In a move that was described as ‘courageous and influential’, Hollywood actor and UN ambassador Angelina Jolie famously made the decision to have a risk-reducing bilateral salpingo-oophorectomy (RR BSO) at the age of 39. This was two years after a bilateral mastectomy. Her actions ignited worldwide discussion about genetic cancers and prophylactic treatment. Jolie wrote an editorial piece in the New York Times about her decision.1 She carries a mutation in the BRCA 1 gene, giving her a significant risk of developing early ovarian and breast cancer. Her editorial captured the attention of worldwide media and suddenly we were all talking about genetic cancers and risk reduction. According to the Tasmanian Clinical Genetic Service, referrals to genetic counsellors saw a marked increase.

Approximately five per cent of endometrial cancers and ten per cent of ovarian cancers can be attributed to an inherited predisposition.2 Hereditary breast and ovarian cancer (HBOC) syndrome and hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) account for most inherited gynaecological cancers. Gynaecologists and gynaecological oncologists have a major role to play in not only identifying women at risk of inherited cancer syndromes, but also managing them appropriately.

However, the issue is much more complex than just referring women for genetic testing and offering them prophylactic treatment. The genetics of hereditary gynaecological cancer is continually evolving and our understanding of the molecular basis of inherited susceptibility to gynaecological cancer has improved considerably.3 Thus, it is the responsibility of the general gynaecologist to keep up to date with advances in this area so as to support patients to make informed decisions.

Basic genetics

Under normal circumstances, the body makes proteins, coded for in the DNA, that control functions within a cell. For example, how quickly it grows, how often it divides or how long it lives. When one or more genes in a cell are mutated, errors in cell regulation can result. If an error causes a defect in the ability of a cell to repair DNA damage, then tumour genesis may occur.4

Cancer cells all share several essential properties, including: self-sufficiency in growth signals; insensitivity to antigrowth signals; evasion of apoptosis; limitless replicative potential; sustained angiogenesis; tissue invasion and metastasis; and the development of genomic instability.5 It is the combination of these properties, which are normally under tight genetic control, that causes the development of a malignancy.

Genetic testing and counselling

Genetic testing is more complex than simply referring a patient for a blood test. In the first instance, there should be a carefully made decision about who is likely to benefit from genetic testing. The approach should be multidisciplinary: involving experts in clinical genetics, oncology, gynaecology and psychology.

Initially, genetic risk assessment should be performed to determine whether a family history is suggestive of an inherited cancer syndrome. Many people who are referred for genetic testing will not qualify for testing once a genetic risk assessment is performed. Genetic counselling is recommended before testing occurs and once results are available. Appropriate counselling includes assessing the patient’s understanding of testing for cancer risks and the benefits and limitations of the tests. Patients should be fully aware of possible test outcomes including: the possibility of finding a gene mutation; finding genetic variations that may or may not be cancer-causing; and finding no mutation, which may or may not mean there is a risk of a hereditary cancer syndrome. In the case of the latter, a false negative result could occur because limitations in testing have not detected the genetic mutation or an as-yet-unknown gene is involved. The impact on the patient’s ongoing healthcare and the implications for their family will also need to be discussed.

Breast and ovarian cancer

HBOC syndrome is caused by mutations in the BRCA1 or BRCA2 genes. BRCA1 is localised to chromosome 17q, whereas BRCA2 is localised to chromosome 13q. Both are tumour suppressor genes that play a role in DNA repair. The frequency of mutations in the general population is estimated to be one in 300 to one in 800; however, this is higher in some populations (for example, the Ashkenazi Jewish population).6 Mutations in BRCA1 confer a lifetime risk of epithelial ovarian cancer of 20–60 per cent. The lifetime risk of epithelial ovarian cancer associated with BRCA2 mutations is estimated between 10–20 per cent.7 BRCA-related ovarian cancers are exclusively epithelial, most are of high-grade serous or undifferentiated histology and tend to be diagnosed younger.

