bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of AMG 386 in combination with sunitinib in patients with metastatic renal cell carcinoma (mRCC) in an open-label multicenter phase II study.
Authors: Atkins Michael B. , Ravaud Alain , Gravis Gwenaelle , Drosik Kazimierz , Demkow Tomasz , Tomczak Piotr , Kracht Karolyn , Puhlmann Markus , Weinreich David Michael
Published: March 2020

4606

Background: AMG 386, an investigational peptide-Fc fusion protein, inhibits angiogenesis by disrupting the angiopoietin/Tie2 axis. We evaluated the safety and efficacy of AMG 386 plus sunitinib in patients (pts) with mRCC. Methods: Adults with mRCC who were naïve to angiogenesis inhibitors were sequentially enrolled to 2 cohorts: sunitinib 50 mg PO QD (4 wks on, 2 wks off) plus AMG 386 at 10 mg/kg (A) or 15 mg/kg (B) IV QW. Primary endpoints: adverse events (AEs), dose interruptions/reductions due to AEs in the first 12 wks of treatment; secondary endpoints included: progression-free survival (PFS) and response rate (ORR). Results: 85 pts received ≥1 dose of study medication (A/B, n=43/42). In A/B, 88%/76% were male and 30%/36% were age ≥65; MSKCC risk scores were low (40%/36%) or intermediate (60%/62%). For A/B: median follow-up time was 19.6/12.0 mos; AMG 386 discontinuations due to AEs were 16%/29%; and grade ≥3 treatment-related AEs occurred in 72%/74% with virtually all attributed to sunitinib. Grade 3 AEs occurring with >5% frequency were hypertension, hand foot syndrome, asthenia, fatigue, elevated lipase, diarrhea, mucositis, vomiting, thrombocytopenia, and neutropenia, with no distinction between dose levels. The percentage of pts with sunitinib dose interruptions within the first 12 wks (A/B, 58%/57%) met the prespecified criteria. One pt in B had fatal acute pulmonary edema. No pt developed anti-AMG 386 antibodies. The Kaplan-Meier estimate (95% CI) of PFS was 13.9 (10.4, 19.2) mos in A; PFS in B is not yet mature with only 21% of pts having disease progression. ORR (95% CI) was 58% (42, 73) in A including 1 CR, and 59% (42, 74) in B. Conclusions: In pts with mRCC, AMG 386 at 10 and 15 mg/kg combined with sunitinib appeared to be tolerable. Reported sunitinib dose modifications for the observation period were within the prespecified range. Efficacy results suggest potential benefit for the addition of AMG 386 to sunitinib.
Prospective exploratory analysis of the association between genetic polymorphisms and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma.
Authors: Farfan Carlos Alberto , Sepulveda Juan , Benitez Julio , de Velasco Guillermo , Villacampa Felipe , de la Rosa Federico , Canamares Irene , Rodriguez de Antona Cristina , Cortes-Funes Hernan , Castellano Daniel E. ,   Uro-Oncology Unit, Hospital Universitario 12 de Octubre
Published: March 2020

4620

Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor treatment that is approved for metastatic renal cell carcinoma (mRCC). However, several patients either do not respond to treatment or they experience significant toxicity.Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods: 30 patients with newly diagnosed mRCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 wks off treatment schedule. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction : 2.33 months vs NR; p<0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased risk of dose reductions due to toxicity vs. other genotypes (Median time to dose reduction: 2.8 vs 9.73 months; p<0.021). Catechol-O-methyltransferase (COMT) V158M polymorphisms, was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS=17.2 months and Val/Val pts PFS=3.3 months; OS= 4.4 months ; p=0.005 for PFS and p=0.003 for OS). Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if these is confirmed, it could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011).
Trends in the use of cytoreductive nephrectomy for metastatic renal cell carcinoma in the VEGFR tyrosine kinase inhibitor era.
Authors: Tsao Che-Kai , Small Alexander C. , Kates Max , Gartrell Benjamin Adam , Wisnivesky Juan P. , Sonpavde Guru , Palese Michael , Hall Simon , Oh William K. , Galsky Matt D.
Published: March 2020

4623

Background: Two large randomized trials (SWOG, EORTC) published in 2001 established the role of cytoreductive nephrectomy (CyNx) for the treatment of metastatic renal cell carcinoma (mRCC) in the cytokine era. A paradigm shift occurred in 2005 with the approval of VEGFR tyrosine kinase inhibitors (TKIs). We hypothesized that uncertainty regarding the role of CyNx in the VEGFR TKI era has resulted in a change in practice patterns. Methods: Using the Surveillance, Epidemiology and End Results (SEER) registry, we identified 2780 patients with histologically-confirmed mRCC between 2000 and 2008 who underwent CyNx or no surgery. Patients were separated into pre- or VEGFR TKI-eras (2000-2005 vs. 2006-2008). Differences in baseline characteristics between these patient groups were assessed and controlled for in a logistic regression analysis to determine the likelihood of undergoing CyNx. Results: Overall, 1202 of 2780 patients (43%) underwent CyNx. CyNx increased from 41% in 2000 to 49% in 2005, and decreased to 35% in 2008, with a 20% decreased likelihood of undergoing CyNx in the VEGFR TKI era compared to the pre-VEGFR TKI era. Logistic regression analysis showed that tumor size, age, race, marital status and pre- versus post-2005 periods were independent predictors of CyNx (Table). Patients who were non-Caucasian, single, with primary tumor <3cm, or older were less likely to undergo CyNx. Conclusions: Use of CyNx increased after supporting level I evidence was published in 2001, and decreased after regulatory approval of VEGFR TKIs in 2005. Racial and demographic differences exist in the utilization of CyNx. The results of pending randomized trials evaluating the role of CyNx in the TKI-era are awaited to optimize use of this modality and address potential disparities. [Table: see text]
Molecular characterization of SETD2, a histone methyltransferase, in clear cell renal cell carcinoma (ccRCC).
Authors: Ho Thai Huu , Monzon Federico A. , Hoang Anh , Tamboli Pheroze , Furge Kyle A. , Dykema Karl , Petillo David , Teh Bin Tean , Tannir Nizar M. , Hung Mien-Chie , Jonasch Eric
Published: March 2020

