bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating tumor DNA in patients with metastatic urothelial cancer: concordance of genomic findings with matched tissue biopsies.
Authors: Lavoie Jean-Michel , Vandekerkhove Gillian , Annala Matti , Sundahl Nora , Sano Takeshi , Struss Werner J. , Todenhöfer Tilman , Ost Piet , Chi Kim N. , Black Peter C. , Eigl Bernhard J. , Wyatt Alexander William
Published: May 2019

e16036

Background: Patients (pts) with metastatic urothelial cancer (mUC) now have access to many different treatment options. This creates an incentive for molecular profiling of their tumors, with the aim of developing biomarkers. Genomic profiling may leverage the presence of circulating tumor DNA (ctDNA), but it has not been shown whether this recapitulates the findings from tissue samples. Methods: Whole blood samples were collected for next-generation sequencing of leukocyte and cell-free DNA (cfDNA). Deep targeted sequencing was performed across a UC-specific custom 50-gene panel (median depth of 986x). Matched archival tissue was profiled using the same assay for 65 pts. Results: Between 11/2011 and 12/2017, 90 pts developed mUC (87 evaluable). Baseline characteristics: median age 67, 83% male, 14% upper-tract disease, 17% stage IV at initial presentation. Treatments delivered: 76% platinum-based chemotherapy, 47% PD-1/PD-L1 inhibitor. At a median follow-up of 12.8 mo., 45% remain alive. We found ctDNA fractions above 2% in at least one blood collection in 81% of cases. For 17 pts, matched metastatic biopsies and cfDNA collection were available; in those cases 82% of coding somatic mutations identified in tissue were independently detected in cfDNA. Half of discordant findings could be attributed to low ctDNA fraction. Most (89%) mutations detected in primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. ctDNA detected mutations in TP53 and ARID1A in 64% and 29% of pts, respectively. A tumor mutation burden ≥25 mutation per Mb was observed in 27% of cases. Conclusions: There is a high concordance between genomic findings from ctDNA and matched tissue of pts with mUC. This supports the use of liquid biopsies to study potential biomarkers in this disease.
Association of immune-related adverse events (irAEs) with clinical benefit in patients with metastatic urothelial carcinoma (mUC) treated with immune-checkpoint inhibitors (ICIs).
Authors: Pier Vitale Nuzzo , Pond Gregory Russell , Abou Alaiwi Sarah , Nassar Amin , Flippot Ronan , Choueiri Toni K. , Harshman Lauren Christine , Sonpavde Guru
Published: May 2019

e16038

Background: In other cancers such as metastatic lung and melanoma, pts who experience irAEs may have a greater degree of clinical benefit. We sought to evaluate whether the development of irAEs correlates with clinical benefits in mUC pts. Methods: We identified mUC pts who received PD-1/L1 inhibitors at the Dana-Farber Cancer Institute (DFCI). The severity of irAEs was graded using CTCAE v.5.0. Clinical benefit was defined as any objective reduction (complete- or partial- response) in tumor burden. Fisher’s exact test was used to evaluate for differences in the proportion of pts experiencing clinical benefit between pts experiencing an irAEs within 90 days after starting therapy and those who did not experience an irAEs. The log-rank test assessed differences in progression-free survival (PFS) and overall survival (OS) between cohorts. Results: A total of 199 mUC pts were enrolled between July 2013 and October 2018 [median (range) age, 69.6 (26.6-89.0) years; 141 men (70.9%), 58 women (29.1%)]. 114 (57.3%) pts were treated with anti-PD-1 and 85 (42.7%) with anti-PD-L1. irAEs were observed in 67 pts (33.7%), of which 34 (17.1%) < 90 days from start of therapy. Common irAEs included 20 (29.9%) hypothyroidism, 17 (25.4%) colitis, 12 (17.9%) rash/pruritus, and 10 (14.9%) transaminitis. Grade ≥3 irAEs were observed in 14 pts (20.9%).13 (40.6%) pts with irAE < 90 days experienced clinical benefit compared with 21 (17.8%) of pts with no irAE (p-value = 0.008). No difference (p = 0.26 and 0.18) was observed for either PFS (6-month PFS = 19.2% vs 35.3% for no irAE and irAE < 90 days) or OS (1-year OS = 41.8% vs 57.7% for no irAE vs irAE < 90 days). Conclusions: The development of irAEs within 90 days from starting therapy in mUC pts may herald clinical benefit in pts with mUC. Further evaluation of this potential relationship in a large prospective study is warranted.
Analysis of three models to predict pathohistology in patients undergoing postchemotherapy RPLND for (pcRPLND) advanced nonseminomatous germ cell tumors (NSGCT).
Authors: Heidenreich Axel , Paffenholz Pia , Pfister David , Hellmich Martin , Albers Peter , Hiester Andreas , Nini Alessandro , Nestler Tim
Published: May 2019

e16053

Background: We aim to validate the two best performing prediction models (Vergouwe and Leao) for final pathohistology in NSGCT patients undergoing pcRPLND and we introduce a new radiomics approach. Methods: A cohort of 496 patients treated between 2008 and 2018 was used to validate the 2 prediction modelsusing published formulas and thresholds.For group comparisons, we used t-test or chi-square test. ROC were plotted (sensitivity against 1-specificity) and AUC was calculated. We determined the optimal cut point and used bootstrapping (1,000 replications) to estimate its variability. A p-value of < 0.05 was considered statistically significant. For radiomics, lymph nodes identified on CT images, were semiautomatically segmented with 93 radiographic features (pyRadiomics package). A linear support vector machine algorithm was applied to analyze reproducible radiomics features. A continuous reduction of features analyzed was performed using Random Forest algorithms and ROC analysis. Results: The Vergouwe model had a significantly better AUC compared to Leao model (0.749 [CI 0.706-0.792] vs. 0.689 [0.642-0.736], p = 0.004) to predict benign histology. At a threshold of > 70% for the probability of benign disease, the Leao model would have avoided RLND in 8.6% with benign disease with an error rate of 5.6% for viable tumor. The Vergouwe model would avoid pcRPLND in 23.4% with benign disease with an error rate of 12.7% for viable tumor/teratoma. Of the 93 radiomic features analyzed, 51 features were reproducible. Applying the trained algorithm resulted in a AUC of 82% with a diagnostic sensitivity of 81% and a specificity of 83%. Conclusions: The discriminatory accuracy of both models is not sufficient to safely select patients for surveillance strategy instead of pcRPLND. The radiomics model is promising but needs prospective validation. Further studies including new biomarkers are needed to optimize the accuracy of potential prediction models.
Long-term sexual impairment in relationship with metabolic health in testicular germ-cell tumor survivors.
Authors: Chovanec Michal , Vasilkova Lucia , Petrikova Lucia , Obertova Jana , Palacka Patrik , Rejlekova Katarina , Sycova-Mila Zuzana , Hapakova Nikola , De Angelis Valentina , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: May 2019

e16060

Background: Treatment for germ-cell tumors (GCT) results in long-term sexual difficulties in GCT survivors, as we have shown previously. This study aimed to correlate the long-term sexual difficulties with serum parameters of metabolic functioning. Methods: GCT survivors (N = 155) from a national cancer center completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire at a median 10 years of follow up (range 5-32). Twenty-nine (18%), 30 (19%) and 20 (13%) survivors have suffered from severe difficulty to achieve erection, maintain erection and achieve orgasm, respectively. Severe difficulty was characterized as a score of 0-2 (scale 0-5) in respective questions from the questionnaire. Sexual impairment was then correlated with parameters of metabolic functioning assessed from peripheral blood of all survivors drawn at the day of the clinical visit. Results: Survivors with difficulty to achieve erection had significantly higher levels of alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and lactate-dehydrogenase (all P < 0.05). Impaired ability to achieve an orgasm also correlated with significantly higher levels of ALT, AST and LDH (all P < 0.05). Survivors with difficulty to maintain erection had higher levels of LDH (P = 0.02) and AST (trend for P = 0.06), but not ALT ( P = 0.5) and their cholesterol levels were significantly higher ( P = 0.04). Furthermore, survivors with higher levels of glucose ( P = 0.04), thyroid stimulating hormone ( P = 0.04), but not of free-thyroxin ( P = 0.3) suffered from difficulty to achieve orgasm. Conclusions: Our prospective study shows that an impairment in sexual function resulting from curative treatment of GCTs may be related to metabolic health. Higher liver enzymes may be indicative of endothelial dysfunction and cardiovascular disorder. Long-term sexual impairment in GCT survivors should be a subject of further translational research to uncover the underlying molecular mechanisms.
Circulating tumor (ct)-DNA alterations in patients with testicular germ tumors.
Authors: Nassar Amin , Agarwal Archana , Nagy Rebecca , Curran Catherine , Abou Alaiwi Sarah , Lanman Richard B. , Talasaz AmirAli , Sweeney Christopher , Sonpavde Guru
Published: May 2019

e16063

Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, ctDNA genomic alterations observed in in testicular GCTs have not been heretofore described. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 31 Pts with testicular GCTs from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Two patients had one serial ctDNA sample. De-identified demographic data were collected in addition to data for ctDNA alterations. Guardant360 is a CLIA-certified ctDNA panel that assesses single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 31 patients with testicular GCTs, 162 ctDNA alterations were detected in 26 patients (84%) across 41 genes (Table). A median number of 3 alterations (range 1-19) was detected per sample. Among the 162 alterations, 88 were believed to be pathogenic and detectable in 20 patients (65%). 12/31 pts (39%) were documented to be post systemic therapy. The median age was 38 years (range 20-61). The most common pathogenic somatic alterations were KRAS (n = 12/88, 14%), CCND2 (n = 8/88, 9%), MET (n = 8/88, 9%), CDK6 (n = 7/88, 8%), TP53 (n = 6/88, 7%), and RAF1 (n = 5/88, 6%). In 2 patients with serial samples, 5 novel pathogenic alterations were detected in the second sample including FGFR2, APC, CDK6, RAF1, and MAPK1. Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to determine it's relevance in clinical practice. [Table: see text]
Novel risk stratification criteria of metastatic renal cell carcinoma (mRCC) patients (pts) treated with immune checkpoint inhibitors (ICI).
Authors: Martini Dylan J , Liu Yuan , Shabto Julie M. , Carthon Bradley Curtis , Russler Greta , Hitron Elise , Caulfield Sarah , Kissick Haydn , Harris Wayne , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim
Published: May 2019

