P73 antisense RNA 1 T (non-protein coding), also known as TP73-AS1, is a long non-coding RNA (lncRNA) which is involved in cell proliferation and the development of tumors. However, the exact effects and molec...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 11 Απριλίου 2017
The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation
The role of microRNA-93 regulating angiopoietin2 in the formation of malignant pleural effusion
Abstract
The biological roles of miRNAs in the development of malignant pleural effusion (MPE) are unclear. In this study, the miRNA microarray analysis was performed in two different prognosis groups of lung adenocarcinoma patients. Expression profiles of miRNAs in MPEs were identified. With the help of quantification PCR, we confirmed the expression differences of miRNAs and further analyzed their biological functions and relative target genes in vitro. The target gene of miR-93 was estimated by online database, and also, the protein was tested. The target gene and the binding sites of specific miRNA were estimated by online database. The combining capacity of binding sites was verified by luciferase reporter gene assay, and the target gene protein was tested by western blot. We detected 107 miRNAs with expression differences (n = 10) and confirmed significant expression differences in miR-93 and miR-146a in two groups of patients (n = 84). By manipulating miR-93 expression of human lymphatic endothelial cells (HLEC) and human umbilical vein endothelial cells (HUVEC), we discovered that high expression of miR-93 inhibited migration, proliferation, and angiogenesis. And also, miR-93 increased not only apoptosis, but also G1 phase cell block. By using luciferase reporter gene assay and western blot, we confirmed that angiopoietin2 (Ang2) was the target of miR-93. The data showed that miR-93 has an inhibiting effect on pleural effusion. By targeting Ang2, miR-93 regulates angiogenesis and lymphangiogenesis and plays a role in pathogenetic mechanism of MPE. MiR-93/Ang2 may shed light on potential new targets in cancer treatment.
The study identified that miR-93 has an inhibiting effect on pleural effusion. By targeting angiopoietin2, miR-93 regulates angiogenesis and lymphangiogenesis so as to play a role in pathogenetic mechanism of malignant pleural effusion. MiR-93/Ang2 may shed light on potential new targets in the cancer treatment.
http://ift.tt/2ps0xf8
The role of microRNA-93 regulating angiopoietin2 in the formation of malignant pleural effusion
Abstract
The biological roles of miRNAs in the development of malignant pleural effusion (MPE) are unclear. In this study, the miRNA microarray analysis was performed in two different prognosis groups of lung adenocarcinoma patients. Expression profiles of miRNAs in MPEs were identified. With the help of quantification PCR, we confirmed the expression differences of miRNAs and further analyzed their biological functions and relative target genes in vitro. The target gene of miR-93 was estimated by online database, and also, the protein was tested. The target gene and the binding sites of specific miRNA were estimated by online database. The combining capacity of binding sites was verified by luciferase reporter gene assay, and the target gene protein was tested by western blot. We detected 107 miRNAs with expression differences (n = 10) and confirmed significant expression differences in miR-93 and miR-146a in two groups of patients (n = 84). By manipulating miR-93 expression of human lymphatic endothelial cells (HLEC) and human umbilical vein endothelial cells (HUVEC), we discovered that high expression of miR-93 inhibited migration, proliferation, and angiogenesis. And also, miR-93 increased not only apoptosis, but also G1 phase cell block. By using luciferase reporter gene assay and western blot, we confirmed that angiopoietin2 (Ang2) was the target of miR-93. The data showed that miR-93 has an inhibiting effect on pleural effusion. By targeting Ang2, miR-93 regulates angiogenesis and lymphangiogenesis and plays a role in pathogenetic mechanism of MPE. MiR-93/Ang2 may shed light on potential new targets in cancer treatment.
The study identified that miR-93 has an inhibiting effect on pleural effusion. By targeting angiopoietin2, miR-93 regulates angiogenesis and lymphangiogenesis so as to play a role in pathogenetic mechanism of malignant pleural effusion. MiR-93/Ang2 may shed light on potential new targets in the cancer treatment.
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Dietary Supplement Use in Older Adults
Abstract
Purpose of Review
Dietary supplement (DS) use among older adults in the USA is prevalent, and thus, healthcare professionals need to be aware of how to best advise this population. The purpose of this review is to highlight key considerations for assessing the potential benefits and risks of supplementation and for evaluating the quality, safety, and efficacy of supplement use specific to older adults.
Recent Findings
Nutrient deficiencies and risk of malnutrition among older adults can result from decreased appetite with aging, poor dietary intake, and nutrient depletions from medications (among many other factors). Nutrient deficiencies are common in this population and could have a negative impact on neurological and cardiovascular health, mood, immune function, vision, blood sugar control, and bone strength. In certain circumstances, older adults may benefit from supplementation. However, risk of choking and concomitant use of DS and prescription medications (which can increase risk of drug-nutrient interactions) are concerns with supplementation.
Summary
Decision-making around appropriateness of supplementation for older adults should be determined by nutrition screening and based on individual need. Healthcare providers, especially registered dietitian nutritionists (RDNs), should work with patients to identify quality products and benefits/risks of supplement use.
http://ift.tt/2prR0ox
Considerations When Using Predictive Equations to Estimate Energy Needs Among Older, Hospitalized Patients: A Narrative Review
Abstract
Purpose of Review
The aim of this narrative review was to summarize the accuracy of predictive equations used to estimate energy expenditure in older, hospitalized adults.
Recent Findings
More than 50% of patients admitted to intensive care units are older adults. Currently accepted prediction equations used to determine energy intake in the older, hospitalized patient were not specifically developed for the aging population. Rates of multimorbidity, polypharmacy, and malnutrition, conditions that influence energy expenditure, are higher in older adults compared to younger adults.
Summary
For these reasons, current equations may not accurately assess energy needs in this population. As the evidence demonstrating the importance of nutritional supplementation in older, hospitalized adults grows, more accurate energy assessment methods that account for age-related conditions are needed to predict nutritional requirements.
http://ift.tt/2nCKZZI
Dietary Supplement Use in Older Adults
Abstract
Purpose of Review
Dietary supplement (DS) use among older adults in the USA is prevalent, and thus, healthcare professionals need to be aware of how to best advise this population. The purpose of this review is to highlight key considerations for assessing the potential benefits and risks of supplementation and for evaluating the quality, safety, and efficacy of supplement use specific to older adults.
Recent Findings
Nutrient deficiencies and risk of malnutrition among older adults can result from decreased appetite with aging, poor dietary intake, and nutrient depletions from medications (among many other factors). Nutrient deficiencies are common in this population and could have a negative impact on neurological and cardiovascular health, mood, immune function, vision, blood sugar control, and bone strength. In certain circumstances, older adults may benefit from supplementation. However, risk of choking and concomitant use of DS and prescription medications (which can increase risk of drug-nutrient interactions) are concerns with supplementation.
Summary
Decision-making around appropriateness of supplementation for older adults should be determined by nutrition screening and based on individual need. Healthcare providers, especially registered dietitian nutritionists (RDNs), should work with patients to identify quality products and benefits/risks of supplement use.