4624

Background: Although the von Hippel-Lindau (VHL) tumor suppressor is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize that loss of SETD2 methyltransferase activity decreases H3K36 trimethylation (H3K36Me3) in ccRCC, and contributes to the cancer phenotype. Methods: H3K36Me3 immunohistochemical (IHC) staining was quantitated in wild-type and mutant SETD2 nephrectomy tissue. To establish frequency of SETD2 loss of heterozygosity (LOH), genomic DNA was isolated from 51 VHL deficient ccRCC specimens and analyzed with Affymetrix single-nucleotide polymorphism (SNP) arrays. To evaluate alterations of histone modifications in advanced ccRCC, H3K36Me3 IHC was quantitated on tissue microarrays (TMAs) representing 28 paired ccRCC specimens with unaffected kidney parenchyma and 40 metastases. To identify kidney-specific H3K36Me3 binding sites, chromatin immunoprecipitation (ChIP) sequencing was performed on nephrectomy specimens. Results: Nephrectomy specimens with SETD2 truncating mutations have decreased H3K36Me3 (>50%) compared to uninvolved kidney tissue. Using SNP arrays, LOH at chromosome 3p (location of VHL and SETD2 genes) was detected in >90% of the tested tumors. IHC reveals a 27.4% and 52.0% decrease in H3K36Me3 positive nuclei in primary ccRCC and metastases, respectively, when compared to matched adjacent unaffected kidney tissue (p <0.0001). Using ChIP sequencing, 421 and 1,718 genomic regions were upregulated in the tumor and unaffected kidney tissue. Conclusions: SETD2 truncating mutations in patient-derived tissue have decreased H3K36Me3 indicating that SETD2 is a non-redundant H3K36 methyltransferase. LOH of VHL and SETD2 occurs in >90% of tested ccRCC tumors. Genomic regions enriched for H3K36Me3 binding are being validated in additional patient-derived tissues. H3K36Me3 is decreased in primary ccRCC and even more in metastases, suggesting that SETD2 methyltransferase activity is progressively misregulated in RCC. Loss of SETD2 activity may cooperate with VHL silencing to promote tumorigenesis.
Updated results on long-term overall survival (OS) of the French randomized phase II trial TORAVA in metastatic renal cell carcinoma (mRCC) patients.
Authors: Bay Jacques-Olivier , Negrier Sylvie , Pérol David , Gravis Gwenaelle , Chevreau Christine , Delva Remy , Blanc Ellen , Geoffrois Lionnel , Legouffe Eric , Ferlay Celine , Escudier Bernard J.
Published: March 2020

4625

Background: Temsirolimus combined with bevacizumab (T+B) failed to improve the progression rate in treatment naive mRCC pts when treated in parallel to sunitinib (S) or B + Interferon (B+I) combination (Lancet Oncol 2011; 12:673-80). Long term updated survival and data on 2d line treatments were analyzed. Methods: 171 pts were treated with T+B (n=88), S (n=42) and B+I (41) respectively. Updated survival data (December 2011) and 2d line therapy after failure of the randomly assigned treatment were updated. OS was defined from the date of randomization until the date of death due to any cause, or the date of last contact. A two-tailed log-rank test was used to compare the OS distribution between the 3 arms with a 5% alpha level. Results: The median follow-up is 35.1 months (range 24.2 to 44.7). In an intent-to-treat analysis, 35-month OS rates were 37% (95% CI 27 to 48), 55% (95% CI 40 to 69) and 62% (95% CI 47 to 76) in arms T+B, S and B+I respectively (3-arm global comparison: p-value=0.0279). OS was not significantly lower in T+B arm than S arm (HR = 0.67, 95% CI 0.40 to 1.12), but significantly lower in T+B arm than B+I arm (HR = 0.48, 95% CI 0.27 to 0.86). Tyrosine kinase inhibitors were administered in 55 (79.7%), 19 (79.2%) and 23 (63.9%) pts in arms T+B, S and B+I respectively, without significant difference between arms (Fisher’s exact test: p=0.20). To note, 21% pts in S arm and 15% pts in B+I arm received an mTOR inhibitor in 2d line therapy. Conclusions: A large majority of pts in all treatment groups received a 2d line therapy after initial treatment failure. The OS rates confirm the absence of synergy or addictive effect of the B+T combination as well as the prolonged survival of pts treated with B+I.
Overall survival (OS) in metastatic renal cell carcinoma (mRCC) sequentially treated with different targeted therapies (TTs): Results from a large cohort of patients.
Authors: Procopio Giuseppe , Verzoni Elena , Iacovelli Roberto , Testa Isabella , Salvioni Roberto , Nicolai Nicola , Porcu Luca , De Braud Filippo G.
Published: March 2020

