bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of sunitinib in recurrent or metastatic endometrial carcinoma: A trial of the PMH Phase II Consortium
Authors: Welch S. , Mackay H. J. , Hirte H. , Fleming G. F. , Morgan R. , Wang L. , Blattler C. , Ivy S. P. , Oza A. M. 
Published: August 2020

5576 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Vascular endothelial growth factor (VEGF) overexpression in EC correlates with poor outcome, thus targeting VEGF is a rational therapeutic approach. We have conducted a two-stage open-label phase II study in advanced EC with sunitinib, an oral tyrosine kinase inhibitor of multiple VEGF receptors. Methods: Eligible pts have recurrent or metastatic EC and have received up to 1 prior chemotherapy (CT) regimen for metastatic disease. Sunitinib is given at 50 mg daily (OD) for 4 consecutive weeks (wks) followed by 2 wks off. Dose could be reduced to 37.5 mg OD and then 25 mg OD in the setting of toxicity. Imaging is repeated every 12 wks. Primary objectives are objective response rate (ORR by RECIST) and rate of 6-month progression-free survival (PFS). If 1 or more responses occur in the first 15 evaluable pts, the study would continue to a second stage (total = 30 pts). Secondary objectives are time to progression (TTP), overall survival (OS), and safety. Results: We report the results of the first stage of this study. Sixteen pts have been treated (median age: 63; range 41–74) with 37 cycles of sunitinib (median 2; range: 1–7). Baseline ECOG PS was 0 (7 pts), 1 (8 pts), or 2 (1 pt). Histology was endometrioid (7 pts), serous (5 pts), clear cell (1 pt), or mixed/other (3 pts). Most pts had high-grade histology (G3: 8; G2: 4; G1: 2; GX: 2). Nine pts had prior adjuvant CT, 8 pts had 1 prior CT for advanced EC, 4 pts had prior hormones and 7 pts had prior radiotherapy. Partial response was achieved by 2 pts (ORR = 12.5%), and 2 other pts had a best response of stable disease; 3 of these pts remained progression-free > 6 months. Median TTP = 2.5 months (95% CI: 2.47-NR), and median OS = 6.2 months (95% CI: 5.1-NR). Grade 3/4 adverse events (AE) in >10% of pts were fatigue (7 pts, 44%) and hypertension (5 pts, 31%). Dose reduction was required for 11 of 16 pts (69%). Two pts were inevaluable after receiving <2 cycles due to AE (grade 4 hyponatremia; grade 3 fatigue) and 1 other pt has yet to complete 2 cycles. Conclusions: Sunitinib shows preliminary activity in EC. This trial will proceed to a second stage of accrual to further explore the efficacy and safety of sunitinib in advanced EC. [Table: see text]
Phase II study of MKC-1 in patients with metastatic or resistant epithelial ovarian cancer or advanced endometrial cancer
Authors: Elser C. , Hirte H. , Kaizer L. , Mackay H. , Bindra S. , Tinker L. , MacAlpine K. , Wang L. , Sidor C. , Oza A. 
Published: August 2020

5577 Background: MKC-1 is a novel oral cell cycle inhibitor with preclinical activity in xenograft models of human ovarian and endometrial cancers. MKC-1 also reduces pAKT, an attractive target in endometrial cancer due to frequent PTEN mutations. Methods: The objective of this phase II study is to assess the efficacy of MKC-1 in 2 patient (pt) populations: metastatic or recurrent platinum-resistant ovarian cancer (EOC) and advanced endometrial cancer (EC). Three prior lines of treatment were allowed in both groups. A two arm, parallel group multicenter 2-stage design was used. The primary endpoint was tumor response by RECIST or CA-125. MKC-1 125 mg/m2 was administered orally twice daily for 14 days in 28-day cycles. Results: Accrual to stage one is complete with 21 pts in each arm. 19 pts with EOC (median age 56 yrs, range 31–71) and 9 patients with EC (median 63 range 50–74) were available for efficacy. A total of 66 cycles (EOC/EC: 39/27cycles) median 2 per patient (range 1–8) were delivered. 11/4 pts had prior adjuvant CT, 14/10 had prior systemic CT for advanced disease, and 2/6 received prior radiation. In pts with EOC, 7 pts have stable disease (SD), 12 progressive disease (PD), 2 remain on study. Median time to progression is 1.8 months. In pts with EC 4 pts had SD, 5 PD, 6 remain on study. Toxicity data are available in 28 pts (17/11). Most common adverse events (AE) possibly related to MKC-1 were fatigue, nausea, elevated ALT or AST, urine discoloration, anemia, anorexia, elevated AP and gastrointestinal disorder in 55%, 39%, 36%, 24%, 23%, 21%, 21%, and 21 % of cycles respectively. The only possibly related grade 3+ AEs were neutropenia, leucopenia and hyponatremia in 9 %, 3 %, and 2% of cycles. Conclusions: MKC-1 was well tolerated in both patient populations. Single agent MKC-1 has insufficient activity in platinum resistant EOC to warrant further investigation. Updated clinical data for both patient groups will be presented at the meeting. [Table: see text]
Different expression of progesterone receptor between uterine serous carcinoma and ovarian serous carcinoma
Authors: Matsuo K. , Eno M. L. , Abouzied A. M. , Im D. D. , Rosenshein N. B. 
Published: August 2020

5578 Background: Clinical presentation and progression of uterine serous carcinoma (USC) often mimicks that of ovarian serous carcinoma (OSC), making the diagnosis difficult. The aim of this study is to compare characteristics of biomarker expression of USC to OSC. Methods: We evaluated all patients with FIGO stage III-IV USC and OSC, who underwent initial cytoreductive surgery between January 1, 1995, and March 31, 2008. Cases that received neoadjuvant chemotherapy were excluded. