Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Cost-effectiveness of ribociclib for premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer: a Brazilian public health care system perspective.

Introduction: The MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system. Methods: We calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs. Results: Ribociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case. Conclusion: Ribociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system.

Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS: Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS: Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION: Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Optimizing the management of HER2-negative metastatic breast cancer in the era of PARP inhibitors-proceedings from breast cancer expert group meeting.

The therapeutic landscape of human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents such as poly-ADP ribose polymerase inhibitors (PARPi), novel chemotherapeutic agents, immunotherapy, and endocrine therapies. In this scenario, optimizing the appropriate treatment sequence is a daunting task for clinicians. To develop evidence-based answers to key clinical questions on treatment selection and appropriate treatment sequence for the management of patients with HER2- mBC in the era of PARPi, a breast cancer expert group meeting was convened. The expert panel comprised of eight key opinion leaders from Argentina, Brazil, Colombia, Egypt, Mexico, Moscow, South Korea, and the United Arab Emirates, who convened and reviewed the literature, discussed the clinical practices across the participating regions, and formulated answers to key clinical questions for optimizing the management of HER2- mBC. In this review, evidence-based answers have been provided pertaining to (I) the specific mBC population to be considered for BRCA testing, optimal time point of BRCA testing, and genetic counselling in mBC patients; (II) the role of PARPi versus platinum therapy in HER2- mBC patients in the metastatic setting; (III) sequencing treatment in metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive HER2- mBC patients, and defining the place of PARPi in the sequencing algorithms; and (IV) the need for a breast cancer registry for patients with HER2- mBC. This expert review will serve as a comprehensive guide to clinicians for optimizing BRCA testing and managing patients with BRCA mutation (BRCAm) and HER2- mBC. The data collected from the proposed HER2- mBC registry will help understand the treatment practices, identify unmet needs, and develop strategic policies regionally to help improve access to optimized care of HER2- mBC.

Cross-Cultural Validity Study of a Medical Education Leadership Competencies Instrument in Latin American Physicians: A Multinational Study.

PURPOSE: Physicians rarely receive formal training in leadership skills. Çitaku and colleagues have identified a set of leadership competencies (LCs) providing validity evidence in North American (NA) and European Union (EU) medical education institutions. We aim to apply this same survey to a sample of Latin American (LA) medical leaders from the oncology community and related areas, compare the results with those of the previous survey, and perform subgroup analyses within the LA cohort. METHODS: The survey was sent to nearly 8,000 physicians of participating professional organizations. In addition to the 63 questions, we also collected data on the type of institution, country, specialty, sex, age, years of experience in oncology, and leadership position. RESULTS: The 217 LA respondents placed the highest value on task management competencies (91.37% reported these as important or very important v 87.0% of NA/EU respondents; P < .0001), followed by self-management (87.45% of LA respondents v 87.55% of NA/EU respondents; P = not significant [NS]), social responsibility (86.83% of LA respondents v 87.48% of NA/EU respondents; P = NS), innovation (86.69% of LA respondents v 85.31% of NA/EU respondents; P = NS), and leading others (83.31% of LA respondents v 84.71% of NA/EU respondents; P = NS). Social responsibility, which was first in importance in the NA/EU survey, was only third in the LA survey. Subgroup analyses showed significant variations in the ratings of specific LCs within the LA population. CONCLUSION: LCs valued by LA leaders somewhat differ from those valued by their NA and EU counterparts, implying that cultural aspects might influence the perception of desired LCs. We also detected variations in the responses within the LA population. Our data indicate that current physician leadership training programs should be tailored to suit specific needs and cultural aspects of each region. Further validity studies of this instrument with other samples and cultures are warranted.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE.

Purpose Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. Methods Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety. Results Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; ≥ 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI. Conclusion Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial.

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor-positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.

Outcomes of breast cancer in Brazil related to health care coverage: a retrospective cohort study.

BACKGROUND: Breast cancer is the most common malignancy in women in Brazil. Differences between patients with public versus private healthcare coverage about general characteristics, disease presentation, treatment of primary tumors, and clinical outcomes have not been fully investigated. METHODS: A national, retrospective cohort of 3,142 patients drawn from a representative sample of Brazilian medical centers was selected. Clinical and demographic data and type of healthcare coverage were retrieved by chart review. Groups were compared using the χ(2) test. The log-rank test was used for comparison of disease-free survival (DFS), postrelapse, and overall survival (OS). Multivariate Cox regression modeling with adjustment for patient characteristics and stage at diagnosis was performed. All P values are two sided. RESULTS: Patients with public health coverage presented with more advanced disease at diagnosis (P < 0.001). DFS and OS for patients presenting with stage 0-II disease did not differ according to the type of healthcare coverage, whereas a significant difference in outcomes was seen for stage III-IV patients (P = 0.002 and P = 0.008, respectively). In a Cox multivariate analysis, no association was found for the type of health coverage with either DFS or OS, but there was an association for postrelapse survival (P < 0.001). CONCLUSION: In Brazil, patients with breast cancer with public health coverage present with more advanced disease, and this possibly explains worse DFS and OS when compared with those with private coverage. IMPACT: Earlier diagnosis and treatment of breast cancer could improve outcomes of women with public health coverage in Brazil.

Analysis of regional timelines to set up a global phase III clinical trial in breast cancer: the adjuvant lapatinib and/or trastuzumab treatment optimization experience.

PURPOSE: This study measured the time taken for setting up the different facets of adjuvant lapatinib and/or trastuzumab treatment optimization (ALTTO), an nternational phase III study being conducted in 44 participating countries. METHODS: Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. RESULTS: South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0-151 days), North America (median: 26 days, range: 22-30 days), and Asia-Pacific (median: 62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high-income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). CONCLUSION: This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.

Breast cancer in Brazil: present status and future goals.

Breast cancer is the most common cancer in women worldwide and 70% of breast cancer deaths occur in women from low-income and middle-income countries. Latin America has about 115,000 new cases of disease every year, with about 50,000 arising in Brazil. We examined the present status of breast cancer in Brazil as an example of the health effects of geographical, ethnic, and socioeconomic diversities on delivery of care. Our goal was to identify deficiencies that could be responsible for disparities in survival from breast cancer. We searched the English and Portuguese published work and reviewed national databases and Brazilian publications. Although the availability of publications specific to Brazil is low in general, we identified several factors that could account for disparities: delays in diagnosis due to low cancer awareness and implementation of mammography screening, unknown quality of surgery, and restricted access to radiotherapy and modern systemic therapies.

Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer.

OBJECTIVE: We and others have previously suggested that pretreatment levels of CA 19-9 correlate with overall survival (OS) among patients with advanced pancreatic cancer treated with gemcitabine. We sought to confirm the prognostic role of the pretreatment level of CA 19-9 in patients with advanced pancreatic cancer treated with chemotherapy. METHODS: We retrospectively identified 50 patients with locally advanced or metastatic pancreatic cancer treated in the first-line with single-agent gemcitabine or combinations. Patients could also have received second-line treatment. Kaplan-Meier estimates of OS were compared with the log-rank test, and multivariate analysis was done using the Cox model. RESULTS: Twenty-seven patients were female with a mean age of 64.3 years, and 82% were metastatic upon diagnosis. The median OS for the entire sample was 11 months, and the median CA 19-9 level was 542 U/mL. Significant predictors of OS in univariate analyses were the first-line use of combined chemotherapy (p=0.006) and use of erlotinib in any line (p=0.002), with borderline significance for pretreatment levels of CA 19-9 (p=0.052). In multivariate analysis, only use of erlotinib (p=0.003) and pretreatment CA 19-9 level (p=0.026) were significantly associated with OS. CONCLUSION: Our study lends further support to use of the pre-chemotherapy level of CA 19-9 as a prognostic indicator in clinical practice and as a stratification factor in clinical trials. The association between erlotinib use and OS may have been biased by patient selection, notwithstanding the positive results from a previous randomized trial.

Cetuximab Plus irinotecan in pretreated metastatic colorectal cancer progressing on irinotecan: the LABEL study.

BACKGROUND: The aim of this multicenter phase II study was to demonstrate the activity of the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody cetuximab combined with irinotecan in the treatment of Latin American patients with EGFR-expressing metastatic colorectal cancer (mCRC) in whom previous treatment with an irinotecan-containing regimen had failed. PATIENTS AND METHODS: Patients received cetuximab, as a 400 mg/m2 initial infusion followed by 250 mg/m2 weekly, plus the same irinotecan regimen that had previously failed, until the occurrence of disease progression or unacceptable toxicity. The primary endpoint was response. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), and safety. RESULTS: Seventy-nine patients received treatment. One patient had a complete response, 20 had partial responses, and disease was stabilized in 23 patients, giving an overall response rate of 27% and a disease control rate of 56%. The median duration of response was 23.9 weeks. Median PFS was 17.4 weeks, median OS was 9.2 months, and the 12-month OS rate was 38%. The most common adverse events according to System Organ Class were skin and subcutaneous tissue disorders (91% of the patients). Grade 3/4 adverse events occurred in 45 patients (57%), with the most common being diarrhea (20%), neutropenia (11%), and rash (6%). Seven patients (9%) had grade 3/4 acne-like skin rash. No grade 3/4 infusion-related reactions were reported. CONCLUSION: Cetuximab in combination with irinotecan is active and tolerable in Latin American patients with mCRC progressing on irinotecan, with a safety profile similar to that described in European studies.

Further evidence of the prognostic role of pretreatment levels of CA 19-9 in advanced pancreatic cancer / Evidência adicional do papel prognóstico do nível pré-tratamento de CA 19-9 em câncer de pâncreas avançado

OBJECTIVE: We and others have previously suggested that pretreatment levels of CA 19-9 correlate with overall survival (OS) among patients with advanced pancreatic cancer treated with gemcitabine. We sought to confirm the prognostic role of the pretreatment level of CA 19-9 in patients with advanced pancreatic cancer treated with chemotherapy. METHODS: We retrospectively identified 50 patients with locally advanced or metastatic pancreatic cancer treated in the first-line with single-agent gemcitabine or combinations. Patients could also have received second-line treatment. Kaplan-Meier estimates of OS were compared with the log-rank test, and multivariate analysis was done using the Cox model. RESULTS: Twenty-seven patients were female with a mean age of 64.3 years, and 82 percent were metastatic upon diagnosis. The median OS for the entire sample was 11 months, and the median CA 19-9 level was 542 U/mL. Significant predictors of OS in univariate analyses were the first-line use of combined chemotherapy (p=0.006) and use of erlotinib in any line (p=0.002), with borderline significance for pretreatment levels of CA 19-9 (p=0.052). In multivariate analysis, only use of erlotinib (p=0.003) and pretreatment CA 19-9 level (p=0.026) were significantly associated with OS. CONCLUSION: Our study lends further support to use of the pre-chemotherapy level of CA 19-9 as a prognostic indicator in clinical practice and as a stratification factor in clinical trials. The association between erlotinib use and OS may have been biased by patient selection, notwithstanding the positive results from a previous randomized trial.

OBJETIVO: Estudos anteriores pelo nosso grupo e por outros autores sugerem que o nível pré-tratamento do marcador tumoral CA 19-9 se correlaciona com a sobrevida global (SG) em pacientes com câncer de pâncreas avançado tratados com gencitabina. Nosso objetivo foi o de confirmar o papel prognóstico do nível pré-tratamento do CA 19-9 em pacientes com câncer de pâncreas avançado tratados com regimes variados de quimioterapia. MÉTODOS: Identificamos retrospectivamente 50 pacientes com câncer de pâncreas localmente avançado ou metastático tratados em primeira linha com gencitabina ou combinações contendo esse agente. Os pacientes poderiam ter recebido ainda tratamento em segunda linha com outros agentes. As estimativas de SG pelo método de Kaplan-Meier foram comparadas pelo teste log-rank, e a análise multivariada foi feita usando-se o modelo de Cox. RESULTADOS: Vinte e sete pacientes eram do sexo feminino, a idade média foi de 64,3 anos, e 82 por cento tinham doença metastática ao diagnóstico. A mediana de SG para a amostra como um todo foi de 11 meses, e o nível mediano de CA 19-9 foi de 542 U/mL. Fatores preditivos de SG em análises univariadas foram o uso de quimioterapia combinada em primeira linha (p=0,006) e o uso de erlotinibe (p=0,002), com nível de significância limítrofe para nível pré-tratamento de CA 19-9 (p=0,052). Na análise multivariada, apenas o uso de erlotinibe (p=0,003) e o nível pré-tratamento de CA 19-9 (p=0,026) estiveram associados com SG de maneira significativa. CONCLUSÃO: Nosso estudo fornece evidência adicional para o uso do nível pré-tratamento de CA 19-9 como indicador prognóstico e como fator de estratificação em ensaios clínicos. A associação entre uso de erlotinibe e SG pode ter sido devida à seleção de pacientes, não obstante o resultado de um estudo randomizado recente mostrando o benefício desse tratamento.

Case studies of fulvestrant ("Faslodex") in postmenopausal women with advanced breast cancer.

Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a "real-life" setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.

Fulvestrant ("Faslodex"): clinical experience from the Compassionate Use Programme.

Fulvestrant ("Faslodex") is a new oestrogen receptor (ER) antagonist with no agonist effects that is licensed in the USA, Brazil, Europe and elsewhere for the treatment of advanced breast cancer (ABC) in postmenopausal women following progression on other endocrine agents. This report consolidates clinical experience from the "Faslodex" Compassionate Use Programme, including a total of 339 patients treated at eight cancer centres. Patients received fulvestrant as first- (n=22), second- (n=125), third- (n=105), fourth- (n=58), fifth- (n=22) or sixth-line (n=5) hormonal treatment for ABC, with two patients receiving fulvestrant after more than six other endocrine therapies. Objective response was achieved by 40 patients and stable disease lasting 6 months by 92 patients, giving overall clinical benefit (CB) in 132/339 patients (39%). The CB rate decreased as fulvestrant was used later in the sequence of endocrine treatments, from 46% (10/22) with first-line fulvestrant to 27% (6/22) with fifth-line fulvestrant. Increased benefit was found in patients with tumours expressing both ER and progesterone receptor (PgR) compared with other combinations, although good activity was reported in patients expressing either ER or PgR as well as in tumours expressing human epidermal growth factor receptor 2. Fulvestrant was well tolerated; adverse events were noted in 18/339 patients (5%). These findings concur with data from the clinical-trial setting and further support the assertion that greater benefit is derived when fulvestrant is used early in the treatment sequence.

Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer.

A large fraction of transcripts are expressed antisense to introns of known genes in the human genome. Here we show the construction and use of a cDNA microarray platform enriched in intronic transcripts to assess their biological relevance in pathological conditions. To validate the approach, prostate cancer was used as a model, and 27 patient tumor samples with Gleason scores ranging from 5 to 10 were analyzed. We find that a considerably higher fraction (6.6%, [23/346]) of intronic transcripts are significantly correlated (P< or =0.001) to the degree of prostate tumor differentiation (Gleason score) when compared to transcripts from unannotated genomic regions (1%, [6/539]) or from exons of known genes (2%, [27/1369]). Among the top twelve transcripts most correlated to tumor differentiation, six are antisense intronic messages as shown by orientation-specific RT-PCR or Northern blot analysis with strand-specific riboprobe. Orientation-specific real-time RT-PCR with six tumor samples, confirmed the correlation (P=0.024) between the low/high degrees of tumor differentiation and antisense intronic RASSF1 transcript levels. The need to use intron arrays to reveal the transcriptome profile of antisense intronic RNA in cancer has clearly emerged.