4629

Background: Targeted Therapies (TTs) have definitely improved survival in patients with mRCC. However the optimal therapeutic strategy is not shared. This study was performed to assess the overall survival (OS) in a consecutive series of mRCC patients receiving TTs. Methods: Characteristics and outcomes of 336 patients affected by mRCC receiving TTs were collected from the database of Istituto Nazionale Tumori of Milan. The main characteristics of patients were: ECOG PS 0/1/2 186 (55%)/131 (39%)/19 (6 %); clear-cell histology 291 (87%); previous nephrectomy 293 (87%). According to Motzer criteria 32% of patients showed low risk, 48% intermediate risk and 20% poor. Overall, 167 (50%) patients received one TTs, while 116 (34%), 42 (13%) and 11 (3.3%) received 2, 3 and 4 TTs, respectively. 245 (73%) patients received sorafenib (So), 212 (63%) sunitinib (Su), 33 (10%) a bevacizumab regimen and 73 (22%) other TTs, including everolimus, temsirolimus and axitinib. The Kaplan Meier curves were used to describe the survival.The uni- and multi-variate analyses for OS were carried out by means of Cox proportional hazard regression analysis. Results: Ata median follow-up of 43 months, 199 patients (57 %) had died. The median OS was 24 months (95%CI: 20.0-27.0) and the 5-year OS was 24.6 % (95 %CI: 18.7-30.8). In univariate analyses, there were no significant differences in the hazard ratios (HR) for So followed by Su compared to Su followed by So (HRSU-SO / SO-SU = 1.16; 95%CI: 0.57-2.33) or compared with other therapies (HROther sequential th. / SO-SU = 1.21; 95%CI: 0.78-1.88; p=0.674).In the multivariate analysis, in terms of OS any statistical difference was reported as regards the sequence used (Su/So vs So/Su; p>0.05) or bevacizumab regimen as compared to Su and/or So used sequentially (p>0.05). In the uni and multivariate analysis ECOG PS, nephrectomy, Fuhrman grade and number of sites of disease are independent predictive factors of outcome (p< 0.01). Conclusions: These data suggest that TTs improve OS in mRCC without any statistical difference when using different sequences of TTs. No cross-resistance between several sequences of TTs was documented.
Longitudinal serum testosterone levels (T) in long-term testicular cancer survivors (TCSs) in relation to testicular cancer (TC) treatment, aging, and TC diagnosis itself.
Authors: Sprauten Mette , Cvancarova Milada , Fossa Sophie D. , Brydoy Marianne , Haugnes Hege Sagstuen , Oldenburg Jan
Published: March 2020

4637

Background: Low T may increase the risk of cardiovascular disease, osteoporosis, and reduced quality of life. T might be reduced by TC, its treatment, ageing, and particularly their combination. Methods: T was retrieved from 311 TCSs after orchiectomy and prior to subsequent management with either surveillance/surgery only (S), radiotherapy (RT) or cisplatin based chemotherapy (CT). Human Chorionic Gonadotropin (hCG) was available for 211 TCSs. T was reassessed at surveys performed 9 (S9) and 18 years (S18) after treatment. T values were categorized into quartiles according to cut-off values derived from 570 healthy controls (C) for each decadal age group. Statistical associations were assessed with Chi2 tests. Results: In TCSs about to receive RT or CT, T and hCG were higher when compared to those subsequently managed by S. TCSs were more likely to belong to the lowest T quartile, more so with increasing treatment intensity (table). The proportions of TCSs belonging to the corresponding T quartiles displayed no significant changes from S9 to S18. Conclusions: TCSs had lower T than C of similar age already after orchiectomy, possibly related to removal of the affected testicle and/or testicular dysgenesis syndrome. TCSs who were to receive RT or CT had slightly increased T when compared to S, probably due to hCG stimulation. T reduction by RT or CT has been described previously but rarely in longitudinal studies. Of note, longitudinal assessment of T without comparison to C might result in overestimation of the treatment burden. Relatively stable age adjusted T levels from S9 to S18 for the TCSs independent of treatment are encouraging. [Table: see text]
Dynamic sentinel lymph node biopsy in patients with invasive squamous cell carcinoma of the penis: A prospective study of the outcome of 500 inguinal basins assessed in a single institution.
Authors: Lam Wayne , Alnajjar Hussain M , La-Touche Susannah , Perry Matthew , Corbishley Catherine M , Pilcher James , Heenan Sue , Watkin Nicholas
Published: March 2020

4640

Background: Dynamic sentinel node biopsy (DSNB) in combination with ultrasound scan (USS) has been the technique of choice at our centre since 2004 for the assessment of non palpable inguinal lymph nodes in patients with squamous cell carcinoma of the penis (SCCp). Sensitivity/false-negative rates may vary depending on whether results are reported per patient or per node basin and with and without USS. The purpose of this study was to determine the long-term outcome of DSNB and ultrasound-guided fine needle aspiration cytology (FNAC) in our cohort of newly diagnosed patients and to analyse any variation in sensitivity of the procedure. Methods: A prospective cohort study over 6 years (2004 to 2010). Inclusion criteria: New diagnosis SCCp, T1G2 or greater definitive histology, non-palpable nodes in inguinal basin. Exclusion: patient with persistent/untreated local disease. Sensitivity of the procedure was calculated, per node basin, per patient, DSNB alone, USS/DSNB combined. Minimum follow up 12 months. Results: 500 inguinal basins in 264 patients underwent USS+/-FNAC and DSNB. 70 (14%) positive inguinal basins in 57(22%) patients were identified. 9 (2%) inguinal basins had no tracer uptake. 2 inguinal basins were confirmed false negative at 8 and 12 months. 2 inguinal basins had positive USS+FNAC and negative DSNB. Overall sensitivity of the technique is reported in the table. Conclusions: DSNB in combination with USS has excellent performance characteristics to stage patients with clinically node-negative penile cancer with a 3% false negative rate. USS improves performance by 4% over DSNB alone. There is no difference in performance of the combined technique if it is reported per node basin or per patient. [Table: see text]
Phase I trial of NY-ESO-1/LAGE1 peptide vaccine for metastatic castration resistant prostate cancer (mCRPC).
Authors: Hayes Teresa Gray , Sonpavde Guru , Wang Mingjun , Wang Yicheng , Joe Teresa , Mims Martha P. , Ittmann Michael M. , Wheeler Thomas M. , Gee Adrian P. , Wang Rongfu F
Published: March 2020

