REVIEWS Bilateral breast cancers Steven A. Narod Abstract | An increasingly large proportion of women with unilateral breast cancer are treated with bilateral mastectomy. The rationale behind bilateral surgery is to prevent a second primary breast cancer and thereby to avoid the resultant therapy and eliminate the risk of death from contralateral breast cancer. Bilateral mastectomy has been proposed to benefit women at high risk of contralateral cancer, such as carriers of BRCA1 and BRCA2 mutations, but for women without such mutations, the decision to remove the contralateral breast is controversial. It is important to evaluate the risk of contralateral breast cancer on an individual basis, and to tailor surgical treatment accordingly. On average, the annual risk of contralateral breast cancer is approximately 0.5%, but increases to 3% in carriers of a BRCA1 or BRCA2 mutation. Risk factors for contralateral breast cancer include a young age at first diagnosis of breast cancer and a family history of breast cancer. Contralateral mastectomy has not been proven to reduce mortality from breast cancer, but the benefit of such surgery is not expected to become apparent until the second decade after treatment. An alternative to contralateral mastectomy is adjuvant hormonal therapy (such as tamoxifen), but the extent of risk reduction is smaller (approximately 50%) compared to 95% or more for contralateral mastectomy. This Review focuses on the risk factors for contralateral breast cancer, and discusses the evidence that bilateral mastectomy might reduce mortality in patients with unilateral breast cancer. Narod, S. A. Nat. Rev. Clin. Oncol. 11, 157–166 (2014); published online 4 February 2014; doi:10.1038/nrclinonc.2014.3
Introduction
Women’s College Research Institute, Women’s College Hospital, 790 Bay Street, Toronto, ON M5G 1N8, Canada. steven.narod@ wchospital.ca
Surgical treatment of breast cancer has evolved since 1980 in response to advances in clinical research, as well as changes in the wishes of cancer patients, and their willingness to advocate for themselves.1 As a result, the shift in procedure from unilateral mastectomy to lumpectomy, a trend that was evident throughout the 1980s and 1990s, is being largely reversed by an increase in the rates of bilateral mastectomy in cancer patients who might have otherwise been treated with breast-conserving surgery.2 In March 2013, CNN reporters questioned why the rates of bilateral mastectomy for unilateral breast cancer should be increasing.3 The CNN reporters claimed that the number of women with early-stage breast cancer treated at the MD Anderson Cancer Center who opted for removal of both breasts (even though only one was affected by cancer) increased by more than 150% between 1998 and 2003.3 The increase in the past 3 years has been particularly steep; 8.0% of patients sought prophylactic removal of their unaffected breast in 2010, 12.6% in 2011 and 14.1% in 2012. According to data from the Surveillance Epidemiology and End Results (SEER) registry, the US national proportions of breast cancer patients undergoing bilateral mastectomy were 1.8% in 1998 and 4.5% in 2003.4 At New York’s Memorial Sloan– Kettering Cancer Center, the percentage of women with cancer in one breast who chose to have both breasts removed went from 6.7% in 1997 to 24% in 2005.5 This sharp rise does not reflect an increased aggressiveness Competing interests The author declares no competing interests.
