IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Optimal adjuvant therapy in older (≥70 years of age) women with low-risk early-stage breast cancer.

Older women are under-represented in breast cancer (BC) clinical trials, and treatment guidelines are primarily based on BC studies in younger women. Studies uniformly report an increased incidence of local relapse with omission of breast radiation therapy. Review of the available literature suggests very low rates of distant relapse in women ≥70 years of age. The incremental benefit of endocrine therapy in decreasing rate of distant relapse and improving disease-free survival in older patients with low-risk BC remains unclear. Integration of molecular genomic assays in diagnosis and treatment of estrogen receptor positive BC presents an opportunity for optimizing risk-tailored adjuvant therapies in ways that may permit treatment de-escalation among older women with early-stage BC. The prevailing knowledge gap and lack of risk-specific adjuvant therapy guidelines suggests a compelling need for prospective trials to inform selection of optimal adjuvant therapy, including omission of adjuvant endocrine therapy in older women with low risk BC.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.

Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial.

Background: Combination pertuzumab, trastuzumab, and docetaxel (D) is considered standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This post hoc, exploratory analysis of CLEOPATRA study data evaluated the clinical effects of D treatment duration within this regimen. The clinical benefits of pertuzumab and trastuzumab by different durations of D treatment were also evaluated. Patients and methods: Patients with HER2-positive metastatic breast cancer received trastuzumab and D plus pertuzumab or placebo. Clinical outcomes were analyzed by the number of D cycles that patients received (<6D, 6D, or >6D). Progression-free survival (PFS) and overall survival (OS) for each treatment arm within each D cycle group were estimated using the Kaplan-Meier approach. Time-dependent, multivariate Cox regression was applied to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HER2-targeted therapy and D cycle groups. Results: Overall, 804 patients received <6D (n = 119), 6D (n = 210), or >6D (n = 475) cycles. After adjusting for pertuzumab benefits versus placebo (PFS HR = 0.61, 95% CI 0.51-0.74, P < 0.0001; OS HR = 0.60, 95% CI, 0.49-0.74, P < 0.0001), >6D versus 6D cycles was not associated with statistically significant improvements in PFS (HR = 0.80, 95% CI 0.63-1.01, P = 0.0640) or OS (HR = 0.88, 95% CI 0.69-1.12, P = 0.3073). Consistent improvements in PFS and OS were observed with pertuzumab versus placebo, irrespective of D duration. The HRs for PFS were 0.395, 0.615, and 0.633 for <6D, 6D, and >6D cycles, respectively (P < 0.05 for all D cycle groups). Corresponding HRs for OS were 0.577, 0.700, and 0.612, respectively (P < 0.05 for <6D and >6D). Conclusions: After accounting for pertuzumab benefits, more than six cycles of D treatment was not associated with significant improvements in either PFS or OS compared with six cycles. The addition of pertuzumab to trastuzumab improved clinical outcomes versus trastuzumab plus placebo, regardless of D treatment duration. ClinicalTrials.gov identifier: NCT00567190.

Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab.

Background: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. Patients and methods: Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data. Results: The incidence of all-grade diarrhea across studies was generally greater for pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%-54%; grade 2, 8%-37%; grade 3, 0%-12%; grade 4, 0%). Incidence was highest during the first pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among pertuzumab-treated patients with diarrhea, 47%-67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with pertuzumab had a higher incidence of grade 3 diarrhea than patients <65 years (19% versus 8%). All-grade diarrhea occurred at greater frequency among pertuzumab-treated Asian versus white patients with metastatic breast cancer (74% versus 63%); the corresponding rates in the control arm were 53% and 45%, respectively. Conclusions: In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon. ClinicalTrials.gov identifiers: NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).

Does CDKN2A loss predict palbociclib benefit?

Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6, was recently approved by the U.S. Food and Drug Administration in combination with letrozole for postmenopausal women with advanced hormone receptor-positive, her2-negative breast cancer. Patients with loss of CDKN2A (p16), an inherent negative regulator of cyclin-dependent kinases 4 and 6, were not separately studied because of the significant response of the patients selected based only on receptor status. Here, we report a patient with metastatic estrogen receptor- positive, her2-negative breast cancer with CDKN2A loss who experienced a clinical response to palbociclib.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA.

BACKGROUND: Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA. PATIENTS AND METHODS: Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m(2). Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan-Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival. RESULTS: The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39-0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39-1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449). CONCLUSIONS: While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel. CLINICALTRIALSGOV: NCT00567190.

Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer.

BACKGROUND: The phase III CLEOPATRA study demonstrated that combining pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA. PATIENTS AND METHODS: Participants were randomly assigned to pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥ 5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥ 2-point deterioration in Breast Cancer Subscale (BCS) score. RESULTS: Time to ≥ 5-point decline in TOI-PFB did not differ significantly between the pertuzumab and placebo arms [hazard ratio (HR), 0.97; P = 0.7161]. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061). CONCLUSIONS: Combining pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.

