Contralateral prophylactic mastectomy

Mastectomia profilática contralateral

Description of the evidence collection method

This guideline followed the standard of a systematic review with evidence retrieval based on evidence-based medicine (EBM), so that clinical experience is integrated with the ability to critically analyze and apply scientific information rationally, thus improving the quality of medical care.

We used the structured mode of formulating questions synthesized by the acronym PICO, where P stands for patient, i.e. women diagnosed with unilateral breast cancer; I for intervention, i.e. simple or total mastectomy, skin-sparing mastectomy, and nipple-areola complex-sparing mastectomy; C for comparison with women who did not undergo contralateral prophylactic mastectomy, and O for the outcome of reduction of the incidence of breast cancer in the contralateral breast.

Based on the structured question, we identified the descriptors that formed the basis of the search for evidence in the databases: Medline-Pubmed and Cochrane. A total of 424 studies were retrieved, of which five were selected to answer the clinical questions (Annex I).

Clinical question

Is contralateral prophylactic mastectomy (CPM) in women with unilateral breast cancer associated with a decline in the incidence of breast cancer in the contralateral breast?

Grades of recommendation and levels of evidence

• A: Experimental or observational studies of higher consistency.

• B: Experimental or observational studies of lower consistency.

• C: Cases reports / non-controlled studies.

• D: Opinion without critical evaluation, based on consensus, physiological studies or animal models.

Objective

This guideline is intended for physicians and medical students and aims to assess whether contralateral prophylactic mastectomy (CPM) in women with unilateral breast cancer is associated with a decline in the incidence of breast cancer in the contralateral breast.

Introduction

Breast cancer is the neoplastic disease that most affects women in Brazil and the world. In Brazil, for the year 2016, 57,960 new cases were expected.¹

Women with a history of breast cancer are at increased risk for developing contralateral breast cancer, and this risk is related to a variety of factors, including genetics, family history and characteristics of the primary cancer itself.^2,3

Although studies have shown the efficacy of adjuvant endocrine therapy to reduce the risk of contralateral breast cancer, a growing proportion of women in the early stages of breast cancer have undergone surgical removal of the non-affected breast through risk reducing mastectomy of the contralateral breast.^4,5 Despite the substantial benefits associated with reducing the risk of breast cancer itself, its risk-benefit ratio is controversial because of the negative impact of surgery on self-image, sexuality and quality of life, in addition to complications related to the procedure itself.⁶ Thus, in order to support decision-making by the indication or not of the contralateral prophylactic mastectomy using robust evidence, a systematic review was carried out to evaluate whether CPM in women with unilateral breast cancer is associated with a decline in the incidence of breast cancer in the unaffected breast.

Data extraction

Data referring to a total of 5,532 patients were analyzed, with 2,700 of these women undergoing contralateral prophylactic mastectomy following a personal history of unilateral breast cancer. The mean age of these patients was 46 (Table 1). With mean follow-up time ranging from 3.5 to 17.3 years, it was observed that the contralateral prophylactic mastectomy was associated with a reduction in the incidence of breast cancer in the contralateral breast with values ranging from 78 to 98% and overall risk reduction of 95% (RR=0.05; 95CI 0.02-0.11) (Table 2).

Table 1
Studies selected.

Authors and publication year	Type of study	Age	N/CPM	N/Control	Follow-up time	Endpoints
Peralta et al., 2000	Retrospective cohort	45.5	0/64	36/182	6.2 years for CPM and 6.8 years for the control group	Overall survival, disease-free survival, incidence of cancer in the contralateral breast
van Sprundel et al., 2005	Retrospective cohort	CPM=41.5±0.9 Control=46.7±1.1	1/79	6/69	3.5 years	Overall survival, incidence of cancer in the contralateral breast
Boughey et al., 2010	Retrospective cohort	NA	2/385	31/385	17.3 years	Overall survival, disease-free survival, incidence of cancer in the contralateral breast, distant metastases
Herrinton et al., 2005	Retrospective cohort	CPM=50 Control=58	5/1,072	69/317	5.7 years	Cancer incidence in the contralateral breast; overall survival
King et al., 2011	Retrospective cohort	CPM=44.8 Control=53.2	0/407	14/2,572	4.4 years for CPM and 6.8 years for the control group	Incidence of contralateral breast cancer, distant metastases

• Age: years ± standard deviation; N: patients with breast cancer; CPM: contralateral prophylactic mastectomy; Control: not treated with CPM; Follow-up time: years; NA: not available.

