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The randomized phase III trial EGF100151 demonstrated that the combination of lapatinib plus capecitabine (L + C) significantly improved time to progression (TTP) compared with capecitabine alone (C) in heavily pretreated patients with HER2+ (ErbB2+) advanced or metastatic breast cancer. This analysis assessed the effects of study treatments on quality of life (QOL) among patients in EGF100151. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQoL (EQ-5D) questionnaires. Patients completed questionnaires during efficacy and safety assessment visits (i.e., at screening visit, every 6 weeks for the first 24 weeks, every 12 weeks thereafter, and at discontinuation of study treatment). Primary analyses compared the treatment groups based on change from baseline QOL. Exploratory analyses compared proportion of patients achieving minimum important differences (MID) in QOL scores and the relationship between QOL and tumor status. Quality of life for patients in both treatment groups was maintained during 24 weeks of follow-up. Adjusted mean changes from baseline in all QOL scores for the L + C arm were comparable to those for the C arm. The between-group differences ranged from 0.7 to 2.2 (FACT-B total) and 0.3 to 1.8 (EQ-5D visual analog scale) and were consistently in favor of the L + C arm, although not statistically significant. Patients with an objective tumor response or stable disease showed clinically meaningful differences in QOL scores compared to patients with progressive disease. A greater proportion of patients receiving L + C versus C achieved the MID for all five QOL scores, although differences were not statistically significant. The addition of lapatinib to capecitabine significantly increases TTP without any evidence of a deleterious effect on patients' QOL, confirming its clinical benefit in this heavily pretreated patient population with advanced HER2+ breast cancer that has progressed on trastuzumab therapy.

Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 18-23% of invasive breast carcinomas and is associated with a worse prognosis. This novel transforming gene was identified in 1985, and in 1987 HER2 amplification was demonstrated to be central to the aggressive, malignant phenotype of these cancers and a significant predictor of both time to relapse and overall survival. These observations led to the development of the first monoclonal antibody targeting the extracellular domain of HER2, trastuzumab (Herceptin, Genentech and Hoffman LaRoche, Switzerland), which was approved by the US FDA for metastatic breast cancer in 1998. In 2005, results from four major trastuzumab adjuvant trials demonstrated a marked reduction in risk of recurrence, and trastuzumab is now an essential component of the adjuvant treatment of HER2-positive early breast cancer. Concerns regarding cardiac safety and mechanisms of resistance to trastuzumab remain important issues and are being addressed in ongoing research efforts.

Purpose: Lapatinib is a small molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor type 2 (HER2). Initial results of a phase III trial demonstrated that lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Updated efficacy and initial biomarker results from this trial are reported., Methods: Women with HER2-positive, locally advanced or metastatic breast cancer previously treated with anthracycline-, taxane-, and trastuzumab-containing regimens were randomized to lapatinib 1,250 mg/day continuously plus capecitabine 2,000 mg/m(2) days 1-14 of a 21-day cycle or capecitabine 2,500 mg/m(2) on the same schedule. The primary endpoint was time to progression (TTP) as determined by an independent review panel. Relationship between progression-free survival (PFS) and tumor HER2 expression and serum levels of HER2 extracellular domain (ECD) were assessed., Results: 399 women were randomized. The addition of lapatinib prolonged TTP with a hazard ratio (HR) of 0.57 (95% CI, 0.43-0.77; P < 0.001) and provided a trend toward improved overall survival (HR: 0.78, 95% CI: 0.55-1.12, P = 0.177), and fewer cases with CNS involvement at first progression (4 vs. 13, P = 0.045). Baseline serum HER2 ECD did not predict for benefit from lapatinib., Conclusion: The addition of lapatinib to capecitabine provides superior efficacy for women with HER2-positive, advanced breast cancer progressing after treatment with anthracycline-, taxane-, and trastuzumab-based therapy. Biomarker studies could not identify a subgroup of patients who failed to benefit from the addition of lapatinib to capecitabine.

