Women with a history of ductal carcinoma in situ (DCIS) have an elevated risk of a subsequent invasive breast cancer, but there are few established potentially modifiable factors known to lower this risk. Bisphosphonates are a commonly used treatment for patients with osteoporosis and have been shown to lower risks of recurrence and mortality in patients with invasive breast cancer; however, their use has not previously been investigated within the context of DCIS. Utilizing a population-based nested case–control design, we compared 301 cases of women diagnosed with DCIS and a subsequent breast cancer and 587 individually matched controls (on age, DCIS diagnosis year, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but never a subsequent breast cancer. Information on recency and duration of bisphosphonate use was ascertained from patient interviews and medical record reviews. Current users of bisphosphonates had a reduced risk of developing an invasive breast cancer compared with never users [OR = 0.50; 95% confidence interval (CI): 0.26–0.99]. Users of bisphosphonates for ≥48 months had a similar reduction in risk (OR = 0.45; 95% CI, 0.24–1.06). This is the first study to document that bisphosphonate use is associated with a lower risk of subsequent invasive breast cancer among women with a history of DCIS. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. If validated by others, bisphosphonates may be an effective risk-reducing approach with the potential added benefits of its positive impacts on bone health and fracture risk.

Significance:

This study finds that bisphosphonate use among women with a history of DCIS is associated with lower risk of subsequent invasive breast cancer, providing a potential preventative approach for this high-risk population.

Ductal carcinoma in situ (DCIS) accounts for approximately 20% of all new breast cancer diagnoses each year in the United States (1). In the United States alone, more than 60,000 new DCIS diagnoses are made each year, so coupled with its nearly 100% 5-year survival rate, there is an ever growing population of women with a history of DCIS globally. A history of DCIS does confer a 3.4- to 4.6-fold higher risk of developing a subsequent invasive breast cancer compared with the risk of developing a first invasive breast cancer among women without a history of DCIS (2–4). While adjuvant hormonal therapy can reduce this risk (5, 6), it is not widely used because of its side effect profile (7). Consequently, there is a need to identify alternate approaches that can lower risk of invasive breast cancer among women with a history of DCIS.

Bisphosphonates are a commonly used treatment for patients with osteoporosis, a condition with a prevalence of approximately 25% among U.S. women age 65 years and older that increases to approximately 50% among women over the age of 85. In addition to reducing risk of fracture among patients with osteoporosis, there is now a substantial body of evidence to support the role of bisphosphonates in primary and secondary breast cancer prevention (8–12). Indeed, several randomized trials have documented the benefits of bisphosphonates in reducing risks of recurrence and mortality among breast cancer survivors (13). We have also documented that bisphosphonate use reduces risk of second primary contralateral breast cancer among women diagnosed with a first primary invasive estrogen receptor–positive breast cancer (14). However, to our knowledge, no prior studies have assessed the relationship between bisphosphonate use and risk of invasive breast cancer among women with a history of DCIS. We evaluated this association in a population-based study designed specifically to characterize risk factors for second breast cancer events among women diagnosed with DCIS.

Study population

This study's methods have been previously described (15–17). Briefly, we conducted a population-based nested case–control study designed to characterize risk factors for a subsequent invasive breast cancer among women diagnosed with DCIS. Women aged 30 to 79 years and diagnosed with DCIS between January 1, 1995 and June 30, 2013 were identified from the Cancer Surveillance System, the Surveillance, Epidemiology, and End Results (SEER) cancer registry that serves western Washington state. Cases were defined as women who were diagnosed with a subsequent invasive breast cancer at least 6 months after their DCIS diagnosis. Controls who did not have a second breast cancer event (in situ or invasive) during the study period were individually matched 2:1 to cases on age (±2 years), year of DCIS diagnosis (±2 years), county of residence at diagnosis, surgical and radiation treatment, DCIS histology, DCIS grade, and disease-free survival time. Written, informed consent was obtained from study participants, and the study was approved by the Institutional Review Board at the Fred Hutchinson Cancer Research Center.

Of the eligible 469 cases and 1,143 controls selected for this study, 337 cases (72%) and 647 controls (57%) were enrolled. Participants missing data on bisphosphonate use were excluded (n = 99, 36 cases and 63 controls). The final analytic sample size was 301 cases and 584 controls.

