Development Of Metastases In Patients Research Articles

What are the Risk Factors for the Development of Metastasis in Patients with Cancer After Receiving the COVID-19 Vaccine?

Introduction: The majority of the studies after the COVID-19 pandemic are saying the necessity of cancer patients to receive the COVID-19 vaccine. The purpose of this study is to demonstrate that patients with cancer have energy deficiency inside the five internal massive organs of the five elements theory of traditional Chinese medicine and the use of any kind of medication, vaccine, or devices such as the use of metallic implants in orthopedic or dentists surgeries can reduce even more the energy of these patients, worsening their immune system leading to more propensity to have metastasis after receiving the COVID-19 vaccine. Methods: Three case reports. Two are females that have breast cancer diagnosed five years before the COVID-19 pandemic. Both received chemotherapy and three doses of the COVID-19 vaccine. One male patient had thyroid cancer (diagnosed four years ago) metastasis after receiving three doses of the COVID-19 vaccine. They were submitted to the measurement of the energy of the five internal massive organs of the five elements of traditional Chinese medicine using the radiesthesia procedure. Results: All three patients were in the lowest level of energy of the Liver, Heart, Spleen, Lungs, and Kidney, rated one out of eight. Both females presented Lung metastasis diagnosed through the computed magnetic resonance and the male patient presented bone metastasis leading to spontaneous femur fracture. All these complications occurred after receiving the COVID-19 vaccine. Conclusion: The conclusion of this study is to demonstrate that cancer patients have energy deficiency inside the five internal massive organs of the five elements of traditional Chinese medicine and the use of highly concentrated vaccines such as the COVID-19 vaccine can reduce even more this energy and cause more immune suppression, leading to more propensity to have metastasis in patients with cancer, as shown in these three patients reported in this article.

What is a useful marker for predicting survival in patients with high-grade soft tissue sarcoma who have non-inflammatory conditions?

BackgroundThe modified Glasgow prognostic score (mGPS) is a reliable system for identifying patients at high risk of death among patients with soft tissue sarcoma (STS). The scoring systems use a combination of C-reactive protein (CRP) and albumin levels. Although patients with high-grade STS are at risk of metastasis and death, even if their mGPS is 0, the prognostic indicators in these patients are unknown. Therefore, we investigated useful prognostic indicators for survival and the development of metastasis in patients with high-grade STS and an mGPS of 0. MethodsOne hundred and four patients with CRP and albumin levels of <1.0 mg/dl and >3.5 g/dl, respectively, indicating an mGPS of 0, were included. The mean follow-up period was 79 months. ResultsThe 5-year disease-specific survival (DSS) rate was 79.2%. Cox proportional analysis showed that tumor size and absolute neutrophil count (ANC) were prognostic variables in multivariate analyses. Patients with higher ANC (ANC>3370/μl) had a worse DSS than those with lower ANC. The 5-year DSS was 74.7% vs. 91.7%, respectively (p = 0.0207). The 5-year metastasis-free survival was 67.2%. Tumor size and ANC remained significant variables for predicting the development of metastasis in the multivariate analysis. Patients with higher ANC had a worse metastasis-free survival than those with lower ANC. The 5-year metastasis-free survival was 59.5% vs. 87.3%, respectively (p = 0.00269). ConclusionsWhen patients with high-grade STS have an mGPS of 0, the ANC and tumor size should be carefully evaluated. A higher neutrophil count and larger tumor size may increase the risk of metastasis development.

Risk Factors Associated with the Development of Metastases in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Retrospective Analysis.

