bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations of natural killer cell receptors as biomarkers associated with the severity of the disease in prostate cancer.
Authors: Pasero Christine , Gravis Gwenaelle , Rocchi Palma , Just-Landi Sylvaine , Livrati Philippe , Thomassin Jeanne , Brunelle Serge , Salem Naji , Walz Jochen , Olive Daniel
Published: March 2020

e15155

Background: Recently, therapeutic vaccines and monoclonal antibody-based therapies have been investigated as promising new treatments against prostate cancer (PC). Natural killer (NK) cells which have anti-tumoral activity thus represent promising candidates for immunotherapy. Our group have reported major impairments of NK in acute myeloid leukemia and recently in metastatic breast cancer. The aim of this work was to evaluate the phenotype and function of NK cells in patients with localized and metastatic PC to determine their role in disease progression. Methods: Activating and inhibitory receptors were analyzed in peripheral NK cells from 14 patients with localized PC, 33 with metastatic disease and 30 healthy donors. NK function was evaluated by measuring CD107 degranulation. Results: The ratio mean fluorescence intensity RMFI (MFI receptor/MFI control isotype) of the activating receptor NKp30 was significantly lower in patients (7.30 +/- 0.68, p=0.0059) than in HD (10.99 +/- 1.34), whereas NKp46 was lower in the metastatic patients only (11.76 +/- 1.18) compared to the localized cases (21.86 +/- 4.25) and HD (19.13 +/- 2.39). The RMFI of 2B4 (47.14 +/- 7.99), the percentage of positive cells for the inhibitory receptor ILT2 (49.34 +/- 3.90, p=0.0003) and the maturation marker CD57 (41.13 +/- 4.69, p=0.0014) were significantly upregulated in patients compared with HD (2B4 23.09 +/- 4.74, ILT2 20.65 +/- 3.09, CD57 21.36 +/- 3.07), with a more pronounced increase in the metastatic groups. The RMFI of other receptors such as NKG2D or CD94 does not differ. NK cells from patients were significantly less effective (17.90% +/- 1.48, p<0.0001) than NK from HD (30.31% +/- 2.70) to degranulate against the K562 target or prostate tumor cell lines. Conclusions: We observed an altered phenotype of NK cells in PC, correlated with decreased NK cell function, with alterations more pronounced during metastatic progression. Prostate tumor cells could have the ability to impair NK cell visibility through the modulation of their receptors and consequently decrease their cytotoxic function. This highlights the possibility of restoring NK cells cytotoxicity as a future therapy against PC.
Treatment patterns in men with castration-resistant prostate cancer receiving docetaxel.
Authors: Davis Keith L. , Gutierrez Benjamin , Zyczynski Teresa Maria , Kaye James A.
Published: March 2020

e15165

Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the US since 2004 (TAX 327), yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the US were reviewed: 48 from oncology (N=344) and 8 from urology (N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising PSA, progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other drugs. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons for docetaxel delay and sub-maximal exposure in some CRPC patients.
Updated safety result of a large Italian early access program (EAP) with cabazitaxel plus prednisone (CbzP) in metastatic castration-resistant prostate cancer (mCRPC) patients who progressed during or after docetaxel (D) therapy.
Authors: Bracarda Sergio , Di Lorenzo Giuseppe , Gasparro Donatello , Marchetti Paolo , Boccardo Francesco , Martoni Andrea , Carteni Giacomo , Fornarini Giuseppe , Baldazzi Valentina , Dogliotti Luigi , Messina Caterina , Sisani Michele
Published: March 2020

e15185

Background: A significant percentage of mCRPC pts, who have progressed on D therapy, have a long life expectancy and are candidates for additional treatments. In TROPIC trial pts who progressed during or after D had a statistically significant OS advantage and clinical benefit with CbzP in respect to mitoxantrone plus prednisone (MP). Benefits observed in the TROPIC study supported a global EAP, to allow pts with mCRPC to have an early access to CbzP and provide confirmatory data in daily clinical practice Methods: We report the safety results of the first 90 pts entered into EAP and treated with CbzP, out of 232 pts enrolled by 25 Italian centers between Jan and Aug 2011 Results: Pts characteristics were median age 70 years (≥ 75 years 22.2%); ECOG PS 0-1, 97.8%; median N. of previous D cycles 8 (median cumulative D 675mg/m2); 14.1% received 675 ÷ 900 mg and 40.0% ≥ 900 mg of D. Median time from last D dose to first CbzP dose was 5.29 months including any other chemotherapy treatment.At the time of this analysis 50% of pts had received 4 cycles of CbzP. 33 pts discontinued CbzP mainly due to PD (42.4%), AEs (related/not related, 27.3%), investigator’s (3.0 %) / pts decision (18.2%) and others (9.1%). AEs resulting in CbzP discontinuation (10.0%) are mainly fatigue, pyrexia and haematological disorders. A total of 57 pts were still on treatment. In the 33 discontinued pts, CbzP has been delayed in 24.2% while a dose reduction occurred in 21.2% of pts. AEs of any grade were observed in 81/90 pts. Most common G 3/4 AEs were leukopenia (25.6%), neutropenia (48.9%), anaemia (6.7%), diarrhoea (1.1%), asthenia (3.3%) and fatigue (5.6%). One death occurred during the study period in a heavily pretreated pt who received 33 cycles of D Conclusions: This preliminary safety analysis suggests the good tolerability of cabazitaxel, in terms of haematological as well as non-haematological AEs even in heavily pretreated pts according to the previous experience of Italian Centers in theTROPIC trial. This is remarkable because of the increased similarity of the patient’ populations treated in the EAP and daily clinical practice
Opportunity for all? Socioeconomic disparities in chemotherapy (CT) use for metastatic prostate cancer (mPC).
Authors: Perlroth Daniella , Luna Yesenia L , Thompson Stephen F , Tangirala Muralikrishna , Ng Daniel B , Nicacio Leonardo , Lakdawalla Darius
Published: March 2020