Table 2
Incidence of breast cancer in the contralateral breast.

Study or subgroup	CPM		Control			Risk ratio	Risk ratio
	Events	Total	Events	Total	Weight	M-H, Random, 95CI	M-H, Random, 95CI
Boughey et al., 2010	2	385	31	385	25.3%	0.06 [0.02, 0.27]
Herrinton et al., 2005	5	1,072	69	317	44.1%	0.02 [0.01, 0.05]
King et al., 2011	0	407	14	2,572	8.2%	0.22 [0.01, 3.64]
Peralta et al., 2000	0	64	36	182	8.5%	0.04 [0.00, 0.62]
van Sprundel et al., 2005	1	79	6	69	13.9%	0.15 [0.02, 1.18]
Total (95CI)		2007		3,525	100.0%	0.05 [0.02, 0.11]
Total events	8		156
Heterogeneity: Tau2 = 0.22; Chi2 = 5.15, df = 4 (p=0.27); I2 = 22%
Test for overall effect: Z = 7.04 (p<0.00001)

Regarding data on overall survival, studies have conflicting results, some with increased survival⁷ and others not confirming this gain.^8-10 Two studies analyzed the incidence of distant metastasis, with a difference between women treated and not treated with CPM (RR=0.65; 95CI 0.46-0.91) (Table 3).^7,11 (B).

Table 3
Incidence of distant metastases.

Study or subgroup	CPM		Control			Risk ratio	Risk ratio
	Events	Total	Events	Total	Weight	M-H, Random, 95CI	M-H, Random, 95CI
Boughey et al., 2010	60	385	82	385	66.2%	0.73 [0.54, 0.99]
King et al., 2011	15	407	187	2,572	33.8%	0.51 [0.30, 0.85]
Total (95CI)		792		2,957	100.0%	0.65 [0.46, 0.91]
Total events	75		269
Heterogeneity: Tau2 = 0.22; Chi2 = 1.51, df = 1 (p=0.22); I2 = 34%
Test for overall effect: Z = 2.46 (p=0.01)

Studies have demonstrated that contralateral prophylactic mastectomy is associated with a decline in the incidence of contralateral breast cancer in approximately 95% of women with a personal history of unilateral breast cancer.^12,13 (B) Supporting these findings, there was a 95% reduction in the incidence of breast cancer; however, the impact on overall survival or even breast cancer-free survival is uncertain, as evidenced in another systematic review that included observational studies.¹³ (B)

In a retrospective study that showed an average follow-up of around 17 years, the authors reported a 94% lower incidence of contralateral breast cancer in women with stage I or II breast cancer who had undergone therapeutic mastectomy combined with contralateral prophylactic mastectomy.⁷ (B) The study, with significant long-term follow-up, showed that contralateral prophylactic mastectomy was also associated with superior overall survival and disease-free survival outcomes, although a difference with respect to the incidence of distant metastases was not found.⁷ (B) On the other hand, other authors, analyzing women with mutations in BRCA1 and BRCA2 genes previously treated for unilateral invasive breast cancer (stage I–IIIa), did not find an increase in overall survival after adjustment for bilateral prophylactic oophorectomy.⁹ (B) These authors, with no adjustment for prophylactic oophorectomy, found greater overall survival at 5 years in patients undergoing contralateral prophylactic mastectomy, but attributed these findings to the higher mortality observed in the group of patients kept under surveillance.⁹ (B)

Supporting these findings, in another retrospective study in which more than 1,000 patients with breast cancer were analyzed, the contralateral prophylactic mastectomy was not associated with greater overall survival.¹⁰ (B) With a mean follow-up of 6.8 years, the authors found greater disease-free survival for patients undergoing contralateral prophylactic mastectomy (55% versus 28%, p=0.01), but did not identify a difference for the rate of overall survival (64% versus 48%, p=0.2).⁸ (B) Even after adjusting the groups for prognostic factors, they did not find an improvement in the overall survival rate after 15 years of follow-up.⁸ (B)

