Real-world treatment outcomes in HR+ HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors: Results from a reference center in Brazil.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been recently developed and introduced into clinical practice. METHODS: We retrospectively analyzed data from patients with confirmed HR+/HER2 metastatic breast cancer treated with hormonal therapy in combination with ribociclib (R), palbociclib (P), or abemaciclib (A). OUTCOMES: median progression-free survival (mPFS), time to treatment discontinuation (mTTD), and objective response rate (ORR). RESULTS: Between January 2016 - June 2021, 142 patients were treated with an CDK4/6i (79 P, 42 R, 21 A). The median age was 59 years and 67.6% had recurrent disease. Roughly 35.2%, 36.6%, 28.2% of the patients had 1, 2 or 3+ metastatic sites, respectively, and 55.6% of the patients received CDK4/6i as a first-line treatment. The mPFS was 28m(R) vs. 14m(P) vs. 6m(A) (P = 0.002), with a higher proportion of patients receiving R in the first-line setting. However, no difference was seen when the analysis was restricted to the first-line scenario (P = 0.193). Sixty-four patients required one dose reduction, and 19 patients required two. ORR was 76.2% (R) vs 62% (P) vs 42.9% (A). More patients achieved a complete response with R and P, with no difference in the incidence of partial response and stable disease. Adverse events occurred in 94.4% of the population, with the most common grade 3-4 AE being neutropenia (59.1%). CONCLUSIONS: Our results confirm the efficacy and tolerability of CDK4/6i in routine clinical practice. This is the first real-world data describing and comparing the efficacy and toxicity of CDK4/6i in the Brazilian population.

Cost-effectiveness analysis of Oncotype DX from a Brazilian private medicine perspective: a GBECAM multicenter retrospective study.

Background: Oncotype DX (ODX) is a validated assay for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and 1-3 positive nodes (N1), hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC). Due to limited access to genomic assays in Brazil, treatment decisions remain largely driven by traditional clinicopathologic risk factors. ODX has been reported to be cost-effective in different health system, but limited data are available considering the reality of middle-income countries such as Brazil. We aim to evaluate the cost-effectiveness of ODX across strata of clinical risk groups using data from a dataset of patients from Brazilian institutions. Methods: Clinicopathologic and ODX information were analyzed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by clinicopathologic criteria were based on binary clinical risk categorization based on the Adjuvant! Algorithm. The ODX score was correlated with the indication of CT according to TAILORx and RxPONDER data. Two decision-tree models were developed. In the first model, low and high clinical risk patients were included while in the second, only high clinical risk patients were included. The cost for ODX and CT was based on the Brazilian private medicine perspective. Results: In all, 645 patients were analyzed; 411 patients (63.7%) had low clinical risk and 234 patients (36.3%) had high clinical risk disease. The ODX indicated low (<11), intermediate (11-25), and high (>25) risk in 119 (18.4%), 415 (64.3%), and 111 (17.2%) patients, respectively. Among 645 patients analyzed in the first model, ODX was effective (5.6% reduction in CT indication) though with an incremental cost of United States Dollar (US$) 2288.87 per patient. Among 234 patients analyzed in the second model (high clinical risk only), ODX led to a 57.7% reduction in CT indication and reduced costs by US$ 4350.66 per patient. Conclusions: Our study suggests that ODX is cost-saving for patients with high clinical risk HR+/HER2- eBC and cost-attractive for the overall population in the Brazilian private medicine perspective. Its incorporation into routine practice should be strongly considered by healthcare providers.

Impressive response to dabrafenib, trametinib, and osimertinib in a metastatic EGFR-mutant/BRAF V600E lung adenocarcinoma patient.

The survival outcomes of the FLAURA trial support osimertinib as the new standard of care for untreated patients harboring activating mutations in the epidermal growth factor receptor (EGFR). Despite the initial response, disease progression invariably occurs. Although uncommon, BRAF V600E mutation arises as a unique mechanism of resistance, and thus far, no prospective studies are available to support concurrent EGFR/BRAF blockade. We report a case of impressive radiological and ctDNA response under dabrafenib, trametinib, and osimertinib in an advanced EGFR-mutant lung adenocarcinoma patient who developed BRAF V600E as one of the acquired resistance mechanisms to second-line osimertinib. Moreover, the patient experienced remarkable clinical improvement and good tolerance to combination therapy. The present case suggests the importance of prospective studies evaluating both efficacy and safety of the combination in later line settings and points towards the potential of ctDNA to monitor resistance mechanisms and treatment benefit in clinical practice.

Alectinib activity in chemotherapy-refractory metastatic RET-rearranged non-small cell lung carcinomas: A case series.

OBJECTIVES: to report outcomes of four cases of chemo-refractory RET-rearranged non-small cell lung carcinomas (NSCLCs) treated with alectinib in a single center. MATERIALS AND METHODS: we retrospectively assessed and reported the activity and tolerability of alectinib 600 mg twice daily in advanced and chemo-refractory RET-rearranged NSCLC patients treated in a Brazilian institution. Identification of RET rearrangements was performed using the FoundationOne® next-generation sequencing (NGS) platform. RESULTS: The four patients herein reported were white, female and non-smokers, ranging between 59-66 years of age. All patients had been previously treated with chemotherapy and were TKI naïve; three of them presented disease progression to nivolumab as well. Molecular tumor profiling showed a KIF5B-RET fusion in three patients and a CCDC6-RET in the fourth. One patient exhibited disease progression and clinical deterioration two months after treatment initiation. Disease control was documented in two patients with PFS ranging from 4 to 5 months (one partial metabolic response and one stable disease). In one of the cases, which developed oligoprogression on alectinib, radiation therapy plus post-progression alectinib were able to provide additional disease control for 9 more months. No grade 3/4 adverse events, dose reductions or discontinuation due to toxicity were documented. CONCLUSION: Although this is a small single center evaluation, alectinib was well tolerated and demonstrated clinical activity against advanced RET-rearranged NSCLCs, suggesting its potential role in this specific subset of malignancies. Clinical trials addressing its efficacy and the optimal dosing schedule in the present context are underway, and results are eagerly awaited.