e15186

Background: CT for mPC is a category 1 recommendation after progression despite hormone therapy (NCCN Clinical Guidelines in Oncology). Having previously documented large regional variations in CT use (Perlroth et al, GU-ASCO, Feb 2-4, 2012), we sought to determine if such disparities exist for patients across socioeconomic status (SES) indicators. Methods: Using Surveillance, Epidemiology, and End Results data linked to Medicare claims, we identified all men diagnosed between 2000 and 2007 with mPC initiated on hormones, excluding patients not continuously enrolled in Medicare Parts A/B or diagnosed with other cancers. We used logistic regression to estimate probability of CT, adjusting for demographic, SES, grade stage and PSA of cancer, and other comorbidities, and tested alternative measures of SES in sensitivity analyses. We report odds ratios (OR) for CT use by socioeconomic status, 95% confidence intervals (CI), and estimates for differences in CT use for high and low SES patients. Results: 7852 patients were in the cohort, mean and median age of 76 and 74 years. 19% advanced to CT, but patients living in regions below the federal poverty level were significantly less likely to do so (OR=0.85, 95% CI: 0.73-0.98). Patients in regions in the bottom quartile of education exhibited OR=0.67 (95% CI: 0.57-0.80) compared with the top quartile. Black race, education, and income factors were not associated with CT use. There were no significant interactions between race and education or income. Median-aged patients residing in the highest-quartile areas versus lowest for education had an estimated 6% higher absolute probability of advancing to CT. After controlling for poverty and education, black race conferred an additional 1% nonsignificant lower probability of advancing to CT over nonblacks. Treatment disparities between groups remained stable during 2000-2007. Conclusions: Education status was the strongest predictor of CT initiation in men with mPC. Poverty and black race also predicted lower CT use. Given that all men in this study were enrolled in Medicare, efforts and research to reduce treatment disparities may need to focus on health system needs serving low socioeconomic communities.
Alternative splicing of Krüppel-like factor 6 (KLF6) enriched in human androgen-deprived prostate cancer (PC).
Authors: Liu XiaoMei , Gomez-Pinillos Alejandro , Loder Charisse , Carrillo-de Santa Pau Enrique , Quiao Rui Fang , Unger Pamela D , Kurek Ralf , Oddoux Carole , Melamed Jonathan , Gallagher Robert E , Mandeli John P , Ferrari Anna C.
Published: March 2020

e15191

Background: Inactivation of KLF6 by mutations and alternative splicing has been implicated in PC. However, there are significant discrepancies among human PC studies concerning the prevalence and significance of KLF6 mutations, and the prevalence of splice variants (SVs) has not been established. The objective of this study was to assess the prevalence and role of KLF6 splicing in human PC progression. Methods: Human specimens were obtained from the tissue banks of three institutions. Representative epithelium of 74 frozen PC specimens [25 primary hormone-naïve (HN) PCs, 21 primary hormone-deprived (HD) PCs, 6 castrate-resistant metastases] and 22 normal prostates (NPs) were microdissected. KLF6 cDNA was amplified by PCR, cloned and sequenced in both forward and reverse directions and compared to the KLF6 GenBank sequence. The transcriptional activity of KLF6 SVs was evaluated in co-transfection assays with a p21-reporter, and their effect on LNCaP cell growth was determined by MTT assays. Results: Sixteen different SVs were identified: 13 were novel; 14 affected the DNA binding domain (DBD) and were transcriptionally inactive. The incidence of SVs was increased in PC versus NP (75% vs 45%; p=0.01) and in HD-PC versus HN-PC (90% vs 64%; p=0.04) HD-PC were significantly enriched in SVs lacking the DBD. Forced expression of dysfunctional KLF6 SVs increased growth of LNCaP cells in androgen-depleted media. Conclusions: KLF6 SVs lacking p21-reporter transactivation activity occur in NP epithelium but are markedly increased in incidence, variety and level of expression in PC tissues that survive androgen-deprivation. This enrichment may enable resistance to hormone therapy and a proliferative advantage under castrate conditions.
Therapeutic target expression in advanced prostate cancer patients submitted for comprehensive molecular profiling.
Authors: Wright Brian , McGinniss Matthew Jerome , Ghazalpour Anatole , Roberts Christopher , Bender Ryan P , Feldman Rebecca A , Brisbin Lori , Basu Gargi D.
Published: March 2020

e15209

Background: Approximately 30,000 men die from advanced PCa annually. The prognosis of this disease stresses a need for novel therapeutic and clinical strategies. Methods: We analyzed targeted genes and proteins in 141 patient specimens using IHC (for as many as 29 different biomarkers), FISH for EGFR, ALK, c-Myc, Her2neu and TOP2A, sequencing for BRAF, c-ckit, EGFR, KRAS, and PIK3CA, and RNA expression microarray. Therapeutic associations from the published literature were then assigned based on the differentially expressed biomarkers. Due to amount of tumor tissue present in the specimen, physician test requests and other factors, the number of biomarkers interrogated varied from case to case. Results: Therapeutic associations based on IHC results included:) 92% HER2 negative (potential lack of benefit from HER2 targeted therapy); 85% AR high (potential benefit from anti-androgen therapy); 79% ERCC1 negative (potential benefit from platinum-based therapies); 70% TS negative (potential benefit from fluorouracil),54% PTEN negative (suggesting activation of PIK3CA pathway), 66% RRM1 low (potential benefit from gemcitabine); 64% TOPO2A low (potential lack of benefit from anthracyclines); 44% TOPO1 high (potential benefit from irinotecan) 34% MGMT high (potential lack of benefit from temozolomide); 28% SPARC high (potential benefit from nab-paclitaxel). Potential therapeutic associations based on FISH and Sequencing included: 82% HER2 negative by FISH (potential minimal benefit to HER2 targeted therapy), 13% EGFR positive by FISH and a majority 90% and 81% wild-type for KRAS (exons 2, 3) and BRAF (exons 11, 15), respectively, indicating potential benefit from EGFR targeted therapies. Interestingly, two drug pumps, PGP and MRP1 were 85% negative and 91% positive, respectively. Conclusions: Advanced PCa is an aggressive disease where a one-size-fit-all approach is not effective. Our data confirms that these tumors are heterogeneous at the molecular level and has important therapeutic implications. When developing biomarker enriched clinical trials or advanced treatment planning, a comprehensive molecular profile may provide important insights not otherwise considered.
Endometrial carcinoma in the Baby Boomer generation: Tumor characteristics and clinical outcome.
Authors: Elshaikh Mohamed A. , Shah Mira , Cattaneo II Richard , Mahan Meredith , Buekers Thomas E.
Published: March 2020

e15512

Background: Baby Boomers (BB) enterring retirement are representing a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize surgically staged BB patients with endometrioid carcinoma and compare the results to pre-Boomers (PB) patients. Methods: After reviewing our database of 1,450 patients with endometrial cancer, we identified 595 patients with 2009 FIGO stage I-II uterine endometrioid carcinoma who were born between 1926 and 1964. Their medical records were reviewed in this IRB-approved study. Patients with non-endometrioid carcinoma and those received preoperative therapy or chemotherapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patient’s demographics, tumor characteristics and survival. Results: All patients were surgically staged with a minimum of two years follow-up.BB group included 234 patients (39%) and PB with 361 patients (61%).Median follow-up for the study cohort was 72 months. Baby boomers had higher BMI (p=0.027), younger age at diagnosis (p=0.002), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of lymph dissected (p=0.008), less lymphovascular space involvement (LVSI) (p=<0.034), and less frequent utilization of adjuvant therapy (p=<0.001). However, there was no statistically significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of local control and disease-specific survival. As to be expected, there was a trend towards shorter overall survival for the PB patients (p=0.063). Conclusions: Athough tumor characteristics were more favorable in the baby boomers generation, local control and survival endpoints were not statistically different compared to pre boomers. As more baby boomers are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences of endometrial carcinoma, if any, in this generation.
Recurrent ovarian cancer and management of elderly patients: Results of a prospective trial of treosulfan focusing on patient's preference and clinical outcome (NOGGO-Preference-Study).
Authors: Chekerov Radoslav , Braicu Ioana , Harter Philipp , Fuxius Stefan , Mahner Sven , Hanker Lars Christian , Müller Lothar , Klare Peter , Heinrich Georg , Sommer Harald Leo , Fotopoulou Christina , Sehouli Jalid
Published: March 2020

e15520

Background: There is an increasing interest in the management of elderly patients in oncology. Treosulfan is effective as oral (p.o.) and intravenous (i.v.) formultion for recurrent ovarian carcinoma. Primary aim of this study was to explore the individual preference and compliance of elderly patients (≥ 65 years) for p.o. or i.v.-treosulfan. Secondary aims were to evaluate the ADL-score, toxicity, response and survival. We present the final analysis of patient’s characteristics and treatment choice, compliance of the treatment and toxicities for 123 included patients. Methods: Patients with platinum sensitive and resistant ovarian cancer had free choice of treosulfan i.v. (7000 mg/m² d1, q28d) or p.o. (600 mg/m² d1-28, q56d) for a maximum of 12 cycles (i.v.) or 12 months (p.o.). Indecisive patients were randomized. Toxicity was evaluated according to the NCI-CTC version 2.0. Results: 123 recruited patients received therapy and were able for analysis (median age 72 years, range 65-87). 102 patients chose i.v. and 17 p.o., 3 were randomized to i.v and 1 to p.o. Median ECOG was 1 (n=0-2), and median number of prior chemotherapy-regimens was 3 (n=1-6). Most common hematological toxicities (grade 3/4) were thrombopenia (18.7%), leukopenia (15.4%) and anemia (3.6%). Most frequent non-hematological toxicities (grade 3/4) were abdominal pain (7.3%), fatigue (5.7%) and constipation (4.9%). The median progressive-free survival was 116 days, and the median overall-survival was 239 days. There was no difference in survival and activities of daily life (ADL) score between i.v. and p.o. treosulfan. Conclusions: Although heavily pre-treated most elderly patients with recurrent ovarian cancer (85%) preferred the i.v.-treosulfan administration following their individual preference. Treosulfan therapy was generally well tolerated. There were no differences in the patient’s characteristics, survival and ADL-scores in both groups.
Outcome of pelvic exenteration for recurrent endometrial and cervical cancers.
Authors: Abboud Christelle , Ngo Charlotte , Meria Paul , Fourchotte Virginie , Mariani Pascale , Baranger Bernard , Petrow Peter , Sastre Xavier , Cottu Paul H. , Delarochefordiere Anne , Alran Severine
Published: March 2020

e15524

Background: Pelvic exenteration has been used as a potentially curative operation in recurrent pelvic malignancies. However, treatment-related morbidity is over 50% in radiated pelves. We evaluated the outcome and the morbidity of pelvic exenteration in women with recurrent cervical and endometrial cancer. Methods: We studied retrospectively all the patients who underwent a pelvic exenteration for recurrent cervical or endometrial cancer in our institution, from January 1999 to November 2011. All medical data were collected. Survival rates were calculated according to Kaplan-Meier method and compared using the log-rank test. Results: twenty-five patients were identified, 17 (68%) had cervical cancer and 8 (32%) endometrial cancer. All patients received a radiation therapy during their initial treatment. All patients had a central pelvic recurrence, in a median time of 30 months [4-384]. 15 patients (60%) had an urinary diversion with incontinent ileoconduit (Bricker). 22 patients (88%) had a complete tumor resection. Severe early complications needing a re-laparotomy occurred in 9 patients (36%) (insufficiencies of intestinal anastomosis, insufficiencies of the ureteral anastomosis and pelvic abscesses). One patient (4%) had a recto-vaginal fistula. Late complications included 1 (4%) vaginal fistula, 1 (4%) intestinal fistula), 2 (8%) intestinal occlusion and 1 (4%) ureteral stenosis. Disease Free and Overall survival rates are better in cervical than in endometrial cancer (median DFS in months 17 [2-145] vs 9.5 [3-21], p= 0.064, median OS in months 20 [2-145] vs 13 [4-42], p=0.019) (table 1). Conclusions: Morbidity of pelvic exenteration remains high. Endometrial cancer is associated with a poorer prognosis. In those patients, the benefit of exenteration should be discussed compared to best supportive care for palliative treatment. [Table: see text]
Weekly ixabepilone with or without concurrent bevacizumab in the treatment of recurrent endometrial cancer.
Authors: Roque Dana Marie , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Rutherford Thomas J. , Santin Alessandro
Published: March 2020

e15526

Background: Ixabepilone for endometrial cancer has only been evaluated in phase II studies administered at 30-40 mg/m2 q21 days (GOG 129P, GOG 86P). The objective of this study is to describe the institutional experience using a weekly dosing strategy of ixabepilone ± bevacizumab in the treatment of paclitaxel/platinum-resistant recurrent endometrial cancer. Methods: Patients who received weekly ixabepilone (16-20 mg/m2 on days 1, 8, 15 of a 28-day cycle) ± bevacizumab (10 mg/kg on days 1, 15 of a 28-day cycle) off-protocol were identified retrospectively. Results: Thirteen patients were included. Demographic/disease characteristics are provided in Table 1. Median time to first recurrence was 15.9 months (IQR: 9.5-21.66). Patients received a mean of 4.8 ± 1.9 cycles of ixabepilone; treatment is ongoing in 4 patients. A total of 46% of patients demonstrated either a partial response (PR, 8%) or disease stabilization (SD, 38%). PR/SD was associated with a mean decline in CA-125 of 56%. Approximately 50% of patients received concurrent bevacizumab. Of patients who did not receive concurrent bevacizumab, 83% experienced progression and 17% demonstrated SD. Median survival after ixabepilone initiation was 12.7 and 6.9 months in patients treated with and without concurrent bevacizumab, respectively (HR 0.42 [0.09-1.98]). Grade 1/2 hematologic (thrombocytopenia, 15.4%) and gastrointestinal toxicities (emesis/constipation, 7.7%) were observed infrequently. Median overall survival of this cohort was 2.88 years. Conclusions: Ixabepilone shows encouraging activity and promising durability in patients with heavily pre-treated paclitaxel/platinum-resistant recurrent endometrial cancer. Weekly dosing at 16-20mg/m2 on days 1, 8, and 15 ± bevacizumab is well-tolerated. Additional investigation of this regimen and long-term follow-up is warranted. [Table: see text]
Interleukine 10 -592 c/a and interleukine 8 -251 t/a polymorphisms in ovary cancer: New prognostic biomarkers?
Authors: De Mello Ramon Andrade , Marques Dania Sofia , Savva-Bordalo Joana , Gomes Monica , Assis Joana , Coelho Ana , Couto Rosario , Sousa Susana , Afonso Noemia , Medeiros Rui , Pereira Deolinda
Published: March 2020

e15532

Background: Interleukine (IL) 10 –592C/A and IL8 –251T/A polymorphisms previous showed an important role in cell proliferation, cell migration and angiogenesis. Therefore, we conduct a study in order to assess the role of those genetic polymorphisms as prognostic biomarkers in epithelial ovary cancer (EOC). Methods: Design: Retrospective study from 1996 to 2010. Setting: Histological confirmed EOC patients treated at our institution. Laboratory: Genotyping of IL10–592 C/A and IL8 -251T/A were performed by PCR-RFLP. DNA samples were obtained from patients’ peripheral blood. Statistical analysis: Logistic regression were used to calculate odds ratio (OR) and 95% confidential interval (95% CI). Overall survival (OS) and progression-free-survival (PFS) were performed using Kaplan-Meier analysis. Statistical significance was considered for p < 0.05. Results: It was recruited 156 participants. Median age was 53 (16 – 80) years-old. Genotype frequency distribution for IL8-251 were T/T (50%), T/A (50%) and for IL10–592, C/C (53.8%), C/A (39.7%), A/A (6.4%). These follow genotypes were associated with lymph node, pelvic and peritoneal relapse: IL10–592C/A (OR 0.229, 95% CI: 0.055 – 0.943, p = 0.041) and IL8–251T/A (OR 6.667, 95% CI: 1.359 – 32.701, p = 0.019). In overall, IL8–251T/A genotype had higher OS than IL8-251T/T genotype: 115 versus 95 months, p = 0.010. In clear cell tumors (CCT), IL8–251T/A genotype had less OS than IL8-251T/T genotype: 92 versus 107 months, p = 0.004. To IL10–592 genotypes, OS were 104 (A/A), 107 (C/A), 103 (C/C) months, p = 0.637, and PFS were 9 (A/A), 14 (C/A), 20 (C/C) months, p = 0.057. However, in CCT, PFS for IL10–592 genotypes were 4 (A/A), 56.73 (C/A), 20 (C/C) months, p = 0.023. Conclusions: Our results suggest that IL8–251T/A polymorphism could represent a prognostic biomarker in overall EOC. IL10–592C/A polymorphisms are associated with relapse and PFS mainly in CCT. Nevertheless, furthers prospective studies are warranted in order to assess its role in pharmacogenomics framework.
Palliative external-beam radiotherapy in recurrent ovarian carcinoma.
Authors: Fackrell David Gareth , Anwar Muhammad Suhail , Fernando Indrajit Nalinika , Doyle Yvonne , El-Modir Ahmed
Published: March 2020

e15534

Background: Up to 80% of patients with advanced ovarian cancer will recur following first-line platinum based chemotherapy. Palliation of focal lesions is often needed to alleviate symptoms. Response rate to second and third-line chemotherapy remain disappointing. The study aim was to characterise the patient population referred for palliative radiotherapy for advanced and recurrent ovarian carcinoma and to assess the effectiveness of radiotherapy in this population. Methods: We retrospectively reviewed the medical records of 94 patients with advanced recurrent ovarian carcinoma referred for palliative radiotherapy between March 1994 and July 2011. The median age of the patients was 62 years (range 33 to 85). One to 16 cycles of a platinum-based chemotherapy regimen were delivered before irradiation (median = 7 cycles). The indications for palliative treatment were: pain (n = 41), mass (n = 32), brain metastases (n = 19), vaginal bleeding (n = 9), rectal bleeding (n = 4), shortness of breath (n = 3), tenesmus (n = 2), skin ulceration (n = 2) and jaundice (n = 1). Some patients received treatment for more than one indication. Sites irradiated included the pelvis (n = 44), brain (n = 19), abdomen (n = 10), bone (n = 5), supraclavicular fossae (n = 4), groins (n = 3), chest (n = 3) and other (n = 6). The median radiotherapy dose was 20 Gy (range: 6 – 50 Gy). The median fraction size was 4 Gy (range: 1.8 – 8 Gy). Results: The overall response rate was 61.7%. Complete palliative response was achieved in 17% of the patients. 27.6% of patients suffered progressive disease during treatment. 10.7% had stable disease. The median duration of palliation was 6 months and closely approximated their survival. The treatment was very well tolerated. Grade 1 or 2 diarrhoea and nausea were the main side effects. Conclusions: External-beam radiotherapy can provide effective and durable palliation of symptoms in patients with recurrent platinum-resistant ovarian carcinoma. The results from palliative radiotherapy are comparable to the published series using second and third-line chemotherapy in the treatment of recurrent focally symptomatic ovarian cancer.
CETUXICOL, a phase II trial randomizing standard treatment with or without cetuximab in primary cervical cancer treatment.
Authors: Scholl Suzy Marie Elisabeth , De la Rochefordiere Anne , Petrow Peter , Floquet Anne , Petit Thierry , Alran Severine , Berton-Rigaud Dominique , Campitelli Maura , Chiara-Bruneaud Claire , Fabbro Michel , Fourchotte Virginie , Guyon Frederic , Joly Florence , Kerr Christine , Maillard Sophie , Minsat Mathieu , Plancher Corine , Pop Marius , Sastre Xavier , Beuzeboc Philippe
Published: March 2020

e15535

Background: Advanced stage cervical cancer (CC) remains a public health issue despite preventive vaccines and screening. EGFR is over-expressed in 50 to 85% of CC and activated in 20%, suggesting that EGFR blockage may be a promising treatment approach. Methods: A randomized phase 2 trial on 78 stage IB2–III patients from 11 French Cancer Centres evaluated the tolerance and early response to cetuximab, an anti EGFR antibody. 40 patients received cetuximab + standard RT and Cisplatinum based chemotherapy (arm A) and 38 patients received standard treatment (B). Primary endpoint is DFS at 2 years and presently not reached. MRI imaging revealed no difference in median (44 vs 40) tumour sizes between arms; there was no difference in age, menopausal status, PI and smoking habits. Parametrial involvement was clinically diagnosed in 19 and 20 cases respectively. Presence of lumbar or para-aortic lymph nodes was an exclusion criterion. Three patients withdrew consent in the cetuximab arm, one accepted standard treatment. Treatment schedules were incomplete in 13 (A) and 14 (B) patients for reasons of haematological or renal toxicity. Results: Surgical resection was feasible in 24 (65%) and 26 (70%) patients in arms A and B respectively.Tolerance was satisfactory in both arms, with significantly more acne form reactions in the cetuximab arm of grade 2 (n= 19) and 3 (n=4). More patients had diarrhea (n=8 vs 4: ns) associated with nausea and vomiting of grade 3 (n=4) and 4 (n=1) in the cetuximab arm (ns).Early results show a complete response at 6 weeks by MRI in 18% and 8% for arms A and B respectively. A central blinded review of the imaging and pathology slides is presently ongoing. Conclusions: The prediction of a response to EGFR targeted therapy in cervical cancer remains a matter of debate since no precise molecular studies are available. Consequently, no decisive results have been achieved in early trials of non selected patients with late stage disease (GOG 76-DD). Biopsy samples are available for the majority of our patients and analyses of EGFR expression, cellular sub-localization and main mutations in the PI3K pathway are ongoing. Molecular studies to allow hierarchical decision making are warranted in future studies.
Neoadjuvant chemotherapy without a fixed number of cycles in advanced ovarian cancer not candidates for optimal primary surgery.
Authors: Mendiola Cesar , Manneh Ray , Pascual Tomas , De Velasco Guillermo , Vega Estela , Manso Luis , Ghanem Ismael , Ciruelos Eva M. , Seoane J, , Cortes-Funes Hernan
Published: March 2020

