Abstract
Purpose:
Lobular carcinoma in situ (LCIS) confers increased cancer risk in either breast, but it remains unclear if this population is at increased risk for bilateral breast cancer (BC) development. Here we report bilateral BC incidence among women with a history of LCIS.
Methods:
Women with classic-type LCIS diagnosed from 1980–2017 who developed unilateral BC (UBC) or bilateral BC were identified. Bilateral BC was categorized as synchronous (bilateral BC diagnosed <6 months apart; SBBC) or metachronous (bilateral BC diagnosed ≥6 months apart; MBBC). Five-year incidence rates of bilateral BC among this population were evaluated. Comparisons were made to identify factors associated with bilateral BC.
Results:
At 7 years’ median follow-up, 249/1651 (15%) women with LCIS developed BC; 34 with bilateral BC (2%). There were no clinicopathologic feature differences between those with UBC and bilateral BC. SBBC occurred in 18 without significant differences versus UBC. Among 211 with UBC and a contralateral breast at risk, 16 developed MBBC at a median follow-up of 3 years. MBBC patients were less likely to receive endocrine therapy and more likely to receive chemotherapy versus UBC. Tumor histology was not associated with MBBC. Estimated 5-year MBBC risk was 6.4%. Index estrogen/progesterone receptor positivity and endocrine therapy were the only factors associated with MBBC risk.
Conclusion:
Bilateral BC occurred in 2% of women with LCIS history at median follow-up of 7 years. Similar to the general BC population, a decrease in MBBC is seen among women with a history of LCIS who develop hormone receptor-positive disease and those who receive endocrine therapy, highlighting the protective effects of this treatment.
Keywords: breast cancer, breast surgery, lobular carcinoma in situ, bilateral breast cancer, contralateral breast cancer, hormone receptor-positive disease
Introduction
Lobular carcinoma in situ (LCIS), originally described in 1941, is now recognized as both a risk factor and a non-obligate precursor for subsequent breast cancer [1–4]. LCIS is a form of lobular neoplasia characterized by the proliferation of loosely cohesive, neoplastic cells that fill and distend most (> 50%) acini of the terminal duct lobular units where they are centered [3,5]. A 2% annual incidence of breast cancer among women with classic-type LCIS has been reported, conferring up to a 10-fold increased breast cancer risk compared with the general population [6].
The development of breast cancer in the contralateral breast following an index cancer is overall a relatively rare event, with decreasing contralateral breast cancer (CBC) rates reported in recent years [7]. While studies estimate the annual risk in the general breast cancer population to be approximately 0.2% to 1% per year [7–18], CBC does represent the most common second malignancy among breast cancer survivors, comprising 30–50% of all second cancers [19–21]. Multiple risk factors are implicated in CBC development, including, but not limited to, genetic predisposition, young age at diagnosis, family history of breast cancer, and primary tumor receptor status [7,9,15,22–25].
While the risk of index breast cancer following an LCIS diagnosis is well established, there is considerable speculation regarding whether a history of LCIS is associated with an increased risk of bilateral breast cancer (BBC), including both concurrent and metachronous CBC development. In this study, we examine the incidence of unilateral breast cancer (UBC) and BBC, including both synchronous bilateral breast cancer (SBBC) and metachronous bilateral breast cancer (MBBC), as well as factors associated with BBC development in a large population of women diagnosed with LCIS and followed in a surveillance program.
Materials and methods
Following Institutional Review Board approval, the outcomes of women diagnosed with LCIS between 1980 and 2017 participating in surveillance at Memorial Sloan Kettering Cancer Center were analyzed from a prospectively maintained database. Women who subsequently developed breast cancer were retrospectively identified and grouped into UBC or BBC cohorts. The BBC group was further divided into those with SBBC or MBBC. Breast cancers diagnosed < 6 months or ≥ 6 months apart were defined as patients with SBBC and MBBC, respectively.
