Contralateral risk reducing mastectomy in Non-BRCA-Mutated patients

Giuseppe Falco 2 , Nicola Rocco 1 , Daniele Bordoni 3 , Luigi Marano 4 , Antonello Accurso 5 , Claudio Buccelli 6 , Pierpaolo Di Lorenzo 6 , Emanuele Capasso 6 , Fabio Policino 6 , Massimo Niola 6 ,  and Guglielmo Ferrari 2
  • 1 Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Napoli, Italy
  • 2 Breast Surgery Unit Arcispedale-IRCCS Santa Maria Nuova, Reggio Emilia, Italy
  • 3 Department of Senology, “Santa Maria della Mi-sericordia” Hospital, Urbino, Italy
  • 4 Robotic Surgery Unit, “San Matteo degli Infermi” Hospital - ASL Umbria 2, 06049, Spoleto (PG), Italy
  • 5 Department of Gastroenterology, Endocrinology and Surgery, Breast Unit, AOU “Federico II”, Naples, Italy
  • 6 Department of Advanced Biomedical Sciences, Naples, Italy, University “Federico II” of Naples, via S. Pan-sini,5, 80131 Naples, Italy
Giuseppe Falco, Nicola Rocco, Daniele Bordoni, Luigi Marano, Antonello Accurso, Claudio Buccelli, Pierpaolo Di Lorenzo, Emanuele Capasso, Fabio Policino, Massimo Niola and Guglielmo Ferrari

Abstract

The use of contralateral risk reducing mastectomy (CRRM) is indicated in women affected by breast cancer, who are at high risk of developing a contralateral breast cancer, particularly women with genetic mutation of BRCA1, BRCA2 and P53. However we should consider that the genes described above account for only 20-30% of the excess familiar risk. What is contralaterally indicated when genetic assessment results negative for mutation in a young patient with unilateral breast cancer? Is it ethically correct to remove a contralateral “healthy” breast? CRRM rates continue to rise all over the world although CRRM seems not to improve overall survival in women with unilateral sporadic breast cancer. The decision to pursue CRRM as part of treatment in women who have a low-to-moderate risk of developing a secondary cancer in the contralateral breast should consider both breast cancer individual-features and patients preferences, but should be not supported by the surgeon and avoided as first approach with the exception of women highly worried about cancer. Prospective studies are needed to identify cohorts of patients most likely to benefit from CRRM.

1 Introduction

Breast cancer represent the second leading cause of cancer-related deaths in the United States [1] and the UK [2]. Although it regards predominantly older women, approximately 12% of new breast cancer cases occur in women younger than 45 years [3]. Younger age is usually related with more aggressive and less responsive tumours and consequently with lower survival rates, higher recurrence rates, and negative prognostic variables [4-6]. Therapeutic interventions include chemotherapy, hormone-therapies and surgery with or without radiotherapy. Systemic treatments impact on fertility prompting early menopause and ovarian decline [7]. Higher depression rates with effect on family life are also reported in these patients [8]. Refer to surgery could be cause of a negative body image that influence post-operative quality of life. Breast surgery includes breast conserving surgery (BCS) followed by radiation-therapy (RT) for early breast cancer or unilateral mastectomy (UM). BCS with RT and UM survival rates are equivalent [9], but preserving the breast, considering an oncoplastic technique could achieve better satisfaction levels and improve post-operative quality of life. Recently, however, numerous papers revealed a consistent growth in the use of both UM and contralateral risk reducing mastectomy (CRRM) [10,11]. CRRM consist in a so-called conservative mastectomy, the Nipple Areola Complex-Sparing Mastectomy that preserve the native breast skin and the nipple-areola complex, resulting in improved aesthetic results with local recurrence rates comparable to the traditional modified radical mastectomy [12]. The use of UM and CRRM is indicated in women affected by breast cancer, who are at high risk of developing a contralateral breast cancer (CBC), particularly women with genetic mutation of BRCA1, BRCA2 and P53. However, we should consider that the genes described above account for only 20-30% of the excess familial risk [13,14]. Consequently, the genetic etiology for the majority of families with an increased familial breast cancer risk remains unknown. Young age at diagnosis is a feature of hereditary disease and it is currently suggested that all women diagnosed with breast cancer younger than 37 should be referred for genetic assessment. But what is indicated in the contralateral breast when genetic assessment results are negative for mutation in a young patient with unilateral breast cancer? Is it ethically correct to remove a contralateral “healthy” breast?

2 Literature search

We reviewed PubMed database using the keywords “contralateral breast cancer”, “contralateral prophylactic mastectomy” and “contralateral risk reducing mastectomy”. We included only articles in English focused on contralateral mastectomy in women who presented a low-to-moderate risk of developing a secondary cancer in the contralateral breast. We considered as low-to-moderate risk patients, all women with a unilateral breast cancer in young age without a genetic mutation of BRCA1, BRCA2, P53 and without an evidence of strong familiarity for breast cancer. All papers reporting BRCA gene mutation carriers and other high-risk women have been excluded.

