PALB2 – risk management

Familial breast cancer predisposition due to a monoallelic germline loss-of-function pathogenic variant in the PALB2 gene is an autosomal dominant condition.

• Known or obligate PALB2 pathogenic variant carrier with no personal history of cancer
• Individuals at 50% risk of being a PALB2 pathogenic variant carrier with no personal history of cancer

Exclusion criteria

• Individuals from a high risk breast and/or ovarian cancer family where genetic testing has not revealed a heritable cause or no DNA testing available
• PALB2 pathogenic variant carrier with a personal history of cancer
• Individuals with a variant of uncertain significance
• Individuals with Fanconi anaemia due to biallelic PALB2 pathogenic variants are NOT covered by this protocol

The risk of breast cancer below varies based on an individual’s family history of breast cancer. The CanRisk tool can be used to determine an individual’s absolute risk of breast or ovarian cancer. 

Cancer/tumour type	Average risk for PALB2 pathogenic variant carriers by age 80 years*	General population risk by age 80 years**
Breast (female)	53% (95% CI, 44% to 63%)r	11.9%
Breast (male)	1% (95% CI, 0.2% to 5%)r	0.15%
Ovarian**	5% (95% CI, 2% to 10%)r	0.84%
Pancreatic	2-3% (95% CI, 1% to 4%)r	1.3%
Prostate	Increased but not well quantified	16.3%

* These are average risks. An individual’s risk can be substantially more or less than average depending on other factors (e.g. family history and non-genetic [lifestyle] factors). Individualised risk information for breast and ovarian cancer should be provided using CanRisk. 
** Source: Australian Institute of Health and Welfare (AIHW) 2022 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation> (2018 data, unadjusted for competing mortality)

Contraception 

Hormonal contraception use requires consideration of potential risks and benefits and alternative contraceptive strategies. An increased risk of breast cancer has been reported for current oral contraceptive pill (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 other hormonal contraceptives, including progesterone- containing implanted devices.^r For women in their 20’s absolute risk increase with hormonal contraception is likely to be small. OCP cannot be used concurrently with breast cancer risk-reducing medications due to interactions. The uncertain impact of hormonal contraceptives on breast cancer risk should be considered when discussing the potential risk and benefits of the OCP.

Breast cancer (female)

As the specific evidence related to PALB2 pathogenic variant carriers is limited, these guidelines are inferred from those recommended for management of breast cancer risk in BRCA2 pathogenic variant carriers, and take into account the knowledge that the cancer risk in some PALB2 pathogenic variant families is lower than the usual threshold for recommending risk-reducing surgery.

Around 60% of PALB2-associated breast cancers are ER+.^r 

Surgical

Bilateral risk-reducing mastectomy (RRM) reduces cancer risk by at least 95%^r (depending on the operation performed) in BRCA2 pathogenic variant carriers. There is no evidence that RRM is associated with improved survival for PALB2 (or BRCA2) carriers over surveillance.

Surveillance

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 especially for women under age 40 years.^r There is no added value of US or clinical breast exam (CBE) in women undergoing MRI for screening. MRI detects tumours which are smaller and more likely to be node-negative than MMG, but whether this translates to improved survival has not been studied. 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%.

For women who do not choose risk-reducing surgery, surveillance is strongly recommended. A recent study modelling the utility of breast screening modalities in PALB2 carriers estimated that MRI breast screening commencing between age 30-35 years and MMG from age 40 years is associated with a 55% reduction in breast cancer mortality compared with no screening.^r

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 (20 mg) or anastrozole (1 mg) reduces risk for at least 20 and 10 years, respectively. Lower dose, shorter-duration tamoxifen (e.g. 5 mg daily for 3 years) is an option if the 20 mg dose is not tolerated.^r To date studies have not included enough PALB2 pathogenic variant carriers to determine efficacy for primary prevention in this setting. As most breast cancers in PALB2 carriers are ER positive, risk-reducing medications might be expected to be efficacious and can be offered to PALB2 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.

Breast cancer (male)

There is no data available that is specifically referable to male PALB2 pathogenic variant carriers.