Clinicopathological data were obtained from the electronic medical record and LCIS database to assess factors associated with BBC, including race, radiographic breast density as defined by the Breast Imaging–Reporting and Data System (BI-RADS) (BI-RADS 1 = fatty; BI-RADS 2 = scattered fibroglandular; BI-RADS 3 = heterogeneous/moderately dense; and BI-RADS 4 = extremely dense); age at LCIS and cancer diagnoses; laterality and year of diagnosis for both the initial LCIS and for any subsequent cancer event; menopausal status; family history of breast cancer (one or more first- or second-degree relatives); chemoprevention use (following LCIS diagnosis, approved in 1998); MRI screening use (available after April 1999; our experience with MRI-screening in this cohort was previously published [26]); breast cancer details including hormone receptor status, grade, tumor size, nodal involvement, stage, histology of each cancer, as well as neoadjuvant, surgical, and adjuvant breast cancer treatments; and date of last follow-up. Invasive cancers and ductal carcinoma in situ (DCIS) were registered as cancer events. Cases of markedly atypical ductal hyperplasia bordering on or focally reaching DCIS were included as DCIS and counted as a cancer diagnosis. Subsequent LCIS diagnoses of any type (classic, pleomorphic) were not considered a cancer diagnosis.
Clinical characteristics of UBC, any BBC, MBBC, and SBBC patients were summarized and compared using the Wilcoxon rank-sum test for continuous variables, and the chi-square test of independence or the Fisher exact test for categorical variables. For SBBC cases, the breast that was diagnosed first was selected as the index tumor for the UBC versus BBC comparisons. For those cases diagnosed on the same date, the tumor with the higher stage was selected for comparison.
To assess factors associated with MBBC risk in women with LCIS, a time-to-event analysis was conducted among the subset of patients with a contralateral breast at risk following index cancer diagnosis. SBBC patients were excluded from this cohort, along with women who had their index tumor diagnosed at the time of a prophylactic bilateral mastectomy. Patients who underwent bilateral mastectomies for treatment of a unilateral breast cancer and those who underwent a contralateral prophylactic mastectomy sometime following a therapeutic mastectomy for their index tumor were kept in the “at-risk” cohort and censored at the time the contralateral prophylactic mastectomy was performed. Ipsilateral (in-breast) recurrence and metastases were not counted as events; therefore, patients who experienced these occurrences remained in the at-risk cohort.
Event distributions were summarized using Kaplan-Meier curves and compared between patient groups stratified by clinical characteristics using log-rank tests. Univariate Cox proportional hazards models were used to assess clinical risk factors for development of MBBC. Variables were analyzed as time-dependent when appropriate. A sensitivity analysis based on univariate associations for MBBC risk was performed omitting women who underwent bilateral mastectomy within 6 months of date of diagnosis. Significance was set as P < 0.05. All analyses were performed in R Version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
At a median follow-up of 7.2 years, 249 of 1651 (15.1%) women with a history of LCIS were diagnosed with breast cancer. This includes UBC detected at the time of bilateral prophylactic mastectomy in 15 of 85 women who opted for risk-reducing surgery (DCIS, n=8; stage 1 invasive ductal carcinoma [IDC], n=3; stage 1 invasive lobular carcinoma [ILC], n=4), cancer that developed in the contralateral breast of 1 woman treated with unilateral mastectomy for initial LCIS, and 233 patients who developed breast cancer while participating in surveillance, for a total of 249 index breast cancer cases (Fig. 1).
Fig 1.
CONSORT Diagram. Abbreviations: LCIS, lobular carcinoma in situ; SBBC, synchronous bilateral breast cancer; UBC, unilateral breast cancer; MBBC, metachronous bilateral breast cancer
General demographics and index tumor characteristics among women with a history of LCIS and an index breast cancer (n = 249) are displayed in Table 1. The mean age at LCIS diagnosis was 52 years, and the mean age at first breast cancer diagnosis was 57 years. Most patients (92%) were White and did not have a family history of breast cancer (61%); 86% had heterogeneously or extremely dense breast tissue. Fifty-four percent of patients participated in MRI screening, while 12% took chemoprevention prior to breast cancer diagnosis with an average period of utilization of 40 months (range 17–59 months). Just over half of the index cancers developed ipsilaterally to the side of known LCIS (51%). The index tumor histology was 34% DCIS, 39% IDC, 24% ILC, and 3% other (4 had missing data). Ninety-four percent of the index tumors were DCIS or T1, 13% were node positive; 93% were estrogen receptor (ER) positive and 91% were human epidermal growth factor receptor 2 (HER2) negative.
Table 1.