e16068

Background: IMDC risk criteria is the gold standard for predicting outcomes for mRCC pts. We developed novel risk groups for mRCC pts treated with ICI. Methods: We performed a retrospective review of 100 ICI-treated mRCC pts at Winship Cancer Institute from 2015-2018. Overall survival (OS) and progression-free survival (PFS) were used to measure outcomes; OS was the primary outcome. We obtained baseline monocyte-to-lymphocyte ratio (MLR), body mass index (BMI), and metastatic (met) sites. We created a new variable (D_met) that combines number and sites of met: 0 = < 2 met sites; 1 = ≥ 2 met sites without liver metastases (mets); 2 = ≥ 2 met sites with liver mets. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS. Recursive partitioning and regression tree analyses were used for risk stratification. Discrimination of the risk score was measured by Uno C-statistics. Results: The pts were 66% males, 78% clear cell RCC (ccRCC), and 71% received anti-PD-1 monotherapy. Very poor risk pts (MLR ≥ 0.93 or MLR < 0.93, BMI < 24, and D_Met = 2) had significantly shorter OS and PFS than good risk pts (MLR < 0.93, BMI ≥ 24, and D_Met = 0) in univariable and multivariable analysis (UVA and MVA, Table). The Uno C-statistic for our risk grouping criteria compared to IMDC is 0.687 vs 0.566 (p = 0.061) for OS and 0.594 vs 0.541 (p = 0.78) for PFS. Conclusions: Risk grouping using MLR, BMI, and number and sites of mets may predict survival in mRCC pts treated with ICI. These results should be validated in a larger, prospective study. [Table: see text]
Long term relative survival (RS) in patients with primary metastatic kidney cancer: An analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Hackl Monika , Rauchenwald Michael
Published: May 2019

e16069

Background: The introduction of thyrosinkinase inhibitors (TKI) changed the treatment of metastatic kidney cancer fundamentally. In Austria, TKI was in troduced in 2006. To elaborate the potential impact of TKI therapies, we studied trends in OS for patients diagnosed with primary metastatic kidney cancer between1998 and 2015 in Austria. Methods: All patients with primary metastatic kidney cancer aged ≥18 years, diagnosed from 1998-2015 were derived from the ANCR (n = 2,490). Patients diagnosed from 2004-2005 (n = 323) were excluded (transition period of systemic therapies). To evaluate survival differences between patients treated before and after the introduction of Sunitinib (preTKI-era and TKI-era), three periods were defined: 1998-2003 (preTKI-era; N = 937), 2006-2010 (TKI-era P1; N = 687) and 2011-2015 (TKI-era P2; N = 543). Follow-up was complete until December 31st, 2016. RS rates were estimated by using method. The Cox proportional hazard model was used to calculate hazard ratios (HR). Results: A total of 2,167 patients was included in the analysis. The median age of the study population was 70 yrs and did not differ between the three eras. The incidence of T1 tumors increased from 6.9% in the preTKI-era to 10% in the TKI-era while T4 tumors decreased from 15% to 8% (p < .001). Surgery rate declined from 50% in the preTKI-era to 43% in 2011-2015 (p = .02). Five-year RS for patients undergoing surgery slightly increased from 18% in the preTKI-era to 23% in TKI-era P1 (p = .04). For patients without (p = .04). For patients without surgery 5-year OS improved from 5.2% in the preTKI-era to 9.1% in TKI-era P1 (p < .001). Apart from surgery, survival gain was observed for younger patients ( < 75 yrs) of +6% (p = .01), older patients ( > = 75 years) of +0.2% (p = .03) and for T3/T4 tumors of +6% (p = .002). The Relative Excess Risk of dying (RER) for patients treated in the TKI-eras was reduced compared to the preTKI-era (HR 0.78, 95% CI 0.76-0.95) adjusted for sex, age, T-stage and surgery. Survival advantage for patients undergoing surgery remained significant (HR: 0.46, 95% CI 0.41-0.52) after adjustment for TKI-era, sex, age, T-stage. Conclusions: Patients with primary metastatic kidney cancer treated in the TKI era show improved RS compared to the cytokine era. Most benefit was observed in non-surgical patients, younger patients and for T3/T4 disease. Surgery remains as an important therapy for additional survival benefit.
Prognostic and predictive biomarkers for clear cell renal cell carcinoma utilizing next generation sequencing.
Authors: Zekri Jamal , Meliti Abdelrazak , Baghdadi Mohammed Abhas , Sobahy Turki , Imtiaz Saba
Published: May 2019

