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Background: Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer. Patients and methods: The EORTC 90091-10093 BIG 1-12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety. Results: Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher's exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4-16.5). The 1-year iDFS was 93.8% (95% CI 77.3-98.4) in the observation versus 84.8% (95% CI 63.4-94.2) in the trastuzumab arm. No grade 2-4 cardiac events were observed in the trastuzumab arm. Conclusion: Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.
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Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/terapia , Células Neoplásicas Circulantes/efeitos dos fármacos , Trastuzumab/administração & dosagem , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Cardiotoxicidade/epidemiologia , Cardiotoxicidade/etiologia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversosRESUMO
BACKGROUND: Taxane-containing adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. This study compared efficacy and tolerability of epirubicin (E)/cyclophosphamide (C) followed by docetaxel (Doc) with a dose-dense 5-fluorouracil (F)+E+ C regimen. METHODS: The ADEBAR study was a randomised phase III trial for women with primary invasive breast cancer and ⩾4 metastatic axillary lymph nodes (n=1364). Treatment consisted of four 21-day cycles of E plus C, followed by four 21-day cycles of Doc (EC-Doc), or six 28-day cycles of E plus F plus C (FEC120). RESULTS: Disease-free survival (DFS) was similar in the two treatment arms as shown by multivariate Cox regression adjusted for other prognostic factors (EC-Doc vs FEC120, hazard ratio (HR): 1.087; 95% confidence interval (CI): 0.878-1.346, P=0.444). In addition, there was no significant difference in overall survival (OS) between the two groups (HR: 0.974; 95% CI: 0.750-1.264, P=0.841). Haematologic toxicity was more common in FEC120 recipients; non-haematologic toxicities occurred more frequently in the EC-Doc arm. The serious adverse event rate was significantly higher in the FEC120 group (29.7% vs 22.5%). CONCLUSIONS: EC-Doc provides a feasible and effective alternative therapy option to FEC120 with a different safety profile in this high-risk breast cancer cohort.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Idoso , Axila/patologia , Quimioterapia Adjuvante/métodos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Epirubicina/administração & dosagem , Epirubicina/uso terapêutico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types. PATIENTS AND METHODS: We evaluated the frequency of SPARC expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS). RESULTS: An increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036). CONCLUSIONS: SPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel. CLINICAL TRIAL NUMBER: NCT00544765.
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Biomarcadores Tumorais/biossíntese , Terapia Neoadjuvante , Osteonectina/biossíntese , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/uso terapêutico , Resultado do TratamentoRESUMO
Obese breast cancer patients have a higher risk of lymph node metastasis and a poorer prognosis compared to patients with normal weight. For obese women with node-positive breast cancer, an association between body weight and prognosis remains unclear. In this retrospective study, we analyzed patient data from the Phase-III ADEBAR trial, in which high-risk breast cancer patients (pT1-4, pN2-3, pM0) were randomized into a docetaxel-based versus epirubicin-based chemotherapy regimen. Patients were grouped according to their BMI value as underweight/normal weight (BMI < 25 kg/m(2); n = 543), overweight (BMI 25-29.9 kg/m(2); n = 482) or obese (BMI ≥ 30 kg/m(2); n = 285). Overweight and obese patients were older, had larger tumors and were more likely to be postmenopausal at the time of diagnosis compared to underweight/normal-weight patients (all p < 0.001). Multivariate Cox regression analyses adjusting for age and histopathological tumor features showed that obese patients had a significantly shorter disease-free survival (DFS; HR 1.43; 95 % CI 1.11-1.86; p = 0.006) and overall survival (OS; HR 1.56; 95 % CI 1.14-2.14; p = 0.006) than non-obese patients. Subgroup analyses revealed that the differences in DFS and OS were significant for postmenopausal but not for premenopausal patients, and that the survival benefit of non-obese patients was more pronounced in women with hormone-receptor-positive disease. Obesity constitutes an independent, adverse prognostic factor in high-risk node-positive breast cancer patients, in particular for postmenopausal women and women with hormone-receptor-positive disease.
