Adjuvant Breast Cancer Setting Research Articles

Abstract P2-09-07: Elevated Pretreatment Serum CA9 (CAIX) (Carbonic Anhydrase 9) Predicts Reduced Progression-Free and Overall Survival in Trastuzumab-Treated Metastatic Breast Cancer

Abstract Background: Approximately one-half of HER2-positive breast cancer patients will respond to first-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Serum HER2, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), CA9, Insulin-like growth factor-1 receptor (IGF-1R), VEGF-165, and endoglin were measured using ELISA assays in 60 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The HER2, TIMP-1, uPA, CA9, IGF-IR, and VEGF-165 ELISAs were from Oncogene Science/Siemens Healthcare Diagnostics, Cambridge, MA; and the endoglin ELISA was from R&D Systems, Minneapolis, MN. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: Pretreatment serum HER2 (p= 0.008), TIMP-1 (p< 0.0001), uPA (p= 0.006), endoglin (p= 0.010), and CA9 (p <0.0001) were all significant as univariate continuous biomarkers for predicting PFS to first-line trastuzumab-containing therapy, but VEGF (p=0.94) and IGF-IR (p=0.11) were not. In multivariate analysis for PFS with all 7 biomarkers, only serum CA9 (p= 0.002) was a significant independent covariate. For OS, pretreatment serum HER2 (p= 0.018), TIMP-1 (P<0.0001), uPA (P<0.0001), endoglin (0.006), CA9 (P<0.0001) were all significant as univariate continuous biomarkers for prognosis, but VEGF (p=0.69) and IGF-IR (p=0.098) were not. In multivariate analysis for OS with all 7 biomarkers, only serum CA9 was a significant independent prognostic covariate (p=0.001), and TIMP-1 trended significant (p=0.069). Conclusions: Elevated pretreatment serum CA9 (a marker of hypoxia) predicts reduced progression-free survival and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-07.

HER2-Targeted Treatment in the Adjuvant Setting for Breast Cancer

HER2-Targeted Treatment in the Adjuvant Setting for Breast Cancer

Use of aromatase inhibitors and bisphosphonates as an anticancer therapy in postmenopausal breast cancer

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.

Breast carcinoma with amplified HER2: a gene expression signature specific for trastuzumab resistance and poor prognosis

Recent trials have shown remarkable efficacy from combined trastuzumab and chemotherapy in the adjuvant setting of breast cancer. In spite of these successes, refractory breast cancer has emerged as a clinically problematic outcome for a subset of patients managed this way. In an effort to clarify and optimize the treatment regimens for breast cancer patients who are candidates to receive trastuzumab, we sought to analyze whether a distinctive genetic signature could be characterized that would reliably predict the treatment outcome. The ability to predict who will respond and who will become refractory to this agent will allow for improved, rational clinical management of these patients and further stratify the personalized nature of this treatment regimen. In this study, 41 consecutive cases of breast carcinoma with well-documented amplification of the human epidermal growth factor receptor-2 gene and corresponding banked fresh-frozen tissue were identified and divided into two separate groups based on whether they received trastuzumab or not. The first group consisted of 12 patients who had received trastuzumab in the adjuvant setting, of which three later experienced tumor recurrence. The second group consisted of 10 patients not treated with trastuzumab, of which 6 were later found to have recurrence. Differentially expressed genetic profiles were determined using human genome-wide Illumina Bead Microarrays. The differentially expressed genes for non-recurrence vs recurrence in the trastuzumab-treated group were distinct from those in the same comparison group in the untreated group. Differential expression of key genes indentified in this study might offer an insight into a possible mechanism of trastuzumab resistance in breast carcinoma, and may emerge as potential predictive biomarkers indicative of trastuzumab resistance.