Clinical characteristics of patients with LCIS and an index cancer
| Characteristic | n = 249 |
|---|---|
| Mean age at LCIS diagnosis, years (range) | 52 (29–83) |
| Mean age at 1st cancer diagnosis, years (range) | 57 (29–93) |
| Mean age at 2nd cancer diagnosis if applicable, years (range) | 57 (43–79) |
| Race | |
| White | 225 (92.2%) |
| African American | 10 (4.1%) |
| Asian | 7 (2.9%) |
| Other | 2 (0.8%) |
| Unknowna | 5 |
| Family history of breast cancer (1st or 2nd degree relative) | |
| Yes | 95 (39.3%) |
| Unknowna | 7 |
| Chemoprevention use | 31 (12.4%) |
| Chemoprevention duration (months), median (IQR) b | 40 (17–59) |
| BI-RADS breast density | |
| 1 | 3 (1.2%) |
| 2 | 31 (12.5%) |
| 3 | 166 (66.9%) |
| 4 | 48 (19.4%) |
| Unknowna | 1 |
| MRI screening | 135 (54.2%) |
| Laterality of index cancer to LCIS diagnosis | |
| Contralateral | 89 (35.7%) |
| Ipsilateral | 128 (51.4%) |
| Index cancer bilateralc | 18 (7.2%) |
| LCIS bilateralc | 14 (5.6%) |
| Index cancer histology | |
| DCIS | 83 (33.9%) |
| IDC | 95 (38.8%) |
| ILC | 60 (24.5%) |
| Other | 7 (2.9%) |
| Unknowna | 4 |
| Index cancer tumor stage | |
| Tis | 83 (34.2%) |
| T1 | 145 (59.7%) |
| T2–4 | 15 (6.2%) |
| Unknowna | 6 |
| Index cancer nodal stage | |
| N0 | 149 (59.8%) |
| N1 | 25 (10%) |
| N2 | 3 (1.2%) |
| N3 | 4 (1.6%) |
| N4 | 0 (0.0%) |
| Nx | 68 (27.3%) |
| Index cancer ER status | |
| Positive | 162 (93.1%) |
| Negative | 12 (6.9%) |
| Characteristic | n = 249 |
| Index cancer ER status | |
| Unknowna | 75 |
| Index cancer PR status | |
| Positive | 120 (76.9%) |
| Negative | 36 (23.1%) |
| Unknowna | 93 |
| Index cancer HER2+ status | |
| Positive | 13 (9%) |
| Negative | 132 (91%) |
| Unknowna | 104 |
| Index cancer grade (invasive primary) | n = 166 |
| 1 | 23 (20.0%) |
| 2 | 39 (33.9%) |
| 3 | 53 (46.1%) |
| Unknowna | 51 |
| Index cancer adjuvant treatment (invasive and DCIS) | n = 249 |
| Surgery | |
| Lumpectomy | 145 (59.2%) |
| Mastectomy | 100 (40.8%) |
| Unknowna | 4 |
| Radiation | |
| Yes | 106 (44.7%) |
| Unknowna | 12 |
| Endocrine therapy | |
| Yes | 144 (60.8%) |
| Unknowna | 12 |
| Index cancer adjuvant treatment (invasive only) | n = 166 |
| Endocrine therapy | |
| Yes | 124 (80%) |
| Unknowna | 7 |
| Chemotherapy | |
| Yes | 48 (28.9%) |
| Unknowna | 5 |
| Anti-HER2 therapy | n = 13 |
Unknown values not calculated into overall percentages or total “n”
Data available for 24 of 31 women on chemoprevention duration
One patient had bilateral LCIS and bilateral index cancer; they were counted only once as part of the ‘bilateral index cancer’ cohort
Abbreviations: LCIS, lobular carcinoma in situ; IQR, interquartile range; BI-RADS, Breast Imaging–Reporting and Data System; DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; Tis, tumor in situ; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2
Bilateral breast cancer
Overall, 34 patients (2%) developed BBC, including 18 with SBBC and 16 with MBBC. There were no significant differences in clinicopathologic features, including age, breast density, tumor histology, stage, receptor status, tumor grade and treatment received, between women who developed UBC compared to any BBC (Supplementary Table 1).
Synchronous bilateral breast cancer
SBBC was diagnosed in 18 women, representing 1% of the entire LCIS cohort (18 of 1651). SBBC tumor characteristics are displayed in Table 2. Eleven women had a known or suspected diagnosis of SBBC preoperatively, while 7 women had a diagnosis of UBC and were diagnosed with occult disease in the contralateral breast at the time of bilateral mastectomy. Overall, 12 of the 18 women with SBBC underwent bilateral mastectomy while 6 opted for bilateral lumpectomies. There were no significant differences in age, family history, index tumor histology, receptor status, stage, use of MRI screening, breast density, or chemoprevention use between patients with SBBC and UBC (all P > 0.05), although more women with SBBC underwent mastectomy (67% versus 40%, P = 0.027, respectively) (Table 3).