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Considerations When Using Predictive Equations to Estimate Energy Needs Among Older, Hospitalized Patients: A Narrative Review
Abstract
Purpose of Review
The aim of this narrative review was to summarize the accuracy of predictive equations used to estimate energy expenditure in older, hospitalized adults.
Recent Findings
More than 50% of patients admitted to intensive care units are older adults. Currently accepted prediction equations used to determine energy intake in the older, hospitalized patient were not specifically developed for the aging population. Rates of multimorbidity, polypharmacy, and malnutrition, conditions that influence energy expenditure, are higher in older adults compared to younger adults.
Summary
For these reasons, current equations may not accurately assess energy needs in this population. As the evidence demonstrating the importance of nutritional supplementation in older, hospitalized adults grows, more accurate energy assessment methods that account for age-related conditions are needed to predict nutritional requirements.
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GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.
http://ift.tt/2prIRjZ
IL-4 primes the dynamics of breast cancer progression via DUSP4 inhibition
The tumor microenvironment supplies pro-inflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL-4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL-4 signaling with the IL-4Rα antagonist IL-4DM compromised breast cancer cell proliferation, invasion and tumor growth by downregulating MAPK pathway activity. IL-4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-kB. Enforced expression of DUSP4 drove conversion of metastatic cells to non-metastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties and spawned metastastic capacity. Targeting IL-4 signaling sensitized breast cancer cells to anti-cancer therapy and strengthened immune responses by enhancing the number of IFN-γ-positive cytotoxic T lymphocytes. Our results showed the role of IL-4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies.
http://ift.tt/2p3Tj4u
An ex vivo platform for the prediction of clinical response in multiple myeloma.
Multiple myeloma (MM) remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, EMMA (Ex vivo Mathematical Myeloma Advisor), consisting of patient-specific mathematical models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of chemosensitivity of primary cells from MM patients, allowing us to predict clinical response to up to 31 drugs within 5 days post-bone marrow biopsy. From a cohort of 52 MM patients, EMMA correctly classified 96% as responders/non-responders and correctly classified 79% according to IMWG stratification of level of response. We also observed a significant correlation between predicted and actual tumor burden measurements (Pearson r=0.5658, P<0.0001). Preliminary estimates indicate that, among the patients enrolled in this study, 60% were treated with at least one ineffective agent from their therapy combination regimen, while 30% would have responded better if treated with another available drug or combination. Two in silico clinical trials with experimental agents ricolinostat and venetoclax, in a cohort of 19 MM patient samples, yielded consistent results with recent phase I/II trials, suggesting that EMMA is a feasible platform for estimating clinical efficacy of drugs and inclusion criteria screening. This unique platform, specifically designed to predict therapeutic response in MM patients within a clinically actionable time frame, has shown high predictive accuracy in patients treated with combinations of different classes of drugs. The accuracy, reproducibility, short turnaround time and high-throughput potential of this platform demonstrates EMMA's promise as a decision support system for therapeutic management of MM.
http://ift.tt/2prMypH
GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.
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IL-4 primes the dynamics of breast cancer progression via DUSP4 inhibition
The tumor microenvironment supplies pro-inflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL-4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL-4 signaling with the IL-4Rα antagonist IL-4DM compromised breast cancer cell proliferation, invasion and tumor growth by downregulating MAPK pathway activity. IL-4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-kB. Enforced expression of DUSP4 drove conversion of metastatic cells to non-metastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties and spawned metastastic capacity. Targeting IL-4 signaling sensitized breast cancer cells to anti-cancer therapy and strengthened immune responses by enhancing the number of IFN-γ-positive cytotoxic T lymphocytes. Our results showed the role of IL-4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies.
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An ex vivo platform for the prediction of clinical response in multiple myeloma.
Multiple myeloma (MM) remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, EMMA (Ex vivo Mathematical Myeloma Advisor), consisting of patient-specific mathematical models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of chemosensitivity of primary cells from MM patients, allowing us to predict clinical response to up to 31 drugs within 5 days post-bone marrow biopsy. From a cohort of 52 MM patients, EMMA correctly classified 96% as responders/non-responders and correctly classified 79% according to IMWG stratification of level of response. We also observed a significant correlation between predicted and actual tumor burden measurements (Pearson r=0.5658, P<0.0001). Preliminary estimates indicate that, among the patients enrolled in this study, 60% were treated with at least one ineffective agent from their therapy combination regimen, while 30% would have responded better if treated with another available drug or combination. Two in silico clinical trials with experimental agents ricolinostat and venetoclax, in a cohort of 19 MM patient samples, yielded consistent results with recent phase I/II trials, suggesting that EMMA is a feasible platform for estimating clinical efficacy of drugs and inclusion criteria screening. This unique platform, specifically designed to predict therapeutic response in MM patients within a clinically actionable time frame, has shown high predictive accuracy in patients treated with combinations of different classes of drugs. The accuracy, reproducibility, short turnaround time and high-throughput potential of this platform demonstrates EMMA's promise as a decision support system for therapeutic management of MM.
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Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer
Purpose: Head and neck cancers (HNC) often induce profound immunosuppression which contributes to disease progression and interferes with immune-based therapies. Body fluids of HNC patients are enriched in exosomes potentially engaged in negative regulation of anti-tumor immune responses. The presence and content of exosomes derived from plasma of HNC patients are evaluated for the ability to induce immune dysfunction and influence disease activity. <p>Experimental Design: Exosomes were isolated by size-exclusion chromatography from plasma of 38 HNC patients and 14 healthy donors. Morphology, size, numbers and protein and molecular contents of the recovered exosomes were determined. Co-culture assays were performed to measure exosome-mediated effects on functions of normal human lymphocyte subsets and natural killer (NK) cells. The results were correlated with disease stage and activity.</p> <p>Results: The presence, quantity and molecular content of isolated, plasma-derived exosomes discriminated HNC patients with active disease (AD) from those with no evident disease (NED) after oncological therapies. Exosomes of patients with AD were significantly more effective than exosomes of patients with NED in inducing apoptosis of CD8+ T cells, suppression of CD4+ T cell proliferation and up-regulation of regulatory T cell (Treg) suppressor functions (all at p < 0.05). Exosomes of AD patients also down-regulated NKG2D expression levels in NK cells.</p> Conclusions: Exosomes in plasma of HNC patients carry immunosuppressive molecules and interfere with functions of immune cells. Exosome-induced immune suppression correlates with disease activity in HNC, suggesting that plasma exosomes could be useful as biomarkers of HNC progression.
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Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features
PURPOSE. To reconcile the heterogeneity of thymic epithelial tumors (TETs) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. <p>EXPERIMENTAL DESIGN. Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.</p> <p>RESULTS. Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild type tumors and represented TETs enriched in expression of genes associated with T cell signaling (TS group; 33%). The remaining 2 groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.</p> <p>CONCLUSIONS. Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging, and in discovery and development of rational treatment options for patients with TETs.
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Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. <p>Experimental design: We evaluated under blinded conditions the ability of cell free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results: Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.</p> <p>Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.