Bisphosphonate in der adjuvanten Therapie des Mammakarzinoms

For more than 10 years, based on the results with the bisphosphonate clodronic acid, it has been discussed, whether the occurrence of breast cancer metastases can be avoided or at least delayed by administration of bisphosphonates. The published results of recent studies applying, e.g., the bisphosphonates zoledronic and ibandronic acid, respectively, seem promising at first glance, especially, if the therapeutic acceptance of bisphosphonates in the indications osteoporosis and bone-related complications of malignancies, respectively, as well as their spectrum of side effects are taken into account and their putative mechanism of action is considered. There is a broad consensus that the existing data basis suffices to demonstrate importance of bisphosphonates in an adjuvant therapeutic setting of breast cancer. Significant relative risk reductions of, e.g., 36% in disease-free survival are very impressing and the corresponding absolute values of 3.2% are second-line communications. However, evaluation of all studies published so far according to the criteria of evidence-based medicine demonstrates many open questions and several methodical insufficiencies. Therefore, effectiveness and benefit of an adjuvant therapeutic application of bisphosphonates in breast cancer patients cannot be drawn out of evidence-based data. A recommendation of this therapy is given only by the German Working Pool of Gynecologic Oncology (AGO), but limited to study participation.

Should bisphosphonates be utilized in the adjuvant setting for breast cancer?

Adjuvant therapies for early breast cancer are associated with substantial decreases in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbidity in patients with bone metastases and in the treatment of osteoporosis. Recently, several trials have demonstrated the efficacy of bone-directed agents for prevention of cancer treatment-induced bone loss in both premenopausal and postmenopausal women with early stage breast cancer. Moreover, it is now becoming evident that bisphosphonates may also exert anticancer effects in the adjuvant setting. For example, long-term follow-up of a study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for clodronate versus placebo, and an ongoing large trial may provide further insights. Addition of twice-yearly zoledronic acid to standard adjuvant endocrine therapy significantly improved disease-free survival and decreased disease recurrence compared with standard therapy alone in 3 clinical trials involving nearly 3,500 patients with stage I-IIIA breast cancer, and monthly zoledronic acid during neoadjuvant therapy decreased residual tumor volume and improved pathologic response in patients with stage II/III breast cancer. Overall, a large and growing body of evidence suggests the potential adjuvant benefits of bisphosphonates in early breast cancer.

Breast carcinoma with amplified HER2: A gene expression signature specific for trastuzumab resistance and poor prognosis.

657 Background: Recent trials have demonstrated remarkable efficacy from combined trastuzumab and chemotherapy in the adjuvant setting of breast cancer. However, trastuzumab resistance continues to be problematic. We intended to explore the possibility of the presence of a gene expression signature for trastuzumab resistance. Methods: Forty-one consecutive breast carcinoma cases that had amplified HER2 and fresh frozen tissue available were collected. Twelve patients were treated with trastuzumab, 3 of which had recurrence. Eleven patients were not treated with trastuzumab, 6 of which had recurrence. Human genome-wide Illumina bead microarrays were used to identify differentially expressed genes (DEGs) for nonrecurrence versus recurrence in trastuzumab treated (TT) patients, and in trastuzumab nontreated (TNT) patients, respectively. Microarrays were also used to identify DEGs from separate comparisons involving collected patients' clinicopathologic data (age, race, tumor stage, hormonal status, and menopausal status). Results: TheDEGs for nonrecurrence versus recurrence in the TT group were distinct from those for nonrecurrence versus recurrence in the TNT group. They were also distinct from the DEGs obtained from comparisons involving other collected patients' clinicopathologic data. While DEGs in the TT group were enriched in the DNA binding, those in the TNT group are enriched in immunity and defense. The HER2 pathway was found to be significantly disregulated only in the TT group. None of the known genes that have been described to be involved in trastuzumab resistance showed any significant changes at transcriptional level. Conclusions: Differential expression of key genes indentified in this study might offer an insight into a possible mechanism of trastuzumab resistance in breast carcinoma, and might emerge as potential biomarkers for diagnosis and treatment of trastuzumab resistance. No significant financial relationships to disclose.

