetic resonance imaging (MRI) should be included in breast screening protocols for women with BRCA1/2 mutations age >/= 50 years. Therefore, we investigated the evidence on age-related screening accuracy in women with BRCA1/2 mutations using individual patient data (IPD) meta-analysis.

PATIENTS AND METHODS: IPD were pooled from six high-risk screening trials including women with BRCA1/2 mutations who had completed at least one screening round with both MRI and mammography. A generalized linear mixed model with repeated measurements and a random effect of studies estimated sensitivity and specificity of MRI, mammography, and the combination in all women and specifically in those age >/= 50 years.

RESULTS: Pooled analysis showed that in women age >/= 50 years, screening sensitivity was not different from that in women age < 50 years, whereas screening specificity was. In women age >/= 50 years, combining MRI and mammography significantly increased screening sensitivity compared with mammography alone (94.1%; 95% CI, 77.7% to 98.7% v 38.1%; 95% CI, 22.4% to 56.7%; P < .001). The combination was not significantly more sensitive than MRI alone (94.1%; 95% CI, 77.7% to 98.7% v 84.4%; 95% CI, 61.8% to 94.8%; P = .28). Combining MRI and mammography in women age >/= 50 years resulted in sensitivity similar to that in women age < 50 years (94.1%; 95% CI, 77.7% to 98.7% v 93.2%; 95% CI, 79.3% to 98%; P = .79).

CONCLUSION: Addition of MRI to mammography for screening BRCA1/2 mutation carriers age >/= 50 years improves screening sensitivity by a magnitude similar to that observed in younger women. Limiting screening MRI in BRCA1/2 carriers age >/= 50 years should be reconsidered.

Rijnsburger, A. J., I. M. Obdeijn, R. Kaas, et al. 2010. "BRCA1-associated breast cancers present differently from BRCA2-associated and familial cases: long-term follow-up of the Dutch MRISC Screening Study." J Clin Oncol 28(36):5265-5273.

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PURPOSE: The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS: Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS: Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis</=1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION: Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Warner, E., K. Hill, P. Causer, et al. 2011. "Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging." J Clin Oncol 29(13):1664-1669.

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PURPOSE: The sensitivity of magnetic resonance imaging (MRI) for breast cancer screening exceeds that of mammography. If MRI screening reduces mortality in women with a BRCA1 or BRCA2 mutation, it is expected that the incidence of advanced-stage breast cancers should be reduced in women undergoing MRI screening compared with those undergoing conventional screening. PATIENTS AND METHODS: We followed 1,275 women with a BRCA1 or BRCA2 mutation for a mean of 3.2 years. In total, 445 women were enrolled in an MRI screening trial in Toronto, Ontario, Canada, and 830 were in the comparison group. The cumulative incidences of ductal carcinoma in situ (DCIS), early-stage, and late-stage breast cancers were estimated at 6 years in the cohorts. RESULTS: There were 41 cases of breast cancer in the MRI-screened cohort (9.2%) and 76 cases in the comparison group (9.2%). The cumulative incidence of DCIS or stage I breast cancer at 6 years was 13.8% (95% CI, 9.1% to 18.5%) in the MRI-screened cohort and 7.2% (95% CI, 4.5% to 9.9%) in the comparison group (P = .01). The cumulative incidence of stages II to IV breast cancers was 1.9% (95% CI, 0.2% to 3.7%) in the MRI-screened cohort and 6.6% (95% CI, 3.8% to 9.3%) in the comparison group (P = .02). The adjusted hazard ratio for the development of stages II to IV breast cancer associated with MRI screening was 0.30 (95% CI, 0.12 to 0.72; P = .008). CONCLUSION: Annual surveillance with MRI is associated with a significant reduction in the incidence of advanced-stage breast cancer in BRCA1 and BRCA2 carriers.

Woodward, E. R., H. V. Sleightholme, A. M. Considine, et al. 2007. "Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective." Bjog 114(12):1500-1509.

