Is the mutant gene truly specific for breast CA? How about the sensitivity and specificity of the diagnostic device? A woman breast is one of her most cherished endowments, so we must be sure of our findings. Mutation in BRCA1 or BRCA2 predisposes to both breast CA and ovarian CA, inf act the risk of developing breast CA is not even as high as that of ovarian CA. So, removing the breast at such an early stage may not really be beneficial. Again, other factors that must be considered is the woman's age, dietary and reproductive status, whether or not there is a positive family history and of course her wish (decision) is the final.

Dear Adewale

I totally agree with you. There are international artists who have removed the breasts and now will remove the ovaries, "prophylactic" and these stories are transmitted worldwide by creating many doubts and insecurities to the people

Thank you very much

Adewale, Nelson:

A DEFENSE OF RISK-REDUCTIVE SURGERY IN BRCA CARRIERS

SUMMARY OF FINDINGS

In fact, the dangers of omission of risk reductive surgeries are real and very high, and consistently rejected by BRCA carriers in their decisions (see below), and the benefits - in terms of outcome, life expectancy, anxiety-reduction and improved QoL - large, and the vast majority (more than 80%; see below) women faced with the decision elect by informed consent to incur the potential harms to body image and sexuality in order to:

(1) vastly reduce their risk of cancers,

(2) avoid crippling cancer anxiety,

(3) avoid the highly frightening prospects of chemotherapeutic interventions and their toxicities and known adverse impact on, and significant disruption of, quality of life (QoL) with associated risks of morbidity and mortality, and

(4) and reap gains in life expectancy.

Indeed, the evidence, systematically reviewed ad critically appraised, with individual studies extracted for quantitative methodological quality assessment, unambiguously confirm benefit in outcome and life expectancy, and - to many professionals' surprise, with exceedingly high degrees of satisfaction (patient satisfaction rate of 94%), significant reduction in anxiety, and improvement in quality of life (QoL), and with both patient satisfaction and QoL improving over time, and most critically, that even weighing in all the potential negative impacts (adverse impact on body appearance, sense of femininity, sexual relationships, and unanticipated re-operations due to reconstruction complications), still the overwhelming large majority (83%) of BRCA carriers undergoing risk reductive surgery by properly informed election were very satisfied with their decision, yielding a highly positive benefit/harm ratio. These facts are also confirmed by the reported experiences of BRCA carriers themselves (I deal with hundreds of these cases, reported directly to me, many also posted on the No Surrender Breast Cancer Foundation (NSBCF) survivor forum (I serve as Director of Medical Research for NSBCF). Here are the facts based on the best evidence to date:

THE RISKS

Heterozygotes for BRCA1 or BRCA2 mutations have a 5- to 7-fold increased lifetime relative risk for breast cancer (60–80% compared with the ~12% in the general population) 8 and a 15–40% lifetime risk for ovarian cancer, which represents an 11- to 28-fold increase in relative risk over the ~1.4% lifetime risk in the general population [1-3]. Note that these are lifetime risks, so that the increase in risk for younger women is far greater. In addition, data from the Breast Cancer Linkage Consortium remind us that 90% of breast cancers developing in BRCA1 carriers are estrogen receptor–negative [4]. Risk reducing bilateral salpingo-oophorectomy and risk reducing mastectomy reduces the risk of breast cancer by 50% and 90-95%, respectively, in carriers of BRCA1 and BRCA2 mutations, with contralateral mastectomy improving survival in women with BRCA1/2 mutations [5-6]. The greatest gains in life expectancy result from conducting prophylactic mastectomy immediately after BRCA1/2 mutation testing, and are 6.8 years for BRCA1 (and 3.4 to 4.4 years for BRCA2) mutation carriers, and adding annual breast screening provides gains of 2.0 years for BRCA1 (and 1.5 years for BRCA2) [7]. And in general, female BRCA1/2 mutation carriers have no less than 5-fold and up to 40-fold higher cancer risks than average-risk women in the United States, motivating a number of recommended intensive risk-reducing strategies including prophylactic mastectomy, prophylactic oophorectomy, breast cancer screening with interleaved mammography and MRI, and chemoprevention with SERMS (tamoxifen and raloxifene) [8,9]. This is cross-confirmed and refined in the EMBRACE Trial [13], the largest ever conducted prospective study of risk for breast and ovarian cancer in a cohort of 978 BRCA1 carriers and 909 BRCA2 carriers. It was demonstrated that among BRCA1 carriers, average cumulative risk by age 70 was 60% for BC, 83% for contralateral BC, and 59% for ovarian cancer, with BC incidence peaking at age 50 to 59 in BRCA1 carriers. Collectively these findings confirm that confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer.

