RESUMO
BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib. METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete. FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related. INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials. FUNDING: Pfizer.
Assuntos
Neoplasias da Mama , Linfopenia , Neutropenia , Humanos , Feminino , Adolescente , Adulto , Fulvestranto , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptores de Estrogênio/análise , Receptor ErbB-2/genética , Receptor ErbB-2/análise , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mutação , Neutropenia/induzido quimicamente , Linfopenia/induzido quimicamente , Intervalo Livre de DoençaRESUMO
OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54â¯years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21â¯months, median PFS was 12.7â¯months and median OS was 35.4â¯months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI)â¯≥â¯12â¯months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFIâ¯≥â¯12â¯months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free intervalâ¯≥â¯12â¯months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Antígeno Ca-125/metabolismo , Intervalo Livre de Doença , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Mutação em Linhagem Germinativa/genética , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.
Assuntos
Anticorpos Monoclonais Humanizados , Terapia Neoadjuvante , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Terapia Neoadjuvante/métodos , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Gradação de Tumores , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inibidores , Imunoterapia/métodosRESUMO
This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Terapia Neoadjuvante , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Pessoa de Meia-Idade , Idoso , Terapia Neoadjuvante/métodos , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Quimioterapia Adjuvante/métodos , Adulto , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Cistadenocarcinoma Seroso/mortalidade , Intervalo Livre de Progressão , Procedimentos Cirúrgicos de Citorredução , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Solitary Fibrous Tumor is a rare type of soft tissue tumor of intermediate malignant potential which may recur or metastasize in 15-20% of cases. Data on the management of patients with advanced SFT is scarce: chemotherapy has been described as ineffective, while recent data suggests that anti-angiogenic therapies may be more efficient. METHODS: We conducted a retrospective study on patients treated for advanced SFT at a single institution: from January 1994 to December 2011, 30 patients were treated in the Centre Léon Bérard for an advanced SFT. RESULTS: Twenty-three patients received cytotoxic chemotherapy as first-line therapy. Best responses were 2 (9%) partial responses, 13 (57%) stable diseases (SD) and 8 (35%) progressive diseases (PD). Median Progression Free Survival (PFS) was 5.2 (95% CI: 3.2-7.1) months and 9 patients were free of progression at 6 months. Ten patients received an anti-angiogenic treatment (sunitinib or pazopanib) as a 2nd, 3rd or 4th line. Best responses were 5 SD and 5 PD; median PFS was 5.1 months (95% CI 0.7-9.6). Four patients (36%) were progression-free for more than 6 months. Two patients receiving pazopanib were without progression at 6 and 8 months and two patients receiving sunitinib were free of progression at 30 months. CONCLUSION: Response rate with standard chemotherapy was low and PFS appear similar between cytotoxic chemotherapy and anti-angiogenic agents.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tumores Fibrosos Solitários/tratamento farmacológico , Tumores Fibrosos Solitários/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Tumores Fibrosos Solitários/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Conventional treatment for locally advanced rectal cancer usually combines neoadjuvant radiochemotherapy and surgery. Until recently, there have been limited predictive factors (clinical or biological) for rectal tumor response to conventional treatment. KRAS, BRAF and PIK3CA mutations are commonly found in colon cancers. In this study, we aimed to determine the mutation frequencies of KRAS, BRAF and PIK3CA and to establish whether such mutations may be used as prognostic and/or predictive factors in rectal cancer patients. METHODS: We retrospectively reviewed the clinical and biological data of 98 consecutive operated patients between May 2006 and September 2009. We focused in patients who received surgery in our center after radiochemotherapy and in which tumor samples were available. RESULTS: In the 98 patients with a rectal cancer, the median follow-up time was 28.3 months (4-74). Eight out of ninety-eight patients experienced a local recurrence (8%) and 17/98 developed distant metastasis (17%). KRAS, BRAF and PIK3CA were identified respectively in 23 (23.5%), 2 (2%) and 4 (4%) patients. As described in previous studies, mutations in KRAS and BRAF were mutually exclusive. No patient with local recurrence exhibited KRAS or PIK3CA mutation and one harbored BRAF mutation (12.5%). Of the seventeen patients with distant metastasis (17%), 5 were presenting KRAS mutation (29%), one BRAF (5%) and one PIK3CA mutation (5%). No relationship was seen between PIK3CA, KRAS or BRAF mutation and local or distant recurrences. CONCLUSION: The frequencies of KRAS, BRAF and PIK3CA mutations in our study were lower than the average frequencies reported in colorectal cancers and no significant correlation was found between local/distant recurrences and KRAS, BRAF or PIK3CA mutations. Future studies with greater number of patients, longer follow-up time and greater power to predict associations are necessary to fully understand this relationship.