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OBJECTIVE: To assess the efficacy of annual CA125 and transvaginal ultrasound (TVU) scan as surveillance for ovarian cancer. DESIGN: Retrospective audit. SETTING: NHS Trust. POPULATION: Three hundred and forty-one asymptomatic women enrolled for ovarian cancer screening: 179 were in a high-risk group ( >10% lifetime risk of developing ovarian cancer), 77 in a moderate risk group (4-10% lifetime risk of developing ovarian cancer) and 71 in a near population risk group ( <4% lifetime risk). METHODS: Retrospective audit of case records, laboratory CA125 results, radiology reports, histology records and local cancer registry data. MAIN OUTCOME MEASURES: Ovarian cancers occurring in study population. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU, and CA125 as a screening tool for ovarian cancer. RESULTS: Four ovarian cancers and one endometrial cancer occurred. One ovarian cancer was detected at surveillance, three occurred in women who presented symptomatically between screenings. Thirty women underwent exploratory surgery because of abnormal findings at surveillance. Two women had cancer (PPV = 6.7%); one had ovarian cancer and the other endometrial cancer. Twenty-eight women (93.3%) had no malignancy. Sensitivity, specificity, PPV and NPV for TVU in the whole cohort were 33.3, 85.8, 0.6 and 99.8%, respectively. For high-risk individuals, the figures for TVU were 33.3, 84.5, 1.1 and 99.6, respectively. Combining both modalities for the whole cohort, the sensitivity, specificity, PPV and NPV were 66.7, 82.9, 1.5 and 99.8% and 50.0, 82.8, 1.3 and 99.7%, respectively, for the high-risk group alone. CONCLUSIONS: Ovarian screening by annual TVU and CA125 is inefficient at detecting early-stage ovarian cancers.

Version 4

Date	Summary of changes
01/08/2023	Protocol reviewed at March 2023 cancer genetics reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made:  Flag added to top of protocol Target population: minor wording changes Lifetime risk of cancer/tumour: Cancer risk figures updated for pancreatic cancer and peritoneal cancer. Uterine cancer added General population risk figures updated with AIHW 2018 data Cancer risk management guidelines: Wording updated in template sentences above table Multiple changes to recommendations in the table - refer to PDF of previous table to compare changes  Management of associated health issues: reviewed and updated Evidence for risk management guidelines: reviewed and updated Version increased to V.4. Review in 2 years.
27/09/2023	Protocol updated with the following changes made: Cancer risk management guidelines: Breast cancer surveillance - added "Optimal timing should be individualised..." Evidence: additional information added under Breast cancer - Surveillance and Ovarian cancer - Surgical subsections.
08/08/2024	Added to Exclusion criteria "Individuals with Fanconi anaemia due to biallelic BRCA1 or BRCA2 pathogenic variants are NOT covered by this protocol"

Version 3

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. Target population: Added to exclusion criteria "Individual with a variant of uncertain significance". 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 "Contraception and fertility" changed to "Contraception". Version number increased to V.3.

Version 2

Date	Summary of changes
04/08/2021	The following changes were made to align with ID 656 BRCA1 or BRCA2 – risk management (male): Cancer risk management guidelines: Pancreatic - Surveillance: "No evidence of benefit from surveillance" changed to "Lack of evidence of benefit from screening. Should be undertaken only as part of a clinical trial". Footnote added "Refer to Australian Pancreatic Cancer Genome Initiative for up-to-date screening trials" with link to website added Website resources: Added link to Australian Pancreatic Cancer Genome Initiative website Version number increased to V.2.
03/06/2022	Protocol updated with the following changes: Lifetime risk of cancer/tumour  Pancreatic Cancer - BRCA1: added 'Unknown but unlikely to be increased' Cancer/tumour risk management guidelines Breast cancer - Risk reducing medication: updated to standard wording used across eviQ breast cancer risk management protocols

