Several studies have suggested that bisphosphonates have an antitumor effect. In the current study, the authors sought to evaluate whether the use of bisphosphonates increased the rate of pathological complete response (pCR) in patients with breast cancer.
The authors identified 1449 patients with breast cancer who were receiving taxane- and anthracycline-based neoadjuvant chemotherapy between 1995 and 2007 at The University of Texas MD Anderson Cancer Center. Patients who received bisphosphonates for osteopenia or osteoporosis while receiving chemotherapy were also identified. The primary outcome was the percentage of patients achieving a pCR. Groups were compared using the chi-square test. A multivariable logistic regression model was fit to examine the relation between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan-Meier method was performed; groups were compared using the log-rank test.
Of the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (P < .001) and less likely to be obese (P = .04). The pCR rate was 25.4% in the bisphosphonate group and 16% in the nonbisphosphonate group (P = .11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (odds ratio, 2.18; 95% confidence interval, 0.90-5.24); however, the difference was not found to be statistically significant. With a median follow-up of 55 months (range, 3 months-145 months), no differences in disease recurrence or survival were observed.
Breast cancer is the second most common cause of cancer death among women in the United States. It is estimated that during 2009, > 194,280 new cases were diagnosed and 40,610 deaths occurred.1 Despite significant advances in the treatment of patients with breast cancer, approximately 10% to 60% of patients with initial localized breast cancer will develop systemic disease recurrence. Neoadjuvant systemic therapy (NST) is the standard approach to treat women with locally advanced and inflammatory breast cancer, and is now being used in patients with earlier stage disease. By downstaging tumors; NST most likely improves available surgical options while concurrently allowing for in vivo assessment of chemosensitivity. Furthermore, attaining a pathological complete response (pCR) after NST has been shown by several investigators to be a surrogate marker for improved long-term outcome, possibly because of the eradication of distant micrometastatic residual disease.2-8 Unfortunately, NST using conventional anthracycline- and/or taxane-based regimens results in pCR rates of only 8% to 31%.4, 6, 9, 10
Bisphosphonates are analogs of pyrophosphates that bind to hydroxyapatite crystals and inhibit bone resorption by osteoclasts. They are widely used for the treatment of osteoporosis and to prevent both skeletal complications in patients with bone metastases and the bone loss associated with cancer treatment.11, 12 There are clinical and preclinical data suggesting that bisphosphonates have osteoclast-independent effects that can be associated with an antitumor effect.13 Proposed mechanisms include the induction of apoptosis; a synergistic effect with chemotherapy; or the inhibition of tumor cells by affecting adhesion, migration, invasion, and cell proliferation.14-16 Recent epidemiological studies have shown that the use of bisphosphonates decreases the incidence of invasive breast cancer in postmenopausal women.17, 18
The purpose of the current study was to determine whether the use of bisphosphonates increased the rates of pCR in a cohort of patients with breast cancer who were treated with taxane- and anthracycline-based neoadjuvant chemotherapy.
MATERIALS AND METHODS
Patients treated with NST were identified in a prospectively maintained database in the Breast Medical Oncology department at The University of Texas MD Anderson Cancer Center. A total of 1449 patients diagnosed with invasive primary breast cancer between 1995 and 2007 and treated with anthracycline- and taxane-based NST were included. We excluded patients with metastatic disease at the time of diagnosis, those with bilateral breast cancer, or males. The variables recorded included patient demographics (race, age, and menopausal status), tumor characteristics (histology; grade; lymphovascular invasion [LVI]; and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2] status), clinical stage at diagnosis (based on the criteria proposed by the sixth edition of American Joint Committee on Cancer criteria19), body mass index (BMI), pathological stage, and recurrence and survival information. Patients who received bisphosphonates for another indication (osteopenia and osteoporosis) while receiving NST were identified by chart review (physician's notes, medication records, and pharmacy records).
All pathology specimens were reviewed by dedicated breast pathologists at the study institution. Histologic type and grade were defined according to the World Health Organization classification system20 and the modified nuclear grade system of Black and Speer,21 respectively. All surgical breast and axillary lymph node specimens were reviewed to identify the presence or absence of residual disease. pCR was defined as no residual invasive cancer in both the breast and the axillary lymph nodes.