4643

Background: The NY-ESO-1 and LAGE-1 antigens are amplified in malignancies including prostate cancer. Preclinical induction of immune responses and anti-tumor activity has been demonstrated upon administration of these peptides. A phase I/II clinical trial evaluated the feasibility of a combined HLA class-I and class-II peptide vaccine in mCRPC. Methods: Men with progressive mCRPC, Performance Status ≤2, PSA ≥10 ng/ml and had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4, DR13) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 was treated with a peptide directed at a HLA class I haplotype (HLA A2), Group 2 was treated with a peptide reacting to a HLA class II haplotype (DR4, DP4, or DR13), and Group 3 received peptides directed at both Class I and II haplotypes. Group I and Group II received 1 dose of 1000 mcg and Group III received doses of 1000 mcg for each of 2 peptides. Androgen-deprivation was continued. Results: Of 14 patients enrolled, all were evaluable for toxicities and 9 patients completed all 6 treatments per amended protocol and were evaluable for efficacy. The median baseline PSA was 85.19 ng/ml. Four patients were chemo naive and 5 were post-docetaxel. One patient had a grade 5 event (myocardial infarction) unlikely therapy-related. Potential therapy related toxicities were local grade 1 injection site erythema (n=5), fatigue (n=2), flu-like symptoms (n=1), myalgias (n=1), anorexia (n=1), nausea (n=1) and leukocytosis (n=1). The median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. The PSA-DT was prolonged compared to baseline in 6 patients, including a negative PSA slope in 2 patients. Antigen-specific immune response determined by ELISPOT was observed, and its association with slowing of PSA-doubling time will be further examined. Conclusions: In men with mCRPC, HLA class-I and/or class-II restricted NY-ESO-1 and LAGE-1 peptides administered subcutaneously demonstrated excellent tolerability, slowing of PSA doubling time and antigen-specific immune responses. Further development of peptide vaccines alone or in combination with other regimens may be warranted.
Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC) from a phase III randomized trial.
Authors: Sonpavde Guru , Pond Gregory Russell , Clarke Stephen John , Vardy Janette L. , Wang S. L. , Paolini Jolanda , Lechuga Mariajose , Michaelson M. Dror , Smith Matthew Raymond , Chen Isan , Maneval Edna Chow
Published: March 2020

4644

Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score was calculated and patients were categorized into risk groups to assess model performance. Results: Data from patients without missing data (n=806) were used to construct an optimal model. The factors used in the model that remained individually significant in multivariate analysis were: log-LDH (HR 2.77 [95% CI=2.23, 3.44], p<0.001), hemoglobin (0.81 [0.76, 0.87], p<0.001), log-NLR (1.63 [1.38, 1.92], p<0.001), >1 organ involved (1.53 [1.24, 1.88], p<0.001), log-alkaline phosphatase (1.14 [1.01, 1.30], p=0.041) and log-PSA (1.07 [1.00, 1.13], p=0.036). No clear cutpoints were identified; thus, these prognostic factors were used to group patients into 3 equally sized risk categories. Low, medium and high risk patients (n=268-270 per group) had median (95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model with readily available variables significantly discriminated between outcomes in post-docetaxel mCRPC and may provide valuable information in future studies. High NLR was associated with an independent poor prognostic impact, and warrants prospective validation.
Molecular determinants of outcome with mTOR inhibition in endometrial cancer (EC).
Authors: Mackay Helen , Eisenhauer Elizabeth A. , Kamel-Reid Suzanne , Clarke Blaise , Walsh Wendy , Karakasis Katherine , Salvesen Helga B , Oza Amit M.
Published: March 2020

5010

Background: Deregulation of PI3K/AKT/mTOR signaling plays a significant role in EC biology. NCIC CTG has completed three phase II trials of 2 mTOR inhibitors (temsirolimus and ridaforolimus) in EC (IND 160A, IND 160B, IND192) demonstrating anti-tumor activity. PTEN expression, however, was not associated with response. In this study we are conducting additional molecular analyses on samples obtained from patients (pts) participating in these trials to identify mutations or other findings associated with mTOR response. Methods: Formalin fixed paraffin embedded (FFPE) tumor samples were collected from pts treated on the three trials. Tumor DNA was isolated and mutational profiling (MP) was performed using theOncoCarta Panel v1.0 which can detect 238 mutations in 19 oncogenes including AKT1, 2, BRAF, CDK-4, EGFR, ERBB2, MET, H-, K-, N- RAS, PDGFRA, PIK3CA, RET. All mutations were verified by Sanger sequencing. For each gene found to be mutated in at least 1 patient, the relationship between presence/absence of mutations in that gene and objective anti-tumor response (RR) was assessed (RR vs. no response; early progression (PD) vs. no PD) using Fisher's exact test. In addition, the presence of any mutation vs. no mutations was assessed in relationship to the same clinical outcomes. Results: MP was feasible in 73 of the 94 eligible pts treated on the three trials. 44% (32 pts) had a mutation in at least one gene: 21 pts (29%) in PIK3CA, 10 (14%) KRAS, 4 (5%) MET, 3 (4%) NRAS, 3 (4%) AKT and 1(1%) EGFR. 9 pts (12%) had > 1 mutation. No significant correlations were seen, in individual trials or within the pooled data set of 3 studies, between the presence/absence of any mutation and RR (p=1.0) or early PD (p=1.0). No significant association was seen between the presence of mutations within individual genes and RR or PD (including PIK3CA). Of interest, no response was observed in any of the 13 pts with a Ras mutation (non-significant). Additional analyses involving gene expression (including stathmin) and correlation of MP with tumor morphology are underway. Conclusions: Mutations are common in EC but we have not identified a statistical association between presence of mutations in PIK3CA or any other gene and response to mTOR inhibition. Further analyses are ongoing.
Phase I trial of metronomic oral topotecan in combination with pazopanib utilizing a daily dosing schedule to treat recurrent or persistent gynecologic tumors.
Authors: Tillmanns Todd D. , Reed Mark E. , Privett Melissa C. , Johns Amanda L. , Walker Mark S. , Houts Arthur C.
Published: March 2020