Version 1

Date	Summary of changes
02/07/2020	ID 162 and ID 170 reviewed at October 2019 eviQ cancer genetics reference committee meeting. Decision made to combine ID 162 and ID 170 into one risk management document. New document created - ID 3814 BRCA1 or BRCA2 - risk management (female). ID 162 and ID 170 archived. Protocol approved for publication with the following changes made: Target group: third bullet point - added "(surgical management not recommended for this group)" and footnote "predictive testing should be strongly considered prior to any risk-reducing surgery being undertaken" Lifetime risk of cancer table: Lifetime risk of pancreatic cancer for BRCA2 mutation carrier changed from "<5%"  to "unknown but increased" as no reference available General female population risk by age 80 years - figures updated with 2016 data Cancer risk management guidelines: Ovarian/fallopian tube - Surgical (BRCA2) - "Recommend RRSO by age 45 years (after family completion)..." changed to "Recommend RRSO from the age of 40 years (and after family completion)..." Management of associated health problems: Management of early menopause Hormone replacement therapy (HRT) changed to menopausal hormone therapy (MHT) Added: "Oestrogen-only MHT (oral or subcutaneous) has not been associated with a higher risk of developing breast cancer. For women with uterus in situ, progesterone is required in addition to oestrogen. Local progesterone is preferred over oral administration. An individualised discussion about options for MHT is advised before surgery with an appropriate specialist." "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 template changes applied throughout document. Approved as V.1. Review in 2 years.
18/12/2020	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Related pages: link to "Cancer predisposition genes: population carrier frequency" added Lifetime risk of cancer: heading changed to "Lifetime risk of cancer/tumour" 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"  Updated link to  "COSA - Medications to lower the risk of breast cancer: clinician guide" (also updated in Evidence section) 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".

 

As ID 3814 replaces two existing approved protocols, their individual history sections are included below for consistency in documentation.

History for ID 170: BRCA1 - risk management (female)

Date	Summary of changes
18/10/2009	Approved
26/07/2010	Chemoprevention updated link to NBOCC.
26/08/2010	Patient information added.
20/12/2010	References moved to link behind the document.
21/07/2011	The following changes have been made following the review of these guidelines at the cancer genetics reference committee meeting on the 16 June 2011: Ranges of  breast and ovarian cancer incidence included. Breast surveillance, chemoprevention, all cancer risk management guidelines reviewed and updated. BSO recommendations changed from "strongly consider" to recommend in the ovarian and fallopian risk management guidelines.  Chemoprevention for ovarian and fallopian tube removed from risk management guidelines. Evidence for cancer risk management guidelines for breast reviewed and updated. Evidence for cancer risk management guidelines for ovarian and fallopian tube reviewed and updated. Ovarian and fallopian tube surgical management has been reviewed.
27/06/2012	Discussed at October 27 2011 reference committee meeting and the following changes made: Exclusion criteria  - known female BRCA2 mutation carrier changed to known BRCA2 mutation carrier. Lifetime risk of cancer - BRCA1 mutation carrier to age 70 yrs figures updated and link to G.Suther's leaflet added. MRI - to be performed between days 6 - 16 of the menstrual cycle deleted Breast - Chemoprevention changed to risk-reducing medication. Links to NBOCC updated to Cancer Australia. Ovarian/fallopian tube - surveillance - The discovery and investigation of abnormal findings can result in unnecessary anxiety and the investigations can carry significant risks. See Cancer Australia link added.  Evidence for cancer risk management guidelines -  for breast surgical reviewed and updated.
11/09/2012	Risk-reducing medication - removal of aromatase inhibitors until further evidence available
22/10/2012	Following group discussion - Cancer risk management guidelines - surveillance - point 3 updated from 30-50 yrs - annual MRI*+MMG*, (if MRI is unavailable annual MMG+US*), consider 6 month interval CBE* in all cases  to 30-50 yrs - annual MRI*+MMG* (+/- US*)
23/12/2013	Discussed at October 30 2013 reference committee meeting and the following changes made: Cancer risk management guidelines table  breast - surgical - minor word changes  breast - surveillance - minor word changes ovarian/fallopian tube - surgical - age to recommend risk-reducing salpingo-oophorectomy (RRSO) adjusted from age <40 yrs to after family completion or by age 40 yrs surveillance - minor wording change all cancers - updated Management of associated health problems and side effect  management of early menopause and contraception and fertility information added Evidence for cancer risk management guidelines breast - surgical and risk-reducing medications updated ovarian and fallopian tube - surgical - updated surveillance - minor word change Website resources - Cancer Council Australia - Position statement - Combined oral contraceptives and cancer risk added Reference list - review and updated and additional references placed in history tab.
19/01/2015	Discussed at October 23 2014 reference committee meeting and the following changes made: Lifetime risk of cancer table minor text changes and pancreatic risk added Cancer risk management guidelines breast surveillance: CBE deleted minor text change to ovarian/fallopian tube surveillance Evidence for cancer risk management guidelines minor text changes to ovarian and fallopian tube pancreatic evidence added Protocol for 2 yearly review.
31/07/2015	AGSA link changed to Genetic Alliance Australia.
07/01/2016	Sentence added to risk management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016	Sentence added to risk management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
28/09/2016	'Unaffected' removed from title.
31/05/2017	Transferred to new eviQ website. Version number changed to V.6.
14/06/2018	Protocol reviewed and presented at the November 2017 eviQ reference committee meeting. Discussion continued over email and document approved for publication with the following changes:  Lifetime risk of cancer table - statistics updated: Breast BRCA1 and general population ovarian/fallopian tube/primary peritoneal BRCA1  row on pancreatic cancer removed age of lifetime risk of ca for BRCA1 carriers changed from 70 to 80. Cancer risk management guidelines: Breast - surgical - removal of bullet point: Alternatively in the absence of bilateral risk-reducing mastectomy, recommend RRSO preferably at age <40 yrs. Breast - surveillance: 30-50 yrs – annual MRI+MMG (+/- US) changed to 30-40 yrs – annual MRI, +/- US and 40-50 yrs – annual MRI, +/- MMG, +/- US. Sentence added on >50 yrs to consider MRI if dense breasts. Ovarian/fallopian tube: RRBSO after family completion or around age 40 yrs changed to RRSO by age 40 years (after family completion), addition of qualifier on histological examination. Management of associated health problems: Management of early menopause: removal of sentence on HRT/RRSO and breast cancer risk. Contraception and fertility: Section updated with evidence on OCP use and ovarian/breast ca risk. Addition of paragraph on progesterone implants/IUDs. Evidence for risk management guidelines: Breast - surgical - updated with recent data questioning benefit of RRSO. Breast - surveillance - updated MRI as preferred technique. Additional information on mammography screening, and MRI added. cancer added to subheadings: Breast/Ovarian and fallopian tube Ovarian and fallopian tube - surgical - section updated with information on risk-reducing bilateral salpingectomy followed by delayed bilateral oophorectomy, and decision to perform hysterectomy at the time of RRSO. Section on pancreatic cancer removed Website resources: Further references section removed - references listed in History tab moved to front of protocol in the Bibliography section. Reference list - reviewed and updated with addition of bibliography section.
18/06/2019	Protocol underwent minor review after Nov 2018 meeting, with the following changes agreed upon and approved for publication: Cancer risk management guidelines section: Ovarian/fallopian tube - surgical: recommendation of RRSO changed from 'by age 40 years' to 'from age 35 years'. 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. Sentences updated in summary and support and information sections to reflect template changes. Version changed to V.8 as recommendations signal practice change. To undergo next major review at October 2019 reference committee meeting.
28/08/2019	Protocol title changed from 'Risk management for a female BRCA1 mutation carrier' to 'BRCA1 – risk management (female)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.9.