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A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High Risk Bladder Cancer Patients
Purpose: Hypoxia modification improves overall survival in muscle invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.<br /><br />Experimental Design: Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation. <br /><br />Results: A 24-gene signature was derived, which was prognostic in four out of six independent surgical cohorts (n=679, meta HR 2·32, 95% CI 1·73-3·12, P<0·0001). The signature was also prognostic in BCON patients receiving radiotherapy alone (n=75, HR for local relapse free survival 2·37, 95% CI 1·26-4·47, P=0·0076). The signature predicted benefit from CON (n=76, HR 0·47, 95% CI 0·26-0·86, P=0·015). Prognostic (P=0·017) and predictive (P=0·058) significance remained after adjusting for clinicopathological variables. A test for interaction between hypoxia status and treatment arms was significant (P=0·0094).<br /><br />Conclusions: A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy.
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Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer
Purpose: Head and neck cancers (HNC) often induce profound immunosuppression which contributes to disease progression and interferes with immune-based therapies. Body fluids of HNC patients are enriched in exosomes potentially engaged in negative regulation of anti-tumor immune responses. The presence and content of exosomes derived from plasma of HNC patients are evaluated for the ability to induce immune dysfunction and influence disease activity. <p>Experimental Design: Exosomes were isolated by size-exclusion chromatography from plasma of 38 HNC patients and 14 healthy donors. Morphology, size, numbers and protein and molecular contents of the recovered exosomes were determined. Co-culture assays were performed to measure exosome-mediated effects on functions of normal human lymphocyte subsets and natural killer (NK) cells. The results were correlated with disease stage and activity.</p> <p>Results: The presence, quantity and molecular content of isolated, plasma-derived exosomes discriminated HNC patients with active disease (AD) from those with no evident disease (NED) after oncological therapies. Exosomes of patients with AD were significantly more effective than exosomes of patients with NED in inducing apoptosis of CD8+ T cells, suppression of CD4+ T cell proliferation and up-regulation of regulatory T cell (Treg) suppressor functions (all at p < 0.05). Exosomes of AD patients also down-regulated NKG2D expression levels in NK cells.</p> Conclusions: Exosomes in plasma of HNC patients carry immunosuppressive molecules and interfere with functions of immune cells. Exosome-induced immune suppression correlates with disease activity in HNC, suggesting that plasma exosomes could be useful as biomarkers of HNC progression.
http://ift.tt/2p3Nhkg
Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features
PURPOSE. To reconcile the heterogeneity of thymic epithelial tumors (TETs) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. <p>EXPERIMENTAL DESIGN. Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.</p> <p>RESULTS. Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild type tumors and represented TETs enriched in expression of genes associated with T cell signaling (TS group; 33%). The remaining 2 groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.</p> <p>CONCLUSIONS. Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging, and in discovery and development of rational treatment options for patients with TETs.
http://ift.tt/2p5Rj8Z
Circulating DNA demonstrates convergent evolution and common resistance mechanisms during treatment of colorectal cancer
Purpose: Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment. <p>Experimental design: We evaluated under blinded conditions the ability of cell free DNA (cfDNA) to detect RAS/BRAF mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab. Results: Prior to treatment, sequencing of archival tissue detected mutations in 25/42 patients (60%), while the cfDNA assay detected mutations in 37/42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41/42 patients (98%) had a cfDNA detected RAS/BRAF mutation. Of 21 patients followed with serial measurements who were RAS/BRAF mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of RAS/BRAF wild type tumors at baseline, 4/5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.</p> <p>Conclusions: Our findings demonstrate the development of new RAS/BRAF mutations in patients regardless of whether they had pre-existing mutations in the pathway, demonstrating a convergent evolutionary pattern.
http://ift.tt/2p3yk1G
A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High Risk Bladder Cancer Patients
Purpose: Hypoxia modification improves overall survival in muscle invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.<br /><br />Experimental Design: Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation. <br /><br />Results: A 24-gene signature was derived, which was prognostic in four out of six independent surgical cohorts (n=679, meta HR 2·32, 95% CI 1·73-3·12, P<0·0001). The signature was also prognostic in BCON patients receiving radiotherapy alone (n=75, HR for local relapse free survival 2·37, 95% CI 1·26-4·47, P=0·0076). The signature predicted benefit from CON (n=76, HR 0·47, 95% CI 0·26-0·86, P=0·015). Prognostic (P=0·017) and predictive (P=0·058) significance remained after adjusting for clinicopathological variables. A test for interaction between hypoxia status and treatment arms was significant (P=0·0094).<br /><br />Conclusions: A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy.
http://ift.tt/2p5RIs8
Changing face of metastatic prostate cancer: the law of diminishing returns holds true
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How to evaluate and assess quality of life issues in head and neck cancer patients
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Targeting of protein translation as a new treatment paradigm for prostate cancer
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The role of transoral robotic surgery in the management of oropharyngeal cancer
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Immunotherapy: a new treatment paradigm in bladder cancer
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Recent developments in the management of germ cell tumors
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Renal cell carcinoma: molecular characterization and evolving treatment paradigms
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New developments in the management of nonmuscle invasive bladder cancer
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New developments in the biology and the treatment of metastatic Merkel cell carcinoma
Purpose of review: Patients with stage IIIB und IV metastatic Merkel cell carcinoma (mMCC), who are not suitable candidates for surgery or radiotherapy, are unlikely to achieve lasting remission or tumor control by chemo or targeted therapy. In the majority of cases, the tumor arises from viral carcinogenesis associated with the Merkel cell polyomavirus (MCPyV). In MCPyV-negative tumors with a presumable ultraviolet carcinogenesis, a high mutational burden resulting in neoantigens was discovered. In two phase II clinical trials in either the first or second-line setting, a high response rate was observed for immunotherapies with antibodies blocking the programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) immune checkpoints. Recent findings: The response rate was 56% with the anti-PD-1 inhibitor pembrolizumab as a first-line and 32% with the anti-PD-L1 antibody avelumab used as second-line therapy. Both treatments were well tolerated. Treatment response was rapid and in most cases maintained during follow-up, which, however, is still rather short. Whether the MCPyV or the PD-L1 status is predictive for treatment response and progression-free survival is still ambiguous. Additionally, clinical criteria for patient selection for immunotherapy of mMCC have not yet been defined. Summary: PD-1/PD-L1 inhibition can be regarded as new first-line therapy for patients with mMCC not amendable by surgery and/or radiation.
http://ift.tt/2oqy6AQ
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A randomized phase II trial of concurrent chemoradiation with two doses of radiotherapy, 60Gy and 66Gy, concomitant with a fixed dose of oral vinorelbine in locally advanced NSCLC
In order to test the best performing radiation dose with a convenient chemotherapy schedule of an oral formulation of radio-sensitizing vinorelbine in inoperable locally advanced non-small cell lung cancer (NSCLC), we performed a randomized phase II trial based on a "pick the winner" design.
http://ift.tt/2oqFg87
Does early resection of presumed low-grade glioma improve survival? A clinical perspective
Abstract
Early resection is standard of care for presumed low-grade gliomas. This is based on studies including only tumors that were post-surgically confirmed as low-grade glioma. Unfortunately this does not represent the clinicians' situation wherein he/she has to deal with a lesion on MRI that is suspect for low-grade glioma (i.e. without prior knowledge on the histological diagnosis). We therefore aimed to determine the optimal initial strategy for patients with a lesion suspect for low-grade glioma, but not histologically proven yet. We retrospectively identified 150 patients with a resectable presumed low-grade-glioma and who were otherwise in good clinical condition. In this cohort we compared overall survival between three types of initital treatment strategy: a wait-and-scan approach (n = 38), early resection (n = 83), or biopsy for histopathological verification (n = 29). In multivariate analysis, no difference was observed in overall survival for early resection compared to wait-and-scan: hazard ratio of 0.92 (95% CI 0.43–2.01; p = 0.85). However, biopsy strategy showed a shorter overall survival compared to wait-and-scan: hazard ratio of 2.69 (95% CI 1.19–6.06; p = 0.02). In this cohort we failed to confirm superiority of early resection over a wait-and-scan approach in terms of overall survival, though longer follow-up is required for final conclusion. Biopsy was associated with shorter overall survival.