e16070

Background: The management of the clear cell renal cell carcinoma (cc-RCC) has evolved over the past decade. Clinical patients’ and tumor characteristics have a limited role in predicting the outcome of these patients. The search for reliable prognostic and predictive biomarkers should be pursued in particular during the current era of next generation sequencing (NGS) technology. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens of cc-RCC were sequenced using NGS and a customized gene panel testing for 72 tumor-related genes. High potential variants were defined by mutation effect (stop-loss, stop-gain, frame-shift substitutions or non-synonymous SNV) and class (pathogenic or likely pathogenic). Cases with identical variants were identified. Results: In total, all 47 cases had 69,052 variants, of which 20,453 were classified as high potential variants. Identical alterations in 15 genes were present in all samples. These genes are: MUC3A, MUC12, MUC7, SRRT, MUC2, MUC5AC, MUC5B, MUC22, MUC6, CR1, MUC4, MUC16, MUC19, MUC17 and MERTK. The numbers of identical and non-identical variants in these 15 genes were counted for each sample. Median number of variants was 377 and was selected as a cut off to define cases with high ( > 377) and low (≤377) variants number (HVN and LVN respectively). For the whole cohort, HVN was associated with shorter overall survival compared to LVN (Median 50 months vs. not reached; Log Rank P = 0.041). In the 11 patients who received anti-angiogenic tyrosine kinase inhibitors (TKIs), HVN was associated with a trend of shorter progression free survival (Median 5 vs. 10 months; Log Rank P = not significant). Conclusions: Alterations in SRRT, CR1, MERTK and MUCIN family genes are very common in RCC. HVN ( > 377) is associated with worse prognosis and may predict decreased benefit from anti-angiogenic TKIs.
The clinical outcome of renal cell carcinoma with rhabdoid and sarcomatoid differentiation.
Authors: Samiei Arash , Tayshetye Pritam , Sanguino Angela , Miller Ralph , Lyne John , Cohen Jeffrey , Mao Shifeng
Published: May 2019

e16083

Background: Renal cell carcinoma (RCC) with rhabdoid (RD) or sarcomatoid differentiation (SD) represents high-grade RCC with an aggressive clinical behavior. Little success has been reported in treating these patients. No standard management has been established and there is a lack of insight in these entities because of their relatively low incidences. We reviewed a cohort of RCC patients with RD and SD and correlated the pathologic features with their clinical outcomes. Methods: A retrospective study of RCC patients with RD or SD feature at a single center from 2008 to 2016 was conducted. Patient characteristics, pathology findings, clinical management, and survival data were collected. Results: A total of 36 RCC patients, with median age of 65 [47-88] years old, were included. The male-to-female ratio was 2.6:1. Among them, 24 were with pure SD and 12 with RD (7 pure and 5 mixed features). At diagnosis, 14 patients (38.9%) presented with stage IV disease. The median follow-up was 21 [2-53] months. Of the 36 patients, 24 developed metastasis, including 16/24 (67%) with SD, 4/7 patients (57%) with pure RD, and 4/5(80%) with mixed features. Mortality rate was 79% for SD, 75% for RD and 100% for those with mixed features. The overall survival was 23, 22, and 13 months for SD, pure RD and those with mixed features, respectively. 12 patients were treated with tyrosine kinase inhibitors (TKI) in first-line and 7 with immune checkpoint inhibitors (ICI) in the second or third line setting. Longer duration of treatment was seen with ICI than TKI, 12.8 [5-25] vs 5.9 [1-18] months (p = 0.03). Partial response was seen in 6/7 (86%) and stable disease in 1/7 (14%) patients treated with ICI. No survival benefit was seen in patients treated with TKI alone (p = 0.60). Patients received ICI had significantly prolonged overall survival compared to those received TKI alone, 31.4 vs 17.8 months (p < 0.001). Conclusions: The presence of RD or SD portends poor outcome in RCC with conventional management, especially in those with mix of both features. However, these patients had exceptionally high response and improved survival if treated with ICI. A prospective study using ICI focusing on RCC patients with these pathologic features is warranted and could provide hope for such dismal entities.
Association of body mass index (BMI) with clinical outcomes in 203 metastatic clear cell renal cell carcinoma (ccRCC) patients (pts) treated with immuno-oncology (IO) agents.
Authors: Ged Yasser , Lee Chung-Han , Sanchez Alejandro , Duzgol Cihan , Chaim Joshua , Carlo Maria Isabel , Foster Ashley , Akin Oguz , Feldman Darren R. , Hakimi A. Ari , Patil Sujata , Motzer Robert J. , Furberg Helena , Voss Martin Henner
Published: May 2019

