Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g226 (Published 11 February 2014) Cite this as: BMJ 2014;348:g226All rapid responses
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Letter to the Editor of BMJ,
Metcalfe et al recently published a survival benefit in BRCA1 and BRCA2 mutation carriers undergoing contralateral risk reducing mastectomy following a diagnosis of breast cancer. This is a timely study given that rates of contralateral mastectomy (mutation carriers and non-carriers) are increasing with US SEER data describing a 150% increase in the last decade(1). The aftermath of Angelina Jolie’s announcement of her risk-reducing surgery has meant that clinicians are frequently faced with patients demanding risk-reducing surgery.
This study’s findings on survival benefit are similar to our own(2). In our series, uptake of contralateral risk-reducing surgery was much lower at 15% compared to nearly 50% in this study and may highlight variations in uptake of surgery between Northern America and Europe(3).
The authors discuss timing of gene mutation testing, showing a difference in type of mastectomy chosen (unilateral vs bilateral) based on knowledge of mutation status. Indeed we showed the lower rates in those having later genetic testing in our recent publication(2) and previously(4). They mention “In the future, if genetic testing is performed routinely at the time of diagnosis, comparisons of the various surgical treatments will become more straightforward”. The 2013 NICE guidelines on Familial Breast Cancer have lowered the threshold for gene testing and we would suggest judicious use of genetic testing using validated models (e.g. BRCAPRO, BOADICEA) as routine testing may impact on psychological well-being, although some studies suggest this may not be so(5).
The impact of routine genetic testing in the clinic will have an effect on patients and clinicians alike. This process and the subsequent decision making process in relation to reconstruction takes time. Where complex procedures are required, such as the DIEP – (Deep Inferior Epigastric Artery Perforator free flap) that utilises skin and fat in the lower abdomen to refashion a new breast mound, operative planning may not be possible in a limited time frame. This may delay important and potentially life-saving chemotherapy in particular in BRCA1 carriers who have predominantly high grade triple negative cancers, that are known to do better with aggressive treatment (6). There may also become a situation where if the threshold for genetic testing is lowered that we may not have sufficient resources to provide bilateral DIEP flap reconstruction. Nonetheless, the survival benefit shown by the authors is a welcome finding as it helps reconstructive surgeons counsel gene mutation carriers with breast cancers on the merits of bilateral mastectomy and reconstruction.
The findings from this paper will have implications on rapid genetic testing at time of breast cancer diagnosis. There is no doubt that knowledge of mutation status impacts on subsequent treatments including adjuvant or neoadjuvant treatment (e.g. cisplatin, PARP inhibitors) and also reconstructive options, but the threshold for genetic testing must be clearly determined.
Refs:
1. Tuttle T Habermann EB, Grund EH, Morris TJ, Virnig BA. Increasing use of contralateral prophylactic mastectomy for breas cancer patients: a trend towards more aggressive surgical treatment. J Clin Oncol 2007;25(33):5203-9.
2. Evans DG, Ingham SL, Baildam A, Ross GL, Lalloo F, Buchan I, Howell A. Contralateral mastectomy improves survival in BRCA1/2 associated breast cancer. Breast Cancer Res Treat 2013;140(1):135-42
3. GuthU, Myrick ME, Viehl CT, Weber WP, Lardi Am, Schmid SM. Increasing rates of contralateral prophylactic mastectomy - a trend made in the USA? Eur J Surg Oncol 2012;38(4):296-301.
4. Evans DGR, Lalloo F, Hopwood P, Maurice A, Baildam A, Brain A, Barr L, Howell A. Surgical decisions made by 160 women detected with breast cancer <50 years of age. Eur J Surg Oncol 2005; 31(10):1112-8.
5. Braithwaite D, Emery J, Walter F, Prevost AT, Sutton S. Psychological impact of genetic counselling for familial breast cancer: a systemic review and meta-analysis. J Natl Cancer Inst 2004;96(2):122-33.
6. Evans DG, Howell A. Are BRCA1- and BRCA2-related breast cancers associated with increased mortality? Breast Cancer Res. 2004;6(1):E7.
Competing interests: No competing interests
The authors do not tell us how women who did not opt for contralateral mastectomy were followed. I assume only a minority had contralateral breast cancer screening with annual MRI, as currently recommended.
It is likely that adding MRI to mammography reduces breast cancer mortality. As a result, had these women benefited from such surveillance protocols, their mortality might have been similar to what was oberved in women with bilateral mastectomy in multivariate analyses.
