Clinical Breast Cancer

The Next Generation of Biologic Agents: Therapeutic Role in Relation to Existing Therapies in Metastatic Breast Cancer

PierFranco Conte, Valentina Guarneri — 2012-06-01

Abstract: The use of more active cytotoxic agents (eg, anthracyclines and taxanes) in the adjuvant setting has impacted treatment options in metastatic breast cancer (MBC). Various new approaches to combination therapy are being investigated, including classic and novel cytotoxic agents and targeted therapies. The heterogeneous molecular pathways involved in the development of breast cancer provide numerous potential targets for therapeutic intervention. Molecular technologies have facilitated the development of various new therapies targeted at disrupting processes as diverse as angiogenesis and DNA repair. Targeted therapies have the potential to improve outcomes in MBC, and their use has increased dramatically over recent years after the introduction of human epidermal growth factor receptor 2 (EGFR2)-targeted therapy with trastuzumab. Lapatinib and bevacizumab have recently been approved for patients with MBC. Numerous other targeted agents are undergoing preclinical investigation or are being evaluated in clinical trials. The maximum benefit of targeted therapies has been realized by their combined use with cytotoxic agents. Overall, single-agent use of targeted therapies has failed to produce dramatic benefit in patients with advanced breast cancer. This article reviews the data from studies of established and emerging targeted therapies in the treatment of MBC and describes how best to incorporate these agents into current treatment paradigms.

A Phase I Study of Ixabepilone in Combination With Epirubicin in Patients With Metastatic Breast Cancer

2012-06-01

Micro-Abstract: In this phase I trial, 42 women with metastatic breast cancer were treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). The maximum-tolerated dose of ixabepilone in combination with epirubicin was 30 mg/m2 (the recommended dose for phase II evaluation), and the dose-limiting toxicity dose was 35 mg/m2 with grade 4 neutropenia. Abstract: Purpose: The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer. Patients and Methods: Patients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m2) and escalating doses of ixabepilone (25, 30, and 35 mg/m2). Results: Forty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m2 (n = 6) in combination with 75 mg/m2 epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m2 was 30 mg/m2, and the DLT dose was 35 mg/m2 with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels. Conclusions: The combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m2, followed by ixabepilone 30 mg/m2 every 3 weeks.

Effect of Different Doses of Metformin on Serum Testosterone and Insulin in Non-Diabetic Women With Breast Cancer: A Randomized Study

2012-06-01

Micro-Abstract: This is a randomized controlled trial to test the effect of different doses of metformin in patients with breast cancer and without diabetes, with the aim of modifying the hormonal and metabolic parameters linked to breast cancer prognosis. Analysis of the results suggest that the dose of 1500 mg/d of metformin causes a significant reduction of insulin and testosterone serum levels. Abstract: Background: Serum levels of insulin and testosterone may affect both breast cancer (BC) incidence and prognosis. Metformin reduces hyperglycemia and insulin levels in patients with diabetes. In women without diabetes and with polycystic ovary syndrome, metformin lowers both insulin and testosterone levels. Patients with diabetes who are treated with metformin showed a lower risk of cancer; a protective effect of metformin also was observed for BC. Recently, studies on metformin use for prevention or treatment of BC have been proposed in patients who are not diabetic. The aim of the present study was to test the effect of different doses of metformin on serum levels of insulin and testosterone in those postmenopausal patients with breast cancer and without diabetes who have basal testosterone levels ≥0.28 ng/mL (median value). Patients and Methods: A total of 125 eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months were invited to continue the study with metformin 1000 mg/d (500 mg twice a day [b.i.d.]) for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose by taking metformin 1500 mg/d (500 mg 3 times a day [t.i.d.]), and the other group continued with metformin 1000 mg /d (500 [b.i.d.]). Results: A total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%. Conclusion: Both these changes might have a prognostic importance.

Improved Outcome of High-Risk Early HER2 Positive Breast Cancer With High CXCL13-CXCR5 Messenger RNA Expression

2012-06-01

Micro-Abstract: The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation. Abstract: Background: Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer. Methods: A total of 595 patients at high risk for early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2). Results: CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively). Conclusions: The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2+ disease.