e16103

Background: Obesity is a known risk factor for the development of ccRCC. For malignant melanoma, higher BMI was recently associated with improved outcomes to IO therapy (McQuade, Lancet Onc, 2018), a potential explanation being an obesity-associated inflammation effect. The association of BMI and clinical outcomes in mccRCC pts treated with IO therapy is unknown. Methods: Baseline characteristics and outcomes on therapy were retrospectively collected for pts with mccRCC who received IO-only regimens for at least 4 weeks at our institution. BMI and IMDC risk categories were determined for all pts at IO initiation. The log-rank statistic was used to test the associations between BMI with overall survival (OS) and progression free survival (PFS) and the chi-square test for the association with objective response rates (ORR). Results: Of the 203 eligible pts, 31% were normal weight, 36.5% were overweight, and 32.5% were obese. 24% of pts received IO as first line treatment. IMDC favorable vs intermediate/poor risk was 11 vs 89% in normal weight pts, 20 vs 80% in overweight pts and 20 vs 80% in obese pts. Median follow up time for survivors was 28.6 months (3.4-88). Obese and overweight pts experienced longer OS than those who were normal weight (P=0.01) (normal weight vs. obese, HR 2.0, 95% CI 1.20-3.37). However, this association became non-significant after adjusting for IMDC risk. RECIST evaluations were available for 107 pts. A higher ORR was seen in obese (41%) compared to overweight (15%) or normal weight (28%) pts (P=0.03). We found no association between BMI and PFS. Findings are summarized in the table below. Conclusions: In mccRCC pts treated with IO, obesity associates with superior outcomes, but does not appear to be independent of IMDC risk score. Research into the underlying mechanisms of obesity as a possible biomarker of IO clinical benefit is warranted. [Table: see text]
A systematic review of the characteristics of thyroid metastases from clear cell renal cell carcinoma.
Authors: Khaddour Karam , Marenych Nadiia , Liu Jerry X. , Ward Wendy , Pappa Theodora
Published: May 2019

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.
Lymphopenia and clinical significance associated with tyrosine kinase inhibitors in metastatic renal cell cancer in Guatemalan cohort.
Authors: Ramirez Rixci , Rosales Lopez Daniel Estuardo , Godinez Jerez Francisco , Mansilla Alfredo , Camey Carolina , Oliva Vega Gustavo
Published: May 2019

e16117

Background: Lymphopenia is associated with toxicity and clinical outcomes in several types of cancer. Decrease in absolute lymphocyte count (ALC) has been observed in the treatment with sunitinib. Objective: characterize lymphopenia ( < 1000/µL) associated with tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma (mRCC) and its relation to progression free survival (PFS). Methods: A retrospective review of the charts was performed in patients with sunitinib and/or sorafenib between April 2000 and May 2017 in Guatemalan Social Security Institute (IGSS). The Kaplan-Meier models, the Cox regression and the log-rank test are within the groups for progression-free survival. Results: Eighty-nine patients were analyzed, 56 men and 33 women. The age groups < 50 from 51 to 75 and > 75 being these 19, 34 and 34 respectively. Regarding treatment received 56 patients received sunitinib and 47 sorafenib. Lymphopenia was found in 55% and 8% of the treated with sunitinib and sorafenib, respectively (p < 0.001). Focusing on patients treated with sunitinib for all subsequent analyzes, the median PFS was 11 months (95% CI, 6-19). The median PFS was 21 months (95% CI, 11-25) for patients who will not develop lymphopenia compared to 4 months (95% CI, 3-8) in patients with lymphopenia (p = 0, 0001). Conclusions: Lymphopenia related to sunitinib is associated with a decrease in PFS in mRCC. The decrease in lymphocytes can be used as a prognostic biomarker for patients treated with sunitinib in this context. [Table: see text]
Tumor growth rate in metastatic adrenocortical carcinoma using two-dimensional computer tomography scan.
Authors: Fuller Sarah N. , Shafiei Ahmad , Ilanchezhian Maran , Bagheri Mohammadhadi , Del Rivero Jaydira
Published: May 2019

e16125

Background: Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5–2 per million people per year. It has a poor prognosis with an overall 5-year mortality of 75-80%. The treatment of choice for a localized primary or recurrent tumor is radical surgical resection. However, patients with recurrent or metastatic disease are infrequently cured by surgery alone and chemotherapy has limited benefits. Little is known about the growth rate of metastatic lesions or how disease burden varies among patients, which poses a considerable obstacle in patient care as 17–53% of patients present with distant metastases at the time of diagnosis. Most ACC metastases are found in the liver, lung, bone, and retroperitoneum. Methods: This study retrospectively analyzed the growth rate of metastatic ACC lesions in the lung, liver, lymph nodes, and adrenal bed using serial two-dimensional segmentation of computer tomography images from 10 patients seen at the National Institutes of Health. All patients were females (mean age of 61 years; range, 49–70 years) who had an ACC diagnosis for a mean of 7 years (range, 3–14 years). Only lesions that exhibited FGD-PET avidity were included with up to five lesions per organ recorded. Results: Of the 10 patients, 7 showed metastatic disease at primary diagnosis, although all patients developed recurrent and/or distant metastatic lesions throughout the course of their disease (3 patients had lung lesions, 6 had liver lesions, 8 had adrenal bed recurrence, and 5 had lymph node involvement). Compared over a 6-month period without treatment alteration (change in chemotherapy, surgical intervention, or ablation) lung lesions increased by 11.6%, liver lesions decreased by 17.9%, retroperitoneal lesions increased by 69.25%, and lymph node lesions increased by 9.2%. Conclusions: Treatment of metastatic lesions, particularly in the liver, can increase long-term survival. Understanding growth rates of metastatic tumors may lead to improved treatment of patients with ACC.
Safety and preliminary immunogenicity of JNJ-64041809, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy, in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Drake Charles G. , Pachynski Russell Kent , Subudhi Sumit Kumar , McNeel Douglas G. , Antonarakis Emmanuel S. , Bauer Todd Michael , Patricia Daniel , Wade Mark , Zudaire Enrique , Mason Gary , Knoblauch Roland Elmar , Stone Nicole L. , Infante Jeffrey R. , Gottardis Marco , Fong Lawrence
Published: May 2019