Phase I trial of dasatinib and ixabepilone in patients with solid tumors.

PURPOSE: Dasatinib is an oral tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family and ixabepilone is an epothilone B analog. Synergistic activity has been reported when combining dasatinib with chemotherapy. This study was conducted to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) for this combination. PATIENTS AND METHODS: Patients with metastatic solid tumors who progressed on standard therapy received dasatinib orally daily and ixabepilone IV every 3 weeks at escalating doses using 3 + 3 design. An expansion cohort was studied after reaching the MTD. Pharmacokinetic studies were performed. RESULTS: Nineteen patients were enrolled. No DLTs were observed at dose level (DL) 1 (dasatinib 100 mg and ixabepilone 30 mg/m(2)). At DL 2 (dasatinib 100 mg and ixabepilone 40 mg/m(2)), one patient had multiple DLTs. At DL 3 (dasatinib 150 mg and ixabepilone 40 mg/m(2)), the first patient developed grade 3 AE during cycle 2, the second patient had a DLT and a grade 3 AE during cycle 2. The accrual to DL 3 was halted without reaching the maximally administered dose (MAD) and MTDs were determined to be dasatinib 100 mg and ixabepilone 40 mg/m(2) (DL 2). One patient had a partial response and 12 patients stable disease as their best response. Fourteen patients came off study due to toxicities. CONCLUSION: The combination of dasatinib and ixabepilone showed modest clinical activity with doses 100 mg orally daily and 40 mg/m(2) IV every 3 weeks, respectively. Treatment related toxicities were seen frequently.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer.

BACKGROUND: To evaluate clinical and pathologic response to neoadjuvant docetaxel therapy in patients with stage III breast cancer. PATIENTS AND METHODS: Forty-five patients were planned to receive four cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery, four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 3 weeks, radiation therapy (RT), and tamoxifen when indicated. RESULTS: After four cycles of neoadjuvant docetaxel, the clinical response rate within the breast was 59% (95% CI 42% to 73%) and overall (breast and axilla) was 49% (95% CI 38% to 72%) in the intention-to-treat (ITT) population. At the time of surgery, 10% (n=4) of patients had a pathologic complete response (pCR) in the breast, 27% (n=11) had a pCR within the axillary lymph nodes, and 7% (n=3) had a pCR in the breast and axilla (95% CI 2% to 21%). An additional 5% (n=2) had minimal residual invasive tumor (<5 mm). The 5-year overall survival rate was 80%. The percentage of patients with grade 3/4 neutropenia was similar during docetaxel (93%) and AC (86%), while a greater percentage of patients had febrile neutropenia during docetaxel treatment (27%) compared with AC treatment (7%). CONCLUSIONS: Neoadjuvant docetaxel followed by surgery, adjuvant AC, hormonal therapy where indicated, and RT is an active regimen for patients with stage III breast cancer.

The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review.

This article summarizes the views of an expert meeting of cardiologists and oncologists on the use of dexrazoxane in anthracycline-based chemotherapy. Anthracycline-induced cardiotoxicity remains a major concern and new trends in treatment (e.g., combination of an anthracycline with other agents) will ensure that it remains a problem. Dexrazoxane reduces this cardiotoxicity in adults and children with a range of tumor types. Further research may help to identify those patients who are at particular risk of cardiotoxicity and who would benefit the most from dexrazoxane. There are also numerous possibilities for dexrazoxane in other clinical situations, which must be addressed in future trials.

Novel agents: clinical trial design.

The development of molecularly targeted anticancer agents has become an attractive therapeutic strategy. However, evaluation of these novel drugs poses special challenges to laboratory and clinical scientists. These include the creation of appropriate models to assess the effect of the agent on its putative target, the validation of new surrogate endpoints, and the use of effective clinical trial designs. An overview of the difficulties in using a new paradigm of drug development for these target-directed compounds is presented and optimal clinical research methodology to determine their efficacy described.

Adjuvant chemotherapy for breast cancer: an update.

Adjuvant chemotherapy in breast cancer has clearly been shown to reduce mortality. The benefits extend to pre- and postmenopausal women and those with node-negative, node-positive, estrogen receptor (ER)-positive, and ER-negative disease. Updated data regarding chemoendocrine therapy in postmenopausal women and anthracycline-based regimens are presented. Dose intensity, dose density, and high-dose therapy have not been proven efficacious to date, but further trials are pending. The incorporation of taxanes and bisphosphonates has been further elucidated, with follow-up studies in progress. The potential role of trastuzumab is the focus of several clinical trials. Recent findings regarding the long-term side effects of adjuvant therapy are reviewed. These risks may outweigh the benefit derived from chemotherapy in a subset of patients who have excellent overall survival (OS) with small tumors, good prognostic features, or favorable histologic subtypes. This report will review the current state of adjuvant chemotherapy for early-stage breast cancer.