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2 Mutation Carriers?
Clinical Oncology 28 (2016) 223e224 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Commentary
Is Breast-conserving Therapy Really a Good Option for BRCA1/2 Mutation Carriers? M.P. Nilsson, N. Loman Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden Received 22 September 2015; received in revised form 24 September 2015; accepted 29 September 2015
In a recent issue of Clinical Oncology, Hallam et al. [1] summarised the results of studies of wide local excision followed by postoperative radiotherapy (breast-conserving therapy; BCT) for BRCA1/2 mutation carriers. Their systematic review was comprehensive and detailed regarding the reported risks of in-breast tumour recurrence (IBTR). As no randomised or even prospective trials were included, any conclusions must be made very cautiously. We agree with the authors that further large prospective trials are required. However, the authors also concluded that they found no robust evidence of increased rates of IBTR after BCT in mutation carriers. Does this lack of robust evidence mean that BCT should be considered an acceptable option for mutation carriers? We would like to add some points to consider. In medicine, some treatments have evolved from a standard one to a more intense, and more effective, treatment. An example of that is the addition of trastuzumab to adjuvant chemotherapy for HER2-positive breast cancer [2]. Other treatments have evolved from a standard one to a less intense, or less radical, but equally effective and thus noninferior, treatment. Both of these scenarios usually require randomised controlled trials (RCTs) before any shifts from the standard treatments are taken. For a long time, mastectomy was the standard local treatment of breast cancer. Then, well-designed and sufficiently powered RCTs convincingly showed that BCT is an equally effective treatment in the general breast cancer population [3,4]. In many countries, the standard treatment for early stage breast cancer therefore shifted from mastectomy to BCT. However, given the strikingly increased risk of cancer, we believe that BRCA1/2 mutation carriers with breast cancer are too different from other breast cancer
DOI of original article: http://dx.doi.org/10.1016/j.clon.2015.06.001.
Author for correspondence: M.P. Nilsson, Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. E-mail address: [email protected] (M.P. Nilsson).
patients for the results of the RCTs to be automatically generalised to them. An RCT comparing BCT with mastectomy in mutation carriers will probably never be carried out. Then, two other options remain. The conservative approach is to say that, because of lack of evidence, the standard treatment (which was mastectomy) should not be changed. The alternative approach is to try to make extrapolations from observational studies of BCT and from studies that have investigated related issues, such as contralateral breast cancer and the effect of adjuvant therapy. The observational studies of BCT for mutation carriers presented to date were all relatively small in sample size and had too short a follow-up time to estimate lifetime risks of IBTR. Studies with longer follow-up seem to show an increased risk of IBTR for mutation carriers compared with non-carriers [5]. In a study from our group comparing BCT with mastectomy in mutation carriers (published after the reviewed studies were collected), we found a 15 year cumulative incidence of IBTR of 32% after BCT [6]. A BRCA1/2 mutation carrier who has had breast cancer is at a very high risk for a new primary breast cancer in the contralateral breast [7]. The annual risk of contralateral breast cancer for a mutation carrier is around 3%, compared with 0.5% in the general breast cancer population [8]. After BCT, breast tissue is left in the treated breast for tumour development. Various adjuvant treatments such as radiotherapy, chemotherapy and hormonal interventions reduce the risk of ipsilateral events, but whether that protective effect is sustained after more than 15e20 years is unclear and may be questionable. An IBTR could be either a true local recurrence or a new primary cancer; most studies have not been able to differentiate between those, and both are denominated IBTR. The rate of true local recurrences after BCT is probably similar between mutation carriers and non-carriers. However, the rate of new primary cancers is probably higher e maybe
http://dx.doi.org/10.1016/j.clon.2015.10.002 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
224
M.P. Nilsson, N. Loman / Clinical Oncology 28 (2016) 223e224
much higher e in mutation carriers. Such a difference is probably evident first after more than 10 years of follow-up. Therefore, a 10 year rate of IBTR cannot be considered a good end point, and not a valid surrogate end point for a long-term outcome, for the evaluation of BCT in BRCA1/2 mutation carriers. These patients are often young at the time of diagnosis, so their life expectancy is hopefully another 40e50 years. Implications on cancer-specific distress, body image and sexuality can vary after BCT and mastectomy. Therefore, personal preferences also have to be taken into account when decisions about the type of surgery are taken. Still, for almost all patients, the risk of recurrence and survival are the most important end points. For BRCA1 and BRCA2 mutation carriers, a survival benefit associated with prophylactic mastectomy and contralateral prophylactic mastectomy has begun to emerge [9,10]. If the lifetime risk for new primary ipsilateral breast cancers is high after BCT, in the long run, one could also expect a survival benefit associated with mastectomy compared with BCT.