e16509

Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live attenuated, double-deleted Listeria monocytogenes (LADD- Lm)-based immunotherapy targeting relevant prostate cancer antigens, was evaluated in a phase 1, multicenter, open-label study in patients (pts) with mCRPC. Methods: Men aged ≥18 years with progressive mCRPC who had received ≥2 prior approved therapies were included. The recommended phase 2 dose (RP2D) and the safety and immunogenicity of JNJ-809 were evaluated. Dose-limiting toxicities (DLTs), adverse events (AEs), T cell response, tumor response, and JNJ-809 bacterial shedding profile were assessed at 2 dose levels, 1 x 108 and 1 x 109 colony forming units (CFU). Results: 26 pts (median age 66.5 years, White 96%) were enrolled (1 x 108 CFU, n = 6; 1 x 109 CFU, n = 20). Median duration of treatment was 2.5 months (range 0-9.7). No DLTs occurred and 1 x 109 CFU was selected as the RP2D. Most common AEs were chills (n = 24, 92%), pyrexia (n = 21, 81%), and fatigue (n = 16, 62%). Grade ≥3 AEs were reported in 18 (69%) pts and serious AEs in 7 (27%) pts including 1 pt with investigator-assessed treatment-related grade 3 intestinal obstruction. At 1 x 108 CFU, all pts had negative blood cultures. At 1 x 109 CFU, 6 pts had LADD- Lm-positive blood cultures on day 1; blood cultures on all subsequent days were negative. JNJ-809 transiently induced peripheral cytokines including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of 7 evaluable pts (1 x 109 CFU), post-treatment T cell responses were demonstrated in 6 pts to the Listeria antigen LLO and in 5 pts to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease (SD) in 13/25 evaluable pts with SD ≥16 weeks in 4 pts. The study was terminated early as the data collected from 26 pts were considered sufficient to evaluate safety and immune responses. Conclusions: JNJ-809 has a manageable safety profile consistent with that of other LADD- Lm-based therapies. Observed activation of immune responses with monotherapy did not translate into clinical activity, and further development of JNJ-809 will likely require a combination approach. Clinical trial information: NCT02625857.
Fracture risk after radium-223 (Ra-223) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Alonzi Roberto , Parker Chris C. , Tunariu Nina , Koh Dow-Mu , Staffurth John , Blackledge Matthew D. , Padhani Anwar R. , Tree Alison , Stidwill Helen , Finch Jessica , Chatfield Peter , Perry Sophie , Tovey Holly , Hall Emma
Published: May 2019

e16513

Background: Ra-223 improves overall survival in patients with mCRPC, but is associated with increased risk of fracture when used in combination with abiraterone and prednisolone. We have assessed time to first new fracture in men with mCRPC receiving Ra-223 monotherapy, imaged using whole body MRI. Methods: In a prospective phase II study, patients with chemotherapy-naïve, bone mCRPC were randomised (1:1) to receive Ra-223 at 55 or 88 kBq/kg for 6 cycles, at 4-week intervals (REASURE; ISRCTN17805587). Whole body MRI was done at baseline, at cycles 2 and 4, and 1 month post-treatment. Subsequent imaging was done as clinically indicated. All scans were centrally reviewed to describe the time to first new fracture and characteristics of fractures. Time to new fracture was analysed using Kaplan Meier methods; comparisons of time to fracture between groups were based on log-rank tests. Results: 36 evaluable patients received a median of 6 cycles of Ra-223; scans were available for 35 patients. For these 35 patients, median age was 75 years (IQR: 73-80). 3 (9%) were receiving bone health agents at trial entry; 8 (23%) had received prior abiraterone or enzalutamide. 21 (60%) patients developed new fractures between randomisation and 2 years after completing treatment with radium-223. The spine was the most common location for fractures (14 patients). Median time to new fracture from randomisation was 10.8 months (95% CI: 6.2-18.2). Freedom from new fracture at 2 years post-randomisation was 21% (95% CI: 7 – 39%). Time to first new fracture was not associated with Ra-223 dose (55 kBq/kg: 10/18 patients experienced a fracture vs 88kBq/kg: 11/17; p = 0.93) or baseline use of bone health agents (3/3 vs 18/32; p = 0.09). Patients with Extent of Disease (EOD) ≥2 (defined as ≥6 metastatic sites/superscan) had earlier time to first new fracture compared to patients with EOD 1 (defined as < 6 metastatic sites) (11/18 vs 10/17; hazard ratio = 2.7, 95% confidence interval = 1.0 – 6.8; p = 0.04). Conclusions: New fractures are commonly seen on imaging in men with mCRPC during and after treatment with Ra-223 monotherapy. This observation supports treatment guidelines that recommend the use of bone health agents in men with mCRPC. Clinical trial information: ISRCTN17805587.
Clinical efficacy of abiraterone and enzalutamide metastatic castration sensitive prostate cancer patients who progressed rapidly on docetaxel with a genomic analysis.
Authors: Chen Gang , VanderWeele David James , Karzai Fatima , Bilusic Marijo , Al Harthy Munjid , Arlen Philip M. , Theoret Marc Robert , Rosner Inger L. , Chun Guinevere , Owens Helen , Couvillon Anna , Hankin Amy , Williams Monique , Gulley James L. , Dahut William L. , Madan Ravi Amrit
Published: May 2019