of approach by the surgeons at the hospital, but rather increased willingness on their part to respect their patients’ preferences.1 The main purpose of contralateral mastectomy is to prevent a second primary cancer and, subsequently, death from a second cancer. It is desirable to avoid a second round of treatment and the accompanying patient’s distress, but it is of primary importance to know whether contralateral mastectomy prevents death. Presumably, any death prevented through contra lateral mastectomy will be from the second (not the first) primary breast cancer. A woman who is consider ing having a preventative procedure will, therefore, need to know her personal risk of developing a second primary breast cancer, whether a contralateral mastectomy will prevent it, and whether bilateral surgery will reduce mortality. In this Review, I discuss the current risks of contra lateral cancer, the various factors that influence these risks, and the evidence that bilateral mastectomy will reduce mortality in patients with unilateral breast cancer. For brevity, I focus on incidence and mortality. I do not discuss other relevant factors (such as the financial costs and benefits of the surgery, quality of life, psychological distress, breast reconstruction or the morbidity related to a second round of treatment), as these topics have been covered elsewhere.1,6
Classification of bilateral cancers Bilateral breast cancers are divided into synchronous (when cancers in both breasts develop simultaneously)
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MARCH 2014 | 157 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ On average, the annual risk of contralateral breast cancer following a diagnosis of breast cancer is 0.5%, but this risk varies between individuals ■■ A young age at first diagnosis is associated with a very high relative risk of contralateral breast cancer ■■ The risk of contralateral breast cancer is increased in women with mutations in BRCA1, BRCA2, CHEK2 or a strong family history of breast cancer ■■ The reduction in mortality associated with contralateral mastectomy is a consequence of the prevention of deaths from contralateral cancer ■■ Risk assessment for contralateral breast cancer is appropriate before recommending contralateral mastectomy
Classification ofcontralateral breast cancer Synchronous When cancer in both breast develop simultaneously
Risk factors 1
Contralateral breast cancer 3
Asynchronous When cancer in both breast develop at different times
?
Bilateral mastectomy
2
Age at diagnosis Mutations (BRCA1, BRCA2, CHEK2) and SNPs Family history Regular alcohol consumption Tumour histology
Figure 1 | Contralateral breast cancer. (1) Contralateral breast cancers are divided into synchronous and asynchronous based on the period of time when the cancers in both breasts develop. (2) The risk factors contributing to bilateral breast cancer are age at diagnosis, germline mutations (such as BRCA1 and BRCA2), family history, tumour histology and regular alcohol consumption. (3) In clinical practice, in terms of mortality it is not yet clear if an individual woman would benefit from having a bilateral mastectomy.
and asynchronous, also termed metachronous (when cancers in each breast develop at different times [Figure 1]). For the purpose of this Review, contralateral cancers are considered to be second primary tumours, although in some patients the second cancer might represent a metastatic event;7 this assumption is consistent with (and an extension of) the self-seeding model of carcinogenesis.8 If bilateral cancers resulted from metastasis, one would expect contralateral cancers to be more common in women with large, node-positive cancers than in women with small node-negative cancers and, moreover, that the clinical course of women with bilateral (synchronous or asynchronous) breast cancer would be similar to that of women with metastatic (stage IV) breast cancers. This is not the case; the prognosis of women with bilateral cancer is not much worse than that of women with unilateral cancer.9,10 Second, the high degree of concordance observed between bilateral cancers for the presence of an extensive ductal carcinoma in situ component argues against a single cell of origin.11 Finally, molecular studies show that the mutation status of bilateral cancers tends to be discordant (discussed further below), which also argues against a common origin and, therefore, against a metastatic event. Synchronous bilateral cancers can be further sub divided into two groups. The first group consists of cancers with signs or symptoms present in both breasts, and the second group consists of contralateral cancers that are not palpable and are diagnosed only as a result of imaging studies precipitated by the initial diagnosis. It is possible that in the absence of such screening, the second cancer might have been diagnosed at a later date, and classified as asynchronous. Some clinicians classify 158 | MARCH 2014 | VOLUME 11
