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BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.
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Neoplasias Ovarianas , Doenças do Sistema Nervoso Periférico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/etiologia , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/etiologia , Paclitaxel , Ftalazinas , Piperazinas , QuinazolinasRESUMO
OBJECTIVE: Around 15% of epithelial ovarian cancer (EOC) patients (pts) harbor a germline BRCA1 or 2 mutation, showing different features than BRCA wild-type pts. The clinical and pathological features of an Italian BRCA mutated EOC cohort were described. METHODS: We retrospectively analyzed clinical, pathological and mutational data from a cohort of Italian BRCA mutated EOC pts. treated in 15 MITO centers between 1995 and 2017. RESULTS: Three-hundred thirty-one pts. were recorded. Two-hundred forty (72%) and 91 (27.5%) pts. harbored a BRCA1 and BRCA2 mutation, respectively. Median age at diagnosis was 52 years. The most frequent diagnosis was a high grade serous FIGO III or IV EOC and platinum doublet in first-line was administered to almost all pts. Fifty-three % of them had no residual disease (R = 0) at surgery. Median progression-free-survival (mPFS) after first-line chemotherapy was 29 months. Expected percentage of pts. alive at 5 years was 72.5% (CI 60.2-80.8%) and R = 0 predicted a significantly longer overall survival (OS). Sixty-six pts. (19,9%) had both an EOC and a breast cancer (BC) diagnosis. The first diagnosis was BC in 81,8% of cases with a mean interval between the two diagnoses (IBTDs) of 132.4 months. Mutational data show that the founder mutation c.5266dupC in BRCA1 was the most frequently recorded. CONCLUSIONS: This is the largest Italian BRCA mutEOC cohort. The only predictor of longer OS was R = 0. EOC pts. that developed subsequently a BC are long-term survivors.
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Proteína BRCA1/genética , Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Demografia , Feminino , Humanos , Itália , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos RetrospectivosRESUMO
BACKGROUND: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients. PATIENTS AND METHODS: ARCC patients, ECOG PSâ¯≤â¯1, were randomized to CP for 6â¯cycles with or without CET (400â¯mg/m2 one week before starting CP, then 250â¯mg/m2 weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5â¯months expected median EFS and a 6.4â¯months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis. RESULTS: 108 patients were assigned to CP (nâ¯=â¯53) or CP-CET (nâ¯=â¯55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23â¯months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0â¯months (one-tail Pâ¯=â¯0.43), median PFS was 5.2 and 7.6â¯months (one-tail Pâ¯=â¯0.20) and median OS was 17.7 and 17â¯months (one-tail Pâ¯=â¯0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance. CONCLUSION: CP-CET was not more active than CP alone in unselected ARCC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Cetuximab/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Paclitaxel/administração & dosagem , Intervalo Livre de Progressão , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias do Colo do Útero/genéticaRESUMO
BACKGROUND: In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits. METHODS: In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6-12 vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity [TWiST] and quality-adjusted progression-free survival [QAPFS]). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01874353, and is closed to new participants. FINDINGS: The adjusted average mean change from baseline over the first 12 months in TOI was -2·90 (95% CI -4·13 to -1·67) with olaparib and -2·87 (-4·64 to -1·10) with placebo (estimated difference -0·03; 95% CI -2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98-8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70-8·96) were significantly longer with olaparib than with placebo. INTERPRETATION: Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies. FUNDING: AstraZeneca.
