Management of women at high breast cancer risk by carriage of a high-risk breast cancer predisposition gene mutation

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Approximately 5% of patients with breast cancer are identified to carry a high risk breast cancer predisposition gene. The majority of these are BRCA1 or BRCA2, with a smaller number identified to have P53, HNPCC, ataxia telangiectasia, Cowden’s syndrome, etc. Carriers of a high risk predisposition gene such as BRCA1 have an increased risk of developing breast cancer, with a penetrance of approximately 60-80% within one’s lifetime. Options for such high risk women are surveillance, chemoprevention or risk reduction mastectomy strategies. The aim of surveillance is to pick up breast cancer at the earliest possible stage to enable efficient treatment strategies for the best possible outcome. Annual mammography between 40-50 years of age, or 5 years younger the earliest effective relative is often recommended. Limitations are the restricted sensitivity and specificity of mammography as screening tools. More recent data provided by the MARIBS study has provided evidence for MRI as a more sensitive tool to pick up early breast cancer but with a recognised limitation in specificity.

Tamoxifen trials demonstrating reduction of cancer risk have been shown in overviews of adjuvant trials of breast cancer by reduction of contralateral breast cancer risks. Chemoprevention trials at women of elevated breast cancer risk, most patients at moderate risk, were shown in the NSABP-P1 and IBIS-1 studies. The NSABP-P1 trial showed a 49% risk reduction of invasive breast cancer and 50% of in- situ disease, with corresponding figures in the IBIS-1 trial of 25% and 69% respectively. The updated results of the Royal Marsden trial comparing tamoxifen with placebo also showed a risk-reducing effect of tamoxifen. The benefit in both trials were mainly in women who ultimately developed oestrogen positive cancers and the ri-sk reducing effect is less evident in those who develop oestrogrn negative tumours. Many women with the BRCA-1 mutation develop oestrogen negative breast cancers and the role of chemoprevention in these high-risk women remains unclear. The adverse effects of tamoxifen chemoprevention are a limiting factor to compliance and acceptance of this approach. Interesting data are awaited on other selective oestrogen receptor modulators such as Raloxifene. Risk reduction by chemoprevention is predominately against cancers that are oestrogen receptor positive.

Bilateral prophylactic mastectomy is a more radical intervention performed pre-emptively to reduce the risk of breast cancer incidence. Several factors limit comparison of current practice with historical studies of longer follow-up. The definition of significant increased risk has improved with greater understanding and, in specific circumstances, the identification of recognised high risk predisposition genes. There are also surgical considerations such as completeness of breast resection that vary with different surgical techniques. The potential aims of risk reduction mastectomy apart from reducing breast cancer incidence include reduction of mortality as well as to reduce anxiety or cancer worry. The potential hazards, however, are regrets, poor aesthetic outcome, and a residual risk of developing breast cancer despite prophylactic mastectomy. The Mayo clinic experience was published by Hartman in 1999 in a retrospective study of women of moderate and high risk, aged between 18-79 (median age 42) years. A reduction in breast cancer incidence of 90% was identified in 639 women; 214 at high risk and 425 at moderate risk. A further evaluation of the high risk women in this study was subsequently published with blood samples obtained from 176 of the 214 high-risk women. Twenty six women with possible breast cancer risk gene mutations were identified, 18 with recognised deleterious gene mutations and 8 with mutations of an uncertain type (Hartman 2001). No breast cancers developed after a median of 13.4 years of follow-up in these 26 women.

Breast cancer after prophylactic mastectomy in women with a recognised BRCA1 or BRCA2 mutation in the Netherlands was published by Meijers-Heijboer and Colleagues in 2001. This was a perspective cohort study of 139 women who either chose bilateral prophylactic mastectomy or surveillance. Seventy six patients in the mastectomy group were free of breast cancer after study entry while 8/63 in the surveillance group developed breast cancer after a median follow-up of 3 years.

The PROSE study was published in 2004 by Rebbeck et al on known BRCA-1 and 2 carriers; 105 had risk-reduction surgery and there were 378 matched controls. Corrections were made to make date analysis more stringent by allowing or excluding prophylactic surgery before ascertainment. Bilateral prophylactic mastectomy resulted in at least a 90% risk reduction of developing breast cancer in the surgical group compared to controls within all study subsets.

The psychosocial impact of bilateral prophylactic mastectomy is an important consideration. Bebbington Hatcher et al (2001) evaluated psychological and sexual morbidity following bilateral prophylactic mastectomy in 154 women: 79 had surgery and 64 accepted surveillance without surgery. Patients who had bilateral prophylactic mastectomy had statistically significant reduction in psychological morbidity, 18 months after surgery compared to those who had surveillance only using GHQ-30 and the Spielberger questionnaire assessment tools. Perception of sexual issues were identical in both groups.

The management of high risk women should be a multidisciplinary team approach. There is an ongoing need to support clinical trials for trials, prospective data collection and continued audit. Women should be informed of their choices and appropriately counselled to make informed decisions of risk reduction strategies to suit individual needs.

References

Bebbington Hatcher M, Fallowfield L, A'Hern R. The psychosocial impact of bilateral prophylactic mastectomy: prospective study using questionnaires and semistructured interviews. BMJ 2001; 322: 76

Cuzick J. A brief review of the current breast cancer prevention trials and proposals for future trials. Eur J Cancer 2000;36: 1298-302.

Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371-88.

Hartmann LC, Schaid DJ, Woods JE, et al, Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 1999; 340: 77-84.

Hartmann LC, Sellers TA, Schaid DJ, et al.Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst 2001; 93: 1633-7.

Leach MO, Boggis CR, Dixon AK, et al; MARIBS study group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet 2005; 365 (9473): 1769-78.

Meijers-Heijboer H, van Geel B, van Putten WL, et al.Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001; 345: 159-64.

Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998; 352: 98-101.

Powles TJ , Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial. J Natl Cancer Inst 2007; 99: 283-290.

Rebbeck TR, Friebel T, Lynch HT, et al.Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2004; 22:1055-62.

Veronesi U, Maisonneuve P, Rotmensz N, et al, Italian Tamoxifen Study Group. Italian randomized trial among women with hysterectomy: tamoxifen and hormone-dependent breast cancer in high-risk women. J Natl Cancer Inst 2003; 95: 160-5.

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