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Optimal surgical management for high-risk populations
The Breast 24 (2015) S91eS95
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The Breast journal homepage: www.elsevier.com/brst
Original article
Optimal surgical management for high-risk populations Tari A. King*, Melissa Pilewskie, Monica Morrow Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 1 October 2015
The recognition that breast cancer is a group of genetically distinct diseases with differing responses to treatment and varying patterns of both local and systemic failure has led to many questions regarding optimal therapy for those considered to be high risk. Young patients, patients with triple-negative breast cancer (TNBC), and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. For both age and the triple-negative subtype, it appears that the intrinsic biology which imparts inferior outcomes is not overcome with mastectomy; therefore, a recommendation for more extensive surgical therapy among these higher-risk groups is not warranted. For those at inherited risk, a more-aggressive surgical approach may be preferable, however; patient age, ER status, stage of the index lesion, and individual patient preferences should all be considered in the surgical decision-making process. © 2015 Published by Elsevier Ltd.
Keywords: Breast cancer Young age Triple-negative subtype BRCA mutation
Introduction
Breast cancer in young women
The recognition that breast cancer is a group of genetically distinct diseases with differing responses to treatment and varying patterns of both local and systemic failure has led to many questions regarding optimal therapy for those considered to be high risk. Young patients, patients with triple-negative breast cancer (TNBC), and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. In addition, there is considerable overlap among these risk factors whereby up to 40% of women <40 years of age with TNBC will be found to harbor a BRCA mutation, adding to the complexity of surgical decision making. This article will summarize current evidence regarding the choice of local therapy and outcomes in these high-risk populations.
It is clear that young breast cancer patients experience higher rates of both local and distant recurrence; they frequently present with more-aggressive clinicopathologic features, including hormone receptor negative and HER2/neu overexpressing disease, and are more likely to be categorized in the high-risk group by molecular subtyping when compared to their older counterparts [1,2]. Given the overlapping risk factors of young age and high-risk features, it is remains unclear whether age itself is an independent prognostic factor. When considered in the context of the 4 intrinsic molecular subytpes (Luminal A, Luminal B, HER2 enriched, and basal-like), the distribution of the molecular subtypes among women <40 years of age differs from that of women 40 years of age, with proportionally fewer luminal cancers, and more HER2 positive and basallike tumors [3,4]. A recent population-based analysis of 1101 women <50 years of age treated from 1986-1992 and 1945 women treated from 2004-2007, using immunohistochemical surrogates to define the 4 molecular subtypes, demonstrates the effect of patient age within each subtype and the impact of modern adjuvant therapy [5]. Within the hormone receptor positive subgroups, both recurrence-free survival (RFS) and overall survival (OS) improved over time with increasing use of anti-estrogen therapy; however, both outcomes remained inferior for women <40 years of age as compared to those 40e49 years of age (2004e2007: 5-year RFS 79% versus 92%, p < 0.001; and 5-year OS 89% versus 95%, p < 0.001). In
Abbreviations: ACOSOG, American college of surgeons oncology group; BCSS, breast cancer-specific survival; BCT, breast-conserving therapy; CI, confidence interval; CBC, contralateral breast cancer; CPM, contralateral prophylactic mastectomy; DFS, disease-free survival; ER, estrogen receptor; PR, progesterone receptor; HR, hazard ratio; HERA, herceptin adjuvant; IHC, immunohistochemistry; OS, overall survival; RFS, recurrence-free survival; TNBC, triple-negative breast cancer; SEER, surveillance, epidemiology, and end results. * Corresponding author. Tel: 1-617-632-3891; fax: 1-617-58-9969. E-mail addresses: [email protected] (T.A. King), [email protected] (M. Pilewskie), [email protected] (M. Morrow). http://dx.doi.org/10.1016/j.breast.2015.07.022 0960-9776/© 2015 Published by Elsevier Ltd.
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contrast, for the HER2 enriched subtype, age <40 years was associated with inferior 5-year RFS and OS in the earlier time period (5year RFS: 39% versus 58%, p ¼ 0.039; OS: 49% versus 66%, p ¼ 0.017), but not in the later years following the introduction of taxanes and trastuzumab into clinical practice (5-year RFS: 81% versus 84%, p ¼ 0.879; 5-year OS: 89% versus 89%, p ¼ 0.879). There was no effect of age observed for either RFS or OS for the triple-negative subtype irrespective of years of treatment, and outcomes for both age groups improved over time. Among women <40 years of age, 5year RFS improved from 60% to 78% (p ¼ 0.014) and 5-year OS improved from 67% to 82% (p ¼ 0.011). The observation that young age is a prognostic factor for hormone receptor positive and HER2 positive subtypes, but not TNBC, was also demonstrated in two Korean studies of patients <35 years of age treated prior to the routine availability of trastuzumab [6,7]. However, in the large Herceptin Adjuvant (HERA) trial, age <40 years was not associated with inferior disease-free survival (DFS) or OS among patients treated with chemotherapy plus trastuzumab [8]. Collectively, these findings demonstrate that advances in systemic therapy have contributed to improvements in survival across all subtypes and have eliminated the impact of age in HER2 positive breast cancer, yet a significant disparity still exists for women < 40 years of age with hormone receptor positive breast cancers, likely driven by the luminal B subtype.