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Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Qualidade de Vida , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Few data are available on the outcome of surgery after a bevacizumab-containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery. METHODS: 400 chemonaïve epithelial ovarian cancer patients, age≥18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m2 d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd. RESULTS: 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease ≤1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each. CONCLUSIONS: In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Idoso , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário , Terapia Combinada , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagemRESUMO
BACKGROUND: In cancer patients, including women with a diagnosis of ovarian cancer, cancer antigen 125 (CA125) is used to evaluate the presence of peritoneal involvement. The aims of the present study were to assess CA125 reference intervals and reference change values (RCV) in postmenopausal reference women, postmenopausal women breast cancer free, reference men and cancer free men. METHODS: The series consisted of 433 subjects: 105 postmenopausal breast cancer free women and 56 cancer free men in addition to a total of 272 reference subjects (145 postmenopausal women and 127 men). Repeated CA125 measurements were made in a subset of 149 women and 54 men to calculate RCV and index of individuality. Serum CA125 levels were evaluated by a chemiluminescent assay. RESULTS: In postmenopausal reference women, the mean CA125 value and 2.5th-97.5th percentiles were 6.70, 2.60-11.00 kU/L, respectively, with a unidirectional RCV of 38.4%. In postmenopausal breast cancer free women, the mean CA125 value and 2.5th-97.5th percentile were 7.45, 4.09-10.92 kU/L, respectively, with a RCV of 34.5%. The difference between the means was statistically significant (t=-3.02, p=0.003). In the two male subgroups, the difference between the means for CA125 was not statistically significant (t=0.43, p=0.665). On considering the entire male population, the mean CA125 value and 2.5th-97.5th percentiles were 7.50 and 2.40-13.2 kU/L, respectively, while the unidirectional RCV was 34.3%. In all the studied groups, the indices of individuality were equal to or below 0.6. CONCLUSIONS: The extremely low index of individuality found underlines the importance of using the RCV instead of absolute values as a parameter when interpreting the CA125 data in the monitoring and follow-up of patients with ovarian cancer.
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Antígeno Ca-125/sangue , Pós-Menopausa/sangue , Antígeno Ca-125/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Fatores de RiscoRESUMO
Background: The use of PARP inhibitor (PARPi) has shown a considerable benefit in progression-free survival (PFS) in relapsed, platinum-sensitive epithelial ovarian cancer (OC). Objective: Our study aimed to investigate the impact of the last platinum-based chemotherapy treatment in response to PARPi. Design: Retrospective cohort study. Patients and methods: The study involved 96 consecutive, pretreated, platinum-sensitive advanced OC patients. Demographics and clinical data were retrieved from clinical records. PFS and overall survival (OS) were calculated from the start of PARPi. Results: Germline BRCA mutation was investigated in all cases. Platinum-based chemotherapy before PARPi maintenance therapy included pegylated liposomal doxorubicin-oxaliplatin (PLD-Ox) in 46 patients (48%) and other platinum-based chemotherapy in 50 patients (52%). During a median follow-up of 22 months from the beginning of PARPi therapy, 57 patients relapsed (median PFS: 12 months) and 64 patients died (median OS: 23 months). During multivariable analysis, receiving PLD-Ox before PARPi was associated with improved PFS [hazard ratio (HR): 0.46, 95% CI: 0.26-0.82] and OS (HR: 0.48, 95% CI: 0.27-0.83). In 36 BRCA-mutated patients, PLD-Ox was associated with improved PFS (2-year PFS: 70.0% versus 25.0%, p = 0.02). Conclusion: Receiving PLD-Ox before PARPi may improve prognosis in platinum-sensitive advanced OC patients and may provide advantages in the BRCA-mutated subgroup.
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CONTEXT: Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE: To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE: Five-year overall mortality. RESULTS: The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
AIMS AND BACKGROUND: To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. METHODS: Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. RESULTS: Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). CONCLUSIONS: Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ascite/etiologia , Carcinoma Papilar/tratamento farmacológico , Cistadenoma Seroso/tratamento farmacológico , Estudos de Viabilidade , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/complicações , Neoplasias Ovarianas/complicações , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/complicações , Compostos de Platina/administração & dosagem , Estudos Retrospectivos , Terapia de Salvação , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: We aimed to evaluate the clinico-pathological characteristics and survival outcomes of patients with synchronous or metachronous breast cancer (BC) and ovarian cancer (OC). MATERIALS AND METHODS: Patients with synchronous or metachronous BC and OC were retrospectively identified at two large cancer centers. Clinico-pathological characteristics, BRCA1/2 status and follow-up data were gathered. Patients were classified according to the first cancer diagnosis in the following groups: Breast Cancer first, Ovarian Cancer first, Synchronous Breast and Ovarian Cancer. Overall survival (OS) was calculated as the time interval between each cancer diagnosis to death or last follow-up. RESULTS: Overall, 270 patients were included: n = 194 (72%) in BC first group, n = 51 (19%) in OC first, and n = 25 (9%) in synchronous. BRCA status was available for 182 (67.4%) patients and 112 (62%) harbored pathogenetic mutations. BC first group included more frequently patients with BRCA mutation, triple negative BC phenotype and more aggressive OC features. Median time between the two diagnosis was longer in BC first group vs OC first group (95 vs 68 months, p = 0.021). A total of 105 OS events occurred, mostly related to OC (70.5%). We observed no differences in terms of OS according to the first cancer diagnosis. Age >50 years and advanced OC stage were negative independent prognostic factors for OS from the first diagnosis. CONCLUSIONS: In this cohort of patients with BC and OC, survival was dominated by OC related mortality. These data may be useful to plan and carry out adequate and timely surveillance programs and preventive measures.
