RESUMO
Importance: The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. Objective: To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. Design, Setting, and Participants: This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. Main Outcomes and Measures: The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. Results: The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). Conclusions and Relevance: This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Metástase Linfática/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Feminino , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/genética , Metástase Linfática/patologia , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Tamoxifeno/efeitos adversosRESUMO
BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Difosfonatos/administração & dosagem , Administração Oral , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ácido Clodrônico/administração & dosagem , Ácido Clodrônico/efeitos adversos , Difosfonatos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Ácido Ibandrônico/administração & dosagem , Ácido Ibandrônico/efeitos adversos , Infusões Intravenosas , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversosRESUMO
LESSONS LEARNED: The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events. BACKGROUND: As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC). METHODS: This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen. RESULTS: We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy. CONCLUSION: Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Etoposídeo/uso terapêutico , Irinotecano/uso terapêutico , Inibidores da Topoisomerase I/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Etoposídeo/farmacologia , Feminino , Humanos , Irinotecano/farmacologia , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores da Topoisomerase I/farmacologiaRESUMO
BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).
Assuntos
Anastrozol/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/administração & dosagem , Fulvestranto/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos Cross-Over , Feminino , Seguimentos , Fulvestranto/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Pós-Menopausa , Intervalo Livre de ProgressãoRESUMO
OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus Assuntos
Neoplasias da Mama/tratamento farmacológico
, Hidrocarbonetos Aromáticos com Pontes/efeitos adversos
, Predisposição Genética para Doença
, Doenças do Sistema Nervoso Periférico/genética
, Taxoides/efeitos adversos
, Negro ou Afro-Americano/genética
, Neoplasias da Mama/complicações
, Neoplasias da Mama/genética
, Neoplasias da Mama/patologia
, Hidrocarbonetos Aromáticos com Pontes/uso terapêutico
, Feminino
, Estudo de Associação Genômica Ampla
, Genômica
, Genótipo
, Humanos
, Doenças do Sistema Nervoso Periférico/patologia
, Polimorfismo de Nucleotídeo Único
, Taxoides/uso terapêutico
, População Branca/genética
RESUMO
AIMS: In the SWOG S0226 trial the combination of anastrozole plus fulvestrant (n = 349) was superior to anastrozole alone (n = 345) in hormone receptor (HR)-positive metastatic breast cancer. Here we report a pharmacokinetic subset analysis investigating a possible drug interaction between anastrozole and fulvestrant. METHODS: Post-menopausal patients with HR-positive metastatic breast cancer were randomized to anastrozole with or without concurrent fulvestrant. Blood samples were collected at 2, 4, 6 and 8 months, just prior to receiving the next dose of anastrozole and fulvestrant. Drug concentrations were measured via LC/MS-MS. Anastrozole concentration was compared in patients on anastrozole alone vs. patients on concomitant fulvestrant. Comparisons were made at each time point using parametric tests and over time using a linear mixed effects model. RESULTS: A total of 483 anastrozole concentration measurements were included, 224 samples from 64 patients on the anastrozole alone arm and 259 from 73 patients on the combination arm. The mean anastrozole concentration in the combination arm was significantly lower than that in the anastrozole alone arm at each sample collection time (all P < 0.01) and in the mixed effects model (an estimated difference of 9.85 ng ml(-1) (95% CI 5.69, 14.00 ng ml(-1) ), P < 0.001). CONCLUSION: A significant pharmacokinetic drug interaction was detected, in which the addition of fulvestrant to anastrozole treatment decreased the trough anastrozole concentration. Further research is needed to verify whether this interaction affects treatment efficacy and to determine the pharmacological mechanism by which this interaction occurs.
Assuntos
Neoplasias da Mama/metabolismo , Estradiol/análogos & derivados , Nitrilas/farmacocinética , Triazóis/farmacocinética , Anastrozol , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Interações Medicamentosas , Estradiol/farmacologia , Feminino , Fulvestranto , Humanos , Nitrilas/sangue , Triazóis/sangueRESUMO
Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using (18)F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.