Table 2.
Characteristics of synchronous bilateral breast cancers
| Synchronous Bilateral Breast Cancer, n = 18 women | |
|---|---|
| Characteristic | n (%) |
| Family history of breast cancer (1st or 2nd degree relative) | 6/18 (33.3%) |
| Prior chemoprevention use | 3/18 (16.7%) |
| Prior MRI imaging | 13/18 (72.2%) |
| Timing of BBC diagnosis | |
| SBBC diagnosed or suspected pre-operatively | 11/18 (61.1%) |
| UBC diagnosed pre-operatively, occult contralateral breast cancer diagnosed on CPM | 7/18 (38.9%) |
| Histology | |
| Bilateral DCIS | 3/18 (16.7%) |
| Bilateral invasive carcinoma | 8/18 (44.4%) |
| Bilateral IDC | 3 |
| Bilateral ILC | 1 |
| Unilateral IDC; Unilateral ILC | 3 |
| Other | 1 |
| Unilateral invasive carcinoma, unilateral DCIS | 7/18 (38.9%) |
| Unilateral IDC; Unilateral DCIS | 3 |
| Unilateral ILC; Unilateral DCIS | 3 |
| Other | 1 |
| Invasive Synchronous Bilateral Breast Cancer Details, n = 23 tumorsa | |
| Characteristic | n (%) |
| T1 tumor | 23/23 (100%) |
| Node positive | 4/23 (17.4%) |
| ER+/HER2− receptor statusa | 22/22 (100%) |
Of the 23 SBBCs with an invasive component (8 women with bilateral invasive tumors and 7 women with a unilateral invasive tumor and unilateral DCIS), 1 was missing hormone receptor data
Abbreviations: MRI, magnetic resonance imaging; BBC, bilateral breast cancer; SBBC, synchronous bilateral breast cancer; UBC, unilateral breast cancer; CPM, contralateral prophylactic mastectomy; DCIS, ductal carcinoma in situ; ILC, invasive lobular carcinoma; IDC, invasive ductal carcinoma; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2
Table 3.
Comparison of index tumor characteristics of unilateral breast cancer versus synchronous bilateral breast cancer and metachronous bilateral breast cancer
| Characteristic | UBC (n = 215) | SBBCa (n = 18) | UBC vs SBBC P-value | MBBC (n = 16) | UBC vs MBBC P-value |
|---|---|---|---|---|---|
| Age at 1st cancer diagnosis, mean (min, max) | 58 (29, 93) | 54 (47, 68) | 0.2 | 54 (41, 70) | 0.3 |
| Age at 2nd cancer diagnosis, mean (min, max) | NA | NA | NA | 60 (43, 79) | NA |
| Family history of breast cancer (1st or 2nd degree relative) | 0.3 | 0.6 | |||
| Yes | 85 (41%) | 5 (28%) | 5 (33.3%) | ||
| Unknown | 6 | 0 | 1 | ||
| BI-RADS breast density score | 0.6 | 0.6 | |||
| 1 | 3 (1.4%) | 0 (0.0%) | 0 (0.0%) | ||
| 2 | 29 (13.6%) | 1 (5.6%) | 1 (6.2%) | ||
| 3 | 144 (67.3%) | 12 (66.7%) | 10 (62.5%) | ||
| 4 | 38 (17.8%) | 5 (27.8%) | 5 (31.3%) | ||
| Unknownb | 1 | 0 | 0 | ||
| Histology | 0.4 | 0.2 | |||
| DCIS | 70 (33.2%) | 4 (22.2%) | 9 (56.3%) | ||
| IDC | 84 (39.8%) | 7 (38.9%) | 4 (25%) | ||
| ILC | 52 (24.6%) | 6 (33.3%) | 2 (12.5%) | ||
| Other | 5 (2.4%) | 1 (5.6%) | 1 (6.2%) | ||
| Unknownb | 4 | 0 | 0 | ||
| Tumor stage | 0.3 | 0.2 | |||
| Tis | 70 (33.5%) | 4 (22.2%) | 9 (56.3%) | ||
| 1 | 125 (59.8%) | 14 (77.8%) | 6 (37.5%) | ||
| ≥ 2 | 14 (6.7%) | 0 (0.0%) | 1 (6.3%) | ||
| Unknownb | 6 | 0 | 0 | ||
| Nodal stage | 0.07 | 0.1 | |||
| 0 | 129 (60%) | 13 (72.2%) | 7 (43.8%) | ||
| 1 | 23 (10.7%) | 1 (5.6%) | 1 (6.3%) | ||
| 2 | 1 (0.5%) | 1 (5.6%) | 1 (6.3%) | ||
| 3 | 3 (1.4%) | 1 (5.6%) | 0 (0.0%) | ||
| 4 | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Nx | 59 (27.4%) | 2 (11.1%) | 7 (43.8%) | ||