Neuroendocrine tumors develop from systemic endocrine and nerve cells, and their occurrence has increased recently. Since these tumors are heterogeneous, pathological classification has been based on the affected organ. In 2019, the World Health Organization introduced a change expected to influence neuroendocrine tumor research, as gastroenteropancreatic neuroendocrine tumors are now included within a unified classification. This retrospective study aimed to investigate the characteristics (e.g., lymph node metastases and all other metastases) of gastroenteropancreatic neuroendocrine tumors using this new classification in 50 cases. Tumor size, depth, MIB-1 index, lymphatic invasion, venous invasion, and neuroendocrine tumor grade were significantly correlated with lymph node metastasis and other metastases. The venous invasion was more strongly correlated with lymph node metastasis and all other types of metastases than with lymphatic invasion. Identification rates for lymphatic invasion were considered lower because of structural problems such as lymphatic vessels being much thinner than veins. However, venous invasion was considered effective in compensating for the low identification rate in cases of lymphatic invasion. In future research, a unified classification and standardized framework for assessment will be important when analyzing the characteristics of neuroendocrine tumors, and large-scale studies are required.

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma.

Simple SummaryTelomere maintenance involving TERT and ATRX genes has been recently described in metastatic pheochromocytoma and paraganglioma, reinforcing the importance of immortalization mechanisms in the progression of these tumors. Thus, the aim of this study was to analyze additional telomere-related genes to uncover potential new markers capable of identifying metastatic-risk patients more accurately. After analyzing 29 telomere-related genes, we were able to validate the predictive value of TERT and ATRX in mPPGL progression. In addition, we were able to identify NOP10 as a novel prognostic risk marker of mPPGLs, which also facilitates telomerase-dependent telomere length maintenance in these tumors. Interestingly, NOP10 overexpression assessment by IHC could be easily included within the current battery of markers for stratifying PPGL patients to fine-tune their clinical diagnoses.One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.

Targeting the Supply Lines of Cancer - A Possible Strategy for Combating the Disease?

Cancer cells alter and up-regulate their metabolic activity in order to facilitate the increased demands of malignancy. This leads to an increased need for metabolic "building materials", for example glucose and amino acids. The blood circulation represents the principal supply lines delivering these materials. It, therefore, becomes relevant to investigate if these supply lines - in terms of the concentrations of building materials in the blood - may exhibit a therapeutic window and could be intervened, as they deliver the most basal components required to exert malignant functioning. A key aspect in this strategy is that it targets - in theory - the thermodynamic foundation enabling the activities that, essentially, "make a cancer a cancer". As an initial step, this review examines if the metabolic supply lines carry clinical implications; specifically, if they impact survival and the development of metastases in patients with cancer. Furthermore, it presents and discusses perspectives on potentially targeting these supply lines.

118P Determinants of timing to metastasis in breast cancer patients in Albania

Development of metastasis in patients with breast cancer (BC) is the most important negative prognostic factor. The prognostic factors and their impact in the timing of distant metastasis has been the focus of different studies. The purpose of the study was to identify the risk factors for distant metastasis in Albanian breast cancer patients and their correlation with time to metastasis.

Clinicopathological predictors of bone metastases in prostate cancer patients.

e17520 Background: To determine if there is association between the clinical-pathological characteristics and the development of bone metastases in patients with prostate cancer treated in Oncosalud during the period 2016-2018. Methods: An observational, analytical, cross-sectional and retrospective study was conducted in 386 men diagnosed with prostate cancer in a Private Clinic in Peru. We presented descriptive and analytic analysis to identify variables associated with bone metastases; in addition, odds ratios were estimated. Results: In reference to the PSA groups, those patients with PSA values higher than 20 ng / ml presented a risk 9.69 times higher to develop bone metastases (95% CI: 5.08-18.45). In regard to Gleason groups, those with a 9-10 score presented a risk of bone metastasis 2.67 times higher than patients with lower Gleason score (95% CI: 1.31-5.45). In regard to the clinical stage, those patients with a T3 stage had a 6.77 higher risk than those with lower clinical stages (95% CI: 3.79-12.09). Conclusions: Clinical-pathological characteristics associated with bone metastasis were identified in patients with prostate cancer, including age, Gleason scale, PSA value and clinical T stage.

Characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: A systematic review.

BACKGROUNDThyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma (CCRCC) and literature is scarce. Due to the variable and often long lag time before development of metastases in patients with CCRCC, thyroid nodules may be misdiagnosed initially as benign. This systematic review aims at a better understanding of the nature of these metastases.METHODSA bibliographic search was performed using PubMed (1990-2019), key words being “renal cell carcinoma, thyroid, kidney cancer, clear cell.” 147 cases were analyzed. The patient’s characteristics assessed were: age, sex, stage, size of metastases, lag time, diagnostic modality, initial symptoms, treatment and outcome in last documented follow up. Binary logistic regression, Spearman’s rho and ANOVA were used to identify differences between the existing variables.RESULTSThe mean age (± SD) was 64 ± (10) years in males and 64 (± 11) in females. The mean lag time to diagnosis of thyroid metastases was 8.7 (± 6.3) years. Gender distribution of the patients was 46.3% male, 52.4% female. There was a weak correlation between lag time and size of metastases, not statistically significant. Size of metastases was significantly higher in symptomatic patients (6.06 ± 3.51 cm) compared to those with painless mass (4.6 ± 0.29 cm) and asymptomatic ones (3.93 ± 1.99 cm) (P = 0.03). Fine Needle Aspiration was diagnostic in 29.4% of cases, 47.1% were non diagnostic. Most patients (80.3%) underwent thyroid surgery. At 1 year follow up, 55.6% of patients operated were alive versus 35.3% who did not have surgery, though this was not statistically significant (P = 0.1).CONCLUSIONA larger size of thyroid metastasis was more likely to present with symptomatology. A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients. There was no significant difference in outcome between patients who underwent surgery and those who did not. With the wider use of immune check-point inhibitors and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study

BackgroundRetrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC.MethodsMulticentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS).ResultsAmong 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36—NA) in the nadroparin arm and 37.7 months (95% CI, 22.7—NA) in the control arm (HR 0.77 (95% CI, 0.53–1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22–0.9, P = 0.05).ConclusionsAdjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year.Clinical trial registrationNetherlands Trial registry: NTR1250/1217.

Abstract 4542: The use of saliva proteins as biomarkers to predict the risk of lymph node metastasis in oral cancer

Abstract Background. The most common oral cancer in the world is squamous cell carcinoma (OSCC), accounting for more than 90% of all cases of cancer in the oral cavity. Thus, the research on molecular markers associated with the development and progress of human diseases has been the subject of intense research. The findings that saliva has molecular profiles indicating systemic diseases urge the study of non-invasive diagnosis using saliva as source of potential diagnosis, prognosis and predictive based on proteomics. Methods. 204 proteotypic peptides were selected previously based on DDA data from our own studies or retrieved from the SRMAtlas. Heavy labeled synthetic peptides were synthetized and SRM method was developed using Skyline v3.6. Saliva samples were collected from patients with lymph node metastasis (n=26) and without lymph node metastasis (n=14). Saliva proteins were digested with trypsin. Samples were randomized in R environment and analyzed in a triple-quadrupole mass spectrometer (Xevo TQ-XS, Waters). A Peptide Retention Time Calibration Mixture was spiked into the samples. Data comparison between groups was performed using Wilcoxon Mann Whitney test in R environment. Results. In the SRM method, we monitored 68 proteins and 24 of them were found decreased in patients with lymph node metastasis in comparison with patients without lymph node metastasis. The data analysis showed that at least one protein has, by itself, a higher relative risk in the development of lymph node metastasis in patients with OSCC. Two other panel of proteins presented the same relative risk described before. Conclusions. This study indicates a panel of potential OSCC marker proteins, which can contribute to the prognostic evaluation, the patient's risk profile and the possibility of recurrence, and guide therapeutic intervention strategies. Note: This abstract was not presented at the meeting. Citation Format: Tatiane De Rossi, Daniela Campos Granato, Ana Carolina Ribeiro, César Rivera, Henry Heberle, Guilherme Pimentel Telles, Carolina Moretto Carnielli, Thais Bianca Brandão, Alan Roger Santos-Silva, Márcio Ajudarte Lopes, Adriana Franco Paes Leme. The use of saliva proteins as biomarkers to predict the risk of lymph node metastasis in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4542.

