Guidelines for Follow-Up of Women at High Risk for Inherited Breast Cancer: Consensus Statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer

Protocols for activity aiming at early diagnosis and treatment of inherited breast or breastovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ’breast awareness’ and annual mammography and Guidelines for Follow-Up of Women at High Risk for Inherited Breast Cancer: Consensus Statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer P. Møller et al. / Guidelines for Follow-Up of Women at High Risk for Inherited Breast Cancer 208 clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention. The Biomed 2 Demonstration Programme on Inherited Breast Cancer has compiled the results of the ongoing prospective studies, leading to the first report on outcome of early diagnosis and treatment of inherited breast cancer evaluated by survival after diagnosis [18]. 5-year event-free survival after diagnosis is 86%, which is substantially better than all retrospective reports on prognosis of inherited breast cancer diagnosed outside specific follow-up programmes. Retrospective reports on age at onset of inherited breast cancer [3,5,10] were verified by the prospective studies. It was demonstrated that, in families ascertained through clinical criteria, new breast cancers arise at a greatly increased rate (compared to the general population) in women aged 30 years or more [13,15,17], and it was verified that, in the subgroup of breast-ovarian cancer kindreds, the majority of such cancers occur in BRCA1 mutation carriers [1]. It was found that uptake of genetic testing in kindred with demonstrated BRCA1 mutations can be as high as 80% without measurable negative effects on quality of life [22]. Different centres made similar use of cytology/biopsy, resulting in a diagnosis of cancer in 11–17% of all such procedures [19]. Comprehensive economic evaluation resulted in an estimated cost of Euro 750–1600 per life year gained through early diagnosis and treatment [11]. In BRCA1 mutation carriers, breast cancer tends to be diagnosed as infiltrating estrogen receptor negative cancers with histopathological signs of unfavorable prognosis [1,12,14,23]. It is not demonstrated, but it is suggested, that this subgroup may benefit from more frequent follow-up examinations. Prophylactic mastectomy is discussed separately [9]. Results of tamoxifen chemoprevention trials to avoid breast cancer are inconclusive. Prophylactic oophorectomy may reduce breast cancer risk in BRCA1 mutation carriers, and use of hormone replacement therapy may not negate this effect [21]. Ongoing studies on the risk of contralateral cancers in BRCA1/2 mutation carriers, will indicate whether or not tamoxifen and/or chemotherapy may prevent breast cancers in mutation carriers. Oral contraceptive use reduces the risk of inherited ovarian cancer [20], but may not be recommended until the potential effect of increasing the breast cancer risk has been evaluated. Insurance issues related to predictive testing are discussed separately [16]. Modalities for treatment of demonstrated inherited breast cancer are discussed separately [7]. Mutations in BRCA1 and BRCA2 are associated with substantial risk of ovarian cancer. Retrospective studies indicate that ovarian cancer in BRCA1 mutation carriers occurs from 40 years of age on [5], while the risk is lower and the onset tends to be later in BRCA2 mutation carriers [10]. Prospective series confirm that breast cancer kindreds with two or more ovarian cancers, and/or cases with both breast and ovarian cancers, were likely to be caused by BRCA1 mutations, that ovarian cancers prospectively detected were rarely seen before 40 years of age, and that almost all ovarian cancers occur in BRCA1 mutation carriers [1,4]. No study on early diagnosis of inherited ovarian cancer has demonstrated safety: conversely, experience in several centres indicates an unfavourable prognosis for prospectively diagnosed cancers. Formal survival analyses from these series are not known to us. Infiltrating cancer has been found in ovaries prophylactically removed from patients declared to be disease-free by the operating gynaecologist [2]. Although a limited number of peritoneal carcinomatoses histopathologically classified as ovarian cancers have been reported after prophylactic oophorectomy, the preventive effect of prophylactic oophorectomy P. Møller et al. / Guidelines for Follow-Up of Women at High Risk for Inherited Breast Cancer 209 is judged to be good. Based on these observations we advocate that the ongoing health programmes in most countries may continue essentially as they are carried out today [6,8,24] and with modifications as indicated below. SUGGESTED GUIDELINES Definition of women at high risk for inherited breast cancer • A family history of two or more first degree relatives (or second degree relatives though males) with early onset (< 50 years) breast cancer, and/or • Multiple cases of breast cancers in the same lineage compatible with dominant inheritance in the family, and/or • A combination of early onset breast cancer and ovarian cancer in the family, and/or • Li Fraumeni syndrome (SBLA) or Cowden disease family, and/or • Demonstrated BRCA1/2 truncating mutation or TP53 or PTEN mutation. • Males with BRCA2 truncating mutation are also considered to be at risk.