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Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway
Abstract
Purpose
Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo.
Methods
In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method.
Results
The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone.
Conclusions
Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.
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COL1A2 is a Novel Biomarker to Improve Clinical Prediction in Human Gastric Cancer: Integrating Bioinformatics and Meta-Analysis
Abstract
Gastric cancer is the third most common cause of cancer-related death in worldwide. It is crucial to target the key genes controlling pathogenesis in the early stage of gastric cancer. This study describes an integrated bioinformatics to identify molecular biomarkers for gastric cancer in patients' cancer tissues. We reports differently expression genes in large gastric cancer cohorts from Gene Expression Ominus (GEO). Our findings revealed that 433 genes were significantly different expressed in human gastric cancer. Differently expression gene profile in gastric cancer was further validated by bioinformatic analyses, co-expression network construction. Based on the co-expression network and top-ranked genes, we identified collagen type I alpha 2 (COL1A2) which encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain, was the key gene in a 37-gene network that modulates cell motility by interacting with the cytoskeleton. Furthermore, the prognostic role of COL1A2 was determined by use of immunohistochemistry on human gastric cancer tissue. COL1A2 was highly expressed in human gastric cancer as compared with normal gastric tissues. Statistical analysis showed COL1A2 expression level was significantly associated with histological type and lymph node status. However, there were no correlations between COL1A2 expression and age, lymph node numbers, tumor size, or clinical stage. In conclusion, the novel bioinformatics used in this study has led to identification of improving diagnostic biomarkers for human gastric cancer and could benefit further analyses of the key alteration during its progression.
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Silence of Long Noncoding RNA NEAT1 Inhibits Malignant Biological Behaviors and Chemotherapy Resistance in Gastric Cancer
Abstract
Gastric cancer (GC) is the most common solid tumor in digestive system. Nuclear-enriched abundant transcript 1 (NEAT1) gene is a lncRNA, and reveal potential oncogene role in several malignant tumors. The aim of this study is to investigate the expression and clinical significance of Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) gene and its influence to malignant biologic behaviors and chemotherapy resistance to adriamycin in GC. This study found NEAT1 was up-regulated in GC tissues and cells, especially in in GC adriamycin-resistant cells. NEAT1 silence in SGC7901 cells could inhibit proliferation and invasion ability, and promote cell apoptosis significantly. NEAT1 silence in adriamycin-resistant SGC7901/ADR cells also depressed the half maximal inhibitory concentration (IC50) for adriamycin, chemotherapy resistance to adriamycin was inhibited significantly. NEAT1 knockdown promoted apoptosis in SGC7901/ADR cells induced by adriamycin. In summary, lncRNA NEAT1 is high-expressed in GC and functions as an oncogene to modulate apoptosis, invasion, proliferation and chemotherapy resistance of GC cells, which might be a novel potential therapeutic target for GC.
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Reproducibility and Prognostic Potential of Ki-67 Proliferation Index when Comparing Digital-Image Analysis with Standard Semi-Quantitative Evaluation in Breast Cancer
Abstract
In this study, the reproducibility of Ki-67 proliferation index (KIPI) was investigated by comparing the semi-quantitative (SQ) results of three assessors with those of digital image-analysis (DIA) methods. The prognostic significance of the two approaches was also correlated with clinical outcome. Tissue microarrays of duplicate 2 mm cores were constructed from representative areas of formalin-fixed and paraffin-embedded tumor blocks of 347 breast cancer patients. SQ evaluation of Ki-67 (MIB1 clone) immunostained slides was performed independently by three pathologists. DIA was completed using a fully automated histological pattern and cell recognition module for KIPI detection (DIA-1) and an adjustable module (DIA-2) with the possibility of manual corrections. To compare SQ and DIA evaluations intra-class correlation (ICC) and concordance correlation coefficients (CCC) were determined. The three SQ evaluations demonstrated a remarkable ICC (0.853). Significant difference and poor concordance occurred between SQ-1 and SQ-2 as well as between SQ-1 and SQ-3 (p ≤ 0.001, CCC ≤ 0.827 for both comparisons). Thus, the reference KIPI value (SQ-RV) was generated from the mean values of SQ-2 and SQ-3. SQ-RV and DIA-2 results showed substantial concordance (CCC = 0.963, at p = 0.754), while SQ-RV and DIA-1 values differed (p ≤ 0.001) at only moderate concordance (CCC = 0.906). In multivariate analysis, lymph node status and SQ-2 assessment were significantly associated with clinical outcome (p ≤ 0.012 for both comparisons). Our results confirm that KIPI is a significant prognostic marker in breast cancer, which can be can be reliably reproduced by using an adjustable DIA-2 image analysis module.
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Does early resection of presumed low-grade glioma improve survival? A clinical perspective
Abstract
Early resection is standard of care for presumed low-grade gliomas. This is based on studies including only tumors that were post-surgically confirmed as low-grade glioma. Unfortunately this does not represent the clinicians' situation wherein he/she has to deal with a lesion on MRI that is suspect for low-grade glioma (i.e. without prior knowledge on the histological diagnosis). We therefore aimed to determine the optimal initial strategy for patients with a lesion suspect for low-grade glioma, but not histologically proven yet. We retrospectively identified 150 patients with a resectable presumed low-grade-glioma and who were otherwise in good clinical condition. In this cohort we compared overall survival between three types of initital treatment strategy: a wait-and-scan approach (n = 38), early resection (n = 83), or biopsy for histopathological verification (n = 29). In multivariate analysis, no difference was observed in overall survival for early resection compared to wait-and-scan: hazard ratio of 0.92 (95% CI 0.43–2.01; p = 0.85). However, biopsy strategy showed a shorter overall survival compared to wait-and-scan: hazard ratio of 2.69 (95% CI 1.19–6.06; p = 0.02). In this cohort we failed to confirm superiority of early resection over a wait-and-scan approach in terms of overall survival, though longer follow-up is required for final conclusion. Biopsy was associated with shorter overall survival.