Data collection

Information on epidemiologic risk factors, demographics, and clinical factors was collected for the time period between DCIS diagnosis and each participant's reference date. For cases, the reference date was the date of invasive breast cancer diagnosis and the median interval between DCIS and invasive breast cancer was 68 months (range: 6–208 months). Reference dates were assigned to controls based on the interval between DCIS diagnosis and invasive breast cancer diagnosis of the case they were matched to. Information on bisphosphonate use was collected from medical records and telephone interviews for the period from 2 years before DCIS diagnosis until reference date. The correlation between medical record and self-reported bisphosphonate use was quite high (kappa = 0.93), and for patients where these two sources were discrepant, the data from medical records were prioritized. For 70% of study participants data on bisphosphonate use came from medical records, and for the remaining 30% it was based on self-report. Ever users of bisphosphonates were defined as women who used bisphosphonates for ≥6 months in the period between the 2 years prior to DCIS diagnosis and their reference date. Current use was defined as bisphosphonate use within the 6 months prior to reference date and former use was defined as last use of bisphosphonates ≥6 months prior to reference date. Duration of use was categorized as the number of months in which women used bisphosphonates during the period between the 2 years prior to DCIS diagnosis and their reference date. Data on osteoporosis and osteopenia were also ascertained both from medical records and telephone interviews.

Statistical analysis

Associations between bisphosphonate use and risk of a subsequent invasive breast cancer among women with a history of DCIS were quantified using conditional logistic regression and ORs and 95% confidence intervals (CI) were computed. All models were implicitly adjusted for the matching factors. Additional confounders (those listed in Table 1) were evaluated, but only adjustment for body mass index (BMI) changed risk estimates by greater than 10% and thus it was added to all models as a potential confounder. We also stratified analyses of our primary outcome by estrogen receptor (ER) status and laterality of the subsequent invasive cancer compared to the original DCIS (ipsilateral vs. contralateral). Analyses were conducted using SAS v9.4 (SAS Institute). To assess potential confounding by indication, we also conducted analyses restricted only to study participants with a history of osteoporosis and/or osteopenia.

Table 1.

Demographic and clinical factors by case–control status.