e15552

Background: Neoadjuvant chemotherapy (N-CT) is a valid alternative for patients with advanced ovarian cancer (AOC) getting similar survival rates to primary debulking surgery (PDS) followed by chemotherapy (CT), with less postoperatory complications (Vergote et al N Engl J Med 2010;363:943-53). Our objective was to evaluate the results of N-CT with a flexible number of cycles according to the clinical and biological evolution of the patients. Methods: 22 patients with stage IIIC-IV AOC, diagnosed by laparoscope or cytology (no primary laparotomy) were registered between January 2007 and September 2011 and treated with N-CT including paclitaxel 175 mg/m2 and carboplatin AUC 6-5 every 3 weeks. The number of cycles of N-CT was dictated by the clinical response, CT scan and CA125 that could allow an interval debulking surgery (IDS) with intent of optimal cytoreduction (R0). After IDS consolidation chemotherapy treatment was given to complete a total of at least 8 cycles. Results: Median age 63.7 years (40 – 80). Histologic types: serous 28%, adenocarcinoma not specified 66%, endometrioid 4.5%. FIGO stage IIIC 57%, IV 43%, Median CA125 at diagnosis: 1744 U (157 – 14483). Mean N-CT cycles 7.8 (4-23). 90.1 % of patients responded before IDS, 2 patients progressed before surgery. Mean CA125 after N-CT was 20.5 U (9-108). 54% of patients achieved complete resection of all macroscopic disease during IDS (R0). 5/22 (22.7%) obtained a pathological complete response (pCR) (no microscopic tumour in all specimens removed). Complications in the postoperatory occurred in 2 patients consisting in suture dehiscence. The range of total number of CT cycles were as follows: <6: 4.54%; 7-8: 31.8%; 9-10: 31.8%, >10: 31.8%. With a mean follow-up of 22.4 months (4 - 57.6), 50% patients live without recurrence. Median PFS has not been reached. Conclusions: N-CT according to clinical and biologic response and not to a fixed number of cycles is an useful tool for patients with stage IIIC-IV AOC not candidates for optimal /R0 PDS, getting a high proportion of patients with optimal /R0 IDS. The complications of IDS are also very limited. pCR as surrogate marker for long-term survival in other tumours, has to be evaluated in AOC.
Correlation of tumor-profiling results with drug selection in ovarian cancer patients.
Authors: Shawver Laura K. , Zajchowski Deborah A.
Published: March 2020

e15555

Background: With the aim of informing therapy-selection decisions for ovarian cancer patients, we have profiled tumors from 190 ovarian cancer patients since 2008 for expression of 25 biomarkers associated with drug response. For 48 patients with mature follow-up data, we asked how frequently the drugs designated as likely to be of clinical benefit based on the tumor profile were administered. Methods: The tumor profiles and therapeutic choices of 48 patients that received a median of 2 (range 1-9) prior therapies for recurrent disease were extracted from our privacy-protected database. Protein levels of drug sensitivity (ER/PR, hormonal agents; TOPO1, topotecan/irinotecan (T-I); TOP2A, liposomal doxorubicin/etoposide (PLD-E); SPARC, nab-paclitaxel, N-P) and resistance (TS, pemetrexed/capecitabine (PC); RRM1, gemcitabine (G)) markers in each tumor were compared to expression in the ovarian cancer population to assign drugs likely to be associated with clinical benefit (values ≥ 25th percentile: sensitivity; ≤ 25th percentile: resistance). Results: A median of two drugs (range 1-5) were prioritized for each patient based on marker expression. 38 patients received one of the 6 drug classes evaluated by the profile. Of those 38, 22 (58%) received a therapy that correlated with the profile and 16 (42%) received drugs that were not prioritized by the profile. G and PLD were most frequently administered both before (68%) and after (48%) profiling but were supported by the tumor profile in only 40% (4/10: G) and 30% (3/10: PLD-E) of the cases. These frequencies are similar to the patient fraction (26-34%) in which those drugs were each prioritized by profiling, suggesting that the profile is not influencing therapy choice. In contrast, 11 of the 14 patients who received N-P, T-I, or hormonal agents had tumor profiles that prioritized those agents, a frequency of profile match to the treatment received that is higher than expected based on the patient fraction assigned to each therapy. Conclusions: These results require confirmation in a much larger study, but suggest that tumor profiling may guide clinical decision-making for some therapies, although frequently used drugs are often given regardless of the tumor profiling evidence.
Preliminary evidence of activity of pralatrexate in relapsed/refractory ovarian cancer.
Authors: Gabrail Nashat Y. , Smith Carrie L.
Published: March 2020

