Results: Patient with breast cancer and a constitutional (germline) PALB2 variant

A 39-year-old woman is diagnosed with a grade-three oestrogen receptor (ER)-negative, human epidermal growth factor receptor-2 (HER2)-negative T2N0M0 left-sided breast cancer. She has a strong family history of breast cancer and is referred for constitutional (germline) testing of the breast cancer susceptibility genes. The National Genomic Test Directory R208 panel is performed, testing for variants in BRCA1, BRCA2 and PALB2 and for truncating variants in ATM, CHEK2, RAD51C and RAD51D. A pathogenic variant in the PALB2 gene is reported.

• PALB2 is a tumour suppressor gene involved in the homologous recombination repair pathway, in which multiple different types of pathogenic variants have been identified.
• Constitutional (germline) pathogenic variants in PALB2 are associated with a high lifetime breast cancer risk, and a moderately increased risk of ovarian, pancreatic and possibly other cancers.
• The female patient in this scenario has an increased risk of developing a second primary breast cancer, and has an estimated lifetime risk of ovarian cancer of 2%–10%, compared with 1.6% in the general population. Her estimated lifetime risk of pancreatic cancer is 1%–5%, compared with 1% in the general population.

Management of the current cancer

• An underlying pathogenic constitutional (germline) variant in a PALB2 gene, and the associated risks of future breast cancers, should be taken into consideration when discussing breast surgery options for the primary breast cancer (if the variant is known about at the time of surgery).
• Radiotherapy is not contraindicated in patients with PALB2 variants based on current evidence.
• PARP inhibitors are not currently licensed for use in patients with constitutional (germline) PALB2 variants. Their effectiveness in this patient group is under investigation in clinical trials.

Further somatic (tumour) testing

• No additional somatic (tumour) testing is routinely indicated in this clinical scenario.
• Whole genome sequencing for triple-negative breast cancers of any stage is available in some areas as part of a pilot study.

Management of the patient’s risk of further primary cancers

Individuals with inherited genetic variants associated with high risk of cancer can manage their cancer risk through a combination of surveillance, risk-reducing surgery and other techniques. The exact advice provided to those with genetic variants will be individualised, depending on their result and associated cancer risk, as well as on the treatment and overall prognosis of their current cancer.

Management of the family’s risk

• Cancer predisposition associated with PALB2 constitutional (germline) variants is inherited in an autosomal dominant pattern. Biallelic variants in PALB2 are associated with Fanconi anaemia, which may be of relevance in family planning for patients in consanguineous relationships.
• First-degree relatives (children or siblings) of an individual with an inherited pathogenic variant in PALB2 are at a 50% risk (one in two) of inheriting the familial variant. Because most pathogenic PALB2 variants are inherited from a parent, the parents of an affected individual should also be offered genomic testing.
• Patients with breast cancer found to have a constitutional (germline) PALB2 variant should be referred to clinical genetics to discuss implications of the result for them and for their family members, and to facilitate cascade testing.

Family planning implications

The Human Fertilisation and Embryology Authority has approved the use of preimplantation genetic testing (formerly called preimplantation genetic diagnosis) for couples in whom one or both intended parents has a likely pathogenic variant in PALB2.

Other options may include prenatal testing (invasive, or non-invasive if the potential father has the variant) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.

For clinicians

• Breast Cancer Now: Genetic testing for altered breast cancer genes
• Memorial Sloan Kettering Cancer Center: About mutations in the PALB2 gene
• NHS England: National Genomic Test Directory
• NICE: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• UK Cancer Genetics Group: PALB2 Pathogenic variant carriers: Management guidelines for healthcare professionals (PDF, one page)

For patients

• Breast Cancer Now: Breast cancer in families
• Breast Cancer Now: PARP inhibitors in breast cancer treatment