The lack of translation to benefit of contralateral breast cancer control, in terms of greater overall survival and disease-free survival, based on a decline in the incidence of breast cancer with the indication of CPM, is not unusual. For many women with early-stage breast cancer, the risk of metastatic disease is greater than that for contralateral breast cancer.² (B) Therefore, it is possible that the benefits of CPM in terms of disease-free survival are observed only in certain patient subgroups. In fact, another study based on the SEER (Surveillance, Epidemiology and End Results) database showed that, in patients with estrogen receptor-positive breast cancer, the contralateral prophylactic mastectomy was not associated with higher specific survival related to breast cancer.¹⁴ (B)

Recommendation

For women who have already been diagnosed with unilateral breast cancer, the contralateral prophylactic mastectomy reduces the incidence of breast cancer in the contralateral breast and distant metastases. With respect to survival (overall or disease-free), the evidence is limited.

References

• ¹
  INCA. Estimativa 2016. Incidência de câncer no Brasil [cited 2017 May]. Available from: http://www1.inca.gov.br/estimativa/2016/index.asp
  » http://www1.inca.gov.br/estimativa/2016/index.asp
• ²
  Schairer C, Brown LM, Mai PL. Inflammatory breast cancer: high risk of contralateral breast cancer compared to comparably staged non-inflammatory breast cancer. Breast Cancer Res Treat. 2011; 129(1):117-24.
• ³
  Storm HH, Jensen OM. Risk of contralateral breast cancer in Denmark 1943-80. Br J Cancer. 1986; 54(3):483-92.
• ⁴
  Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group., Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008; 9(1):45-53.
• ⁵
  Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998; 351(9114):1451-67.
• ⁶
  Frost MH, Slezak JM, Tran NV, Williams CI, Johnson JL, Woods JE, et al. Satisfaction after contralateral prophylactic mastectomy: the significance of mastectomy type, reconstructive complications, and body appearance. J Clin Oncol. 2005; 23(31):7849-56.
• ⁷
  Boughey JC, Hoskin TL, Degnim AC, Sellers TA, Johnson JL, Kasner MJ, et al. Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. Ann Surg Oncol. 2010; 17(10):2702-9.
• ⁸
  Peralta EA, Ellenhorn JD, Wagman LD, Dagis A, Andersen JS, Chu DZ. Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer. Am J Surg. 2000; 180(6):439-45.
• ⁹
  van Sprundel TC, Schmidt MK, Rookus MA, Brohet R, van Asperen CJ, Rutgers EJ, et al. Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J Cancer. 2005; 93(3):287-92.
• ¹⁰
  Herrinton LJ, Barlow WE, Yu O, Geiger AM, Elmore JG, Barton MB, et al. Efficacy of prophylactic mastectomy in women with unilateral breast cancer: a cancer research network project. J Clin Oncol. 2005; 23(19):4275-86.
• ¹¹
  King TA, Sakr R, Patil S, Gurevich I, Stempel M, Sampson M, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol. 2011; 29(16):2158-64.
• ¹²
  Portschy PR, Kuntz KM, Tuttle TM. Survival outcomes after contralateral prophylactic mastectomy: a decision analysis. J Natl Cancer Inst. 2014; 106(8). pii: dju160.
• ¹³
  Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev. 2010; (11):CD002748.
• ¹⁴
  Bedrosian I, Hu CY, Chang GJ. Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients. J Natl Cancer Inst. 2010; 102(6):401-9.
• ¹⁵
  Bernardo WM. The systematic review in the evidence based clinical practice. Femina. 2008; 36(6):335-44.
• ¹⁶
  Higgins JPT, Altman DG. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (updated September 2008). The Cochrane Collaboration, 2008. Available from: http://www.cochrane-handbook.org
  » http://www.cochrane-handbook.org
• ¹⁷
  Levels of Evidence and Grades of Recommendations - Oxford Centre for Evidence Based Medicine. Available from: http://www.cebm.net/oxfordcentre-evidence-based-medicine-levels-evidence-march-2009/
  » http://www.cebm.net/oxfordcentre-evidence-based-medicine-levels-evidence-march-2009/

Publication Dates

• Publication in this collection
  Jan 2018

History

• Accepted
  29 June 2017