Genetic testing for women diagnosed with ovarian cancer


In 2017 in Australia, it is estimated that 1,580 new cases of ovarian cancer will be diagnosed and that there will be 1,047 deaths from ovarian cancer.3 Ovarian cancer is the eighth most common cancer in women and the sixth most common cause of death from cancer in women in Australia.3

Most ovarian cancers start in the epithelial cells of the ovary or fallopian tube. Epithelial ovarian cancer is the most common type of ovarian cancer, comprising around 90% of ovarian cancers. Epithelial ovarian cancers may be mucinous or non-mucinous, and non-mucinous epithelial ovarian cancers include serous, endometrioid, clear cell, mixed and undifferentiated tumours.4

Epithelial ovarian cancer is often diagnosed at an advanced stage and survival outcomes are poor. Women diagnosed with invasive epithelial ovarian cancer in Australia have a 44% chance of surviving for 5 years compared to the general population.3

Epithelial ovarian cancer may be associated with heritable, or germline, mutations in genes including: BRCA1 and BRCA2 (BRCA 1/2), and DNA mismatch repair (MMR) genes associated with Lynch syndrome.5 Heritable mutations may be carried by both male and female blood relatives. There can also be gene mutations that are only in the tumour itself called somatic mutations, which are not inherited.6

BRCA1/2 heritable mutations in women with invasive epithelial ovarian cancer

Heritable BRCA1/2 mutations are found in approximately 14% of women in Australia with non-mucinous invasive epithelial ovarian cancer unselected for family history, and in approximately 17% of women with high grade serous (non-mucinous) epithelial ovarian cancer unselected for family history.7

Heritable mutations in BRCA1/2 are not associated with low malignant potential, or borderline, ovarian tumours,8 and are rarely detected in mucinous ovarian cancer (less than 1%).9, 10

For women with a personal history of both breast and ovarian cancer, heritable BRCA1/2 mutations are found in approximately 50%.7, 9

Heritable BRCA1/2 mutations are found in approximately 38% of women in Australia with non-mucinous invasive ovarian cancer who have a family history of breast or ovarian cancer.7 However there is no known family history of breast or ovarian cancer in over one-third of women with invasive epithelial ovarian cancer in whom a heritable BRCA1/2 mutation is identified.7, 9, 11
The prevalence of BRCA1/2 mutations in women with ovarian cancer varies with age and is greatest for women in their 40s and 50s.9 Over one-quarter of women with invasive epithelial ovarian cancer in whom a heritable BRCA1/2 mutation is identified, are over 60 years at diagnosis.7, 9 Based on a limited number of studies, prevalence of BRCA1/2 mutations for women with ovarian cancer aged 70 years or older at diagnosis, is less than 10%.10, 12-15

In some ethnic populations such as the Ashkenazi Jewish population, prevalence of heritable BRCA1/2 mutations in women with ovarian cancer is high due to common founder mutations. The frequency of BRCA1/2 mutations for the Ashkenazi Jewish population has been estimated at approximately 2.5% in Australia compared to less than 1% in the general population.16, 17 Heritable BRCA1/2 mutations are found in approximately 30% of Ashkenazi Jewish women with ovarian cancer.17, 18

There are tools such as BOADICEA, BRCAPRO and the Manchester score that predict the likelihood of a BRCA1/2 mutation based on family and personal history, and breast cancer histopathology.19-21 Sufficient information to guide genetic risk assessment is usually provided by age, histology and family history for women with ovarian cancer.

Lynch syndrome

Lynch syndrome is associated with increased risk for endometrial, colorectal, ovarian and other cancers. Ovarian cancer associated with Lynch syndrome is commonly non-serous. Lynch syndrome has autosomal dominant inheritance and is due to a heritable mutation that causes dysfunction in a DNA mismatch repair gene.

Women with ovarian cancer who meet specific criteria based on personal or family history of cancer, have an increased likelihood of Lynch syndrome.22, 23

Analysis of the tumour tissue is undertaken as an initial step wherever possible, to screen tumours for abnormal mismatch repair. 22 Methods for screening tumours for abnormal mismatch repair include immunohistochemistry for the MLH1, MSH2, MSH6 and PMS2 proteins, microsatellite instability studies and MLH1 promoter methylation studies.22

If an abnormality associated with Lynch syndrome is identified in the tumour, genetic testing for a heritable mutation in a mismatch repair gene can be offered. A deficiency of mismatch repair protein identified in the tumour can indicate which mismatch repair gene to be tested.22

Other heritable gene mutations and gene panel tests

Heritable mutations in other genes are also associated with ovarian cancer, though the ovarian cancer risk is uncertain.10, 24

Gene panel tests for heritable mutations in multiple genes are available. Depending on the genes selected for the panel and the clinical situation, the results may be complex and difficult to interpret and the clinical significance of the results may be uncertain.25, 26

Genetic Counselling

Genetic counselling provides genetic risk assessment, and information about genetic tests, possible outcomes of tests and implications of test results, including for insurance.26

When genetic testing is offered to a patient with cancer, relevant pre-test information for informed consent includes possible outcomes and implications, including opportunities for personalised treatment decisions. Pre-test information may be provided by a range of appropriately trained health professionals.26-28

Post-test genetic counselling provides interpretation of the genetic testing results, including for variants of uncertain significance, and information on the implications for family members.26-28

Implications of a heritable gene mutation for a woman with ovarian cancer

For a woman diagnosed with ovarian cancer, identification of a heritable mutation by genetic testing may inform her treatment decisions. 

Response to platinum-based therapy is generally more favourable in women with heritable BRCA1/2 mutations.7 Women with a BRCA1/2 mutation benefit most from the use of PARP inhibitors as maintenance therapy in platinum-sensitive relapsed ovarian cancer.29 30, 31

Women with a heritable BRCA1/2 mutation are at increased risk for breast cancer.32  Risk- reducing strategies for breast cancer which may be considered include bilateral prophylactic mastectomy and risk-reducing medications such as selective estrogen receptor modulators (e.g. tamoxifen, raloxifene) or aromatase inhibitors.33, 34 Increased surveillance for breast cancer as appropriate, may include mammography, ultrasound or MRI.33, 34

Implications for family members

Family members of a woman with an identified heritable mutation can be offered predictive genetic testing for the known mutation. Pre-test counselling by a genetic healthcare professional is needed for family members prior to predictive testing, and should include discussion on implications for insurance. Informed consent should be obtained prior to testing.

If the known mutation is not detected in the family member, they can usually be reassured and avoid unnecessary surveillance and intervention. 

If the known mutation is identified in the family member, they can consider cancer-specific risk management options, including surveillance and risk-reducing strategies.33 The most effective risk-reducing strategy for women at high risk of ovarian cancer is bilateral salpingo-oophorectomy. There is no effective screening for ovarian cancer 35, 36.

New models of genetic counselling and testing

New models for genetic counselling and testing are being introduced. These include mainstreaming genetic testing into routine cancer care, where pre-test information may be provided and consenting undertaken by a range of appropriately trained health professionals.12, 14, 37