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Neoplasias da Mama/complicações , Neoplasias da Mama/mortalidade , Obesidade/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Índice de Massa Corporal , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Estadiamento de Neoplasias , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: We were able to demonstrate a predictive value of serum HER2 (sHER2) in patients receiving trastuzumab in the neoadjuvant GeparQuattro trial. However, the role of sHER2 in patients receiving neoadjuvant therapy (NT) with lapatinib is still unclear. METHODS: The neoadjuvant GeparQuinto trial compared trastuzumab vs lapatinib in addition to chemotherapy in HER2-positive primary breast cancer patients. The sHER2 levels were measured by enzyme-linked immunosorbant assay in 210 patients, of whom 109 (52%) patients received trastuzumab and 101 (48%) lapatinib at three different time points. RESULTS: Twenty-two percent of patients had elevated baseline sHER2 levels (>15 ng ml⻹). A decrease of sHER2 levels (>20%) in the trastuzumab and lapatinib-treated group during NT was seen in 44% and 24% of the patients, an increase of sHER2 levels (>20%) was seen in 6% and 41% of patients, respectively. Higher pre-chemotherapy sHER2 levels were associated with higher pathological complete remission (pCR) rates in the entire study cohort (OR 1.8, 95% CI 1.02-3.2, P=0.043). A decline of sHER2 levels (>20%) during NT was a predictor for pCR in the lapatinib-treated patient group (OR: 11.7, 95% CI 1.3-110, P=0.031). CONCLUSION: Results of this study demonstrate that sHER2 levels change differently during NT depending on the anti-HER2 treatment strategy. Elevated baseline sHER2 levels (>15 ng ml⻹) and a decrease of sHER2 levels (>20%) early after therapy initiation are both relevant criteria to predict response to lapatinib-based treatment.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Quinazolinas/uso terapêutico , Receptor ErbB-2/sangue , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Esquema de Medicação , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante/métodos , Valor Preditivo dos Testes , Quinazolinas/administração & dosagem , Receptores de Estrogênio/sangue , Pesquisa Translacional Biomédica , Trastuzumab , Resultado do TratamentoRESUMO
BACKGROUND: Circulating tumor cells (CTCs) have been reported to predict clinical outcome in metastatic breast cancer (MBC). Biology of CTCs may differ from that of the primary tumor and HER2-positive CTCs are found in some patients with HER2-negative tumors. PATIENTS AND METHODS: Patients with HER2-negative MBC were screened for participation in DETECT III and IV trials before the initiation of a new line of therapy. Blood samples were analyzed using CELLSEARCH. CTCs were labeled with an anti-HER2 antibody and classified according to staining intensity (negative, weak, moderate, or strong staining). RESULTS: Screening blood samples were analyzed in 1933 patients with HER2-negative MBC. As many as 1217 out of the 1933 screened patients (63.0%) had ≥1 CTC per 7.5 ml blood; ≥5 CTCs were detected in 735 patients (38.0%; range 1-35 078 CTCs, median 8 CTCs). HER2 status of CTCs was assessed in 1159 CTC-positive patients; ≥1 CTC with strong HER2 staining was found in 174 (15.0%) patients. The proportion of CTCs with strong HER2 staining among all CTCs of an individual patient ranged between 0.06% and 100% (mean 15.8%). Patients with estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors were more likely to harbor ≥1 CTC with strong HER2 staining. CTC status was significantly associated with overall survival (OS). Detection of ≥1 CTC with strong HER2 staining was associated with shorter OS [9.7 (7.1-12.3) versus 16.5 (14.9-18.1) months in patients with CTCs with negative-to-moderate HER2 staining only, P = 0.013]. In multivariate analysis, age, ER status, PR status, Eastern Cooperative Oncology Group performance status, therapy line, and CTC status independently predicted OS. CONCLUSION: CTC detection in patients with HER2-negative disease is a strong prognostic factor. Presence of ≥1 CTC with strong HER2 staining was associated with shorter OS, supporting a biological role of HER2 expression on CTCs.
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Neoplasias da Mama , Células Neoplásicas Circulantes , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapêuticoRESUMO
BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.