Does Adjuvant Bisphosphonate in Early Breast Cancer Modify the Natural Course of the Disease? A Meta-Analysis of Randomized Controlled Trials

To address whether the use of bisphosphonates in the adjuvant setting of breast cancer might have any effect on the natural course of the disease, a meta-analysis was conducted of published and unpublished randomized controlled trials found in PubMed, the Cochrane Central Register of Controlled Trials, the ISI Web of Knowledge, and abstracts of major international conferences up to January 2009. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with any bisphosphonate versus non-use were considered eligible. Analysis included data from 13 eligible trials involving 6886 patients randomized to treatment with bisphosphonates (n = 3414) or either placebo or no treatment (n = 3472). Compared with no use, adjuvant breast cancer treatment with bisphosphonates did not reduce the overall number of deaths (odds ratio [OR], 0.708; 95% CI, 0.482-1.041; P = .079), bone metastases (OR, 0.925; 95% CI, 0.768-1.114; P = .413), overall disease recurrences (OR, 0.843; 95% CI, 0.602-1.181; P = .321), distant relapse (OR, 0.896; 95% CI, 0.674-1.192; P = .453), visceral recurrences (OR, 1.051; 95% CI, 0.686-1.609; P = .820), or local relapses (OR, 1.056; 95% CI, 0.750-1.487; P = .756). No significant heterogeneity was observed among the trials except for estimates of deaths and disease recurrences (P = .034 and P = .016, respectively). In subgroup analyses, use of zoledronic acid was associated with a statistically significant lower risk for disease recurrence (OR, 0.675; 95% CI, 0.479-0.952; P = .025). However, these results should be interpreted with caution because the statistical significance for this association was weak and might be attributed to chance from multi-test analyses. Use of zoledronic acid was not associated with any significant difference in death (OR, 0.642; 95% CI, 0.388-1.063) and bone metastasis rates (OR, 0.661; 95% CI, 0.379-1.151). Currently available evidence does not support the hypothesis that use of bisphosphonates in adjuvant treatment of early breast cancer will alter the natural course of the disease. Nonetheless, a nonsignificant trend seems to exist for better outcomes in patients undergoing bisphosphonate treatment. Until further evidence from new clinical trials becomes available, adjuvant bisphosphonates should not be recommended routinely.

Can we Consider Zoledronic Acid a New Antitumor Agent? Recent Evidence in Clinical Setting

New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

Radiation impact in breast cancer

Four questions were considered pivotal by the organizers of the Controversies in Breast Cancer 2009 meeting in Edinburgh, September 2009 with regards to the radiation (RT) effect in the adjuvant setting of early breast cancer: What are the data indicating that local radiotherapy is associated with long-term survival benefit? What must be irradiated to obtain a long-term effect? What is the mechanism of action whereby local RT can influence long-term outcome? Is the RT effect applicable to different subsets? Answers to these questions constitute the present contribution.

Reply to R.M. Memmott et al

We thank the authors for their excellent summary of potential mechanisms of anticancer action of metformin. The assays they suggest were included as core embedded correlative research activities in a proposal for a large scale phase III trial of metformin in the adjuvant breast cancer setting developed by our group. The proposal was recently approved by the Breast Committee of the Clinical Therapy Evaluation Program of the National Cancer Institute. We anticipate activation of the trial early in 2010, under the leadership of the NCIC Clinical Trials Group (Kingston, Canada).

Trastuzumab-Induced Cardiotoxicity

To review trastuzumab-related cardiotoxic effects in the breast cancer adjuvant setting, present a system for pretreatment screening for cardiovascular risk factors, describe monitoring recommendations, provide a tool to facilitate adherence to monitoring guidelines, and discuss implications for patient education. Literature regarding cardiotoxicity and trastuzumab in breast cancer. Trastuzumab was approved in 2006 for use in the adjuvant setting. A small percentage of women (approximately 4%) developed heart failure during or after treatment. However, the trials excluded women with cardiac disease. Current screening for cardiotoxicity relies on sequential left ventricular function measurements with either echocardiography or multigated acquisition scanning at baseline and every three months. Treatment modifications are recommended if changes from baseline are detected. Long-term and late effects have yet to be determined. Although a small number of women experienced cardiotoxicity in the adjuvant setting, an increase may be seen because women with preexisting heart disease receive this treatment. Guidelines and tools will be helpful for appropriate and consistent screening of cardiac risk factors and disease prior to initiation of trastuzumab and for monitoring during and after administration. Nurses are instrumental in assessing, monitoring, and treating women receiving trastuzumab. Implementing guidelines to promote adherence to recommended monitoring is important in the early detection of cardiotoxicity in this population. Educating women about their treatment and side effects is an important aspect of care.