Intraglandular Flap Technique for Tumors Located in the Upper Outer Quadrant of the Breast

2012-04-16

Micro-Abstract: We applied the intraglandular flap technique with racquet incision for tumors located in the upper outer quadrant of medium to small size breasts of 47 patients. It is an easy and safe technique with respect to cosmetic results, surgical margins, and complications. Abstract: Background: The intraglandular flap is a volume replacement technique in which glandular tissue is used to close the tissue defect. We applied the intraglandular flap technique with racquet incision for tumors located in the upper outer quadrant of medium to small size breasts of 47 patients. In this report, we present our preliminary results of this technique. Patients and Methods: The intraglandular flap technique using a racquet incision was used on 47 consecutive breast cancer patients with T1 and T2 tumors, and analyzed prospectively. Results: The median age of the patients was 46.5 (range, 24-63 years). The mean tumor size was 2.53 ± 0.8 cm. The volume of the resected specimen was 185 ± 29 cm3. The mean length of incision was 9.68 ± 1.8 cm. The mean distance from the tumor to the nearest surgical margin was 1.65 ± 0.4 cm. Fat necrosis was evident in 8 patients (17%) and hematoma in 2 patients (4.2%). The other complications like seroma, glandular, and flap necrosis were not observed. Discussion: Intraglandular flap technique with racquet incision used for tumors located in the upper outer quadrant of patients with medium and small breasts is an easy and safe technique with respect to cosmetic results, surgical margins and complications. The learning period of this technique is quite short. When used in patients with dense breasts the incidence of fat necrosis was found to be low.

Poly(Lactide-Co-Glycolide) Ultrasonographic Microbubbles Carrying Sudan Black for Preoperative and Intraoperative Localization of Lymph Nodes

2012-03-09

Micro-Abstract: Current strategies for lymph node (LN) examination have limitations. A novel imaging agent, poly(lactide-co-glycolide) (PLGA) ultrasonographic microbubbles carrying Sudan black B (SB) (PLGA-SB) microbubbles) has been developed. Results have shown that the SB-PLGA microbubbles could be a suitable imaging agent for preoperative and intraoperative localization of LNs as well as for ultrasonographically guided core needle biopsy of LNs. Abstract: Lymph node (LN) examination plays a critical role in the staging and treatment of several kinds of cancer such as lesions of the breast. However current strategies have limitations. This study aimed to develop a novel imaging agent, a polymeric ultrasonographic contrast agent carrying Sudan black (SB), for ultrasonographic imaging of the regional LNs before surgery and to directly localize the LNs during surgery. The poly(lactide-co-glycolide) (PLGA) ultrasonographic microbubbles carrying Sudan black B (SB) (SB-PLGA microbubbles) were prepared by the double emulsion method. The SB-PLGA microbubbles had a diameter of 1.5 ± 0.5 μm and the SB encapsulation efficiency was (86.2 ± 1.56%). Results from MTT assays suggested that these bubbles have little cytotoxicity to mouse macrophages after incubation. Confocal laser scanning microscopy showed that the PLGA microbubbles carrying the fluorescent dye rhodamine 6G were taken up by macrophages after 2-hour incubation. In addition, these SB-PLGA microbubbles were able to enhance ultrasonographic contrast of 12 popliteal LNs of 6 rabbits. Furthermore, the LNs were easily identifiable by the naked eye during surgery because of the blue color of the SB-PLGA microbubbles inside the LNs. By cryosectioning and hematoxylin and eosin (H&E) staining of LN tissue, our results showed that these SB-PLGA microbubbles were internalized inside the macrophages of the LNs. To conclude, the SB-PLGA microbubbles could be a suitable imaging agent for preoperative and intraoperative localization of LNs as well as for a preoperative ultrasonographically guided core needle biopsy of suspicious sentinel lymph nodes (SLNs) in cancer patients, hence enhancing treatment outcome.

Metronomic Chemotherapy Combined With Bevacizumab and Erlotinib in Patients With Metastatic HER2-Negative Breast Cancer: Clinical and Biological Activity

2012-04-23

Micro-Abstract: The aim of this study was to determine the safety and efficacy of metronomic chemotherapy combined with targeted drugs in patients with metastatic breast cancer (MBC). We included 26 untreated patients with HER2-negative (HER−) MBC and poor hormone receptor expression. The analysis of the results suggests that the metronomic chemotherapy combined with bevacizumab and erlotinib is effective and well tolerated. Abstract: Background: The object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combination with bevacizumab and erlotinib in patients with HER2-negative (HER2−) metastatic breast cancer (MBC) and poor hormone receptor expression. Patients and Methods: Patients with untreated MBC were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) and erlotinib (100 mg daily). Results: Of 24 patients assessable for response, we observed 1 complete response (CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks' duration (SD, 21%), and 1 patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD > 24 weeks) was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4). Conclusion: Treatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in HER2−, estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer.