Assuntos
Osso e Ossos/metabolismo , Osso e Ossos/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagemRESUMO
The proliferative effect of adjuvant tamoxifen on the endometrium can potentially result in endometrial abnormalities, including cancer in postmenopausal women. We conducted a randomized, controlled trial to assess endometrial pathological diagnoses in postmenopausal women with early stage, ER-positive breast cancer without endometrial pathology at baseline. They were assigned to tamoxifen alone versus tamoxifen plus cyclical medroxyprogesterone acetate (MPA 10 mg for 14 days every 3 months) for 5 years. Endovaginal sonograms (EVS) +/- endometrial biopsies (EMB) were required at baseline, 2 and 5 years. Of 313 patients registered, 296 were eligible and 169 (57%; 89, tamoxifen; 80, tamoxifen+MPA) were evaluable (completed year-2 EVS, with an EMB if stripe width was ⩾5 mm). Sixty (67%) of these in the tamoxifen arm had an endometrial stripe width ⩾5 mm (and underwent subsequent EMB) compared with 48 (60%) in the tamoxifen+MPA arm (P=0.40). There were four cases of proliferative endometrium and one simple hyperplasia on the tamoxifen arm (6% (95% confidence interval (CI): 2-13%) among evaluable patients and one proliferative endometrium on the tamoxifen+MPA arm (P=0.11). The overall fraction with benign endometrial abnormalities at year 2 was 3.6% (6/169; 95% CI: 1.3-7.6%), with only 1 (of 102) new benign proliferative event at year 5. The event rate in both arms was much lower than projected, making treatment arm comparisons less informative. A normal endometrium prior to tamoxifen may provide reassurance regarding future endometrial events. However, validation in a larger trial is needed before changing practice in asymptomatic, postmenopausal women.
RESUMO
Leptomeningeal carcinomatosis (LMC) secondary to metastatic breast cancer (MBC) has increased in incidence with improved systemic disease control. Current treatment options include radiation therapy (to symptomatic sites) and systemic treatment [intrathecal (IT) or intravenous (IV) chemotherapy]. Methotrexate (MTX), thiotepa and cytarabine are the most commonly used IT agents, while high-dose MTX is the most common IV regimen. While IT treatments are generally well tolerated, complications like chemical meningitis, leukoencephalopathy, etc. occur. LMC may cause a breakdown in the blood-brain barrier and thus allow systemic agents to penetrate; however, efficacy is reported only for agents administered at high doses (MTX). We report our institution's experience in using IV thiotepa as treatment for LMC secondary to MBC. We conducted a retrospective chart review of 13 patients with MBC who developed LMC and treated with IV thiotepa at our institution. It was administered at 40 mg/m(2) every 21 days; median number of thiotepa cycles administered was 5 with the major dose-limiting toxicity being myelosuppression. Four had partial response, 3 had stable disease and 6 had progressive disease. The 6-month survival rate was 69 % and 1-year survival rate was 31 %. Despite retrospective nature of our case series, we found the use of IV thiotepa as sole treatment for LMC in patients with MBC to be well tolerated, easily administered in the ambulatory setting, and with efficacy comparable to the other chemotherapeutic agents commonly used in the treatment of LMC. This regimen warrants further investigation in prospective studies.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Neoplasias da Mama/patologia , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/secundário , Tiotepa/administração & dosagem , Administração Intravenosa , Adulto , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Commonly used adjuvant systemic therapies harbor high rates of severe short-term and long-term side effects but are often justified to patients because of curative intent in early-stage breast cancer. One of the oldest and least toxic adjuvant regimens, CMF (oral cyclophosphamide given with intravenous methotrexate and 5-fluorouracil), has been largely abandoned because of the perception that it underperforms for survival outcomes compared with modern regimens containing anthracycline and/or taxanes. MATERIALS AND METHODS: To address this misperception, we performed a review of all consecutive breast cancer patients at the Seattle Cancer Care Alliance over the past decade who received 6 months of adjuvant CMF as their sole chemotherapy regimen and determined rates for relapse-free survival (RFS), overall survival (OS), and major organ toxicity. From January 2003 to August 2013, 248 patients (median age of 52 years at the start of chemotherapy) met criteria for inclusion in this series and had a median follow-up of 67 months. RESULTS: RFS and OS at 5 years was 94.5% (91.3%-97.9%) and 98% (96%-100%), respectively. The only major organ toxicity that occurred in > 5% of patients was Grade 3 neutropenia (18.1%, 24 patients). One patient died during therapy from pneumocystis pneumonia attributed to previously undiagnosed AIDS. CONCLUSION: In a modern cohort of patients thoroughly characterized for Grade and hormone receptor status, CMF was a well-tolerated and effective adjuvant regimen for early-stage breast cancer and should be considered for appropriately selected patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Coortes , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor-associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m(2) for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte-derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion-related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Biópsia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Paclitaxel/administração & dosagem , Receptor ErbB-2/deficiência , Receptor ErbB-2/metabolismo , Resultado do TratamentoRESUMO
PURPOSE: To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. PATIENTS AND METHODS: A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. RESULTS: Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). CONCLUSION: Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Neutropenia Febril/induzido quimicamente , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Modelos de Riscos Proporcionais , Adulto JovemRESUMO
PURPOSE: Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). PATIENTS AND METHODS: Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). RESULTS: Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). CONCLUSION: This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Substituição de Medicamentos , Células Neoplásicas Circulantes/patologia , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Falha de TratamentoRESUMO
Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m(2)) was given intravenously on Day 1, vinorelbine (27.5 mg/m(2)) intravenously on Days 8 and 15, and filgrastim on Days 2-21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64-82 %) with a median OS of 22.3 months (95 % CI 18.8-31.4 months). One-year PFS was 34 % (95 % CI 24-43 %) with median of 7.2 months (95 % CI 6.4-10.3). OS at 2 and 3 years were 49 % (95 % CI 38-59 %) and 30 % (95 % CI 21-40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Taxoides/uso terapêutico , Vimblastina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Docetaxel , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/metabolismo , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Sobrevida , Taxoides/efeitos adversos , Resultado do Tratamento , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , VinorelbinaRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is a rare, highly aggressive form of breast cancer. The mechanism of IBC carcinogenesis remains unknown. We sought to evaluate potential genetic risk factors for IBC and whether or not the IBC cell lines SUM149 and SUM190 demonstrated evidence of viral infection. METHODS: We performed single nucleotide polymorphism (SNP) genotyping for 2 variants of the ribonuclease (RNase) L gene that have been correlated with the risk of prostate cancer due to a possible viral etiology. We evaluated dose-response to treatment with interferon-alpha (IFN-α); and assayed for evidence of the putative human mammary tumor virus (HMTV, which has been implicated in IBC) in SUM149 cells. A bioinformatic analysis was performed to evaluate expression of RNase L in IBC and non-IBC. RESULTS: 2 of 2 IBC cell lines were homozygous for RNase L common missense variants 462 and 541; whereas 2 of 10 non-IBC cell lines were homozygous positive for the 462 variant (p= 0.09) and 0 of 10 non-IBC cell lines were homozygous positive for the 541 variant (p = 0.015). Our real-time polymerase chain reaction (RT-PCR) and Southern blot analysis for sequences of HMTV revealed no evidence of the putative viral genome. CONCLUSION: We discovered 2 SNPs in the RNase L gene that were homozygously present in IBC cell lines. The 462 variant was absent in non-IBC lines. Our discovery of these SNPs present in IBC cell lines suggests a possible biomarker for risk of IBC. We found no evidence of HMTV in SUM149 cells. A query of a panel of human IBC and non-IBC samples showed no difference in RNase L expression. Further studies of the RNase L 462 and 541 variants in IBC tissues are warranted to validate our in vitro findings.
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BACKGROUND: The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer. METHODS: Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome. RESULTS: The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups. CONCLUSIONS: The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos Cross-Over , Intervalo Livre de Doença , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/efeitos adversos , Feminino , Fulvestranto , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Nitrilas/efeitos adversos , Pós-Menopausa , Triazóis/efeitos adversosRESUMO
BACKGROUND: In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or 'flare' response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response. METHODS: Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis. RESULTS: Forty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%. CONCLUSIONS: Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.
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BACKGROUND: Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC. METHODS: The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor-positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1-14, and capecitabine, 1,500 mg twice daily on days 8-21, in 21-day cycles. RESULTS: In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7-8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1-22.0 months). The RR was 36% (95% CI, 26%-48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%-48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths. CONCLUSIONS: PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Capecitabina , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Pessoa de Meia-Idade , Mucina-1/análise , Estudos ProspectivosRESUMO
SWOG trial S0102 showed significant activity of the combination of docetaxel and vinorelbine in HER2-negative metastatic breast cancer (MBC). For HER2-positive patients, additional benefit may occur with the addition of trastuzumab due to its synergy with docetaxel and vinorelbine. Patients with HER2-positive MBC, but without prior chemotherapy for MBC or adjuvant taxane, were eligible. Docetaxel (60 mg/m²) was given intravenously on Day 1, vinorelbine (27.5 mg/m²) intravenously on Days 8 and 15, and filgrastim (5 µg/kg) on Days 2-21 of a 21-day cycle. In addition, patients received weekly infusions of trastuzumab (2 mg/kg) after an initial bolus of 4 mg/kg. The primary outcome was 1 year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. Due to slow accrual (February 2003-December 2006), enrollment was stopped after 76 of 90 planned patients. There have been 32 deaths and 51 progressions among the 74 eligible patients who received treatment. The estimated 1 year OS was 93% (95% CI 84-97%) with a median of 48 months. One-year PFS was 70% (95% CI 58-79%) with a median of 20 months. Response rate for measurable disease was 84%. No deaths were attributed to treatment. Grade 4 toxicities were reported for 19% with neutropenia the most common (15%). The most common grade 3 toxicities (33%) were leucopenia (14%) and fatigue (10%). The combination of trastuzumab, docetaxel, and vinorelbine is effective as first-line chemotherapy in HER2-positive MBC with minimal toxicity. One-year survival estimates are among the highest reported in this population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Docetaxel , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Recombinantes/administração & dosagem , Taxoides/administração & dosagem , Trastuzumab , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
PURPOSE: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy. EXPERIMENTAL DESIGN: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with (18)F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue-dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured. RESULTS: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01). CONCLUSIONS: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use.