bilateral breast cancers as asynchronous if their detection is separated in time by 1 year or longer, but this definition is not standard, and others have proposed that shorter intervals are appropriate. 9,12 The proportion of cancers that present bilaterally depends largely on the extent of imaging that is conducted at the time of diagnosis. Various studies estimate the prevalence of contralateral cancer identified by MRI to be 2–6%.13–15 The results of a meta-analysis 13 showed that when MRI-based screening was employed, a contralateral cancer was found in 4% of 3,253 women, two-thirds of whom had invasive cancers and one-third had ductal carcinoma in situ. Assuming that the true prevalence of contralateral breast cancers at diagnosis is in fact 4%, this value is considerably higher than the reported incidence of contralateral breast cancer (0.5% per year).16 Given the relatively high prevalence and relatively low incidence rates, either many subclinical contralateral cancers could be detectable by MRI up to 8 years before clinical presentation, or they might regress spontaneously (overdiagnosis). It is also possible that some subclinical contralateral cancers might regress in response to treatment of the clinically-identified breast cancer. Currently, no guidelines recommend the use of MRI to identify a contralateral breast cancer at the time of diagnosis (or soon thereafter), owing to the fact that such screening has not yet been shown to reduce mortality. In what can appear as a paradox, a surgeon will consider doing a contralateral mastectomy to prevent a possible future cancer, yet does not expect to see a mortality benefit from identifying and removing an existing tumour. It is, however, standard practice to recommend screening with bilateral mammography (but not with MRI) in the routine follow-up of a patient with breast cancer, to identify an asynchronous nonpalpable cancer.17 In this respect, it would be useful to have an accurate estimate of how many nonpalpable contralateral cancers represent overdiagnoses or adversely affect survival. In a large observational study from Italy, 589 women who developed a contralateral breast cancer were followed for a median of 14 years.18 Mortality was much lower for women with a nonpalpable rather than palpable second primary cancer (HR 0.53, 95% CI 0.40–0.72). The authors interpreted these data as evidence that screening for second primary cancers reduces mortality through early detection; however, another plausible interpretation is that detection of the nonpalpable cancers represents overdiagnosis. Furthermore, in another study, having an MRI examination of the contralateral breast at diagnosis did not result in a diminution in the risk of contralateral breast cancer or death from breast cancer thereafter.19 The latter finding, however, is not surprising given the relatively short duration of this trial (median follow-up 4.6 years).
Risk of contralateral breast cancer The incidence of first primary breast cancer varies widely from country to country,20 but unfortunately very little is known about the risk of contralateral breast cancer.
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Most of the large cohort studies are from North America and Europe (Sweden in particular) and the rates reported therein might not be applicable to other countries, especially those with a low incidence of primary breast cancer. Furthermore, a proportion of the patients in all studies can be expected to have received tamoxifen as adjuvant treatment, and thereby to have a reduced risk of contralateral breast cancer. Finally, the annual risk might depend on the age distribution of the patients studied and the duration of the follow-up period used to calculate the annual rate, as is evident from the studies described here. For example, in one study from Sweden, the risk of contralateral breast cancer at 10 years from diagnosis was estimated to be 8% in postmenopausal patients who did not receive tamoxifen,21 whereas in another study from Sweden, the annual risk of asynchronous contralateral cancer was 0.4%, based on a 30-year follow-up period.9 In a third Swedish study, the average annual risk of contralateral cancer from diagnosis until age 80 was 0.6%.22 The annual risk was not constant at all ages—the peak incidence of contralateral breast cancer (0.9% per year) occurred in the 30–34 years age group.22 Similarly, in a large study of patients with breast cancer of all ages from the Netherlands, the risk of contralateral cancer in a 6-year follow-up period was estimated to be 0.4% per year.10 Finally, in a review of 16 cohort studies, reported annual rates of contralateral cancer ranged from 0.4% to 0.8%.16 Although none of these estimates for the annual or cumulative risk of contralateral cancer can be used as a single reference value (or baseline), the range of published estimates is reasonably narrow, and most fall within 0.3–0.8% per annum. For simplicity, I assume the annual risk of contralateral cancer to be 0.5%. The annual risk of contralateral cancer depends on a number of factors (Box 1, Figure 1), which are di scussed in detail below.