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Successful one-lung ventilation using a bronchial blocker tube for a large tracheal carcinoma resection
The informed consent was obtained from the patient. A 57-year old woman was diagnosed as a trachea adenoid cystic carcinoma. A large tumor was found in the upper tracheal under fiber bronchoscopy (FBO), which the lower edge of the tumor was about 3cm proximal to the carina and the tumor size was about 4cm, obstructing the tracheal lumen by 92%. The gap at the narrowest intraluminal point was about 0.5cm (Fig.1A, B). Abnormal FEV 1% FVC: 22.07 and PaO2: 6.5kPa were detected by pulmonary function test and arterial blood gas test on room air respectively.
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Risk-Reducing Strategies for Ovarian Cancer in BRCA Mutation Carriers: A Balancing Act
Objective.
The objective of this study was to review the role of bilateral salpingo-oophorectomy in BRCA mutation (mBRCA) carriers and alternative interventions in risk reduction of ovarian cancer (OC).
Materials and Methods.A systematic review using PubMed, MEDLINE, EMBASE, and the Cochrane library was conducted to identify studies of different strategies to prevent OC in mBRCA carriers, including bilateral salpingo-oophorectomy, prophylactic salpingectomy with delayed oophorectomy, intensive surveillance, and chemoprevention.
Results.Risk-reducing bilateral salpingo-oophorectomy is an effective intervention, but its associated morbidity is substantial and seems to curtail uptake rates among the target population. Although there is much interest and a strong theoretical basis for salpingectomy with delayed oophorectomy, data on its clinical application are scarce with regard to screening, the use of an algorithmic protocol has recently shown favorable albeit indefinite results in average-risk postmenopausal women. Its incorporation into studies focused on high-risk women might help solidify a future role for screening as a bridge to surgery. The use of oral contraceptives for chemoprevention is well supported by epidemiologic studies. However, there is a lack of evidence for advocating any of the other agents proposed for this purpose, including nonsteroidal anti-inflammatory drugs, vitamin D, and retinoids.
Conclusion.Further studies are needed before salpingectomy with delayed oophorectomy or intensive surveillance can be offered as acceptable, less morbid alternatives to upfront oophorectomy for mBRCA carriers. The Oncologist 2017;22:450–459
Implications for Practice.Risk-reducing bilateral salpingo-oophorectomy is currently the most effective method for reducing the risk of ovarian cancer in BRCA mutation (mBRCA) carriers. Unfortunately, it is associated with significant short- and long-term morbidity, stemming from reduced circulating estrogen. In recent years, much research has been devoted to evaluating less morbid alternatives, especially multimodal cancer screening and prophylactic salpingectomy with delayed oophorectomy. This review describes the present state of the art, with the aim of informing the counseling provided to mBRCA carriers on this complicated issue and encouraging additional research to facilitate the incorporation of such alternatives into routine practice.
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Academic Cancer Center Phase I Program Development
Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator-initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand-alone operation, but mature phase I programs work well when many of the activities are transferred to disease-oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs. The Oncologist 2017;22:369–374
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On the Interpretation of the Hazard Ratio and Communication of Survival Benefit
This brief communication will clarify the difference between a relative hazard and a relative risk. We highlight the importance of this difference, and demonstrate in practical terms that 1 minus the hazard ratio should not be interpreted as a risk reduction in the commonly understood sense of the term. This article aims to provide a better understanding of the type of risk reduction that a hazard ratio implies, thereby clarifying the intent in the communication among practitioners and researchers and establishing an accurate and realistic foundation for communicating with patients. The Oncologist 2017;22:484–486
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Randomized Phase II Trial of Parsatuzumab (Anti-EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First-Line Metastatic Colorectal Cancer
Lessons Learned.
These negative phase II results for parsatuzumab highlight the challenges of developing an agent intended to enhance the efficacy of vascular endothelial growth factor inhibition without the benefit of validated pharmacodynamic biomarkers or strong predictive biomarker hypotheses.
Any further clinical development of anti-EGFL7 is likely to require new mechanistic insights and biomarker development for antiangiogenic agents.
Background.EGFL7 (epidermal growth factor-like domain 7) is a tumor-enriched vascular extracellular matrix protein that supports endothelial cell survival. This phase II trial evaluated the efficacy of parsatuzumab (also known as MEGF0444A), a humanized anti-EGFL7 IgG1 monoclonal antibody, in combination with modified FOLFOX6 (mFOLFOX6) (folinic acid, 5-fluorouracil, and oxaliplatin) bevacizumab in patients with previously untreated metastatic colorectal cancer (mCRC).
Methods.One-hundred twenty-seven patients were randomly assigned to parsatuzumab, 400 mg, or placebo, in combination with mFOLFOX6 plus bevacizumab, 5 mg/kg. Treatment cycles were repeated every 2 weeks until disease progression or unacceptable toxicity for a maximum of 24 months, with the exception of oxaliplatin, which was administered for up to 8 cycles.
Results.The progression-free survival (PFS) hazard ratio was 1.17 (95% confidence interval [CI], 0.71–1.93; p = .548). The median PFS was 12 months for the experimental arm versus 11.9 months for the control arm. The hazard ratio for overall survival was 0.97 (95% CI, 0.46–2.1; p = .943). The overall response rate was 59% in the parsatuzumab arm and 64% in the placebo arm. The adverse event profile was similar in both arms.
Conclusions.There was no evidence of efficacy for the addition of parsatuzumab to the combination of bevacizumab and chemotherapy for first-line mCRC. The Oncologist 2017;22:375–e30
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Retrospective Review of Atypical Femoral Fracture in Metastatic Bone Disease Patients Receiving Denosumab Therapy
Background.
Denosumab therapy is used to reduce skeletal-related events in metastatic bone disease (MBD). There have been reports of atypical femoral fracture (AFF) in osteoporotic patients treated with denosumab but none in the context of higher dose and more frequent denosumab therapy for MBD. The goal of this study was to assess the incidence of AFF in MBD.
Patients and Methods.We conducted a retrospective review of 253 patients who received a minimum of 12 doses of denosumab at 120 mg each for MBD. To identify patients with asymptomatic atypical stress reactions in the lateral subtrochanteric femur (which precede fractures), we reviewed the skeletal images of 66 patients who had received at least 21 doses of denosumab for AFF features.
Results.These patients received a median of 17 doses, with a median treatment duration of 23 months. There was 1 case of undiagnosed clinical AFF detected after chart review and 2 cases of subclinical atypical femoral stress reaction observed on imaging review after 23 doses of denosumab over 33 months, 28 doses over 27 months, and 21 doses over 21 months, respectively. Scout computed tomography films showed diffuse cortical thickening of diaphysis with localized periosteal reaction of lateral femoral cortex. Bone scan and magnetic resonance imaging scan of 2 patients with stress reactions confirmed the diagnosis.
Conclusion.The incidence of clinical AFF in this context is 0.4% (1/253; 95% confidence interval [CI] 0.1%–2.2%), and the incidence of atypical femoral stress reaction based on imaging review is 4.5% (3/66; 95% CI 1.6%–12.5%). Clinicians should be aware of the clinical prodrome (which may or may not be present) and antecedent imaging changes associated with AFF. The Oncologist 2017;22:438–444
Implications for Practice: Among patients with metastatic bone disease treated with denosumab, cases of clinical and subclinical atypical femoral fracture (AFF) are rare. The one detected case of clinical fracture went unrecognized despite prodromic symptoms. Clinicians should be aware of (a) the potential prodrome of anterior thigh/groin pain and (b) subclinical imaging changes in the lateral femur, both of which may precede clinical AFF.
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Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
Lessons Learned.
Despite involvement of PI3K pathway activation in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown modest clinical activity.
Preclinical evidence suggests that combining PI3K pathway inhibitors and chemotherapy can enhance antitumor effects.
In patients with solid tumors, the PI3K inhibitor pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin.
Further clinical evaluation is warranted to identify effective combination strategies with PI3K pathway inhibitors.
Background.Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in capsule and tablet formulations, administered in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
Methods.A 3 + 3 design was used. Pilaralisib was administered once daily (QD); paclitaxel (up to 175 mg/m2) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.
Results.Fifty-eight patients were enrolled. Six patients (10.3%) had dose-limiting toxicities, of which only rash (two patients, 3.4%) occurred in more than one patient. The MTD of pilaralisib tablets in combination with paclitaxel and carboplatin was determined to be 200 mg QD. The most frequently reported adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data showed no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients had a partial response (PR; 13.5%).
Conclusion.Pilaralisib had a favorable safety profile but did not enhance the antitumor activity of paclitaxel plus carboplatin in solid tumors. The Oncologist 2017;22:377–378
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Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis
Background.
Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy.
Methods.PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration–approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1–4) or high-grade (3–4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated.
Results.A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors.
Conclusion.PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors. The Oncologist 2017;22:470–479
Implications for Practice.We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.
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The Incidence and Health Care Resource Burden of the Myelodysplastic Syndromes in Patients in Whom First-Line Hypomethylating Agents Fail
Background.
Although hypomethylating agents (HMAs) are effective and approved therapies for patients with myelodysplastic syndromes (MDS), many patients do not benefit from treatment, and nearly all ultimately stop responding to HMAs. The incidence and cost burden of HMA failure are unknown yet needed to appreciate the magnitude and significance of such failure.
Methods.We analyzed a de-identified dataset of over 5 million individuals with private health insurance in the U.S. to estimate MDS incidence, prevalence, and treatments. Based on MDS provider interviews, a conceptual model of MDS patient management was constructed to create a new, claims-relevant and drug development-relevant definition of HMA treatment failure. This algorithm was used to define resource encumbrance of MDS patients in whom HMA treatment failed.
Results.We estimated an MDS incidence rate of ~70 cases per 100,000 enrollees per year and a prevalence of 155 cases per 100,000 enrollees. The proportion of MDS patients receiving HMA treatment was low (~3%), and treatment was typically initiated within 1 year of the first MDS claim. Notably, HMA-treated individuals were older and had more comorbidities than the overall MDS cohort. Total health care costs of managing MDS patients after HMA failure were high (~$77,000 during the first 6 months) and were driven primarily by non-pharmacy costs.
Conclusion.This study quantifies for the first time the burden of significant unmet need in caring for MDS patients following HMA treatment failure. The Oncologist 2017;22:379–385
Implications for Practice: U.S.-based treatment patterns among MDS patients demonstrate the significant clinical, financial, and health care burden associated with HMA failure and call for active therapies for this patient population.
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Factors Associated with Early Mortality Among Patients with De Novo Metastatic Breast Cancer: A Population-Based Study
Background.
Although improvements in survival have been achieved for patients with metastatic breast cancer, some patients experience early death after diagnosis.
Patients and Methods.Using Surveillance, Epidemiology, and End Results data, we identified 26,538 patients with de novo metastatic breast cancer diagnosed between January 1, 2000 and June 30, 2011. We evaluated time trends for deaths at 1 and 6 months after diagnosis. We then restricted the cohort to patients diagnosed between 2010 and 2011 (n = 3,317), when human epidermal growth factor receptor 2 was routinely collected, and examined factors associated with early death.
Results.In 2000, 15.9% of patients died within 1 month of diagnosis and 33.2% within 6 months. In 2011, the proportion of women dying within 1 month decreased to 13.4% and 26.3% within 6 months (p < .001). Older age and uninsured status were associated with early death (at both time points, age ≥70 [versus age <40] had >8.5 higher odds of dying, and uninsured [versus insured] patients had >2.5 higher odds of death). In addition, in some subgroups (e.g., no insurance and triple negative disease), more than half of patients died within 6 months. Region was also associated with early death.
Conclusion.Although we observed improvements in the proportion of patients experiencing early death, one quarter of patients with de novo metastatic disease diagnosed in 2011 died within 6 months of diagnosis. In addition to tumor factors and older age, geography and uninsured status were associated with early death. Our findings highlight the need for focused interventions for metastatic patients at highest risk for poor outcomes. The Oncologist 2017;22:386–393
Implications for Practice.With nearly one quarter of patients in our dataset diagnosed in 2011 dying within 6 months of diagnosis, our findings highlight the persistent and critical need of further characterization and identification of patients who are risk for poor outcomes in order to optimize care, impact change, and improve outcomes for all women with metastatic breast cancer. Our data also emphasize the need for interventions among those at highest risk for early death. These interventions would likely promote immediate referral for clinical trial participation, early palliative care referrals, and additional supportive services, optimizing equitable patient access to cancer treatment and care.
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Role of MGMT Methylation Status at Time of Diagnosis and Recurrence for Patients with Glioblastoma: Clinical Implications
Background.
MGMT methylation status represents a powerful prognostic factor in newly diagnosed glioblastoma (GBM). Recently, its role in recurrent tumors has also been suggested; however, few data investigating the stability of this biomarker during the clinical course of the disease are available. In this study, we evaluated the rate of change of MGMT methylation status between diagnosis and first recurrence in patients who received tumor resection for recurrent GBM.
Methods.We included patients who received temozolomide concurrent with and adjuvant to radiotherapy after diagnosis of GBM and had a second surgery performed at least 3 months after radiotherapy completion. Other eligibility criteria were age ≥18 years and Eastern Cooperative Oncology Group performance status 0–2. We evaluated the MGMT methylation status by methylation-specific polymerase chain reaction.
Results.From our institutional data warehouse, 295 patients with recurrent GBM who underwent second surgery were evaluated. MGMT methylation status at both first and second surgery was available for 108 patients. MGMT was methylated in both surgeries in 38 patients (35.2%), while it was unmethylated in 43 patients (39.8%). We found a significant concordance between the first and the second MGMT methylation assessments (K = 0.500, p < .001), MGMT methylation being stable in 75% of the cases.
Conclusion.MGMT methylation presents relative stability during the clinical course of GBM. The Oncologist 2017;22:432–437
Implications for Practice.MGMT methylation is a prognostic factor in newly diagnosed glioblastoma. In this study, we evaluated the rate of change of MGMT methylation during the clinical course of the disease, and we found a significant concordance between the first and the second MGMT methylation assessments, with MGMT methylation being stable in 75% of the cases. Thus, re-testing this biomarker at recurrence does not provide further information for clinicians. MGMT methylation at first surgery, extent of resection at second surgery, and time between first and second surgery are significantly correlated with overall survival. Age and extent of resection are correlated with post-progression survival.