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The classical cancer stem cell (CSC) model places CSCs at the apex of a hierarchical scale, suggesting different genetic alterations in non-CSCs compared to CSCs, since an ill-defined number of cell generations and time intervals separate CSCs from the more differentiated cancer cells that form the bulk of the tumor. Another model, however, poses that CSCs should be considered a functional state of tumor cells, hence sharing the same genetic alterations. Here, we review the existing literature on the genetic landscape of CSCs in various tumor types and as a case study investigate the genomic complexity of DNA obtained from matched CSCs and non-CSCs from five ovarian cancer patients, using a genome-wide single-nucleotide polymorphism (SNP) microarray.
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BACKGROUND: The aim of the study was to assess the efficacy of pegylated liposomal doxorubicin (PLD) and oxaliplatin in patients affected by relapsed epithelial ovarian cancer with a family history of BRCA and p53 mutations. METHODS: Seventy-two women received a median of 7.5 courses of PLD at 30 to 35 mg/m2 plus oxaliplatin at 70 mg/m2, and associations between BRCA1/2 and TP53 status and overall survival (OS) were determined. Thirty-eight had a short platinum-free interval (PFI; <12 months), and 34 had a long PFI (> or =12 months). RESULTS: Nine patients had BRCA1 mutations, and 1 had a BRCA2 mutation. Platinum sensitivity was associated with OS (P = 0.0001). At a median follow-up of 9.3 months, objective response rate, median time to progression, and OS were 47.3%, 5.8 months, and 12.9 months, respectively, in short PFI compared with the 76.5%, 11.5 months, and 47.7 months in long PFI. p53 status did not correlate to these parameters. The median time to progression was 11.5 months for high-risk patients versus 6.5 months for patients with sporadic cancer (P = 0.0188), and the median OS from the start of treatment was 48.7 and 16.2 months (P = 0.0032), respectively. Toxicity was mostly grade 1 or 2. CONCLUSIONS: High response rates in the long-PFI patients indicate that this treatment is beneficial and well tolerated. Platinum sensitivity and positive family history and/or a BRCA1/BRCA2 mutation are a useful predictor of response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/diagnóstico , Carcinoma/tratamento farmacológico , Saúde da Família , Genes p53 , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/mortalidade , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Genes p53/fisiologia , Humanos , Pessoa de Meia-Idade , Mutação/fisiologia , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Oxaliplatina , Polietilenoglicóis/administração & dosagem , Prognóstico , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
Receptors tyrosine kinase (RTK) enable normal and tumor cells to perceive and adapt to stimuli present in the microenvironment. These stimuli, also known as growth factors, are important molecular cues actively supporting cancer stem cell (CSC) self-renewal and viability. Since in epithelial ovarian cancer (EOC) the expression of c-Kit (CD117) has been identified as a CSC hallmark, we investigated the existence of a tumor growth-promoting loop between c-Kit and its ligand Stem Cell Factor (SCF). SCF exists as a soluble or transmembrane protein and through c-Kit interaction regulates cell viability, proliferation, and differentiation both in physiological and pathological conditions. High amounts of SCF were found in the ascitic effusions collected from EOC patients. While tumor cells and CSC only expressed the membrane-associated SCF isoform, both secreted and membrane-bound isoforms were expressed by tumor-associated macrophages (TAM, here shown to be M2-like) and fibroblasts (TAF). Circulating monocytes from EOC-bearing patients and healthy donors did not express both SCF isoforms. However, monocytes isolated from healthy donors produced SCF upon in vitro differentiation into macrophages, irrespectively of M1 or M2 polarization. In vitro, both SCF isoforms were able to activate the Akt pathway in c-Kit+ cells, and this effect was counteracted by the tyrosine kinase inhibitor imatinib. In addition, our results indicated that SCF could help c-Kit+ CSC survival in selective culture conditions and promote their canonical stemness properties, thus indicating the possible existence of a juxtacrine/paracrine circuit in EOC.
