2.1 Introduction

At present the value of general population screening remains uncertain and cannot be recommended. Results from the current UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) are not expected until 2011. Screening in the high risk population is discussed in section 2.3.

2.2 Identifying women at high risk of developing ovarian cancer

2.2.1 DEFINING HIGH RISK GROUPS USING FAMILY HISTORY

Family history can be used to define women who are at increased risk of ovarian cancer.⁹ Individuals at high risk are those with a first degree relative (mother, father, sister, brother, daughter or son) affected by cancer within a family that meets one of the following criteria:

• two or more individuals with ovarian cancer, who are first degree relatives of each other
• one individual with ovarian cancer at any age, and one with breast cancer diagnosed under age 50 years, who are first degree relatives of each other*
• one relative with ovarian cancer at any age, and two with breast cancer diagnosed under 60 years, who are connected by first degree relationships*
• known carrier of relevant cancer gene mutations (eg BRCA 1 or 2)
• untested first degree relative of a predisposing gene carrier
• three or more family members with colon cancer, or two with colon cancer and one with stomach, ovarian, endometrial, urinary tract or small bowel cancer in two generations. One of these cancers must be diagnosed under age 50 years
• an individual with both breast and ovarian cancer

* In these categories a second degree relative may be counted if the transmission is via the paternal line (eg a sister and a paternal aunt or a sister and two paternal aunts).

Women with a family history that appears to place them at high risk of developing ovarian cancer should be offered referral to a Clinical Genetics Service for assessment and confirmation of their family history. They may then be eligible for referral for screening via a research trial.

2.2.2 DEFINING HIGH RISK GROUPS USING GENETIC TESTING

In most cases risk estimates are based on a family history. The lifetime risk estimate for individuals who have one first degree relative with ovarian cancer is two to five times the population risk.^{4, 10} Evidence regarding the lifetime risk when an individual has more than one affected relative is sparse but this is estimated at 3 to 23%.^{4, 11} Evidence level 2++

Two types of ovarian cancer susceptibility genes have been identified: the breast and ovarian cancer tumour suppressor genes (BRCA1 and BRCA2) and the mismatch repair genes associated with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) families.¹² Mutations in the BRCA1 gene are estimated to confer a 30% lifetime risk of ovarian cancer up to age 60 years and mutations in BRCA2 gene are estimated to confer an ovarian cancer risk of 27% up to age 70 years.^{4, 13} The mismatch repair genes confer an increased lifetime risk of ovarian cancer of approximately 9 to 12% in addition to an increased risk of endometrial cancer.¹⁴ Relatively few Scottish patients are classed as high risk from BRCA1 or BRCA2 mutations already detected in other members of the family. Such highly penetrant cancer predisposing genes are estimated to account for only a small proportion, perhaps 5 to 10% of all ovarian cancers.⁴ Evidence level 3

2.2.3 REFERRAL TO CANCER GENETICS

Referral rates to most UK cancer genetics centres are approximately 200 per year per million of the population.²⁴ This is 30-fold lower than that suggested by a survey of breast cancer family history.¹⁵ General practitioners (GPs) and practice nurses are unhappy about taking responsibility for controlling access to these specialist services.^{16, 17, 18, 19, 20, 21, 22} Although GPs are highly selective in the cases they refer to cancer genetics clinics, over 25% of patients seen at these clinics are judged to be at low (close to population) risk.¹⁵ Evidence level 4

One randomised controlled trial (RCT) demonstrated that the provision of an education pack helped GPs to reach the correct decisions in relation to familial cancer risk. The addition of face-to-face teaching sessions added no further value.²³ GPs benefit from expert support from a specialist genetics service.²² Highest demand and utilisation of familial cancer services relates to breast and/or ovarian cancer.²⁴ Evidence level 1+,4

Close collaboration between primary care and specialist cancer genetics services should be developed and encouraged so that genetic cancer risk assessment can be carried out efficiently.

Primary care clinicians should formally enquire about the woman’s family history.

