A good drug made better: the Fulvestrant Dose Response Story

Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, prior to use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for treatment of postmenopausal women with ER+ advanced breast cancer following failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was revised to 500 mg (500 mg/month plus 500 mg on Day 14 of Month 1) following demonstration of improved progression-free survival versus fulvestrant 250 mg. We have reviewed the dose-dependent effects of fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the pre-surgical setting (three previously reported studies: Study 18, NEWEST [Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors] and Trial 57), and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of pre-surgical data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant dose resulting in greater reductions in ER, progesterone receptor and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer following failure of prior antiestrogen therapy. Although it remains to be determined in a Phase III trial, cross-trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, supporting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose

Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro–B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro–B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10–1.71), P = 0.02; PlGF 3.78 (1.30–11.0), P = 0.047; GDF-15 1.71 (1.15–2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts

Time trends of left ventricular ejection fraction and myocardial deformation indices in a cohort of women with breast cancer treated with anthracyclines, taxanes, and trastuzumab

Background: Trastuzumab, a HER2 monoclonal antibody, has transformed the prognosis of patients with the aggressive HER2-positive breast cancer type. Trastuzumab augments the cardiotoxic effects of anthracyclines, but its effect is thought to be at least partially reversible. The objective of this study was to examine the time trends of left ventricular (LV) size and function in a cohort of women treated with anthracyclines and trastuzumab. Methods: Twenty-nine patients >18 years of age with first-time breast cancer treated with anthracyclines and trastuzumab were monitored using echocardiography before, at the completion of, and at a median follow-up of 24.7 months (interquartile range, 15.9-34 months) after the end of their cancer treatment. LV volume, LV ejection fraction, and global peak systolic longitudinal strain and strain rate were measured in the apical four- and two-chamber views. Left ventricular ejection fraction was measured using a modified Simpson's biplane method. Results: LV end-diastolic and end-systolic volumes increased at the end of treatment compared with baseline and did not recover during follow-up. Left ventricular ejection fraction, strain, and strain rate decreased at the end of treatment compared with baseline (from 64 +/- 6% to 59 +/- 8%, from -20.0 +/-2.5% to -17.6 +/- 2.6%, and from -1.26 +/- 0.23 to -1.13 +/- 0.16 sec2 years after the end of anthracycline and trastuzumab treatment, without significant recovery after trastuzumab cessation, suggestive of long-term underlying cardiac damage and remodeling

Multicenter Phase II Study of Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer

PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate. This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer. PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease. RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients. CONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home

Interactions reported in the literature.

<p>Interaction between fulvestrant sensitivity genes (green) and resistance genes (red) and the known estrogen receptor signal transduction pathways (blue). Each interaction is taken from the literature and can be both at the transcription level and at the protein-protein interaction level. ERE means estrogen responsive element in the promoter of a gene. A number of resistance genes have been reported to interact with the actin cytoskeleton.</p