5014

Background: Metronomic oral topotecan has antiangiogenic properties. Oral pazopanib is also a potent inhibitor of VEGF angiogenesis with clinical benefit. This study investigated the safety and efficacy of daily topotecan and pazopanib. Methods: This phase I, single-center, open-label, dose ranging study comprised 28-day cycles of daily oral topotecan/pazopanib at dose levels of 0.50/400, 0.25/800, 0.25/600, and 0.25/400 mg. A standard 3+3 dose escalation design was used. Dose limiting toxicity (DLT) was defined as ≥ grade 3 adverse event (AE) occurring in cycle 1, noncompletion of cycle 1 at prescribed dose, or inability to start cycle 2 as scheduled due to toxicities. Imaging was conducted after every 2 cycles for response assessment. Confirmed responses were evaluated per RECIST 1.0. Results: 25 extensively pretreated patients (pts) with gynecologic tumors (6 cervical, 7 endometrial, 8 ovarian, 4 other) were enrolled. Mean age was 61 years; 19 Caucasian, 6 African American. Median number of cycles received was 4 (range 1-19). DLTs occurred ≥ 2 pts for A (2/6), B (2/7), C (3/7). For level D, 1/5 had a DLT, but one dose level C pt with a DLT received level D dosing due to unavailability of pazopanib. 9/25 pts had any serious adverse event (SAE), and respiratory SAEs were most common (4/16 SAEs). Nausea, fatigue, dysgeusia, diarrhea, and vomiting were the most common conditions reported as non-serious AEs. The Table shows best overall response (28%) by dose level. Conclusions: DLTs in dose levels C and D were effectively managed with minor dose and schedule adjustments. 4 pts with DLTs at these doses remained on treatment for 4, 5, and 6 months, with one pt still on treatment at 9 months. Given the initial biologically favorable signal in this heavily pretreated group and low toxicity, we recommend a randomized phase II trial to define efficacy using the 0.25/600 regimen allowing for dose reduction if needed. [Table: see text]
Safety of front-line bevacizumab (BEV) combined with weekly paclitaxel (wPAC) and q3w carboplatin (C) for ovarian cancer (OC): Results from OCTAVIA.
Authors: Gonzalez-Martin Antonio , Gladieff Laurence , Tholander Bengt , Stroyakovsky Daniel , Gore Martin Eric , Segalla J.G.M. , Reyners An K.L , Kovalenko Nadezhda , Oaknin Ana , Selle Frédéric , Bollag David T. , Pignata Sandro ,   OCTAVIA Investigators
Published: March 2020

5017^

Background: In two randomized phase III trials in OC (GOG218 and ICON7), front-line BEV + q3w PAC + q3w C followed by BEV alone significantly improved progression-free survival (PFS) vs chemotherapy (CT) alone. In the Japanese NOVEL trial, wPAC + q3w C was more effective than q3w PAC + C, but toxicity limited CT delivery. The single-arm OCTAVIA study evaluated front-line BEV + wPAC + q3w C. Methods: Patients (pts) received 6–8 cycles of BEV (7.5 mg/kg, d1) + wPAC (80 mg/m2 d1, 8, 15) + C (AUC6, d1) iv q3w, with BEV q3w continued alone for a total of up to 17 cycles (1 y) as front-line therapy for newly diagnosed OC (FIGO stage I–IIa [grade 3/clear cell] or stage IIb–IV [any grade]). The trial was designed to recruit a pt population similar to that enrolled in ICON7. The primary endpoint was PFS. Secondary endpoints included response rate, duration of response, overall survival, biological progression-free interval, and safety. Previously we reported safety findings from the concurrent CT phase. Here we present final safety results from the entire treatment period. Results: Between Jun 2009 and Jun 2010, 189 eligible pts were enrolled. Baseline characteristics: median age 55 y (range 24–79 y); ECOG 0 74%; FIGO stage I/II/III/IV 10%/10%/63%/17%; serous/clear cell/mixed 65%/6%/6%; 71% optimally debulked. Pts received a median of 6 CT cycles (range 1–8) and 17 BEV cycles (range 0–18). Of the 168 pts who received single-agent BEV, 135 completed 1 y of therapy. In the entire treatment period, BEV was discontinued for adverse events (AEs) in 12% and disease progression (PD) in 10%. The most common grade ≥3 hematologic AEs were neutropenia (60%), anemia (8%), and thrombocytopenia (7%). The incidences of grade ≥3 AEs of special interest for BEV were: hypertension 4.2% (grade 2/3/4: 9.0%/3.2%/1.1%); thromboembolic events 6.3% (grade 3/4: 3.7%/2.6%); bleeding 0.5% (grade 3), wound-healing complications 0.5% (grade 3), and GI perforation 0.5% (grade 4). There was no grade ≥3 proteinuria or fistula/abscess. At the time of data cut-off, 9 pts had died, all from PD. Conclusions: BEV combined with wPAC is feasible and well tolerated. BEV AEs were no more frequent with wPAC in OCTAVIA than with q3w PAC in ICON7.
Efficacy and safety of the APE (actinomycin D, cisplatin, etoposide) regimen for the management of high-risk gestational trophoblastic neoplasia.
Authors: Lhomme Catherine , Even Caroline , Duvillard Pierre , Pautier Patricia , Floquet Anne , Kerbrat Pierre , Troalen Frederic , Rey Annie , Balleyguier Corinne , Morice Philippe , Fizazi Karim , Droz Jean Pierre
Published: March 2020

