RESUMO
BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto , Receptor ErbB-2 , TrastuzumabRESUMO
BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.
Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Capecitabina/uso terapêutico , Família de Proteínas EGF/uso terapêutico , Humanos , Piperazinas , Piridinas , Qualidade de Vida , Receptor ErbB-2/genética , Receptores de EstrogênioRESUMO
PURPOSE: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. MATERIALS AND METHODS: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. RESULTS: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). CONCLUSION: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Lapatinib/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Estudos Retrospectivos , Espanha , Resultado do TratamentoRESUMO
BACKGROUND: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results. PATIENTS AND METHODS: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria. RESULTS: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33). CONCLUSION: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity. TRIALS REGISTRATION: ClinicalTrial.Gov NCT00545077 and NCT00601900.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Tecidos Moles/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Fulvestranto/administração & dosagem , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/secundário , Taxa de Sobrevida , Tamoxifeno/administração & dosagemRESUMO
BACKGROUND: The appropriate selection criteria for breast-conserving surgery (BCS) or mastectomy after neoadjuvant chemotherapy (NAC) are poorly defined. The aim of this study is to analyse the incidence and prognostic factors for locoregional recurrence (LRR) in patients with breast cancer (BC) treated with NAC to develop a prognostic score to help with clinical decision-making. MATERIALS AND METHODS: Using our retrospective maintained BC database, we identified 730 patients treated with NAC (327 patients treated with BCS and 403 patients treated with mastectomy) between 1998 and 2014. To identify variables associated with an increased LRR rate, we performed firstly Kaplan-Meier curves, with comparisons among groups using log-rank test, and then, significant variables were included in a multivariate analysis using Cox proportional hazards. The prognostic index was developed by assigning score 0 (favourable) or score 1 (unfavourable) for each significant variable of multivariate analysis and was created separately for patients with BCS and mastectomy. RESULTS: At a median follow-up of 72 months, the 6-year cumulative incidence of LRR was 7.2% ( ± 3%) for BCS and 7.9% ( ± 3%) for mastectomy. By univariate analysis, variables associated with an increased LRR were for BCS: HER2 positive, grade III, ductal carcinoma in situ (DCIS), No-pCR (ypTis, ypN0), and age < 40 years; and for mastectomy, HER2-positive, DCIS, No-pCR, and LVI. By multivariate analysis, variables associated with an increased LRR were for BCS: HER2 positive (HR: 11.1, p = 0.001), DCIS (HR: 3.1, p = 0.005), and age < 40 years (HR: 2.8, p = 0.02); and for mastectomy: HER2 positive (HR: 9.5, p = 0.03), DCIS (HR: 2.7, p = 0.01), No-pCR (HR: 11.4, p = 0.01), and age < 40 years (HR: 2.8, p = 0.006). The score stratified patients into three subsets with statistically different levels of risk for LRR. For BCS, the six-year LRR rates were 3%, 13%, and 33% for the low (score 0, n = 120), intermediate (score 1, n = 95) and high (score 2-3, n = 27) risk groups, respectively (p = 0.001). For mastectomy, the six-year LRR rates were 0%, 8%, and 27% for the low (score 0, n = 20), intermediate (score 1-2, n 191), and high (score 3-4, n = 30) risk groups, respectively (p = 0.001). Of note, 21 patients that had a LRR event were HER2 positive, all of them had received trastuzumab. CONCLUSIONS: Patients with a score of 0, which made up to 19% of the study population, had very low risk of LRR. The score enabled the identification of a small group (7%) of patients with very high risk of LRR, and who may benefit from alternative treatment.
RESUMO
Urethral cancer is an uncommon tumor (<0.1% of all genitourinary neoplasms). Most of them are squamous carcinoma, adenocarcinomas are about 5% of all urethral cancer. Surgery is the only curative treatment. Surgical technics depend of tumoral location and extension. Conservative surgery is elective if survival is not compromised. Extensive surgery is needed in large lesions. Chemotherapy (CT) and radiotherapy (RT) must be used in patients in which surgery is not possible. Due to the low incidence of this neoplasm is not well established the best therapeutic approach. We present the case of a female (35 years old) with a diagnosis of urethral adenocarcinoma. The initial stage was IV due to non-regional lymph nodes metastases. Surgery was impossible and the patient received chemotherapy and radiotherapy. The patient achieved complete response with CT but a progression was observed in course of RT. The patient died due to systemic progression.
Assuntos
Adenocarcinoma/terapia , Neoplasias Uretrais/terapia , Adenocarcinoma/patologia , Adulto , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Neoplasias Uretrais/patologiaAssuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Fígado/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Parede Abdominal/patologia , Idoso , Carcinoma Hepatocelular/diagnóstico por imagem , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Transplante de Fígado/patologia , Tomografia Computadorizada por Raios XRESUMO
Introducción: el término Pseudomixoma Peritoneal es una entidad rara que hace referencia a la diseminaciónperitoneal de un tumor cuyas células producen gran cantidad de mucina. Suele proceder de un tumorapendicular perforado, y se distribuyen de una forma característica por la superficie peritoneal. Aunque histológicamentepuedan no mostrar agresividad, clínicamente sí lo son. Material y métodos: presentamos el caso de una mujer diagnosticada de carcinomatosis peritonealpor un carcinoma apendicular. Fue tratada mediante cirugía y quimioterapia sistémica basada en 5FU. De estaforma conseguimos una larga supervivencia con un buen control sintomático. Conclusiones: no existen tratamientos de elección para esta enfermedad. Basándose en su peculiarcomportamiento clínico, algunos autores intentan una aproximación curativa, mediante cirugías agresivas yquimioterapia intraperitoneal. Se trata de un procedimiento complicado, no validado en ensayos clínicos. El casoque presentamos muestra que una opción razonable de tratamiento puede basarse en cirugía convencional yquimioterapia sistémica
Purpose: Mucinous ascites by mucus-producing tumour epithelial cells with peritoneum disseminationis a rare condition known as pseudomyoma peritonaei. In nearly all the cases the cause is a primary tumour ofthe appendix. It is an entity with multifocal peritoneal epithelial implants, distributed in a characteristic way.Although it can be not aggressive histologically, it is invariably fatal clinically. Material and methods: We present the case of a woman diagnosed of peritoneal carcinomatosis byan appendicular carcinoma, who was treated by surgery and systemic chemotherapy based on 5-FU. With thisapproach we got a long survival with a good symptomatic control. Conclusion: There are no standard treatments for this disease. Based on its particular behaviour, theapproach of some specialists is an aggressive surgery combined with intraperitoneal chemotherapy. However,it is a complex procedure, not validated by clinical studies. Our case shows that it can be achieved a goodclinical control with conservative surgery and systemic chemotherapy
Assuntos
Feminino , Pessoa de Meia-Idade , Humanos , Pseudomixoma Peritoneal/patologia , Neoplasias do Apêndice/patologia , Neoplasias Peritoneais/secundário , Pseudomixoma Peritoneal/terapia , Biomarcadores Tumorais/análiseRESUMO
El carcinoma primario de uretra es un tumor de escasa incidencia, ocupa menos del 0,1 por ciento de las neoplasias genitourinarias. La mayoría de tumores corresponden a carcinomas escamosos, siendo mucho menos frecuentes los adenocarcinomas. El tratamiento curativo es la cirugía y las técnicas dependen de la localización del tumor. La cirugía conservadora será de elección siempre que ésta no comprometa la curación. Determinadas localizaciones o extensión de enfermedad pueden requerir cirugía mutilante. En aquellos casos en los que no es posible un tratamiento quirúrgico se emplean otras estrategias terapéuticas (radioterapia o quimioterapia), sin que se disponga de estudios con número suficiente de pacientes que permitan establecer la mejor actitud terapéutica. Presentamos el caso de una mujer de 35 años afecta de adenocarcinoma parauretral avanzado al diagnóstico. Ante la imposibilidad de recibir tratamiento quirúrgico fue tratada con quimioterapia más radioterapia. El tratamiento combinado produjo respuesta completa pero posteriormente apareció una recaída precoz que condicionó el exitus (AU)