Emergence of nonanthracycline regimens in the adjuvant treatment of breast cancer

Long-term toxicity of adjuvant regimens is a critical consideration given improvements in survival and consequential management of treatment-related side effects. Despite their well-documented long-term side effects, including a cumulative dose-dependent cardiotoxicity and an increase in the incidence of secondary leukemia, anthracyclines remain an integral component of many adjuvant regimens for breast cancer. The utility of HER-2/TOP2A coamplification in predicting sensitivity to anthracycline chemotherapy has been widely suggested but requires substantiation. The recent maturation of two large phase III trials that directly examined the substitution of a taxane for an anthracycline in the adjuvant setting provides further data to critically evaluate the standard use of anthracyclines in the treatment of early-stage breast cancer. Results from both US Oncology 9735 and BCIRG 006 demonstrated equivalent efficacies in taxane- and anthracycline comparator arms. However, in both trials, the taxane-based regimen(s) resulted in less relative toxicity than the anthracycline-based regimen(s). These trial results pose legitimate questions regarding the future application of anthracyclines in the adjuvant breast cancer setting.

Preliminary results of a phase II study of liposomal cisplatin-vinorelbine combination as first-line treatment in HER2/neu negative metastatic breast cancer (MBC)

1068 Background: The frequent use of anthracyclines and taxanes in breast cancer's adjuvant setting has lead to drug resistance and cardiac toxicity. This has raised the need for new agents in the metastatic setting. Cisplatin-vinorelbine combination recently showed interesting results with an overall response rate of 64%. Nevertheless, the use of cisplatin was limited by the frequently induced nausea, vomiting, and nephrotoxicity. Liposomal cisplatin (Lipoplatin) is a nontoxic alternative agent to cisplatin. The aim of this study is to evaluate the efficacy and safety of liposomal cisplatin-vinorelbine combination in first line MBC patients (pts). Methods: From August 2007 to October 2008, 30 of 35 programmed pts with MBC and no prior treatment for their metastatic disease, PS 0–2, HER2/neu negative, and at least one measurable lesion, were enrolled. Of these 30 recruited pts, 26 with available data were analyzed. Treatment included I.V. vinorelbine 30 mg/m2 on days 1 and 8, and liposomal cisplatin 120 mg/m2 on days 1, 8, and 15. Cycles were repeated every 3 weeks for a total of 6 cycles. Primary objectives: objective response rate, time to treatment failure (TTF), and time to progression (TTP). Secondary objectives: overall survival and treatment-related toxicity. Results: The median age was 49 years (29–74). 69% of pts had visceral metastases. 35% had one metastatic site, 46% had 2, 19% had 3 or more. A total of 120 cycles were administered with a median number of 6 per patient. At the time of the analysis 22 pts were evaluable for response. An objective tumor response was observed in 11 pts (50%) and complete response in 1 patient (4.5%). Ten (45.5%) pts had stable disease. The median TTF and TTP were 5 and 8 months respectively. All pts (26) were evaluable for toxicity. The majority of adverse events were mild to moderate. No WHO grade 3–4 nephrotoxicity or neuropathy was noted. Grade 3–4 nausea/vomiting was observed in 3 pts (11.5%). Three pts (11.5%) had grade 3 anemia and 18 pts (69.2%) had grade 3–4 neutropenia. Three pts (11.5%) developed febrile neutropenia with no secondary mortality. Conclusions: The new combination of liposomal cisplatin and vinorelbine shows promising activity and good tolerance as first line treatment for HER2/neu negative MBC. Pts’ enrollment is ongoing. Updated results will be presented at the meeting. [Table: see text]

Use of pretreatment serum CA9 (carbonic anhydrase 9) to predict PFS and survival in trastuzumab-treated metastatic breast cancer

11092 Background: Approximately half of HER2-positive breast cancer patients will respond to first-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a vexing clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Serum HER2, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), CA9, VEGF-165, and endoglin were measured using ELISA assays in 66 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The HER2, TIMP-1, uPA, CA9, and VEGF-165 ELISAs were from Oncogene Science/Siemens Healthcare Diagnostics, Cambridge, MA; and the endoglin ELISA was from R&D Systems, Minneapolis, MN. Progression-free (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: Pretreatment serum HER2 (p= 0.005), TIMP-1 (p< 0.0001), uPA (p= 0.006), endoglin (p= 0.008), and CA9 (p <0.0001) were all significant as univariate continuous biomarkers for predicting PFS to first-line trastuzumab-containing therapy, but VEGF was not. In multivariate analysis for PFS with all six biomarkers, only serum CA9 (p= 0.002) was a significant independent covariate. For OS, pretreatment serum HER2 (p= 0.018), TIMP-1 (p< 0.0001), uPA (p< 0.0001), endoglin (p= 0.002), and CA9 (p< 0.0001) were all significant as univariate continuous biomarkers for prognosis, but serum VEGF was not. In multivariate analysis for OS with all six biomarkers, only serum CA9 was a significant independent prognostic covariate (p= 0.001). Conclusions: Elevated pretreatment serum CA9 (a marker of hypoxia) predicts reduced progression-free survival and overall survival in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure. [Table: see text]

Traitement adjuvant du cancer du sein par le tamoxifène : réflexions sur le risque de carcinosarcome utérin

A descriptive analysis of available data on reported cases of uterine carcinosarcomas associated with tamoxifen therapy is undertaken. The role of aromatase inhibitors as alternative to tamoxifen therapy in the adjuvant setting of breast cancer is discussed. The eventual implications of the presumed association of uterine carcinosarcoma and tamoxifen therapy on the choice of the therapeutic agent in the adjuvant setting of hormone-sensitive breast cancer are discussed.

The evolving role of zoledronic acid in early breast cancer.

Most women with early breast cancer (BC) have an excellent prognosis and will remain disease-free for many years after treatment. However, bone-specific side effects of cancer therapies can have a negative effect on patients' long-term bone health. The accelerated bone loss associated with BC therapies, especially endocrine therapy, can put women at risk for osteoporosis and fractures later in life. Recent treatment guidelines have now begun to address the need for bone-preserving measures to be included in adjuvant therapy regimens. Bisphosphonates have long been used to treat osteoporosis, as well as bone metastases in patients with advanced cancers. Furthermore, in the adjuvant BC setting, the intravenous bisphosphonate zoledronic acid has emerged to play an important role. Several large, randomized phase III trials involving a total of approximately 4,000 premenopausal and postmenopausal women with early BC demonstrated the bone-protective effects of adjuvant zoledronic acid (4 mg every 6 months). Additionally, these same trials also showed significant improvement in disease-free survival for patients receiving adjuvant endocrine therapy plus zoledronic acid that was over and above the benefit achieved with endocrine therapy alone. The results of these zoledronic acid trials will be reviewed herein, and evidence supporting the antitumor effects of adjuvant zoledronic acid will be discussed.

Utility of Tissue Doppler and Strain Rate Imaging in the Early Detection of Trastuzumab and Anthracycline Mediated Cardiomyopathy

Trastuzumab provides considerable therapeutic benefits in the adjuvant setting of breast cancer. However, its use is limited by an elevated incidence of cardiotoxicity when used in combination with doxorubicin. Although Myocet (liposomal encapsulated doxorubicin) is less cardiotoxic, its cardiac safety profile with trastuzumab is not well known. The aim of this study was to determine if sensitive indices of left ventricular (LV) dysfunction, specifically Doppler tissue imaging (DTI), would be useful for addressing the early detection of trastuzumab and anthracycline-mediated cardiotoxicity. In an acute murine model, wild-type C57Bl/6 mice (n = 60) received one of the following drug regimens: (1) control, (2) doxorubicin, (3) Myocet, (4) trastuzumab, (5) doxorubicin plus trastuzumab, or (6) Myocet plus trastuzumab. DTI-derived peak endocardial systolic velocity, strain rate, and LV ejection fraction were measured serially for 5 days. On day 5, the hearts, lungs, and livers were removed for histopathologic and Western blot analyses. Mice treated with Myocet plus trastuzumab demonstrated minimal cardiotoxicity compared with those treated with doxorubicin plus trastuzumab. Progressive LV dilatation and LV systolic dysfunction were observed by day 4 of treatment with doxorubicin plus trastuzumab, compared with preserved LV ejection fraction in the remaining groups. DTI parameters decreased within 24 hours in the doxorubicin alone and doxorubicin plus trastuzumab groups and predicted early mortality. The survival rate was only 20% at day 5 of the experiment in the doxorubicin plus trastuzumab group, whereas 100% of mice receiving trastuzumab, Myocet, or Myocet plus trastuzumab survived the 5 days. DTI can detect early LV dysfunction prior to alterations in conventional echocardiographic indices and predicts early mortality in mice receiving doxorubicin plus trastuzumab.