The role of histone deacetylase inhibitors in metastatic breast cancer.

Histone deacetylase inhibitors (HDACi) are a relatively new class of drug that plays an important role in the epigenetic and non-epigenetic regulation in cancer, inducing death, apoptosis and cell cycle arrest in cancer cells. Although HDACi are approved only for hematologic malignancies, there are several trials in the breast cancer setting with promising results. In this review, we summarize the latest studies with HDACi in breast cancer from the emerging data in the translational research until its possible applicability in the clinical practice.

Bevacizumab as first-line therapy in advanced non-small-cell lung cancer: a brazilian center experience.

OBJECTIVES: Bevacizumab has been approved by the US Food and Drug Administration as a first-line therapy for metastatic non-small-cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel. A single Latin American center experience was reviewed to determine the safety and efficacy of adding bevacizumab to first-line chemotherapy in a local population. METHODS: We retrospectively identified patients with non-squamous NSCLC treated with bevacizumab plus chemotherapy combinations as first-line chemotherapy between July 1, 2006, and January 30, 2011, at Sirio Libanes Hospital in Sao Paulo, Brazil. We collected data on patient characteristics, treatment combinations, toxicities, response to treatment, and survival. Overall survival (OS) and progression-free survival (PFS) were calculated by Kaplan-Meier analysis, and prognostic factors were identified by the Cox regression model. RESULTS: A total of 56 patients were included in the final analysis (median age 62.4 years; 70% male). In 35 patients (62.5%), bevacizumab was combined with carboplatin and paclitaxel, and in 16 patients (28.6%), it was combined with pemetrexed and carboplatin. The response rate evaluated by the reference clinical team reached 74.5%, the median PFS was 5.3 months, and the median OS was 14.8 months. In multivariate analysis, use of maintenance therapy was the only predictive factor for OS (hazard ratio 6.85, 95% confidence interval 2.94-15.22). No treatment-related deaths were identified, and the overall incidence of grade 3-4 non-hematologic toxicities was 16%. CONCLUSION: Our results confirm the efficacy and safety data of bevacizumab first-line combinations for NSCLC in a Brazilian population.

Livedoid vasculopathy: fast involution after anticoagulant and hyperbaric oxygen therapy.

The livedoid vasculopathy is a rare condition characterized by the presence of recurrent painful ulcers in distal extremities of lower limbs. Histologically there is thickness of dermal vessels, occlusion of its light by fibrin thrombi associated with minimal inflammatory infiltrate. It might occur as an isolated condition or be associated with an underlying systemic disease, including coagulation and collagen disorders, or neoplasms. Because it is a rare disease there is no consensus for its treatment. We report a case of a 41-year-old man with painful ulcers in the lower extremities. We did not find any associated diseases. The lesions improved dramatically after treatment with anticoagulant and hyperbaric therapy. We concluded that anticoagulation associated with hyperbaric oxygenation may be benefit for the treatment of patients with livedoid vasculopathy. However, further studies should be done with a larger population to confirm our results.

Vasculopatia livedoide: rápida involução com câmara hiperbárica e terapia anticoagulante / Livedoid vasculopathy: fast involution after anticoagulant therapy and hiperbaric oxigen therapy

The livedoid vasculopathy is a rare condition characterized by the resence of recurrent painful ulcers in distal extremities of lower limbs. Histologically there is thickness of dermal vessels, occlusion of its light by fibrin thrombi associated with minimal inflammatory infiltrate. It might occur as an isolated condition or be associated with an underlying systemic disease, including coagulation and collagen disorders, or neoplasms. Because it is a rare disease there is no consensus for its treatment. We report a case of a 41-year-old man with painful ulcers in the lower extremities. We did not find any associated diseases. The lesions improved dramatically after treatment with anticoagulant and hyperbaric therapy. We concluded that anticoagulation associated with hyperbaric oxygenation may be benefit for the treatment of patients with livedoid vasculopathy. However, further studies should be done with a larger population to confirm our results.

A vasculopatia livedoide é uma doença que se caracteriza pela presença de úlceras dolorosas recorrentes localizadas nas extremidades distais dos membros inferiores. Histologicamente, apresenta-se com espessamento dos vasos da derme, oclusão de sua luz por trombos de fibrina, associados a um mínimo infiltrado inflamatório. Pode se apresentar isoladamente ou em associação a trombofilias, desordens do colágeno ou doenças neoplásicas. Por ser uma entidade rara, não há consenso sobre seu tratamento. Relatamos o caso de um paciente de 41 anos, do sexo masculino, com úlceras dolorosas de membros inferiores. Nenhum fator associado foi encontrado. Houve dramática regressão do quadro após instituição de terapia anticoagulante concomitante à aplicação de sessões de câmara hiperbárica. Concluímos que a terapia anticoagulante associada a sessões de câmara hiperbárica parece ser benéfica na vasculopatia livedoide; entretanto, sua aplicação em maior número de pacientes faz-se necessária para confirmarmos nossos resultados.