bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of adaptive HER2-specific immunity in HER2 breast cancer patients by addition of trastuzumab to chemotherapy in the adjuvant setting: NCCTG (Alliance) study N9831.
Authors: Knutson Keith L. , Perez Edith A. , Ballman Karla V. , Erskine Courtney L. , Fox Nicholas , McCarl Christie-Ann , Norton Nadine , Sumrall Susan V. , Northfelt Donald W. , Tan Winston , Calfa Carmen Julia , Pegram Mark D. , Clynes Raphael
Published: March 2020

522

Background: In the adjuvant setting, patients with HER2 breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy in patients with HER2+ metastatic breast cancer. It remained unclear from those studies, however, whether the HER2-specific immunity played a role and if antibody immunity was associated with improved disease free survival in the adjuvant setting. In the present study, we addressed these questions by analyzing sera samples from a subset of patients enrolled in the NCCTG adjuvant trial, N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831 (22 Arm A; 14 Arm B, and 14 Arm C). Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and presented as an index (>0.2 was considered a positive response). Results: Prior to therapy, across all three arms, N9831 patients had similar mean HER2 IgG levels (0.19 units in Arm A, 0.14 in Arm B, and 0.23 in Arm C, P=0.85). Following treatment, the mean levels of antibodies increased in Arm B to 0.35 units and in Arm C to 0.56 units and were higher (p<0.001) than in Arm A where levels did not increase. The proportion of patients who demonstrated antibody immunity increased by 9% in Arm A, 50% in Arm B and 28% in Arm C (P=0.026). Although the event rate was low in this cohort, Cox modeling suggested that larger increases in antibodies were associated with improved disease free survival (HR=0.23; p=0.04). Conclusions: These results show that the increased antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant and results from the inclusion of trastuzumab. The findings may have important implications for improving treatment outcomes in patients treated with trastuzumab.
ACOSOG Z1041 (Alliance): Cardiac events (CE) among those receiving neoadjuvant anthracyclines (A) and taxanes with trastuzumab (T) for HER2+ breast cancer.
Authors: Ewer Michael , Suman Vera J. , Buzdar Aman , McCall Linda Mackie , Meric-Bernstam Funda , Leitch A. Marilyn , Ellis Matthew James , Boughey Judy Caroline , Unzeitig Gary Walter , Royce Melanie , Hunt Kelly
Published: March 2020

526

Background: Z1041 randomized women with HER2+ operable breast cancer to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2). Treatment administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2weekly x 12 and T 4 mg/kg once then 2 mg/kg weekly x 11. T was to continue q3 weeks post-op for 40 weeks. A secondary aim was to examine the cardiotoxicity (CE). Methods: Ejection fraction (EF) was measured at baseline (BL), between regimens (wk 12), prior to surgery (wk 24) and PRN. Eligibility: BL EF ≥ 55%. CEs included decline in EF of > 15%, or >10% points to a value < LLN. Reversibility was adjudicated by blinded investigators as reversible (R: recovery of EF to ≤ 5% below BL), partially reversible (PR: recovery of > 10% points from nadir, but ≤ 5% points below BL), indeterminate (IN: no additional EF data), or irreversible (IRR:follow-up EF studies showed no improvement). Results: Of the 280 patients (Arm 1: 138) who began treatment, 15 pts (Arm 1: 10; Arm 2: 5) did not receive T. The number of weeks of T was 13 (range: 1-18) in Arm 1 and 24 (range: 1-31) in Arm 2. Changes in EF and severe treatment related cardiac toxicities prior to surgery (sx) are tabled below. There were 271 pts (Arm 1: 131) who had post-BL EFs. Prior to sx, there were 11 CE (8.3%) in Arm 1 and 13 CE (9.2%) in Arm 2. CEs were R in 12 pts (Arm 1: 5; Arm 2: 7); PR in 6 pts (Arm 1: 4; Arm 2: 2); IN in 4 pts (Arm 1: 2; Arm 2: 3) and IRR in 1 Arm 2 pt. Conclusions: The number of CE events in arms 1 and 2 showed no significant difference; greater scatter was observed in arm 2 patients. While concern for late cardiac events makes ongoing cardiac surveillance prudent due to A, concomitant use of A and T appear to not be associated with increased cardiac risk. Clinical trial information: NCT00513292. [Table: see text]
The prognostic role of androgen receptor in early-stage breast cancer patients: A meta-analysis.
Authors: Bozovic-Spasojevic Ivana , Zardavas Dimitrios , De Azambuja Evandro , Ameye Lieveke , Sotiriou Christos , Piccart-Gebhart Martine J. , Paesmans Marianne
Published: March 2020