Competing interests: No competing interests
I have a comment on Figure 2. "Survival from 10-20 years after breast cancer, by contralateral mastectomy. I wonder why the authors opted to present the survival curses in a "non-traditional" way for classic survival analysis, i.e. what was the reason and why the follow-up starts with the 10th year, when by all means and statistical rules of survival analysis (Altman D, 1991) it should start at time point "ZERO". This, in my opinion, should be corrected. Otherwise, the graph creates an inflated impression of advantage of survival between bilateral and unilateral mastectomy groups, as way too many death events occur prior to the 10 year cut point.
Also, the adjusted analysis seems to show no survival advantage of bilateral mastectomy. This seems to contradict the main conclusion of this paper.
Competing interests: No competing interests
This study highlights the fact that Women who carry a germline mutation in either the BRCA1 or BRCA2 gene had significant reduction (48%) of Death from breast cancer within 20 years diagnosis of this condition following bilateral mastectomy compared to those who had undergone contralateral mastectomy. If this study is confirmed by further studies involving more patients, then this information will have to be shared with patients at the time of the initial consultation after the diagnosis. I think breast surgeons must offer this option to their patients given that the evidence is so compelling. Besides, the other members of the family need to be counselled by their GPs or breast clinic to get them tested & plan for the treatment ahead of the disease even if there are no symptoms present. Surely that could confirm more breast cancers & save so many lives.
Competing interests: No competing interests
Re: Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis
Letter to the editor,
Our Journal Club recently reviewed this article and felt that it was an important study to truly appreciate a topical issue within the field. Upon reading the article we found a few points that weakened the study or needed further clarification which are mentioned below.
The authors went to a great deal of effort to ensure that BRCA mutations were truly identified. However, it is unclear to us why 29 patients were excluded due to the fact that they did not have BRCA 1/2 and yet 14% of the study was not clearly known to have either mutation. We appreciate that an estimate of 2 participants would be the error included inappropriately, however, it is unclear whether the data provided to come to this conclusion are truly comparable since the populations are not strictly mentioned. Whilst BRCA mutations are autosomal dominant, this only predicts that those with a family history have a 50% chance of having the mutation [1]. This may contribute 53/2= 26.5- 27 patients. This may not seem significant, however, when you consider that 16 deaths separated the groups this is a significant proportion without BRCA.
It is unclear why women aged over 65 were excluded as this accounted for 70 possible participants. This reduces generalizability of the findings, as they are not applicable to those with known BRCA1/2 gene mutations over the age of 65 years.
An issue that needs to be addressed is whether the patients undergoing prophylactic mastectomy did indeed have that. It is unclear whether patients with bilateral mastectomy had a tissue diagnosis confirming that a healthy breast had been removed rather than a pathological one. This would class patients in a different category - those who had received appropriate treatment for bilateral cancer, rather than prophylactic mastectomy. Removing this cohort from the analysis may indeed remove differences noted in the study.
In the article there is no clarification regarding the location and policies of the 12 genetic clinics. This creates potential for marked regional and treatment discrepancies depending on where these clinics are located and whether they offered single or bilateral mastectomies as standard. Furthermore, without more information regarding location and therefore target population, there is no way to know if the cases as sufficiently representative of patients from a wide range of socio-economic profiles and thus for this prophylactic treatment to be generalizable to the whole spectrum of breast cancer sufferers.
The authors acknowledge that randomisation of the groups was not achieved. Although this is not necessary in a retrospective study, this does introduce possible confounding. In the United States, private healthcare is the principal method of healthcare. It is therefore conceivable that those electing to undergo a double mastectomy did so because of better healthcare cover than those undergoing unilateral mastectomy. It is well documented that socioeconomic inequalities exist in healthcare that have a direct effect on mortality [2] and this could confound the argument that double mastectomy reduces mortality when in fact it is the wealth of the individuals that determines what procedure can be undertaken. The authors do not account or attempt to measure this possibility.
Although the authors do consider BRCA1/2 gene mutations, there is no inclusion of other mutations now known to be associated with increased risk of breast cancer such as EGFR [3] and it is therefore unclear whether bilateral mastectomy would also apply to such patients.
The authors only consider mortality as an outcome in this trial. Although mortality may be lower in the double mastectomy group, no consideration of the psychological stress and morbidity associated with undergoing a second procedure was accounted for.
[1] Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2013 Sep 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1247/
[2] Mackenbach J, Stirbu I, Roskam A-J, Schaap M, Menvielle G, Leinsalu M, Kunst AE. Socioeconomic Inequalities in Health in 22 European Countries. New England Journal of Medicine 2008; 358: 2468–2481.
[3] Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat.2012;136(2):331–345.
Competing interests: No competing interests