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Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Terapias Complementares , Letrozol/efeitos adversos , Dor Musculoesquelética/induzido quimicamente , Idoso , Artralgia/induzido quimicamente , Feminino , Alemanha/epidemiologia , Humanos , Pessoa de Meia-Idade , Mialgia/induzido quimicamente , Pós-MenopausaRESUMO
Large-scale genotyping studies have identified over 70 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. However, knowledge regarding genetic risk factors associated with the prognosis is limited. The aim of this study was therefore to investigate the prognostic effect of nine known breast cancer risk SNPs. BC patients (n = 1687) randomly sampled in an adjuvant, randomized phase III trial (SUCCESS A study) were genotyped for nine BC risk SNPs: rs17468277 (CASP8) , rs2981582 (FGFR2) , rs13281615(8q24), rs3817198 (LSP1) , rs889312 (MAP3K1) , rs3803662 (TOX3) , rs13387042(2q35), rs4973768 (SLC4A7) , rs6504950 (COX11) . Cox proportional hazards models were used to test the SNPs' association with overall survival (OS) and progression-free survival (PFS). Additional analyses were carried out for molecular subgroups. rs3817198 in LSP1 (lymphocyte-specific protein 1) was the only SNP that significantly influenced OS (p = 0.01) and PFS (p < 0.01) in the likelihood ratio test comparing the genetic survival model with the clinical survival model. In the molecular subgroups, triple-negative patients with two minor alleles in rs3817198 had a much better prognosis relative to OS (adjusted HR 0.03; 95% CI 0.002â-â0.279) and PFS (HR 0.09; 95% CI 0.02â-â0.36) than patients with the common alleles. The same effect on PFS was shown for patients with luminal A tumors (HR 0.19; 95% CI 0.05â-â0.84), whereas patients with luminal B tumors had a poorer PFS with two minor alleles (HR 2.13; 95% CI 1.02â-â4.40). The variant in rs3817198 has a prognostic effect particularly in the subgroup of patients with triple-negative BC, suggesting a possible link with immunomodulation and BC.
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BACKGROUND: Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS: We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS: Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS: In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.
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Hormônio Antimülleriano/sangue , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Taxoides/administração & dosagem , Adulto , Amenorreia/induzido quimicamente , Quimioterapia Adjuvante/efeitos adversos , Feminino , Humanos , Terapia Neoadjuvante/efeitos adversos , Fatores de TempoRESUMO
BACKGROUND: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy. METHODS: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining. RESULTS: 258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC. CONCLUSION: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Células Neoplásicas Circulantes/patologia , Receptor ErbB-2/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/sangue , Pesquisa Translacional Biomédica , Trastuzumab/administração & dosagemRESUMO
BACKGROUND: The ADEBAR study is a prospective multicenter Phase III trial to examine whether high-risk breast cancer patients > or =4 involved axillary lymph nodes) benefit from a sequential anthracycline-docetaxel regimen compared to standard chemotherapy with anthracyclines. With a median recruitment of 33 patients per month at 198 actively-recruiting centers, the ADEBAR study was the best recruiting study in Germany until the end of the trial. MATERIALS AND METHODS: A standardized questionnaire was sent to all participating centers in order to determine the extent to which treatment strategies and patient care are affected by participation in the ADEBAR study. The questionnaire covered 5 areas of interest: previous inclusion of patients at the same tumor stage in other studies, the type of chemotherapy received by comparable patients previously outside the study, change in the intensity of medical care since participating in the ADEBAR study, the information gained through participation in the study and changes in the overall quality of medical care. RESULTS: 51.0% (n=98) of the questionnaires were returned, from which 3 were excluded from the analysis due to being incomplete. In the year preceding the ADEBAR study, 63.2% of participating centers had not entered their high-risk patients into a clinical trial. Before participating in the ADEBAR protocol, 44.2% of patients with the same indication had received inadequate therapy by today's standards, such as CMF, EC/CMF or 4x EC. 59.0% of the centers noted an increase in the intensity of patient care as a result of participation in the study, independent of the care provided purely because of the study. By being part of a research network, with a regular flow of information via newsletters, study meetings and the like, 80.0% noted an improvement in their professional knowledge in the field of breast cancer. Moreover, 31.6% of the centers reported an improvement in the overall quality of their patient care since the start of the trial. CONCLUSION: The results of the survey demonstrate that both physicians and patients benefit from participation in clinical trials as this is associated with optimized decision-making as regards therapy and patient care.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resultado do Tratamento , Ciclofosfamida/administração & dosagem , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Estudos Prospectivos , Inquéritos e Questionários , Taxoides/administração & dosagemRESUMO
INTRODUCTION: From the early days of pathology back in the nineteenth century until now, there has been an ongoing search for the missing link between solid tumors such as breast cancer and distant metastases, which sometimes occur many years after removal of the primary tumor. The "seed and soil" theory hypothesizes the early dissemination of occult tumor cells into blood or bone marrow, which can persist in a dormant state for a long time and then become precursors of metastases in distant organs which offer appropriate conditions. METHOD: Advances in immunocytochemical methods have enabled the enrichment and visualization of those disseminated tumor cells in bone marrow (DTC-BM) or circulating tumor cells (CTC) in blood. Many studies could demonstrate prognostic significance of the detection of DTC-BM or CTC in different stages of breast cancer. CONCLUSION: Further characterization of those cells by immunocytochemical stainings, fluorescence in situ hybridizations, or PCR-based molecular methods will help to understand the biology of tumor cell dissemination and metastasis formation, as well as to define potential drug targets.