References [1] Hallam S, Govindarajulu S, Huckett B, Bahl A. BRCA1/2 mutation-associated breast cancer, wide local excision and radiotherapy or unilateral mastectomy: a systematic review. Clin Oncol 2015;27(9):527e535.
[2] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. New Engl J Med 2005;353(16):1659e1672. [3] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med 2002;347(16):1233e1241. [4] Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year followup of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med 2002;347(16):1227e1232. [5] Valachis A, Nearchou AD, Lind P. Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis. Breast Cancer Res Treat 2014;144(3):443e455. [6] Nilsson MP, Hartman L, Kristoffersson U, et al. High risk of inbreast tumor recurrence after BRCA1/2-associated breast cancer. Breast Cancer Res Treat 2014;147(3):571e578. [7] Narod SA, Tung N, Lubinski J, et al. A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers. Curr Oncol 2014;21(2):64e68. [8] Narod SA. Bilateral breast cancers. Nat Rev Clin Oncol 2014;11(3):157e166. [9] Heemskerk-Gerritsen BA, Menke-Pluijmers MB, Jager A, et al. Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis. Ann Oncol 2013;24(8):2029e2035. [10] Metcalfe K, Gershman S, Ghadirian P, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. Br Med J 2014;348:g226.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Commentary
Is Breast-conserving Therapy Really a Good Option for BRCA1/2 Mutation Carriers? M.P. Nilsson, N. Loman Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden Received 22 September 2015; received in revised form 24 September 2015; accepted 29 September 2015
In a recent issue of Clinical Oncology, Hallam et al. [1] summarised the results of studies of wide local excision followed by postoperative radiotherapy (breast-conserving therapy; BCT) for BRCA1/2 mutation carriers. Their systematic review was comprehensive and detailed regarding the reported risks of in-breast tumour recurrence (IBTR). As no randomised or even prospective trials were included, any conclusions must be made very cautiously. We agree with the authors that further large prospective trials are required. However, the authors also concluded that they found no robust evidence of increased rates of IBTR after BCT in mutation carriers. Does this lack of robust evidence mean that BCT should be considered an acceptable option for mutation carriers? We would like to add some points to consider. In medicine, some treatments have evolved from a standard one to a more intense, and more effective, treatment. An example of that is the addition of trastuzumab to adjuvant chemotherapy for HER2-positive breast cancer [2]. Other treatments have evolved from a standard one to a less intense, or less radical, but equally effective and thus noninferior, treatment. Both of these scenarios usually require randomised controlled trials (RCTs) before any shifts from the standard treatments are taken. For a long time, mastectomy was the standard local treatment of breast cancer. Then, well-designed and sufficiently powered RCTs convincingly showed that BCT is an equally effective treatment in the general breast cancer population [3,4]. In many countries, the standard treatment for early stage breast cancer therefore shifted from mastectomy to BCT. However, given the strikingly increased risk of cancer, we believe that BRCA1/2 mutation carriers with breast cancer are too different from other breast cancer
DOI of original article: http://dx.doi.org/10.1016/j.clon.2015.06.001.
Author for correspondence: M.P. Nilsson, Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. E-mail address: [email protected] (M.P. Nilsson).
patients for the results of the RCTs to be automatically generalised to them. An RCT comparing BCT with mastectomy in mutation carriers will probably never be carried out. Then, two other options remain. The conservative approach is to say that, because of lack of evidence, the standard treatment (which was mastectomy) should not be changed. The alternative approach is to try to make extrapolations from observational studies of BCT and from studies that have investigated related issues, such as contralateral breast cancer and the effect of adjuvant therapy. The observational studies of BCT for mutation carriers presented to date were all relatively small in sample size and had too short a follow-up time to estimate lifetime risks of IBTR. Studies with longer follow-up seem to show an increased risk of IBTR for mutation carriers compared with non-carriers [5]. In a study from our group comparing BCT with mastectomy in mutation carriers (published after the reviewed studies were collected), we found a 15 year cumulative incidence of IBTR of 32% after BCT [6]. A BRCA1/2 mutation carrier who has had breast cancer is at a very high risk for a new primary breast cancer in the contralateral breast [7]. The annual risk of contralateral breast cancer for a mutation carrier is around 3%, compared with 0.5% in the general breast cancer population [8]. After BCT, breast tissue is left in the treated breast for tumour development. Various adjuvant treatments such as radiotherapy, chemotherapy and hormonal interventions reduce the risk of ipsilateral events, but whether that protective effect is sustained after more than 15e20 years is unclear and may be questionable. An IBTR could be either a true local recurrence or a new primary cancer; most studies have not been able to differentiate between those, and both are denominated IBTR. The rate of true local recurrences after BCT is probably similar between mutation carriers and non-carriers. However, the rate of new primary cancers is probably higher e maybe
http://dx.doi.org/10.1016/j.clon.2015.10.002 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
224
M.P. Nilsson, N. Loman / Clinical Oncology 28 (2016) 223e224
much higher e in mutation carriers. Such a difference is probably evident first after more than 10 years of follow-up. Therefore, a 10 year rate of IBTR cannot be considered a good end point, and not a valid surrogate end point for a long-term outcome, for the evaluation of BCT in BRCA1/2 mutation carriers. These patients are often young at the time of diagnosis, so their life expectancy is hopefully another 40e50 years. Implications on cancer-specific distress, body image and sexuality can vary after BCT and mastectomy. Therefore, personal preferences also have to be taken into account when decisions about the type of surgery are taken. Still, for almost all patients, the risk of recurrence and survival are the most important end points. For BRCA1 and BRCA2 mutation carriers, a survival benefit associated with prophylactic mastectomy and contralateral prophylactic mastectomy has begun to emerge [9,10]. If the lifetime risk for new primary ipsilateral breast cancers is high after BCT, in the long run, one could also expect a survival benefit associated with mastectomy compared with BCT.
References [1] Hallam S, Govindarajulu S, Huckett B, Bahl A. BRCA1/2 mutation-associated breast cancer, wide local excision and radiotherapy or unilateral mastectomy: a systematic review. Clin Oncol 2015;27(9):527e535.
[2] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. New Engl J Med 2005;353(16):1659e1672. [3] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. New Engl J Med 2002;347(16):1233e1241. [4] Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year followup of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. New Engl J Med 2002;347(16):1227e1232. [5] Valachis A, Nearchou AD, Lind P. Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis. Breast Cancer Res Treat 2014;144(3):443e455. [6] Nilsson MP, Hartman L, Kristoffersson U, et al. High risk of inbreast tumor recurrence after BRCA1/2-associated breast cancer. Breast Cancer Res Treat 2014;147(3):571e578. [7] Narod SA, Tung N, Lubinski J, et al. A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers. Curr Oncol 2014;21(2):64e68. [8] Narod SA. Bilateral breast cancers. Nat Rev Clin Oncol 2014;11(3):157e166. [9] Heemskerk-Gerritsen BA, Menke-Pluijmers MB, Jager A, et al. Substantial breast cancer risk reduction and potential survival benefit after bilateral mastectomy when compared with surveillance in healthy BRCA1 and BRCA2 mutation carriers: a prospective analysis. Ann Oncol 2013;24(8):2029e2035. [10] Metcalfe K, Gershman S, Ghadirian P, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. Br Med J 2014;348:g226.