Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid.

BACKGROUND: In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases. METHODS: The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double-blind, double-dummy phase 3 study comparing denosumab with ZA for preventing skeletal-related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory-Short Form at baseline and monthly thereafter. RESULTS: Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2-point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4-month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use. CONCLUSIONS: Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab-treated patients shifted to strong opioid analgesic use.

Gene expression profile of residual breast cancer after doxorubicin and cyclophosphamide neoadjuvant chemotherapy.

In breast cancer patients, primary chemotherapy is associated with the same survival benefits as adjuvant chemotherapy. Residual tumors represent a clinical challenge, as they may be resistant to additional cycles of the same drugs. Our aim was to identify differential transcripts expressed in residual tumors, after neoadjuvant chemotherapy, that might be related with tumor resistance. Hence, 16 patients with paired tumor samples, collected before and after treatment (4 cycles doxorubicin/cyclophosphamide, AC) had their gene expression evaluated on cDNA microarray slides containing 4,608 genes. Three hundred and eighty-nine genes were differentially expressed (paired Student's t-test, pFDR<0.01) between pre- and post-chemotherapy samples and among the regulated functions were the JNK cascade and cell death. Unsupervised hierarchical clustering identified one branch comprising exclusively, eight pre-chemotherapy samples and another branch, including the former correspondent eight post-chemotherapy samples and other 16 paired pre/post-chemotherapy samples. No differences in clinical and tumor parameters could explain this clustering. Another group of 11 patients with paired samples had expression of selected genes determined by real-time RT-PCR and CTGF and DUSP1 were confirmed more expressed in post- as compared to pre-chemotherapy samples. After neoadjuvant chemotherapy some residual samples may retain their molecular signature while others present significant changes in their gene expression, probably induced by the treatment. CTGF and DUSP1 overexpression in residual samples may be a reflection of resistance to further administration of AC regimen.

Phase I/II pharmacokinetic study of pemetrexed and epirubicin in patients with locally advanced or metastatic breast cancer.

BACKGROUND: Pemetrexed and epirubicin are each active in patients with advanced/metastatic breast cancer (MBC). This phase I/II study evaluated these drugs as a combination regimen. PATIENTS AND METHODS: Women with locally advanced or MBC were enrolled. Pemetrexed 400-600 mg/m2 and epirubicin 60-90 mg/m2 were administered on day 1 every 21 days. The recommended phase II dose was evaluated in a 2-stage design. RESULTS: Phase I enrolled 34 patients and evaluated 5 dose levels. Dose-limiting toxicities were neutropenia and febrile neutropenia. Patients received a median of 7.5 cycles (range, 1-8 cycles), and promising efficacy (partial response [PR], 32%; stable disease [SD], 50%) was observed. Pharmacokinetics of pemetrexed was unchanged when combined with epirubicin. Selected phase II regimen (pemetrexed 600 mg/m2 and epirubicin 75 mg/m2) was administered to 22 patients (median, 4.5 cycles; range 1-13 cycles). Five patients experienced a PR (23%), and 10 experienced SD (46%). This response was below the predefined efficacy requirements for subsequent enrollment, and accrual was stopped. Median time to progression was 5.3 months (95% CI, 3.1-8.9 months), and median time to treatment failure was 3.5 months (95% CI, 2.6-5.9 months). CONCLUSION: The regimen is safe but cannot be recommended as first-line chemotherapy in advanced breast cancer because of the low response rate.

Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) trial.

BACKGROUND: The Pre-Operative "Arimidex" Compared to Tamoxifen (PROACT) study was a randomized, multicenter study comparing anastrozole with tamoxifen as a preoperative treatment of postmenopausal women with large, operable (T2/3, N0-2, M0), or potentially operable (T4b, N0-2, M0) breast cancer. The effect of preoperative endocrine therapy in patients scheduled for mastectomy or with inoperable tumors at baseline was also investigated. METHODS: Patients with hormone receptor-positive breast cancer received anastrozole (n = 228) or tamoxifen (n = 223) with or without chemotherapy for 12 weeks before primary surgery. RESULTS: Objective responses for anastrozole and tamoxifen occurred in 39.5% and 35.4% of patients, respectively (ultrasound measurements), and 50.0% and 46.2% of patients, respectively (caliper measurements). In hormonal therapy-only patients (n = 314), feasible surgery at baseline improved after 3 months in 43.0% of patients receiving anastrozole and 30.8% receiving tamoxifen (P = .04). In the intent-to-treat population, improvement in feasible surgery at baseline to actual surgery at 3 months was found to be numerically higher in the anastrozole group compared with the tamoxifen group, although this difference did not reach significance. Drug-related adverse events were reported in 20.2% and 18.1% of patients, respectively, in the anastrozole and tamoxifen groups. CONCLUSIONS: Anastrozole is an effective and well-tolerated preoperative therapy, producing clinically beneficial tumor downstaging and reductions in tumor volume. These effects enable more minimal surgical interventions in patients scheduled for mastectomy, and mastectomy in patients with previously inoperable tumors. Anastrozole appears to be at least as effective as tamoxifen in this setting, and more effective than tamoxifen in certain clinically relevant subgroups. Cancer 2006. (c) 2006 American Cancer Society.

Gene expression profile associated with response to doxorubicin-based therapy in breast cancer.