3 Results

Between January 1, 2005 and March 1, 2016 more than 300 papers were retrieved. Only 10% of retrieved papers addressed the impact of contralateral risk reducing mastectomy on overall survival [16-31]. Contralateral risk reducing mastectomy is estimated to reduce the risk of developing a contralateral breast cancer by approximately 94% [15]. Some studies showed a disease free survival (DSF) benefit associated with CRRM, but not an overall survival benefit [25,29].

4 Discussion

As a preventive measure, CRRM in women with low-to-moderate risk of developing a secondary cancer in contralateral breast remains controversial and potential benefits and disadvantages need to be discussed. The risk of mortality from contralateral disease must always be weighed against risk of mortality from primary tumour metastases, without an overall survival benefit. Different studies in fact showed as patients prognosis is strongly related to the features of their first breast cancer [32-34]. Moreover, mastectomy does not remove all breast tissue and therefore cannot eliminate risk of breast cancer at all, even if this surgery is shown to be effective in reducing risk. Presently, we are participating in a serious paradox: “a lesser surgical procedure is always more used in patients with an invasive breast cancer thanks to the screening program that allows an early detection of small cancer while mastectomy is offered in healthy breast for cancer prevention [32]”. In addition, there is no demonstrated survival benefit [35] and CRRM may cause significant physical morbidity: complication including infection, nipple areola complex necrosis, bleeding with a reoperation rate up to 16% of patients [36]. Chronic pain and unsatisfactory aesthetic results are also been reported respectively up to 50% and 84% of the CRRM affecting irreparably post-operative quality of life [37,38]. Women should be thoroughly informed about achievable outcomes in breast reconstructive surgery when considering undergoing risk reducing procedures. On the other side, CRRM in non affected breast have potential benefits connected with the reduction of both risk of cancer and anxiety patient. Given the potential complications and no demonstration of survival benefits, CRRM could be safely omitted in patients with low-to-moderate breast cancer risk.

5 Conclusion

CRRM rates continue to rise all over the world although CRRM seems not to improve overall survival in women with unilateral sporadic breast cancer. The decision to pursue CRRM as part of treatment in women who have a low-to-moderate risk of developing a secondary cancer in the contralateral breast should consider both breast cancer individual-features and patients preferences, but should not be supported by the surgeon and avoided as first line approach with the exception of women highly worried about cancer. Prospective studies are needed to identify cohorts of patients most likely to benefit from CRRM.

Conflict of interest statement: Authors state no conflict of interest.

References

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    • Crossref
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    Cancer Research UK Cancer incidence - UK statistics. Available from: http://info.cancerresearchuk.org/cancerstats/incidence/; 2011

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    Neuburger J, Macneill F, Jeevan R, et al. Trends in the use of bilateral mastectomy in England from 2002 to 2011: retrospective analysis of hospital episode statistics. BMJ Open. 2013;3:e003179

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    Dragun AE, Huang B, Tucker TC, et al. Increasing mastectomy rates among all age groups for early stage breast cancer: a 10-year study of surgical choice. Breast J. 2012;18:318-325

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    Maretoja TJ, Rasia S, Von Smitten KA, et al. Late results of skin-sparing mastectomy followed by immediate breast reconstruction. Br J Surg 2007;94:1220-1225

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    Michailidou K, Holm NV, Verkasalo PK, et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet. 2015;47(4):373-380

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    Quan G, PommierSJ, Pommier RF. Incidence and outcomes of contralateral breast cancers. Am J Surg. 2008;195(5):645-650; discussion 650

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    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;102:401-409

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    Stucky CC, Gray RJ, Wasif N, DueckAC, Pockaj BA. Increase in contralateral prophylactic mastectomy: echoes of a bygone era? Surgical trends for unilateral breast cancer. Ann Surg Oncol. 2010;17 Suppl 3:330-337

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    McLaughlin CC, Lillquist PP, Edge SB, Surveillance of prophylactic mastectomy: trends in use from 1995 through 2005. Cancer. 2009;115:5404-5412

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    Tuttle TM, JarosekS, Habermann EB, Arrington A, Abraham A, Morris TJ, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27:1362-1367

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    DamleS, TealCB, LenertJJ, Marshall EC, Pan Q, McSwain AP. Mastectomy and contralateral prophylactic mastectomy rates: an institutional review. Ann Surg Oncol. 2011;18:1356-1363

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    Yi M, Hunt KK, Arun BK, Bedrosian I, Barrera AG, Do KA, et al. Factors affecting the decision of breast cancer patients to undergo contralateral prophylactic mastectomy. Cancer Prev Res (Phila). 2010;3:1026-1034