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Carcinoma Epitelial do Ovário/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Células-Tronco/metabolismo , Antineoplásicos/farmacologia , Carcinoma Epitelial do Ovário/genética , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/genética , Feminino , Fibroblastos/metabolismo , Células HEK293 , Humanos , Mesilato de Imatinib/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Ovarianas/genética , Comunicação Parácrina/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Isoformas de Proteínas/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-kit/química , Transdução de Sinais/genética , Fator de Células-Tronco/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
AIM: To evaluate the accuracy of magnetic resonance imaging in assessing tumor response following neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: Twenty-six patients entered a phase II study of neoadjuvant chemotherapy, undergoing bilateral breast magnetic resonance imaging before therapy and before surgery. Tumor response was classified using RECIST criteria, using tumor size at magnetic resonance imaging. The latter was then compared to residue found at histopathological examination. RESULTS: Magnetic resonance imaging showed 6 (23%) complete responses, 17 (65%) partial responses, 3 (11.5%) disease stabilizations and no disease progressions. Twenty-three tumors (88.5%) were considered responsive and 3 (11.5%) unresponsive. Pathological tumor response was: 6 complete responses (23%), 17 partial responses (65%), 2 stable disease (8%), 1 progression (4%). When results of the preoperative magnetic resonance imaging were compared to pathological tumor response, magnetic resonance imaging overestimated tumor size in 12 cases (46%) and underestimated it in 9 (35%). However, preoperative magnetic resonance imaging failed to detect invasive tumor in 2 false-negative cases (8%), 1 of which was multifocal. Mastectomy was performed in 12 cases: 1 case of disease progression even though the neoplasm appeared smaller at magnetic resonance imaging, 3 cases with stable disease, and 4 cases with T3 or T4 disease. The 9th patient was T2N2 with initial retroareolar disease and negative magnetic resonance imaging after chemotherapy. The 10th patient, affected by lobular cancer, was in partial remission but was T3N1. The 11th patient was 57 years old but was not interested in conservative surgery. The 12th patient requested bilateral prophylactic mastectomy due to her positive family history of breast cancer. CONCLUSIONS: Magnetic resonance imaging of the breast allowed conservative surgery in 54% of the patients. This low value is primarily due to overestimation of tumor size, with a negative predictive value of 67% in our population. However, surgeons were able to choose conservative surgery with relative safety in cases of small residual disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética , Terapia Neoadjuvante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Ciclofosfamida/administração & dosagem , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Imuno-Histoquímica , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , VinorelbinaRESUMO
Ovarian cancer is typically a disease of elderly women, usually occurring after menopause with a peak incidence in the eighth decade of life. Elderly patients are more likely to suffer the adverse effects of chemotherapy, which may influence successive lines of treatment. We describe the case of an elderly woman with platinum-sensitive ovarian cancer treated with several lines of chemotherapy who developed acute cardiogenic pulmonary edema with her first line of therapy, which included paclitaxel, and her fourth line containing gemcitabine. However, a complete regimen of pegylated liposomal doxorubicin in association with oxaliplatin was well tolerated. Other authors have reported absence of cardiotoxicity with liposomal doxorubicin in their study populations, but no mention was made of patients with a known prior susceptibility to transient heart failure when treated with other chemotherapeutic agents. Our case provides evidence that even in these more difficult-to-treat cases, where cumulative cardiotoxicity may be relatively unpredictable, liposomal doxorubicin does not affect cardiac function.
Assuntos
Débito Cardíaco/efeitos dos fármacos , Doxorrubicina/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/complicações , Oxaliplatina , Polietilenoglicóis/toxicidade , Edema Pulmonar/induzido quimicamenteRESUMO
Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors with a high mortality rate owing to tumor relapse after anticancer therapies. It is widely accepted that a rare tumor cell population, known as cancer stem cells (CSC), is responsible for tumor progression and relapse; intriguingly, these cells are able to survive nutrient starvation (such as in vitro culture in the absence of glucose) and chemotherapy treatment. Recent data also indicated that chemotherapy resistance is associated with autophagy activation. We thus decided to investigate both in vitro and in vivo the autophagic activity and the effects of the perturbation of this pathway in CSC isolated from EOC ascitic effusions. Ovarian CSC, identified according to their CD44/CD117 co-expression, presented a higher basal autophagy compared with the non-stem counterpart. Inhibition of this pathway, by in vitro chloroquine treatment or CRISPR/Cas9 ATG5 knockout, impaired canonical CSC properties, such as viability, the ability to form spheroidal structures in vitro, and in vivo tumorigenic potential. In addition, autophagy inhibition showed a synergistic effect with carboplatin administration on both in vitro CSC properties and in vivo tumorigenic activity. On the whole, these results indicate that the autophagy process has a key role in CSC maintenance; inhibition of this pathway in combination with other chemotherapeutic approaches could represent a novel effective strategy to overcome drug resistance and tumor recurrence.