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Medula Óssea/patologia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Proliferação de Células , Feminino , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendênciasRESUMO
Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5â%, p < 0.001), as was leukopenia (64.1 vs. 58.5â%, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8â%, FEC-D: 36.3â%, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3â%, SGOT: 2â%), whereas neuropathy (1.2â%), arthralgia (1.6â%) and bone pain (2.6â%) were more common using FEC-D. Dose reductions > 20â% (4 vs. 2.4â%) and postponement of treatment cycles (0.9 vs. 0.4â%) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.
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PURPOSE: The presence of isolated tumor cells in the bone marrow (ITC-BM) is an independent prognostic factor in all stages of breast cancer. Both the expression/amplification of human epithelial growth factor receptor 2 (HER2) and Topoisomerase IIalpha (TOP IIa), a key enzyme of DNA replication and main target of anthracyclins, in breast cancer tissue seem to have predictive value regarding the effectiveness of systemic therapies. METHODS: To investigate the correlation between these factors and their influence on clinical outcome, tumor tissue of 54 patients who were screened for ITC-BM before and after anthracyclin-based chemotherapy (abCTX) was examined for HER2 and TOP IIa by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: By IHC, 31% of the tumors showed positive for HER2 (2+/3+), 14.6% were amplified in FISH. TOP IIa expression (>50%) was found in 13/53 patients (25%), FISH was positive in 5/47 cases (11%). TOP IIa amplification was not seen in cases without HER2 amplification, five of the seven HER2 amplified cases also were amplified for TOP IIa (71% co-amplification). Forty-three patients had adjuvant, seven neo-adjuvant, four palliative abCTX. ITC-BM were present in 24% of patients before and 31% after CTX. Patients with HER2 (IHC, P = 0.29) and TOP IIa (FISH, P = 0.16) positive tumors tended to stay or become negative in BM status after abCTX and vice versa. After a median follow-up of 44 months (6-127), none of the factors reached significance for overall survival. Yet, patients with HER2 (P = 0.16) and TOP IIa (P = 0.09) positive tumors showed a trend towards prolonged disease-free survival. Remarkably, none of the TOP IIa FISH-positive patients developed distant metastases (P = 0.099) or died (P = 0.19) after CTX so far. CONCLUSIONS: HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.