e15557

Background: Pralatrexate, a novel antifolate, is approved in the US for the treatment of relapsed/refractory peripheral T-cell lymphoma at a dose of 30mg/m2 weekly for 6 weeks of a 7-week cycle. Previous studies in solid tumors have focused on a q2w schedule at 190mg/m2. As pralatrexate is 30-40% renally excreted, an ongoing renal impairment study is investigating the impact of mild, moderate and severe renal impairment on pralatrexate distribution in patients with hematological malignancies and solid tumors. As folate receptor alpha is frequently overexpressed in epithelial ovarian cancers, we hypothesized that ovarian cancer may be a target for pralatrexate treatment and therefore have included a number of ovarian cancer patients in this trial. Methods: Patients with solid tumors and hematological malignancies were enrolled in a phase I clinical trial. Patients are treated in cohorts depending on renal function normal, mild renal insufficiency, moderate renal insufficiency and severe non-dialysis dependent renal failure. This analysis is limited to 6 patients with refractory ovarian cancer. The dose of pralatrexate is 30mg/m2 weekly for 6 weeks of a 7-week cycle, with dose adjustment depending on toxicity. Results: The 6 patients, all with stage 4 refractory ovarian cancer had received 4 or more prior chemotherapy regimens and had refractory disease, defined as, nonresponsive to the last chemotherapy regimen or progression within 3 months of the last dose of chemotherapy. Of the 6 patients, 2 experienced objective responses lasting 9 months and 4 months respectively. Disease response was assessed by CA- 125 and RECIST criteria. Two patients experienced stable disease for 4 months and 5 months respectively. One patient had grade 5 mucositis after the second weekly dose and one patient had progressive disease after disease stabilization for 3 months. Conclusions: Pralatrexate given at a dose of 30mg/m2 to patients with refractory ovarian cancer has demonstrable activity that needs to be confirmed in well-designed efficacy trials. Importantly, this is the first demonstration of clinical activity in a solid tumor at the currently approved dose.
PDGFR and c-Kit as therapeutic targets and p53 and ki67 as prognostic markers for low-grade endometrial stromal sarcoma.
Authors: Park Jeong-Yeol , Kim Jong-Hyeok , Kim Kyu-Rae , Nam Joo-Hyun
Published: March 2020

e15559

Background: To determine whether proteins targeted by currently available targeted agents are expressed in low-grade endometrial stromal sarcoma (LGESS) and to test these can be prognostic markers for LGESS. Methods: Of 48 patients with LGESS, 39 patients whose paraffin blocks of tumor in hysterectomy specimen were available were included. Using tissue microarrays, immunohistochemical expression of five therapeutic targets (EGFR, HER-2/neu, VEGFR, PDGFR and c-kit), and three proteins involved in cell proliferation (p16, p53, and ki67) were investigated. The association of these targets and markers with other clinopathologic factors and disease-free (DFS) and overall survival (OS) were analyzed. Results: EGFR and HER-2/neu were not expressed in 39 patients. VEGFR, PDGFR, c-kit, p16, p53, and ki67 was expressed in 10 (25.6%), 28 (71.8%), 32 (82.1%), 18 (46.2%), 4 (10.3%), and 21 (53.8%) patients, respectively. Expression of each marker was not significantly associated with other clinicopathologic factors. In multivariate analysis, p53 and ki67 were associated with significantly poorer DFS and OS. The 5-year DFS was 88%, 46% and 0% for p53(-)/ki67(-) group (n=18), p53(-)/ki67(+) group (n=17), and p53(+)/ki67(+) group (n=4), and the 5-year OS was 100%, 71%, and 0%, respectively. The time interval to recurrence was longer and more patients had distant recurrence in p53(+)/ki67(+) group. Conclusions: In patients with LGESS, c-kit and PDGFR were expressed in high portion of patients, suggesting imatinib mesylate may be a potential target agent. Both p53 and ki67 had strong prognostic implication, suggesting the combination of these proteins may be used as a prognostic marker.
Causes of discontinuation of intraperitoneal chemotherapy in patients with ovarian cancer.
Authors: Tamburelli Mercedes , Gatica Gabriela , Sena Susana , Castillo Javier Omar , Roca Fernanda , Bas Carlos Arturo , Gomez-Abuin Gonzalo
Published: March 2020

