bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening for Lynch syndrome in unselected women with endometrial cancer.
Authors: Ferguson Sarah E. , Aronson Melyssa , Eiriksson Lua R , Mojtahedi Golnessa , Pollett Aaron , Gallinger Steven , Oza Amit M. , Mackay Helen , Bernardini Marcus , Lerner-Ellis Jordan , Clarke Blaise
Published: March 2020

5508

Background: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch Syndrome (LS) however it is often not recognized in this population. A prospective cohort study comparing family history, immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and tumour morphology to germline mutation status in MMR genes was performed in unselected women with EC to determine which screening strategy was superior in identifying women with LS. Methods: All women with newly diagnosed EC between July 2010 and June 2011 were asked to participate in the prospective screening protocol for LS which included completing an extended family history questionnaire (eFHQ), tumor assessment for LS-associated morphologic features and IHC as well as germline mutation testing. Results: 119 (n = 182, 65%) consented to the study. The median age was 61 (26-91), 96 (81%) stage I, and 42 (35%) had high risk histology. There were 6 (7.4%, n = 81) women that were germline mutation positive (MLH1 N=3; MSH6 n = 2; MSH2 n =1), representing a mutation positive rate of at least 5% in this cohort (6/119). All 3 MLH1 mutation positive women had low grade histology while mutations in MSH2/6 were exclusively found in women with high risk histology. Two of the six mutation positive women were not identified by family history. Mutation positivity was higher in women under age 50 (23%; 5/22) compared to women > age 50 (1%; 1/97)( (p = 0.0008). LS-morphologic features were found in 58 (59%, n = 98) women. The sensitivity, specificity, PPV and NPV of the LS-associated features in predicting LS mutation status was 100%, 42.6%, 7.9% and 100% compared to IHC which was 100%, 76%, 18% and 100% and eFHQ which was 67%, 84%, 27%, 97%. Conclusions: In this unselected population of women with newly diagnosed EC the germline mutation rate for LS was 2-3 times that has previously been reported. Previously described LS-associated morphologic features were not specific to germline mutation status and family history missed one third of women with LS. IHC was the best strategy to identify women with EC who should undergo germline mutation testing.
Prognostic significance of differential expression of angiogenic genes in women with invasive high-grade serous ovarian carcinoma.
Authors: Siamakpour-Reihani Sharareh , Owzar Kouros , Jiang Chen , Turner Taylor , Berchuck Andrew , Marks Jeffrey , Dewhirst Mark , Secord Angeles Alvarez
Published: March 2020

5509

Background: High-grade serous ovarian carcinoma (HGSC) is an aggressive type of epithelial ovarian cancer associated with numerous genetic alterations and poor survival. Our objective was to identify novel angiogenic biomarkers that are associated with tumor angiogenesis and clinical outcome in women with HGSC. Methods: Between 1988 and 2001, 51 snap frozen samples from women with advanced HGSC were obtained. RNA was extracted and analyzed by the Affymetrix GeneChip U133A array. A panel of 285 probe sets (features) linked to 145 genes involved in angiogenesis were screened. Microvessel density (MVD) counts, surrogates of angiogenesis, were determined using CD31 and CD105, markers of proliferating endothelial cells. The association between mRNA expression levels and overall survival (OS) were assessed using a rank score statistic. The effect size was estimated parametrically as a hazard ratio (HR) under a proportional hazards model. We accounted for multiple testing within the false-discovery rate (FDR) framework using the Storey q-value method. The associations between expression level and OS for the implicated genes were further assessed in a published HGSC cohort from the “The Cancer Genome Atlas” (TCGA) database. Results: A panel of 43 features linked to 31 angiogenic genes were significantly associated with long term OS (FDR q-value (q) < 0.05). In the TCGA cohort, four genes exhibited some level of significance and concordant direction of effect as assessed by HRs: AKT1 (q = 0.018, HR = 0.44; TCGA unadjusted p-value (p) <0.011, HR = 0.81), and CD44 (q < 0.003, HR = 0.48; TCGA p < 0.054, HR = 0.89) were associated with better survival; while EPHB2 (q < 0.009, HR = 8.12; TCGA p < 0.051, HR = 1.23) and ERBB2(q < 0.019, HR = 2.86, TCGA p < 0.055, HR = 1.19) were associated with worse survival. After adjusting for multiple comparisons, CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions: Our data demonstrated that mRNA levels of 31 angiogenic genes were associated with OS in advanced HGSC. Among these 4 were externally confirmed using TCGA data. Further evaluation is warranted to verify our preliminary findings.
Ki-67 level in hormone reptor positive breast cancer patients: A retrospective review of 9,061 Korean women.
Authors: Kim Jisun , Han Wonshik , Park Yeon Hee , Jung So Youn , Lee Eun Sook , Ro Jungsil , Moon Hyeong-Gon , Ahn Soo Kyung , Lee Jun Woo , Kim Min Kyoon , Im Seock-Ah , Han Sae-Won , Kim Tae-Yong , Lee Kyung-Hun , Park In Ae , Noh Dong Young
Published: March 2020

551

Background: Although young age breast cancer represents poor prognosis, no definitive explanation could have been made for the phenomenon. A tumor proliferation marker Ki67 is known to be a marker for both prognosis and prediction for chemotherapy responsiveness, and its level varies widely depending on the breast cancer subtype. This study was aimed to analyze Ki67 in relationship with age in hormone receptor positive breast cancer patients. Methods: We retrospectively reviewed 9061 consecutive cases of hormone receptor positive invasive breast cancer from data base at Seoul National University Hospital (SNUH) (between 2000 and 2012), Samsung Medical Center (SMC) (between 2004 and 2010), and National Cancer Center (NCC) (between 2001 and 2010) in Korea. Patients with estrogen receptor (ER) or progesterone receptor (PR) positive tumors were included irrespective of HER2 amplification. A multicenter data of Ki67 level identified by immunohistochemistry (IHC) and age at diagnosis were analyzed. Patients who underwent neoadjuvant systemic therapy were excluded. Results: Total 6222 cases from SNUH, 976 from SMC and 1863 from NCC were included. The three datasets were analyzed separately due to variable IHC methods in each institute. Mean ages were 49.30 years (range 20-86), 47.75 years (range 22-81) and 45.31 years (range 25-59), and mean Ki67 levels were 4.66% (range 1-100), 22.98% (range 1-97) and 14.58% (range 1-90), at SNUH, SMC, NCC respectively. Ki67 level was inversely proportional with age at diagnosis in all three datasets, and the level was significantly higher for patients <40 years compared to ≥40 years (mean Ki67: 5.97 vs 4.41, p<0.001; 28.60 vs 21.88, p<0.001; 17.01 vs 14.03, p<0.001, respectively). There was an inverse relation with age as well when Ki67 level was categorized into ‘<10% vs ≥10% (p<0.001)’, ‘<20% vs ≥20% (p=0.03)’ and ‘<14% vs ≥14% (p<0.001)’ respectively. Conclusions: Despite the variability of assessing Ki67 expression, Ki67 level was significantly higher in young age hormone receptor positive breast cancer from all three analyses. This could partly explain the poor prognosis and substantial responsiveness to chemotherapy in this age group of patients.
Pazopanib (Paz) monotherapy in Asian women who have not progressed after first-line chemotherapy for advanced ovarian, Fallopian tube, or primary peritoneal carcinoma.
Authors: Zang Rongyu , Wu Lingying , Zhu Jianqing , Kong Beihua , Kim Byoung-Gie , Yao Yuanquing , Yin Rutie , Liu Jihong , Wu Qiang , Ngan Hextan Yuen Sheung , Xie Xing , Wang Kung-Liahng , Li Xiuqin , Yen Ming-Shyen , Wei Lihui , Wang Qiong , Mitrica Ionel , Carpenter Christopher , Zhang Pingkuan
Published: March 2020

5512

Background: Paz, an oral multikinase inhibitor of VEGF, PDGF and c-Kit has showed activity in advanced ovarian cancer. This study evaluated paz as maintenance therapy in Asian women with advanced ovarian cancer. Methods: Subjects with FIGO stage II, III, or IV ovarian, fallopian tube, or primary peritoneal cancer whose disease had not progressed after debulking surgery and followed by chemotherapy were randomized 1:1 to paz 800 mg once daily or placebo for up to 24 months. Primary endpoint was PFS by RECIST v1.0 based on visit date. If a progression occurred between the 2 scheduled visits (6 mos apart), progression was considered to have occurred at the next scheduled scan date. This minimized potential bias due to any imbalance of visit frequency between the arms. Results: 145 Asian subjects were randomized; 144 were treated. Mean age was 52.9 years. At diagnosis 17% were FIGO stage II, 73% stage III and 10% stage IV. After debulking surgery, 30% (n = 44) had no residual disease and 41% (n = 59) had. 47% (28/59) had residual disease ≤1cm. Prior to randomization, all subjects received median 8 cycles of chemotherapy; all subjects received platinum and taxane. At randomization 81% had ECOG status 0, 97% were disease free and all had normal CA-125. At clinical data cut-off median PFS was 18.1 months in both arms. Because of the small sample size a HR was not calculated but the KM curves indicated a trend in favor of paz from 6 to 18 mos; the curves crossed after 18 mos. The adverse event (AE) profile for paz was similar to previous reports except rates of hypertension and neutropenia were higher. The most frequent AEs (≥ 20%) on the paz arm were hypertension (76%), neutropenia (64%), leucopenia (53%), diarrhea (47%), hair color changes (40%), palm-plantar erythrodysaethesia syndrome (29%), ALT increase (28%), thrombocytopenia (24%), AST increase (22%) and TSH increase (21%). Most of these AEs were Grade 1-2. Conclusions: The results of this study alone cannot confirm the efficacy of paz maintenance treatment in Asian women with ovarian cancer, but should be interpreted in conjunction of AGO-OVAR16 study. Clinical trial information: NCT01227928.
Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: A randomized phase II study of the Sarah Cannon Research Institute.
Authors: Thompson Dana Shelton , Dudley B. Stephens , Bismayer John A. , Gian Victor G. , Merritt William McIver , Whorf Robert C. , Burris Howard A. , Hainsworth John D.
Published: March 2020

5513

Background: The combination of paclitaxel and carboplatin is the most widely used chemotherapy regimen for patients (pts) with advanced ovarian cancer, producing a median survival of approximately 36 months. Recently, the addition of bevacizumab, an angiogenesis inhibitor, has improved progression-free survival (PFS) when compared to paclitaxel/carboplatin alone. Sorafenib is an oral multi-kinase inhibitor with effects on tumor angiogenesis through inhibition of the VEGF receptor. The purpose of this randomized phase II study was to compare efficacy of paclitaxel/carboplatin with and without sorafenib. Methods: Women with histologically confirmed, maximally debulked, previously untreated stage III/IV epithelial ovarian carcinoma were randomized to receive paclitaxel 175 mg/m2and carboplatin AUC 6 (PC) or PC + sorafenib 400 mg PO BID (S). All patients received 6 cycles, given every 3 weeks; pts receiving PC+S continued single agent sorafenib for 52 weeks total. The primary endpoint was 2-year PFS rate. Results: 85 pts were randomized between 1/07 and 10/11 (PC+S 43; PC 42). Pt characteristics were similar between groups, except that more patients with only CA125 elevation received PC+S (65% vs 43%). Overall, 67 pts (79%) completed 6 cycles of chemotherapy (PC+S 74%; PC 83%). More patients stopped PC+S due to toxicity (14% vs 7%). 22 pts (51%) receiving PC+S began single agent S after 6 cycles PC, and 12 pts (28%) completed 52 weeks of S. There was no difference in the 2-year PFS rates: PC+S 40%, PC 39%. Overall survival comparisons were also similar (p = 0.36). Pts receiving PC+S had more grade 3 rash (33% vs 0%) and hand-foot syndrome (9% vs 0%). Conclusions: The addition of sorafenib did not improve the efficacy of standard first-line PC in pts with stage III/IV ovarian carcinoma, and resulted in additional toxicity. Clinical trial information: NCT00390611.
A randomized placebo-controlled trial of saracatinib (AZD0530) plus weekly paclitaxel in platinum-resistant ovarian, fallopian-tube, or primary peritoneal cancer (SaPPrOC).
Authors: McNeish Iain A. , Ledermann Jonathan A. , Webber Lee C. , James Lindsay E. , Kaye Stanley B. , Rustin Gordon J. S. , Hall Geoff , Clamp Andrew , Earl Helena Margaret , Banerjee Susana N. , Kristeleit Rebecca Sophie , Raja Fharat , Feeney Amanda , Lawrence Cheryl , Dawson-Athey Linda , Persic Mojca , Khan Iftekhar
Published: March 2020

5514

Background: Weekly paclitaxel (wPxl) has activity in platinum-resistant ovarian cancer (PROC). Upregulated Src kinase activity is seen in Pxl-resistant ovarian cancer models. This trial investigated the combination of wPxl and the oral Src inhibitor saracatinib (AZD0530) in PROC. Methods: Patients with PROC (defined as relapse within 6 months of prior platinum chemotherapy, confirmed either by CT scan or symptomatic CA125 rise) were randomised 2:1 to receive four 8 week cycles of wPxl (80mg/m2/week x6 with 2 week break) plus saracatinib (S; 175mg od) or placebo (P) continuously, starting 1 week prior to wPxl, until disease progression. Patients were stratified as <6 months or ≥6 months taxane interval/no prior taxane. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate (RR), duration of response (DoR), time to progression (TTP) and toxicity. Results: 107 patients were randomised during 2011-12, 71 (66.4%) to wPxL+S and 36 (33.6%) to wPxL+P. Taxane interval was <6 months in 23 (22.1%), ≥6 months in 76 (72.4%). 43 (41.0%) had received >2 lines of prior chemotherapy; 78% (wPxL+S) vs 72% (wPxL+P) of patients received ≥1 cycle of wPxl; relative dose intensity was 96% vs 98% for wPxL+S and wPxL+P respectively. The 6-month PFS rate was 29% (wPxL+S) vs 35% (wPxL+P). Median PFS was 3.9 vs 5.3 months (HR 1.04; 95% CI 0.68, 1.59; p=0.86); median OS was 12.7 vs 12.8 months (HR 1.50, 95% CI 0.63, 3.56; p=0.36); RR were 0.0% vs 2.9% (CR) and 29% vs 38.9% (PR) for wPxL+S vs wPxL+P respectively. Median DoR was 5.6 vs 3.6 months; TTP was 3.9 vs 5.5 months (HR 1.10; 95% CI 0.71, 1.72;p=0.67). Grade 3+ Serious Adverse Events were 36.2% vs 30.6%; the most frequent toxicities (any grade) were abdominal pain (4.3%) and febrile neutropenia (4.3%) for wPxL+S, and vomiting (5.6%) for wPxL+P. Conclusions: In this randomised phase II trial, the addition of saracatinib to wPxl did not improve 6-month PFS in patients with PROC. Clinical trial information: NCT01196741.
Effect of metformin on recurrence-free survival and overall survival in diabetic patients affected by advanced ovarian cancer.
Authors: Simonelli Cecilia , Bertolotti Monica , Sabbatini Paul , Berek Jonathan S. , Pfisterer Jacobus , Binaschi Monica , Otranto Isabella , Maggi Carlo Alberto , Scartoni Simona , Capriati Angela
Published: March 2020

5522^

Background: Metformin, has recently shown some anti-cancer activities in ovarian cancer, both in vitro and in vivo. Methods: Analysis of Recurrence Free Survival (RFS) and Overall Survival (OS) was performed in patients (pts) with diabetes (D) treated with metformin (DMet+) or not (DMet-) enrolled in the MIMOSA trial, a randomized double-blind placebo-controlled international trial of Abagovomab maintenance therapy in 888 pts with advanced ovarian cancer. In the MIMOSA trial, no differences in the RFS and OS were observed between Abagovomab (n = 593) and Placebo arm (n = 295); hence, the present RFS and OS analysis (DMet+ vs DMet-) was run regardless of treatment allocation. A Cox proportional hazards model was used for adjusting the analysis for the predefined prognostic factors: Figo stage (III, IV), tumor size after debulking (residual tumor <1 cm, >1cm); CA125 serum level after 3th cycle (<35U/ml, >35U/ml). In addition, comparison of RFS and OS was done between DMet+and the overall MIMOSA population not exposed to metformin (ALLMet-), and between the overall diabetic pts (ALLD+) and non-diabetic pts (ALLD-). Results: In the ALL population (n = 888), 42 pts were affected by diabetes (ALLD+) divided to DMet+ (n = 27) and DMet- (n = 15), without difference in the prognostic factors distribution. When analysis was done in ALLD+, RFS median time was not reached in the DMet+ group whereas it was 328 days [CI: 30-660] in DMet- group with HR favoring DMet+=0.419 [CI:0.175-1.002]; p = 0.05. Median OS time was also not reached in the DMet+ group whereas it was 786 days [CI:262-NE] in DMet- group with HR=0.295 [CI:0.109-0.803]; p = 0.02. Interestingly HR for RFS time was still in favour of DMet+ group when compared to the ALLMet- (n=861) with HR=0.575 (CI=0.324-1.022); p = 0.06. When ALLD+ were compared with ALLD-(n = 846), no significant differences was detected in RFS and OS time. Conclusions: The present results are the first prospectively analyzed data demonstrating a favourable impact of metformin treatment on RFS and OS in pts affected by advanced ovarian cancer. Clinical trial information: NCT00418574.
GOG0076-GG: A limited access phase II trial of pemetrexed (LY231514) (NSC #698037) in combination with cisplatin (NSC #119875) in the treatment of advanced, persistent, or recurrent carcinoma of the cervix—A Gynecologic Oncology Group study.
Authors: Miller David S. , Blessing John A. , Ramondetta Lois M. , Pham Huyen , Tewari Krishnansu Sujata , Landrum Lisa Michelle , Brown Jubilee , Mannel Robert S. ,   Gynecologic Oncology Group
Published: March 2020