| ER status a | > 0.9 | 0.1 | |||
| Positive | 142 (93.4%) | 13 (100%) | 7c | ||
| Unknownb | 63 | 5 | 7 | ||
| PR status | 0.7 | 0.08 | |||
| Positive | 107 (78.7%) | 9 (75%) | 4c | ||
| Unknownb | 79 | 6 | 8 | ||
| HER2+ status | 0.6 | 0.5 | |||
| Positive | 12 (9.6%) | 0 (0.0%) | 1 (14.3%) | ||
| Unknownb | 90 | 5 | 9 | ||
| Grade (invasive only) | n = 145 | n = 14 | 0.2 | n = 7 | 0.6 |
| 1 | 18 (18.4%) | 5 (41.7%) | 0 (0%) | ||
| 2 | 34 (34.7%) | 4 (33.3%) | 1 (20%) | ||
| 3 | 46 (46.9%) | 3 (25%) | 4 (80%) | ||
| Grade (invasive only) | n = 145 | n = 14 | 0.2 | n = 7 | 0.6 |
| Unknownb | 47 | 2 | 2 | ||
| Index cancer treatment (invasive and DCIS) | n = 215 | n = 18 | n = 16 | ||
| Surgery | 0.03 | 0.2 | |||
| Lumpectomy | 127 (60.2%) | 6 (33.3%) | 12 (75%) | ||
| Mastectomy | 84 (39.8%) | 12 (66.7%) | 4 (25%) | ||
| Unknown | 4 | 0 | 0 | ||
| Radiation | 0.7 | 0.8 | |||
| Yes | 91 (44.8%) | 7 (38.9%) | 8 (50.0%) | ||
| Unknownb | 12 | 0 | 0 | ||
| Endocrine therapy | 0.4 | 0.02 | |||
| Yes | 126 (62.0%) | 13 (72%) | 5 (31%) | ||
| Unknownb | 12 | 0 | 0 | ||
| Index cancer treatment (invasive only) | n = 145 | n = 14 | n = 7 | ||
| Endocrine therapy | 0.7 | 0.05 | |||
| Yes | 109 (79%) | 12 (85.7%) | 3 (42.9%) | ||
| Unknownb | 7 | 0 | 0 | ||
| Chemotherapy | >0.9 | 0.03 | |||
| Yes | 39 (27.9%) | 4 (28.6%) | 5 (71.4%) | ||
| Unknownb | 5 | 0 | 0 | ||
| Anti-HER2 therapy | n = 12 | n = 0 | n = 1 | ||
| Yes | 6 (50.0%) | 0 (0.0%) | 0 (0.0%) |
For SBBC cases, the breast that was diagnosed first was selected as the index tumor for UBC comparisons. For those cases diagnosed on the same date, the tumor with the higher stage was selected for comparison. For treatment strategies including radiation therapy, endocrine therapy, chemotherapy, and anti-HER2 therapy, any receipt of treatment for either cancer was included
Unknown values not calculated into overall percentages or total “n”
Percentages not shown due to small numbers and substantial missing data
Abbreviations: UBC, unilateral breast cancer; MBBC, metachronous bilateral breast cancer; NA, not applicable; min, minimum; max, maximum; BI–RADS, Breast Imaging-Reporting and Data System; DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; Tis, tumor in situ; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2
Metachronous bilateral breast cancer
Among the remaining patients with an index UBC, 211 had a contralateral breast at risk following biopsy of the index cancer; 16 of 211 developed MBBC, representing 1% of the entire LCIS cohort (16 of 1651) (Fig. 1). Comparisons between the MBBC cohort and the UBC cohort are shown in Table 3. Women with MBBC were less likely to receive endocrine therapy (31% versus 62%, P = 0.015), and more likely to receive chemotherapy for their initial invasive breast cancer (71% [5/16] versus 28% [39/215], P = 0.025). Of the 16 MBBC events, 7 DCIS lesions had unknown receptor status while 7 of the remaining 9 tumors were hormone receptor positive. Among women who developed MBBC, 12 of 16 index cancers were treated with lumpectomy and 4 of 16 with unilateral mastectomy; for the CBC event, 8 of 16 underwent lumpectomy, 3 of 16 underwent a unilateral mastectomy, and 5 of 16 opted for bilateral mastectomy.