e15570

Background: Intraperitoneal chemotherapy (IP) showed benefit in efficacy in patients with ovarian cancer but with high rates of complications and/or toxicity. We reviewed our experience and the identification of factors for discontinuing treatment. Methods: We conducted a retrospective review of electronic medical records of patients undergoing IP catheter placement at our medical center from May 2006 to December 2012; our institutional protocol for stages II/III ovarian carcinoma after optimal surgical resection is the following: 2 cycles of IV carboplatin/paclitaxel follow by 4 cycles of IP chemotherapy (paclitaxel 135 mg/m2 day 1 IV, cisplatin 75mg/m2 day 2 IP, paclitaxel 60mg/m2 day 8 IP). For statistical analysis, we used Fisher's exact test. Results: Thirty-seven patients underwent IP catheter placement. Median follow-up was 31.2 months. Eight patients did not receive IP chemotherapy: 3 patients for stage I, 2 patients stage IV, 1 patient synchronous breast cancer, one for unusual histology, and 1 patient for partial bowel obstruction. IP chemotherapy was administered to 29 patients. In total, 94 cycles IP chemotherapy were given with a median of 3 cycles per patient. IP chemotherapy was completed as planned in 24 patients (82.7%). The reason for treatment discontinuation: abdominal pain in 2 patients, extravasation in 1 patient, one patient due to peptic stricture, and other for esophageal ulcer. Grade 3-4 toxicity for IP chemotherapy was observed in 20% of patients. Median body mass index (BMI) was 24.3. IP chemotherapy was completed as planned in 94% of patients with BMI<25 and in 64% of patients with BMI> 25, p <0.05. Conclusions: This modified IP chemotherapy regimen is feasible with acceptable toxicity. Most patients completed the scheduled treatment with IP. BMI > 25 was identified as a possible risk factor for discontinuation of treatment.
Angiogenesis biomarker study of a phase II trial of pazopanib (P) in recurrent or persistent ovarian (EOC), peritoneal (PPC), or fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study.
Authors: Lopez-Guerrero Jose Antonio , Oaknin Ana , González-Martín Antonio , García Yolanda , Catot Silvia , Caballero Cristina , Garcia-Donas Jesus , Bover Isabel , Santaballa Ana , Guerra Alia Eva , Pardo Beatriz , Vidal Boixader Laura , Marquez Raul , Freixinos Víctor , Romero Ignacio , Ruiz-Sauri Amparo , Poveda Andres
Published: March 2020

e15575

Background: Angiogenesis is essential to tumor growth, invasion, and metastasis in EOC. The aim of this study was to identify angiogenic biomarkers to predict response to P, a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit, in a clinical phase II trial. Methods: We analyzed a series of 20 out of 25 women enrolled in a GEICO Phase II trial that studied the Clinical Benefit Rate (CBR) of P in platinum-resistant EOC, PPC and FTC (results will be presented in an additional abstract). Formalin-fixed, paraffin-embedded tumors at diagnosis were evaluated for the microvessel density (MVD) by using CD31 immunostaining and the Image Pro-Plus 7.0 Image Analysis System (Media-Cybernetics). In addition, several angiogenic factors were evaluated by means of immunohistochemistry (IHC) on tissue arrays sections, and quantitative real-time PCR (qRT-PCR) using the Human Angiogenesis Arrays (Applied Biosystems). Serum samples were also collected at different moments of the treatment schedule and a panel of 14 citokines and growth factors were evaluated using the Luminex technology (Millipore). Results: Fifteen (75%) of the tumors were high grade serous EOC. Eight patients (40%) showed a CBR on treatment.MVD analysis, (number of vessels/mm2) was 2025 (835-3242) and 2410 (1449-3543) in patients with and without CBR respectively (p=0.278). IHC showed very low expression of angiogenesis-related factors including VEGF and VEGFRs, PDGF and PDGFRs, HIF and pAKT. Expression analysis by qRT-PCR and serum levels of cytokines and growth factors revealed no statistical differences between patients with and without CBR. Conclusions: No predictive biomarkers of CBR to P in platinum-resistant EOC could be identified in a population of patients with low expression level of angiogenic factors at diagnosis.
Demographics of uterine serous cancer (USC) patients: A single institutional experience.
Authors: de Leon Maria , Lu Lingeng , Hui Pei , Santin Alessandro , Rutherford Thomas J. , Arin-Silasi Dan , Azodi Masoud , Ratner Elena , Schwartz Peter E.
Published: March 2020

e15581

Background: The common uterine cancer (UC) occurs in obese, diabetic (DM), hypertensive (HTN), postmenopausal women and are estrogen dependent. Small institutional series suggest USC occurs in older, thin women and is not associated with estrogen dependency. The objective of this study is to report demographic features of USC patients (pts) in a large single-institution experience and compared them with SEER data for UC (National Cancer Institute, SEER 2004-2008, uterine cancer. http://seer.cancer.gov/statistics/ ). Methods: Institutional records were reviewed from 1987 to 2009. Pts age, menopause status, race, disease stage, histology, past medical history (PMH) and additional demographics were collected. Results: 334 USC (pts) were identified. Their average age at diagnosis was 69.1 years (range 37-92). 282 (88.1%) were Caucasian and 32 (10%) were African Americans. The FIGO stage was IA 121 (36.2%), IB 36 (10.8%), II 27 (8.1%), IIIA 39 (11.7%), IIIB 2 (0.6%), IIIC1 32 (9.6%), IIIC2 9 (2.7%), IVA 28 (8.4%) and IVB 40 (12%). PMH revealed 177 of 221 (80%) had HTN and 69 of 221 (32%) had DM. 132 of 292 (45.3%) were obese; 95 (32.5%) had BMI between 30-39,31 (10.6%) had BMI between 40-49 and 6 (2.1%) had BMI >50. 89 of 315 (28.2%) smoked cigarettes, 48 of 250 (19.2%) used oral contraceptives for an average of 4 years (range 1-15) and 42/299 (14%) used HRT for an average of 4 years (range 1-20). 35 (17.3%) had a prior history of breast cancer, 5 (2.5%) colon cancer and 13 (6.4%) had other forms of cancer. Compared to published SEER data1 for all UC, more USC pts were diagnosed with advanced stage disease (II-IVB) 53% vs. 28%. USC patients were older at diagnosis (mean age of 69 vs. 61 years). Conclusions: Like UC, USC often presents in obese (45.3%), hypertensive (80%) diabetic (33%) women who have a prior history of breast cancer (17%). However, USC typically is found in older pts and at a more advanced stage.