Controls, n (%)Cases, n (%)
Characteristicsn = 587n = 301
Age at DCIS diagnosis 
 <50 201 (34.2) 103 (34.2) 
 50–59 200 (34.1) 97 (32.2) 
 60–69 135 (23.0) 75 (24.9) 
 70–79 51 (8.7) 26 (8.6) 
Year of DCIS diagnosis 
 1995–1997 150 (25.6) 60 (19.9) 
 1998–2000 132 (22.5) 87 (28.9) 
 2001–2004 160 (27.3) 75 (24.9) 
 2005–2013 145 (24.7) 79 (26.2) 
Race/ethnicity 
 Non-Hispanic white 533 (90.8) 266 (88.4) 
 Hispanic white 7 (1.2) 8 (2.7) 
 Black 11 (1.9) 8 (2.7) 
 Asian/Pacific Islander 26 (4.4) 11 (3.7) 
 Native American 10 (1.7) 7 (2.3) 
 Unknown 
DCIS grade 
 Well differentiated 13 (2.7) 13 (5.4) 
 Moderately differentiated 152 (32.0) 62 (25.7) 
 Poorly differentiated 137 (28.8) 71 (29.5) 
 Undifferentiated 173 (36.4) 95 (39.4) 
 Unknown 112 60 
Primary DCIS treatment 
 Biopsy only 6 (1.0) 4 (1.3) 
 Lumpectomy without radiation 168 (28.6) 79 (26.2) 
 Lumpectomy with radiation 301 (51.3) 160 (53.2) 
 Total mastectomy 112 (19.1) 58 (19.3) 
Adjuvant hormonal therapy for DCIS 
 No 351 (59.8) 214 (71.1) 
 Yes 236 (40.2) 87 (28.9) 
Family history of breast cancer 
 No 412 (72.4) 199 (67.7) 
 Yes 157 (27.6) 95 (32.3) 
 Missing 18 
History of osteoporosis/osteopenia 
 No 368 (62.7) 199 (66.1) 
 Yes 219 (37.3) 102 (33.9) 
BMI at DCIS diagnosis, kg/m2 
 <25.0 296 (51.5) 125 (42.1) 
 25.0–29.9 162 (28.2) 87 (29.3) 
 ≥30.0 117 (20.3) 85 (28.6) 
 Unknown 12 
Controls, n (%)Cases, n (%)
Characteristicsn = 587n = 301
Age at DCIS diagnosis 
 <50 201 (34.2) 103 (34.2) 
 50–59 200 (34.1) 97 (32.2) 
 60–69 135 (23.0) 75 (24.9) 
 70–79 51 (8.7) 26 (8.6) 
Year of DCIS diagnosis 
 1995–1997 150 (25.6) 60 (19.9) 
 1998–2000 132 (22.5) 87 (28.9) 
 2001–2004 160 (27.3) 75 (24.9) 
 2005–2013 145 (24.7) 79 (26.2) 
Race/ethnicity 
 Non-Hispanic white 533 (90.8) 266 (88.4) 
 Hispanic white 7 (1.2) 8 (2.7) 
 Black 11 (1.9) 8 (2.7) 
 Asian/Pacific Islander 26 (4.4) 11 (3.7) 
 Native American 10 (1.7) 7 (2.3) 
 Unknown 
DCIS grade 
 Well differentiated 13 (2.7) 13 (5.4) 
 Moderately differentiated 152 (32.0) 62 (25.7) 
 Poorly differentiated 137 (28.8) 71 (29.5) 
 Undifferentiated 173 (36.4) 95 (39.4) 
 Unknown 112 60 
Primary DCIS treatment 
 Biopsy only 6 (1.0) 4 (1.3) 
 Lumpectomy without radiation 168 (28.6) 79 (26.2) 
 Lumpectomy with radiation 301 (51.3) 160 (53.2) 
 Total mastectomy 112 (19.1) 58 (19.3) 
Adjuvant hormonal therapy for DCIS 
 No 351 (59.8) 214 (71.1) 
 Yes 236 (40.2) 87 (28.9) 
Family history of breast cancer 
 No 412 (72.4) 199 (67.7) 
 Yes 157 (27.6) 95 (32.3) 
 Missing 18 
History of osteoporosis/osteopenia 
 No 368 (62.7) 199 (66.1) 
 Yes 219 (37.3) 102 (33.9) 
BMI at DCIS diagnosis, kg/m2 
 <25.0 296 (51.5) 125 (42.1) 
 25.0–29.9 162 (28.2) 87 (29.3) 
 ≥30.0 117 (20.3) 85 (28.6) 
 Unknown 12 

Abbreviation: BMI, body mass index.

Compared with controls, cases were somewhat less likely to have received adjuvant hormonal therapy for their DCIS and to have a history of osteoporosis/osteopenia and somewhat more likely to have a first-degree family history of breast cancer and to be obese (Table 1). The distributions of other characteristics were similar between cases and controls. In this study, 92% of bisphosphonates users used an oral bisphosphonate and 77% used alendronate.

Current users of bisphosphonates had an appreciably lower risk of developing an invasive breast cancer compared with never users (OR = 0.50; 95% CI, 0.26–0.99), and the risk among former users was equivalent to never users (Table 2). A reduction in risk of similar magnitude was also observed among users of bisphosphonates for 48 months or longer (OR = 0.50; 95% CI, 0.24–1.06). No differences in the magnitude or direction of these reductions in risk were observed when results were stratified by the laterality or estrogen receptor status of the second primary breast cancer (Supplementary Table S1).

Table 2.

Relationship between bisphosphonate use and risk of a subsequent invasive breast cancer among women with DCIS.