Assuntos
Carcinoma/genética , Carcinoma/terapia , Recidiva Local de Neoplasia/genética , Neoplasias Retais/genética , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/secundário , Quimiorradioterapia Adjuvante , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Terapia Neoadjuvante , Metástase Neoplásica , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Transcrição/genética , Proteínas ras/genéticaRESUMO
BACKGROUND: The long term outcome of advanced sarcoma patients treated with trabectedin outside of clinical trials and the utility of maintenance treatment has not been reported. METHODS: Between 2003 and 2008, patients with advanced sarcoma failing doxorubicin could be treated within a compassionate use program (ATU, Temporary Use Authorization) of trabectedin in France using the standard 3-weekly regimen. Data from 181 patients (55%) were collected from 11 centres and analyzed. RESULTS: Trabectedin was given in first, second, third or fourth line in metastatic phase in 6%, 37%, 33% and 23% of patients respectively. With a median follow-up of 6 years, median PFS and OS were 3.6 months and 16.1 months respectively. The median number of cycles was 3 (range 1-19). Best response were partial response (PR, n = 18, 10%), stable disease (SD, n = 69, 39%) and progressive disease (PD, n = 83, 46%), non evaluable (NE, n = 9, 5%). Thirty patients (17%) had to be hospitalized for treatment- related side effects. Independent prognostic factors in multivariate analysis (Cox model) were myxoid LPS and line of trabectedin for PFS, and myxoid LPS and retroperitoneal sarcomas for OS. Patients in PR or SD after 6 cycles continuing treatment had a better PFS (median 5.3 vs 10.5 months, p = 0.001) and OS (median 13.9 vs 33.4 months, p = 0.009) as compared to patients who stopped after 6 cycles. CONCLUSIONS: In this compassionate use program, trabectedin yielded similar or better PFS and OS than in clinical trials. Maintenance treatment beyond 6 cycles was associated with an improved survival.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Tetra-Hidroisoquinolinas/uso terapêutico , Adulto , Idoso , Ensaios de Uso Compassivo , Feminino , França , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Sarcoma/mortalidade , Trabectedina , Resultado do TratamentoRESUMO
Purpose: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide. Experimental Design: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon's minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS). Results: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4+ T cells and higher CD8+ T cells to macrophage ratios in the tumor. This impact on CD4+ and CD8+ T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4+ and CD8+ memory T cells was observed in other patients. Conclusion: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.
RESUMO
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis. METHODS: We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin. RESULTS: Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months. CONCLUSION: Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Doxorrubicina/administração & dosagem , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
PURPOSE: Genomic tests can identify ER-positive HER2-negative localized breast cancer patients who may not benefit from adjuvant chemotherapy. Such tests seem especially interesting in "intermediate" clinico-pathological risk categories. The psychological impact of the decision uncertainty in these women remains largely unexplored. We assessed the clinical and psychological impact of EndoPredict® (EpClin), a clinico-genomic test, in these patients. METHODS: This multicenter, single arm prospective study (NCT02773004) enrolled patients for which adjuvant chemotherapy was uncertain, based on predefined criteria. The primary endpoint was the proportion of change between initial adjuvant decision and final administration of chemotherapy. Secondary endpoints included post-test (Day 17) and 1-year patient reported outcomes. RESULTS: One third of 200 evaluable patients had a high EpClin score (≥3.32867; 10 years cumulative risk of distance failure ≥10%). The overall change rate of chemotherapy decision was 72/200 (35.8%, 95% CI 29.2-42.4). Chemotherapy was withdrawn in 57 cases (28.4% [22.2-34.8]) and added in 15 (7.5% [3.8-11.2]. 6 changes (8%) were based on patients' decisions. Anxiety and distress levels increased at Day 17 when adding chemotherapy after the test result (p < 10-7 and 0.00022 respectively), while stable in other situations. At 1-year, all patients had returned to the baseline anxiety and distress levels (mean anxiety 51.5, +/- SD = 2.5 [max. 80], mean distress 3±1 [max. 10]). CONCLUSIONS: EndoPredict ® (EpClin) is clinically useful in deciding whether or not to administer adjuvant chemotherapy in patients with intermediate risk. A single-step decision is preferable since adding chemotherapy at a later stage increases anxiety and distress.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Regras de Decisão Clínica , Tomada de Decisão Clínica/métodos , Genes erbB-2 , Testes Genéticos/métodos , Receptores de Estrogênio/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Ansiedade/diagnóstico , Ansiedade/etiologia , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Marcadores Genéticos , Genômica , Humanos , Mastectomia , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos , Angústia Psicológica , Medição de Risco , IncertezaRESUMO
OBJECTIVES: The objectives of this study were to identify actionable genomic alterations in the gynaecological subpopulation of the ProfiLER programme and to report clinical efficacy of recommended targeted treatment (RTT). METHODS: The ProfiLER programme (NCT01774409) is a multicentric prospective trial aiming to implement molecular profiling in patients with advanced refractory cancers. In this programme, tumour DNA is analysed by targeted next-generation sequencing (69 genes) and by whole genome array comparative genomic hybridisation. Clinical cases and genomic profiles are presented in a dedicated molecular tumour board to guide treatment strategies. We report here an analysis of patients with gynaecological cancers included in this trial. RESULTS: From February 2013 to February 2017, 309 patients with gynaecologic cancer were included; 279 (90%) had sufficient quality, and 131 patients (42.4%) had at least one actionable genomic alteration in cancer cells. Four alterations were shared by at least 3% of the patients: 27 (9.7%) PIK3CA mutations, 15 (5.4%) KRAS mutations, 11 (3.9%) ERBB2 amplifications and 9 (3.2%) CDKN2A deletions. Forty-one treatments were initiated among 39 patients (12.6% of the screened population): 8 (20%) had a partial response, and other 10 (24%) had a stable disease. The median progression-free survival was 2.7 months. The median overall survival was 15.6 months for patients who received a RTT. CONCLUSION: Molecular profiling identified actionable alterations in 42.4% of patients with advanced refractory gynaecologic cancer, but only 12.6% were treated with a RTT. Among them, 46% derived clinical benefit (5.8% of the screened population).
Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neoplasias dos Genitais Femininos/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Hibridização Genômica Comparativa , Progressão da Doença , Feminino , França , Amplificação de Genes , Deleção de Genes , Predisposição Genética para Doença , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias dos Genitais Femininos/patologia , Neoplasias dos Genitais Femininos/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Sequenciamento Completo do GenomaRESUMO
Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients.Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort.Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2 After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20-0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; P = 0.001).Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326-33. ©2017 AACR.
Assuntos
Proteína BRCA2/genética , Biomarcadores Tumorais , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Feminino , Loci Gênicos , Genótipo , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Prognóstico , Resultado do TratamentoRESUMO
PURPOSE: The outcome of sarcoma has been suggested in retrospective and non-exhaustive studies to be better through management by a multidisciplinary team of experts and adherence to clinical practice guidelines (CPGs). The aim of this prospective and exhaustive population based study was to confirm the impact of adherence to CPGs on survival in patients with localized sarcoma. EXPERIMENTAL DESIGN: Between 2005 and 2007, all evaluable adult patients with a newly diagnosis of localized sarcoma located in Rhone Alpes region (n = 634), including 472 cases of soft-tissue sarcoma (STS), were enrolled. The prognostic impact of adherence to CPGs on progression-free survival (PFS) and overall survival (OS) was assessed by multivariate Cox model in this cohort. RESULTS: The median age was 61 years (range 16-92). The most common subtypes were liposarcoma (n = 133, 28%), unclassified sarcoma (n = 98, 20.7%) and leiomyosarcoma (n = 69, 14.6%). In the initial management phase, from diagnosis to adjuvant treatment, the adherence to CPGs for patients with localized STS was 36% overall, corresponding to 56%, 85%, 96% and 84% for initial surgery, radiation therapy, chemotherapy and follow-up, respectively. Adherence to CPGs for surgery was the strongest independent prognostic factor of PFS, along with age, gender, grade, and tumor size. For OS, multivariate analysis adherence to CPGs for surgery was a strong independent prognostic factor, with an important interaction with a management in the regional expert centers. CONCLUSIONS: This study demonstrates impact of CPGs and treatment within an expert center on survival for STS patients in a whole population-based cohort.
Assuntos
Sarcoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Lipossarcoma/mortalidade , Lipossarcoma/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Prospectivos , Sarcoma/mortalidade , Adulto JovemRESUMO
INTRODUCTION: Whether mutation status should be used to guide therapy is an important issue in many cancers. We correlated mutation profile in radioiodine-refractory (RAIR) metastatic thyroid cancers (TCs) with patient outcome and response to tyrosine kinase inhibitors (TKIs), and discussed the results with other published data. MATERIALS AND METHODS: Outcome in 82 consecutive patients with metastatic RAIR thyroid carcinoma prospectively tested for BRAF, RAS and PI3KCA mutations was retrospectively analyzed, including 55 patients treated with multikinase inhibitors. RESULTS: Papillary thyroid carcinomas (PTCs) were the most frequent histological subtype (54.9 %), followed by poorly differentiated thyroid carcinoma [PDTC] (30.5 %) and follicular thyroid carcinoma [FTC] (14.6 %). A genetic mutation was identified in 23 patients (28 %) and BRAF was the most frequently mutated gene (23 %). Median progression-free survival (PFS) on first-line TKI treatment was 14.6 months (95% CI 9.9-18.4). BRAF mutation positively influenced median PFS, both in the entire TKI-treated cohort (median PFS 34.7 months versus 11.6 months; hazard ratio [HR] 0.29; 95% CI 0.09-0.98; p = 0.03) and in the TKI-treated PTC cohort (n = 22) [log-rank p = 0.086; HR 2.95; 95 % CI 0.81-10.70). However, in TKI-treated patients, PDTC histologic subtype was the only independent prognostic factor for PFS identified in the multivariate analysis (HR 2.36; 95% CI 1.01-5.54; p = 0.048). CONCLUSION: Patients with BRAF-mutant PTC had a significantly longer PFS than BRAF wild-type when treated with TKIs. However, due to the small number of BRAF-mutant patients, further investigations are required, especially to understand the potential positive effect of BRAF mutations in RAIR TC patients while having a negative prognostic impact in RAI-sensitive PTC patients.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Papilar/genética , Radioisótopos do Iodo/efeitos adversos , Terapia de Alvo Molecular , Mutação/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/patologia , Carcinoma Papilar/terapia , Gerenciamento Clínico , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Tolerância a Radiação , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapiaRESUMO
UNLABELLED: Epithelioid hemangioendothelioma is a rare connective tissue tumor of vascular origin. It is most commonly found in young to middle aged women, and its clinical behavior is remakably variable from an indolent metastatic tumor to an aggressive rapidly growing neoplasm. Most tumors are diagnosed in an advanced unresectable phase and when clinically aggressive, require systemic cytotoxic treatment of sarcoma. Then, the 5-year survival rate after chemotherapy does not exceed 30%. Antiangiogenics are active in selected sarcoma subtypes: pazopanib, the only anti angiogenic registered agent for sarcoma provides a median PFS of 4.5 months only in the pivotal study. Their activity in EHE has been reported but long term outcome of these patients remain unreported. We report a case of a female patient with HEH who was treated with pazopanib for almost 8 years. Pazopanib therapy resulted in clinical improvement of symptoms and durable stabilization of liver tumors and lung lesions. CONCLUSION: Pazopanib is a promising therapeutic option in patients with HEH.
RESUMO
The current refinement of nosological classification of sarcoma which integrates molecular typing with a growing number of subtypes contrasts with the one-size-fits-all approach proposed in clinical practice guidelines for both local treatment and systemic treatment in the past. However, there is a growing proportion of sarcomas in which specific treatment strategies are proposed as standard. As a consequence, central review by expert sarcoma pathologists should be organised to ensure the optimal management of all patients. The key parameters in the pathology report influencing treatment decisions are therefore rapidly evolving. First a diagnostic biopsy, ideally an imaged guided microbiopsy performed by an experienced team, is a recommended practice. On the resection specimen, the size, histological grade, location, depth, surgical margins and tumour fragmentation are essential parameters to guide the treating physician. Molecular characterisation of the driving genomic event is becoming increasingly important for treatment decision making, in routine practice and in clinical trials. Molecular grade is a research tool with potentially high utility, and requires further evaluation and validation in prospective clinical trials.
Assuntos
Sarcoma/patologia , Sarcoma/terapia , Tomada de Decisões , Humanos , Gradação de Tumores/métodos , Patologia Molecular/métodos , Papel do Médico , Guias de Prática Clínica como Assunto , Sarcoma/diagnósticoRESUMO
There is a markedly increasing contrast between the current refinement of nosologic classification of sarcoma integrating molecular typing with a growing number of subtypes and the usually standardized approach proposed in clinical practice guidelines for both local and systemic treatment. Although gastrointestinal stromal tumor (GIST), dermatofibrosarcoma protuberans, and a few other subtypes now have specific therapeutic strategies, the majority of sarcomas are still lumped together in clinical trials investigating novel therapeutic options. These trials may not provide sufficient information to guide routine clinical practice. Proof-of-concept trials exploring a targeted agent in a selected molecular subtype, randomized phase II trials, and trials focusing on histologic subtypes-all integrating translational research and aiming to identify the mechanisms of sensitivity and resistance to the treatment-are needed. This paper discusses the limitations of previous clinical trial designs to guide clinical practice in this complex context.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Medicina Baseada em Evidências/métodos , Projetos de Pesquisa , Sarcoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Determinação de Ponto Final , Humanos , Técnicas de Diagnóstico Molecular , Seleção de Pacientes , Medicina de Precisão , Valor Preditivo dos Testes , Sarcoma/classificação , Sarcoma/genética , Sarcoma/metabolismo , Sarcoma/mortalidade , Sarcoma/patologia , Resultado do TratamentoRESUMO
Giant-cell tumor of bone (GCTB) is a rare osteolytic tumor of the bone. Although classified as a benign tumor, GCTB is characterized by local aggressiveness and risk of local recurrence. In addition, GTCB can in some cases lead to the development of so-called 'benign' chest metastases. Surgical resection by intralesional curettage with high-speed burring and polymethylmethacrylate cement is the standard treatment for resectable tumors. In cases of metastatic or unresectable disease (when planned surgical procedure is impossible or would result in severe morbidity), medical treatments such as cytotoxic chemotherapy or interferon-α have limited efficacy. Bisphosphonates have been proposed as a therapeutic option to reduce osteoclast activity. In bone, various pathological states may result from an imbalance in the RANK (receptor activator of nuclear factor kappa-B)/RANKL (receptor activator of nuclear factor kappa-B ligand)/OPG (osteoprotegerin) pathway. Involvement of the RANKL pathway in pathogenesis of GCTB was first proposed in 2000. Denosumab is a fully human monoclonal antibody that binds and inhibits RANKL, thereby preventing the activation of the RANK pathway. As it showed the possibility to counteract osteoclast activation in GCTB and prevent the known physiopathological role of RANKL, denosumab has been under evaluation in the clinic as a treatment for GCTB since 2005. Results of a first Phase II trial demonstrate the therapeutic potential of denosumab to inhibit progressive bone destruction and metastatic progression in patients with unsalvageable giant-cell tumor (GCT), and have also provided key insights into the biology of GCT. Denosumab is currently a therapeutic option for patients with unresectable GCTB but its place in the global therapeutic strategy has not yet been defined.
RESUMO
Pazopanib is a multikinase inhibitor which potently inhibits the activity of major receptor tyrosine kinases, including vascular endothelial growth factor receptor-1, vascular endothelial growth factor receptor-2, vascular endothelial growth factor receptor-3, platelet-derived growth factor receptor-a, platelet-derived growth factor receptor-a, and c-Kit. Approved by the Food and Drug Administration in 2009 in the United States for the treatment of metastatic renal cell carcinoma, pazopanib has been tested in advanced or metastatic soft-tissue sarcoma. Unlike other tyrosine kinase inhibitors, a statistically significant efficacy in phase II but also in randomized phase III studies has been shown. In comparison with sunitinib or sorafenib, pazopanib has a similar toxicity profile and is generally well tolerated. This review details the development of this new therapeutic class in the treatment of metastatic soft-tissue sarcomas.
RESUMO
Dose intensity has been demonstrated to be one determinant for treatment efficacy in younger adults with high-risk (relapsed and refractory) acute myelogenous leukemia. Between 2000 and 2006, 56 patients entered the EMA 2000 study and received timed sequential reinduction chemotherapy. From 2004, chemotherapy was also followed by one subcutaneous dose of pegfilgrastim. Thirty-six patients reached a complete remission, while nine obtained a partial remission. Median time to granulocyte and platelet recovery was 34 and 38 days respectively. The major non-hematologic toxicities were severe infections but despite this 23 remitters could proceed to their post-remission treatment, although 13 did not because of severe toxicity or early relapse. The median overall survival was 9.3 months. The EMA 2000 regimen is a highly effective treatment with a response rate of 64% and a low early death rate. The period of critical neutropenia was relatively short in both phases and the supportive use of pegfilgrastim, although showing a trend toward reduced neutropenic period, did not appear to reduce the risk of infection in this group and may not be a critical requirement for reducing the risk of treatment-related toxicity.