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Recently approved agents for post-vascular endothelial growth factor/post-vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors treatment of metastatic renal-cell carcinomas (mRCC), such as axitinib, nivolumab, and cabozantinib were shown to improve prognosis and substituted everolimus in this setting. We studied practice patterns, efficacy, and tolerability of these agents in a real-world series of Greek patients. We included patients with mRCC who received everolimus, axitinib, or nivolumab after progression on first-line anti-VEGF/VEGFRs therapy. Patients were stratified into three groups. Group A received nivolumab with or without cabozantinib at some point in their disease. Group B received axitinib but without nivolumab or cabozantinib. Group C received only everolimus among the four approved agents. Overall, 131 patients were included in the analysis. Everolimus and nivolumab were mainly used in the second line, while axitinib and cabozantinib were mostly used in the third and fourth lines. Median overall survival (OS) from first-line initiation was 8.7 [95% confidence interval (CI), 4-not reached], 3.6 (95% CI, 2-6), and 2.1 years (95% CI, 1.4-2.6) for Group A, B, and C, respectively ( P < 0.001). Median OS from the initiation of second-line therapy was 3.5, 2.7, and 1.3 years, respectively ( P < 0.001). There was no impact of first-line agent or treatment timing on survival. International Metastatic Renal Cell Carcinoma Database Consortium risk stratification was associated with OS. Toxicities observed were within expected frequencies. Grade ≥3 events were rare. Adoption of modern standards in everyday treatment of mRCC results in prolongation of survival. Real-world datasets are the new landmarks of survival for future research.
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Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Antineoplásicos/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Fator A de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising in the gastrointestinal tract. Their systemic treatment is based on the use of tyrosine kinase inhibitors (TKIs) with imatinib, sunitinib, and regorafenib being the preferred agents. Assessment of tumor response to TKI treatment in GISTs is traditionally done according the Response Evaluation Criteria in Solid Tumors (RECIST), while Choi criteria have also been proposed as alternative tool assessing both volumetric and density changes on computer tomography (CT) scans. EORTC STBSG 1317 'CaboGIST' was a single-arm prospective Phase 2 trial which met its primary endpoint, as 60% of patients previously treated with imatinib and sunitinib were progression-free at 12 weeks (95% CI 45-74%) based on local RECIST assessment. MATERIALS AND METHODS: We report here an exploratory analysis of local versus central RECIST version 1.1 assessment and a comparison of RECIST version 1.1 versus Choi criteria. RESULTS: Comparisons between local and central RECIST version 1.1 at week 12 revealed discrepancies in 17/43 evaluable cases (39.5%). When comparing Choi with local and central RECIST version 1.1, discrepancies were observed in 27/43 (62.8%) and 21/43 (48.8%) cases, respectively. A total of 68% of evaluable patients were progression-free and alive at week 12 based on local RECIST, 84% according to central RECIST analysis and 81% when applying Choi criteria. Central assessment upgraded the treatment response both with RECIST version 1.1 and Choi. CONCLUSIONS: The results of this exploratory analysis support the conclusion that cabozantinib is active in patients with metastatic or recurrent GIST after treatment with imatinib and sunitinib and confirm once again the limitations of RECIST to capture response to TKI in GIST, and the importance to include density changes in the response evaluation in this setting. Clinical trial number: EORTC 1317, NCT02216578.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Anilidas , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/uso terapêutico , Estudos Prospectivos , Piridinas , Sunitinibe/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: BCOR rearranged sarcomas comprise a group of malignant mesenchymal tumors that until recently were classified as Ewing sarcomas or as undifferentiated round cell sarcomas. The identification of alterations involving BCOR gene such as BCOR-CCNB3, BCOR-MAML3, ZC3H7B-BCOR fusion genes and BCOR internal tandem duplication (ITD) is characteristic for the differential diagnosis of BCOR rearranged sarcomas. Due to the rarity of these tumors there is no consensus or guidelines regarding the optimal therapeutic algorithm, that clinicians should follow. PATIENTS AND METHODS: Herein we have conducted a meta-analysis of the current reports dealing with the therapeutic approach of BCOR rearranged sarcomas. RESULTS: Meta-analysis of the 57 eligible cases from 10 studies resulted to similar Incidence Rate Ratio (IRR) and overall survival (OS) for patients who received Ewing protocols and non-Ewing oriented treatment. Further similar death rate was reported for both strategies (non-Ewing 20% Vs Ewing 21.8%). CONCLUSION: Our data support that non-Ewing treatment strategy can be considered a safe option, being at least equal to Ewing protocols. The current study provides a hint toward the optimal therapeutic approach of BCOR rearranged sarcomas. Further, the present study challenges the use of the term Ewing-like sarcomas, since the current literature supports that BCOR rearranged sarcomas deserve their own distinct classification in terms of genetics, pathology and therapy.
