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.

Time interval between diagnosis to treatment of breast cancer and the impact of health insurance coverage: a sub analysis of the AMAZONA III Study (GBECAM 0115).

PURPOSE: Breast cancer (BC) is the most common type of cancer among women in Brazil. Evidence shows that delayed treatment onset is associated with increased mortality. This study aimed to evaluate median days between diagnosis and treatment and factors associated with delayed start of treatment (> 60 days after diagnosis): stage, treatment received, subtype, epidemiological characteristics, and type of healthcare coverage. METHODS: This analysis included 1709 stage I-III BC patients from AMAZONA III, a prospective, observational study, diagnosed from January 2016 to March 2018 in 22 centers in Brazil. RESULTS: The median number of days from diagnosis to beginning of first oncologic treatment was 46 days (IQR 28-75) overall, 43 days (IQR 25-75) for stage I disease, 49 days (IQR 28-81) for stage II, and 44 days (IQR 30-68) for stage III, (p = 0.1180). According to first treatment received, diagnosis-to-treatment interval was 43 days (IQR 29-65) for neoadjuvant chemotherapy and 48 days (IQR 26-81) for surgery. Diagnosis-to-treatment interval was higher in women treated in the public system versus the private system (56 vs. 34 days, p < 0.0001). Patients in the public system had an increased odds of delayed treatment initiation (OR 4.74 95% CI 3.09-7.26, p < .0001). The longer interval from diagnosis to treatment in the public system was independent of clinical stage, type of treatment (systemic vs surgery first), subtype and region of the country. CONCLUSION: By characterizing the delays in care delivery, our study will aid stakeholders to better design interventions and allocate resource to improve timely treatment for breast cancer in Brazil. CLINICALTRIALS: gov Identifier: NCT02663973, registered on January, 26th, 2016.

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.

Optimizing treatment selection, and sequencing decisions for Management of HR-Positive, HER2-Negative advanced breast cancer - Proceedings from breast cancer expert group meeting.

PURPOSE: The therapeutic landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) has evolved considerably with the introduction of newer targeted agents and their combinations with endocrine therapies. In this scenario, optimizing treatment selection and sequencing is daunting for clinicians. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection and sequencing for the management of HR + HER2 - mBC. DESIGN: A panel of nine key opinion leaders from Argentina, Brazil, Colombia, Mexico, Moscow, Singapore, South Korea, Taiwan, and UAE convened in October 2018. They reviewed the literature and formulated answers to clinical questions on optimizing the management of HR + HER2 - mBC. RESULTS: Evidence-based answers were formulated for: (1) optimal initial treatment choice; (2) ovarian function suppression, optimal endocrine partner, and role of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (in premenopausal women); (3) better first-line standard of care than aromatase inhibitors; (4) preferred second-line treatment; (5) treatment of oligometastatic disease; (6) factors influencing first-line single-agent endocrine therapy choice; (7) influence of endocrine resistance on treatment selection; (8) optimal maintenance regimen in visceral crisis; and (9) need for a breast cancer registry for patients with HR + HER2 - mBC. The panel also proposed a treatment-sequencing algorithm for the management of HR + HER2 - mBC. CONCLUSION: The current article will serve as a comprehensive guide for optimizing the management of HR + HER2 - mBC. The proposed breast cancer registry will help identify unmet needs and develop strategic regional policies to help improve access to optimized care for HR + HER2 - mBC.

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.

The impact of sociodemographic factors and health insurance coverage in the diagnosis and clinicopathological characteristics of breast cancer in Brazil: AMAZONA III study (GBECAM 0115).

PURPOSE: In Brazil, the available cancer registries are deficient in number and quality and, hence, little information is known regarding sociodemographic, clinicopathological characteristics, treatment patterns, and outcomes of breast cancer (BC) patients. We performed the AMAZONA III/ GBECAM 0115 study and in this analysis, we describe patients' characteristics at diagnosis and their association with health insurance type. METHODS: This is a prospective cohort study developed in 23 sites in Brazil including women with newly diagnosed invasive BC from January 2016 to March 2018. In order to compare healthcare insurance type, we considered patients who were treated under the Brazilian public health system as publicly insured, and women who had private insurance or paid for their treatment as privately insured. RESULTS: A total of 2950 patients were included in the study. Median age at diagnosis was 53.9 years; 63.1% were publicly insured. The majority of patients (68.6%) had stage II-III breast cancer and ductal carcinoma histology (80.9%). The most common breast cancer subtype was luminal A-like (48.0%) followed by luminal B-HER2 positive-like (17.0%) and triple-negative (15.6%). Luminal A was more frequent in private (53.7% vs. 44.2%, p < .0001) than public, whereas Luminal B HER2-positive (19.2% vs. 14.2%, p = 0.0012) and HER2-positive (8.8% vs. 5.1%, p = 0.0009) were more common in patients with public health system coverage. Only 34% of patients were diagnosed by screening exams. Privately insured patients were more frequently diagnosed with stage I disease when compared to publicly insured patients; publicly insured patients had more stage III (33.5% vs. 14.7%; p-value < 0.0001) disease than privately insured ones. Breast cancer was detected by symptoms more frequently in publicly than in privately insured patients (74.2% vs 25.8%, respectively; p-value < 0.0001). CONCLUSIONS: Patients with public health coverage were diagnosed with symptomatic disease, later stages and more aggressive subtypes when compared to privately insured patients.