Ovarian cancer

Surgical

Although there are no specific risk-reducing salpingo-oophorectomy (RRSO) studies to date including PALB2 pathogenic variants, evidence suggests that ≥4% lifetime risk of ovarian cancer warrants consideration of RRSO in premenopausal women on the basis of family history of ovarian cancer.^r The recommendation for surgery is generally after age 50 years as the likelihood of developing ovarian cancer prior to this age is less than 1%.^r

Pancreatic cancer

Surveillance

The Cancer of Pancreas Screening -5 (CAPS5) study of individuals at increased risk for pancreas cancer showed that screen-detected pancreas cancer was stage I in 78%, resectable in 89% (8/9) participants and was associated with long term survival (73.3% at 5 years). The screening protocol used annual endoscopic US and/or pancreas MRI/MRCP. This study included individuals who carry a PALB2 pathogenic variant AND have a family history of pancreatic cancer in a 1st degree relative.^r

If surveillance is offered it should be undertaken in an experienced high-volume centre after detailed discussion regarding the 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.

Prostate cancer

Surveillance

There is no evidence to inform the utility or otherwise of prostate cancer screening for PALB2 carriers. Annual PSA screening in BRCA2 carriers with prostate biopsy at a threshold of 3 ng/mL detected more clinically significant prostate cancer in carriers compared with non-carriers. Longer term follow up is required to understand whether this affects outcome.^r PALB2 carriers with a strong family history of prostate cancer may consider PSA screening.

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.

Delaloge, S., O. Caron and J. Feunteun. 2015. "Effect of PALB2 status on breast cancer precision medicine." Lancet Oncol 16(6):598-600.

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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.

Kurian, A. W., B. M. Sigal and S. K. Plevritis. 2010. "Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers." J Clin Oncol 28(2):222-231.

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PURPOSE: Women with BRCA1/2 mutations inherit high risks of breast and ovarian cancer; options to reduce cancer mortality include prophylactic surgery or breast screening, but their efficacy has never been empirically compared. We used decision analysis to simulate risk-reducing strategies in BRCA1/2 mutation carriers and to compare resulting survival probability and causes of death. METHODS: We developed a Monte Carlo model of breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years, prophylactic mastectomy (PM) at various ages, and/or prophylactic oophorectomy (PO) at ages 40 or 50 years in 25-year-old BRCA1/2 mutation carriers. RESULTS: With no intervention, survival probability by age 70 is 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers is PO at age 40, yielding a 15% absolute survival gain; for BRCA2 mutation carriers, the most effective single intervention is PM, yielding a 7% survival gain if performed at age 40 years. The combination of PM and PO at age 40 improves survival more than any single intervention, yielding 24% survival gain for BRCA1 and 11% for BRCA2 mutation carriers. PM at age 25 instead of age 40 offers minimal incremental benefit (1% to 2%); substituting screening for PM yields a similarly minimal decrement in survival (2% to 3%). CONCLUSION: Although PM at age 25 plus PO at age 40 years maximizes survival probability, substituting mammography plus MRI screening for PM seems to offer comparable survival. These results may guide women with BRCA1/2 mutations in their choices between prophylactic surgery and breast screening.

Moorman, P. G., L. J. Havrilesky, J. M. Gierisch, et al. 2013. "Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis." J Clin Oncol 31(33):4188-4198.

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PURPOSE: To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history. METHODS: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer. RESULTS: From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned. CONCLUSION: Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

Phillips, K. A., R. L. Milne, M. A. Rookus, et al. 2013. "Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers." J Clin Oncol 31(25):3091-3099.

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PURPOSE: To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. METHODS: Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. RESULTS: Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). CONCLUSION: This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.

Rebbeck, T. R., T. Friebel, H. T. Lynch, et al. 2004. "Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group." J Clin Oncol 22(6):1055-1062.

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PURPOSE: Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. PATIENTS AND METHODS: Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. RESULTS: Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. CONCLUSION: Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.

Rebbeck, T. R., T. Friebel, T. Wagner, et al. 2005. "Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group." J Clin Oncol 23(31):7804-7810.

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PURPOSE: Bilateral prophylactic oophorectomy (BPO) is widely used for cancer risk reduction in women with BRCA1/2 mutations. Many premenopausal women choose to take hormone replacement therapy (HRT) after undergoing BPO to abrogate immediate symptoms of surgically-induced menopause. Thus, we evaluated whether the breast cancer risk reduction conferred by BPO in BRCA1/2 mutation carriers is altered by use of post-BPO HRT. METHODS: We identified a prospective cohort of 462 women with disease-associated germline BRCA1/2 mutations at 13 medical centers to evaluate breast cancer risk after BPO with and without HRT. We determined the incidence of breast cancer in 155 women who had undergone BPO and in 307 women who had not undergone BPO on whom we had complete information on HRT use. Postoperative follow-up was 3.6 years. RESULTS: Consistent with previous reports, BPO was significantly associated with breast cancer risk reduction overall (hazard ratio [HR] = 0.40; 95%CI, 0.18 to 0.92). Using mutation carriers without BPO or HRT as the referent group, HRT of any type after BPO did not significantly alter the reduction in breast cancer risk associated with BPO (HR = 0.37; 95% CI, 0.14 to 0.96). CONCLUSION: Short-term HRT use does not negate the protective effect of BPO on subsequent breast cancer risk in BRCA1/2 mutation carriers.