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Sarcoma , Neoplasias de Tecidos Moles , Biomarcadores Tumorais , Humanos , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sarcoma/tratamento farmacológico , Sarcoma/genéticaRESUMO
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1-2% of gastrointestinal neoplasms. About 75-80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5-10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10-15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).
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Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genéticaRESUMO
Neoadjuvant Chemotherapy (NACT) followed by Interval Debulking Surgery (IDS) is an accepted frontline treatment in patients with advanced Epithelial Ovarian Cancer (EOC). Histopathologic assessment of tumor post NACT may provide a surrogate for response to treatment. The present study aims to characterize the pathological response and to examine its prognostic significance in these patients. Medical records of women with EOC treated in our institution from 2011 to 2016 were retrospectively identified. IDS specimens were reviewed by study pathologist and Chemotherapy Response Score (CRS), lymphocytic infiltration, necrosis and mitosis were assessed. 55 patients with EOC treated with NACT were identified and 48 had complete clinical and pathological data. Median age was 63 years. CRS assessed at omentum predicted PFS when adjusted for age, stage, debulking status (complete, optimal, suboptimal) and post IDS bevacizumab administration (mPFS CRS 1 vs 2 vs 3: 10.3-14-18.7 months 95% CI [7.4-15.7], [12.2-22.9], [13.5-31.3]). Presence of lymphocytic infiltration was associated with improved OS (log-rank test P = 0.015). Post IDS bevacizumab was associated with shorter PFS in patients with lymphocytic infiltration. BRCA status was known for 25 patients and presence of BRCA1/2 mutations was strongly correlated with lymphocytic infiltration (P = 0.011) but not CRS omentum (P = 0.926). Our study confirms the predictive value of CRS in EOC patients treated with NACT and IDS, but also demonstrates the prognostic significance of lymphocytic infiltration as well as its possible interaction with bevacizumab treatment.
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Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linfócitos/metabolismo , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , PrognósticoRESUMO
BACKGROUND: Uterine sarcomas consist a heterogeneous group of mesenchymal gynecological malignancies with unclear therapeutic recommendations and unspecific but poor prognosis, since they usually metastasize and tend to recur very often, even in early stages. METHODS: We retrospectively analyzed all female patients with uterine sarcomas treated in our institution over the last 17 years. Clinico-pathological data, treatments and outcomes were recorded. Kaplan-Meier curves were plotted and time-to-event analyses were estimated using Cox regression. RESULTS: Data were retrieved from 61 women with a median age of 53 (range: 27-78) years, at diagnosis. Fifty-one patients were diagnosed with leiomyosarcoma (LMS), 3 with high grade endometrial stromal sarcoma (ESS), 5 with undifferentiated uterine sarcoma (UUS), 1 with Ewing sarcoma (ES) and 1 with Rhabdomyosarcoma (RS). 24 cases had stage I, 7 stage II, 14 stage III and 16 stage IV disease. Median disease-free survival (DFS) in adjuvant approach was 18.83 months, and median overall survival (OS) 31.07 months. High mitotic count (> 15 mitoses) was significantly associated with worse OS (P < 0.001) and worse DFS (P = 0.028). CONCLUSIONS: Mitotic count appears to be independent prognostic factor while further insights are needed to improve adjuvant and palliative treatment of uterine sarcomas.