5028

Background: Patients (pts) with high risk gestational trophoblastic neoplasia (GTN) or who fail low risk single agent chemotherapy (CT) require multi agent CT to be cured. The most common regimen is etoposide (E), methotrexate and actinomycin D (A) alternating weekly with cyclophophamide and vincristine (EMA/CO). Cisplatin (P) is a very active drug but its role is controversial and usually restricted to second line. We report results of a platinum based therapy: APE. Methods: We evaluated the efficacy and safety on 103 pts treated at Institut Gustave Roussy (IGR) (n=80) or other French centers (n=23) between 1983 and 2010 with APE for high risk GTN (defined by IGR criteria [Azab, Cancer, 1988] and/or FIGO score >6). Pts with brain metastasis were excluded. Results: Efficacy was evaluated on 59 pts treated for high risk GTN in first line, and on 39 pts in >2nd line including 13 pts after multi agent CT. We excluded pts with placental site trophoblastic tumors (n=2), or with FIGO score <7 and without IGR criteria (n=3). Complete remission (CR) rate was 95%. Seven pts (7 %) relapsed and a second CR was obtained for all with surgery and/or CT. Only one patient died due to GTN, after successive CRs obtained with 3 regimens. Five year overall survival (median follow-up 6.6 years) was 98%. Toxicity was evaluated on 95 pts. No toxic death occurred. Given good efficacy and to avoid acute hematotoxicity and long-term G>1 neuro and ototoxicity APE regimen was modified as detailed in the Table (below). Long-term neuro (5 pts, G1), oto (2 pts, G1 and 2 pts, G2) and renal toxicities (1 pt, G1 ) were recorded. No long-term G2 toxicities were observed with APE3. One pt developed an AML 4 after 4cy APE and 6 cy EMA/CO. 37 pts of 40 who wished to be pregnant succeeded and all of them had at least one live birth. Conclusions: With a 98% long-term overall survival rate, an excellent reproductive outcome, and no detectable long-term toxicity, APE-3 should be regarded as an alternative standard option to EMA/CO for high-risk GTN. [Table: see text]
Application of micro-RNA (miRNA) expression profiles for prognostication in low-risk endometrial carcinoma (LEC).
Authors: Weberpals Johanne Ingrid , Snowdon Jaime , Bougie Olga , Zhang Xiao , Tron Victor , Childs Timothy , Bambury Ian Garfield , Feilotter Harriet
Published: March 2020

5032

Background: Reliably predicting which LEC patients are most likely to recur is a challenge for the clinician with implications on adjuvant therapy. MiRNAs have been exploited for diagnosis and prognostication in a number of malignancies. We hypothesize that miRNA expression profiles differ in tumors from patients with recurrence compared to those without recurrence. Methods: The inclusion criteria for this study are informed consent, stage 1 disease, grade 1 or 2 tumors and endometrioid histology. RNA was extracted from formalin-fixed paraffin-embedded tissues and miRNA profiling was done using Agilent Human miRNA. Differentially expressed miRNAs were identified using GeneSpring GX software and the two groups were compared using the student t-test. Results: The expression levels of 866 miRNAs were determined from LEC patients with recurrence (n=15) and without recurrence (n=16). The mean follow-up interval was 61.5 months. The average age of cancer diagnosis for patients with and without recurrence was 60.2 (range 42-75) and 59.7 (range 44-86), respectively (p=0.91). Three of 15 patients with recurrence and 6 of 16 patients without recurrence received adjuvant brachytherapy following their primary surgery (p=0.43). 17 miRNAs were identified which can distinguish between the tumors with recurrence and those without recurrence (p<0.05). MiR-146a, miR-18a, miR-222, and miR-30a showed the highest fold change difference (>5 fold) in the tumors with recurrence compared to that did not recur. A decision tree prediction model for recurrent LEC was developed where a miRNA cutoff was used as a branch in the decision tree. This model identified those patients who were most likely to recur based on the expression of 4 dysregulated miRNAs (miR-222, miR-361-3p, miR-181c and miR-125b). Conclusions: These preliminary results show the miRNA expression profile differs among LEC and can be used to distinguish an aggressive sub-group. Should future validation studies confirm this result, this information would be valuable in the design of a biomarker study to help decide which patients would benefit most from extended adjuvant treatment.
Intrinsic subtype and its clinical significance in early node-negative breast cancer: Results from two randomized trials of adjuvant chemoendocrine therapy.
Authors: Millar Ewan K.A , Coates Alan Stuart , O'Toole Sandra , Selinger Cristina , Musgrove Elizabeth A. , Yan Max , Viale Giuseppe , Regan Meredith M. , Price Karen N. , Sun Zhuoxin , Castiglione Monica M. , Colleoni Marco , Gelber Richard D. , Goldhirsch Aron , Sutherland Robert L. ,   International Breast Cancer Study Group
Published: March 2020