Age at diagnosis The findings of several studies indicate that the risk of developing a contralateral cancer decreases with increasing age at diagnosis of the first cancer. In Sweden, women aged 30–34 years had a higher risk of contralateral cancer than did postmenopausal women.22 The effect of young age is dramatic when expressed in terms of relative risk rather than annual risk (that is, when compared with the risk of a woman in the general population of the same age of developing a first breast cancer). For example, in a population-based study from the Netherlands, the standardized incidence ratio (SIR) of contralateral breast cancer was 11.4 for women aged under 35 years and 1.5 for women aged 60 years or older.10 In a detailed study, the relative risk of all contra lateral breast cancers was 2.46 (95% CI 2.40–2.52). 23 Among women with hormone-receptor-positive breast cancer, the hazard ratio for contralateral breast cancer was much higher for women aged ≤30 years at first diagnosis, (43.8, 95% CI 27.1–66.9) than for those age 70 years at diagnosis (1.85, 95% CI 1.74–1.96).23 Women diagnosed with hormone-receptor-negative breast cancer by age 30 years also had a greatly elevated risk
Box 1 | Risk factors for contralateral breast cancer ■■ ■■ ■■ ■■ ■■ ■■ ■■
Patient-related factors Early age at diagnosis Family history of cancer: 10-year risk 10–15%* Tumour-related factors Lobular histology BRCA1 or BRCA2 mutation: 10-year risk 25–30% CHEK2 mutation: 10-year risk 10–20%
*Versus 5–8% in patients without a family history of cancer.
of a second hormone-receptor-negative cancer (SIR 169, 95% CI 106–256).23 The effect of a young age at diagnosis of breast cancer, expressed in terms of relative risk of developing contralateral breast cancer, is of interest for understanding the nature of susceptibility, but in practical terms, the absolute risk of bilateral cancer is more relevant to the decision to undergo a contralateral mastectomy.
Presence of mutations For the purpose of counselling women with regard to contralateral mastectomy, patients with mutations associated with breast cancer can be divided into those carrying a BRCA1 or BRCA2 mutation and those carry ing a CHEK2 mutation. Rare germline mutations do occur in other genes,24 but there is too little clinical information for a discussion of them to be included in this Review. BRCA1 and BRCA2 Among BRCA1 and BRCA2 mutation carriers, the risk of contralateral breast cancer is about 2.5% per year, or approximately 36% in the 15-year period following an initial diagnosis.25,26 The risk of contralateral breast cancer is estimated to be increased by 4.5-fold and 3.4-fold in the presence of a BRCA1 or BRCA2 mutation, respectively.27 Surprisingly, in two large studies of BRCA1 and BRCA2 mutation carriers, the risk of contra lateral breast cancer exceeded that of the first primary cancer, suggesting the presence of risk-modifying factors that are presumably enriched among women diagnosed with a first cancer.26,28 Indeed, several factors influence the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2 mutations, including age at first diagnosis of cancer,25,29 a family history of breast cancer,25 oophorectomy 25,26 and tamoxifen treatment.25,30,31 In a large study of BRCA1 mutation carriers from Germany, the cumulative risk of contralateral breast cancer at 25 years of follow-up was 63% for women who were younger than 40 years of age at first diagnosis of breast cancer, compared to 20% for those who were older than 50 years of age.29 The importance of this effect of age at diagnosis on risk of contralateral breast cancer was confirmed in another study involving a cohort of 810 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation.25 After 15 years of follow-up, the cumulative risk of contralateral breast cancer was 36% for women with a BRCA1 mutation and 29% for women with a BRCA2 mutation.25 The risk was 38% for women aged
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MARCH 2014 | 159 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS ≤50 years at the time of breast cancer diagnosis, compared with 17% for those aged >50 years (P = 0.003). In this study, among women aged 30 kg/m2) was a risk factor for contralateral breast cancer among postmenopausal women with oestrogen receptor (ER)-negative first primary tumours (RR 5.64, 95% CI 1.76–18.1), when compared with women whose body weight was in the low or normal range (BMI ≤25 kg/m2).51 However, among premenopausal women, or postmenopausal women with ER‑positive first primary cancers, no association between BMI and contralateral breast cancer risk was seen.51 Benign disease Assuming that women with bilateral breast cancer represent a subgroup of highly predisposed women, and that benign disease is a precursor to breast cancer, then we might expect benign predisposing conditions to be more prevalent among women with bilateral breast cancer than among women with unilateral breast cancer. This suggestion does not seem to be true. For example, one study failed to show that an extensive ductal carcinoma in situ component was a characteristic feature of bilateral breast cancer.11 High breast density is an established risk factor for both breast cancer 52 and local recurrence,53 but this risk factor has not been studied in detail with regard to the risk of contralateral cancer. However, a decline in breast density after diagnosis of cancer, achieved through menopause or tamoxifen use, has been associated with a decreased risk of contralateral breast cancer.54 Treatment Several treatments for breast cancer have the potential to modify the risk of cancer in the opposite breast,