Histor​y for ID 162: BRCA2 - risk management (female) 

Date	Summary of changes
18/10/2009	Approved
26/07/2010	Chemoprevention updated and link to NBOCC.
26/08/2010	Patient information added.
20/12/2010	References moved to link behind document.
21/07/2011	The following changes have been made following the review of these guidelines at the cancer genetics reference committee on the 16 June 2011: Ranges of  breast and ovarian cancer incidence included Breast surveillance, chemoprevention, all cancer risk management guidelines reviewed and updated BSO recommendations changed from "strongly consider" to recommend in the ovarian and fallopian risk management guidelines  Chemoprevention for ovarian and fallopian tube removed from risk management guidelines Evidence for cancer risk management guidelines for breast reviewed and updated Evidence for cancer risk management guidelines for ovarian and fallopian tube reviewed and updated Ovarian and fallopian tube surgical management has been reviewed.
27/06/2012	Following discussion at October 27, 2011 reference committee meeting, this protocol has been reviewed and updated. The following changes have been made: Target and exclusion groups updated. Lifetime risk of cancer CI for breast and ovarian added. Link to G.Suthers leaflet added. Cancer risk management guidelines breast surgical reviewed and updated: chemoprevention changed to risk-reducing medication. Links to NBOCC updated to Cancer Australia. ovarian/fallopian tube - surveillance - The discovery and investigation of abnormal findings can result in unnecessary anxiety and the investigations can carry significant risks. See Cancer Australia link added. melanoma - removed MRI - to be performed between days 6-16 of the menstrual cycle deleted. Evidence for cancer risk management guidelines - for ovarian and fallopian tube reviewed and updated. Evidence for cancer risk management guidelines melanoma removed. Reference List updated Kurian et al 2010 added, Antoniou et all 2003 moved to History tab.
11/09/2012	Risk-reducing medication - removal of aromatase inhibitors until further evidence available.
22/10/2012	Following group discussion - cancer risk management guidelines - surveillance - point 3 updated from: 30-50 yrs - annual MRI*+MMG*, (if MRI is unavailable annual MMG+US*) consider 6 month interval US + CBE* in all cases to 30-50 yrs - annual MRI*+MMG* (+/- US*)
23/12/2013	Discussed at October 30 2013 reference committee meeting and the following changes made: Cancer risk management guidelines table breast - surgical - greatest benefit predicted updated from The greatest predicted benefit is obtained when surgery occurs <40 yrs to The greatest benefit is predicted when surgery occurs at age <40 yrs breast- surveillance - minor word changes ovarian/fallopian tube - surgical age to recommend risk-reducing salpingo-oophorectomy(RRSO) adjusted from age <45 yrs to after family completion or around age 40 yrs surveillance - minor wording change Management of associated health problems and side effects management of early menopause and contraception and fertility information added Evidence for cancer risk management guidelines breast - surgical and risk-reducing medications updated ovarian and fallopian tube - surgical - updated surveillance - minor word change Website resources - Cancer Council Australia - position statement - combined oral contraceptives and cancer risk added Reference list - review and updated and additional references placed in history tab.
20/01/2015	Discussed at October 2014 reference committee meeting and the following changes made: Lifetime risk of cancer table ovarian and fallopian tube cancer - minor text changes primary peritoneal - minor text changes Cancer risk management guidelines ovarian and fallopian tube - minor text change to ovarian/fallopian tube surveillance Evidence for cancer risk management guidelines ovarian and fallopian tube: minor text changes Protocol for 2 yearly review.
31/07/2015	Link to AGSA changed to Genetic Alliance Australia.
12/01/2016	Sentence added to risk management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016	Sentence added to risk management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".
28/09/2016	'Unaffected' removed from title.
31/05/2017	Transferred to new eviQ website. Version number changed to V.6.
14/06/2018	Protocol reviewed and presented at the November 2017 eviQ reference committee meeting. Discussion continued over email and document approved for publication with the following changes:  Lifetime risk of cancer table - statistics updated: Breast BRCA2 and general population ovarian/fallopian tube/primary peritoneal BRCA2  pancreatic general population age of lifetime risk of ca for BRCA1 carriers changed from 70 to 80. Cancer risk management guidelines: Breast - surgical - removal of bullet point: Alternatively in the absence of bilateral risk-reducing mastectomy, recommend RRSO preferably around age 40 yrs. Breast - surveillance: 30-50 yrs – annual MRI+MMG (+/- US) changed to 30-40 yrs – annual MRI, +/- US and 40-50 yrs – annual MRI, +/- MMG, +/- US. Sentence added on >50 yrs to consider MRI if dense breasts. Ovarian/fallopian tube: RRBSO after family completion or around age 40 yrs changed to RRSO by age 45 years (after family completion), addition of qualifier on histological examination. Management of associated health problems: Management of early menopause: removal of sentence on HRT/RRSO and breast cancer risk. Contraception and fertility: Section updated with evidence on OCP use and ovarian/breast ca risk. Addition of paragraph on progesterone implants/IUDs. Evidence for risk management guidelines: Breast - surgical - updated with recent data of benefit on RRSO. Breast - surveillance - updated MRI as preferred technique. Additional information on mammography screening, and MRI added. cancer added to subheadings: Ovarian and fallopian tube/pancreatic Ovarian and fallopian tube - surgical - section updated with information on risk-reducing bilateral salpingectomy followed by delayed bilateral oophorectomy, and decision to perform hysterectomy at the time of RRSO. Website resources: Research studies section removed Further references section removed - references listed in History tab moved to front of protocol in the Bibliography section. Reference list - reviewed and updated with addition of bibliography section.
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. Table caption in cancer risk management guidelines section amended to include 'and avoid excessive sun exposure.' Formatting of table captions in lifetime risk of cancer and cancer risk management guidelines sections amended. Version kept at V.7.
28/08/2019	Protocol title changed from 'Risk management for a female BRCA2 mutation carrier' to 'BRCA2 – risk management (female)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.8.