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Performance of Mid-Treatment Breast Ultrasound and Axillary Ultrasound in Predicting Response to Neoadjuvant Chemotherapy by Breast Cancer Subtype
Background.
The primary objective was to determine whether mid-treatment ultrasound measurements of index breast tumors and index axillary nodes of different cancer subtypes associate with residual cancer burden (RCB).
Methods.Patients with invasive breast cancer who underwent neoadjuvant chemotherapy and had pre-treatment and mid-treatment breast and axillary ultrasound were included in this single-institution, retrospective cohort study. Linear regression analysis assessed associations between RCB with (a) change in index breast tumor size, (b) change in index node size, and (c) absolute number of abnormal nodes at mid-treatment. Multivariate linear regression was used to calculate best-fit models for RCB.
Results.One hundred fifty-nine patients (68 triple negative breast cancer [TNBC], 45 hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]–, and 46 HR–/HER2+) were included. Median age at diagnosis was 50 years, range 30–76. Median tumor size was 3.4 cm, range 0.9–10.4. Pathological complete response/RCB-I rates were 36.8% (25/68) for TNBC patients, 24.4% (11/45) for HR+/HER2– patients, and 71.7% (33/46) for HR–/HER2+ patients. Linear regression analyses demonstrated associations between percent change in tumor ultrasound measurements at mid-treatment with RCB index score in TNBC and HR+/HER2– (p < .05) but not in HR–/HER2+ (p > .05) tumors and an association between axillary ultrasound assessment of number of abnormal nodes at mid-treatment with RCB index score across all subtypes (p < .05).
Conclusion.Performance characteristics of breast ultrasound associated with RCB vary by cancer subtype, whereas the performance characteristics of axillary ultrasound associated with RCB are consistent across cancer subtype. Breast and axillary ultrasound may be valuable in monitoring response to neoadjuvant therapy. The Oncologist 2017;22:394–401
Implications for Practice.The differential performance characteristics of breast ultrasound by molecular subtype and the consistent performance characteristics of axillary ultrasound across molecular subtypes can have clinical utility in monitoring response to neoadjuvant therapy.
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Using Metaphors to Explain Molecular Testing to Cancer Patients
Background.
Molecular testing to identify targetable molecular alterations is routine practice for several types of cancer. Explaining the underlying molecular concepts can be difficult, and metaphors historically have been used in medicine to provide a common language between physicians and patients. Although previous studies have highlighted the use and effectiveness of metaphors to help explain germline genetic concepts to the general public, this study is the first to describe the use of metaphors to explain molecular testing to cancer patients in the clinical setting.
Methods.Oncologist-patient conversations about molecular testing were recorded, transcribed verbatim, and coded. If a metaphor was used, patients were asked to explain it and assess its helpfulness.
Results.Sixty-six patients participated. Nine oncologists used metaphors to describe molecular testing; 25 of 66 (38%) participants heard a metaphor, 13 of 25 (52%) were questioned, 11 of 13 (85%) demonstrated understanding and reported the metaphor as being useful. Seventeen metaphors (bus driver, boss, switch, battery, circuit, broken light switch, gas pedal, key turning off an engine, key opening a lock, food for growth, satellite and antenna, interstate, alternate circuit, traffic jam, blueprint, room names, Florida citrus) were used to explain eight molecular testing terms (driver mutations, targeted therapy, hormones, receptors, resistance, exon specificity, genes, and cancer signatures).
Conclusion.Because metaphors have proven to be a useful communication tool in other settings, these 17 metaphors may be useful for oncologists to adapt to their own setting to explain molecular testing terms. The Oncologist 2017;22:445–449
Implications for Practice: This article provides a snapshot of 17 metaphors that proved useful in describing 8 complicated molecular testing terms at 3 sites. As complex tumor sequencing becomes standard of care in clinics and widely used in clinical research, the use of metaphors may prove a useful communication tool, as it has in other settings. Although this study had a small sample, almost all of the patients who were exposed to metaphors in explaining molecular testing reported it as being helpful to their understanding. These 17 metaphors are examples of potentially useful communication tools that oncologists can adapt to their own practice.
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Platinum-Fluoropyrimidine and Paclitaxel-Based Chemotherapy in the Treatment of Advanced Anal Cancer Patients
Background.
Although treatment of localized anal cancer (AC) is well established, very little evidence is available to inform the management of advanced tumors, and the prognosis of these patients remains poor. We have analyzed treatment pathways and outcomes of a single-institution series of advanced AC patients in order to provide insight into the management of this rare condition.
Materials and Methods.Inclusion criteria included epidermoid histology, inoperable locally recurrent or metastatic disease, and availability of full medical records. The primary objective was overall survival (OS). Prognostic factors were analyzed in univariate models.
Results.Sixty-four patients (1997–2014) were included: 16 (25.0%) with inoperable locally advanced and 48 (75.0%) with metastatic tumors. Fifty-one (79.7%) received at least one line of chemotherapy; of these, 37% underwent multimodality treatment. A combination of a platinum agent plus a fluoropyrimidine was the most common first-line regimen (74.5%), with an objective response rate (ORR) of 34.4% (95% confidence interval [CI], 18.6%–53.2%). Paclitaxel-based chemotherapy was used in 15 patients as front-line or salvage treatment, and the overall ORR was 53.3% (95% CI, 26.6%–78.7%). Median progression-free survival (PFS) after first- and second-line chemotherapy was 5.8 (interquartile range [IQR], 2.8–7.6) and 3.2 (IQR, 2.5–7.1) months, respectively. Five-year OS in the overall population was 15% (95% CI, 7.0%–25.0%). Age ≤65 years and liver metastases were predictive of better PFS (hazard ratio [HR], 0.39; 95% CI, 0.16–0.97; p = .04) and worse OS (HR, 2.25; 95% CI, 1.25–4.03; p = .01), respectively.
Conclusion.A platinum agent plus a fluoropyrimidine and paclitaxel-based chemotherapy are active regimens for advanced AC. Clinical trials are needed to standardize treatment pathways, investigate the potential of novel therapeutics, and improve the poor prognosis of this rare condition. The Oncologist 2017;22:402–408
Implications for Practice: Because of the lack of randomized trials, the optimal management of advanced anal cancer is uncertain. Despite its retrospective analysis and relatively small sample size, this is the second largest study ever conducted in this setting, and, as such, it has the potential to serve as a valuable source of information for everyday clinical practice. These findings suggest that chemotherapy with a platinum agent plus a fluoropyrimidine or paclitaxel-containing regimens are reasonable treatment options for patients with inoperable locally recurrent or metastatic anal carcinoma.
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Escalating Health Care Expenditures in Cancer Decedents' Last Year of Life: A Decade of Evidence from a Retrospective Population-Based Cohort Study in Taiwan
Background.
No population-based longitudinal studies on end-of-life (EOL) expenditures were found for cancer decedents.
Methods.This population-based, retrospective cohort study examined health care expenditures from 2001 to 2010 among 339,546 Taiwanese cancer decedents' last year of life. Individual patient-level data were linked from administrative datasets. Health care expenditures were converted from Taiwan dollars to U.S. dollars by health-specific purchasing power parity conversions to account for different health-purchasing powers. Associations of patient, physician, hospital, and regional factors with EOL care expenditures were evaluated by multilevel linear regression model by generalized estimating equation method.