2.3 Screening in high risk groups

One systematic review²⁵ and three small cohort studies^{26, 27, 28} suggest that presymptomatic screening by grey scale ultrasound (with or without Doppler), CA125 (see section 3.1.2), pelvic examination, or combinations of these, are not effective in detecting tumours at an early stage (see Annex 1). No clear evidence was identified as to whether screening in high risk groups has an impact on mortality from ovarian cancer. Evidence level 1+,3

Screening for ovarian cancer in high risk groups should only be offered in the context of a research study designed to gather data on: sensitivity and specificity of the screening tool FIGO stages of cancers detected through screening residual risk of primary peritoneal cancer following prophylactic oophorectomy.

2.4 Psychological consequences of screening

Five case series studies^{29, 30, 31, 32, 33} and one qualitative study³⁴ demonstrate that women with a family history of ovarian cancer who seek advice and screening may have higher levels of anxiety and depression than are found in the general population. Evidence level 3

Two studies regarding the long term psychological consequences of screening in women who require surgical intervention for false positive results highlight the need for screening tools with higher specificity and the importance of incorporating support services in screening programmes.^{30, 34} Evidence level 3

Screening programmes for women at increased risk of ovarian cancer should include mechanisms for providing emotional and psychological support.

2.5 Prophylactic oophorectomy

Women identified as being at high risk of ovarian cancer can be offered prophylactic oophorectomy. The decision whether or not to proceed to prophylactic oophorectomy is influenced by the fact that most women at increased risk of ovarian cancer are also at increased risk of breast cancer and there is evidence that oophorectomy reduces breast cancer risk in these cases.³⁵ Evidence level 2++

Two large cohort studies confirm the benefits of prophylactic oophorectomy for carriers of BRCA1 or BRCA2 mutations, reducing the risk of primary peritoneal carcinoma to between 0.1%³⁶ and 0.5% per year.³⁵ This is considerably less than the lifetime risk of ovarian cancer for those who retain their ovaries. Evidence level 2++

Studies have shown that 2.3% of patients undergoing prophylactic oophorectomy had previously unsuspected early stage ovarian cancer.^{28, 35} These studies also confirm the substantial reduction in breast cancer risk for mutation carriers who undergo prophylactic oophorectomy. This does not appear to be abrogated by giving hormone replacement therapy (HRT) to women whose ovaries are removed before the natural menopause. Evidence level 2++,3

Women who are carriers of the BRCA1 or BRCA2 mutations should be advised that a proportion of intraperitoneal epithelial cancers arise in the Fallopian tubes so that these should be removed along with the ovaries. Evidence level 2++,3

Women with genetic mutations of BRCA1 or BRCA2 genes should be counselled regarding prophylactic oophorectomy and removal of Fallopian tubes at a relevant time of their life.

High risk women in whom mutations have not been identified should be counselled at around the age of 40 years regarding prophylactic oophorectomy.

2.5.1 QUALITY OF LIFE ISSUES

One qualitative study,³⁷ one retrospective case control study³⁸ and one cohort study³⁹ were identified. Two of the studies report that women with BRCA1 or BRCA2 mutations regard prophylactic oophorectomy as an acceptable option for ovarian cancer risk reduction.^{37, 39} The cohort study found that these patients do not expect prophylactic oophorectomy to impair their quality of life.³⁹ The qualitative study found that women with BRCA1 or BRCA2 mutations have strong opinions regarding the costs and benefits of prophylactic oophorectomy and that they would like more information about the physical and emotional after-effects of prophylactic oophorectomy both before, and after, surgery.³⁷ Evidence level 3,4

The retrospective case control study investigated women who had chosen prophylactic oophorectomy instead of prolonged screening and suggested that these women may have more physical and emotional symptoms than women who remain on an ovarian cancer screening programme but that they report equivalent levels of cancer worry.³⁸ Evidence level 3

The studies identified highlight the importance of counselling, support and information for women making a decision about prophylactic oophorectomy. There is insufficient evidence to make a recommendation.

Women who decide to have prophylactic oophorectomy should be offered counselling, support and information before and after surgery.