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    Sorbero ME, DickAW, Beckjord EB, Ahrendt G. Diagnostic breast magnetic resonance imaging and contralateral prophylactic mastectomy. Ann Surg Oncol. 2009;16:1597-1605

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    King TA, Sakr R, PatilS, Gurevich I, Stempel M, Sampson M, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol. 2011;29: 2158-2164

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    Quan G, Pommier SJ, Pommier RF. Incidence and outcomes of contralateral breast cancers. Am J Surg. 2008;195:645-50; discussion 650

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    BougheyJC, HoskinTL, 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;17:2702-2709

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    Chung A, Huynh K, Lawrence C, Sim MS, Giuliano A. Comparison of patient characteristics and outcomes of contralateral prophylactic mastectomy and unilateral total mastectomy in breast cancer patients. Ann Surg Oncol. 2012;19(8):2600-2606

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    Roberts A, Sandhu L, CilTD, Hofer SO, ZhongT. Contralateral prophylactic mastectomy rate stable at major Canadian breast cancer center. World J Clin Oncol. 2016 Jun 10;7(3):302-307

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    Ager B, Butow P, Jansen J, Phillips KA, Porter D; CPM DA Advisory Group. Contralateral prophylactic mastectomy (CPM): A systematic review of patient reported factors and psychological predictors influencing choice and satisfaction. Breast. 2016 Jun 8;28:107-120

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    Roukos DH, Kappas AM, Tsianos E. Role of surgery in the prophylaxis of hereditary cancer syndromes. Annals of surgical oncology 2002;9(7):607-609

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    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. British Journal of Cancer 2005;93(3):287-292

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    Lise M, Zavagno G, Meggiolaro F. Prophylactic mastectomy in women at high risk of breast cancer. Forum 1997;7.1(2 Suppl):112-116

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    Lostumbo L, Carbine NE, WallaceJ. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev. 2010:(11):CD002748

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    Miller ME, Czechura T, Martz B, et a l. Operative risks associated with contralateral prophylactic mastectomy: a single institution experience. Ann Surg Oncol. 2013;20:4113-4120

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    Brummett CM. Chronic pain following breast surgery. Tech Reg Anesth Pain Manag. 2011;15:124-132

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    Altschuler A, Nekhlyudov L, Rolnick SJ, et al. Positive, negative, and disparate: women’s differing long-term psychosocial experiences of bilateral or contralateral prophylactic mastectomy. Breast J. 2008;14:25-32

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  • [1]

    Jemal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin 2010;60(5):277e300.

    • Crossref
    • Export Citation
  • [2]

    Cancer Research UK Cancer incidence - UK statistics. Available from: http://info.cancerresearchuk.org/cancerstats/incidence/; 2011

  • [3]

    Howlader N, Noone AM, Krapcho M, et al., eds. SEER cancer statistics review, 1975-2010. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, 2013, 2012

  • [4]

    Anders CK, Hsu DS, Broadwater G, et al. Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol. 2008;26(20): 3324-3330.

    • Crossref
    • Export Citation
  • [5]

    ElSaghir NS, SeoudM, KhalilMK, etal. Effects of young age at presentation on survival in breast cancer. BMC Cancer. 2006;6:194.

    • Crossref
    • Export Citation
  • [6]

    Hartley MC, McKinley BP, Rogers EA, et al. Differential expression of prognostic factors and effect on survival in young (o or yi40) breast cancer patients: a case-control study. Am Surg. 2006;72(12):1189-1194 discussion 94-95

  • [7]

    Partridge AH, GelberS, Peppercorn J, Sampson E, Knudsen K, Laufer M, etal. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004;22(20):4174e83.

    • Crossref
    • Export Citation
  • [8]

    Gluhoski VL, Siegel K, Gorey E. Unique stressors experienced by unmarried women with breast cancer. J Psychosoc Oncol 1998;15(3e4):173e83.

    • Crossref
    • Export Citation
  • [9]

    National Institutes of Health. Treatment of early-stage breast cancer. June 18-211990. JAMA. 1991;265:391-395

  • [10]

    Neuburger J, Macneill F, Jeevan R, et al. Trends in the use of bilateral mastectomy in England from 2002 to 2011: retrospective analysis of hospital episode statistics. BMJ Open. 2013;3:e003179

  • [11]

    Dragun AE, Huang B, Tucker TC, et al. Increasing mastectomy rates among all age groups for early stage breast cancer: a 10-year study of surgical choice. Breast J. 2012;18:318-325

  • [12]

    Maretoja TJ, Rasia S, Von Smitten KA, et al. Late results of skin-sparing mastectomy followed by immediate breast reconstruction. Br J Surg 2007;94:1220-1225

  • [13]

    Michailidou K, Holm NV, Verkasalo PK, et al. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet. 2015;47(4):373-380