groups, and type of local therapy was not a predictor of OS, BCSS, or local regional RFS on multivariable analysis. Similar to the report by van Laar et al. [10], chemotherapy was found to improve locoregional recurrence in both treatment groups. The effect of local therapy on survival was also studied in 9285 young patients (<50 years of age) from a population-based Danish registry. After adjusting for tumor size, surgical treatment, lymph node status, histologic grade, year of treatment, and protocol allocation, survival was not inferior following BCT in any age group, and was improved following BCT compared to mastectomy in women 45e49 years of age (hazard ratio [HR] for risk of death: age <35 years, 0.87; age 35e39 years, HR 1.02; age 40e44 years, HR 0.80; age 45e49 years, HR 0.66; p < 0.05) [13]. Similarly, after controlling for clinicopathologic factors, none of the previously reported retrospective studies comparing BCT to mastectomy among young women have demonstrated reduced survival in young women treated with BCT [11,14e17]. Thus, while one may postulate that more extensive surgery would mitigate risk factors for local recurrence leading to improved outcomes in young patients, the accumulating evidence suggests that breast cancer biology and appropriate use of systemic therapy, rather than the extent of surgery, is the major determinant of survival outcomes [9].
Age, local recurrence, and survival
Age, contralateral breast cancer risk, and contralateral prophylactic mastectomy
Although earlier studies comparing rates of local recurrence following breast-conserving therapy (BCT) versus mastectomy in young women report conflicting results (reviewed in Pilewskie and King [9]), more recent data demonstrate dramatic improvements in local control among young women over time, and no difference in local recurrence or survival between BCT and mastectomy. A report by van Laar et al. [10] evaluated rates of local recurrence in women 40 years of age treated with BCT in the Netherlands between 1988 and 2010. The overall 5-year local recurrence rate was 7.5%; however, when broken down by time period, rates of local recurrence decreased significantly over time, from 9.8% in the earliest time period (1988e1998) to 5.9% (1999e2005), and to 3.3% in the most recent years of the report (2006e2010, p ¼ 0.006). Local recurrence was also significantly impacted by the use of systemic therapy (10year local recurrence rates with and without systemic therapy were 9.9% and 21.6%, respectively; p < 0.0001), and the improvement in local recurrence over time appeared closely related to the increased use of systemic therapy. In an early population-based study, Coulombe et al. [11] reported no significant difference in locoregional recurrence based on surgery type (BCT versus modified radical mastectomy) for women 20e39 years of age or 40e49 years of age, and no difference in breast cancer-specific survival (BCSS) in the younger cohort. In those 40e49 years of age, BCSS was superior following BCT, likely due to significant differences in tumor characteristics, and a subgroup analysis among patients considered “ideal candidates” for BCT demonstrated no significant difference in local recurrence or survival between BCT and mastectomy-treated patients in either age cohort. These findings have now been updated and expanded by Cao et al. [12] in a recent report of 965 women 20e39 years of age treated with either BCT (n ¼ 616) or modified radical mastectomy (n ¼ 349) as reported to the British Columbia Breast Cancer Agency [12]. At a median follow-up of 14.4 years there remains no difference in BCSS (76.0% versus 74.1%, p ¼ 0.62), OS (74.2% versus 73.0%, p ¼ 0.75), local RFS (85.4% versus 86.5%, p ¼ 0.95), local regional RFS (82.2% versus 81.6% p ¼ 0.61), or distant RFS (74.4% versus 71.6%, p ¼ 0.40) between the 2 surgical treatment groups. The rate of local recurrence was 15% at 15 years in both treatment
The use of contralateral prophylactic mastectomy (CPM) has increased dramatically in the United States. First reported by Tuttle et al. [18], rates of CPM among women with invasive breast cancer increased from 4% to 11% between 1998 and 2003. Subsequent reports from both population-based registries [19,20] and singleinstitution series [21,22] confirmed the persistence of this trend, and, more recently, Kurian et al. [23] reported that among women <40 years of age, nearly 40% will pursue bilateral mastectomy for the management of unilateral breast cancer. Factors associated with the receipt of CPM are multifactorial and include both patient factors (age, family history, breast density) and treatment factors (genetic testing, use of preoperative MRI, immediate breast reconstruction), yet the majority of patients choosing CPM are not at elevated risk of contralateral breast cancer [19,20,22,24,25]. BRCA mutation carriers and those with a history of mantle irradiation comprised only 13% of women undergoing CPM in a large series from Memorial Sloan Kettering Cancer Center [22]. Even among the youngest patient cohorts, the risk of contralateral breast cancer with