All patients were treated with a multidisciplinary approach and received NST with an anthracycline- and taxane-based regimen. Taxanes administered included paclitaxel at a dose of 175 to 250 mg/m2 intravenously (iv) on day 1 every 21 days for 4 cycles; paclitaxel at a dose of 80 mg/m2 weekly for 12 doses; or docetaxel at a dose of 100 mg/m2 iv on day 1 every 3 weeks for 4 cycles. Anthracycline regimens included 3 to 6 cycles of 1 of the following: 5-fluorouracil at a dose of 500 mg/m2, epirubicin at a dose of 100 mg/m2, and cyclophosphamide at a dose of 500 mg/m2 iv on day 1, every 3 weeks; 5-fluorouracil at a dose of 500 mg/m2 on days 1 and 4, epirubicin at a dose of 75 mg/m2, and cyclophosphamide at a dose of 500 mg/m2 iv on day 1, every 3 weeks; 5-fluorouracil at a dose of 500 mg/m2 iv on days 1 and 4, doxorubicin at a dose of 50 mg/m2 iv by continuous infusion over 72 hours, and cyclophosphamide at a dose of 500 mg/m2 on day 1 every 3 weeks; or doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 iv on day 1, every 3 weeks. There were a total of 258 patients with tumors that overexpressed HER2-neu; none of these patients received trastuzumab in the neoadjuvant setting. At the completion of NST, all patients underwent definitive surgery; eligibility for breast conservation was determined based on recommendations made by the multidisciplinary team and patient preferences. All patients underwent axillary lymph node staging with axillary lymph node dissection or sentinel lymph node biopsy. Radiation therapy was delivered if patients underwent breast conservation surgery or had locally advanced disease, a primary tumor measuring > 5 cm, or ≥ 4 involved lymph nodes. Adjuvant hormonal therapy was administered according to standard practice. The Institutional Review Board of The University of Texas MD Anderson Cancer Center approved the study.
Statistical Analysis and Outcome Measures
We computed descriptive statistics. Patient characteristics were compared based on whether patients received bisphosphonates, and groups were compared using the chi-square test. Rates of pCR were compared among groups. An exploratory analysis was performed to compare the pCR rates by bisphosphonate status according to tumor subtype. A multivariable logistic regression model was fit to examine the relation between the use of bisphosphonates and pCR. Variables in the model included age, stage of disease, tumor grade, tumor subtype, LVI, and BMI. Exploratory survival analyses were performed to examine the recurrence-free survival (RFS) and overall survival (OS) between groups. RFS was calculated from the date of diagnosis to the date of first documented local or distant recurrence or last follow-up. Patients who died before experiencing a disease recurrence were considered censored at their date of death. OS was calculated from the date of diagnosis to the date of death or last follow-up. The Kaplan-Meier product limit method was used to estimate the survival outcomes and groups were compared with the log-rank statistic. P values < .05 were considered to be statistically significant. All tests were 2-sided. Statistical analyses were performed using SAS (version 9.1; SAS Institute Inc, Cary, NC) and S-Plus 7.0 (Insightful Corporation, Seattle, Wash) statistical software.
A total of 1449 patients were included, of whom only 39 (2.7%) received bisphosphonates concurrently with NST. Among the patients who received bisphosphonates, 66.7% (n = 26), 28.2% (n = 11), and 5.1% (n = 2) received alendronate, risedronate, and ibandronate, respectively. Patients who received bisphosphonates were more likely to be older and postmenopausal (P < .001 for both) and were less likely to be overweight (P = .04). Patient and tumor characteristics stratified by bisphosphonate use are summarized in Table 1.
Table 1. Patient and Tumor Characteristics According to Bisphosphonate Use
Nonbisphosphonate Group (N=1410)
Bisphosphonate Group (N=39)
Abbreviations: +, positive; BMI, body mass index; HER2, human epidermal growth factor receptor 2; LVI, lymphovascular invasion.
Among the patients not treated with bisphosphonates, 16.0% achieved a pCR. A higher rate of pCR (25.6%) was observed among those patients treated with bisphosphonates; however, this difference did not achieve statistical significance (P = .11). When the rates of pCR in the bisphosphonate and nonbisphosphonate groups were compared according to tumor subtype, the same trend was observed, but in all cases the results were not statistically significant. In the patients with hormone-positive tumors, the pCR rates between the bisphosphonate and nonbisphosphonate groups were 7.6% versus 16.7% (P = .10); in those patients with tumors overexpressing HER2-neu, the rates were 26.8% versus 37.5% (P = .50); and among patients with triple receptor-negative tumors, the rates were 26.9% versus 42.9% (P = .35). The results of the multivariable model for pCR are shown in Table 2. After adjusting for age, stage, tumor subtype, grade, LVI, and BMI, bisphosphonate use was found to be associated with higher pCR rates (odds ratio [OR], 2.16; 95% confidence interval [95% CI], 0.90-5.24 [P = .08]); however, statistical significance was not reached.