Implementation and Outcomes of a Multidisciplinary High-Risk Breast Cancer Program: The William Beaumont Hospital Experience

2012-04-16

Micro-Abstract: Limited data are available on the implementation of a high-risk assessment program in the construct of a community clinical oncology program. The development of a high-risk breast cancer screening program at our institution identified 15%-20% of patients screened as high risk, with limited increases in structural or personnel requirements. Identification of patients as high risk could potentially improve outcomes by allowing for individualized prevention strategies and more appropriate high-risk surveillance. Abstract: Purpose: The implementation of a program that incorporates a risk assessment questionnaire (RAQ) to identify high-risk patients in a community-based health system was evaluated. Materials and Methods: Women with no history of breast cancer or ductal carcinoma in situ who were undergoing annual screening mammography were offered an RAQ. Cases determined to be high risk (Gail lifetime risk ≥20% or as indicated through personal and/or family history) were offered referral to our High-risk Breast Cancer Program. A retrospective data review was conducted on completed questionnaires. Results: A total of 5878 women underwent evaluation with the RAQ between September 2009 and August 2010. The mean age of the cohort was 55 years old, with 84.9% (4990) of participants being white, and 6.8% (400) African American. In the entire population, 45.7% (2446) had at least 1 first-degree relative with breast cancer (BC), and 923 (17.2%) women were found to be high risk by the Gail model. Beyond the Gail model, 53 (0.9%) women had undergone prior chest radiation, 34 (0.6%) had a male relative with BC, 200 (3.4%), had 3 or more relatives with BC on one side of their family, 308 (5.2%) had a relative with breast and ovarian cancer on one side of the family, and 105 (1.8%) noted 2 relatives with BC with onset under age 50 years on the same side of the family. Conclusions: Our experience indicates that the identification of women at high risk for BC can be easily incorporated into an annual screening mammography visit. Identification of these patients as high risk can allow for individualized, more-appropriate surveillance and prevention.

Jejunal Intussusception Due to Malignant Phyllodes Tumor of the Breast

2012-03-01

Reversible Posterior Leukoencephalopathy Syndrome Induced by Vinorelbine

Yen-Hao Chen, Cheng-Hua Huang — 2012-03-16

Does Hormonal Therapy Have a Therapeutic Role in Metastatic Primary Small Cell Neuroendocrine Breast Carcinoma? Case Report and Literature Review

Homam Alkaied, Kassem Harris, Arnold Brenner, Michael Awasum, Seema Varma — 2012-03-19

Editorial Board/Masthead

2012-06-01

Clinical Breast Cancer

The Next Generation of Biologic Agents: Therapeutic Role in Relation to Existing Therapies in Metastatic Breast Cancer

A Phase I Study of Ixabepilone in Combination With Epirubicin in Patients With Metastatic Breast Cancer

Effect of Different Doses of Metformin on Serum Testosterone and Insulin in Non-Diabetic Women With Breast Cancer: A Randomized Study

Improved Outcome of High-Risk Early HER2 Positive Breast Cancer With High CXCL13-CXCR5 Messenger RNA Expression

Intraglandular Flap Technique for Tumors Located in the Upper Outer Quadrant of the Breast

Poly(Lactide-Co-Glycolide) Ultrasonographic Microbubbles Carrying Sudan Black for Preoperative and Intraoperative Localization of Lymph Nodes

Metronomic Chemotherapy Combined With Bevacizumab and Erlotinib in Patients With Metastatic HER2-Negative Breast Cancer: Clinical and Biological Activity

Implementation and Outcomes of a Multidisciplinary High-Risk Breast Cancer Program: The William Beaumont Hospital Experience

Jejunal Intussusception Due to Malignant Phyllodes Tumor of the Breast

Reversible Posterior Leukoencephalopathy Syndrome Induced by Vinorelbine

Does Hormonal Therapy Have a Therapeutic Role in Metastatic Primary Small Cell Neuroendocrine Breast Carcinoma? Case Report and Literature Review

Editorial Board/Masthead

Table of Contents