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Purpose Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate. Methods Multiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. Results PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. Conclusions The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.

Background Adjuvant systemic therapy decreases recurrence and death from breast cancer, but late relapse still occurs. Therapeutic decisions are based heavily on receptor tissue characterization. Even though the vast majority of metastatic sites do not have receptor conversions, they can occur at the time of metastasis and/or during the course of treatment. However, multiple receptor conversions are uncommon. Case presentation We present an unusual case of a Caucasian patient originally diagnosed with an estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative primary breast cancer who had a recurrence after 15 years of therapy. Her metastatic tumor had a different receptor status than the original tumor. During the course of therapy, at the time of progression, a new biopsy showed that her tumor had changed once more. Conclusion/Discussion Tracking receptor conversions is important in metastatic breast cancer treatment. Single receptor conversions have been documented to occur, but not much is known of multiple receptor conversions. This case sheds light on the possibility of patients having multiple receptor conversions and the importance of performing multiple biopsies during the course of metastatic treatment.

Background: High-dose estrogens (HDEs) are an efficacious but widely overlooked treatment option for patients with metastatic breast cancer (MBC). This is due in part to the introduction of tamoxifen in the 1970s, which was proven to be equivalent in efficacy and associated with fewer adverse events (AEs). Objective: The aim of this study was to report our experience with the use of HDE in postmenopausal women with advanced breast cancer. Methods: Local institutional review board approval was obtained to conduct a retrospective chart review of patients with MBC treated with HDEs at the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, from 2001 through March 2009. Demographic information, response rates, and tolerability profiles were collected. Results: Of the 426 patients with MBC identified, we found 26 patients with MBC who were prescribed HDEs as a treatment in any line of therapy for advanced breast cancer. The median age at the start of HDE therapy was 59 years (range, 42–92 years). Three of the 26 patients (11.5%) were human epidermal growth factor receptor 2-positive determined via fluorescent in situ hybridization analysis. With the exception of 1 patient who had received no prior systemic treatment for metastatic disease, all patients received multiple lines of treatment (both chemotherapy and hormonal treatments) in the advanced setting (median, 7 lines; range, 0–12) prior to the initiation of HDE. Five of 20 patients (25%) with measurable metastatic disease (visceral and/or soft tissue metastases) had objective antitumor responses defined as either a partial response (PR) or a complete response (CR). Four additional patients (20%) had prolonged stable disease (SD) for ≥6 months. Three of 6 patients (50%) with nonmeasurable metastatic disease (bone-only) had prolonged SD for ≥6 months. Clinical benefit rate (defined as CR + PR + SD ≥6 months) for all patients was 46% (12/26), with a median duration of 10 months. Overall median progression-free survival for the 26 subjects was 5 months. Median survival from the start of HDE was 17 months (range, 3–54 months). AEs included fluid retention (8 [31%]), vaginal bleeding (7 [27%]), and nausea (4 [15%]). Two patients discontinued therapy after 1 month. Three of the remaining 24 patients discontinued estrogen therapy due to AEs. Conclusions: This retrospective chart review details our facility's experience with the use of HDE in patients with advanced breast cancer, most of whom had received multiple prior treatments. Our data suggest that this treatment is another option for heavilytreated patients in whom further endocrine manipulation might still be appropriate.

Background Our original paper, published in 1992, reported a median overall survival after first relapse in breast cancer of 26 months. The current retrospective review concentrates more specifically on patients with first systemic relapse, recognizing that subsets of patients with local recurrence are potentially curable. Methods Records of 5,168 patients from a largely breast-cancer-specific oncology practice were reviewed to identify breast cancer patients with their first relapse between 1996 and 2006 after primary treatment. There were 189 patients diagnosed with metastatic disease within 2 months of being seen by our therapeutic team and 101 patients diagnosed with metastatic disease greater than 2 months. The patients were divided in order to account for lead-time bias than could potentially confound the analysis of the latter 101 patients. Results Median survival for our primary study population of 189 patients was 33 months. As expected, the median survival from first systemic relapse (MSFSR) for the 101 patients excluded because of the potential for lead-time bias was better at 46 months. Factors influencing prognosis included estrogen receptor (ER) status, disease-free interval (DFI), and dominant site of metastasis. Compared with our original series, even with elimination of local-regional recurrences in our present series, the median survival from first relapse has improved by 7 months over the past two decades. Conclusion The new benchmark for MSFSR approaches 3 years.

Approximately 15–20% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive, with clinical studies having validated the HER2 receptor tyrosine kinase pathway as an important therapeutic target. Presently, two HER2-targeted therapies are approved by the Food and Drug Administration for treatment of HER2-positive breast cancer: the HER2-targeted humanized monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib. Despite use of these HER2-targeted agents, many patients still experience disease progression. For this reason, numerous new agents and therapeutic strategies are under investigation. Based on preclinical data suggesting synergistic effects from dual therapy targeting HER2, clinical trials that test the effects of combining anti-HER2 agents have been conducted and are ongoing. Here, we review recently presented data from several clinical trials, which indicate that the strategy of combining HER2 blockade therapies can offer greater clinical efficacy, with adverse effects of varying degrees. Specifically, we review new data reported at the 2010 San Antonio Breast Cancer Symposium (SABCS 2010), including the phase II NeoSphere and phase III NeoALTTO clinical trials, and data from three clinical trials reported at the 2011 American Society of Clinical Oncology (ASCO 2011) meeting. Together these trials elucidate the potential role of combining trastuzumab with lapatinib or pertuzumab. We also discuss additional ongoing studies that will help further define the role of dual HER2 blockade therapies and its impact on clinical practice.