Standard criteria exist for identifying women at risk of a BRCA mutation and include the following:

  • early onset breast cancer (less than 45 years old);
  • two breast primaries in one individual;
  • breast and ovarian cancer in the same individual;
  • breast cancer and more than one close blood relative with breast cancer less than age 50 years, or more than one close relative with ovarian cancer at any age, or more than two close relatives with breast cancer at any age;
  • breast or ovarian cancer at any age and Ashkenazi Jewish ancestry;
  • a family history of male breast cancer;
  • ovarian cancer and family history of breast or ovarian cancer; and
  • women from families that meet the above criteria.

Maternal and paternal sides of families should be considered independently. A three-generational history is the standard for determining risk. Close attention should be paid to the type of cancer, bilaterality, age of diagnosis and history of chemoprevention or risk-reducing surgeries.

When carrying out genetic testing, individuals with affected family members who have early onset disease, bilateral disease or multiple primaries are preferred as they are more likely to have an identifiable mutation. Negative tests in an unaffected family member are less informative as there is an absence of a known mutation. Thus, women should be fully informed of these limitations before testing.

Once a mutation is known, what should we do about it? Combined oral contraceptive pill (COCP) use by women with BRCA mutation has been shown to be associated with a lower risk of ovarian cancer.8 An estimated 50 per cent reduction has been observed. There has been no proven association with increased breast cancer in mutation carriers that used oral contraception. Transvaginal ultrasound and serum CA 125 levels as a means of surveillance are associated with high false-positive rates and show no proven benefit. In fact, it is associated with late-stage presentation in affected women. Currently there are no recommendations for its use. RR BSO greatly reduces the risk of ovarian cancer and mortality. Risk reduction is estimated to be 85–95 per cent, especially if performed by the age of 40.9 In BRCA-positive women who have not previously been diagnosed with breast cancer, hormone replacement therapy can be considered for quality-of-life issues.

Women undergoing RR BSO have an approximately three per cent risk of having a tubo-ovarian malignancy at the time of their surgery.10 Women need to be counselled about this risk and their options at the time of surgery, in other words to proceed with a full staging operation or to establish the diagnosis and further counsel the patient. Some women want a ‘one-stop shop’ and request definitive surgery in this situation. Others need time with their families to consider their options. This counselling is best done by a gynaecological oncologist and careful consideration needs to be given to this risk before performing the surgery.

Lynch syndrome

HNPCC or Lynch syndrome is the most common cause of hereditary endometrial cancer, accounting for approximately three per cent of all endometrial cancers. It is the second most common cause of inherited epithelial ovarian cancer.11 Lynch syndrome is an AD condition that predisposes to colorectal, endometrial and ovarian malignancies, as well as hepatobiliary, urinary, small bowel, brain and sebaceous tumours. It is caused by mutations in multiple genes that produce proteins responsible for mismatch repair, these include: MLH1, MSH2, MSH6 and PMS2. The lifetime risk of endometrial and ovarian cancers in women with Lynch syndrome is 20–60 per cent and approximately ten per cent, respectively. Women typically have an earlier age of onset of disease and are more likely to have multiple primary cancers.

Identifying women for whom genetic risk assessment is recommended is done using the Modified Bethesda Guidelines, as follows:

  • Colorectal cancer (CRC) or endometrial cancer diagnosed before age 50; 
  • CRC or endometrial cancer with a synchronous, metachronous or other Lynch-associated malignancy at any age;
  • CRC characterised by tumour-infiltrating lymphocytes, peritumoral lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern diagnosed before age 50 years;
  • CRC or endometrial cancer and a first-degree relative diagnosed with CRC, endometrial or a Lynch-associated malignancy diagnosed before age 50 years; or
  • CRC or endometrial cancer diagnosed at any age with two or more first or second-degree relatives with Lynch-associated malignancies diagnosed at any age.