Rebbeck, T. R., N. D. Kauff and S. M. Domchek. 2009. "Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers." J Natl Cancer Inst 101(2):80-87.

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BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not. METHODS: All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis. RESULTS: Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers. CONCLUSION: The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

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 8

Date

Summary of changes

13/07/2023

Protocol reviewed at October 2022 and March 2023 cancer genetics reference committee meetings. Discussions continued via email and MS Teams. Approved for publication with the following changes made: 2023 cancer genetics risk management template changes applied throughout document Flag added to top of protocol Target population: minor wording changes Lifetime risk of cancer/tumour: Prostate cancer added to the table 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: section added to protocol Evidence for risk management guidelines: Prostate cancer added. All other sections updated. Version increased to V.8. Approved on 13/07/2023, published on 03/08/2023. Review in 2 years.

Version 7

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 the table. Version number increased to V.7.

Version 6

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 website for up-to-date screening trials. Link in Website resources section." Website resources: Added link to Australian Pancreatic Cancer Genome Initiative website Version number increased to V.6.

Version 5

Date	Summary of changes
14/04/2020	Protocol reviewed by CG reference committee. Discussion continued via email. Protocol approved for publication with the following changes made: Title changed from "PALB2 – risk management (female)" to "PALB2 – risk management" Summary: minor wording changes Target group:  First bullet: "obligate female carrier..." changed to "obligate carriers..." Second bullet: "Woman at 50% risk..." changed to "Individuals at 50% risk..." Exclusion criteria "Male with a loss-of-function PALB2 mutation" removed "Individuals with a missense variant not verified as loss-of-function" added Note: "biallelic pathogenic variants cause Fanconi anaemia and are NOT covered by this protocol" moved down from summary section  Lifetime risk of cancer: All data in table updated. Risk to age 80 years for PALB2 carriers and general population listed (previously listed risk to age 70 and age 85 respectively) Breast (male) and ovarian cancer added to table Cancer risk management guidelines table Breast (female) - Surgical: wording revised. Link to CanRisk added Breast (female) - Surveillance: wording revised. Age to begin and Strategy and frequency aligned with BRCA2 protocol Breast (male) - Surgical, Surveillance and Risk reducing medication: added to table, aligned with the BRCA 1 or BRCA2 - risk management (male) protocol Ovarian - Surgical and Surveillance: added to table Footnote added: "Encourage participation in clinical trials of pancreatic cancer screening in high risk individuals" Evidence for cancer risk management guidelines: Breast (female) - Surgical: paragraph regarding RRSO for breast cancer risk reduction removed Breast (female) - Surveillance: wording updated, aligned with BRCA2 protocol Breast (male) - paragraph added, from BRCA1 or BRCA2 - risk management (male) protocol Ovarian - paragraph added Pancreas - paragraph added  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.5. Protocol to be reviewed in 2 years
02/07/2020	Protocol edited. Cancer risk management guidelines table underwent minor formatting changes to align with table in BRCA1 or BRCA 2 - risk management (female) protocol.
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 table: Heading changed to "Lifetime risk of cancer/tumour" Risk for general population updated to include 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"  Update link to "COSA - Medications to lower the risk of breast cancer: clinician guide" (also updated in evidence) 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 4

Date	Summary of changes
28/08/2019	Protocol title changed from 'Risk management for a female PALB2 mutation carrier' to 'PALB2 – risk management (female)' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.4.

Version 3

Date	Summary of changes
02/04/2014	Discussed at October 30, 2013 & March 5, 2014 reference committee meetings and approved for publication. Review second yearly
31/07/2015	Link to AGSA changed to Genetic Alliance Australia.
07/01/2016	Sentence added to risk management template: "The impact of lifestyle of 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".
24/05/2016	Reviewed via email and the following changes made: Target population - amended Lifetime risk of cancer table - updated  Cancer risk management guidelines - amended Evidence for cancer risk management guidelines - updated References - updated  For yearly review.
28/09/2016	'Unaffected' removed from title.
31/05/2017	Transferred to new eviQ website. Version number changed to V.3.
25/07/2019	Link in Cancer risk management guidelines and Evidence for risk management guidelines sections 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.3.