GAINS IN RISK REDUCTION AND LIFE EXPECTANCY

On the risk reductive side, studies estimate a 90% to 95% reduction in breast cancer incidence for women with BRCA1/2 mutations who undergo prophylactic mastectomy, as shown in the PROSE trial and other studies [10,11]. And the Stanford University model [12] suggests that the gain in life expectancy for a 30-year-old BRCA1 mutation carrier is 5.2 years from prophylactic mastectomy alone, and 10.3 years if prophylactic oophorectomy is also elected. Given these gains, it is not surprising that in the very first US report to prospectively examine the full spectrum of long-term risk management outcomes and predictors after BRCA1/2 testing prospectively [14] of the long-term outcomes of BRCA1/BRCA2 testing and risk reductive surgery, it was clearly found that the vast majority, more than 80%, of carriers obtain risk reductive surgery (37% of BRCA1/2 carriers opted for risk reductive mastectomy and 65% opted for risk reductive oophorectomy), and the investigators concluded that: "These data, combined with reports of the risk and mortality reduction benefits of these behaviors, strongly suggest that the receipt of a positive BRCA1/2 test result is likely to have a favorable effect on long-term breast and ovarian cancer outcomes". The authors further note that a trend of increasing use of these surgeries . . . These data, coupled with emerging evidence of reduced mortality after risk-reducing surgery suggest that BRCA1/2 testing may beneficially impact cancer mortality".

RISK-MODULATING GENETIC VARIANTS

But we hasten to note that BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants, and can result in large differences in the absolute risk of developing breast or ovarian cancer for BRCA1 between genotypes. Soberingly, based on a novel breast cancer risk modifiers loci at 1q32 and 4q32.3 for BRCA1 carriers, the breast cancer lifetime risks for BRCA1 carriers at lowest risk are predicted to be 28–50% compared to 81–100% for those at highest risk. As to ovarian cancer, BRCA1 mutation carriers at lowest risk will have a lifetime risk of developing ovarian cancer of 28% or lower compared to those at highest risk with a lifetime risk of 63% or higher. Therefore based on the pioneer work of the CIMBA (Studies by the Consortium of Investigators of Modifiers of BRCA1/2) investigators [15,28], genetic risk modifiers should ultimately be incorporated into the clinical management of BRCA1 mutation carriers.

COLLATERAL DAMAGE: MORE AGGRESSIVE CANCERS

In addition, the prognostic unfavorably of unremediated BRCA-mutated disease is even greater, something often not appreciated. There is the issue of the risk-grade and receptor type of tumors associated with BRCA-mutations: in both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1). Cancers occurring among BRCA1 carriers exhibit higher grade and mitotic count than sporadic controls, and have a higher percentage of medullary cancers [16], as shown also in the Breast Cancer Linkage Consortium Study and others [4;17,18].

And numerous studies have linked the estrogen receptor (ER)-negativity of breast tumors with BRCA1 mutation carrier status [4;19-26]. In addition, tumors arising in BRCA1 carriers tend to lack progesterone receptors (PR) and HER2, and therefore, display the triple negative (TNBC) phenotype [4;20]. The majority of BRCA1 tumors express basal cytokeratins [27] and fall into the ‘basal' subtype in gene expression studies. And Foulkes and colleagues [22] found that, at every age group, the proportion of ER-negative tumors was higher in BRCA1 mutation carriers than non-carriers, in agreement with the findings of the CIMBA Study [15,28], the largest collaborative study of BRCA1 and BRCA2 mutation carriers, analysis of more than 4,000 BRCA1 and 2,000 BRCA2 carriers, represented by more than 37 groups from more than 20 countries, which confirmed that the majority of BRCA1 breast cancers are ER-negative and TNBC tumors.

Furthermore, ER-negative tumors arising in BRCA1 and BRCA2 mutation carriers presented higher genomic instability and patterns of genomic alteration than ER-positive tumors [29,30]. This is further confirmed in the recent finding that BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability [31]. These genetic/genomic findings collectively demonstrated the highly challenging nature of cancers associated with BRCA1/2 mutations or deficiencies.

PSYCHOLOGICAL IMPACT AND PATIENT SATISFACTION

Several studies have evaluated the psychological impact of bilateral risk reducing mastectomies, the balance of which show good levels of satisfaction and reduced anxiety after the procedure [32,33]. With prophylactic mastectomy, there is an overall patient satisfaction rate of 94%, accompanied by no mortality, and an oncologic long-term outcome of 0% of ulterior development of breast cancer [34].

In addition, we know from the comprehensive analysis done by Lombardi Comprehensive Cancer Center investigators [35], the largest prospective report of long-term outcomes related to surgical decision making in affected and unaffected BRCA1/2 carriers, that BRCA1/2 carriers are satisfied with their testing and risk management decisions and report good quality of life years after testing, and more importantly, electing to have risk reductive surgery predicts increased satisfaction and improved quality of life, and importantly, these data can provide some reassurance for women undergoing reductive risk surgical procedures that in fact most women are clearly satisfied with their decision and that their satisfaction and overall quality of life (QoL) seem to increase over time, findings further confirmed in the results of the IRCCS investigators [36] in Italy that highlight the positive impact of risk-reducing surgery in reducing the perceived risk and cancer worry. And other studies [37-39] have also shown highly positive results, noting that even the potential negative impact of contralateral mastectomy (adverse impact on body appearance, sense of femininity, sexual relationships, and unanticipated re-operations due to reconstruction complications), the overwhelming large majority (83%) were very satisfied with their decision to undergo prophylactic mastectomy.

LESSONS LEARNED

NCCN guidelines advocate surgery by age of 35–40. The utility of identifying individuals who carry pathogenic BRCA1 or BRCA2 mutations is clear. When historic controls are used, the identification of individuals who carry known pathogenic mutations in BRCA1 or BRCA2 and the implementation of risk-reducing surgery decreases the risk for breast and ovarian/Fallopian tube cancer 10-fold [40-43] and such interventions improve life expectancy [10-12;44,45]. And risk-reducing “pre-emptive” surgery is used widely by properly informed and knowledgeable women at elevated genetic risk of breast (and ovarian) cancer across the world (in one recent study [46] more than 80% of carriers had undergone risk-reducing mastectomy, salpingo-oophorectomy, or both within 5 years after diagnosis).

Therefore the overwhelming weight of the evidence confirm clear benefit in outcome and life expectancy, accompanied by exceptionally high degrees of satisfaction (patient satisfaction rate of 83 - 94%), significant reduction in cancer anxiety, and improvement in quality of life (QoL), and that even weighing in all the potential negative impacts on body image and sexuality, the vast majority (no less than 83%) of BRCA carriers undergoing risk reductive surgery by properly informed election remain very satisfied with their decision, yielding a highly positive benefit/harm ratio.

METHODOLOGY OF THE REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE/MedlinePlus, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health), and scope-qualified Boolean searches submitted to Google Scholar and SLIM, was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations), OpenThesis or Proquest. Sources in languages foreign to this reviewer were translated by language translation software.

REFERENCES

1. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007; 25:1329–1333.

2. Chen S, Iversen ES, Friebel T, et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 2006; 24:863–871.

3. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Human Genet 2003; 72:1117–1130.

4. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 2002;20:2310–8.

5. Evans DG, Ingham SL, Baildam A, Ross GL, Lalloo F, Buchan I, et al. Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res Treat2013;140:135-42.

6. Metcalfe K, Gershman S, Ghadirian P, Lynch HT, Snyder C, Tung N, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ2014;348:g226.

7. Sigal BM, Munoz DF, Kurian AW, Plevritis SK. A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012; 21(7):1066-77.

8. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003; 72:1117–30.

9. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007;25:1329–33.

10. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004;22:2328–35.

11. Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van ‘t Veer L, Garber JE, 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.

12. Sigal BM, Munoz DF, Kurian AW, Plevritis SK. A simulation model to predict the impact of prophylactic surgery and screening on the life expectancy of BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2012; 21(7):1066-77.

13. Mavaddat N, Peock S, Frost D, … EMBRACE. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013 Jun 5; 105(11):812-22.

14. Schwartz MD, Isaacs C, Graves KD, et al. Long-term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance. Cancer 2012 Jan 15; 118(2):510-7.

15. Couch FJ, Wang X, McGuffog, et al. . . . on behalf of CIMBA. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk. PLoS Genet 2013; 9(3): e1003212.

16. Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, Van De Vijver MJ, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998;90:1138–45.

17. Phillips KA. Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers. J Clin Oncol 2000;18:107S–12S.

18. Tung N, Wang Y, Collins LC, Kaplan J, Li H, Gelman R, et al. Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res 2010;12:R12.

19. Armes JE, Trute L, White D, Southey MC, Hammet F, Tesoriero A, et al. Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. Cancer Res 1999;59:2011–7.

20. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282–8.

21. Cortesi L, Turchetti D, Bertoni C, Bellei R, Mangone L, Vinceti M, et al. Comparison between genotype and phenotype identifies a high-risk population carrying BRCA1 mutations. Genes Chromosomes Cancer 2000;27:130–5.

22. Foulkes WD, Metcalfe K, Sun P, Hanna WM, Lynch HT, Ghadirian P, et al. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 2004;10:2029–34.

23. Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:362–71.

24. Karp SE, Tonin PN, Begin LR, Martinez JJ, Zhang JC, Pollak MN, et al.Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer 1997;80:435–41.

25. Loman N, Johannsson O, Bendahl PO, Borg A, Ferno M, Olsson H. Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations or unknown susceptibility genes. Cancer 1998;83:310–9.

26. Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, et al. Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 2005;90:5–14.

27. Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 2005;11:5175–80.

28. Mavaddat N, Barrowdale D, Andrulis IL, … Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 2012; 21(1):134-47.

29. Melchor L, Honrado E, Huang J, Alvarez S, Naylor TL, Garcia MJ, et al. Estrogen receptor status could modulate the genomic pattern in familial and sporadic breast cancer. Clin Cancer Res 2007;13:7305–13.

30. Melchor L, Honrado E, Garcia MJ, Alvarez S, Palacios J, Osorio A, et al. Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. Oncogene 2008;27:3165–75.

31. Savage KI, Matchett KB, Barros EM, et al. BRCA1 Deficiency Exacerbates Estrogen Induced Dna Damage And Genomic Instability. Cancer Res 2014 Mar 17.

32. Hallowell N, Baylock B, Heiniger L, Butow PN, Patel D, Meiser B, et al. Looking different, feeling different women’s reactions to risk-reducing breast and ovarian surgery. Fam Cancer2012;11:215-24.

33. Montgomery LL, Tran KN, Heelan MC, Van Zee KJ, Massie MJ, Payne DK, et al. Issues of regret in women with contralateral prophylactic mastectomies. Ann Surg Oncol1999;6:546-52.

34. de la Peña-Salcedo JA, Soto-Miranda MA, Lopez-Salguero JF. Prophylactic mastectomy: is it worth it? Aesthetic Plast Surg 2012; 36(1):140-8.

35. Hooker GW, King L, Vanhusen L, et al. Long-term satisfaction and quality of life following risk reducing surgery in BRCA1/2 mutation carriers. Hered Cancer Clin Pract 2014; 12(1):9.

36. Borreani C, Manoukian S, Bianchi E, et al. The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers. Clin Genet 2014; 85(1):7-15.

37. Stolier AJ, Fuhrman GM, Mauterer L, Bolton JS, Superneau DW. Initial experience with surgical treatment planning in the newly diagnosed breast cancer patient at high risk for BRCA-1 or BRCA-2 mutation. Breast J, 10 (6) (2004 Nov), pp. 475–480.

38. Tercyak KP, Peshkin BN, Brogan PM, et al. Quality of life after contralateral prophylactic mastectomy in newly diagnosed high-risk breast cancer patients who underwent BRCA1/2 gene testing. J Clin Oncol, 25 (3) (2007 Jan 20), pp. 285–291.

39. Francken AB, Schouten PC, Bleiker EM, Linn SC, Rutgers EJ. Breast cancer in women at high risk: the role of rapid genetic testing for BRCA1 and -2 mutations and the consequences for treatment strategies. Breast 2013; 22(5):561-8.

40. Stefanek M, Hartmann L, Nelson W. Risk-reduction mastectomy: clinical issues and research needs. J Natl Cancer Inst, 93 (2001), pp. 1297–1306.

41. 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, 340 (1999), pp. 77–84.

42. McDonnell SK, Schaid DJ, Myers JL, et al. Efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. J Clin Oncol, 19 (2001), pp. 3938–3943.

43. Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst, 93 (2001), pp. 1633–1637.

44. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 304 (2010), pp. 967–975.

45. Grann VR, Jacobson JS, Thomason D, Hershman D, Heitjan DF, Neugut AI. Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: an updated decision analysis. J Clin Oncol, 20 (2002), pp. 2520–2529.

46. Metcalfe K, Gershman S, Lynch HT, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer, 104 (2011), pp. 1384–1392.

Dear Constantine

Thank you for your accurately and objectively answer.

Best regards

Dear Nelson:

Thanks. And your insight is a shrewd one, and has even been a topic at several conferences, namely what is sometimes called "media-driven decisions", where high-profile public and entertainment personalities are used consciously or unconsciously as part of the decision process, which only serves to minimize the realities of a complex decision. That is why I spoke only of properly informed election of risk-reductive surgery, when the BRCA carrier is made to understand both all the potential harms and disadvantages, as well as the benefits, in order to render the most considered determination (some women for example are not aware that with small breasts mastectomy may not be a viable option or if it is, that cosmetic outcome may be compromised). And a highly knowledgeable oncologist or geneticist will need to weigh factors that are typically not considered by the leading risk tools like BRCAPRO and BOADICEA, such as TP53 status, non-basality, and a number of others that might dramatically reduce risk assessment, making conservative management and proactive surveillance a more attractive option in certain cases. It's an individual decision with some considerable variability, and new prophylaxis options are beginning to emerge: for example the Phase III LIBER Trial is currently evaluating the efficacy of 5-year letrozole to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers (and from some unannounced chatter about the trial, I suspect we may see some positive results in the not too distant future), and options such as medical ovarian suppression and many others are also being explored.

Thanks - once again - for a great and stimulating question!

Kind regards

Constantine

Dear Constantine

Thank you

Best regards