e16536

Background: Docetaxel has become a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). A PCR-based NGS panel (OncoMine Comprehensive Assay v3) will evaluate available tissue from these patients. Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (7 with high volume disease and 5 with low volume disease). The median age was 62 (41-83) years. 6/12 patients (50%) initiated enzalutamide and 6/12 patients (50%) initiated abiraterone. The median duration of treatment for both was 7.43 (1.53 – 16.0) months, the median time to prostate-specific antigen (PSA) progression was 2 (0 – 11) months; the median duration of PSA decline was 2 months in patients with both high and low volume disease. Of note, 3/12 (25%) of patients did not have PSA response, all of them had high volume disease. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.
Comparison of enzalutamide versus abiraterone in castration-resistant prostate cancer before docetaxel: Results of a propensity score-matched analysis.
Authors: Cesca Marcelle Goldner , Silveira Maysa Tamara , Pandolfi Natasha Carvalho , Oliveira Thiago Bueno , Rinck José Augusto , Da Costa Alexandre Andre B. A. , Corassa Marcelo , Formiga Maria Nirvana , Dettino Aldo A.
Published: May 2019

e16540

Background: Metastatic castration-resistant prostate cancer (mCRPC) phenotype involves androgen-receptor signalling mechanisms that support the use of enzalutamide (EZ) and abiraterone (Abi). These therapies improve overall survival (OS) and quality-of-life, with a favourable safety profile. There is no validated data defining the best drug or sequence to be used. Methods: A retrospective cohort of mCRPC patients (pts) was analysed at AC Camargo Cancer Center. The primary objective was to compare progression-free survival (PFS) and OS in patients treated with EZ or Abi as first line (docetaxel naïve pts). Kaplan-Meier, Log-Rank Test and Cox Regression were used for survival analysis. To address unbalanced characteristics between the two treatment groups treatment efficacy was compared in a propensity score matched cohort. Results: From May, 2002 to September, 2017, 120 pts were treated with Abi (84%) or EZ (36%). Median follow-up was 21.2 months. Median age at diagnosis was 66 (48-84), the majority were Gleason score 7 (34%) and median baseline PSA was 14. Median PFS was 17.4 months in EZ and 10.6 months in Abi group (HR = 0.65; 95%CI: 0.39-1.10; p = 0.11). Median OS was not reached and 31.6 months for EZ and Abi, respectively (HR = 0.60; 95%CI: 0.27-1.36; p = 0.22). EZ was associated with a better PSA response in the first 4 months of treatment (p < 0.001). Independent prognostic factors for worse OS and PFS were ECOG ≥ 1, treatment toxicity ≥ G1 and lower PSA doubling time before treatment and for better OS and PFS were PSA response in the first 4 months and alkaline phosphatase and lactate dehydrogenase response at any time. In the propensity score matched cohort including 72 patients PFS was better in EZ group (HR = 0.36; 95%CI: 0.20-0.64; p < 0.001) but there was no difference in OS (HR = 0.66; 95%CI: 0.27-1.63; p = 0.37). Conclusions: EZ was associated with prolonged PFS and better PSA response, with no OS improvement when compared with Abi for mCRPC before docetaxel, in a propensity score matched analysis.
An open label phase 1/2A study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer.
Authors: Rathkopf Dana E. , Saleh Mansoor N. , Tsai Frank Yung-Chin , Bilen Mehmet Asim , Rosen Lee S. , Gottardis Marco , Infante Jeffrey R. , Adams Bonne J. , Liu Lilian , Theuer Charles P. , Freddo James L. , Agarwal Neeraj
Published: May 2019