The estimated 5-year risk of MBBC development among women with a remaining contralateral breast at risk was 6.4% (95% confidence interval [CI] 1.9–10.7). Cumulative MBBC incidence overall, and stratified by index tumor, ER status, and index tumor histology, are displayed in Fig. 2A–C. While there were few (n = 12) ER negative tumors, the 3-year estimated MBBC risk was significantly higher among ER negative compared to ER positive tumors (16.7% versus 3.9%, P = 0.004). Similarly, the 5-year estimated MBBC risk among women who took endocrine therapy was 3.5%. Univariate Cox regression analysis examining factors associated with MBBC development is shown in Table 4. There was no significant difference in MBBC development based on index tumor histology. ER positivity (hazard ratio [HR] 0.13, 95% CI 0.02–0.68, P = 0.015), progesterone receptor positivity (HR 0.24, 95% CI 0.06–0.98, P = 0.047), and use of endocrine therapy (HR 0.17, 95% CI 0.05–0.59, P = 0.005) were the only factors associated with risk of MBBC development on univariate analysis. A sensitivity analysis that excluded 45 women who underwent bilateral mastectomy within 6 months of diagnosis showed that the direction and significance of univariate associations with risk of MBBC did not change when these patients were omitted.
Fig 2.
Contralateral metachronous breast cancer incidence (a) overall and (b) stratified based on estrogen receptor status and (c) primary tumor histology. Abbreviations: CI, confidence interval
Table 4.
Univariate Cox analysis of factors associated with metachronous bilateral breast cancer
| Characteristic | Total “N” | HR | 95% CI | P-value |
|---|---|---|---|---|
| Age 1st cancer diagnosis * | 211 | 0.3 | ||
| ≤ 60 years | --- | |||
| > 60 years | 0.54 | 0.17–1.70 | ||
| Family history | 204 | 0.6 | ||
| Yes | --- | |||
| No | 1.37 | 0.47–4.03 | ||
| Histology | 209 | |||
| DCIS only | --- | --- | ||
| IDC | 0.38 | 0.12–1.24 | 0.1 | |
| ILC | 0.34 | 0.07–1.57 | 0.2 | |
| Other | 1.43 | 0.18–11.4 | 0.7 | |
| ER status | 154 | 0.02 | ||
| Negative | --- | --- | ||
| Positive | 0.13 | 0.02–0.68 | ||
| PR status | 138 | 0.05 | ||
| Negative | --- | --- | ||
| Positive | 0.24 | 0.06–0.98 | ||
| HER2+ status | 126 | 0.6 | ||
| Negative | --- | --- | ||
| Positive | 1.74 | 0.21–14.5 | ||
| MRI | 211 | 0.7 | ||
| Yes | --- | --- | ||
| No | 0.81 | 0.30–2.19 | ||
| Tumor stage | 208 | |||
| Tis | 0.69 | 0.08–5.84 | 0.7 | |
| 1 | 0.25 | 0.03–2.22 | 0.2 | |
| ≥ 2 | --- | --- | ||
| Nodal stage | 211 | |||
| 0–1 positive | --- | --- | ||
| 2–4 positive | 6.76 | 0.81–56.2 | 0.08 | |
| Nx | 1.95 | 0.70–5.40 | 0.2 | |
| BI-RADS breast density | 210 | 0.2 | ||
| 1–2 | --- | --- | ||
| 3–4 | 3.57 | 0.46–27.1 | ||
| Prior chemoprevention use | 211 | 0.3 | ||
| Yes | --- | --- | ||
| No | 0.49 | 0.11–2.18 | ||
| Endocrine therapy use a | 202 | 0.005 | ||
| Yes | 0.17 | 0.05–0.59 | ||
| No | --- | --- |
Age assessed as a continuous variable was also not significantly associated with MBBC risk
Analyzed as a time-dependent variable
Abbreviations: HR, hazard ratio; CI, confidence interval; DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; MRI, magnetic resonance imaging; Tis, tumor in situ; BI-RADS, Breast Imaging–Reporting and Data System
Discussion
LCIS is an established breast cancer risk factor, associated with a 2% annual incidence of breast cancer development and up to a 10-fold increased breast cancer risk compared with the general population [2–4,6]. Prior work has shown that women with LCIS who are diagnosed with a subsequent breast cancer are often diagnosed at an early stage with hormone receptor positive tumors and have excellent breast cancer-specific survival (98.9% and 96.3% at 10 and 20 years, respectively), but data regarding the risk of subsequent CBC development in this population are lacking [27]. In our study, we identified overall low rates of bilateral breast cancer among a large cohort of women with a history of LCIS, including 1% presenting with SBBC and an overall ~1.3% annual risk of MBBC, with an estimated 6.3% 5-year MBBC risk among women with UBC and a contralateral breast at risk. To our knowledge, this is the first estimate of CBC development in a cohort of women with LCIS and an index cancer.