Assuntos
Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Medula Óssea/patologia , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/análise , Proteínas de Ligação a DNA/análise , Receptor ErbB-2/análise , Neoplasias da Medula Óssea/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Valor Preditivo dos Testes , Prognóstico , Fatores de RiscoRESUMO
PURPOSE: Circulating tumor cell (CTC) counts might display a superior prognostic value for overall survival (OS) compared to objective response criteria (OR) in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: CTCs were detected using the CellSearch™ System out of 122 samples during docetaxel chemotherapy (75 mg/m(2)) at baseline (q0) and after 1 (q1), 4 (q4) and 10 (q10) cycles, in mCRPC patients (n = 33). OR was evaluated by morphologic RECIST and clinical criteria after 4 (q4) and 10 (q10) cycles. RESULTS: For OS, analyses revealed a significant prognostic value for categorical (<5 vs. ≥5) CTC counts (q0, p = 0.005; q1, p = 0.001; q4, p < 0.001; q10, p = 0.002), RECIST (q4, p < 0.001; q10, p = 0.02) and clinical criteria (q4, p < 0.001; q10, p = 0.02). Concordance of CTC counts with OR revealed a sensitivity of 83.3-87.5 % and a specificity of 68.0-76.5 % with complementary discriminatory power for OS. Comparing CTC counts with concomitant OR at q4 in multivariate analyses, an independent prognostic value for OS was found for CTC counts (HR 3.3; p = 0.02) similar to clinical (HR 4.9; p = 0.02) and radiologic response (HR 3.4; p = 0.051). Comparing the predictive value for death, early post-treatment CTC counts at q1 demonstrated significant accuracy with an area under the curve of 79.5 % (p = 0.004) similar to CTC counts at q4 (76.7 %; p = 0.009). Radiologic and clinical response at q4 displayed accuracy similar to early CTC counts at q1 (72.2 %; p = 0.03 and 75.0 %; p = 0.02) despite low sensitivities. CONCLUSIONS: CTC counts appear to be an earlier and more sensitive predictor for survival and treatment response than current OR approaches and may provide complementary information toward individualized treatment strategies.
Assuntos
Antineoplásicos/uso terapêutico , Células Neoplásicas Circulantes/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos/sangue , Biomarcadores Tumorais/sangue , Contagem de Células , Docetaxel , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Prognóstico , Neoplasias de Próstata Resistentes à Castração/sangue , Análise de SobrevidaRESUMO
Introduction: Use of hormone therapy (HT) has declined dramatically in recent years. Some studies have reported that HT use before a diagnosis of breast cancer (BC) may be a prognostic factor in postmenopausal patients. This study aimed to examine the prognostic relevance of HT use before BC diagnosis. Methods: Four BC cohort studies in Germany were pooled, and 4492 postmenopausal patients with HT use data were identified. Patient data and tumor characteristics were compared between users and nonusers, along with overall survival (OS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Cox proportional hazards models were stratified by study center and adjusted for age at diagnosis, tumor stage, grading, nodal status, and hormone receptors. Results: Women with HT use before the diagnosis of BC were more likely to have a lower tumor stage, to be estrogen receptor-negative, and to have a lower grading. With regard to prognosis there were effects seen for OS, DMFS and LRFS, specifically in the subgroup of women with a positive hormone receptor. In these subgroups, BC patients had a better prognosis with previous HT use. Conclusions: HT use before a diagnosis of BC is associated with a more favorable prognosis in women with a positive hormone receptor status. It may be recommended that the prognostic factor HT should be documented and analyzed as a confounder for prognosis in studies of postmenopausal hormone-responsive breast cancers.
RESUMO
ANAMNESIS: A 60-year-old patient underwent breast-preserving surgery for breast cancer of TNM stage pTla (m), pN2a (8/12), G2, pMO. After the operation, she received 4 cycles of epirubicin/cyclophosphamide (90/600 mg/m2), followed by 2 cycles of docetaxel (100 mg/m2). Four days after the second cycle of docetaxel, the patient presented with abdominal pain, nausea, vomiting and obstipation of 3 days' duration. FINDINGS: The physical examination showed a distended abdomen, absence of peristaltic sounds and pressure pain in the lower left abdomen. The laboratory examination was conspicuous for granulocytopenia of NCI grade Ill and an increased CRP concentration of 7.7 mg/dl. DIAGNOSIS: The main diagnosis was suspected chemotherapy-associated enterocolitis with signs of paralytic ileus; the latter was confirmed by computer tomography and laparotomy. THERAPY AND COURSE: Primary treatment consisted of placing a stomach tube, infusion therapy, broad-spectrum antibiotics and G-CSF. Later on, 5 explorative laparotomies with abdominal lavage were performed due to deterioration of the general condition and suspicion of intra-abdominal compartment syndrome. After a temporary improvement, the patient died of protracted multi-organ failure 8 weeks after hospitalization. CONCLUSION: Chemotherapy-associated enterocolitis is a very rare but potentially lethal side effect of cytostatic therapy. Therefore, gastrointestinal symptoms should be carefully noted in order to minimize the mortality risk by a timely therapeutic intervention.