In this phase III, multinational, randomized trial, the International Breast Cancer Study Group, Breast International Group, and the National Surgical Adjuvant Breast and Bowel Project will attempt to define the effectiveness of cytotoxic therapy for patients with locoregional recurrence of breast cancer. We will evaluate whether chemotherapy prolongs disease-free survival and, secondarily, whether its use improves overall survival and systemic disease-free survival. Quality of life measurements will be monitored during the first 12 months of the study. Women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery and who have undergone complete surgical excision of all macroscopic disease but who subsequently develop isolated local and/or regional ipsilateral invasive recurrence are eligible. Patients are randomized to observation/no adjuvant chemotherapy or to adjuvant chemotherapy; all suitable patients receive radiation, hormonal, and trastuzumab therapy. Radiation therapy is recommended for patients who have not received previous adjuvant radiation therapy but is required for those with microscopically positive margins. The radiation field must encompass the tumor bed plus a surrounding margin to a dose of >or= 40 Gy. Radiation therapy will be administered before, during, or after chemotherapy. All women with estrogen receptor-positive and/or progesterone receptor-positive recurrence must receive hormonal therapy, with the agent and duration to be determined by the patient's investigator. Adjuvant trastuzumab therapy is permitted for those with HER2- positive tumors, provided that intent to treat is declared before randomization. Although multidrug regimens are preferred, the agents, doses, and use of supportive therapy are at the discretion of the investigator.

Background: This phase II protocol of neoadjuvant chemotherapy with gemcitabine/epirubicin/paclitaxel (GET) was designed to determine the pathologic complete response (pCR) rate in the breast, clinical response rate, disease-free survival, and overall survival at 2 years as well as toxicity in patients with locally advanced breast cancer. This trial also evaluated the feasibility of tissue collection for gene-expression profiling., Patients and Methods: Seventy-six women with stage IIB, IIIA, and IIIB breast cancer were entered into this trial. Patients received a maximum of 6 cycles of neoadjuvant GET chemotherapy every 21 days (gemcitabine 1000 mg/m2 intravenously [i.v.] on days 1 and 4, epirubicin 90 mg/m2 i.v. bolus on day 1, and paclitaxel 175 mg/m2 i.v. on day 1). After chemotherapy, patients underwent surgery and were assessed for pathologic response., Results: The pCR rate among the 74 patients evaluable for efficacy was 23% (95% CI, 14%-34.2%). Adverse events among the 76 patients evaluable for toxicity included anemia requiring transfusion (14.5%), infection with grade 3/4 neutropenia (10.5%), febrile neutropenia (7.9%), and platelet transfusion (6.6%). Infectious complications occurred in 24 patients (31.6%), of whom 18.4% were in the setting of neutropenia. High-quality RNA and successful probe synthesis were obtained from all pretreatment core biopsy specimens that contained tumor cells (n=66; 88%)., Conclusion: Neoadjuvant GET chemotherapy is an active regimen but with substantial toxicity. Tissue collection for gene-expression profiling is feasible in a multi-institutional setting.

In breast cancer, overexpression of HER2 is associated with an aggressive tumor phenotype and poor prognosis. Lapatinib has demonstrated benefit in combination with capecitabine in patients with HER2-positive locally advanced and metastatic breast cancer that has progressed after prior treatment with an anthracycline, a taxane, and trastuzumab. It has also demonstrated benefit with paclitaxel in patients with metastatic disease not previously treated with chemotherapy. This review discusses results from clinical trials suggesting an advantage with the use of lapatinib with other treatment modalities in the setting of metastatic and locally advanced disease.

This was a phase II multi-institutional trial to determine the efficacy and tolerability of gefitinib (Iressatrade) and docetaxel as first-line treatment in patients with metastatic breast cancer. All patients had histologically confirmed breast cancer with metastatic disease. They were permitted to have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m(2) every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Thirty-three patients were enrolled and received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5-69.2%). There were 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9-57.9%). Four patients had stable disease for > or =24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0-17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (ten patients). Toxicities were mainly attributable to docetaxel, including > or =grade 3 neutropenia in 43% of patients. The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer, with a clinical benefit rate and toxicity profile in the range of that reported for docetaxel alone.

Objectives: To describe new clinical findings, efficacy, and safety regarding the use of targeted agents in the treatment of HER2-positive metastatic breast cancer., Data Sources: Published research articles, abstracts, and clinical experience., Conclusion: HER2-positive cases of breast cancer tend to be more aggressive and more likely to become resistant to therapy than HER2-negative tumors. The current standard approach to patients with HER2-positive metastatic breast cancer includes the use of trastuzumab. Because cellular mechanisms can arise that can block the efficacy of this approach (and result in clinical resistance), recent research has led to the development of lapatinib, a targeted therapy that can act on HER2 inside the cell to disrupt the signaling pathways thought to be part of tumorigenic mechanisms., Implications for Nursing Practice: Oncology nurses should be aware of the treatment strategies for HER2-positive metastatic breast cancer and its limitations, which is essential for providing optimal nursing care.

