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
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.
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 aloner 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
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.
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
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.
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.