A systematic review of the characteristics of thyroid metastases from clear cell renal cell carcinoma.

e16113 Background: Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma (CCRCC) and literature is scarce. Due to the variable and often long lag time before development of metastases in patients with CCRCC, thyroid nodules may be misdiagnosed initially as benign. This systematic review aims at a better understanding of the nature of these metastases. Methods: A bibliographic search was performed using PubMed (1990-2019), key words being “renal cell carcinoma, thyroid, kidney cancer, clear cell.” 147 cases were analyzed. The patient’s characteristics assessed were: age, sex, stage, size of metastases, lag time, diagnostic modality, initial symptoms, treatment and outcome in last documented follow up. Binary logistic regression, spearman and ANOVA were performed to identify differences between the existing variables. Results: The mean age (±SE) was 64± (10) years in males and 64 (±11) in females. The mean lag time to diagnosis of thyroid metastasis was 8.7 (±6.3) years. Gender distribution of the patients was 46.3% male, 52.4% female. There was a weak correlation between lag time and size of metastases, not statistically significant. Size of metastases was significantly higher in symptomatic patients (6.06±3.51cm) compared to those with painless mass (4.6±0.29cm) and asymptomatic ones (3.93±1.99cm) (p = 0.03). Fine Needle Aspiration (FNA) was diagnostic in 29.4% of cases, 47.1% were non diagnostic. Most patients (80.3%) underwent thyroid surgery. At 1 year follow up, 55.6% of patients operated were alive versus 35.3% who did not have surgery, though this was not statistically significant (p = 0.1). Conclusions: A larger size of thyroid metastasis was more likely to present with symptomatology. A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients. There was no significant difference in outcome between patients who underwent surgery and those who did not. With the wider use of immune check-point and tyrosine kinase inhibitors in metastatic CCRCC, surgery may eventually be reserved only for palliative purposes.

Role of serum cholinesterase in patients treated with salvage radical prostatectomy

BackgroundSerum cholinesterase (ChE) a serine hydrolase that catalyses the hydrolysis of esters of choline, is involved in cellular proliferation and differentiation, therefore affecting carcinogenesis. The aim of this study was to understand the prognostic role of preoperative serum ChE in patients with radiation-recurrent prostate cancer (CaP) treated with salvage radical prostatectomy (SRP). Material and methodsThis retrospective study included 214 patients with radiation-recurrent CaP treated with SRP from January 2007 to December 2015 at 5 academic centers. Patients were considered with abnormal/decreased ChE levels if <5 kU/l. Biochemical recurrence-free and metastases-free (MFS) survival analyses were performed. ResultsMedian serum ChE level was 6.9 (interquartile range) 6–7.7) kU/l. Serum ChE level (<5 kU/l) was decreased in 25 (11.7%) patients. Decreased serum ChE level was associated with lower body mass index (P = 0.006) and metastasis to lymph nodes (P = 0.004). In multivariable analysis, continuous ChE was an independent predictor of MFS (hazard ratio [HR] 0.48, confidence interval [CI] 0.33–0.71, P < 0.001), overall survival (HR 0.68, CI 0.48–0.96, P = 0.03) and cancer-specific survival (HR 0.41, CI 0.2–0.84, P = 0.01). Serum ChE improved the C-index (by 2.54%) to 87.8% for prediction of overall survival and (by 3%) to 92% for prediction of MFS. ConclusionPreoperative serum ChE is associated with the development of metastasis in patients with radiation-recurrent CaP who underwent SRP. The biological underpinning of this association with the biological and clinical aggressiveness of CaP needs to be further elucidated.