Inibidores da aromatase no câncer de mama: da doença metastática ao tratamento adjuvante / Aromatase inhibitors in breast cancer: from metastatic disease to adjuvant treatment

Os tratamentos hormonais continuam a ter papel importante no manejo clínico das pacientes com câncer de mama. Entre os avanços mais recentes, os inibidores da aromatase de terceira geração vêm ocupando lugar de destaque no contexto da doença metastática. A aromatase, presente em diversos tecidos, é responsável pela conversão de andrógenos em estradiol e estrona. Antes da menopausa, a maior parte dos estrógenos femininos se origina nos ovários. Com a insuficiência ovariana, as glândulas supra-renais passam a ser a principal fonte de andrógenos, que são convertidos pela aromatase em estrógenos; esta conversão ocorre em tecidos periféricos como gordura, músculos, fígado e o próprio tumor de mama. A inibição da aromatase é uma estratégia com base racional sólida, e comprovadamente eficaz no sentido de reduzir os níveis séricos de estrógenos em mulheres pós-menopausa. Os inibidores de aromatase de primeira e segunda geração caracterizaram-se por alta toxicidade ou baixa eficácia, quando comparados ao tamoxifeno. No entanto, o tamoxifeno apresenta, além de sua ação antiestrogênica, um efeito pró-estrogênico, responsável por efeitos colaterais, tais quais proliferação do endométrio e fenômenos tromboembólicos. Estudos recentes, discutidos neste artigo, demonstraram a superioridade dos inbidores da aromatase de terceira geração, com relação ao megestrol, no tratamento hormonal de segunda linha do câncer de mama metastático em mulheres pós-menopausa. Além disto, estas drogas têm conquistado papel de destaque no tratamento de primeira linha da doença metastática, no tratamento neo-adjuvante, e no tratamento adjuvante de pacientes com câncer de mama.

Pretreatment CA 19-9 level as a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine.

BACKGROUND: Serum levels of CA 19-9 correlate with survival among patients with pancreatic cancer treated with surgery or radiation therapy. In addition, CA 19-9 responses have been shown to predict for a better prognosis among patients with advanced disease treated with chemotherapy. The present study evaluates the predictive role of CA 19-9 pretreatment levels and response among patients treated with gemcitabine. METHODS: We retrospectively identified 28 patients with advanced pancreatic cancer and baseline elevations of CA 19-9 (> 37 U/mL) who were treated with single agent gemcitabine. CA 19-9 response was defined as a > or = 50% decline at any time after treatment. Survival was estimated with the Kaplan-Meier method, and curves were compared with the log-rank test. RESULTS: Eleven patients (39%) had a CA 19-9 response. The median survival of responding patients was longer than that of non-responding patients (13.8 vs 8 mo, p = .0272). When pretreatment CA 19-9 levels were analyzed, patients who had CA 19-9 below the median for the entire sample (1212 U/mL) lived significantly longer than patients with a CA 19-9 above the median (14.9 vs 7.4 mo, p = .0013). On multivariable analysis, pretreatment CA 19-9 level was an independent, and stronger predictor of survival (p = .0005) than CA 19-9 response (p = .0497). Other variables were not associated with survival. CONCLUSIONS: CA 19-9 may be a useful adjunct to response evaluation is this setting. In addition to CA 19-9 responses, prechemotherapy levels of this marker seem to have strong prognostic significance.