528

Background: Androgen receptor (AR) expression has been observed in ~70% of breast cancer (BC) patients, but its prognostic role is not established yet. To assess this we performed a meta-analysis of studies that evaluated the impact of AR on disease free survival (DFS) and/or on overall survival (OS) in early stage BC. Methods: Published studies were identified by an electronic search on PubMed using the MeSH terms "breast neoplasm" and "androgen receptor" (up to June 2012). Identified studies were assessed against the following criteria for inclusion in the analysis: early stage BC and reported results of AR status in correlation with clinical outcome. We report combined HRs with 95% confidence intervals (CI) using AR negative patients as reference. Results: Twenty studies were eligible for the meta-analysis out of 493 initially identified and 12 among them, including 6,525 patients, were considered as evaluable (i.e., reporting enough information to allow aggregation of results). AR positivity was associated with lower risk of relapse in all breast cancer patients, and better overall survival in both univariate (U) and multivariate (M) analysis. AR prognostic impact in different subtypes was also assessed (see Table). Conclusions: Our analysis demonstrated that AR delivers prognostic information overall, serving as a positive prognostic factor in early stage BC. Further studies are needed to delineate its prognostic impact within the different subtypes of the disease. [Table: see text]
Relative effectiveness of letrozole alone or in sequence with tamoxifen for patients diagnosed with invasive lobular carcinoma.
Authors: Metzger Filho Otto , Giobbie-Hurder Anita , Mallon Elizabeth A , Viale Giuseppe , Winer Eric P. , Thurlimann Beat J. K. , Gelber Richard D. , Regan Meredith M. , Colleoni Marco , Ejlertsen Bent , Bonnefoi Herve , Forbes John F. , Neven Patrick , Wardley Andrew M. , Lang Istvan , Smith Ian E. , Price Karen N. , Coates Alan S. , Goldhirsch Aron ,   International Breast Cancer Study Group
Published: March 2020

529

Background: BIG 1-98 is a randomized, phase III study that compares five years of tamoxifen (tam) or letrozole (let), (monotherapy arms), or their sequences (tam-let or let-tam) in post-menopausal women with ER+ early BC. In the monotherapy arms, the magnitude of benefit of adjuvant let compared with tam varies by histology (greater in invasive lobular carcinoma (ILC) than invasive ductal carcinoma (IDC)). In this analysis we investigate the magnitude of benefit of let compared to tam-let and let-tam according to histology (IDC and ILC) at 96 months of median follow-up. Methods: There were 4,634 patients enrolled in the let, tam-let and let-tam arms of BIG-98. This analysis includes patients with centrally-reviewed histological subtype (n=4,223); classified as classic ILC or IDC (n=3,790); and with centrally reviewed ER, PgR and Ki67 (n=3,212). Results: The 8-year DFS and OS univariate estimates (±SE) for IDC and ILC are presented in the Table. When correcting for classic clinicopathological variables, treatment assignment was not a significant predictor of DFS and OS. Conclusions: We observed a trend toward greater magnitude of benefit in favor of let monotherapy for ILC than IDC. In the ILC subset, improvements for both DFS and OS were seen for let when compared to tam-let or let-tam, though not statistically significant. This may be due to the reduced number of ILC patients across subgroups. The present analysis is consistent with previous data from the monotherapy arms where let was associated with better DFS and OS than tam for ILC, and suggests that let might be the preferred upfront regimen for patients diagnosed with ILC. Clinical trial information: NCT00004205. [Table: see text]
Expression of enhancer of zeste homologue 2, correlated with HIF-1α, to refine relapse risk and predict poor outcome for breast cancer.
Authors: Dong Min , Fan XinJuan , Chen Zhan-Hong , Li Xing , Wang Tian tian , Chen Jie , Lin Qu , Wen Jing-Yun , Ma Xiao-Kun , Wei Li , Ruan Dan-Yun , Lin Ze-Xiao , Liu Quentin , Wan XiangBo , Wu Xiang-Yuan
Published: March 2020

538

Background: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior for breast cancer. In vitro, hypoxia-inducible factor 1 alpha (HIF-1α) transcriptionally activates EZH2 and promotes breast tumor initiating cells progression. Here, we characterized the clinicopathological effect of HIF-1α and EZH2 in breast cancer patients. Methods: Tumor specimens from 410 luminal subtype breast cancer patients were used to construct tissue microarray. EZH2 and HIF-1α level were examined by immunohistochemistry staining and Western blot analysis. With the 5-year follow up, the prognostic effect of EZH2 was subjected to multivariate analysis. Results: EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with high histological grade (P=0.030), lymphatic invasion (P=0.025), HER2 overexpression (P=0.005) and hypoxic condition (P<0.001). Forced expression of EZH2 predicted a poor 5-year overall survival (OS, 74.8% vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2% vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7% vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4% vs. 90.5%, P=0.039). However, the prognostic effect of HIF-1α was not detected for breast cancer. Cox multivariate analysis confirmed that EZH2 was an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was detected between EZH2 and HIF-1α (r=0.299, P<0.001). Importantly, tumors with HIF-1α and EZH2 co-overexpression were correlated with a worsened OS (P=0.007). Conclusions: EZH2 was an independent negative prognostic biomarker for luminal subtype breast cancer. Targeting HIF-1α transcriptionally regulated EZH2 pathway might be of benefit in the treatment of luminal subtype of breast cancer.
Factors predicting endoxifen levels in breast cancer patients taking standard-dose tamoxifen and following dose escalation.
Authors: Fox Peter , Gao Bo , Balakrishnar Bavanthi , Menzies Alexander M , Yeap Shang Heng , Ali Sayed Sahanawaz , Gebski Val , Provan Pamela , Coulter Sally , Liddle Christopher , Hui Rina , Kefford Richard , Lynch Jodi , Wilcken Nicholas , Balleine Rosemary L , Gurney Howard
Published: March 2020

543

Background: Tamoxifen (TAM) is transformed via CYP2D6 to its major active metabolite endoxifen (Endox). Recent data suggest that 15nM Endox may be a therapeutic threshold for breast cancer . This study identified predictors of achieving specified Endox target levels (15nM and 30nM) on standard dose TAM, and following dose escalation. Methods: Baseline Endox was measured in 122 breast cancer pts on TAM 20mg pd. Pts with baseline Endox <30nM underwent incremental dose escalation to a maximum of 60mg pd until Endox reached 30nM or dose limiting toxicity. Clinical data were collected and CYP2D6 genotype was used to specify extensive, intermediate or poor metabolizer categories (EM, IM, PM). Multiple regression analyses examined associations between Endox and potential predictive factors. Results: Baseline Endox ranged from 3.1-72.2nM (mean 27.6nM). In 19% (n=23), baseline Endox was below 15nM and 62% (n=76) were below 30nM. Low baseline Endox was associated with CYP2D6 genotype (IM or PM, p<0.001) and younger age (p=0.02). Following dose escalation, 96% (n=117) attained an Endox level of 15nM and 76% (n=93) reached 30nM. Baseline Endox level was the only variable independently associated with achieving both targets (p=0.02, p<0.001 respectively). CYP2D6 genotype did not independently predict attainment of Endox targets following dose escalation (p>0.4). The ratio of Endox to its precursor N-desmethylTAM, an indicator of CYP2D6 activity, was stable with dose escalation, suggesting that CYP2D6 was not saturated. Conclusions: Although IM/PM predict for low Endox on 20mg TAM, only low baseline Endox predicted failure to achieve both 15nM and 30nM targets following dose escalation. These results suggest a role for Endox level monitoring to determine optimal TAM dose. Clinical trial information: NCT01075802. [Table: see text]
Phase III placebo controlled double blind randomized trial of radiation therapy for stage 2B-4A cervical cancer with immunomodulator Z-100: JGOG-DT101 study.
Authors: Fujiwara Keiichi , Ohashi Yasuo , Ochiai Kazunori , Noda Kiichiro
Published: March 2020

5506

Background: We previously reported that the lower dose (0.2 μg) of immunomodulator Z-100 showed better overall survival (OS) compared to higher dose (40 μg) in patients with locally advanced cervical cancer who received radiation therapy (RT). Therefore, we conducted a placebo controlled double-blind randomized trial to elucidate the role of additive immunotherapy in standard RT. Methods: Patients of stages 2B to 4A squamous cell carcinoma of the uterine cervix, who were scheduled to receive standard RT with or without platinum-based chemotherapy, were eligible. Z-100 at 0.2 μg (Z) or placebo (P) was given subcutaneously twice a week during the RT, followed by maintenance therapy by administering either Z or P once every two weeks. Therapy was continued until disease progression or termination of the trial in2011. Primary endpoint was OS, secondary endpoints were recurrent-free survival (RFS), response rate (RR), and safety. Sample size was calculated by assuming 5-year survival rates (5YSR) as 60% in Arm Z and 38-44% for Arm P, (hazard ratio HR: 0.526-0.625), and was determined to be 120 patients in each arm. Results: Between 2004 and 2006, 249 patients were randomized. Total of 244 patients were eligible for safety analysis, and 243 patients were eligible for survival analysis. In Arm Z, 29 deaths were reported, and in Arm P, 42. 5YSR was 75.7% (95%CI: 66.4-82.8%) for Arm Z and 65.8 % (95%CI: 56.2-73.8%) for Arm P; HR was 0.646 (95%CI: 0.400-1.043). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There were no differences between arms in terms of RR and RFS, and side effects. Neoplasms, including benign cases, observed were 4 in Arm Z, and 13 in Arm P. Conclusions: Immunomodulator Z-100, used as an adjuvant therapy after radiation, showed clinically significant improvement of OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Further exploration of Z-100 is warranted. Clinical trial information: C000000221.
Prognostic relevance of gene signatures in high-grade serous ovarian carcinoma.
Authors: Konecny Gottfried E. , Wang Chen , Winterhoff Boris , Dering Judy , Ginther Charles , Chen Hsiao-Wang , Hamidi Habib , Podratz Karl C. , Cliby William , Dowdy Sean Christopher , Haluska Paul , Hartmann Lynn C. , Kalli Kimberly , Goode Ellen L. , Slamon Dennis J.
Published: March 2020

5510

Background: Transcriptional profiling of ovarian cancers has proven to be complex. As such it has been difficult to validate existing signatures across studies. Cancer Genome Atlas (TCGA) researchers have identified four molecular subtypes of high-grade serous ovarian cancer (HGSOC). However, survival duration did not differ significantly for the TCGA subtypes. Potential limitations of the TCGA data include short clinical follow-up (45% were alive at the time of last follow-up) and the need to unify gene expression measures from multiple platforms. Methods: Clinically annotated stage-II–IV HGSOC samples (n = 175) with >70% tumor cell content were profiled using the Agilent Whole Human Genome 4 x 44K chip. To identify subtypes non-negative matrix factorization (NMF) of mRNA expression was performed using ~2000 genes with the highest variability across patients. In parallel differentially expressed genes were identified using the Rosetta Similarity Search Tool as well as analysis of variance based on genes known to be involved in epithelial to mesenchymal transition. Results: Median follow-up time was 35 months (range, 0–202 months, 12% were alive at the time of last follow-up). NMF clustering confirmed four HGSOC subtypes (immunoreactive, differentiated, proliferative, and mesenchymal) on the basis of gene content in the clusters. Pathway signatures with therapeutic potential were identified for individual or multiple subtypes. Survival differed significantly between the four molecular subgroups in univariate (Hazard Ratio [HR] 2.4, 95% CI 1.5-4.1, p = 0.007) and multivariate (HR 2.3, 95% CI 1.3-4.0, p = 0.003) analyses when accounting for age, stage, grade, and postoperative residual tumor. Using the supervised clustering approach two distinct molecular subtypes of HGSOC based on epithelial and mesenchymal gene expression signatures were identified with significantly different survival outcomes. Conclusions: Here we independently validate and expand upon the molecular TCGA classification of HGSOC. The potential of these two prognostic classifiers may lie in their ability to recognize categories of patients that are more likely to respond to particular therapies.
Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC).
Authors: Myers Andrea P. , Broaddus Russell , Makker Vicky , Konstantinopoulos Panagiotis A. , Drapkin Ronny , Horowitz Neil S. , Liu Joyce , Van Hummelen Paul , Meric-Bernstam Funda , Birrer Michael J. , Doyle L. Austin , Coleman Robert L. , Aghajanian Carol , Mills Gordon B. , Cantley Lewis , Matulonis Ursula A , Westin Shannon Neville ,   SU2C Dream Team: PI3K in Women's Cancers
Published: March 2020

5524

Background: EC has high rates of PI3K pathway alteration including PTEN mutation (50%) or IHC loss (>50%), PIK3CA mutation (25-40%) and PIK3R1 (20%) mutation. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized that pts whose tumors harbored PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. Methods: Pts had recurrent or advanced EC; all histologies except MMMT were eligible. Up to 2 prior chemo lines were permitted; excluding prior treatment with PI3K/MTOR inhibitors. The first 19 pts were treated with MK-2206 200mg QW; due to initial skin toxicity rates, the starting dose was amended to 135mg QW. Co-primary endpoints were objective response and 6 mo PFS. The first 37 pts were stratified retrospectively. PIK3CA MT included R88Q, K111N, E110K, E418K, C420R, E453K, E542K/V,E545K, Q546R, H701P, M1043V, H1047R/L/Y changes. Independent Simon 2-stage tests were planned within PIK3CA MT and WT stratum: for MT, n1=15 and n2=10 pts would allow discrimination of RR<5% and 6moPFS<10% versus RR>25% or 6moPFS>35%; for WT, n1=31 and n2=24 pts would discriminate RR<5% and 6moPFS<10% versus RR>20% or 6moPFS>25%. Results: 37 pts were enrolled (1 ineligible) before accrual was stopped as timely CLIA-compliant prospective mutation analysis was not feasible. By PIK3CA mutation analysis, 9 pts were MT: 1 pt had both PR and 6moPFS. 27 pts were WT: 1 pt had PR and 3 pts had 6moPFS. 2 pts with 6moPFS were treated at 200mg; 2 pts with 6moPFS were treated at 135mg. Each group had 1 PR. The most common toxicity was grade 3 rash (19%). Grade 3 and 4 toxicities occurred in 50% and 8% of pts. Exploratory analysis of histology found all pts with 6moPFS were classified as serous (4 of 8) as compared to all other histologies (0 of 28, p=.001). Targeted exome sequencing and copy number analysis of the PI3K pathway and PTEN IHC are underway. Associative studies will be reported. Conclusions: There is limited single agent activity of MK-2206 in both PIK3CA MT and PIK3CA WT EC populations. Activity was detected in pts with serous histology tumors and warrants further study. Clinical trial information: NCT01307631. [Table: see text]
Recombinant adenovirus-p53 combined with chemotherapy in treatment of locally advanced cervical cancer (a phase II study).
Authors: Zhou Jian , LIU Fumin , Xiao Jie
Published: March 2020

5525

Background: To evaluate the efficacy and safety of recombinant adenovirus-p53 (rAd-p53) combined with chemotherapy in treatment of locally advanced cervical cancer. Methods: Forty patients with stage IIb2 IV locally advanced cervical cancer were randomly divided into 2 groups: 20 patients receiving gene plus chemotherapy (PCG) and 20 receiving sole chemotherapy (CG). The patients in PCG were given one course of PVB (cisplatin + vincristine + pingyangmycin) and 5 times intratumoral injections of rAd-p53 at a dose of 2 x 1012 viral particles once per 3 days. The CG patients received a sole course of PVB. The study patients were followed up for at least one year. The VEGF, p53, Bax, and p21 protein expression in pre- and post-treatment tumor tissues were examined by immunohistochemistry. Results: The response was evaluated at 3 months after treatments. The response rates (CR + PR) were 95% and 75% for the PCG and CG patients, respectively. P53 proteins were strongly expressed in the tumor tissues from both groups. There were no significant changes in expression level of the p53 protein in the tumor tissue from pre- and post-treatment. However, the VEGF, Bax, and p21 protein expressions significantly increased in PCG after treatment. The overall one-year survive rates were 90% and 65%, respectively. A mild to medium grade of fever was found in 90% of the PCG patients. No serious of adverse events relative to rAd-p53 were observed. Conclusions: Combined the rAd-p53 gene with chemotherapy is an effective treatment for the patients with advanced cervical cancer. The rAd-p53 gene therapy is a safe treatment.
Locally advanced adenocarcinoma and adenosquamous carcinoma of the cervix compared to squamous cell carcinoma of the cervix in Gynecologic Oncology Group trials of chemoradiation.
Authors: Rose Peter Graham , Java James , Whitney Charles W. , Keys Henry , Lanciano Rachael , Thomas Gillian
Published: March 2020

5530

Background: Conflicting results have been reported for adeno- and adenosquamous carcinomas the cervix with respect to their response to therapy and prognosis. Adeno- and adenosquamous carcinoma comprise the majority of non-squamous carcinomas of the cervix enrolled in GOG trials of chemoradiation. Methods: Adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. Results: Among 1672 patients enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.8%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB (27% versus 20%) and fewer were stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous carcinomas, but adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). Among patients that received cis-platinum during radiation therapy, 843 with squamous cell carcinoma were compared to 112 with adeno- or adenosquamous carcinoma for overall survival, with no significant difference in risk of death (p=0.472). However, among patients that did not receive cis-platinum, 647 with squamous cell carcinoma and 70 with adeno- or adenosquamous carcinoma, there was a slightly higher risk of death for the adeno- or adenosquamous group (p=0.049). Adverse effects to treatment were similar across histologies. Conclusions: Patients with adeno- and adenosquamous carcinomas of the cervix have worse overall survival when treated with radiation alone, but have progression-free and overall survival similar to patients with squamous cell carcinomas of the cervix when treated with cis-platinum based chemoradiation.
An evaluation of survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: A Gynecologic Oncology Group experience.
Authors: Farley John H. , Brady William E. , Birrer Michael J. , Gershenson David Marc , Fleming Gini F. ,   Gynecologic Oncology Group
Published: March 2020

5534

Background: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). Methods: Data from stage I-IV epithelial ovarian cancer (EOC) patients who participated in 12 randomized GOG protocols using platinum-based chemotherapy were reviewed. Proportional hazards models adjusted for age and stratified by protocol, treatment arm, stage, performance status (PS), and race were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). Results: There were 10,803 patients enrolled, 1272 were not eligible: leaving 9,531, of whom 544 (6%) had OCCC, 7,054 (74%) had SOC, and 1,933 (20%) had other; only the OCCC and SOC are considered here. OCCC were significantly younger, more often of Asian race, stage I, good PS, and optimally surgically debulked than SOC patients. Prior to adjustment, OCCC had better PFS and OS due to better prognostic factors. There was no significant difference in PFS or OS for early stage OCCC patients compared to high-grade (HG) SOC patients. For late stage patients, OCCC had poorer PFS and OS compared to SOC, OS HR= 1.66 (1.43, 1.91; p < 0.001). For both optimal, HR = 1.34 (1.10, 1.63; p = 0.003) and suboptimal, HR = 3.18 (2.13, 4.75; p < 0.001) OCCC had a significantly poorer OS than SOC. After adjusting for age and stratified by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR= 1.53 (1.33,1.76; p < 0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly taxol versus observation in SOC compared to OCCC (p = 0.048). Conclusions: This is one of the largest analyses to date of OCCC treated in a uniform manner . OCCC patients have better PFS and OS compared to SOC; this, is due to their better prognostic factors. There was no observed difference in PFS or OS for early stage OCCC versus HGSOC. In late-stage patients, OCCC was significantly associated with decreased OS which was true for both optimal and suboptimally debulked patients. Finally, treatment effect was influenced by histology.
The retention index calculated with dual-phase 18F-FDG PET/CT in ovarian carcinoma: Determination of the optimal cutoff level using ROC analysis.
Authors: Hong Jin Hwa , Kim Sungeun , Min Kyung Jin , So Kyeong A , Lee Jae Kwan
Published: March 2020

5539

Background: Although 18F-fluorodeoxyglucose (FDG) positron emission tomography /computed tomography (PET/CT) is useful as a clinical tool in various malignancies, the maximum standardized uptake value (SUVmax) overlap between malignant and benign lesions is significant. The dual-phase PET/CT has shown its usefulness to differentiate benign from malignant conditions in some solid tumors, but its usefulness has not yet been evaluated in patients with ovarian cancers. Methods: Twenty consecutive patients (thirteen with ovarian cancers and seven with benign lesions) were evaluated preoperatively by dual-phase 18F-FDG PET/CT (Time of Flight, Philips), performed 1 and 2 hour after injection of 370-555 MBq of 18F-FDG. The SUVmax at 1 hour (SUVmax1) and at 2 hour (SUVmax2) were determined, and the retention index (RI) was calculated by subtracting the SUVmax1 from the SUVmax2 and dividing by SUVmax1. Results: Area under the receiver operating characteristic (ROC) curve of SUVmax1 and SUVmax2 were 0.753 and 0.835, respectively (95% CI; 0.512, 0.915 versus 0.604, 0.961; p = 0.062 versus 0.001). Area under the ROC curve of RI was 0.901 (95% CI; 0.684, 0.988; p <0.001). When the SUVmax1 cutoff was set to 3.2, the sensitivity and the specificity of the SUVmax1 were 100% and 57.1%, respectively. When the SUVmax2 cutoff was set to 3.9, the sensitivity and the specificity of the SUVmax2 were 100% and 57.1%, respectively. The sensitivity and the specificity of RI were 92.3% and 71.4% when the cutoff was set to 16.67. By pairwise comparisons, the area under the ROC curve of SUVmax2 was significantly higher than that of SUVmax1 (p = 0.032). The area under the ROC curve of the RI was higher than those of SUVmax1 and SUVmax2, but not statistically significant (p = 0.166 and 0.459, respectively). Conclusions: The RI and SUVmax2 are proved to be useful in differentiating ovarian cancers from benign lesions. The use of dual-phase 18F-FDG PET/CT should be taken into account when the preoperative imaging is ambiguous. Acknowledgements: This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, (A070001) Republic of Korea.
MDS/AML risk post-breast cancer and association with age: SEER data 2001-2009.
Authors: Kaplan Henry G. , Malmgren Judith April , Calip Gregory Sampang , Li Christopher
Published: March 2020

554

Background: Increased acute myeloid leukemia (AML) incidence has been identified post chemotherapy and radiation treatment for primary breast cancer (BC). Risk has not been evaluated in large populations or included myelodysplastic syndrome (MDS). Methods: We used 2001-2009 Surveillance, Epidemiology and End Results (SEER) database records to identify a cohort of first primary stage I-III BC patients. We identified subsequent MDS/AML diagnoses in the BC cohort, using SEER to query appropriate ICD-O-3 codes. We compared observed MDS/AML rates in the BC cohort to expected rates, estimated for first primary MDS/AML in the entire population, and calculated observed/expected rate ratios with 95% confidence intervals (CI) with age adjustment. Due to SEER data limitations, disease stage was used as a proxy for likelihood of radiation and chemotherapy treatment. Results: BC case distribution by stage was 51% stage I, 39% stage II and 11% stage III. Age distribution was 26% 20-49, 38% 50-64 and 36% 65+ years. Out of 306,691 BC cases, 470 had a subsequent diagnosis of MDS or AML (.15%) with 19% among women age 20-49 years, 36% women age 50-64 and 45% among women age 65+ years. Age adjusted number of expected myeloid leukemia cases is 171. Follow up time to myeloid leukemia diagnosis was on average 2.92 years post BC diagnosis (range .25-8.75 years). Myeloid leukemia cases were 56% AML and 44% MDS. We found an overall increased risk of MDS/AML among all age (20-65+)/all stage (I-III) breast cancer cases compared to the general population (RR=2.75, 95% CI 2.51, 3.00). Risk increased with increasing BC stage: stage I (RR=1.87, 95% CI 1.61, 2.16), stage II (RR=3.57, 95% CI 3.12, 4.06), and stage III (RR=5.66, 95% CI 4.45, 7.07) and decreased with increasing age with the highest risk among women age 20-49 (RR=10.60, 95% CI 8.57, 12.92) (age 50-64 (RR=5.60, 95% CI 4.79, 6.49), age 65+ (RR=1.81, 95% CI 1.57, 2.06)). Conclusions: Patients with stage I-III breast cancer have a significant high risk of MDS/AML post BC diagnosis increasing with higher stage cancer, most likely the result of radiation and/or chemotherapy treatment. Younger age women, 20-49 years, appear to be the most susceptible to this outcome.
Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients not candidates for optimal primary surgery: Safety and effectivenes.
Authors: Miranda Vanessa Costa , Fede Angelo Bezerra de Sousa , Dos Anjos Carlos Henrique , da Silva Juliana Ribeiro , Sanchez Fernando Barbosa , Bessa Lyvia Rodrigues da Silva , Carvalho Jesus Paula , Filho Dr Elias Abdo , Freitas Daniela , Barros Laryssa Almeida Borges de , Silva Samantha Cabral Severino da , Estevez-Diz Maria Del Pilar
Published: March 2020

5540

Background: Primary debulking surgery (PDS) has been considered the standard of treatment in advanced ovarian cancer, while neoadjuvant chemotherapy, three cycles followed by interval debulking (ID) surgery, is a valid treatment alternative for patients with non-resectable disease. This study aimed to show the efficacy and safety of six cycles of neoadjuvant chemotherapy (N-CT) followed by cytoreduction, a single institution experience. Methods: Aretrospective analysis was performed of all patients (pts) with advanced ovarian cancer treated with platinum based N-CT, between January/2004 and February/2012. Results: 97 pts underwent N-CT in our institution; 78.1% and 18.8% the patients had extensive stage IIIC or IV disease at diagnosis, respectively. Median age 60 years (36 – 82). Histologic types: serous 84.5%, adenocarcinoma not specified 11.3%, endometrioide 1.0%. A median of six cycles of chemotherapy were performed. Patients did not received chemotherapy after debulking surgery. During the treatment 31.4% had grade 3/4 toxicity, the most commonly observed toxicities were hematologic toxicities and nausea, four (4.1%) patients died during chemotherapy due to disease progression. After N-CT 24.7% achieved clinical complete response, 57.7% partial response and 12.4% disease progression. From this cohort 63.1% underwent a complete resection of all macroscopic and microscopic disease (R0). Median length of hospital stay and postoperative ICU stay was 5 and 0.8 days respectively, surgical complications were not common however five (7.1%) patients needed second surgery due to operatory complications and 19 pts (27.1%) needed blood transfusion after debulking. With a median follow up of 21.8 months (0.5-139.7), median overall survival and chemotherapy-free interval were 57,7 and 9,5 months, respectively. Conclusions: Six cycles of neoadjuvant carboplatin and paclitaxel is safe, effective and does not increase perioperative and postoperative complications for patients with stage IIIC-IV not candidates for optimal/R0 PDS. The overall survival of this cohort is higher than those treated with interval debulking surgery.
Expression III: What do primary and recurrent ovarian cancer (OC) patients expect from their doctors and therapy management? Results of a survey in eight European countries with 1,743 patients (NOGGO/ENGOT-OV9 study).
Authors: Oskay-Özcelik Gülten , Keller Maren , Pignata Sandro , Lorusso Domenica , Joly Florence , Berton-Rigaud Dominique , Vergote Ignace , De Roover Joke , Maciejewski Michal , Jedryka Marcin , Casado Herraez Antonio , Mendiola C. , Gonzalez-Martin Antonio , Achimas Patrick , Reimer Daniel Uwe , Zeimet Alain G , Hindenburg Hans-Joachim , Richter Rolf , Sehouli Jalid
Published: March 2020

5569

Background: The primary aim of this study was to investigate information needs and preferences among patients with ovarian cancer, focusing especially on doctor-patient relationships and therapy management in different European countries. Methods: A questionnaire was developed based on the experiences of expression II, a German survey, and then provided to primary and recurrent ovarian cancer patients via internet (online) or as a print-version in 8 countries in Europe (Austria, Belgium, France, Germany, Italy, Poland, Rumania, Spain). In the first part basic data (age, tumour status, therapy) were requested from the patient. In the second part, most of the questions tried to evaluate the expectations and needs concerning their therapy management and doctor-patient communication. Results: From December 2009 to October 2012, a total of 1743 patients with ovarian cancer from 8 European countries participated in the survey.The median age was 58 years (range 16-89). Nearly all patients (96,3%) had a primary surgery and a first-line chemotherapy (91,5%). About 423 (25,7%) patients were included in another clinical trial.Most of the patients in each country were pleased with the completeness and understandability of the explanations about the therapies from their doctors. About 68% of patients would be interested in having the opportunity to have a second opinion. The three most important aspects, which were proposed by patients to improve therapy against ovarian cancer were: “the therapy should not induce alopecia” (42%), “there must be more done to counter fatigue” (34%), and “the therapy should be more effective” (29%). Conclusions: This study underlines the high need of ovarian cancer patients to discuss all details concerning treatment options and clinical management with only minor difference between the countries. Patients also need more information about side effects of cancer therapies and second opinion opportunities. Besides effectiveness of therapy, alopecia and fatigue are the most important side effects bothering the patients.
Analysis of plasma biomarker and tumor genetic alterations from a phase II trial of lenvatinib in patients with advanced endometrial cancer.
Authors: Funahashi Yasuhiro , Penson Richard T. , Powell Matthew A. , Miller David S. , Fan Jean , Ren Min , Meneses Nicole , Sachdev Pallavi , Kadowaki Tadashi , O'Brien James P. , Vergote Ignace
Published: March 2020

5591

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. A phase 2 study in patients with advanced endometrial cancer following 1 or 2 prior platinum-based treatments was performed and is presented in a separate abstract. Here we report potential predictive markers of clinical benefit. Methods: Pre- and post-treatment plasma samples collected from 122 of 133 treated subjects were analyzed for 50 circulating cytokine and angiogenic factors (CAFs) using ELISA and multiplex assay platforms; 107 archival tumor tissues obtained from 133 enrolled subjects were analyzed for gene mutation (mut) (81 samples) and gene expression profiling (GEP) (64 samples). For GEP analysis, the NanoString nCounter platform was used to measure the expression level of approximately 300 genes identified preclinically as relevant. Correlation with clinical outcome measures including maximal tumor shrinkage (MTS), objective response rate (ORR), PFS, and OS was performed. Results: Clinical correlation identified baseline levels of 7 CAFs related to angiogenesis (Ang-2, IL-8, HGF, VEGFA, PlGF, Tie-2, and TNFa) that associated with survival. Only baseline levels of Ang-2 associated with greater MTS (R=0.36 [Spearman], P<0.001), ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) as determined using a defined cut-off value for baseline Ang-2. In gene mut analysis, no significant correlations were observed among the genes tested. Mut in PIK3CA showed a trend toward shorter OS (p = 0.085). In GEP analysis, expression levels of approximately 90 genes correlated with clinical outcome. Combination of GEP and CAF signatures identified signaling pathways, including Ang-2, that associated with OS. Clinical and preclinical GEP analysis identified overlapping gene signatures involving MAPK and PI3K signaling pathways that contributed to lenvatinib resistance. Conclusions: Baseline circulating Ang-2 levels may potentially predict outcomes in patients with advanced endometrial cancer and require further examination. This may provide a basis for stratification of patients in future clinical trials. Clinical trial information: NCT01111461.
L1-CAM as a predictor of survival in endometrial cancer: An analysis of The Cancer Genome Atlas (TCGA).
Authors: Dellinger Thanh Hue , Warden Charles , Han Ernest Soyoung , Wakabayashi Mark Tsuneo
Published: March 2020