Prophylactic hysterectomy and RR BSO should be discussed with women with Lynch syndrome who have completed child bearing. However, women should be made aware that surgery will significantly reduce, but not eliminate, their risk. Low dose oestrogen-only hormone therapy can be used to control menopausal symptoms. For younger women, COCP, systemic progesterone and progesterone intrauterine devices have been shown to reduce the risk of developing endometrial cancer in the general population.12 COCP use is also associated with a reduced risk of ovarian epithelial cancers in low-risk populations. The American College of Obstetricians and Gynecologists recommends endometrial biopsy starting at age 30–35 years and repeating every one to two years. Women should also keep a menstrual diary and promptly report any abnormal uterine bleeding. Neither ultrasound nor CA 125 levels are recommended for screening for ovarian cancer for reasons discussed above.

Peutz-Jeghers syndrome

Peutz-Jeghers syndrome (PJS) is rare, with an estimated prevalence of one in 8 000 to one in 200 000. Males and females are equally affected. It is an AD disorder that is most often owing to germline mutations in the STK11 (LKB1) gene mapped to chromosome 19p13.3. PJS is characterised by pigmented mucocutaneous macules (melanin spots), multiple gastrointestinal polyps and an increased risk of gastrointestinal and non-gastrointestinal cancer. Melanin spots are present in more than 95 per cent of patients and gastrointestinal hamartomatous polyps are present in most patients. The most common sites of gastrointestinal tract malignancy are the colon and pancreas. The most common site of extraintestinal tract cancer is the breast.

Women have an increased lifetime risk of gynaecological cancers. Specifically, women with PJS have a 21 per cent lifetime risk of ovarian cancer and a ten per cent lifetime risk of cervical cancer.13 Sex cord tumours with annular tubules (SCTAT tumours) occur commonly and are often associated with signs of hyperoestrogenism such as sexual precocity. Cervical tumours include cervical adenoma malignum, a highly differentiated mucinous adenocarcinoma.

Cowden syndrome

Cowden syndrome was first reported in 1963. It is also a rare AD inherited disease, with an estimated prevalence of one in 200 000 to 250 000. Cowden syndrome appears in patients with germline mutations in the PTEN gene (a tumour suppressor gene) located on chromosome 10q23. Clinical manifestations include hamartomatous tumours in multiple organ systems, both mucocutaneous and extracutaneous, and an increased risk for malignancy. Nearly every internal malignancy has been reported in the setting of Cowden syndrome, the most common is breast cancer. Skin and oral findings are distinctive, common and are often the initial finding that leads to the diagnosis.

The lifetime risk of endometrial cancer is reported to be 13–28 per cent for women with Cowden syndrome. There are rare reports of endometrial cancer occurring in adolescents as young as 14. The National Comprehensive Cancer Network recommendations are to educate women with Cowden syndrome regarding endometrial cancer and prompt response to symptoms, to consider annual random endometrial biopsies and transvaginal ultrasound at age 30–35 years and to discuss options of risk-reducing hysterectomy.

Li-Fraumeni syndrome

Li-Fraumeni syndrome is an AD disorder that is manifested by a wide range of malignancies that appear at an unusually early age. It is also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) cancer syndrome. It results from germline mutations in the tumour protein p53 gene located on chromosome 17p13.1. A wide variety of malignancies have been reported and patients who develop cancer are at markedly increased risk of developing a second malignancy.

For women with Li-Fraumeni syndrome, the lifetime risk of cancer approaches 100 per cent, and has been estimated to be about 90 per cent by 60 years of age. Specifically, women are at markedly increased risk of premenopausal breast cancer at an early age. Gynaecological malignancies are not common, although the most frequently diagnosed gynaecological cancer associated with Li-Fraumeni syndrome is ovarian adenocarcinoma, with an average age of onset of 39.5 years.

Summary
Patients with possible or known hereditary syndromes with increased cancer risk can be difficult to manage. Patients often want clear information about exactly what their risk is and how best to reduce that risk. Often the answers are unknown and the soundest advice is to tailor a management strategy that best suits each individual patient. While there has been considerable advance in our knowledge of inherited cancer syndromes in recent times, there are still no comprehensive guidelines on the most appropriate action of management for these patients.