Prevalence and risk factors of medication-related osteonecrosis of the jaw in osteoporotic and breast cancer patients: a cross-sectional study.

PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) has been reported as a side effect of bisphosphonate (BP). The aim of this study was to identify the prevalence of MRONJ in women taking BP for osteoporosis and for metastatic breast cancer and correlate it with risk factors and biochemical markers of bone metabolism. METHODS: Patients taking oral or intravenous BP with osteoporosis (G1; n = 153; median 72.8 years) and with metastatic breast cancer (G2; n = 134; median 58.2 years) had their hospital charts reviewed, were submitted to dental inspection, and answered a health questionnaire. Fasting blood samples were randomly collected from both groups to measure osteocalcin, carboxy-terminal cross-linking telopeptide of type I collagen, intact parathyroid hormone and procollagen type 1 amino-terminal propeptide (P1NP), 25 hydroxyvitamin D (25OHD), creatinine, and total calcium. RESULTS: G1 was older (p = 0.001) and had more cases of diabetes (p = 0.043). P1NP was higher (p = 0.022) and 25OHD lower (p = 0.004) in G2 compared with G1. MRONJ was not found in the G1, whereas 4 cases (3%) were detected in G2. Positive risk factors for MRONJ were number of BP doses and number of visits to the dentist and dental extractions. The biochemical parameters, however, could not identify those who developed MRONJ. CONCLUSIONS: The prevalence of MRONJ was 3% in women with metastatic breast cancer receiving BP. No cases were identified in women receiving oral BP chronically for osteoporosis. P1NP was higher in women with metastatic breast cancer, even during treatment with antiresorptives, but could not differentiate those with MRONJ.

Advanced Stage at Diagnosis and Worse Clinicopathologic Features in Young Women with Breast Cancer in Brazil: A Subanalysis of the AMAZONA III Study (GBECAM 0115).

PURPOSE: Breast cancer (BC) in young women is uncommon and tends to present with more aggressive characteristics. To better understand and characterize this scenario in Brazil through real-world data, we performed a subanalysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973). METHODS: The AMAZONA III study (GBECAM 0115) is a prospective registry that included 2,950 women newly diagnosed with invasive BC in Brazil from January 2016 until March 2018 at 22 sites. Valid data were obtained from 2,888 patients regarding age at diagnosis and complete baseline information. To compare epidemiologic and clinicopathological features at the time of diagnosis, patients with BC were divided into two groups according to age: ≤ 40 years and > 40 years. Quantitative variables were described as means, and categorical variables were described as frequencies and percentages and compared using the Pearson's χ2 test. RESULTS: Of 2,888 women diagnosed with BC, 486 (17%) were ≤ 40 years old. Young women had higher educational level, most were employed and a significant number were married (P < .001 for all associations). Younger patients were more symptomatic at BC diagnosis (P < .001), and they also presented more frequently with stage III, T3/T4, grade 3 tumors, HER-2-positive, luminal B, and triple-negative subtypes. CONCLUSION: Brazilian women younger than age 40 years have unfavorable clinicopathological features of BC at diagnosis, with more aggressive subtypes and advanced stage when compared with older women. These differences are not explained by socioeconomic or ethnic imbalances. The causes of a higher prevalence of BC among young women in Brazil deserve additional investigation.

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.

Characteristics and prognosis of stage I-III breast cancer subtypes in Brazil: The AMAZONA retrospective cohort study.