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias da Mama/tratamento farmacológico , Enterocolite Necrosante/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Docetaxel , Esquema de Medicação , Enterocolite Necrosante/diagnóstico , Epirubicina/administração & dosagem , Epirubicina/toxicidade , Evolução Fatal , Feminino , Humanos , Pseudo-Obstrução Intestinal/induzido quimicamente , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/cirurgia , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reoperação , Taxoides/administração & dosagem , Taxoides/toxicidade , Falha de TratamentoRESUMO
INTRODUCTION AND OBJECTIVE: A clinically important myelosuppression due to adjuvant chemotherapy is seen more frequently as dosage is intensified and new drugs are used. The assessment of the cytopenia expected is frequently hampered by a lack of directly comparable data. The aim of this study was to compare - in our own patient population - the chemotherapy-associated myelosuppression of four chemotherapeutic regimens used in gynecological oncology. METHODS: 79 patients with primary breast cancer and 26 patients with epithelial ovarian carcinoma underwent cytostatic treatment, and the associated myelosuppression was evaluated by the determination of cytopenia and the need for supportive therapy. The chemotherapy regimens investigated were CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), 6xq3w), EC/CMF (epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2), 4xq3w, followed by CMF, 3xq3w), DE (docetaxel 75 mg/m(2), epirubicin 90 mg/m(2), 6xq3w) and CC (cyclophosphamide 600 mg/m(2), carboplatin AUC 6, 6xq3w). RESULTS: The EC/CMF and DE regimens were used significantly more frequently for more advanced tumor stages, but there were no differences concerning tumor-dependent prechemotherapeutic myelosuppression. Hemopoiesis was most impaired in the CC group with a mean drop of serum hemoglobin of 1.5 g/dl to the end of the cytostatic treatment; correspondingly, most transfusions of concentrated erythrocytes were needed in this group. The strongest suppression of leukopoiesis was found in the DE group, with a mean drop in leukocyte counts of 6.2 x 10(3)/microliter per cycle; in this group, a mean of 7.6 ready-made syringes with 263 microgram Lenogastrim was used to stimulate leukopoiesis. The severest drop in the mean thrombocyte count, i.e. 171.7 x 10(3)/microliter, was found in the CC group. CONCLUSIONS: The CC regimen impairs thrombo- and erythropoiesis most, whereas the DE regimen causes marked leukopenia. The regimen with the smallest myelosuppression was CMF. No severe cytopenia-associated complications were detected in any of the cases investigated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Cisplatino/efeitos adversos , Ciclofosfamida/efeitos adversos , Etoposídeo/efeitos adversos , Fluoruracila/efeitos adversos , Metotrexato/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Radioisótopos de Cobalto/uso terapêutico , Terapia Combinada , Interpretação Estatística de Dados , Feminino , Hematopoese/efeitos dos fármacos , Humanos , Leucopoese/efeitos dos fármacos , Excisão de Linfonodo , Metástase Linfática , Mastectomia Segmentar , Pessoa de Meia-Idade , Neoplasias Ovarianas/cirurgia , Contagem de Plaquetas , Teleterapia por Radioisótopo , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Evidence is accumulating that circulating tumor cells (CTC) out of peripheral blood can serve as prognostic marker not only in metastatic but also in early breast cancer (BC). Various methods are available to detect CTC. Comparisons between the different techniques, however, are rare. MATERIAL AND METHODS: We evaluate two different methods for CTC enrichment and detection in primary BC patients: the FDA-approved CellSearch System (CSS; Veridex, Warren, USA) and a manual immunocytochemistry (MICC). The cut-off value for positivity was ≥1 CTC. RESULTS: The two different nonoverlapping patient cohorts evaluated with one or the other method were well balanced regarding common clinical parameters. Before adjuvant CHT 21.1% (416 out of 1972) and 20.6% (247 out of 1198) of the patients were CTC-positive, while after CHT 22.5% (359 out of 1598) and 16.6% (177 out of 1066) of the patients were CTC-positive using CSS or MICC, respectively. CTC positivity rate before CHT was thus similar and not significantly different (P = 0.749), while CTC positivity rate immediately after CHT was significantly lower using MICC compared to CSS (P < 0.001). CONCLUSION: Using CSS or MICC for CTC detection, we found comparable prevalence of CTC before but not after adjuvant CHT.