5527

Background: To estimate the antitumor activity of Pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, to determine the effects of this regimen on progression-free survival and overall survival. Methods: Eligible, consenting patients received pemetrexed 500mg/m2 and cisplatin 50 mg/m2 IV repeated every 21 days until disease progression or adverse effects prohibited further therapy. Patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior radiation therapy. Results: From September 2008 to November 2011, 55 patients were enrolled by 5 GOG member institutions. Of those, 49 patients were eligible and assessable. The regimen was well tolerated with 14 (29%) receiving >9 cycles. Common grade >2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial responses). The median response duration was 7 months and survival 12 months. Conclusions: Pemetrexed in combination with cisplatin has demonstrated activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population. Clinical trial information: NCT00691301.
Phase II trial of oral etoposide plus IV irinotecan for patients with platinum-resistant and taxane-pretreated ovarian cancer (JCOG0503).
Authors: Matsumoto Koji , Katsumata Noriyuki , Shibata Taro , Takano Tadao , Nishimura Ryuichiro , Kasamatsu Takahiro , Satoh Toyomi , Saitoh Motoaki , Nishimura Sadako , Matsumura Noriomi , Kobayashi Hiroaki , Aihara Satomi , Nogawa Takayoshi , Saito Toshiaki , Ushijima Kimio , Fukuda Haruhiko , Konishi Ikuo , Kamura Toshiharu
Published: March 2020

5537

Background: Developing effective chemotherapy for patients (pts) with platinum (Pt) resistant ovarian cancer is unmet medical needs. Topoisomerase inhibitors, such as oral etoposide and iv irinotecan, have been reported to show some efficacy for Pt - resistant ovarian cancer as monotherapy. Combining these two agents should be an intriguing idea. Following phase 1 and feasibility study reported in ASCO2002 and 2005, this study aimed to assess safety and efficacy of oral etoposide plus iv irinotecan for pts with Pt -resistant and taxane pre-treated ovarian cancer (UMIN-CTR ID: UMIN000001837). Methods: Eligible pts are given etoposide at 50 mg/m2 p.o. from day 1 to 21, and irinotecan 70 mg/m2iv, at day1 and day15, repeated every 28 days, up to 6 cycles. Primary endpoint is response rate (RR), secondary endpoints are adverse events, progression-free survival (PFS), and overall survival (OS). As a SWOG two-stage design, at least 55 pts are required with one-sided alpha of 0.05, beta of 0.2 and expected and threshold value for primary endpoint as 35% and 20%. Sixty pts are to be registered. Results: From April 2009 to January 2012, 61 pts were entered to this study. One patient was ineligible, thus 60 pts were analyzed for the study. RR was 21.7% (1 CR + 12 PR, 89% C.I. 13.5 – 31.9 %, one-sided p=0.42). At the data cut-off at November 2012, median PFS and OS were 4.1 (95% C.I. 3.5 – 5.6) and 12.4 (95% C.I. 10.1 – 14.8) months, respectively. Six months-PFS was 35.0 %. For pts with Pt --free interval (PFI) >= three months (n = 33), RR was 30.3 % (95% C.I. 15.6 -48.7 %), median PFS and OS was 5.8and 16.9 months, respectively. For safety, G3/4 neutropenia, anemia, and thrombocytopenia were 60.0 %, 36.7 % and 11.7%, respectively. G3/4 non-hematological toxicities over 10 % were febrile neutropenia (FN) (18.3%), fatigue (13.3%), nausea (11.7 %) and anorexia (11.7 %). FN was more frequent in elderly pts of 65 years or older (28.6 %). Two treatment-related deaths occurred, both in elderly. Conclusions: As a whole, this regimen did not meet primary endpoint for further phase 3 study. Elderly pts should be treated very cautiously with this regimen. However, promising efficacy could be expected for those with PFI >= 3 months. Clinical trial information: UMIN000001837.
Benefit in progression-free survival (PFS) to expect based on CA125 reduction at week 6 in recurrent ovarian cancer (ROC) patients: CALYPSO phase III trial data (a GINECO-GCIG study).
Authors: Wilbaux Melanie , Henin Emilie , Colomban Olivier , Oza Amit M. , Pujade-Lauraine Eric , Freyer Gilles , Tod Michel , You Benoit
Published: March 2020

5547

Background: Prediction of the expected survival benefit based on CA125 change in treated recurrent ovarian cancer (ROC) patients would be very useful. It may help for early selection of the best drug candidates during drug development, and for clinical trials. We used mathematical modeling to: 1) quantify the links between CA125 kinetics and progression-free survival (PFS) benefit, and 2) to estimate the CA125 decline required to observe a 50% PFS improvement. Methods: CALYPSO randomized phase III trial database, comparing 2 platinum-based regimens in ROC patients was used. The cohort was randomly split into a “learning dataset” (N=356) to estimate model parameters and a “validation dataset” (N=178) to validate model performances. A full parametric survival model was developed to quantify the links between tumor size changes; CA125 kinetics; prognostic factors and PFS. The predictive performance of the model was evaluated with simulations on the validation dataset. Results: PFS from 534 ROC patients was properly described by a parametric model with log-logistic distribution. The factors significantly linked to PFS were fractional changes in CA125 (ΔCA125) and in tumor size (ΔTS) from baseline at week 6; baseline CA125 (CA125BL); and patient therapy free interval. By reducing this model, ΔCA125 was a better predictor of PFS than ΔTS. Simulations verified the predictive performance of this model. Patients should achieve at least 49% ΔCA125 decline induced by treatment to observe 50% PFS improvement. This effect was independent on treatment arm. Conclusions: This is the first drug-independent parametric survival model quantifying links between PFS and CA125 kinetics in ROC. The CA125 modeled decline required to observe a 50% improvement in PFS in treated ROC patients was defined. It may be a surrogate marker of PFS gain, and may embody an early predictive tool for go/no go drug development decisions and for clinical trials. Validation in other datasets is warranted.
Does alopecia predict response to chemotherapy and prognosis in patients with advanced ovarian cancer? A meta-analysis of prospective randomized phase III trials with 5,114 patients of the AGO meta data base.
Authors: Sehouli Jalid , Erol Edibe , Richter Rolf , Reuss Alexander , Fotopoulou Christina , Mahner Sven , Pfisterer Jacobus , Du Bois Andreas
Published: March 2020

5553

Background: Alopecia is a relevant side effect of chemotherapy. Our aim was to validate and unconfirmed broad patient´s opinion that a low rate of alopecia may predict poor response to chemotherapy and poor overall survival (OS). Methods: Individual patient data analysis of 5114 patients from four prospective randomised phase III trials conducted between 1995 and 2004 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Uni- and multivariate analyses were performed adjusted for age, number of cycles, individual trial, residual mass, tumor stage and histology. Results: 5,114 patients with ovarian cancer (OC) were analyzed. Most patients presented with advanced stage FIGO III/IV (87.8%). A median of 6 cycles were applied (range 0-11). Worst alopecia grade was 0 in 2.2%, 1 in 2.7% and 2 in 87.1%. In 8% patients no data about alopecia were documented. Patients with complete alopecia were more likely to achieve remission (OR 2.83, 95% CI 1.68-4.78 for grade 2 compared to grade 0/1) and had favourable progression-free survival of 19.0 months, (95%CI 18,2-19.7) compared to patients with grade 0/1 (13.8, 95%CI 12.2-15.3 and 14.3, 95%CI 10.8-17.8). Median OS was also significantly longer after grade 2 alopecia 48.8 months (95%CI 47.0-50.5), compared to 28.1 months (95%CI 22.3-33.9) and 33.9 months (95%CI24.3-43.6) for grade 0 and 1, respectively. This prognostic impact was not reteined in multivariate analysis. However, onset of alopecia was an independent prognostic factor for OS: patients with complete alopecia after cycle 3 had a favourable outcome compared to patient who experienced alopecia later during therapy (HR 1.22, 95%CI 1.02-1.46) or no alopecia (HR 1.29, 95%CI 0.98-1.70). Conclusions: We could show for the very first time that there is no evidence that the rate of alopecia is associated with the effect of chemotherapy is of any prognostic relevance. The observation that early onset of alopecia is associated with OS should be confirmed.
Comparison of two multimarker serum tests for the prediction of ovarian cancer in women with a pelvic mass.
Authors: Grenache David G. , Vucetic Zivjena
Published: March 2020

5555

Background: Distinguishing between benign and malignant disease in women with a pelvic mass is difficult. OVA1 and ROMA are two multi-marker serum tests that are FDA-cleared to assess risk of malignancy in individuals with a pelvic mass. This study compared the accuracy of these tests for the prediction of ovarian cancer (OCa) in women with a pelvic mass. Methods: OVA1 and ROMA risk scores were determined in a subset of 146 serum samples obtained prospectively from pelvic mass patients. Patients were categorized by an initial cancer risk assessment (ICRA) performed by a physician and true cancer status determined surgically. 31 patients with malignancy (6 with a benign ICRA) and 115 patients with benign disease (25 with a malignant ICRA) were evaluated. Quest Diagnostics performed the OVA1 tests (CA-125, prealbumin, apolipoprotein A-1, β2-microglobulin, transferrin) and calculated and interpreted the risk score. ROMA tests (CA-125 and HE-4) were determined by automated immunoassay using an Abbott Architect analyzer. ROMA risk scores were calculated using published formulas and interpreted against cutpoints previously established for automated CA-125 and HE-4 performed by manual ELISA. Results: There were 70 pre- and 76 post-menopausal subjects. Of the 31 with malignancy, 26 had OCa (54% >stage II), 5 with an ICRA of benign. ROC curve analysis of the entire cohort produced an AUC of 0.88 (95% CI 0.80-0.95) and 0.93 (95% CI 0.87-0.99) for OVA1 and ROMA, respectively. OVA1 had a sensitivity of 0.97 and a specificity of 0.55. ROMA had a sensitivity of 0.84 and a specificity of 0.83. The sensitivity of OVA1 for OCa in the ICRA benign cohort (N = 5) was 0.80 and for ROMA was 0.40. The respective specificity for benign disease in this cohort (N=90) was 0.64 and 0.90. The sensitivity of ROMA for OCa increased to 0.60 with a slight decrease in specificity (0.87) when a cutpoint determined by ROC curve analysis was used. Conclusions: Overall, OVA1 and ROMA have similar performance characteristics. In women with an ICRA of benign, OVA1 was more sensitive among those who had OCa but ROMA was more specific among those who did not. The use of a ROMA cutpoint specific for the combination of automated CA-125 and HE-4 tests improved sensitivity.
Clinical relevance of VEGF-receptor status in primary ovarian cancer: A pilot study for future biomarker analyses.
Authors: Wimberger Pauline , Chebouti Issam , Kuhlmann Jan Dominik , Kimmig Rainer , Kuhlisch Eberhart , Lachmann Robert , Kasimir-Bauer Sabine
Published: March 2020

5556

Background: Antiangiogenic treatment in addition to platinum/taxane based chemotherapy was shown to improve progression-free survival in first- and second-line chemotherapy in ovarian cancer patients. Predictive markers for antiangiogenic treatment are of high interest. Therefore we investigated VEGF-receptor (VEGFR) expression as possible biomarker candidate in primary ovarian cancer tissue and its clinical impact. Methods: A total of 82 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGFR1, VEGFR2 and VEGFR3 by immunhistochemistry. Moreover, the presence of circulating tumor cells (CTC) in the blood was detected by immunomagnetic enrichment and multiplex reverse transcriptase-polymerase chain reaction (Adnatest Ovarian Cancer, Adnagen). Disseminated tumor cells (DTC) in the BM were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and subsequent automatic detection based on staining and cytomorphology. Results: Positivity for at least one VEGFR was observed in 43% of cases. The positivity rates for VEGFR1, -2 and -3 were 34%, 17% and 27%, respectively. VEGFR-status of the primary tumor neither correlated with established clinicopathogical parameters (age, FIGO-stage, nodal status, grading, histological subtype) nor with the presence of CTC or DTC. In addition, VEGFR-status does not provide prognostic significance in regard to progression-free and overall survival (OS). Nevertheless, a trend was observed that patients, being positive for VEGFR3 at primary diagnosis, were more likely to experience suboptimal debulking (p = 0.074). CTC-positivity after adjuvant therapy significantly correlated with OS, but multivariable analysis showed only residual tumor as prognostic factor for OS. Conclusions: The VEGFR-family, albeit frequently expressed in our patient cohort, provided neither prognostic nor predictive relevance, but could probably be a predictor for debulking efficiency. The implementation of VEGFR-status into future biomarker studies should carefully be considered.
Relationship of microRNA expression profiles and recurrence in advanced serous ovarian carcinoma.
Authors: Nam Eun Ji , Yim Ga Won , Kim Jae Hoon , Kim Sunghoon , Kim Sang Wun , Kim Jae-Wook , Kim Young-Tae
Published: March 2020

5557

Background: Most patients with epithelial ovarian cancer eventually succumb to chemo-resistant disease. Although microRNAs have been recognized as important regulators of gene expression, little is known about microRNA expression profiles in recurrent serous ovarian carcinoma. We assessed the microRNA expression profiles which contribute to recurrence in advanced serous ovarian carcinoma. Methods: Eight pairs of primary and recurrent tumor samples from 8 patients with advanced serous ovarian carcinoma and 4 normal ovarian samples from patients treated for benign uterine disease between May 2006 and Dec 2012 were examined using miRNA microarray. microRNA profiling were validated using real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: Alterations of microRNA expression profiles in primary and recurrent tumor samples have similar patterns when compared with normal ovarian tissues. Among 31 up-regulated microRNAs more than 4-fold in primary tumors, 27 microRNAs were also significantly up-regulated in recurrent tumor samples. Likewise, Among 35 down-regulated microRNAs more than 4-fold in primary tumors, 34 microRNAs were also significantly down-regulated in recurrent tumor samples. Comparing to primary tumor, we found 60 microRNAs which were significantly up-regulated, including miR-630, 370, and 575, and 52 microRNAs which were significantly down-regulated, including miR-509-3p, 514a-3p, and 506-3p in recurrent serous ovarian carcinoma. Conclusions: Our results indicate that dysregulation of microRNAs may play a role in recurrence of serous ovarian carcinoma.
Clinical study of intraperitoneal injection bevacizumab (BV) combined with intraperitoneal hyperthermic perfusion chemotherapy (CT) in treatment of malignant ascites of ovarian cancer (OC).
Authors: Zhao Hui , Du Nan , Fu Yan , Wang Haibin , Fan Zhongyi
Published: March 2020

5558

Background: To study the efficacy and safety of intraperitoneal injection BV combined with intraperitoneal perfusion CT in treatment of malignant ascites of OC and to investigate the clinical significance of the concentration change of vascular endothelial growth factor (VEGF). Methods: Patients with malignant ascites of OC were randomly divided into treatment group (n = 31) and control group (n = 27). All enrolled patients received TC (paclitaxel 135mg/m2, iv d1+ carboplatin AUC=5, iv d1), 1 time/3 weeks for 6 weeks. Patients in the control group were treated with intraperitoneal perfusion CT combined with intraperitoneal cisplatin (40mg/m2)1 time/2 weeks for 6 weeks. Besides the treatment of the control group, patients in the treatment group received intraperitoneal injection with BV 300mg after each intraperitoneal perfusion CT for 6 weeks. The improvement of life quality, efficacy and adverse effects were evaluated. The concentrations of VEGF and CA-125 in ascites of the two groups were assayed by ELISA method. Results: No severe side effect was observed in all the patients. The response rate of the treatment group was higher than that of the control group (90.32% vs. 59.26%, p < 0.05). The improvement rate of quality of life (QOL) of the patients in the treatment group was also higher than that of the patients in the control group (93.55 % vs. 48.15%, p < 0.05). The concentration of VEGF in ascites of the treatment group after treatment was lower than that before treatment (p < 0.05). And after treatment, the concentration of VEGF in ascites of treatment group was lower than that of the control group (p < 0.05). Conclusions: Intraperitoneal injection BV combined with intraperitoneal perfusion CT in the treatment of malignant ascites of OC is effective and safe. The concentration of VEGF and CA-125 levels, in ascites may be used as monitoring index for treatment effect of malignant ascites of OC with intraperitoneal injection BV.
Prognostic impact of estrogen receptor (ER) level changes during progression for patients with both ER-positive (ER+) primary breast cancer and paired recurrence.
Authors: Dieci Maria Vittoria , Barbieri Elena , Goubar Aicha , Andre Fabrice , Omarini Claudia , Bettelli Stefania Raffaella , Piacentini Federico , Ficarra Guido , Conte Pier Franco , Guarneri Valentina
Published: March 2020

556

Background: We have previously reported that ER+ breast cancer (BC) patients (pts) who become ER-negative at relapse have a poorer overall survival (OS) as compared to those still ER+ at relapse [Dieci et al., Ann Oncol 2013]. Our aim is to evaluate whether, among the group of patients with an ER+ status on both primary and recurrence, changes in the level of ER expression may be of prognostic value. Methods: A total of 81 pts with ER+ primary BC and ER+ paired recurrence who underwent relapse biopsy at Modena University Hospital were studied. ER status was assessed by IHC and the cutoff for ER-positivity was >=10%. Samples were defined as ER-high (>50%) and ER-low (>=10% and <=50%). HER2-status was defined according to IHC and/or FISH results. OS was calculated as the time interval between primary BC diagnosis and death or last follow up. Results: Biopsied recurrences were: distant (86%) and local relapses (14%). Fifteen percent of primary and 21% of recurrent tumors were HER2-positive. Sixty-two pts maintained the same ER level (i.e. high or low) on both primary and relapse (ER-level concordant), whereas 19 changed from ER-high to ER-low or viceversa (ER-level discordant). No difference in OS was observed between the ER-level concordant and the ER-level discordant groups (p=0.3). However, we identified those pts whose ER-high primary BC turned into ER-low as having a particularly poor outcome. Indeed, 10yrs-OS rates were 51% for the ER-level concordant group, 50% for pts changing from ER-low to ER-high and 14% for pts changing from ER-high to ER-low (p=0.0019). Finally, we focused on the subset of pts starting from an ER-high primary BC and showing an ER+/HER2-negative phenotype on both primary and relapse (n=51). The drop of ER-level expression below the 50% cut-off at relapse was confirmed as a poor prognostic factor, as compared to pts maintaining an ER-high level (10yrs-OS 53% vs 17%, p=0.0063). Conclusions: We demonstrated that, even in the case of maintenance of the same single-receptor status (ER+) and/or tumor phenotype (ER+/HER2-negative) between primary BC and recurrence, relapse biopsy may provide relevant prognostic information.
Evaluating the accuracy of frozen section in borderline ovarian tumors.
Authors: Gupta Natasha , Rajpal Tanuja , Sharma Sameer
Published: March 2020

5564

Background: The objective of this study was to evaluate accuracy of frozen section in borderline ovarian tumors and to determine the tumor characteristics that lead to higher likelihood of inaccurate intraoperative diagnosis (IAIOD). IAIOD is a clinical problem that restricts the diagnostic accuracy of frozen section in borderline ovarian tumors. Methods: This was a retrospective chart review of 622 consecutive cases that were diagnosed with pelvic mass and underwent surgery at busy gynecology services of two institutions, between 2006-2011. Of these cases, 52 were diagnosed as borderline ovarian tumors by frozen section. Experienced pathologists performed frozen section with second opinion from specialized gynecologic pathologists as needed. Terms such as “at least borderline” were also evaluated to help stratify patients. Frozen section and final permanent histology reports were compared. Patient and tumor characteristics that may cause IAIOD such as age of patient, histological subtype, size of tumor, bilaterality, CA-125 levels were studied. Staging was performed when borderline or malignant ovarian tumors were identified by frozen section. Results: Agreement of the frozen section results with final pathology was observed in 37 out of 52 patients with a diagnostic accuracy of 71.15 %. Under diagnosis occurred in 12 out of 52 patients and over diagnosis occurred in 3 out of 52 patients. Age >40 years, size of tumor >5 cm, bilaterality of tumors and CA-125 were not found significant in causing IAIOD when chi-square analysis was performed. Characterization by “at-least” borderline terminology at the time of frozen section did not help identify patients with higher likelihood of IAIOD. Conclusions: In our study, the rate of IAIOD was high, at 23% despite experienced pathologists and using “at-least borderline” terminology. Traditionally described features leading to inaccuracy with frozen sections, such as large tumors with mucinous histology did not increase the risk of IAIOD in this study. Patients with unilateral, small tumors and non-mucinous histology had greatest risk for IAIOD. Given this information, full staging of all borderline ovarian tumors identified at time of frozen section should remain the standard of practice.
Characterization of patients who received prior chemotherapy for advanced breast cancer (ABC) in BOLERO-2.
Authors: Campone Mario , Lebrun Fabienne , Noguchi Shinzaburo , Pritchard Kathleen I. , Burris Howard A. , Beck J. Thaddeus , Ito Yoshinori , Yardley Denise Aysel , Bachelot Thomas Denis , Pistilli Barbara , Melichar Bohuslav , Petrakova Katarina , Arena Francis P. , Erdkamp Frans , Harb Wael A. , Litton Jennifer Keating , Panneerselvam Ashok , El-Hashimy Mona , Taran Tanya , Gnant Michael
Published: March 2020

557

Background: In patients with hormone-receptor–positive (HR+) breast cancer, endocrine therapy is the standard of care both in the adjuvant setting and as first-line treatment for ABC. For selected HR+ patients with ABC, chemotherapy (CT) may be utilized if disease burden is high and rapid symptom control is required (Barrios CH. GAMO.2010). In the phase 3 BOLERO-2 study (NCT00863655), 1 line of prior CT in the ABC setting was allowed. This subset analysis examined disease characteristics and the efficacy of everolimus (EVE) plus exemestane (EXE) in patients who received CT for ABC prior to BOLERO-2 study entry. Methods: In BOLERO-2, 724 patients with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC whose disease recurred or progressed during/after a nonsteroidal aromatase inhibitor were randomized 2:1 to EVE (10 mg/d) + EXE (25 mg/d) or placebo (PBO) + EXE. The primary endpoint was progression-free survival (PFS) by local investigator review and confirmed by blinded independent central review. Results: A subset of 186 patients (26%) received prior CT for ABC: 125 in the EVE + EXE group and 61 in PBO + EXE. In this subset, 54% (67 of 186) of patients received prior CT only in the advanced setting and 46% (58 of 186) of patients received prior CT in both the neoadjuvant/adjuvant and advanced settings. Incidences of visceral metastases (67% vs 56%), multiple metastases (79% vs 66%), and ≥ 4 metastatic sites (18.3% vs 15%) were higher in ABC patients with prior CT for ABC at study entry versus those with no prior CT for ABC. Disease recurrence < 6 months from initial diagnosis was recorded in 32.2% (n = 60) of prior CT patients versus 17.3% (n = 93) of patients with no prior CT. Median PFS (by local assessment) in patients who received prior CT for ABC was substantially longer with EVE + EXE versus PBO + EXE (6.1 vs 2.7 mo; HR = 0.38; 95% CI, 0.27-0.53). PFS by central review showed similar results (7.1 vs 2.8 mo, respectively; HR = 0.42; 95% CI, 0.27-0.65). Conclusions: These results demonstrate that patients with HR+, HER2– ABC who received previous CT in the advanced setting had a higher tumor burden and derived clinically significant benefit from combination treatment with EVE + EXE. Clinical trial information: NCT00863655.
γ-synuclein expression in ovarian cancer.
Authors: Mori Kristina , Akers Stacey , Bshara Wiam , Buttin Barbara , Frederick Peter J. , Helenowski Irene B. , Morrison Carl D , Odunsi Kunle , Schink Julian C. , Scholtens Denise M. , Wei Jian-Jun , Kim J. Julie
Published: March 2020

5574

Background: γ-synuclein (SNCG) expression is associated with advanced disease and chemo-resistance in multiple solid tumors. Our goal was to determine if SNCG expression in ovarian cancer was correlated with clinicopathologic variables and patient outcomes. Methods: Tissue microarrays from primary tumors of 358 ovarian, fallopian tube, and primary peritoneal cancer patients, who underwent primary surgery at Roswell Park Cancer Institute between 1995 and 2007 were constructed and stained for SNCG. A blinded pathologist scored tumors as positive if ≥10% of the sample stained. Medical records were reviewed for clinicopathologic and demographic variables. Between the positive and negative groups, Wilcoxon rank-sum test was used to compare the median ages and Fisher’s exact test was used to compare groups in categorical variables. Cox proportional hazard models were used to determine associations between SNCG and overall (OS) and progression-free survival (PFS). Results: The median follow-up was 36 months, median OS was 39 months, and median PFS was 18 months. SNCG presence was significant in patients with serous histology, grade 3 disease, suboptimal debulking, ascites at surgery, FIGO stage III-IV cancer, or initial CA-125 level >485. There was no significant difference in OS (HR 1.06 95% CI 0.81-1.39 P 0.69) or PFS (HR 1.16 95% CI 0.89-1.50 P 0.28) for patients with SNCG expression. Conclusions: SNCG expression in ovarian cancer is more frequent in patients with high-risk features, but it does not correlate with chemotherapy response, OS, or PFS. [Table: see text]
Inhibition of gamma-secretase activity in combination with paclitaxel to reduce platinum-resistant ovarian tumor growth.
Authors: Groeneweg Jolijn W , DiGloria Celeste M , Growdon Whitfield Board , Sathyanarayanan Sriram , Foster Rosemary , Rueda Bo R
Published: March 2020

5578

Background: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States. Chemotherapy is effective but seldom curative, mainly due to the development of chemoresistant recurrent disease. Our current research investigates the efficacy of inhibiting the Notch pathway with a gamma-secretase inhibitor (GSI), MRK-003, in an OvCa xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Mice bearing xenografts derived from clinically platinum sensitive human ovarian serous carcinomas were treated with GSI or vehicle, or with either vehicle, GSI alone, paclitaxel and carboplatinum (T/C) alone, or the combination of GSI and T/C. In addition, mice bearing xenografts derived from patients with clinically platinum resistant disease were given GSI with or without paclitaxel. Gene transcript levels of several factors in the Notch pathway were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated by western blotting. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and Notch3 was highly variable across all analyzed OvCa samples. Treatment with GSI alone significantly decreased tumor growth in 3 of 4 platinum sensitive ovarian tumors (all p < 0.05), as well as in 1 of 3 platinum resistant tumors (p = 0.04). Furthermore, the combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of T/C in platinum sensitive tumors. Although the response of each tumor to GSI did not correlate with its endogenous level of Notch expression, 2 of the 3 tumors resistant to paclitaxel but sensitive to the combination of GSI and paclitaxel showed elevated Notch activity by RT-PCR. Conclusions: Inhibition of the Notch signaling cascade with a gamma-secretase inhibitor reduces tumor growth in vivo, most notably in combination with paclitaxel in a platinum resistant setting. These promising findings underscore the need for further investigation of the preclinical and clinical effectiveness of Notch inhibitors in OvCa.