504

Background: Gene expression profiling has identified four main intrinsic subtypes of breast cancer which have distinct clinical behaviours and responses to therapy. A simplified immunohistochemical (IHC) panel can provide meaningful discrimination and help guide patient management. Methods: Using tissue microarrays (TMA) created from two randomized trials of adjuvant chemoendocrine therapy in node negative early breast cancer (IBCSG VIII and IX,n= 1220) we assessed intrinsic subtype as follows: “luminal A” (LA): ER and/or PR present, Ki-67 low (=19% median) and/or HER2+ (IHC 3+ or FISH amplified); HER2 enriched: ER and PR negative, HER2 positive (IHC 3+ or FISH amplified), Triple Negative (TNP): ER, PR and HER2 negative. p53+ and high cyclin D1 expression were then assessed to determine if they provided any further additive discriminatory value. Results: The standard definitions of intrinsic subtype demonstrated a significant difference in disease-free survival between the subtypes in both trials VIII and IX (p= 0.02), but this was not significant in multivariate analysis. The discrimination between luminal A and B tumors could not be improved upon by the addition of p53 or cyclin D1 expression. The standard definitions demonstrated that TNP and HER2-enriched tumors benefited from the addition of chemotherapy to endocrine therapy, but LA and LB did not. p53+ was associated with a poorer prognosis in ER+ luminal tumors but improved prognosis in ER- non-luminal tumors (Interaction p = 0.002). Conclusions: Intrinsic subtyping using a panel of ER, PR, HER2 and Ki67 provides meaningful prognostic information to help guide patient management in early breast cancer. Whilst it predicts benefit from the addition of chemotherapy in TNP and HER2-enriched tumors it did not in this series do so for LB. Although p53 status did not improve the definition of luminal tumors, p53+ appeared to have a divergent effect on outcome dependent on ER status.
BRCA1 immunohistochemistry in high-grade serous ovarian cancers (HGS-OC) characterized for BRCA1 germ-line mutations.
Authors: Hyman David Michael , Garg Karuna , Grisham Rachel Nicole , Bhatia Jasmine , Arnold Angela G. , Aghajanian Carol , Kauff Noah D. , Levine Douglas A. , Soslow Robert A , Spriggs David R.
Published: March 2020

5043

Background: The optimal use of BRCA1 germline testing in patients with HGS-OC is unclear. Moreover, BRCA1 germline testing does not provide information on non-germline mechanisms of BRCA1 loss. We investigated the performance of BRCA1 immunohistochemistry (IHC) testing in HGS-OC with known BRCA1 mutation status. Methods: Eligible patients had HGS-OC, underwent surgery at a single institution between 1997 and 2010, and were tested for germline BRCA1 mutations under IRB-approved protocols. FFPE tumor tissue was used in triplicate to construct a tissue microarray (TMA). Two pathologists, blinded to BRCA1 status, independently scored each sample as BRCA1 IHC present (normal) or absent (abnormal). Whole sections were stained for all samples with absent BRCA1 staining on TMA. A commercially available monoclonal antibody against BRCA1, clone MS110 from Calbiochem (OP92) was used with previously optimized conditions. Results: 123 samples (30 BRCA1 +; 93 BRCA1 wild-type) were analyzed and 47 (38%) had abnormal BRCA1 IHC. Inter-observer agreement on BRCA IHC was high (kappa=0.87). BRCA IHC had a sensitivity of 83.3% (CI: 70.0-96.7%), specificity of 76.3% (CI: 67.7-85.0%), PPV of 53.2% (CI: 38.9-67.5%), and NPV of 93.4% (CI: 87.9-99.0%) for BRCA1 germline mutation. There was a trend towards improved overall survival in the BRCA IHC abnormal vs. normal patients (median survival 82 vs 61 wks, HR 0.70, p=0.12). Conclusions: BRCA1 IHC is a reproducible and inexpensive test with a high NPV for absence of a BRCA1 germline mutation. The 22 (17.7%) cases with abnormal BRCA1 IHC and wild-type BRCA1 germline status may have other mechanisms of protein loss such as promoter hypermethylation or somatic mutation and are currently being tested for these changes. This rate of non-germline BRCA1 loss in HGS-OC is consistent with data generated by the Tumor Cancer Genome Atlas Network. BRCA1 IHC may be useful as a reliable biomarker for risk stratification in HGS-OC. [Table: see text]
Neo-escape: Neoadjuvant extended sequential chemotherapy with adjuvant postoperative treatment for epithelial nonmucinous advanced inoperable peritoneal malignancy.
Authors: Poole Christopher John , Marshall Andrea , Higgins Helen B , Fletcher Julie , Williams Sarah Jane , Lo Nangi , Fernando Indrajit Nalinika , Osborne Richard , Crawford S. Michael , Rafii Saeed , Gill Sandeep , Dunn Janet A
Published: March 2020