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Gerenciamento Clínico , Rabdomiossarcoma/diagnóstico , Sarcoma do Estroma Endometrial/diagnóstico , Sarcoma de Ewing/diagnóstico , Adulto , Idoso , Feminino , Grécia/epidemiologia , Humanos , Pessoa de Meia-Idade , Índice Mitótico/métodos , Índice Mitótico/tendências , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/epidemiologia , Rabdomiossarcoma/terapia , Sarcoma do Estroma Endometrial/epidemiologia , Sarcoma do Estroma Endometrial/terapia , Sarcoma de Ewing/epidemiologia , Sarcoma de Ewing/terapiaRESUMO
BACKGROUND/AIM: Uterine leiomyosarcomas (uLMS) are the most common mesenchymal tumors of the female genital tract. uLMS genetics encompass complex karyotypes with no specific molecular alterations. The Hippo pathway has been implicated in the pathogenesis of epithelioid hemangio-endotheliomas and endometrial sarcomas. Hippo pathway effectors are YAP1 and TAZ co-transcriptional factors. PATIENTS AND METHODS: We studied Hippo pathway in a series of 32 uLMS patients and its association with clinicopathological parameters. MATERIALS AND METHODS: Immunohistochemical analysis of YAP1 and TAZ proteins accompanied with fluorescent in situ hybridization study of YAP1 gene was performed in patient samples. Age, sex, tumor size, stage at the time of diagnosis and treatment have been analyzed. Overall survival (OS) was calculated from the time of diagnosis until death, loss of follow up or data cut-off. RESULTS: Hippo signaling was found to be dysregulated in 20 (62.5%) patients with uLMS. Regarding OS we detected a trend of Hippo deregulation, designating it as a positive prognostic factor. CONCLUSION: The Hippo pathway is implicated in uLMS oncogenesis, since nuclear expression of YAP1 was detected in 17 (53.1%) of the 32 patients with immunohistochemistry and YAP1 amplification was found in 8 (25%) patients.
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Proteínas Adaptadoras de Transdução de Sinal , Via de Sinalização Hippo , Leiomiossarcoma , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Fatores de Transcrição , Neoplasias Uterinas , Proteínas de Sinalização YAP , Humanos , Feminino , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Leiomiossarcoma/metabolismo , Neoplasias Uterinas/patologia , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/genética , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Idoso , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Prognóstico , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Regulação Neoplásica da Expressão Gênica , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Background/Aim: Ewing sarcoma is an aggressive mesenchymal malignancy commonly affecting children and young adolescents. The molecular basis of this neoplasia is well reported with the formation of the EWSR1/FLI1 fusion gene being the most common genetic finding. However, this fusion gene has not been targeted therapeutically nor is being used as a prognostic marker. Its relevance regarding the molecular steps leading to Ewing sarcoma genesis are yet to be defined. The generation of the oncogenic EWSR1/FLI1 fusion gene, can be attributed to the simultaneous introduction of two DNA double-strand breaks (DSBs). The scope of this study is to detect any association between DNA repair deficiency and the clinicopathological aspects of Ewing's sarcoma disease. Patients and Methods: We have conducted an expression analysis of 35 patients diagnosed with Ewing sarcoma concerning the genes involved in non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. We have analyzed the expression levels of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLµ) and 9 genes involved in HR (RAD51, RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) using real time PCR. Age, sex, location of primary tumor, tumor size, KI67, mitotic count, invasion of adjacent tissues and treatment were the clinicopathological parameters included in the statistical analysis. Results: Our results show that both these DNA repair pathways are deregulated in Ewing sarcoma. In addition, low expression of the xrcc4 gene has been associated with better overall survival probability (p=0.032). Conclusion: Our results, even though retrospective and in a small number of patients, highlight the importance of DSBs repair and propose a potential therapeutic target for this type of sarcoma.
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Precise classification of sarcomas is crucial to optimal clinical management. In this prospective, multicenter, observational study within the Hellenic Group of Sarcoma and Rare Cancers (HGSRC), we assessed the effect of expert pathology review, coupled with the application of molecular diagnostics, on the diagnosis and management of sarcoma patients. Newly diagnosed sarcoma patients were addressed by their physicians to one of the two sarcoma pathologists of HGSRC for histopathological diagnostic assessment. RNA next-generation sequencing was performed on all samples using a platform targeting 86 sarcoma gene fusions. Additional molecular methods were performed in the opinion of the expert pathologist. Therefore, the expert pathologist provided a final diagnosis based on the histopathological findings and, when necessary, molecular tests. In total, 128 specimens from 122 patients were assessed. Among the 119 cases in which there was a preliminary diagnosis by a non-sarcoma pathologist, there were 37 modifications in diagnosis (31.1%) by the sarcoma pathologist, resulting in 17 (14.2%) modifications in management. Among the 110 cases in which molecular tests were performed, there were 29 modifications in diagnosis (26.4%) through the genomic results, resulting in 12 (10.9%) modifications in management. Our study confirms that expert pathology review is of utmost importance for optimal sarcoma diagnosis and management and should be assisted by molecular methods in selected cases.