5599

Background: Despite a good survival rate for early-stage endometrial cancers (ECs), the prognosis for advanced-stage ECs remains poor, with no biomarkers and few therapeutic options currently in existence. L1-cell adhesion molecule (L1-CAM), a glycoprotein which functions in adhesion and migration of tumor cells, has been associated with a poor prognosis in Type I endometrial cancer (ASCO 2011 Abstract #5091). We evaluated the role of L1-CAM among both Type I and II ECs in TCGA. Methods: Partek Genomics Suit was used to define differentially expressed genes with p-values for clinical associations (ANOVA with linear contrast for discrete variables and linear regression for continuous variables). Differences in survival between “high” and “low” expression groups (defined by median expression) were compared using Cox regression analysis, with p-values calculated via log-rank test, using the ‘survival’ package in R. Results: Of 451 downloadable tumor samples, 335 tumors with both clinical and gene expression data were analyzed. Median age was 63 yrs. (range 31-90 yrs.). Stage I, II, III, and IV comprised 65%, 7%, 23%, and 5%, respectively. 82% were endometrioid; 16% (n = 52) serous. Grade 1, 2, and 3 comprised 24%, 27%, and 49%, respectively. Median follow-up was 19.5 months. High L1-CAM expression was found in older (p = 0.0005), suboptimally debulked (p=0.002), and African-American patients (p = 0.0003), and those with high grade (p = 0.008), serous histology (p <0.00001), higher stage (p = 0.0004), positive peritoneal cytology (p = 0.007), deep myometrial invasion (p = 0.02), and positive pelvic (p = 0.003) and para-aortic lymph nodes (p = 0.002). High L1-CAM expression was associated with poor survival with a median overall survival of 17.2 months compared to 21.3 months for low L1-expressing endometrial tumors (HR= 3.1, CI=1.3 -7.3, p = 0.007). Conclusions: L1-CAM expression is associated with poorer survival and high-risk clinicopathologic factors in endometrial cancer. Its prevalence in Type II ECs, such as high-grade, serous ECs, makes it a particularly attractive target for both novel biomarker discovery and therapeutic targeting.
Preoperative risk assessment model for identification of lymph node metastasis in early cervical cancer.
Authors: Shim Seung-Hyuk , Kim Dae-Yeon , Lee Shin-Wha , Park Jeong-Yeol , Kim Jong-Hyeok , Kim Yong-Man , Kim Young-Tak , Nam Joo-Hyun
Published: March 2020

5600

Background: The aim of this study was to develop a preoperative risk prediction model for lymph node metastasis in patients with early cervical cancer. Methods: The medical records of 504 patients with early cervical cancer who underwent hysterectomy and pelvic/paraaortic lymphadenectomy between 2007and 2012 in our center were retrospectively reviewed. According to the order of surgery performed, data between 2007 and 2010 were allocated to a model development cohort (n=314), and data between 2011 and 2012 were allocated to an external validation cohort (n=190). By using preoperative clinicopathologic data, magnetic resonance imaging (MRI) data, and positron emission/computed tomography (PET/CT) data, a multivariate logistic model was created. Based on this model, predictive nomogram was developed and externally validated. Results: Age, tumor size measured by MRI, and lymph node metastasis on PET/CT were found to be independent risk factors for nodal metastasis. Developed nomogram incorporating these three predictors showed good discrimination and calibration, with a bootstrap-adjusted concordance index of 0.772. Also, the validation set showed good discrimination with a bootstrap-adjusted concordance index of 0.783. Conclusions: We have developed a robust model to predict lymph node metastasis in patients with early cervical cancer. This new tool may be useful to clinicians and patients when deciding lymphadenectomy and maybe useful in designing clinical trials. [Table: see text]
Racial disparities in cervical cancer mortality over time.
Authors: Rauh-Hain Jose Alejandro , del Carmen Marcela G , Schorge John O. , Boruta David M. , Growdon Whitfield Board , Goodman Annekathryn , Clark Rachel Marie , Bradford Leslie Siriya , Clemmer Joel
Published: March 2020

5604

Background: The aim of this study is to examine changes over time in survival for African-American (AA) and white women diagnosed with cervical cancer (CeCa). Methods: Surveillance, Epidemiology, and End Results (SEER) Program data 9 for 1983-2007 were used for this analysis. Kaplan–Meier and Cox proportional hazards survival methods were used to assess differences in survival by race at 5-year intervals. Results: The study included 23,722 women; including 19,777 whites and 3,945 AA. AAs were older (51.4 vs. 49 years; p<0.001), had a higher rate of regional (38.3% vs. 31.7; p<0.001) and distant metastasis (10.5% vs. 8.5; p<0.001). AAs received less frequently cancer-directed surgery (53.1% vs. 65.7%; p<0.001), and more frequently radiotherapy (56.9% vs. 47.3%; p<0.001). AAs had a hazard ratio (HR) of 1.40 (95% CI, 1.31-1.49) of CeCa mortality compared to whites. Adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, AA women had a HR of 1.15 (95% CI, 1.07-1.24) of CeCa related mortality. AAs had a higher HR of all cause mortality and CeCa related mortality for all the five-year diagnosis cohorts (Table). After adjusting for the same variables, there was a significant difference in survival in the 1988-1992 group (HR 1.26; 95% CI 1.09-1.47). Conclusions: The present data indicates significant survival differences by race for women with invasive CeCa. After adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, only between 1988-1992 there was a difference in survival between the groups. [Table: see text]