Bisphosphonates as adjuvant therapy for breast cancer

Breast cancer is the most common malignancy among women worldwide. Emerging results from clinical trials in patients with breast cancer suggest that, in addition to preventing cancer treatment-induced bone loss, bisphosphonates may improve disease-free survival (DFS). Although the first adjuvant studies using the early generation oral bisphosphonate clodronate suggested potential reductions in distant recurrence versus placebo in patients with early breast cancer, subsequent results with clodronate were inconsistent, and oral pamidronate produced no disease recurrence benefits versus chemotherapy alone in this setting. In contrast, addition of the newer bisphosphonate zoledronic acid to adjuvant therapy reduced disease recurrence rates and improved DFS compared with adjuvant endocrine therapy alone in two phase 3 studies in postmenopausal women with early breast cancer. Adjuvant zoledronic acid also significantly improved DFS compared with endocrine therapy alone in premenopausal women with breast cancer. Data from ongoing and future trials will further define the role of bisphosphonates in the adjuvant breast cancer setting.

Canadian pattern of care for anemia: comparison of chemotherapies in adjuvant breast cancer setting.

Abstract Abstract #2118 Background: Anemia is a common side effect of chemotherapy in adjuvant breast cancer patients (pts) but its treatment may be inconsistent. Erythropoiesis-stimulating agents (ESAs) are the only alternative to blood transfusion in the treatment of chemotherapy-induced anemia, yet their appropriate use continues to be defined. The purpose of this study was to determine the frequency of anemia associated with adjuvant chemotherapy in Canadian breast cancer pts and to explore the corrective interventions which were undertaken.
 Methods: A retrospective chart review was conducted at 11 cancer centres in Ontario, Canada. Beginning on September 1, 2004 data were collected for 60 consecutive cases of adjuvant breast cancer at each centre, giving a total of 620 patients. Chemotherapy consisted mainly of FEC100, AC-T, AC, CEF, FEC50, and AC-T Dose Dense. Overall, 8% of pts were enrolled in a clinical trial and 76% received adjuvant radiotherapy. Hemoglobin level (Hb), supportive therapy (antibiotics, GCSF, ESA, and transfusion) and type of chemotherapy were recorded at each cycle.
 Results: The median pt age was 53. The mean baseline Hb was 132.8 (92.0-163) g/L, 11.6% of pts had Hb<120g/L. During the course of chemotherapy, the percentage of subjects with Hb<120 at least once was 55.8%, Hb<110 was 37.8%, Hb<100 was 21.2 % and Hb<90 was 11.5%, with a median of 36.0, 52.5, 71.0, and 75.0 days to develop anemia respectively. For pts whose Hb dropped below 100 g/L, 45.4% occurred after the 1st cycle, 68.8% after the 2nd, 83.7% after the 3rd, and 92.2% after the 4th chemotherapy cycle. Overall, 13.2% of subjects received prophylactic antibiotics, 26.3% were supported by G-CSF, 9.0% received an ESA (epoetin alfa) during their chemotherapy and 7.4% were transfused. The rates of anemia as well as means of intervention are summarized in Figure 1. ESAs were not used prophylactically in this setting.
 Conclusions: In Canada, breast cancer patients receiving adjuvant chemotherapy commonly become anemic during their course of treatment. This retrospective study demonstrated that ESAs play an important role in the management of anemia in the adjuvant setting. Canadian treatment guidelines recommend that ESA therapy be initiated when Hb <100 g/L. Our finding shows that ∼42% of patients whose Hb dropped below 100g/L were treated with ESAs, suggesting that ESAs were not overused in Canadian practice.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2118.