Prognostic factors for metastasis in cutaneous melanoma

BackgroundMelanoma is a malignant neoplasia that shows high mortality when diagnosed in advanced stages. Early identification of high-risk patients for the development of melanoma metastases is the main strategy to reduce mortality.ObjectiveTo assess the influence of eight epidemiological and histopathologic features on the development of metastases in patients diagnosed with primary cutaneous melanoma.MethodsOur historical cohort comprised patients with invasive primary cutaneous melanoma seen between 1995 and 2012 at a public university hospital and a private oncologic surgery institution in Southeastern Brazil. The following variables were analyzed: gender, age, family history of melanoma, site of the primary tumor, clinical and histologic subtype, Breslow thickness, histologic ulceration and the mitotic index. Kaplan-Meier univariate test and multivariate Cox proportional hazard analysis were used to assess factors associated with disease-free survival.ResultsFive hundred and fourteen patients were enrolled. The univariate analysis identified the following significant risk factors: gender, age, site of the tumor, clinical and histologic subtype, Breslow thickness, histologic ulceration and mitotic index. Multivariate analysis included 244 patients and detected four significant prognostic factors: male gender, nodular clinical and histologic subtype, Breslow thickness > 4mm, and histologic ulceration. The mitotic index was not included in this analysis.Study limitationsSmall number of patients in multivariate analysis.ConclusionsThe following prognostic factors to the development of melanoma metastasis were identified in the study: male gender, nodular histologic subtype, Breslow thickness > 4mm and ulceration.

Evaluation of miRNA-21 and miRNA Let-7 as Prognostic Markers in Patients With Breast Cancer

BackgroundBreast cancer remains one of the top threats to women’s health. The current lack of tumor markers with desirable sensitivity and specificity is a major obstacle toward the future management of breast cancer. Many studies are directed to reveal the diagnostic and prognostic potentials of circulating miRNAs in breast cancer. In this study, we attempt to evaluate the feasibility and clinical utility of circulating miRNA-21 and let-7 as prognostic biomarkers for breast cancer. MethodsReal-time quantitative polymerase chain reaction technique was used. Levels of miRNA-21 and let-7 expression were determined in sera from 125 participants representing 3 different groups. With fold-change analysis, the expression of miRNA-21 and let-7 in the decided groups were assessed. ResultsPatients with breast cancer showed significantly higher expression of miRNA-21 compared with controls and other participants with benign breast lesions (P < .001). The mean expression levels of serum miRNA-21 was 3.27 ± 2.10-fold in patients with breast cancer. The expression of miRNA let-7 was significantly decreased in patients with breast cancer (2.45 ± 2.20-fold) than the control group and the benign breast lesions group (5.27 ± 3.30-fold and 6.22 ± 4.90-fold, respectively; P < .001). Levels of miRNA let-7 expression negatively correlated with development of metastases in patients with breast cancer (P < .001). ConclusionsOur study establishes the association between altered levels of miRNA let-7 and metastases risk in patients with breast cancer, implying a role of miRNA let-7 in disease progression and prognosis.

Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

2007 Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p &lt; 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, &lt; 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.

Abstract P1-12-03: Association between tumor genotype and development of brain metastases in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer

Abstract Introduction: Historically, brain metastases are considered to be uncommon in HR+/HER2- breast cancer compared to triple-negative or HER2+ breast cancer. However, improved systemic therapy and prolonged overall survival in patients with metastatic HR+/HER2- breast cancer may result in increased incidence of brain metastases as most currently available therapeutic agents do not penetrate blood-brain barrier giving the brain a sanctuary site status. Although certain tumor cells may also exhibit brain-specific tropism or may have selective growth advantage in the brain microenvironment, biological factors that govern metastases to brain, including role of PIK3CA mutations, are poorly understood. In this study, we review our clinical experience with the brain metastases among patients with metastatic ER+/HER2- breast cancer, including their association with PIK3CA genotype. Methods: Since 2008, at our institution, a multiplexed tumor genotyping assay (SNaPshot), has been utilized to assess for presence of potentially actionable oncogenic driver mutations, including PIK3CA, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. We identified patients with metastatic HR+/HER2- breast cancer who had tumor genotyping performed at any point during their care and who had at least 6 months of follow-up in our clinic. Relevant clinical information, including development of brain metastases, was gathered from chart reviews. Results: From a total of 251 patients with HR+/HER2- metastatic breast cancer, 23.5% (N=59) developed brain metastases. Approximately 1/3rd of patients (31.7%, N = 20) had brain metastases seen on imaging as an incidental finding, while others presented with 1-2 symptoms that could be associated with CNS disease, including ataxia/weakness (34.9%), visual/speech difficulties (26.9%), headaches (23.8%), altered mental status (14.3%), seizures (14.3%), and nausea (9.5%). PIK3CA mutations were identified in 45.2% of all patients, including mutations in both helical (exon 9) and kinase (exon 20) domains. Patients with tumors harboring PIK3CA mutations had significantly higher incidence of brain metastases, as compared to those without PIK3CA mutations (30.7%, versus 18.7%; p = 0.034). The median time between diagnosis of metastatic disease and diagnosis of brain metastasis was longer among those patients with PIK3CA mutation (32 months) as compared to those without PIK3CA mutation (18 months). Conclusion: Brain metastases are common among patients with HR+/HER2- breast cancer, particularly HR+/HER2- breast cancer harboring PIK3CA mutations where it approaches the incidence historically seen in HER2+ breast cancer. Early recognition and appropriate diagnostic work-up of any symptoms potentially associated with presence of CNS disease is necessary in PIK3CA-mutant HR+/HER2- breast cancer. Further studies are needed to explain the mechanistic link between the PIK3CA mutant phenotype, phosphatidylinositol 3-kinase (PI3K) pathway activation and CNS disease. Citation Format: Fitzgerald DM, Henderson LE, Isakoff SJ, Moy B, Oh K, Shih HA, Dias-Santagata D, Borger DR, Iafrate AJ, Brastianos PK, Bardia A, Juric D. Association between tumor genotype and development of brain metastases in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-03.

Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma.

BackgroundEpigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis.ResultsmiR profiling of tumors by microarray found six miRs over-expressed and 19 under-expressed in 33 tumors with monosomy-3 compared to 22 without. None of the miRs differentially expressed in tumors with and without monosomy-3 was differentially expressed in tumors with and without tumor infiltrating lymphocytes. Tumors manifesting monosomy-3 were also characterized by higher levels of TARBP2 and DDX17 and by lower levels of XPO5 and HIWI, miR biogenesis factors. miR profiling of plasma by a quantitative nuclease protection assay found elevated levels of 11 miRs and reduction in four in patients with tumor monosomy-3. Only three miRs differentially expressed in the tumor arrays were detectable in plasma. miRs implicated in uveal melanoma development were not differentially expressed. Elevated plasma levels in patients with tumor monosomy-3 of miR-92b, identified in the tumor array, and of miR-199-5p and miR-223, identified in the plasma array, were confirmed by quantitative real-time polymerase chain reaction. Levels were also higher in patients compared to normal controls.ConclusionsThese results support a role for epigenetic mechanisms in the development of metastasis in patients with uveal melanoma and the analysis of miRs as biomarkers of metastatic risk. They also suggest that potentially useful blood miRs may be derived from the host response as well as the tumor.

Identification of high-risk Dukes B colorectal cancer by microRNA expression profiling: a preliminary study.

MicroRNAs (miRNAs) from tumour tissue and common gene mutations were studied to determine whether they predict the development of metastasis in patients with Dukes B colorectal cancer. Patients who underwent curative resection for Dukes B colorectal cancer who subsequently developed distant metastatic disease at some stage in the following 5 years ('high-risk B') were compared with case-matched controls of Dukes A, Dukes B (no metastases, 'low-risk B') and Dukes C patients without any detectable metastasis at 5 years of follow-up. MiRNAs from tumour and adjacent normal tissue and common gene mutations (KRAS, BRAF, PIK3CA) in primary cancer tissue were analysed to identify prognostic tissue markers for the development of metastasis in patients with Dukes B colorectal cancer. Expression of miR-15b and miR-135b was significantly downregulated (P < 0.001) in 'high-risk B' tumours compared with Dukes A, 'low-risk B' and C without metastasis. No significant differences were noted for mutation status and the development of metastasis. The study suggests that the development of metastasis in Dukes B tumours may be predictable based on the miRNA expression of miR-15b and miR-135b. This requires further study on a much larger cohort.