Table 2. Multivariable Logistic Regression Model for pCR
95% CI, 95% confidence interval; BMI, body mass index; HER2, human epidermal growth factor receptor 2; LVI, lymphovascular invasion; OR, odds ratio; pCR, pathologic complete response.
Bisphosphonate use: yes vs no
Age: ≥50 y vs <50 y
Stage: III vs I/II
Grade: III vs I/II
Subtype: HER2 positive vs hormone positive
Subtype: triple negative vs hormone positive
LVI: positive vs negative
BMI: overweight vs normal
BMI: obese vs normal
The median follow-up was 55 months (range, 3 months–155 months). Among all patients, there were 413 recurrences. The RFS rate at 5 years was 71.0% (95%CI, 68.0%-73.0%) among patients who did not receive bisphosphonates and 81% (95%CI, 64%-90%) among those who did (P = .28). There were a total of 359 deaths. The OS rate at 5 years was 77.0% (95%CI, 74.0%-79.0%) among those patients who did not receive bisphosphonates compared with 83% (95%CI, 65.0%-92.0%) for those who did (P = .42). The RFS and OS estimates by bisphosphonate group according to tumor subtype are shown in Table 3. Kaplan-Meier curves for RFS and OS by bisphosphonate group are presented in Figure 1.
Table 3. Five-Year Recurrence-Free Survival and 5-Year Overall Survival Among Patients Who Received and Those Who Did Not Receive Bisphosphonatesa
Estimates are shown for all patients and according to tumor subtype.
The objective of the current study was to describe the effect of bisphosphonate use on the pCR rates among patients with breast cancer who are treated with anthracycline- and taxane-based neoadjuvant chemotherapy. In this retrospective, single-institution study, the results demonstrated that pCR rates were higher among patients who received bisphosphonates; however, the difference was not statistically significant. Similarly, in a multivariable model, patients who received oral bisphosphonates during NST tended to have higher rates of pCR; however, this association only approached statistical significance. We did not find an association between bisphosphonate use and RFS or OS.
Despite being inconclusive, these results of the current study could suggest that bisphosphonates may have tumor effects outside the bone, maybe even enhancing the effect of chemotherapy. We observed that 16% of the patients in the current study who did not receive bisphosphonates achieved a pCR compared with 25.6% of the patients who did. These results are in concordance with previously reported data. The AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial evaluated whether zoledronic acid (ZA) when added to systemic chemotherapy improved disease-related outcomes. In a subset analysis evaluating 195 patients who received NST,22 the mean residual tumor size was smaller in the ZA group compared with the non-ZA group (P = .024). The rates of pCR favored the group treated with ZA (6.9% vs 11.7%) and in the multivariable analysis, the use of ZA increased the odds of achieving a pCR (OR, 2.1; 95%CI, 0.8-6.3).22 The estimate did not achieve statistical significance, and the authors attributed it to the small number of patients achieving a pCR. In a phase 2 clinical trial (n = 120), Aft et al evaluated the addition of ZA to anthracycline- and taxane-based NST.23 In an exploratory analysis evaluating tumor responses at the time of surgery, a pCR rate of 15.5% was observed in the patients who did not receive ZA compared with 21.6% in the patients who did (P = .63). In addition, in a tumor subtype analysis, they observed an effect among patients with triple-negative tumors, with a pCR rate of 10.5% in the non-ZA group compared with 28.6% in the ZA acid group. More recently, the ANZAC trial randomized 40 patients to receive chemotherapy with or without ZA. The biomarker analysis indicated a greater reduction in VEGF and in cell turnover at day 5 in the ZA arm; however, this marker recovered by day 21, suggesting that ZA may have relevant biologic effects that require further exploration.24
Despite being insignificant, the results of the current and some of the previously discussed studies suggest that bisphosphonates may have an antitumor effect when used in combination with NST. However, the small numbers mandate a cautious interpretation of the data. Bisphosphonates, and in particular ZA, have been demonstrated to have a synergistic antitumor effect in preclinical models when used in combination with doxorubicin,14, 15 and all the patients included in the previously discussed studies were treated with anthracyclines. The possible antitumor effect of bisphosphonates is also supported by epidemiological studies suggesting that the use of bisphosphonates is associated with a reduced risk of developing breast cancer. Data from the Women's Health Initiative evaluated the association between the use of bisphosphonates and the development of invasive breast cancer. In a large cohort of 154,768 postmenopausal women, a statistically significant association between the use of oral bisphosphonates and a lower incidence of invasive breast cancer (hazard ratio [HR], 0.68; 95% CI, 0.52-0.88) was observed.17 Similarly, Rennert et al18 reported that the use of bisphosphonates for > 1 year was associated with a 28% reduction in the risk of postmenopausal breast cancer.
The potential antitumor effect of bisphosphonates has been reported in the adjuvant setting, but the data are still inconclusive. Diel et al25 randomized 302 patients to receive clodronate for 2 years versus standard of care. After 36 months of follow-up, a reduction in the incidence of bone and visceral metastases (P = .003) and an increase in OS (P = .001) in the clodronate treatment arm were observed. However, after an extended follow-up of 53 months, the effect of clodronate on visceral metastases was no longer significant. A similar large multicenter study26 compared the use of clodronate against placebo in 1069 patients with breast cancer. After 2 years of treatment, patients in the clodronate group had a reduction in the incidence of bone metastases; however, the effect did not reach statistical significance. In contrast, Saarto et al27 did not observe any reduction in the incidence of bone metastases in those patients who were randomized to receive clodronate. The patients treated with clodronate were actually found to have a higher risk of nonskeletal recurrences (43% vs 25%; P = .0007), leading to lower disease-free survival (DFS) in the treatment arm.
The Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 study (n = 1803), a phase 3, 2 × 2, 4-arm trial, randomized patients to receive goserelin acetate or tamoxifen with or without ZA.28 No difference was observed among the tamoxifen and goserelin treatment arms, however; patients who received ZA experienced an improvement in RFS (HR, 0.64; 95%CI, 0.46-0.91), but no difference in OS was noted. A recently published meta-analysis29 including data from 13 clinical trials evaluated the use of bisphosphonates in the adjuvant setting in 6886 patients with breast cancer. Treatment with ZA was not found to be associated with any statistically significant difference in rates of death (OR, 0.642; 95%CI, 0.388-1.063) or bone metastasis (OR, 0.661; 95%CI, 0.379-1.151). The AZURE trial22 randomized 3360 patients with breast cancer to receive 5 years of ZA or no treatment. With a median follow-up of 58.6 months, no differences with regard to rates of local or distant recurrence or DFS (HR, 0.98; 95%CI, 0.85-1.10) or OS (HR, 0.88; 95%CI, 0.72-1.01) were observed. However, in an analysis performed according to menopausal status, an improvement in DFS and OS was observed among patients with established menopause, suggesting that ZA may have a benefit when administered in a low-estrogen environment.
To appreciate the findings of the current study, some strengths and limitations need to be addressed. The current study is retrospective in nature, and therefore is associated with the limitations inherent to this type of study design. All the patients were treated at The University of Texas MD Anderson Cancer Center. Despite the different chemotherapy regimens used, patients were treated in similar way regardless of whether they were treated with bisphosphonates. Therefore, if differences in treatment occurred, they were nondifferential. Information regarding bisphosphonate intake during NST was obtained by chart review. However, despite a thorough review of physician's notes, medication records, and pharmacy records, it is possible that not all the patients receiving bisphosphonates were correctly identified, likely diluting any possible association. The observed estimates suggest that bisphosphonates may have a positive effect in increasing the rates of pCR among patients with breast cancer; however, the small percentage of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference. In addition, it is important to mention that all the patients identified as bisphosphonate users received oral bisphosphonates. We cannot exclude the possibility that the use of iv, more potent bisphosphonates could have a significant effect on the rates of pCR. In addition, we did not observe any differences in RFS or OS. It is important to mention that the impact of adjuvant radiation, endocrine, and trastuzumab therapy was not taken into account in the current analysis. It is possible that any potential differences in survival were diluted by differences in treatment in the adjuvant setting.
In conclusion, the results of the current study demonstrate that in this cohort of patients, bisphosphonate use was not associated with pCR rates. Although all our estimates suggest a positive effect, the small percentage of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference. Given the preclinical and clinical data suggesting bisphosphonate-induced antitumor effects, prospective studies evaluating the effect of potent bisphosphonates are needed. Several questions regarding the use of bisphosphonates remain unanswered; it is unclear what dose and frequency will be appropriate and further studies should address this issue. In addition, further epidemiological studies and molecular characterization of the tumors are needed to explore whether the antitumor effect of bisphosphonates predominates in specific subsets of patients with breast cancer.
This work was funded by National Institutes of Health grant K23 CA121994 (to A.M.G-A).