e16542

Background: TRC253 is a high-affinity, orally active small molecule antagonist of the androgen receptor (AR) and specific mutated variants of AR that does not possess agonist activity towards either wild type or mutated AR. TRC253 inhibits AR nuclear translocation as well as AR binding to DNA and is a transcription antagonist. TRC253 treatment is efficacious in an LNCaP xenograft model driven by F877L mutant AR. Methods: In P1 dose escalation, pts with mCRPC previously treated with an AR inhibitor were assigned to increasing TRC253 doses of 40-320 mg daily. Dose escalation followed single-pt dose escalation design for the 40, 80 mg cohorts and expanded to 3+3 design in the 160, 240, 280, and 320 mg cohorts to assess safety, determine the recommended phase 2 dose (RP2D), and evaluate prostate-specific antigen response at week 12. Toxicity and efficacy assessments used NCI-CTCAE v4.03 and PCWG3 criteria, respectively. Pts were centrally screened by circulating tumor DNA using the BEAMing digital PCR assay. Results: Twenty-two pts were enrolled in phase 1 at TRC253 doses of 40 (n = 1), 80 (n = 1), 160 (n = 2), 240 (n = 6), 280 (n = 4), and 320 mg (n = 8) daily in 28-day cycles. One DLT of G3 QTcF prolongation occurred at 320 mg. No drug-related SAEs were reported. Drug-related AEs ≥ G2 included QTcF prolongation (2 G2, 2 G3), elevated lipase (1 G3), fatigue (4 G2), arthralgia (1 G2), diarrhea (1 G2), and platelet count decrease (1 G2). One pt on study had AR F877L at baseline and remained on treatment for 49 wks with PR by RECIST. The remaining 21 pts did not have AR F877L at baseline and of these, 48% (10) remained on study > 6 cycles and one pts had a > 50% decrease in PSA. Target PK exposures were achieved consistently at 280 mg. 280 mg was selected as the RP2D based on safety and PK data. Conclusions: TRC253 daily at 280 mg was well-tolerated and selected as the RP2D. P2 dose expansion is currently enrolling 2 cohorts: 15 pts with AR F877L and 30 pts without AR F877L. The objectives of P2 include collection of additional data for safety, PK, PET and efficacy of TRC253 in mCRPC pts with specific AR mutations. Clinical trial information: NCT02987829.
A single-center retrospective analysis of the effect of Radium-223 (Xofigo) on pancytopenia in patients with metastatic castration-resistant prostate cancer.
Authors: Skelton William Paul , Dibenedetto Samantha Welniak , Pang Sarah , Pan Kelsey , Barish Jacob , Nwosu-Iheme Adaeze , Dang Long H.
Published: May 2019

e16546

Background: Radium-223 (Xofigo) has been shown to increase overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) via the phase 3 ALSYMPCA study. The side effect of persistent pancytopenia was noted in 2% of the patients, however, the incidence seen in our institutional clinical practice is higher than reported in the literature. This analysis serves to identify predictive factors and thereby help impact future therapy directions in this patient population. Methods: A retrospective analysis was performed analyzing patients with mCRPC who received xofigo at UFHealth in a 3 year span (from January 2014 to January 2017). Data collected included CBC, ECOG functional status, kidney and liver function, evidence of bony disease on imaging, prior chemotherapy regimens, total radiation dose, and PSA. This study was IRB approved. Results: 52 patients with mCRPC were identified, 27 of which received xofigo. 23 patients received treatment at UF, and one was lost to follow-up. 16 patients (73%) completed the full course (6 doses) of xofigo, while 6 did not. 10 patients (45%) developed pancytopenia, with 2 recovering counts within eight months while the other 8 had persistent cytopenias (6 of which were transfusion-dependent). Older age (74.0 ± 8.8 vs 68.7 ± 10.2) and higher ECOG score (1.6 ± 0.7 vs 1.2 ± 0.6) correlated with increased risk of pancytopenia. In addition, a higher percentage of patients who received prior radiation therapy were more likely to develop pancytopenia (90% vs 75%). All patients studied had bony disease and received prior chemotherapy. Conclusions: Albeit with a limited sample size, we found a higher rate of xofigo-induced pancytopenia in our patient population than the 2% reported in the literature. This may influence clinical decision making in the treatment of mCRPC, as pancytopenia may preclude patients from other survival-prolonging therapies. Factors such as age, functional status, and prior radiation therapy are important to keep under consideration prior to xofigo treatment. Additional larger studies are necessary to further quantify this effect.
Classification of prostate cancer based on clinical and omics data using neural networks techniques to improve prognostic power.
Authors: Marin Laura , Casado Fanny Lys , Racoceanu Daniel , Pinto Joseph A.
Published: May 2019

e16569

Background: In 2017, prostate cancer (PCa) was the second most common cancer in men after lung cancer. While there are different courses of action to treat the disease, its mortality in Peru is higher than 50%. Conventionally, PCa is diagnosed by evaluating tissue biopsies, and classified according to the Gleason grading system. Novel molecular classifications of PCa have been proposed for diagnostic and prognostic purposes. The main goal of this work is to implement a tool predicting the disease free time of patient according to the genomic expression and highlight the genes playing an influential role on the prediction. Methods: Modern techniques to classify data keep getting broader and more accurate, in particular with the introduction of Neural Networks(NN). We implement an Artificial Neural Network automatic genomic classification strategy based on a Local Interpretable Model-Agnostic Explanations (LIME) algorithm because it allows the network to choose the features of major discriminative significance. As a proof-of-concept, we selected a sub-set of 3530 genes related to recurrence from 499 PCa genomes to build the neural networks. Results: The resulting neural network, trained and tested on cancer cell 2010 database and validate on the MSKCC data the can predict the time of recurrence within a range of three months based on the genomic expression with an accuracy of 96,9% and a loss of less than 9%. Using the implemented LIME algorithm, our results indicate that this subset of genes is informative of recurrence and plays a substantial role in the prediction. Conclusions: Instead of using a classic fully connected layer, we implemented different types of Deep Learning networks where the final network provides the predicted survival rate or time to recurrence. This information will allow the doctors to propose the best course of treatment. Our method is able to generate an augmented score, enabling a more accurate evaluation of risk and personalized treatment strategy