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Cutaneous sarcomas comprise a broad group of rare, heterogeneous mesenchymal tumours. The present report describes a single centre experience regarding the management and the outcomes of patients with superficial soft tissue sarcomas (SSTS). Key prognostic factors in predicting overall survival (OS) and local relapse-free survival were determined. Data from 66 patients with SSTS treated surgically within Edinburgh and Lothian were collected in the context of a service evaluation. Patient demographics, tumour specifics and treatment, as well as 5-year OS and local recurrence, were analysed. Kaplan-Meier analysis was applied for survival curves, and mortality rate estimation and Cox regression were used to establish independent predictors. The mean estimated OS time was 57.2 months, with a 95% CI between 55.0 and 59.5 months. The median OS time could not be estimated because there is no time point during which the survival function has a value <50%. The death risk for a person with SSTS was increased by 7.3% (odds ratio, 1.073; 95% CI, 1.012-1.138) for every additional year of life. The estimated mean local relapse time was 58.5 months, with a 95% CI between 56 and 61 months. The median local relapse time could not be estimated since there is no time point during which the local recurrence function has a value <50%. In conclusion, out of all independent variables considered, none could statistically significantly explicate local relapse recurrence time. It is important that these rare tumours are treated in the context of a multidisciplinary team with consensus guidelines to assist decision-making.
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INTRODUCTION: Clear cell sarcoma (CCS) is an ultrarare soft tissue sarcoma (STS) with a poor prognosis due to its propensity to metastasize and its low chemosensitivity. The standard treatment of localized CCS consists of wide surgical excision with or without additive radiotherapy. However, unresectable CCS is generally treated with conventional systemic therapies available for treatment of STS despite the weak scientific evidence to support its use. AREAS COVERED: In this review, we discuss the clinicopathologic characteristics of CSS, as well as the current treatment landscape and future therapeutic approaches. EXPERT OPINION: The current treatment strategy of advanced CCSs, based on STSs regimens, shows a lack of effective options. Combination therapiesin particular, the association of immunotherapy and TKIs, represent a promising approach. Translational studies are needed in order to decipher the regulatory mechanisms involved in the oncogenesis of this ultrarare sarcoma and identify potential molecular targets.
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Sarcoma de Células Claras , Neoplasias de Tecidos Moles , Humanos , Sarcoma de Células Claras/terapia , Imunoterapia , Neoplasias de Tecidos Moles/tratamento farmacológicoRESUMO
Advanced osteosarcomas (OSs) and Ewing sarcomas (ESs) tend to have poor prognosis with limited therapeutic options beyond first-line therapy. Aberrant angiogenesis and MET signaling play an important role in preclinical models. The anti-angiogenic drug cabozantinib was tested in a phase 2 trial of advanced OS and ES and was associated with clinical benefits. We retrospectively analyzed the off-label use of cabozantinib in adult patients with advanced OS and ES/primitive neuroectodermal tumors (PNETs) in three centers of the Hellenic Group of Sarcoma and Rare Cancers (HGSRC). Between April 2019 and January 2022, 16 patients started taking 60 mg of cabozantinib for advanced bone sarcoma or PNET. Median age at cabozantinib initiation was 31 years (17-83). All patients had received peri-operative chemotherapy for primary sarcoma and between 0 and 4 lines of treatment (median; 2.5) for advanced disease. The most common adverse effects included fatigue, anorexia, hypertransaminasemia, weight loss, and diarrhea. One toxic death was noted (cerebral hemorrhage). Dose reduction to 40 mg was required in 31.3% of the patients. No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) months. Our study demonstrates that cabozantinib has antitumor activity in this population. In the real-life setting, we observed similar adverse events as in the CABONE study and in other neoplasms.