including tamoxifen, aromatase inhibitors, various chemotherapeutic agents and radiotherapy.21,55–58 Both tamoxifen and aromatase inhibitors substantially reduce the risk of contralateral breast cancer. A standard course of tamoxifen is associated with a reduction of approximately 50% in the risk of contralateral breast cancer, and the decrease in risk lasts for at least 15 years.21,55 Hormonal therapy was associated with a 43% reduction in the risk of contralateral breast cancer (HR 0.57, P
Introduction
Women’s College Research Institute, Women’s College Hospital, 790 Bay Street, Toronto, ON M5G 1N8, Canada. steven.narod@ wchospital.ca
Surgical treatment of breast cancer has evolved since 1980 in response to advances in clinical research, as well as changes in the wishes of cancer patients, and their willingness to advocate for themselves.1 As a result, the shift in procedure from unilateral mastectomy to lumpectomy, a trend that was evident throughout the 1980s and 1990s, is being largely reversed by an increase in the rates of bilateral mastectomy in cancer patients who might have otherwise been treated with breast-conserving surgery.2 In March 2013, CNN reporters questioned why the rates of bilateral mastectomy for unilateral breast cancer should be increasing.3 The CNN reporters claimed that the number of women with early-stage breast cancer treated at the MD Anderson Cancer Center who opted for removal of both breasts (even though only one was affected by cancer) increased by more than 150% between 1998 and 2003.3 The increase in the past 3 years has been particularly steep; 8.0% of patients sought prophylactic removal of their unaffected breast in 2010, 12.6% in 2011 and 14.1% in 2012. According to data from the Surveillance Epidemiology and End Results (SEER) registry, the US national proportions of breast cancer patients undergoing bilateral mastectomy were 1.8% in 1998 and 4.5% in 2003.4 At New York’s Memorial Sloan– Kettering Cancer Center, the percentage of women with cancer in one breast who chose to have both breasts removed went from 6.7% in 1997 to 24% in 2005.5 This sharp rise does not reflect an increased aggressiveness Competing interests The author declares no competing interests.
of approach by the surgeons at the hospital, but rather increased willingness on their part to respect their patients’ preferences.1 The main purpose of contralateral mastectomy is to prevent a second primary cancer and, subsequently, death from a second cancer. It is desirable to avoid a second round of treatment and the accompanying patient’s distress, but it is of primary importance to know whether contralateral mastectomy prevents death. Presumably, any death prevented through contra lateral mastectomy will be from the second (not the first) primary breast cancer. A woman who is consider ing having a preventative procedure will, therefore, need to know her personal risk of developing a second primary breast cancer, whether a contralateral mastectomy will prevent it, and whether bilateral surgery will reduce mortality. In this Review, I discuss the current risks of contra lateral cancer, the various factors that influence these risks, and the evidence that bilateral mastectomy will reduce mortality in patients with unilateral breast cancer. For brevity, I focus on incidence and mortality. I do not discuss other relevant factors (such as the financial costs and benefits of the surgery, quality of life, psychological distress, breast reconstruction or the morbidity related to a second round of treatment), as these topics have been covered elsewhere.1,6
Classification of bilateral cancers Bilateral breast cancers are divided into synchronous (when cancers in both breasts develop simultaneously)
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MARCH 2014 | 157 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ On average, the annual risk of contralateral breast cancer following a diagnosis of breast cancer is 0.5%, but this risk varies between individuals ■■ A young age at first diagnosis is associated with a very high relative risk of contralateral breast cancer ■■ The risk of contralateral breast cancer is increased in women with mutations in BRCA1, BRCA2, CHEK2 or a strong family history of breast cancer ■■ The reduction in mortality associated with contralateral mastectomy is a consequence of the prevention of deaths from contralateral cancer ■■ Risk assessment for contralateral breast cancer is appropriate before recommending contralateral mastectomy
Classification ofcontralateral breast cancer Synchronous When cancer in both breast develop simultaneously
Risk factors 1
Contralateral breast cancer 3
Asynchronous When cancer in both breast develop at different times
?
Bilateral mastectomy
2
Age at diagnosis Mutations (BRCA1, BRCA2, CHEK2) and SNPs Family history Regular alcohol consumption Tumour histology
Figure 1 | Contralateral breast cancer. (1) Contralateral breast cancers are divided into synchronous and asynchronous based on the period of time when the cancers in both breasts develop. (2) The risk factors contributing to bilateral breast cancer are age at diagnosis, germline mutations (such as BRCA1 and BRCA2), family history, tumour histology and regular alcohol consumption. (3) In clinical practice, in terms of mortality it is not yet clear if an individual woman would benefit from having a bilateral mastectomy.
and asynchronous, also termed metachronous (when cancers in each breast develop at different times [Figure 1]). For the purpose of this Review, contralateral cancers are considered to be second primary tumours, although in some patients the second cancer might represent a metastatic event;7 this assumption is consistent with (and an extension of) the self-seeding model of carcinogenesis.8 If bilateral cancers resulted from metastasis, one would expect contralateral cancers to be more common in women with large, node-positive cancers than in women with small node-negative cancers and, moreover, that the clinical course of women with bilateral (synchronous or asynchronous) breast cancer would be similar to that of women with metastatic (stage IV) breast cancers. This is not the case; the prognosis of women with bilateral cancer is not much worse than that of women with unilateral cancer.9,10 Second, the high degree of concordance observed between bilateral cancers for the presence of an extensive ductal carcinoma in situ component argues against a single cell of origin.11 Finally, molecular studies show that the mutation status of bilateral cancers tends to be discordant (discussed further below), which also argues against a common origin and, therefore, against a metastatic event. Synchronous bilateral cancers can be further sub divided into two groups. The first group consists of cancers with signs or symptoms present in both breasts, and the second group consists of contralateral cancers that are not palpable and are diagnosed only as a result of imaging studies precipitated by the initial diagnosis. It is possible that in the absence of such screening, the second cancer might have been diagnosed at a later date, and classified as asynchronous. Some clinicians classify 158 | MARCH 2014 | VOLUME 11
bilateral breast cancers as asynchronous if their detection is separated in time by 1 year or longer, but this definition is not standard, and others have proposed that shorter intervals are appropriate. 9,12 The proportion of cancers that present bilaterally depends largely on the extent of imaging that is conducted at the time of diagnosis. Various studies estimate the prevalence of contralateral cancer identified by MRI to be 2–6%.13–15 The results of a meta-analysis 13 showed that when MRI-based screening was employed, a contralateral cancer was found in 4% of 3,253 women, two-thirds of whom had invasive cancers and one-third had ductal carcinoma in situ. Assuming that the true prevalence of contralateral breast cancers at diagnosis is in fact 4%, this value is considerably higher than the reported incidence of contralateral breast cancer (0.5% per year).16 Given the relatively high prevalence and relatively low incidence rates, either many subclinical contralateral cancers could be detectable by MRI up to 8 years before clinical presentation, or they might regress spontaneously (overdiagnosis). It is also possible that some subclinical contralateral cancers might regress in response to treatment of the clinically-identified breast cancer. Currently, no guidelines recommend the use of MRI to identify a contralateral breast cancer at the time of diagnosis (or soon thereafter), owing to the fact that such screening has not yet been shown to reduce mortality. In what can appear as a paradox, a surgeon will consider doing a contralateral mastectomy to prevent a possible future cancer, yet does not expect to see a mortality benefit from identifying and removing an existing tumour. It is, however, standard practice to recommend screening with bilateral mammography (but not with MRI) in the routine follow-up of a patient with breast cancer, to identify an asynchronous nonpalpable cancer.17 In this respect, it would be useful to have an accurate estimate of how many nonpalpable contralateral cancers represent overdiagnoses or adversely affect survival. In a large observational study from Italy, 589 women who developed a contralateral breast cancer were followed for a median of 14 years.18 Mortality was much lower for women with a nonpalpable rather than palpable second primary cancer (HR 0.53, 95% CI 0.40–0.72). The authors interpreted these data as evidence that screening for second primary cancers reduces mortality through early detection; however, another plausible interpretation is that detection of the nonpalpable cancers represents overdiagnosis. Furthermore, in another study, having an MRI examination of the contralateral breast at diagnosis did not result in a diminution in the risk of contralateral breast cancer or death from breast cancer thereafter.19 The latter finding, however, is not surprising given the relatively short duration of this trial (median follow-up 4.6 years).
Risk of contralateral breast cancer The incidence of first primary breast cancer varies widely from country to country,20 but unfortunately very little is known about the risk of contralateral breast cancer.
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Most of the large cohort studies are from North America and Europe (Sweden in particular) and the rates reported therein might not be applicable to other countries, especially those with a low incidence of primary breast cancer. Furthermore, a proportion of the patients in all studies can be expected to have received tamoxifen as adjuvant treatment, and thereby to have a reduced risk of contralateral breast cancer. Finally, the annual risk might depend on the age distribution of the patients studied and the duration of the follow-up period used to calculate the annual rate, as is evident from the studies described here. For example, in one study from Sweden, the risk of contralateral breast cancer at 10 years from diagnosis was estimated to be 8% in postmenopausal patients who did not receive tamoxifen,21 whereas in another study from Sweden, the annual risk of asynchronous contralateral cancer was 0.4%, based on a 30-year follow-up period.9 In a third Swedish study, the average annual risk of contralateral cancer from diagnosis until age 80 was 0.6%.22 The annual risk was not constant at all ages—the peak incidence of contralateral breast cancer (0.9% per year) occurred in the 30–34 years age group.22 Similarly, in a large study of patients with breast cancer of all ages from the Netherlands, the risk of contralateral cancer in a 6-year follow-up period was estimated to be 0.4% per year.10 Finally, in a review of 16 cohort studies, reported annual rates of contralateral cancer ranged from 0.4% to 0.8%.16 Although none of these estimates for the annual or cumulative risk of contralateral cancer can be used as a single reference value (or baseline), the range of published estimates is reasonably narrow, and most fall within 0.3–0.8% per annum. For simplicity, I assume the annual risk of contralateral cancer to be 0.5%. The annual risk of contralateral cancer depends on a number of factors (Box 1, Figure 1), which are di scussed in detail below.
Age at diagnosis The findings of several studies indicate that the risk of developing a contralateral cancer decreases with increasing age at diagnosis of the first cancer. In Sweden, women aged 30–34 years had a higher risk of contralateral cancer than did postmenopausal women.22 The effect of young age is dramatic when expressed in terms of relative risk rather than annual risk (that is, when compared with the risk of a woman in the general population of the same age of developing a first breast cancer). For example, in a population-based study from the Netherlands, the standardized incidence ratio (SIR) of contralateral breast cancer was 11.4 for women aged under 35 years and 1.5 for women aged 60 years or older.10 In a detailed study, the relative risk of all contra lateral breast cancers was 2.46 (95% CI 2.40–2.52). 23 Among women with hormone-receptor-positive breast cancer, the hazard ratio for contralateral breast cancer was much higher for women aged ≤30 years at first diagnosis, (43.8, 95% CI 27.1–66.9) than for those age 70 years at diagnosis (1.85, 95% CI 1.74–1.96).23 Women diagnosed with hormone-receptor-negative breast cancer by age 30 years also had a greatly elevated risk
Box 1 | Risk factors for contralateral breast cancer ■■ ■■ ■■ ■■ ■■ ■■ ■■
Patient-related factors Early age at diagnosis Family history of cancer: 10-year risk 10–15%* Tumour-related factors Lobular histology BRCA1 or BRCA2 mutation: 10-year risk 25–30% CHEK2 mutation: 10-year risk 10–20%
*Versus 5–8% in patients without a family history of cancer.
of a second hormone-receptor-negative cancer (SIR 169, 95% CI 106–256).23 The effect of a young age at diagnosis of breast cancer, expressed in terms of relative risk of developing contralateral breast cancer, is of interest for understanding the nature of susceptibility, but in practical terms, the absolute risk of bilateral cancer is more relevant to the decision to undergo a contralateral mastectomy.
Presence of mutations For the purpose of counselling women with regard to contralateral mastectomy, patients with mutations associated with breast cancer can be divided into those carrying a BRCA1 or BRCA2 mutation and those carry ing a CHEK2 mutation. Rare germline mutations do occur in other genes,24 but there is too little clinical information for a discussion of them to be included in this Review. BRCA1 and BRCA2 Among BRCA1 and BRCA2 mutation carriers, the risk of contralateral breast cancer is about 2.5% per year, or approximately 36% in the 15-year period following an initial diagnosis.25,26 The risk of contralateral breast cancer is estimated to be increased by 4.5-fold and 3.4-fold in the presence of a BRCA1 or BRCA2 mutation, respectively.27 Surprisingly, in two large studies of BRCA1 and BRCA2 mutation carriers, the risk of contra lateral breast cancer exceeded that of the first primary cancer, suggesting the presence of risk-modifying factors that are presumably enriched among women diagnosed with a first cancer.26,28 Indeed, several factors influence the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2 mutations, including age at first diagnosis of cancer,25,29 a family history of breast cancer,25 oophorectomy 25,26 and tamoxifen treatment.25,30,31 In a large study of BRCA1 mutation carriers from Germany, the cumulative risk of contralateral breast cancer at 25 years of follow-up was 63% for women who were younger than 40 years of age at first diagnosis of breast cancer, compared to 20% for those who were older than 50 years of age.29 The importance of this effect of age at diagnosis on risk of contralateral breast cancer was confirmed in another study involving a cohort of 810 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation.25 After 15 years of follow-up, the cumulative risk of contralateral breast cancer was 36% for women with a BRCA1 mutation and 29% for women with a BRCA2 mutation.25 The risk was 38% for women aged
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | MARCH 2014 | 159 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS ≤50 years at the time of breast cancer diagnosis, compared with 17% for those aged >50 years (P = 0.003). In this study, among women aged 30 kg/m2) was a risk factor for contralateral breast cancer among postmenopausal women with oestrogen receptor (ER)-negative first primary tumours (RR 5.64, 95% CI 1.76–18.1), when compared with women whose body weight was in the low or normal range (BMI ≤25 kg/m2).51 However, among premenopausal women, or postmenopausal women with ER‑positive first primary cancers, no association between BMI and contralateral breast cancer risk was seen.51 Benign disease Assuming that women with bilateral breast cancer represent a subgroup of highly predisposed women, and that benign disease is a precursor to breast cancer, then we might expect benign predisposing conditions to be more prevalent among women with bilateral breast cancer than among women with unilateral breast cancer. This suggestion does not seem to be true. For example, one study failed to show that an extensive ductal carcinoma in situ component was a characteristic feature of bilateral breast cancer.11 High breast density is an established risk factor for both breast cancer 52 and local recurrence,53 but this risk factor has not been studied in detail with regard to the risk of contralateral cancer. However, a decline in breast density after diagnosis of cancer, achieved through menopause or tamoxifen use, has been associated with a decreased risk of contralateral breast cancer.54 Treatment Several treatments for breast cancer have the potential to modify the risk of cancer in the opposite breast,
including tamoxifen, aromatase inhibitors, various chemotherapeutic agents and radiotherapy.21,55–58 Both tamoxifen and aromatase inhibitors substantially reduce the risk of contralateral breast cancer. A standard course of tamoxifen is associated with a reduction of approximately 50% in the risk of contralateral breast cancer, and the decrease in risk lasts for at least 15 years.21,55 Hormonal therapy was associated with a 43% reduction in the risk of contralateral breast cancer (HR 0.57, P