PURPOSE: This study was designed to identify genes that could predict response to doxorubicin-based primary chemotherapy in breast cancer patients. EXPERIMENTAL DESIGN: Biopsy samples were obtained before primary treatment with doxorubicin and cyclophosphamide. RNA was extracted and amplified and gene expression was analyzed using cDNA microarrays. RESULTS: Response to chemotherapy was evaluated in 51 patients, and based on Response Evaluation Criteria in Solid Tumors guidelines, 42 patients, who presented at least a partial response (> or =30% reduction in tumor dimension), were classified as responsive. Gene profile of samples, divided into training set (n = 38) and independent validation set (n = 13), were at first analyzed against a cDNA microarray platform containing 692 genes. Unsupervised clustering could not separate responders from nonresponders. A classifier was identified comprising EMILIN1, FAM14B, and PBEF, which however could not correctly classify samples included in the validation set. Our next step was to analyze gene profile in a more comprehensive cDNA microarray platform, containing 4,608 open reading frame expressed sequence tags. Seven samples of the initial training set (all responder patients) could not be analyzed. Unsupervised clustering could correctly group all the resistant samples as well as at least 85% of the sensitive samples. Additionally, a classifier, including PRSS11, MTSS1, and CLPTM1, could correctly distinguish 95.4% of the 44 samples analyzed, with only two misclassifications, one sensitive sample and one resistant tumor. The robustness of this classifier is 2.5 greater than the first one. CONCLUSION: A trio of genes might potentially distinguish doxorubicin-responsive from nonresponsive tumors, but further validation by a larger number of samples is still needed.

Tumor residual pós-quimioterapia neoadjuvante para câncer de mama: impacto sobre o tratamento cirúrgico conservador / Residual tumor after neoadjuvant chemotherapy for breast cancer: impact on conservative surgical treatment

Objetivo: analisar as alteraçöes histopatológicas provocadas pela açäo da quimioterapia neoadjuvante (fluoracil, epirrubicina e ciclofosfamida; FEC - 4 ciclos) na área tumoral, no tecido mamário adjacente e nos linfonodos homolaterais, em peças cirúrgicas obtidas de pacientes portadoras de carcinomas primários de mama. Método: estudo histológico detalhado de 30 peças cirúrgicas obtidas por mastectomia radical (Patey) de pacientes portadoras de carcinomas primários da mama, previamente submetidas a esse tipo de terapêutica sistêmica. Resultados: observamos regressäo tumoral, de grau variável, em todas as peças analisadas. Esta regressäo ocorreu de forma irregular, restando inúmeros focos refretários na área ocupada pelo tumor primário. Observamos focos celulares residentes independentes do tumor primário no tecido mamário. Detalhamos outros achados histopatológicos decorrentes da açäo quimioterápica nos tecidos tumoral e mamário, como calcificaçöes e fibrose, e nos linfonodos axilares homolaterais. Conclusäo: concluímos que a açäo da quimioterapia neoadjuvante näo é uniforme, restando focos tumorais refratários, tanto na área do tumor inicial, quanto à distância. A regressäo do tumor independente da resposta de regressäo dos linfonodos axilares metastáticos. A utilizaçäo da cirurgia conservadora pós- quimioterapia neoadjuvante (FEC) deve ser evitada.

Resposta terapêutica à poliquimioterapia isolada, e associada ao acetato de medroxiprogesterona em câncer de mama avançado / Therapeutic response to polychemotherapy alone and combined with medroxyprogesterone acetate in advanced breast cancer

Estudou-se uma populaçäo de 25 mulheres pós-menopáusicas com câncer de mama em fase avançada. Compararam-se dois grupos semelhantes que receberam diferentes esquemas terapêuticos. O grupo A, com 13 pacientes, foi submetido a poliquimioterapia isolada (adriamicina e ciclofosfamida), enquanto que o grupo B, com 12 pacientes, recebeu a mesma poliquimioterapia, porém associada ao acetato de medroxiprogesterona. Em ambos os grupos obteve-se percentagem e duraçäo aceitáveis de resposta à terapêutica empregada, sem diferenças estatisticamente significativas. No entanto, houve menor incidência de toxicidade medular, leucopenia e anemia nos pacientes que receberam a associaçäo da poliquimioterapia com hormonioterapia, em relaçäo aos tratados com poliquimioterapia isolada

Tratamento médico das neoplasias cerebrais / Medical treatment of brain neoplasms

O fracasso fundamental do tratamento deo tipo localizado (cirurgia e radioterapia), influenciado a evoluçäo dos gliobastomas (para um menor número de meduloblastomas), deixa para a quimioterapia a possibilidade teórica de além disso melhorar a sobrevida das neoplasias do Sistem Nervoso Cetral. A medida da resposta tumoral à quimioterapia, é o maior problema dos tumores cerebrais. A avaliaçäo objetiva da regressäo do tumor determinada por angiograma, cintilografia cerebral e tomografia axial computadorizada, näo permite uma definiçäo exata para a avaliaçäo da eficácia da droga. Isto entäo deixará a avaliaçäo da resposta objetiva forçosamente ao exame neurológico. Por essa razäo, os estudos sobre a eficácia da quimioterapia em tumores cerebrais necessariamente se baseiam na sobrevida. Os resultados encontrados em vários agentes antitumorais foram revistos. Entre os agentes avaliados, as nitrosureas (BCNU, CCNU E Metil-CCNU) säo as drogas mais efetivas e induzem respostas objetivas de 40 a 50% em pacientes com tumores inoperáveis ou recidivantes em SNC. Esses agentes realmente säo lipossolúveis e atravessam rapidamente a barreira hemato-encefálica. Desde que os compostos nitrosureicos säo considerados como drogas essenciais pela sua significativa atividade contra glioblastomas inoperáveis ou recidivantes, foram também utilizados como quimioterapia adjuvante em pacientes que receberam cirurgia e radioterapia com a finalidade de aumentar o tempo livre de doença e a sobrevida. A experiência obtida em tratamento adjuvante com nitrosureas em glioblastomas é relatada