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OBJECTIVES: The aim of this pilot study was to evaluate the presence of somatic mutations in matched tumor and circulating DNA (ctDNA) samples from patients with primary head and neck squamous cell carcinoma (HNSCC) and assess the association of changes in ctDNA levels with survival. MATERIALS AND METHODS: Our study included 62 patients with stage I-IVB HNSCC treated with surgery or radical chemoradiotherapy with curative intent. Plasma samples were obtained at baseline, at the end of treatment (EOT), and at disease progression. Tumor DNA was extracted from plasma (ctDNA) and tumor tissue (tDNA). The Safe Sequencing System was used assess the presence of pathogenic variants in four genes (TP53, CDKN2A, HRAS and PI3KCA) in both ctDNA and tDNA. RESULTS: Forty-five patients had available tissue and plasma samples. Concordance of genotyping results between tDNA and ctDNA at baseline was 53.3%. TP53 mutations were most commonly identified at baseline in both ctDNA (32.6%) and tDNA (40%). The presence of mutations in this restricted set of 4 genes in tissue samples at baseline was associated with decreased overall survival (OS) [median 58.3 months for patients with mutations vs. 89 months for patients without mutations, p < 0.013]. Similarly, patients presenting with mutations in ctDNA had shorter OS [median 53.8 vs. 78.6 months, p < 0.037]. CtDNA clearance at EOT did not show any association with PFS or OS. CONCLUSIONS: Liquid biopsy enables real-time molecular characterization of HNSCC and might predict survival. Larger studies are needed to validate the utility of ctDNA as a biomarker in HNSCC.
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Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Humanos , DNA Tumoral Circulante/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias Pulmonares/genética , Projetos Piloto , Mutação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Biomarcadores Tumorais/genéticaRESUMO
We present two patient cases (one with bladder carcinoma and one with renal cell carcinoma) who consulted our department of General Medical Oncology, after having been treated in other hospitals in two clinical trials with immune checkpoint inhibitors and having been dismissed from the trials after 5 months of therapy for progressive disease. They consulted to discuss consecutive treatment opportunities. However, longer follow-up has shown that both patients were dismissed equivocally from both trials. We are worried that equivocal response evaluation in the context of clinical trials with immune checkpoint inhibitors, due to pseudo-progression or delayed responses, can negatively impact trial outcomes as well as biomarker research.
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Carcinoma de Células Renais , Neoplasias Renais , Neoplasias da Bexiga Urinária , Biomarcadores , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Renais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Myxoid spindle cell sarcoma is a rare sarcoma with a demanding histopathologic diagnosis due to the absence of pathognomic immunohistochemistry markers. Genetics include complex karyotypic alterations without characteristic molecular abnormalities for this entity. NTRK alterations are rare findings with great clinical importance since they can be therapeutically targeted with two NTRK inhibitors. Herein we present a case of an adult unclassified myxoid spindle cell sarcoma with ETV6/NTRK3 fusion gene, which is a molecular finding characteristic for infantile fibrosarcoma.
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Fibrossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Adulto , Humanos , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fibrossarcoma/genética , Fibrossarcoma/diagnóstico , Fibrossarcoma/patologia , Imuno-Histoquímica , Proteínas de Fusão Oncogênica/genéticaRESUMO
Background: Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers, while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations. Beyond these mutations, germline or somatic aberrations in genes of the homologous recombination (HR) pathway such as RAD51B/C/D, PALB2, ATM, BRIP1 may confer an HR deficiency in up to 50% of ovarian tumors. Next-generation sequencing (NGS) is a high-throughput massive parallel sequencing method that enables the simultaneous detection of several mutations in entire genomes. Methods: We performed NGS analysis in 86 patients with ovarian cancer treated in the Oncology Department of Alexandra University Hospital in order to identify the molecular landscape of germline and somatic mutations in ovarian cancer. Results: The genes with the highest number of pathogenic somatic mutations in high grade serous carcinoma (HGSC) patients were TP53 [68%; 34/50] and BRCA1 [22%; 11/50] followed by somatic mutations in RB1 [2%; 1/50], NF1 [2%; 1/50], BRCA2 [2%; 1/50], AKT1 [2%; 1/50], RAD50 [2%; 1/50], PIK3CA [2%; 1/50] genes. Of note, the most common TP53 genetic polymorphism was c.524G>A p.Arg175His in exon 5. Variants of unknown significance (VUS) detected in HGSC included ROS1 [26%; 13/50], RAD50 [6%; 3/50], BRCA2 [6%; 3/50], NOTCH1 [6%; 3/50], TP53 [6%; 3/50], AR [6%; 3/50]. As for germline mutations, BRCA1 [8/30; 27%] and BRCA2 [4/30; 13%] were the most common genes bearing pathogenic alterations in HGSC, while VUS germline mutations commonly affected HRR-related genes, including ATM (c.7816A>G), BRIP (c.2327 C>A), CHEK2 (c.320-5T>A). Conclusion: Overall, genetic testing should be offered in most patients with ovarian cancer to identify mutations in HRR genes and determine the population that would be susceptible to poly ADP ribose polymerase (PARP) inhibitors.