While variable rates of SBBC and MBBC in the general population are reported in the literature, ranging from 0.8–2.9% and 1.0–7.0%, respectively, interpreting these data is inherently challenging given the number of factors that are known to affect BBC rates, including patient age, tumor subtype, genetic predisposition, family history of breast cancer, and treatment-related factors [10,15,28–33]. Additionally, there are differing definitions in the literature of the time interval used to define a metachronous breast event [10,15,28–31,33]. We selected the cut-off of 6 months to distinguish between synchronous and metachronous disease in our cohort and included clinicopathological information on well-recognized risk factors for BBCs in an effort to best predict the factors associated with SBBC and MBBC in women with a history of LCIS.
We observed a 1% rate of SBBC in our cohort of women with LCIS, which is comparable with SBBC rates seen in the general population (0.8–2.9%) [10,15,28–31,33]. While SBBC rates vary somewhat by era of study and definition of SBBC, a study by Nichol and colleagues reported on rates and outcomes of patients with SBBC compared to UBC diagnosed in British Columbia, Canada from 1989 to 2000 and reported an identical 1% rate of SBBC from a cohort of over 15,000 breast cancer patients [34]. Importantly, tumor histology (lobular versus ductal), age, breast density, and family history were not significantly associated with risk of SBBC development in the current study.
The overall 5-year and 10-year estimated MBBC risks were 6.4% (95% CI 1.9–10.7) and 16.7% (95% CI 7.4–25.2), respectively, with a significant difference noted by hormone receptor status (ER positive tumor HR 0.13, P = 0.02) and no significant difference conferred by index tumor histology. Notably, presentation of an index ILC does not appear to independently increase the risk of MBBC among women with a history of LCIS.
While earlier literature suggested that lobular histology was an independent risk factor for SBBC and MBBC, our findings are consistent with more recent studies that have found no increased risk of CBC by tumor histology [21,35–37]. Further, a recent study using the Netherlands Cancer Registry found a minimal absolute difference in SBBC between lobular and ductal index cancers (0.6%); as such, it is now recognized that imaging and surgical treatment for the contralateral breast should not differ between women with ILC and IDC. Our findings support this practice and demonstrate that the development of an index ILC, even among women with LCIS, is associated with low rates of BBC.
Ultimately, having an ER and/or progesterone receptor positive index cancer and the use of endocrine therapy were the only factors associated with MBBC risk. On univariate analysis, use of endocrine therapy was associated with over an 80% reduction in the rate of CBC development (HR 0.17, P = 0.005). Our findings are in line with prior studies that have consistently shown an association between ER positivity and reduced CBC risk [25,38,39], emphasizing the significant impact of adjuvant endocrine therapy for contralateral breast protection. Studies report downward trends in CBC rates, likely due to increasing use of adjuvant systemic therapies, including chemotherapy, endocrine therapy, and anti-HER2 therapy, which have all been shown to reduce MBBC risk [7,15,29–31,40–42]. A report of patients in the U.S. Surveillance, Epidemiology, and End Results cancer registries from 1992–2015 found decreasing rates of MBBC—with the largest decline noted among women with ER positive tumors—resulting in a 5-year cumulative incidence of contralateral breast cancer of 1% among women < 50 years of age with an ER positive tumor [32]. Reassuringly, the vast majority of patients with LCIS who develop an index breast cancer have ER positive disease and benefit from endocrine therapy. The current analysis shows a < 1% per year risk of MBBC for those women with ER positive tumors, and an overall 5-year estimated MBBC risk of 3.5% for women treated with endocrine therapy—rates similar to the reported ranges in the literature.
Chemoprevention with anti-estrogen treatment has been shown to significantly reduce breast cancer development among high-risk women, including those with LCIS. Data from large randomized controlled trials have proven the efficacy of tamoxifen, raloxifene, and aromatase inhibitors for breast cancer prevention in women who are at high risk [43–49]. The National Surgical Adjuvant Breast and Bowel Project Prevention-1 trial randomized 13,388 high-risk women to 5 years of tamoxifen or placebo and reported a significant reduction in invasive breast cancer (49%) with tamoxifen use, including a 56% risk reduction among women with LCIS [46]. In our prior investigation of 1060 women with LCIS, a total of 1004 were monitored either with chemoprevention (n = 173) or surveillance alone (n = 831). At a median follow-up of 81 months, 150 patients developed 168 breast cancers. Breast cancer incidence was significantly reduced in those taking chemoprevention (10-year cumulative risk: 7% with chemoprevention versus 21% with no chemoprevention, P < 0.001), and on multivariate analysis, chemoprevention use was strongly associated with reduced risk (HR 0.27, 95% CI 0.2–0.5) [6]. In the current analysis, only 12% of women took chemoprevention prior to their index cancer development, and we were not able to discern a relationship between chemoprevention use and subsequent BBC risk. Prior studies examining chemoprevention uptake have suggested that patient refusal due to fear of adverse effects is a common reason for limited uptake, indicating an ongoing role for educational efforts regarding the absolute risks and benefits of these agents in the context of overall breast cancer risk [50]. Nevertheless, our findings highlight the durable protection of endocrine therapy for the contralateral breast among patients with unilateral, ER positive cancers, and a history of LCIS.
Strengths and limitations
Limitations of this study include those inherent to a retrospective review. Additionally, the median follow-up period for time to development of MBBC was only 3 years, which may underestimate the true incidence of MBBC events over time; longer follow-up of this cohort is necessary. The strengths of this analysis include its reliance on a prospectively maintained database with robust supplemental clinicopathologic data, which is, to our knowledge, the largest cohort of women with LCIS observed longitudinally over time with institutional pathology review.
Conclusions
Among a large cohort of women with a history of LCIS, we found a 2% overall incidence of any BBC development (1% synchronous and 1% metachronous), with an estimated 5-year risk of MBBC of 6.4% among women with LCIS and an initial unilateral cancer diagnosis. Index lobular histology did not influence BBC development. ER positive/progesterone receptor positive status and the use of endocrine therapy were the only factors associated with reduced risk of MBBC, highlighting the contralateral breast protection associated with endocrine therapy use in this population. These data will aid in counseling women with a prior history of LCIS about their future CBC risks, and support the recommendation for endocrine therapy for risk reduction in this population.
Supplementary Material
Supplementary Table 1 Comparison of characteristics of unilateral breast cancer versus any bilateral breast cancer
Acknowledgments and Funding Information:
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant No. P30 CA008748 to Memorial Sloan Kettering Cancer Center. Dr. Tari A. King reports speakers’ honoraria from Exact Sciences (formerly Genomic Health), advisory board participation for Exact Sciences, faculty membership with PrecisCa, and Global Advisory Board membership with Besins Healthcare. All other authors have no conflicts of interest or commercial interests to disclose. This study was presented in poster format at the Virtual 2020 Society of Surgical Oncology International Conference on Surgical Cancer Care, August 17–18, 2020. This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Memorial Sloan Kettering Cancer Center approved this study.
Footnotes
Competing Interests: Dr. Tari A. King reports speakers’ honoraria from Exact Sciences (formerly Genomic Health), advisory board participation for Exact Sciences, faculty membership with PrecisCa, and Global Advisory Board membership with Besins Healthcare. All other authors have no conflicts of interest or commercial interests to disclose.
Prior Presentation: This study was presented in poster format at the Virtual 2020 Society of Surgical Oncology International Conference on Surgical Cancer Care, August 17–18, 2020.
Ethical Approval: This retrospective chart review study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Memorial Sloan Kettering Cancer Center approved this study.
Data Availability:
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1 Comparison of characteristics of unilateral breast cancer versus any bilateral breast cancer
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.