5046

Background: Neo-Escape was designed to exploit fully the modest non-cross resistance of carboplatin (CBDCA) and paclitaxel (ptx) in an extended sequential regimen, with dose-dense ptx, and address feasibility of combining gemcitabine (gem) with either CBDCA or ptx. Methods: A randomised phase II trial in patients (pts) with untreated (FIGO stage 3C/4) inoperable ovarian, fallopian, or primary peritoneal carcinoma to assess feasibility of two regimens of sequential neoadjuvant-then-adjuvant chemotherapy (CT); (a) CBDCA AUC 2.5 and gem 1000mg/m2 repeated days 1 and 8 q 3 wks x 6 cycles, then ptx 175mg/m2 q 2 wks x 6 cycles (CG-P) or (b) CBDCA AUC 6 q 3 wks x 6 cycles, then ptx 175mg/m2 and gem 2000mg/m2 q 2 wks x 6 cycles (C-PG). All pts were considered for delayed 1o debulking surgery after neoadjuvant CT. The 1o feasibility outcome was % pts completing 12 cycles of CT. Using Fleming’s single stage procedure 44 patients on each arm were needed to test null hypothesis of feasibility ≤60% with 5% 1-sided significance level and 90% power. 2o outcomes included safety, PFS and ORR. Pts were stratified by serum albumin, stage and tumor differentiation. Results: 75 pts were recruited Sept 2007 - May 2011 (28 CG-P; 47 C-PG), median age 62 yr (range 21-75). Recruitment to CG-P closed early due to futility. 52% had albumin >35g/L, 68% FIGO stage 3C and 80% poorly differentiated tumors. 64% on CG-P and 55% on C-PG had debulking surgery as planned and a further 4% on CG-P and 13% on C-GP after completion of all CT. For CG-P 35% achieved 0cm, 35% <1cm and 30% ≥ 1cm residuum; for C-GP 34% 0cm, 13% <1cm and 34% ≥1cm, 19% TBC. 14/28 pts on CG-P completed all 12 cycles (feasibility 50%; 95% CI 31-67%); 37/47 pts on C-PG (feasibility 79% (95% CI 64-88). Main reason for early discontinuation was toxicity on CG-P and disease progression on C-PG. Similar proportions of pts on each arm had dose reductions (68%) or delays (86% on CG-P; 89% on C-PG), mainly for toxicity. 82% of pts experienced grade 3/4 toxicity on CG-P; 72% on C-PG. Median PFS for CG-P is 14.3 mths (95% CI 11.6-15.7mths) and 13.0 mths (95% CI 11.5-15.4mths) for C-PG. Conclusions: CG-P was not feasible at these doses using pre-specified criteria, but C-PG is feasible.
An updated safety analysis of OCEANS, a randomized, double-blind, phase III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or placebo (PL) followed by BV or PL to disease progression (PD) in patients with platinum-sensitive (Plat-S) recurrent ovarian cancer.
Authors: Aghajanian Carol , Blank Stephanie V. , Goff Barbara Ann , Judson Patricia Lynn , Nycum Lawrence R. , Sovak Mika A. , Yi Jing , Husain Amreen
Published: March 2020

5054

Background: OCEANS met its primary end point with a statistically significant and clinically meaningful hazard ratio for progression-free survival (PFS) of 0.484. Secondary end points included objective response rate, overall survival, and safety. Eleven additional months of safety data were collected after the data cut-off date for the final PFS analysis event and updated safety analyses were performed. Methods: Eligible patients (pts) were randomized to arm A: GC (G [1000 mg/m2 days 1 and 8] and C [AUC 4, day 1], q21d for 6–10 cycles) + concurrent PL (q21d), followed by PL until PD or unacceptable toxicity; or arm B: GC + concurrent BV (15 mg/kg q21d), followed by BV until PD or unacceptable toxicity. All adverse events (AE) were recorded and graded per NCI-CTCAE v3.0. Results: The incidence of any grade AE was 100% in both arms and of SAEs was 25.3% (PL arm) and 35.6% (BV arm). The rates of proteinuria, hypertension (HTN), reversible posterior leukoencephalopathy syndrome (RPLS), thrombocytopenia and epistaxis were higher in the BV arm. More pts in the BV arm (20.6%) than in the PL arm (4.7%) experienced an AE that led to discontinuation of study drug, in the BV arm most commonly due to HTN (4%), proteinuria (2.8%), epistaxis (1.2%), thrombocytopenia (1.6%) and RPLS (0.8%). Median number of BV cycles in pts with G ≥3 proteinuria was 22.5 and the AE resolved in 91.7% of pts. Among the pts with G ≥3 HTN, the median number of BV cycles was 16.5 and the AE resolved in 72.7% of pts. Conclusions: The overall safety profile was similar to that seen at the time of the final PFS analysis. Higher incidences of proteinuria and HTN were possibly related to longer BV treatment duration and resolved in the majority of pts. [Table: see text]
The impact of interval cytoreduction and age in advanced-stage ovarian cancer: A GOG ancillary study.
Authors: Lichtman Stuart M. , Java James , Lovecchio John L. , Chi Dennis , Tew William P. , Bookman Michael A. , Menzin Andrew
Published: March 2020

5056

Background: To determine if an age group exists for which interval cytoreductive surgery (ICS) in patients with suboptimal residual disease at primary surgery influences progression free survival (PFS) and overall survival (OS) among women with advanced ovarian cancer treated on GOG 182. Methods: GOG 182 was a prospective, randomized trial of first-line chemotherapy in patients with advanced ovarian cancer. Patients with both optimal and suboptimal residual disease were included, and those with suboptimal residual were considered for ICS, with intent registered and stratified prior to randomization. Patients were randomized to one of five chemotherapy arms, employing combinations of either two or three agents delivered intravenously, with a control arm of paclitaxel and carboplatin. A retrospective analysis was approved by the GOG Ancillary Study Committee to investigate the influence of age on treatment and outcomes. In that analysis, Cox regression was used to identify independent prognostic factors and estimate their covariate effects on the adjusted PFS and OS of patients with suboptimal residual disease. Statistical significance was set at p<0.05. Results: Among the entire eligible study population, 28% (n=1,042) were registered with suboptimal residual disease (> 1 cm) and 109 of these patients elected to undergo ICS. Hazard ratios (HR) were determined for patients undergoing ICS with reference to patients with suboptimal disease not undergoing ICS. Based on the most current follow-up data, the HR for progression or death was not statistically different between the groups, but the HR of death alone was significant at 0.72 (95% CI: 0.57–0.92, p=0.008). There was no significant association of age with ICS in either the PFS or the OS model. Conclusions: In this trial, a patient’s age did not influence the effect of ICS on PFS or OS. There is no demonstrable benefit in PFS associated with ICS, but there was a statistically significant improvement in OS. To elucidate this finding, further study is warranted, likely in the form of a meta-analysis incorporating data from other prospective trials.