ControlsCases
Bisphosphonate usen (%)n (%)OR (95% CI)a
Ever use 
 Never 473 (80.6) 259 (86.0) 1.00 (ref) 
 Ever 114 (19.4) 42 (14.0) 0.71 (0.45–1.12) 
Recency of use 
 Current 55 (9.5) 16 (5.4) 0.50 (0.26–0.99) 
 <24 months of use 23 (4.0) 4 (1.3) 0.17 (0.04–0.77) 
 ≥24 months of use 32 (5.6) 12 (4.0) 0.76 (0.35–1.64) 
 Former 51 (8.8) 24 (8.1) 0.97 (0.53–1.76) 
Duration of use, months 
 <24 45 (7.7) 22 (7.3) 0.87 (0.46–1.61) 
 24–47 20 (3.4) 9 (3.0) 0.84 (0.35–2.04) 
 48–147 43 (7.4) 11 (3.7) 0.50 (0.24–1.06) 
ControlsCases
Bisphosphonate usen (%)n (%)OR (95% CI)a
Ever use 
 Never 473 (80.6) 259 (86.0) 1.00 (ref) 
 Ever 114 (19.4) 42 (14.0) 0.71 (0.45–1.12) 
Recency of use 
 Current 55 (9.5) 16 (5.4) 0.50 (0.26–0.99) 
 <24 months of use 23 (4.0) 4 (1.3) 0.17 (0.04–0.77) 
 ≥24 months of use 32 (5.6) 12 (4.0) 0.76 (0.35–1.64) 
 Former 51 (8.8) 24 (8.1) 0.97 (0.53–1.76) 
Duration of use, months 
 <24 45 (7.7) 22 (7.3) 0.87 (0.46–1.61) 
 24–47 20 (3.4) 9 (3.0) 0.84 (0.35–2.04) 
 48–147 43 (7.4) 11 (3.7) 0.50 (0.24–1.06) 

aModels were implicitly adjusted for matching factors [age (±2 years), year of DCIS diagnosis (±2 years), county of residence at diagnosis, surgical and radiation treatment, DCIS histology, DCIS grade, and disease-free survival time] and for BMI at DCIS diagnosis and use of adjuvant hormonal therapy for DCIS.

To assess potential confounding by indication, we also evaluated these relationships in analyses restricted to women with a history of osteopenia or osteoporosis (Table 3). Within this subset of patients, approximately equal numbers of controls were never versus ever bisphosphonate users. The directions of all of the main findings were the same as the primary analysis. While the magnitudes of the associations were stronger, some individual risk estimates did not reach statistical significance due to the more limited available sample size for this subanalysis.

Table 3.

Relationship between bisphosphonate use and risk of a subsequent invasive breast cancer among women with DCIS with a history of osteopenia or osteoporosis.

ControlsCases
Bisphosphonate usen (%)n (%)OR (95% CI)a
Ever use 
 Never 111 (50.7) 62 (60.8) 1.00 (ref) 
 Ever 108 (49.3) 40 (39.2) 0.47 (0.23–0.98) 
Recency of use 
 Current 51 (24.2) 15 (15.0) 0.37 (0.12–1.16) 
 <24 months of use 19 (9.0) 3 (3.0) 0.12 (0.01–1.14) 
 ≥24 months of use 32 (15.2) 12 (12.0) 0.50 (0.15–1.67) 
 Former 49 (23.2) 23 (23.0) 0.53 (0.24–1.21) 
Duration of use, months 
 <24 40 (18.8) 20 (19.6) 0.63 (0.25–1.56) 
 24–47 20 (9.4) 9 (8.8) 0.52 (0.16–1.67) 
 48–147 42 (19.7) 11 (10.8) 0.31 (0.11–0.86) 
ControlsCases
Bisphosphonate usen (%)n (%)OR (95% CI)a
Ever use 
 Never 111 (50.7) 62 (60.8) 1.00 (ref) 
 Ever 108 (49.3) 40 (39.2) 0.47 (0.23–0.98) 
Recency of use 
 Current 51 (24.2) 15 (15.0) 0.37 (0.12–1.16) 
 <24 months of use 19 (9.0) 3 (3.0) 0.12 (0.01–1.14) 
 ≥24 months of use 32 (15.2) 12 (12.0) 0.50 (0.15–1.67) 
 Former 49 (23.2) 23 (23.0) 0.53 (0.24–1.21) 
Duration of use, months 
 <24 40 (18.8) 20 (19.6) 0.63 (0.25–1.56) 
 24–47 20 (9.4) 9 (8.8) 0.52 (0.16–1.67) 
 48–147 42 (19.7) 11 (10.8) 0.31 (0.11–0.86) 

aModels were implicitly adjusted for matching factors [age (±2 years), year of DCIS diagnosis (±2 years), county of residence at diagnosis, surgical and radiation treatment, DCIS histology, DCIS grade, and disease-free survival time] and for BMI at DCIS diagnosis and use of adjuvant hormonal therapy for DCIS.

To our knowledge, this is the first study to document that bisphosphonate use is associated with a lower risk of a subsequent invasive breast cancer among women with a history of DCIS. This relationship was strongest among current and longer-term bisphosphonate users and did not appear to be confounded by indication. This finding is consistent with the protective effect of bisphosphonates observed in other breast cancer settings. Specifically, there is existing observational data indicating that bisphosphonate use may prevent breast cancer in the general population (8–11), and multiple randomized control trials show that bisphosphonates reduce risks of recurrence and mortality among patients with breast cancer (13). In the primary prevention setting, results from a recent meta-analysis suggest that longer durations of bisphosphonate use are more strongly inversely associated with risk, consistent with our findings in the context of DCIS (12).

Bisphosphonates have the potential to lower invasive breast cancer risk among women with a history of DCIS through direct inhibition of tumor growth and spread. In preclinical models, bisphosphonates have been shown to inhibit metastases and angiogenesis and induce apoptosis, and more recent data indicate that bisphosphonates can modulate tumor immune response (18–22). In addition, bisphosphonates impact the bone microenvironment in ways that can disrupt the presence of dormant disseminated tumor cells residing in the bone (23, 24).

One potential limitation of an observational study of this type is confounding by indication. This is relevant in this setting given that the primary indication for bisphosphonates is osteoporosis, a condition characterized by low bone mineral density that can often be the consequence of low levels of circulating estrogen. Given the well-established positive association between endogenous estrogen levels and breast cancer risk (25), it is possible that the association between bisphosphate use and breast cancer risk could be due to lower levels of estrogen in bisphosphonate users versus nonusers. However, in our analyses restricted to women with a history of osteopenia/osteoporosis, the same inverse associations between bisphosphonate use and breast cancer risk were observed. Anthropometric factors are also potential proxies for bone density, and our risk estimates are all adjusted for body mass index. Thus, confounding by indication is unlikely to have had an appreciable impact on our results. While well powered for our main analyses, another limitation of this study was our inability to assess risks by subtypes of DCIS associated with clinical aggressiveness due to sample size considerations. Key strengths of this study are its population-based design and minimization of recall bias through using data from medical records as the primary source of data on history of bisphosphonate use. Furthermore, because invasive breast cancer is a reportable disease in Washington state surveillance bias is likely negligible as all invasive breast cancers occurring among the women included in this study should have been identified by our cancer registry.

The population of women with a history of DCIS continues to grow in the United States and globally as utilization of mammographic screening is widespread. Despite having a nearly 100% 5-year survival rate, DCIS does confer an appreciable 3.4- to 4.6-fold higher risk of developing a subsequent invasive breast cancer compared with the risk of developing a first invasive breast cancer among women without a history of DCIS (2–4). Identifying safe and effective strategies to mitigate this risk remains important. If validated in other studies, bisphosphonates may be an effective risk reducing approach with the potential added benefits of its positive impact on bone health and reducing fracture risk. However, it is also important to note its well-established adverse effects that include osteonecrosis of the jaw and atrial fibrillation. Nevertheless, given that bisphosphonates are generally well tolerated, further investigation of their role in reducing risk of invasive breast cancer within the high-risk population of women with a history of DCIS is warranted.

C.I. Li reports grants from NCI during the conduct of the study. M.-T.C. Tang reports grants from NCI during the conduct of the study. P.L. Porter reports grants from NCI during the conduct of the study. K.E. Malone reports grants from NCI during the conduct of the study. No disclosures were reported by the other author.

C.I. Li: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, methodology, writing–original draft, project administration, writing–review and editing. M.R. Flanagan: Writing–review and editing. M.-T.C. Tang: Formal analysis, methodology, writing–review and editing. P.L. Porter: Funding acquisition, writing–review and editing. K.E. Malone: Resources, funding acquisition, methodology, writing–review and editing.

This study was funded by the NCI (R01-CA097271).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Supplementary data