modern adjuvant therapy is low and has decreased over the past decade. In a recent SEER study, the risk of contralateral breast cancer (CBC) for patients <30 years of age was 4.5%, and 12.6% at 10 years for patients with estrogen receptor (ER) positive and ER negative disease, respectively [26]; rates well below that of local and distant recurrence events in women <40 years of age treated with unilateral mastectomy as reported by Cao et al. [12]. Studies specifically addressing the potential survival benefit associated with CPM have generated conflicting results, largely driven by their retrospective nature and inability to account for selection bias [22,27e30]. In a Surveillance, Epidemiology, and End Results (SEER) study of 107,106 women with unilateral breast cancer undergoing mastectomy between 1998 and 2003, 8902 (8.3%) underwent CPM [31]. Notably, in the subset of 4854 women 18e49 years of age with stage I and II ER negative breast cancer, CPM reduced the rate of CBC from 0.9% to 0.16% and, in an adjusted analysis, was associated with a 4.8% improvement in diseasespecific survival, yet it remains unclear how a <1% reduction in CBC incidence can result in such a large difference in BCSS. A similar
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study from the National Cancer Data Base [32] addressed the same question in 14,627 women <45 years of age with stage I and II breast cancer treated between 2004 and 2006. After adjusting for clinical and pathologic factors, there was no difference in OS for those undergoing CPM compared to unilateral mastectomy (HR 0.93, p ¼ 0.39). This remained true when restricted to only those patients with T1N0 index lesions (HR 0.85, p ¼ 0.37) and when restricted to those with ER negative disease (HR 1.12, p ¼ 0.32). Thus, it is reasonable to conclude that even among young women with breast cancer, CPM is not likely to result in improved survival. Triple-negative breast cancer TNBC accounts for an estimated 15% of breast cancers in women in the United States and is over-represented in African-American women compared to White/Caucasian-American women [4,33e35]. Using the most rigorous definition as set forth by the American Society of Clinical Oncology/College of American Pathologists guidelines, TNBC is defined as ER and PR staining <1%, by immunohistochemistry (IHC), and HER2 negative by IHC or FISH. It is becoming increasingly clear, however, that TNBC is itself heterogeneous and includes a large number of molecular subtypes which are beyond the scope of this review. There is a significant association between TNBC and BRCA1 mutation status; whereby 8e30% of TNBC tumors are found to occur in BRCA1 mutation carriers [33]. The yield from BRCA mutation testing in TNBC patients varies by age and race/ ethnicity. In a study of 469 TNBC patients, BRCA1 mutations were identified in 44% of patients <40 years of age compared to 13% of patients 60e69 years of age, and 20% of the African-American TNBC cases tested positive for a BRCA1 mutation, compared to 33% of the White/Caucasian TNBC cases [36]. The 2013 National Comprehensive Cancer Network guidelines recommend genetic counseling referral for any TNBC patient diagnosed at 60 years of age or younger; however, this may evolve as Kwon et al. [37] demonstrated that BRCA testing is cost efficient for any TNBC diagnosed younger than age 50 years, regardless of family history. Multiple studies have shown an increased rate of local recurrence after BCT for the triple-negative subtype, even for tumors 1 cm or less in size [38], raising questions as to whether this subtype might influence the selection of BCT versus mastectomy. In a meta-analysis of 7174 cases, the relative risk of local recurrence after BCT for non-TNBC compared to TNBC was 0.49 (95% confidence interval [CI], 0.33e0.73) [39]. When HER2 overexpressing cancers not treated with trastuzumab were removed from analysis, the relative risk fell to 0.33 (95% CI, 0.1e0.61). However, a metaanalysis of local recurrence after mastectomy (n ¼ 5418) also demonstrated an increased rate of local recurrence for TNBC with a relative risk of 0.66 (95% CI, 0.53e0.83) for non-TNBC when all subtypes were considered, which fell to 0.51 (95% CI, 0.36e0.73) when HER2 overexpressing cases were removed [39]. Gangi et al. [40] found that TNBCs were more likely to occur in younger patients, be larger, and be of higher grade and higher stage than other subtypes, and that after adjustment for these features, the 5-year rate of local recurrence did not vary by subtype. Three retrospective studies that directly compared the outcome of mastectomy and BCT in TNBC [41e43] also found no difference in rates of local recurrence or survival between procedures. Collectively, these studies suggest that the behavior of TNBC is not influenced by the choice of BCT versus mastectomy. It is also noteworthy that although rates of local recurrence are increased in TNBC, the 5-year cumulative rate of locoregional recurrence was only 4.2% and 5.4%, respectively, for patients having BCT and mastectomy in the most recent of these studies [43].