The co-chaperone p23 promotes prostate cancer motility and metastasis

Prostate cancer is an androgen receptor (AR)-dependent malignancy at initiation and progression, therefore hormone therapy is the primary line of systemic treatment. Despite initial disease regression, tumours inevitably recur and progress to an advanced castration-resistant state a major feature of which is metastasis to the bone. Up-regulation of AR cofactors and chaperones that overcome low hormone conditions to maintain basal AR activity has been postulated as a mechanism of therapy relapse.p23, an essential component of the apo-AR complex, acts also after ligand binding to increase AR transcriptional activity and target gene expression, partly by increasing chromatin-loaded holo-receptor-complexes. Immunohistochemical studies have demonstrated increased p23 expression in advanced prostate cancer. Here, we further characterise p23 roles in AR signalling and show that it modulates cytosolic AR levels in the absence of hormone, confirming a chaperoning function in the aporeceptor complex and suggesting p23 upregulates AR signalling at multiple stages. Moreover, p23 protein levels significantly increased upon treatment with not only androgen but also clinically relevant anti-androgens. This was in contrast to the HSP90 inhibitor 17-AAG, which did not modulate expression of the cochaperone – important given the HSP90-independent roles we and others have previously described for p23.Further, we demonstrate p23 is implicated in prostate cancer cell motility and in acquisition of invasiveness capacity through the expression of specific genes known to participate in cancer progression. This may drive metastatic processes in vivo since analysis of prostate tumour biopsies revealed that high nuclear p23 significantly correlated with shorter survival times and with development of metastases in patients with lower grade tumours. We propose that increased p23 expression may allow cells to acquire a more aggressive phenotype, contributing to disease progression, and that p23 is a plausible secondary target in combination with HSP90 inhibition as a potential therapy for advanced prostate cancer.

Association of the development of bone metastases with the development of brain metastases in patients with non-small cell lung cancer.

e13030 Background: In patients (pts) with non-small cell lung cancer (NSCLC), it is unknown whether pts with bone metastases are predisposed to the development of brain metastases. The impact of bevacizumab (Bev) on the development of bone and brain metastases is not fully characterized. Methods: Retrospective review of pts with stage IV NSCLC without brain metastasis at diagnosis was undertaken. The primary endpoint was to determine whether the development of bone metastases is predictive of the development of brain metastases. Secondary endpoints involved the proportion of pts who developed brain and/or bone metastases while being treated with Bev. Data were analyzed using competing risks methods. Results: A total of 175 pts (52% males, median (range) age: 60 y (35-80)) were studied. Of whom 79% received Bev and 21% did not receive Bev as part of their treatment. Overall 34% of pts had bone metastases at the start of therapy. Pts with pre-existing bone metastases tended to develop new bone disease more frequently than pts who did not initially have bone metastases (39% vs. 19%, p =. 01). The incidence of the development of brain metastases among pts who had pre-existing bone metastases was 17% vs.16 % in pts without pre-existing bone metastases. However, the incidence of brain metastases among pts with pre-existing bone disease who developed new bone metastases was 33% vs. 6% in pts who did not develop new bone disease but had pre-existing bone metastases. Adjusting for initial bone disease, development of new bone metastases was associated with a shorter brain metastases-free interval HR 5.06 (2.03-12.65; p = 0.005). In a subgroup analysis based on Bev exposure, the likelihood of developing brain and bone metastases within 2 years of starting Bev was estimated to be 25% and 27%, respectively, while the likelihood of developing brain and bone metastases without Bev treatment was 33% and 43 %, respectively. Conclusions: In pts with NSCLC, the development of new bone metastases may be indicative of the subsequent development of brain metastases. Additionally, Bev therapy may have an effect on the development of both bone and brain metastases. A prospective investigation may be warranted.