PurposeMetastatic breast cancer is regarded as an incurable entity. In heavily pretreated patients with increasingly limited options for palliative management, ensuring proper quality of life continues is to be an elusive issue. With this in mind, the authors evaluated the efficacy and safety of the Vinorelbine/Capecitabine doublet (VINOCAP).Patients and methodsThe investigators retrospectively analyzed a cohort of 67 women with HER2 negative MBC treated at a large breast cancer practice and a local cancer center with Vinorelbine 22.5 mg/m2 IV on days 1 and 8 combined with Capecitabine 1 g PO BID for 14 consecutive days of 21 day cycles. Patients had been treated with an average of 4 prior lines of chemotherapy. Patient characteristics and outcomes were evaluated.ResultsA total of 67 patients received VINOCAP, and an additional 2 underwent repeat exposure yielding a cohort of 69. Clinical benefit rate, defined as complete response (CR), partial response (PR) or stable disease ≥ 6 months (SD), was 55.07%. Complete response was seen in 4.34%, PR in 18.8% and SD ≥ 6 months in 31.9%. Median progression-free survival was 6.2 months and overall survival 35.47 months after VINOCAP exposure. The most common grade 3–4 toxicity was neutropenia in 10% of cases. Dose had to be reduced in 18% of cases due to toxicity of any type. The regimen was well tolerated, and serious side effects were uncommon.ConclusionVinorelbine/Capecitabine appears to be an active and well-tolerated regimen in women with MBC. In particular, encouraging was the efficacy of VINOCAP as fourth or greater line of chemotherapy.

Approximately 6 % of patients with breast cancer are diagnosed with de-novo distant metastases. We set out to look at two cohorts of patients seen at breast cancer-specific practices, compare the results to other reports and larger databases, and see how advances in treatment have impacted overall survival (OS). The records from a large breast cancer oncology private practice and a second data set from the University of Miami/Sylvester Comprehensive Cancer Center (UM/SCCC) tumor database were, retrospectively, reviewed to identify patients with de-novo metastases. We included those patients identified to have metastatic disease within 3 months of diagnosis of a breast primary cancer. Patients diagnosed between 1996 and 2006 were chosen for our study population. The OS for the private practice was 41.0 months (46.0 for ER positive and 26.0 for ER negative) and 36.0 months for UM/SCCC (52 months for ER positive and 36 months for ER negative). ER negativity and CNS- or visceral-dominant disease were associated with a significantly worse prognosis within the private practice. Dominant site was associated with a significantly worse prognosis within the UM/SCCC database but with a trend also for ER negativity. Age and ethnicity did not contribute significantly to the survival of patients within either cohort. The median survival in both cohorts and most other reported series was larger than that seen in the surveillance, epidemiology, and end results program and the National Cancer Database. The median OS among patients with de-novo metastatic breast cancer treated within two breast-specific oncology practices was over 3 years, which appears better than larger, more inclusive databases and publications from earlier decades.

The pivotal phase II and III Herceptin ® trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for ≧6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.

Combination therapy with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and an aromatase inhibitor (AI) for first-line treatment of postmenopausal women with advanced breast cancer (ABC) has demonstrated improvement in progression-free survival (PFS) over AI monotherapy without adding substantial toxicity. However, CDK4/6 inhibitor plus AI therapy is not uniformly used as first-line therapy for ABC, indicating that barriers to CDK4/6 inhibitor use exist. Such barriers may include the following perceptions: patients with bone-only metastases, with a long disease-free interval, or who are older may respond to AI monotherapy and may not benefit from a CDK4/6 inhibitor; tumor response rates may be lower and delayed with CDK4/6 inhibitor plus AI therapy than chemotherapy; the increased incidence of adverse events with CDK4/6 inhibitor plus AI therapy outweighs benefits; and the cost of CDK4/6 inhibitors may be prohibitive. Some of these barriers are addressed with data from follow-up analyses of CDK4/6 inhibitor trials, which have shown a PFS benefit of combination therapy in all subgroups assessed, including older patients, those with bone-only metastatic disease, and those with a long disease-free interval. Tumor response rates with CDK4/6 inhibitor plus AI therapy are comparable to those with first-line cytotoxic chemotherapy. Finally, adverse events associated with CDK4/6 inhibitor plus AI therapy are manageable and occur with decreasing severity during treatment, with similar reports of quality of life to those with AI monotherapy. These data support CDK4/6 inhibitor plus AI therapy as the standard of care in first-line treatment of ABC.

A pilot safety study of focused microwave phased array thermotherapy in the treatment of primary breast carcinomas was conducted. Ten patients with breast carcinomas beneath the skin surface that ranged in maximal clinical size from 1 to 8 cm (mean, 4.3 cm) were treated with the breast compressed in the prone position. We planned to deliver a tumor thermal dose equivalent to 60 minutes at 43 degrees C. Breast imaging and pathology data were used to assess efficacy. For the 10 patients, the mean tumor equivalent thermal dose was 51.7 minutes, the mean peak tumor temperature was 44.9 degrees C, and the mean treatment time was 34.7 minutes. Ultrasound imaging demonstrated a significant reduction in tumor size (mean, 41%) 5 to 18 days after thermotherapy in 6 (60%) of 10 patients. A significant tumor response on the basis of reduction in tumor size or significant tumor cell kill occurred in 8 (80%) of 10 patients. With sufficient skin cooling, delivery of focused microwave phased array thermotherapy is safe in treating breast carcinomas when used alone, and some potential efficacy was demonstrated at the tumor thermal doses administered. Increased tumor thermal dose efficacy studies in larger patient populations for improved breast conservation should be investigated.