Results.Mean annual EOL care expenditures for Taiwanese cancer decedents increased from 2000 to 2010 from U.S. $49,591 to U.S. $68,773, respectively, with one third of spending occurring in the patients' last month. Increased EOL care expenditures were associated with male gender, younger age, being married, diagnosed with hematological malignancies and cancers other than lung, gastric, and hepatic-pancreatic cancers, and dying within 7–24 months of diagnosis. Patients spent less at EOL when they had higher comorbidities and metastatic disease, died within 6 months of diagnosis, were under care of oncologists, gastroenterologists, and intensivists, and received care at a teaching hospital with more terminally ill cancer patients. Higher EOL care expenditures were associated with greater EOL care intensity at the primary hospital and regional levels.
Conclusion.Taiwanese cancer decedents consumed considerable National Health Insurance disbursements at EOL, totaling more than was consumed in six developed non-U.S. countries surveyed in 2010. To slow increasing cost and improve EOL cancer care quality, interventions to ensure appropriate EOL care provision should target hospitals and clinicians less experienced in providing EOL care and those who tend to provide aggressive EOL care to high-risk patients. The Oncologist 2017;22:460–469
Implications for Practice: Cancer-care costs are highest during the end-of-life (EOL) period for cancer decedents. This population-based study longitudinally examined EOL expenditures for cancer decedents. Mean annual EOL-care expenditures for Taiwanese cancer decedents increased from U.S. $49,591 to U.S. $68,773 from the year 2000 to 2010, with one third of spending in patients' last month and more than for six developed non-U.S. countries surveyed in 2010. To slow the increasing cost of EOL-cancer care, interventions should target hospitals/clinicians less experienced in providing EOL care, who tend to provide aggressive EOL care to high-risk patients, to avoid the physical suffering, emotional burden, and financial costs of aggressive EOL care.
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Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome
Background.
Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far.
Patients and Methods.A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method.
Results.Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 x Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%–50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively.
Conclusion.In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409–415
Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.
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Response to Tyrosine Kinase Inhibitors in Myeloproliferative Neoplasia with 8p11 Translocation and CEP110-FGFR1 Rearrangement
This brief communication reports on a patient with an exceedingly rare "8p11 (eight-p-eleven) myeloproliferative syndrome" (EMS) with CEP110-FGFR1 rearrangement who responded to treatment with the multi-tyrosine kinase inhibitor (TKI) dasatinib. Dasatinib improved quality of life substantially by increasing blood counts and reducing the need for transfusions. This report demonstrates that the second-generation TKI may provide a therapeutic option for elderly and frail EMS patients who cannot be offered aggressive therapy, including allogeneic hematopoietic cell transplantation. The Oncologist 2017;22:480–483
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Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common CDKN2A Alteration
Background.
Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy.
Materials and Methods.This study analyzed 279 clinically advanced/recurrent uLMS samples. Median patient age was 54 years (range, 23–83 years). DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections, and CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 405 cancer-related genes plus introns from up to 31 genes frequently rearranged in cancer. Sequencing data were analyzed for base pair substitutions, insertions/deletions, copy number alterations, and rearrangements.
Results.CGP shows that 97.1% of uLMS harbor at least one alteration, and approximately 57% harbor alterations in one or more therapeutically targetable pathways. CDKN2A mutations that inactivate p16INK4a were identified in 11% of uLMS. We report the first demonstration of clinical benefit in response to palbociclib treatment for a uLMS patient with a CDKN2A mutation, resulting in disease stabilization and significant symptom reduction.
Conclusion.A patient with uLMS harboring a CDKN2A mutation experienced clinical benefit from treatment with palbociclib, and genomic analysis of 279 uLMS samples revealed that 19% of patients had mutations affecting the cyclin-dependent kinase (CDK) pathway. These observations provide a rationale for a clinical trial investigating treatment with CDK pathway inhibitors for uLMS harboring relevant genomic alterations. The Oncologist 2017;22:416–421
Implications for Practice: Comprehensive genomic profiling (CGP) of individuals with uterine leiomyosarcoma (uLMS) indicates that nearly 20% of patients may harbor a mutation affecting the cyclin-dependent kinase (CDK) pathway. The case presented demonstrates that a CDK inhibitory drug may provide clinical benefit to such individuals. Given the lack of curative therapies for uLMS, CGP could be performed on all cases of advanced uLMS and a CDK inhibitor could be recommended (preferably as part of a clinical trial) for individuals harboring a mutation in the CDK pathway.
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Intratumoral Heterogeneity in Breast Cancer: A Comparison of Primary and Metastatic Breast Cancers
Intratumoral heterogeneity presents challenges in the management of cancer. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases and/or recurrences for immunohistochemical expression of estrogen receptors, progesterone receptors, human epidermal growth receptor 2, and Ki67 on all tissue blocks in both primary and metastatic tumors. The Oncologist 2017;22:487–490
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Risk-Reducing Strategies for Ovarian Cancer in BRCA Mutation Carriers: A Balancing Act
Objective.
The objective of this study was to review the role of bilateral salpingo-oophorectomy in BRCA mutation (mBRCA) carriers and alternative interventions in risk reduction of ovarian cancer (OC).
Materials and Methods.A systematic review using PubMed, MEDLINE, EMBASE, and the Cochrane library was conducted to identify studies of different strategies to prevent OC in mBRCA carriers, including bilateral salpingo-oophorectomy, prophylactic salpingectomy with delayed oophorectomy, intensive surveillance, and chemoprevention.
Results.Risk-reducing bilateral salpingo-oophorectomy is an effective intervention, but its associated morbidity is substantial and seems to curtail uptake rates among the target population. Although there is much interest and a strong theoretical basis for salpingectomy with delayed oophorectomy, data on its clinical application are scarce with regard to screening, the use of an algorithmic protocol has recently shown favorable albeit indefinite results in average-risk postmenopausal women. Its incorporation into studies focused on high-risk women might help solidify a future role for screening as a bridge to surgery. The use of oral contraceptives for chemoprevention is well supported by epidemiologic studies. However, there is a lack of evidence for advocating any of the other agents proposed for this purpose, including nonsteroidal anti-inflammatory drugs, vitamin D, and retinoids.
Conclusion.Further studies are needed before salpingectomy with delayed oophorectomy or intensive surveillance can be offered as acceptable, less morbid alternatives to upfront oophorectomy for mBRCA carriers. The Oncologist 2017;22:450–459
Implications for Practice.Risk-reducing bilateral salpingo-oophorectomy is currently the most effective method for reducing the risk of ovarian cancer in BRCA mutation (mBRCA) carriers. Unfortunately, it is associated with significant short- and long-term morbidity, stemming from reduced circulating estrogen. In recent years, much research has been devoted to evaluating less morbid alternatives, especially multimodal cancer screening and prophylactic salpingectomy with delayed oophorectomy. This review describes the present state of the art, with the aim of informing the counseling provided to mBRCA carriers on this complicated issue and encouraging additional research to facilitate the incorporation of such alternatives into routine practice.
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