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Pilewskie et al. [44] examined the impact of margin width on local recurrence after BCT in a series of 535 consecutive TNBC patients and found no difference in local recurrence at 60 months between negative margins widths of 2 mm or >2 mm (4.7% and 3.7%, respectively; p ¼ 0.11), further supporting the concept that excellent local control can be achieved with BCT in TNBC. The impact of TNBC on axillary management has also been controversial. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of sentinel node biopsy alone for patients with metastases in 1 or 2 sentinel nodes undergoing BCT with whole-breast irradiation [45], but 83% of the patients in this study had ER or PR positive cancers. Despite a higher risk of local recurrence, several studies have shown that the incidence of nodal metastases is less frequent in TNBC [46,47]. Ugras et al. found that after adjustment for other features, patients with TNBC were also significantly less likely to have metastases to 4 nodes compared to those with other subtypes (p < 0.0001) [48]. Additionally, large studies examining factors associated with nodal recurrence after axillary dissection have not identified ER status as a significant predictor [49,50]. In summary, an increased risk of local recurrence in triplenegative cancers is apparent; however, this increased local recurrence risk is present following surgical treatment with both BCT and mastectomy, highlighting the importance of future systemic therapies targeting the triple-negative subtype in improving local outcomes. The strong association between BRCA mutation status and TNBC raises the possibility that poly ADP ribose polymerase inhibitors may be one such strategy; this concept is currently being tested in the adjuvant setting (NCT02032823). BRCA mutation carriers Lifetime estimates of breast cancer risk among BRCA mutation carriers range from 36 to 90% [50,51], and once a woman is diagnosed, she also faces an increased risk of CBC. There is a strong association between BRCA mutation status and breast cancer subtype, with 70e90% of BRCA1 mutation-associated breast cancers being triple negative and approximately 80% of BRCA2 mutationassociated cancers being hormone receptor positive [52]. In addition, BRCA1-associated cancers also tend to occur at an earlier age than BRCA2-associated cancers. Thus, surgical decision making for affected BRCA mutation carriers must take into account both the risk of in-breast recurrence and the risk of CBC in the context of ER status of the index tumor, available adjuvant therapy options, and risk of distant disease. Studies comparing risk of ipsilateral breast cancer recurrence following BCT between carriers and non-carriers are largely retrospective and have generated conflicting results. A recent meta-analysis of 10 studies, which included 526 BRCA mutation carriers and 2320 controls, demonstrated no significant difference in local recurrence between carriers and controls in studies with a median follow-up <7 years (6 studies: 1212 patients, local recurrence 11.7% carriers versus 8.9% controls, risk ratio [RR] 1.38, 95% CI 0.53e3.60, p ¼ 0.51); however, in studies with longer follow-up (5 studies, 1634 patients) the incidence of local recurrence among BRCA mutation carriers increased substantially to 23.7% as compared to 15.9% among controls (RR 1.51, 95% CI 1.15e1.98, p ¼ 0.003) [53]; suggesting that these later events may be new primary cancers versus true in-breast recurrences. Among 4 studies that analyzed risk of local recurrence according to type of mutation (405 BRCA1 carriers versus 203 BRCA2 carriers), there was no difference in risk of local recurrence (RR 0.76, 95% CI 0.49e1.16, p ¼ 0.20). Importantly, the use of adjuvant chemotherapy and oophorectomy were both associated with reduced rates of local recurrence [53].
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In contrast, the risk of CBC is consistently higher in carriers than non-carriers and does vary by type of mutation. Pooled rates of CBC in the meta-analysis of 11 studies including 807 carriers and 3163 controls were 23.7% and 6.8% respectively (RR 3.56, 95% CI 2.50e5.08, p < 0.001) and among 7 studies investigating risk between BRCA1 and BRCA2 carriers, rates of CBC were 21.1% and 15.1%, respectively (RR 1.42, 95% CI 1.01e1.95, p ¼ 0.04) [53]. Factors consistently associated with a decreased risk for CBC include oophorectomy (RR 0.52, 95% CI 0.37e0.74), tamoxifen use (RR 0.57, 95% CI 0.43e0.75) and increasing age. Although a cumulative HR for the impact of increasing age could not be calculated in the metaanalysis, Metcalfe et al. [54] demonstrated that age >50 years at diagnosis was associated with decreased risk of CBC at 15 years compared to age at diagnosis <50 years (16.8% versus 37.6%, p ¼ 0.001). Similarly, in an earlier study by Graeser et al. [55], age >50 years at diagnosis was associated with decreased risk of CBC in BRCA1 families but not BRCA2 families. However, it is reasonable to speculate that tamoxifen and prophylactic oophorectomy may have a stronger protective effect in BRCA2 mutation carriers given the higher rate of ER positive disease in this group. Taken together, available data suggest that young patients with BRCA1-associated breast cancers would potentially derive the most benefit from an aggressive surgical approach including unilateral therapeutic mastectomy, CPM, and prophylactic oophorectomy, whereas an older patient with BRCA2-associated ER positive breast cancer may achieve adequate local control and assume an acceptable risk of CBC with a less-aggressive surgical approach followed by anti-estrogen therapy. However, prophylactic oophorectomy to reduce the risk of ovarian cancer should always be considered.
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Summary Young patients, patients with TNBC, and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. For both age and subtype, it appears that the intrinsic biology which imparts inferior outcomes is not overcome with mastectomy; therefore, a recommendation for more extensive surgical therapy among these higher-risk groups is not warranted. For those at inherited risk, a more-aggressive surgical approach may be preferable, however; patient age, ER status, stage of the index lesion, and individual patient preferences should all be considered in the surgical decision-making process.
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mastectomy in women with T1-2N0 triple-negative breast cancer. Ann Surg Oncol 2013;20:3469e76. Pilewskie M, Ho A, Orell E, Stempel M, Chen Y, Eaton A, et al. Effect of margin width on local recurrence in triple-negative breast cancer patients treated with breast-conserving therapy. Ann Surg Oncol 2014;21:1209e14. Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. Jama 2011;305:569e75. Crabb SJ, Cheang MC, Leung S, Immonen T, Nielsen TO, Huntsman DD, et al. Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer. Clin Breast Cancer 2008;8: 249e56. Wiechmann L, Sampson M, Stempel M, Jacks LM, Patil SM, King T, et al. Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol 2009;16:2705e10. Ugras S, Stempel M, Patil S, Morrow M. Estrogen receptor, progesterone receptor, and HER2 status predict lymphovascular invasion and lymph node involvement. Ann Surg Oncol 2014;21:3780e6. Grills IS, Kestin LL, Goldstein N, Mitchell C, Martinez A, Ingold J, et al. Risk factors for regional nodal failure after breast-conserving therapy: regional nodal irradiation reduces rate of axillary failure in patients with four or more positive lymph nodes. Int J Radiat Oncol Biol Phys 2003;56:658e70. Yates L, Kirby A, Crichton S, Gillett C, Cane P, Fentiman I, et al. Risk factors for regional nodal relapse in breast cancer patients with one to three positive axillary nodes. Int J Radiat Oncol Biol Phys 2012;82:2093e103. Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, et al. Variation of breast cancer risk among BRCA1/2 carriers. Jama 2008;299: 194e201. Da Silva L, Lakhani SR. Pathology of hereditary breast cancer. Mod Pathol 2010;23(Suppl. 2):S46e51. 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;144:443e55. Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2011;104:1384e92. Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2009;27:5887e92.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Optimal surgical management for high-risk populations Tari A. King*, Melissa Pilewskie, Monica Morrow Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Available online 1 October 2015
The recognition that breast cancer is a group of genetically distinct diseases with differing responses to treatment and varying patterns of both local and systemic failure has led to many questions regarding optimal therapy for those considered to be high risk. Young patients, patients with triple-negative breast cancer (TNBC), and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. For both age and the triple-negative subtype, it appears that the intrinsic biology which imparts inferior outcomes is not overcome with mastectomy; therefore, a recommendation for more extensive surgical therapy among these higher-risk groups is not warranted. For those at inherited risk, a more-aggressive surgical approach may be preferable, however; patient age, ER status, stage of the index lesion, and individual patient preferences should all be considered in the surgical decision-making process. © 2015 Published by Elsevier Ltd.
Keywords: Breast cancer Young age Triple-negative subtype BRCA mutation
Introduction
Breast cancer in young women
The recognition that breast cancer is a group of genetically distinct diseases with differing responses to treatment and varying patterns of both local and systemic failure has led to many questions regarding optimal therapy for those considered to be high risk. Young patients, patients with triple-negative breast cancer (TNBC), and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. In addition, there is considerable overlap among these risk factors whereby up to 40% of women <40 years of age with TNBC will be found to harbor a BRCA mutation, adding to the complexity of surgical decision making. This article will summarize current evidence regarding the choice of local therapy and outcomes in these high-risk populations.
It is clear that young breast cancer patients experience higher rates of both local and distant recurrence; they frequently present with more-aggressive clinicopathologic features, including hormone receptor negative and HER2/neu overexpressing disease, and are more likely to be categorized in the high-risk group by molecular subtyping when compared to their older counterparts [1,2]. Given the overlapping risk factors of young age and high-risk features, it is remains unclear whether age itself is an independent prognostic factor. When considered in the context of the 4 intrinsic molecular subytpes (Luminal A, Luminal B, HER2 enriched, and basal-like), the distribution of the molecular subtypes among women <40 years of age differs from that of women 40 years of age, with proportionally fewer luminal cancers, and more HER2 positive and basallike tumors [3,4]. A recent population-based analysis of 1101 women <50 years of age treated from 1986-1992 and 1945 women treated from 2004-2007, using immunohistochemical surrogates to define the 4 molecular subtypes, demonstrates the effect of patient age within each subtype and the impact of modern adjuvant therapy [5]. Within the hormone receptor positive subgroups, both recurrence-free survival (RFS) and overall survival (OS) improved over time with increasing use of anti-estrogen therapy; however, both outcomes remained inferior for women <40 years of age as compared to those 40e49 years of age (2004e2007: 5-year RFS 79% versus 92%, p < 0.001; and 5-year OS 89% versus 95%, p < 0.001). In
Abbreviations: ACOSOG, American college of surgeons oncology group; BCSS, breast cancer-specific survival; BCT, breast-conserving therapy; CI, confidence interval; CBC, contralateral breast cancer; CPM, contralateral prophylactic mastectomy; DFS, disease-free survival; ER, estrogen receptor; PR, progesterone receptor; HR, hazard ratio; HERA, herceptin adjuvant; IHC, immunohistochemistry; OS, overall survival; RFS, recurrence-free survival; TNBC, triple-negative breast cancer; SEER, surveillance, epidemiology, and end results. * Corresponding author. Tel: 1-617-632-3891; fax: 1-617-58-9969. E-mail addresses: [email protected] (T.A. King), [email protected] (M. Pilewskie), [email protected] (M. Morrow). http://dx.doi.org/10.1016/j.breast.2015.07.022 0960-9776/© 2015 Published by Elsevier Ltd.
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contrast, for the HER2 enriched subtype, age <40 years was associated with inferior 5-year RFS and OS in the earlier time period (5year RFS: 39% versus 58%, p ¼ 0.039; OS: 49% versus 66%, p ¼ 0.017), but not in the later years following the introduction of taxanes and trastuzumab into clinical practice (5-year RFS: 81% versus 84%, p ¼ 0.879; 5-year OS: 89% versus 89%, p ¼ 0.879). There was no effect of age observed for either RFS or OS for the triple-negative subtype irrespective of years of treatment, and outcomes for both age groups improved over time. Among women <40 years of age, 5year RFS improved from 60% to 78% (p ¼ 0.014) and 5-year OS improved from 67% to 82% (p ¼ 0.011). The observation that young age is a prognostic factor for hormone receptor positive and HER2 positive subtypes, but not TNBC, was also demonstrated in two Korean studies of patients <35 years of age treated prior to the routine availability of trastuzumab [6,7]. However, in the large Herceptin Adjuvant (HERA) trial, age <40 years was not associated with inferior disease-free survival (DFS) or OS among patients treated with chemotherapy plus trastuzumab [8]. Collectively, these findings demonstrate that advances in systemic therapy have contributed to improvements in survival across all subtypes and have eliminated the impact of age in HER2 positive breast cancer, yet a significant disparity still exists for women < 40 years of age with hormone receptor positive breast cancers, likely driven by the luminal B subtype.
groups, and type of local therapy was not a predictor of OS, BCSS, or local regional RFS on multivariable analysis. Similar to the report by van Laar et al. [10], chemotherapy was found to improve locoregional recurrence in both treatment groups. The effect of local therapy on survival was also studied in 9285 young patients (<50 years of age) from a population-based Danish registry. After adjusting for tumor size, surgical treatment, lymph node status, histologic grade, year of treatment, and protocol allocation, survival was not inferior following BCT in any age group, and was improved following BCT compared to mastectomy in women 45e49 years of age (hazard ratio [HR] for risk of death: age <35 years, 0.87; age 35e39 years, HR 1.02; age 40e44 years, HR 0.80; age 45e49 years, HR 0.66; p < 0.05) [13]. Similarly, after controlling for clinicopathologic factors, none of the previously reported retrospective studies comparing BCT to mastectomy among young women have demonstrated reduced survival in young women treated with BCT [11,14e17]. Thus, while one may postulate that more extensive surgery would mitigate risk factors for local recurrence leading to improved outcomes in young patients, the accumulating evidence suggests that breast cancer biology and appropriate use of systemic therapy, rather than the extent of surgery, is the major determinant of survival outcomes [9].
Age, local recurrence, and survival
Age, contralateral breast cancer risk, and contralateral prophylactic mastectomy
Although earlier studies comparing rates of local recurrence following breast-conserving therapy (BCT) versus mastectomy in young women report conflicting results (reviewed in Pilewskie and King [9]), more recent data demonstrate dramatic improvements in local control among young women over time, and no difference in local recurrence or survival between BCT and mastectomy. A report by van Laar et al. [10] evaluated rates of local recurrence in women 40 years of age treated with BCT in the Netherlands between 1988 and 2010. The overall 5-year local recurrence rate was 7.5%; however, when broken down by time period, rates of local recurrence decreased significantly over time, from 9.8% in the earliest time period (1988e1998) to 5.9% (1999e2005), and to 3.3% in the most recent years of the report (2006e2010, p ¼ 0.006). Local recurrence was also significantly impacted by the use of systemic therapy (10year local recurrence rates with and without systemic therapy were 9.9% and 21.6%, respectively; p < 0.0001), and the improvement in local recurrence over time appeared closely related to the increased use of systemic therapy. In an early population-based study, Coulombe et al. [11] reported no significant difference in locoregional recurrence based on surgery type (BCT versus modified radical mastectomy) for women 20e39 years of age or 40e49 years of age, and no difference in breast cancer-specific survival (BCSS) in the younger cohort. In those 40e49 years of age, BCSS was superior following BCT, likely due to significant differences in tumor characteristics, and a subgroup analysis among patients considered “ideal candidates” for BCT demonstrated no significant difference in local recurrence or survival between BCT and mastectomy-treated patients in either age cohort. These findings have now been updated and expanded by Cao et al. [12] in a recent report of 965 women 20e39 years of age treated with either BCT (n ¼ 616) or modified radical mastectomy (n ¼ 349) as reported to the British Columbia Breast Cancer Agency [12]. At a median follow-up of 14.4 years there remains no difference in BCSS (76.0% versus 74.1%, p ¼ 0.62), OS (74.2% versus 73.0%, p ¼ 0.75), local RFS (85.4% versus 86.5%, p ¼ 0.95), local regional RFS (82.2% versus 81.6% p ¼ 0.61), or distant RFS (74.4% versus 71.6%, p ¼ 0.40) between the 2 surgical treatment groups. The rate of local recurrence was 15% at 15 years in both treatment
The use of contralateral prophylactic mastectomy (CPM) has increased dramatically in the United States. First reported by Tuttle et al. [18], rates of CPM among women with invasive breast cancer increased from 4% to 11% between 1998 and 2003. Subsequent reports from both population-based registries [19,20] and singleinstitution series [21,22] confirmed the persistence of this trend, and, more recently, Kurian et al. [23] reported that among women <40 years of age, nearly 40% will pursue bilateral mastectomy for the management of unilateral breast cancer. Factors associated with the receipt of CPM are multifactorial and include both patient factors (age, family history, breast density) and treatment factors (genetic testing, use of preoperative MRI, immediate breast reconstruction), yet the majority of patients choosing CPM are not at elevated risk of contralateral breast cancer [19,20,22,24,25]. BRCA mutation carriers and those with a history of mantle irradiation comprised only 13% of women undergoing CPM in a large series from Memorial Sloan Kettering Cancer Center [22]. Even among the youngest patient cohorts, the risk of contralateral breast cancer with modern adjuvant therapy is low and has decreased over the past decade. In a recent SEER study, the risk of contralateral breast cancer (CBC) for patients <30 years of age was 4.5%, and 12.6% at 10 years for patients with estrogen receptor (ER) positive and ER negative disease, respectively [26]; rates well below that of local and distant recurrence events in women <40 years of age treated with unilateral mastectomy as reported by Cao et al. [12]. Studies specifically addressing the potential survival benefit associated with CPM have generated conflicting results, largely driven by their retrospective nature and inability to account for selection bias [22,27e30]. In a Surveillance, Epidemiology, and End Results (SEER) study of 107,106 women with unilateral breast cancer undergoing mastectomy between 1998 and 2003, 8902 (8.3%) underwent CPM [31]. Notably, in the subset of 4854 women 18e49 years of age with stage I and II ER negative breast cancer, CPM reduced the rate of CBC from 0.9% to 0.16% and, in an adjusted analysis, was associated with a 4.8% improvement in diseasespecific survival, yet it remains unclear how a <1% reduction in CBC incidence can result in such a large difference in BCSS. A similar
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study from the National Cancer Data Base [32] addressed the same question in 14,627 women <45 years of age with stage I and II breast cancer treated between 2004 and 2006. After adjusting for clinical and pathologic factors, there was no difference in OS for those undergoing CPM compared to unilateral mastectomy (HR 0.93, p ¼ 0.39). This remained true when restricted to only those patients with T1N0 index lesions (HR 0.85, p ¼ 0.37) and when restricted to those with ER negative disease (HR 1.12, p ¼ 0.32). Thus, it is reasonable to conclude that even among young women with breast cancer, CPM is not likely to result in improved survival. Triple-negative breast cancer TNBC accounts for an estimated 15% of breast cancers in women in the United States and is over-represented in African-American women compared to White/Caucasian-American women [4,33e35]. Using the most rigorous definition as set forth by the American Society of Clinical Oncology/College of American Pathologists guidelines, TNBC is defined as ER and PR staining <1%, by immunohistochemistry (IHC), and HER2 negative by IHC or FISH. It is becoming increasingly clear, however, that TNBC is itself heterogeneous and includes a large number of molecular subtypes which are beyond the scope of this review. There is a significant association between TNBC and BRCA1 mutation status; whereby 8e30% of TNBC tumors are found to occur in BRCA1 mutation carriers [33]. The yield from BRCA mutation testing in TNBC patients varies by age and race/ ethnicity. In a study of 469 TNBC patients, BRCA1 mutations were identified in 44% of patients <40 years of age compared to 13% of patients 60e69 years of age, and 20% of the African-American TNBC cases tested positive for a BRCA1 mutation, compared to 33% of the White/Caucasian TNBC cases [36]. The 2013 National Comprehensive Cancer Network guidelines recommend genetic counseling referral for any TNBC patient diagnosed at 60 years of age or younger; however, this may evolve as Kwon et al. [37] demonstrated that BRCA testing is cost efficient for any TNBC diagnosed younger than age 50 years, regardless of family history. Multiple studies have shown an increased rate of local recurrence after BCT for the triple-negative subtype, even for tumors 1 cm or less in size [38], raising questions as to whether this subtype might influence the selection of BCT versus mastectomy. In a meta-analysis of 7174 cases, the relative risk of local recurrence after BCT for non-TNBC compared to TNBC was 0.49 (95% confidence interval [CI], 0.33e0.73) [39]. When HER2 overexpressing cancers not treated with trastuzumab were removed from analysis, the relative risk fell to 0.33 (95% CI, 0.1e0.61). However, a metaanalysis of local recurrence after mastectomy (n ¼ 5418) also demonstrated an increased rate of local recurrence for TNBC with a relative risk of 0.66 (95% CI, 0.53e0.83) for non-TNBC when all subtypes were considered, which fell to 0.51 (95% CI, 0.36e0.73) when HER2 overexpressing cases were removed [39]. Gangi et al. [40] found that TNBCs were more likely to occur in younger patients, be larger, and be of higher grade and higher stage than other subtypes, and that after adjustment for these features, the 5-year rate of local recurrence did not vary by subtype. Three retrospective studies that directly compared the outcome of mastectomy and BCT in TNBC [41e43] also found no difference in rates of local recurrence or survival between procedures. Collectively, these studies suggest that the behavior of TNBC is not influenced by the choice of BCT versus mastectomy. It is also noteworthy that although rates of local recurrence are increased in TNBC, the 5-year cumulative rate of locoregional recurrence was only 4.2% and 5.4%, respectively, for patients having BCT and mastectomy in the most recent of these studies [43].