Background: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients., Methods: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions., Results: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events., Conclusions: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].)., (Copyright 2006 Massachusetts Medical Society.)

Purpose: The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known., Methods: The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS., Results: A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (> or = 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit., Conclusion: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

Purpose: This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS)., Patients and Methods: Women with operable breast cancer (N = 2,411) were randomly assigned to receive preoperative AC followed by surgery, AC followed by T and surgery, or AC followed by surgery and then T. Tamoxifen was initiated concurrently with chemotherapy. Median time on study for 2,404 patients with follow-up was 77.9 months., Results: Addition of T to AC did not significantly impact DFS or OS. There were trends toward improved DFS with addition of T. The addition of T reduced the incidence of local recurrences as first events (P = .0034). Preoperative T, but not postoperative T, significantly improved DFS in patients who had a clinical partial response after AC (hazard ratio [HR] = 0.71; 95% CI, 0.55 to 0.91; P = .007). Pathologic complete response, which was doubled by addition of preoperative T, was a significant predictor of OS regardless of treatment (HR = 0.33; 95% CI, 0.23 to 0.47; P < .0001). Pathologic nodal status after chemotherapy was a significant predictor of OS (P < .0001)., Conclusion: The addition of preoperative or postoperative T after preoperative AC did not significantly affect OS, slightly improved DFS, and decreased the incidence of local recurrences. The sample size of this study was not sufficient to yield significance for the moderate DFS improvement. Concurrent use of tamoxifen may have limited the impact of adding T.

Purpose: The purpose of this study was to assess the feasibility of administering exatecan, a water-soluble, potent camptothecin analogue, as a protracted 21-day continuous i.v. infusion (CIVI). The study also sought to determine the maximum tolerated dose (MTD) of exatecan on a 21-day CIVI schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity., Experimental Design: Exatecan dose-schedule development was performed in two stages using the modified Continual Reassessment Method and single patient cohorts. First, patients with advanced solid malignancies were treated with exatecan (0.15 mg/m(2)/day) as a CIVI for 5 days, and the duration of the CIVI was incrementally increased from 5 to 21 days. In the second stage of the study, the dose was incrementally increased to derive a tolerable dose of exatecan administered as 21-day CIVI. The MTD was defined for both minimally pretreated (MP) and heavily pretreated (HP) patients as the highest dose level at which the incidence of dose-limiting toxicity does not exceed 20%., Results: Thirty-one patients were treated with 100 courses of exatecan at 6 dose-schedule levels. The incidence of the principal dose-limiting toxicities, neutropenia and thrombocytopenia, was unacceptably high at exatecan doses exceeding 0.15 mg/m(2)/day as a 21-day CIVI, which was determined to be the MTD for both MP and HP patients. The pharmacokinetics of exatecan were dose-proportional, and mean [coefficient of variation (percentage) steady-state concentration (plasma concentration at steady-state)] values ranged from 6.88 (80.6) to 19.41 (74.2) ng/ml at exatecan dose levels ranging from 0.15 to 0.30 mg/m(2)/day, which are similar to IC(50) values against human tumor cell lines treated for shorter periods. Mean pharamacokinetic parameters for total exatecan derived from a compartmental model included clearance and volume of distribution values of 1.39 (86.9) liters/h/m(2) and 39.66 (197.4) liters, respectively. Two HP patients with non-small cell lung and unknown primary carcinomas had partial responses, and objective evidence of anticancer activity and clinical benefit were noted in several other individuals., Conclusions: The administration of exatecan as a 21-day CIVI at doses as high as 0.15 mg/m(2)/day is safe and feasible for both MP and HP patients. The characteristics of the myelosuppressive effects of exatecan on this schedule, the paucity of severe nonhematological toxicities, and documented anticancer activity in several drug-refractory malignancies warrant further evaluation of the merits of administering exatecan by either a CIVI or alternate drug delivery systems to achieve protracted systemic exposure.