OBJECTIVE: To describe stage I-III breast cancer (BC) molecular subtypes and outcomes among a cohort of patients from Brazil. METHODS: AMAZONA study is a retrospective cohort conducted from June 2008 to January 2009 including women of at least 18 years old, with histologically proven breast cancer, diagnosed in 2001 (n = 2198) and 2006 (n = 2714). In this analysis, we included patients who underwent surgery, had stage I-III disease and available pathological information (n = 2296). We estimated molecular subtypes by local immunohistochemical stains. Data was obtained from medical charts and public databases. RESULTS: Mean age at diagnosis was 54 years and 41.1% were younger than 50 years. 23.3% were diagnosed in stage I, 53.5% in stage II and 23.2% in stage III. 80.8% were treated in the public health system. 71.3% had hormonal receptor positive disease, 15.7% were HER-2 positive and 21.1% had triple-negative breast cancer. 55.6% were treated with mastectomy and 96.2% received adjuvant treatment (82.2% chemotherapy). 13.4% of HER-2 positive patients received adjuvant trastuzumab. Overall survival rate at 5 years was 96.84% for stage I, 94.16% for stage II and 70.48% for stage III. Molecular subtypes were independent prognostic factor in stages II and III patients. CONCLUSIONS: Brazilian women have a higher risk of being diagnosed with late stage breast cancer and younger age than in high-income countries. Luminal-like disease is the most common molecular subtype in the country. Triple negative and HER-2 positive had the worst prognosis.

Efficient Synthesis of Glutamate Peptide-Estradiol Conjugate for Imaging Estrogen Receptor-Positive Diseases.

Molecular imaging of estrogen receptor-positive (ER+) pathway-activated system serves the basis of ER+ disease management such as cancers and endometriosis. ER+ patients have better response to endocrine therapy and survive twice as long as negative ER patients. However, tumor resistance resulting from clinical used aromatase inhibitors and antiestrogens is unpredictable. Radiolabeled ER+ ligand could quantify ER+ tissue uptake which helps to stage and restage of the cancer as well as endometriosis. The differential diagnosis of ER+ lesions by using a labeled ligand helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. In addition, radiolabeled ER+ ligand serves as basis for image-guided response follow-up. Glutamate receptors are cell surface receptors which are overexpressed in inflammation and infection. Using glutamate peptide as a drug carrier helps to target intracellular genes via glutamate receptor-mediated process. Reports have shown that polyglutamate is a drug carrier that could alter drug solubility and enhance estrogen receptor-ligand binding pocket. However, polyglutamate was a blend of mixed polymer with a wide range of molecular weight. Thus, the structural confirmation and purity of the conjugates were not optimized. To overcome this problem, the efficient synthesis of glutamate peptide-estradiol (GAP-EDL) conjugate was achieved with high purity. EDL was conjugated site-specific at the first glutamate of GAP. The average cell uptake of 68Ga-GAP-EDL was 5-fold higher than the previous reported synthesis. The efficient synthesis of GAP-EDL has greatly enhanced sensitivity and specificity in cell uptake studies. In vivo PET imaging studies indicated that 68Ga-GAP-EDL could image ER (+) tumors in MCF-7 tumor-bearing mice. Therefore, GAP-EDL makes it possible to image ER-enriched endometriosis and cancer.

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.

Incidental Findings in Reduction Mammoplasty Specimens in Patients with No Prior History of Breast Cancer. An Analysis of 783 Specimens.

Breast reduction surgery is a common procedure and the rate of incidental findings in the removed specimens varies between 0% and 4.6%. There are no guidelines about pathological evaluation of breast reduction surgery. We reviewed all pathology reports of patients undergoing breast reduction surgery in a single tertiary institution in Brazil from January 2008 to August 2014. Exclusion criteria were a personal history of breast cancer, unclear reason for mastectomy and incomplete data on the pathology report. We considered "relevant findings" flat epithelial atypia, atypical hyperplasia, carcinomas in situ and invasive carcinoma. Of 1672 specimens from breast reduction surgery, 783 met inclusion criteria. Median patient age was 40 (8-77), 91% underwent bilateral mastectomy and 57% of the specimens weighted less than 200 g. In 55% of cases, 4 or more paraffin blocks were sampled. There were 40 (5.1%) relevant findings and the most common was atypical lobular hyperplasia (16-2%). There were 3 invasive carcinomas (0.38%). In multivariate analysis, the only variables associated with a higher odds of relevant pathological findings were patient age ≥ 40 (OR 4.73 CI95% 1.98-11.3 p < 0.001) and sampling of ≥4 paraffin blocks from each specimen (OR 6.69 95% CI 2.25-19.9 p < 0.001). The incidence of pre-malignant and malignant lesions in specimens from breast reduction surgery is around 5%, but this risk is significantly higher for patients older than 40 years-old. Sampling at least 4 paraffin blocks from each specimen significantly increases detection rates.

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.

Higher overall survival in metastatic pancreatic cancer: the impact of where and how treatment is delivered / Maior sobrevida global em pacientes com câncer pancreático metastático: o impacto de onde e como o tratamento é realizado

Objective To determine the overall survival of patients with advanced pancreatic cancer and evaluate factors that impact prognosis in a private cancer center.Methods Data from the Hospital Cancer Registry at Hospital Israelita Albert Einstein were retrospectively collected. The patients enrolled had metastatic cancer at diagnosis or earlier staging and subsequent recurrence. Cases of neuroendocrine tumors were excluded.Results A total of 65 patients were evaluated, including 63 with adenocarcinoma. The median overall survival for patients in all stages was 20.7 months (95%CI: 15.6-25.7), while the overall survival of metastatic disease was 13.3 months. Among the 33 cases with stage IV cancer, there was no evidence of a statistically significant association between median survival and CA19-9 dosage (p=0.212), tumor location (p=0.482), first treatment performed (p=0.337), lymphovascular invasion (p=0.286), and age (p=0.152). However, the number of lines of chemotherapy was significantly associated with survival (log-rank p=0.013), with an estimated median survival of 10.2 months for patients who received up to two lines of treatment and 23.5 months for those receiving more than two lines of chemotherapy.Conclusion The survival of patients treated was longer than that reported in the literature. The only statistically significant factor related to increased survival was higher number of lines of chemotherapy received. We believe that the higher socioeconomic status of patients surveyed in this study, as well as their greater access to treatment options, may have influenced their overall survival.

Objetivo Determinar a sobrevida global dos pacientes com câncer pancreático avançado e avaliar fatores com impacto prognóstico em um centro de câncer privado.Métodos Foram coletados retrospectivamente os dados do Registro de Câncer do Hospital Israelita Albert Einstein. Os pacientes incluídos apresentaram câncer metastático ao diagnóstico ou em estádio mais precoce com recorrência subsequente. Os casos de tumores neuroendócrinos foram excluídos.Resultados Foram avaliados 65 pacientes, incluindo 63 com adenocarcinoma. A sobrevida global mediana dos pacientes em todos os estádios foi 20,7 meses (IC95%: 15,6-25,7), enquanto a sobrevida global de doença metastática foi de 13,3 meses. Entre os 33 casos com câncer em estádio IV, não houve evidência de associação estatisticamente significativa entre a sobrevida mediana e CA19-9 ao diagnóstico (p=0,212), localização do tumor (p=0,482), primeiro tratamento realizado (p=0,337), invasão vasculo-linfática (p=0,286) e idade (p=0,152). No entanto, o número de linhas de quimioterapia foi significativamente associado com a sobrevida (log-rankp=0,013), com uma sobrevida mediana estimada de 10,2 meses para os pacientes que receberam até duas linhas de tratamento e de 23,5 meses para os que receberam mais de duas linhas.Conclusão A sobrevida dos pacientes tratados foi maior do que o relatado na literatura. O único fator estatisticamente significativo relacionado à maior sobrevida foi maior número de linhas de quimioterapia recebidas. Acreditamos que o nível socioeconômico dos pacientes pesquisados neste estudo, assim como seu maior acesso a opções de tratamento, pode ter influenciado em sua sobrevivência global.

Higher overall survival in metastatic pancreatic cancer: the impact of where and how treatment is delivered.

OBJECTIVE: To determine the overall survival of patients with advanced pancreatic cancer and evaluate factors that impact prognosis in a private cancer center. METHODS: Data from the Hospital Cancer Registry at Hospital Israelita Albert Einstein were retrospectively collected. The patients enrolled had metastatic cancer at diagnosis or earlier staging and subsequent recurrence. Cases of neuroendocrine tumors were excluded. RESULTS: A total of 65 patients were evaluated, including 63 with adenocarcinoma. The median overall survival for patients in all stages was 20.7 months (95%CI: 15.6-25.7), while the overall survival of metastatic disease was 13.3 months. Among the 33 cases with stage IV cancer, there was no evidence of a statistically significant association between median survival and CA19-9 dosage (p=0.212), tumor location (p=0.482), first treatment performed (p=0.337), lymphovascular invasion (p=0.286), and age (p=0.152). However, the number of lines of chemotherapy was significantly associated with survival (log-rank p=0.013), with an estimated median survival of 10.2 months for patients who received up to two lines of treatment and 23.5 months for those receiving more than two lines of chemotherapy. CONCLUSION: The survival of patients treated was longer than that reported in the literature. The only statistically significant factor related to increased survival was higher number of lines of chemotherapy received. We believe that the higher socioeconomic status of patients surveyed in this study, as well as their greater access to treatment options, may have influenced their overall survival.

The impact of erlotinib use in non-small-cell lung cancer patients treated in a private reference general hospital and in a private cancer clinic from 2005 to 2011.

OBJECTIVE: To report the demographic data and clinical outcomes of non-small-cell lung cancer patients exposed to erlotinib in any line of treatment. METHODS: This was a retrospective cohort study of nonsmall-cell lung cancer patients from a reference general hospital and a private oncology clinic, who received erlotinib from 2005 to 2011. Statistical analysis was performed and we evaluated demographic data and response to treatment, by correlating the results of this first cohort published in Brazil with results of current literature. RESULTS: A total of 44 patients were included; 65.9% were diagnosed with adenocarcinoma, and 63.6% had metastatic disease. The mean age was 63.3 years. The median follow-up was 47.9 months. Epidermal growth factor receptor mutation screening was performed in 22.7% of patients (n=10), with mutation present in 30% of patients. The median overall survival was 46.3 months, and there was a higher probability of survival at 60 months for females compared to males (29.4% versus 15.8%; p=0.042). The other variables did not present significant statistical difference. CONCLUSION: We collected the largest cohort of patients with non-small-cell lung cancer who have used erlotinib in Brazil to date, and demonstrated that outcomes of patients treated at our clinic during the study period were consistent with the results of current literature in similar patients.

The impact of erlotinib use in non-small-cell lung cancer patients treated in a private reference general hospital and in a private cancer clinic from 2005 to 2011 / O impacto do uso do erlotinibe em pacientes portadores de neoplasia de pulmão de não pequenas células tratados em um hospital geral de referência e clínica particular de oncologia no período de 2005 a 2011

ABSTRACT Objective: To report the demographic data and clinical outcomes of non-small-cell lung cancer patients exposed to erlotinib in any line of treatment. Methods: This was a retrospective cohort study of nonsmall-cell lung cancer patients from a reference general hospital and a private oncology clinic, who received erlotinib from 2005 to 2011. Statistical analysis was performed and we evaluated demographic data and response to treatment, by correlating the results of this first cohort published in Brazil with results of current literature. Results: A total of 44 patients were included; 65.9% were diagnosed with adenocarcinoma, and 63.6% had metastatic disease. The mean age was 63.3 years. The median follow-up was 47.9 months. Epidermal growth factor receptor mutation screening was performed in 22.7% of patients (n=10), with mutation present in 30% of patients. The median overall survival was 46.3 months, and there was a higher probability of survival at 60 months for females compared to males (29.4% versus 15.8%; p=0.042). The other variables did not present significant statistical difference. Conclusion: We collected the largest cohort of patients with non-small-cell lung cancer who have used erlotinib in Brazil to date, and demonstrated that outcomes of patients treated at our clinic during the study period were consistent with the results of current literature in similar patients. .

RESUMO Objetivo: Relatar as características demográficas e a evolução de pacientes com neoplasia de pulmão de não pequenas células que receberam erlotinibe em qualquer linha de tratamento. Métodos: Coletamos retrospectivamente dados de pacientes portadores de neoplasia de pulmão de não pequenas células que receberam erlotinibe em qualquer linha de tratamento em um hospital geral de referência e em uma clínica particular de oncologia em São Paulo, no período de 2005 a 2011. Foi realizada a análise estatística e foram avaliados aspectos demográficos e resposta ao tratamento estabelecido, correlacionando os resultados dessa primeira coorte publicada no Brasil com resultados da literatura vigente. Resultados: Foram avaliados 44 pacientes, dos quais 65,9% eram portadores de adenocarcinoma e 63,6% tinham doença metastática. A média de idade foi de 63,3 anos. O seguimento mediano foi de 47,9 meses. A pesquisa de mutação do receptor do fator de crescimento epidérmico foi realizada em 22,7% dos pacientes (n=10), resultando positiva em 30% dos avaliados. A sobrevida global mediana foi de 46,3 meses, e observou-se uma probabilidade maior de sobrevida em 60 meses para o grupo feminino, quando comparado ao grupo masculino (29,4% versus 15,8%; p=0,042). As demais variáveis não apresentaram diferença estatística significativa. Conclusão: Coletamos a maior sequência de pacientes com neoplasia de pulmão de não pequenas células que fizeram uso de erlotinibe no Brasil até a data vigente e demonstramos que a evolução dos pacientes tratados no período avaliado teve resultados concordantes com os da literatura vigente em pacientes semelhantes. .