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Pilewskie et al. [44] examined the impact of margin width on local recurrence after BCT in a series of 535 consecutive TNBC patients and found no difference in local recurrence at 60 months between negative margins widths of 2 mm or >2 mm (4.7% and 3.7%, respectively; p ¼ 0.11), further supporting the concept that excellent local control can be achieved with BCT in TNBC. The impact of TNBC on axillary management has also been controversial. The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of sentinel node biopsy alone for patients with metastases in 1 or 2 sentinel nodes undergoing BCT with whole-breast irradiation [45], but 83% of the patients in this study had ER or PR positive cancers. Despite a higher risk of local recurrence, several studies have shown that the incidence of nodal metastases is less frequent in TNBC [46,47]. Ugras et al. found that after adjustment for other features, patients with TNBC were also significantly less likely to have metastases to 4 nodes compared to those with other subtypes (p < 0.0001) [48]. Additionally, large studies examining factors associated with nodal recurrence after axillary dissection have not identified ER status as a significant predictor [49,50]. In summary, an increased risk of local recurrence in triplenegative cancers is apparent; however, this increased local recurrence risk is present following surgical treatment with both BCT and mastectomy, highlighting the importance of future systemic therapies targeting the triple-negative subtype in improving local outcomes. The strong association between BRCA mutation status and TNBC raises the possibility that poly ADP ribose polymerase inhibitors may be one such strategy; this concept is currently being tested in the adjuvant setting (NCT02032823). BRCA mutation carriers Lifetime estimates of breast cancer risk among BRCA mutation carriers range from 36 to 90% [50,51], and once a woman is diagnosed, she also faces an increased risk of CBC. There is a strong association between BRCA mutation status and breast cancer subtype, with 70e90% of BRCA1 mutation-associated breast cancers being triple negative and approximately 80% of BRCA2 mutationassociated cancers being hormone receptor positive [52]. In addition, BRCA1-associated cancers also tend to occur at an earlier age than BRCA2-associated cancers. Thus, surgical decision making for affected BRCA mutation carriers must take into account both the risk of in-breast recurrence and the risk of CBC in the context of ER status of the index tumor, available adjuvant therapy options, and risk of distant disease. Studies comparing risk of ipsilateral breast cancer recurrence following BCT between carriers and non-carriers are largely retrospective and have generated conflicting results. A recent meta-analysis of 10 studies, which included 526 BRCA mutation carriers and 2320 controls, demonstrated no significant difference in local recurrence between carriers and controls in studies with a median follow-up <7 years (6 studies: 1212 patients, local recurrence 11.7% carriers versus 8.9% controls, risk ratio [RR] 1.38, 95% CI 0.53e3.60, p ¼ 0.51); however, in studies with longer follow-up (5 studies, 1634 patients) the incidence of local recurrence among BRCA mutation carriers increased substantially to 23.7% as compared to 15.9% among controls (RR 1.51, 95% CI 1.15e1.98, p ¼ 0.003) [53]; suggesting that these later events may be new primary cancers versus true in-breast recurrences. Among 4 studies that analyzed risk of local recurrence according to type of mutation (405 BRCA1 carriers versus 203 BRCA2 carriers), there was no difference in risk of local recurrence (RR 0.76, 95% CI 0.49e1.16, p ¼ 0.20). Importantly, the use of adjuvant chemotherapy and oophorectomy were both associated with reduced rates of local recurrence [53].
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In contrast, the risk of CBC is consistently higher in carriers than non-carriers and does vary by type of mutation. Pooled rates of CBC in the meta-analysis of 11 studies including 807 carriers and 3163 controls were 23.7% and 6.8% respectively (RR 3.56, 95% CI 2.50e5.08, p < 0.001) and among 7 studies investigating risk between BRCA1 and BRCA2 carriers, rates of CBC were 21.1% and 15.1%, respectively (RR 1.42, 95% CI 1.01e1.95, p ¼ 0.04) [53]. Factors consistently associated with a decreased risk for CBC include oophorectomy (RR 0.52, 95% CI 0.37e0.74), tamoxifen use (RR 0.57, 95% CI 0.43e0.75) and increasing age. Although a cumulative HR for the impact of increasing age could not be calculated in the metaanalysis, Metcalfe et al. [54] demonstrated that age >50 years at diagnosis was associated with decreased risk of CBC at 15 years compared to age at diagnosis <50 years (16.8% versus 37.6%, p ¼ 0.001). Similarly, in an earlier study by Graeser et al. [55], age >50 years at diagnosis was associated with decreased risk of CBC in BRCA1 families but not BRCA2 families. However, it is reasonable to speculate that tamoxifen and prophylactic oophorectomy may have a stronger protective effect in BRCA2 mutation carriers given the higher rate of ER positive disease in this group. Taken together, available data suggest that young patients with BRCA1-associated breast cancers would potentially derive the most benefit from an aggressive surgical approach including unilateral therapeutic mastectomy, CPM, and prophylactic oophorectomy, whereas an older patient with BRCA2-associated ER positive breast cancer may achieve adequate local control and assume an acceptable risk of CBC with a less-aggressive surgical approach followed by anti-estrogen therapy. However, prophylactic oophorectomy to reduce the risk of ovarian cancer should always be considered.
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
Summary Young patients, patients with TNBC, and those who harbor a deleterious mutation in BRCA1 or BRCA2 are frequently considered to be at highest risk of local failure, leading to speculation that more-aggressive surgical treatment is warranted in these patients. For both age and subtype, it appears that the intrinsic biology which imparts inferior outcomes is not overcome with mastectomy; therefore, a recommendation for more extensive surgical therapy among these higher-risk groups is not warranted. For those at inherited risk, a more-aggressive surgical approach may be preferable, however; patient age, ER status, stage of the index lesion, and individual patient preferences should all be considered in the surgical decision-making process.
[18]
[19]
[20]
[21]
[22]
[23]
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