  • [14]

    Michailidou K, Hall P, Gonzalez-Neira A, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353-361, 361. e1-e2

  • [15]

    Quan G, PommierSJ, Pommier RF. Incidence and outcomes of contralateral breast cancers. Am J Surg. 2008;195(5):645-650; discussion 650

  • [16]

    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;102:401-409

  • [17]

    Stucky CC, Gray RJ, Wasif N, DueckAC, Pockaj BA. Increase in contralateral prophylactic mastectomy: echoes of a bygone era? Surgical trends for unilateral breast cancer. Ann Surg Oncol. 2010;17 Suppl 3:330-337

  • [18]

    Yao K, Stewart AK, Winchester DJ, Winchester DP. Trends in contralateral prophylactic mastectomy for unilateral cancer: a report from the National Cancer Data Base, 1998-2007. Ann Surg Oncol. 2010;17:2554-2562.

  • [19]

    McLaughlin CC, Lillquist PP, Edge SB, Surveillance of prophylactic mastectomy: trends in use from 1995 through 2005. Cancer. 2009;115:5404-5412

  • [20]

    Tuttle TM, JarosekS, Habermann EB, Arrington A, Abraham A, Morris TJ, et al. Increasing rates of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ. J Clin Oncol. 2009;27:1362-1367

  • [21]

    Tuttle TM, Habermann EB, Grund EH, Morris TJ, VirnigBA. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol. 2007;25:5203-5209

  • [22]

    Hoover DJ, Paragi PR, Santoro E, Schafer S, Chamberlain RS. Prophylactic mastectomy in high risk patients: a practice-based review of the indications. Do we follow guidelines? Breast Dis. 2010;31:19-27

  • [23]

    DamleS, TealCB, LenertJJ, Marshall EC, Pan Q, McSwain AP. Mastectomy and contralateral prophylactic mastectomy rates: an institutional review. Ann Surg Oncol. 2011;18:1356-1363

  • [24]

    Yi M, Hunt KK, Arun BK, Bedrosian I, Barrera AG, Do KA, et al. Factors affecting the decision of breast cancer patients to undergo contralateral prophylactic mastectomy. Cancer Prev Res (Phila). 2010;3:1026-1034

  • [25]

    Sorbero ME, DickAW, Beckjord EB, Ahrendt G. Diagnostic breast magnetic resonance imaging and contralateral prophylactic mastectomy. Ann Surg Oncol. 2009;16:1597-1605

  • [26]

    King TA, Sakr R, PatilS, Gurevich I, Stempel M, Sampson M, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol. 2011;29: 2158-2164

  • [27]

    Quan G, Pommier SJ, Pommier RF. Incidence and outcomes of contralateral breast cancers. Am J Surg. 2008;195:645-50; discussion 650

  • [28]

    BougheyJC, HoskinTL, 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;17:2702-2709

  • [29]

    Chung A, Huynh K, Lawrence C, Sim MS, Giuliano A. Comparison of patient characteristics and outcomes of contralateral prophylactic mastectomy and unilateral total mastectomy in breast cancer patients. Ann Surg Oncol. 2012;19(8):2600-2606

  • [30]

    Roberts A, Sandhu L, CilTD, Hofer SO, ZhongT. Contralateral prophylactic mastectomy rate stable at major Canadian breast cancer center. World J Clin Oncol. 2016 Jun 10;7(3):302-307

  • [31]

    Ager B, Butow P, Jansen J, Phillips KA, Porter D; CPM DA Advisory Group. Contralateral prophylactic mastectomy (CPM): A systematic review of patient reported factors and psychological predictors influencing choice and satisfaction. Breast. 2016 Jun 8;28:107-120

  • [32]

    Roukos DH, Kappas AM, Tsianos E. Role of surgery in the prophylaxis of hereditary cancer syndromes. Annals of surgical oncology 2002;9(7):607-609

  • [33]

    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. British Journal of Cancer 2005;93(3):287-292

  • [34]

    Lise M, Zavagno G, Meggiolaro F. Prophylactic mastectomy in women at high risk of breast cancer. Forum 1997;7.1(2 Suppl):112-116

  • [35]

    Lostumbo L, Carbine NE, WallaceJ. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev. 2010:(11):CD002748

  • [36]

    Miller ME, Czechura T, Martz B, et a l. Operative risks associated with contralateral prophylactic mastectomy: a single institution experience. Ann Surg Oncol. 2013;20:4113-4120

  • [37]

    Brummett CM. Chronic pain following breast surgery. Tech Reg Anesth Pain Manag. 2011;15:124-132

  • [38]

    Altschuler A, Nekhlyudov L, Rolnick SJ, et al. Positive, negative, and disparate: women’s differing long-term psychosocial experiences of bilateral or contralateral prophylactic mastectomy. Breast J. 2008;14:25-32

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