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BACKGROUND/AIM: The Hippo pathway is a molecular pathway recently associated with tumorigenesis, metastasis, and drug resistance. Pregnancy-associated breast cancer (PABC) is the most common malignancy diagnosed during gestation; however, the molecular mechanisms underlying PABC are largely unknown. The aim of the present study was to evaluate Hippo pathway transducers TAZ and YAP1 expression in PABC in relation to the clinicopathological characteristics of the disease. PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues from 21 PABC patients treated at Alexandra Hospital in Athens, Greece, were analyzed with immunohistochemistry. RESULTS: Strong nuclear TAZ/YAP1 stanning was found in 48% of the PABC patients analyzed. Hormone receptor negative patients had a statistically significant correlation with strong positive expression of TAZ/YAP1 co-transcription factors. No association was observed with overall and disease-free survival. CONCLUSION: The Hippo pathway is de-regulated in a subset of PABC patients, highlighting the complex molecular background of the disease, which certainly requires further investigation.
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Proteínas Adaptadoras de Transdução de Sinal , Neoplasias da Mama , Gravidez , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transativadores , Transdução de Sinais , Neoplasias da Mama/genética , Proteínas de Sinalização YAP , Carcinogênese/genética , Transformação Celular NeoplásicaRESUMO
Introduction: The clinical outcome of HER2-positive breast cancer patients changed with the use of anti-Her therapies, though it still remains an aggressive and fatal disease. Implementation of immune checkpoint inhibitors in HER2-positive Breast cancer is a concept supported by the reported biological and preclinical data. Methods: We conducted a systematic review of the current literature involving immune checkpoint inhibitors alone or in combination with targeted therapies or chemotherapy finalized or running in HER2-positive breast cancer. Results: Twelve clinical trials and 2 case reports were identified in our study. Conclusion: The reported clinical trials highlight that checkpoint inhibition seems to be promising in metastatic, neoadjuvant, and adjuvant settings of HER2-positive breast cancer.
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Background: Joint manifestations are ill-defined adverse events that were frequently reported of bevacizumab in ovarian cancer patients. The aim of this study is to describe the incidence and severity of joint manifestations among bevacizumab treated patients as well as their relation to clinical outcomes. Methods: Medical charts of all ovarian cancer patients that received bevacizumab from 2012 through 2017 were reviewed. Joint manifestations were staged. Kaplan-Meier Survival curves were generated; survival differences were estimated. Results: 76 Patients diagnosed with stage III or IV ovarian cancer were included. 23 patients (30.3%) developed joint manifestations, 12 of them had Grade I, 4 Grade II and 7 Grade III. Only 3 patients developed arthritis. In 8 cases (34.8%) one joint was affected and in the remaining 15, multiple sites. Median number of bevacizumab cycles to arthralgia development was 7. 3 patients were managed with corticosteroids or methotrexate, all had grade 3 AEs. The remaining received common analgesics. Median duration of the AE was 4.8 months. 7 patients discontinued bevacizumab due to AE. In all but 3 patients AE was finally resolved. Median number of bevacizumab cycles received, frequency of treatment completion or treatment discontinuation due to disease progression did not differ significantly among patients that developed joint manifestations or not. Median PFS and median OS did not differ statistical significantly. Conclusion: Joint manifestations are common AEs in bevacizumab treated ovarian cancer patients and led to treatment discontinuation in 9% of the patients. However, this has not adversely affected the clinical outcome of the patients. Further research is needed for the appropriate management of these patients.
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Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.