Assuntos
Proteína 5 Relacionada à Autofagia/metabolismo , Autofagia , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Proteína 5 Relacionada à Autofagia/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
Deregulated glucose metabolism is observed in cancer but whether this metabolic trait influences response to or is modulated by cytotoxic drugs is unknown. We show here that tumor cells from epithelial ovarian cancer (EOC) patients can be categorized, according to their in vitro viability under glucose starvation, into glucose deprivation-sensitive (glucose-addicted, GA) and glucose deprivation-resistant (glucose non-addicted, GNA). When EOC cells were cultured in the absence of glucose, all samples from platinum (PLT)-sensitive patients felt into the GA group; they disclosed higher expression of glucose metabolism enzymes, higher proliferation rates and in vitro sensitivity to PLT. Moreover, GA patients showed reduced multi-drug resistance pump expression and autophagy, compared to GNA samples. The close association between PLT sensitivity and glucose metabolic profile was confirmed in a xenograft model, where a stringent parallelism between PLT sensitivity/resistance and glucose metabolism was identified. Finally, in a cohort of naïve EOC patients categorized as GA or GNA at diagnosis, Kaplan Meier curves showed that the GA phenotype was associated with significantly better progression-free survival, compared to GNA patients.
Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Glucose/deficiência , Glicólise/efeitos dos fármacos , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Animais , Carcinoma Epitelial do Ovário , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Camundongos SCID , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Our aim was to analyze the impact of intraperitoneal chemotherapy (IPC), administered with direct peritoneal puncture, on the survival of patients with pretreated ovarian cancer in a real-life setting. PATIENTS AND METHODS: This was a retrospective study comparing patients with advanced ovarian cancer treated with IPC (N=33) and patients treated with standard intravenous (i.v.) chemotherapy matching cases for known prognostic factors (age, platinum sensitivity, histological subgroup and grade). Data were then analyzed for survival with nested Cox multivariate regression. RESULTS: The case matching resulted in two homogeneous cohorts by age, platinum sensitivity, resistance to therapy and histology. When analyzed by hazard ratio (HR), the number of previous treatments and IPC vs. i.v. therapy were significant (HR=1.97 for i.v. and HR=1.90 for each incremental previous treatment line, multivariate p<0.001). When analyzing the patients with fewer than three previous treatment lines, IPC conferred a survival advantage of about 2.2 months (IPC=10.0 vs. i.v.=7.8 months, p=0.011). However, the survival advantage in heavily pre-treated patients (with three or more previous treatments) was not significant. One case, pre-treated with more lines of chemotherapy, with renal failure after intraperitoneal cisplatin was followed by death. None of the patients had bowel sub-occlusions and we recorded a lower incidence of local toxicity, such as cellulite, with IPC (two out of 33 cases). Two patients thereafter refused IPC due to abdominal pain. CONCLUSION: Our findings confirm that IPC is an effective approach compared to systemic chemotherapy for advanced ovarian cancer, even in pre-treated patients, including platinum-resistant cases. The survival benefit appears to be confined to non-heavily treated patients. Overall, direct intraperitoneal drug injection (without permanent devices) appears to be feasible, safe and possibly advantageous.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Feminino , Humanos , Infusões Parenterais , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Estudos RetrospectivosRESUMO
PURPOSE: This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy. METHODS: Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%). CONCLUSIONS: The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Dioxóis/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Compostos de Platina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Estudos Retrospectivos , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , Resultado do TratamentoRESUMO
Recurrent type I endometrial cancer (EC) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced EC treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed EC G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong (18)F-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findings--albeit limited to a single case--suggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation.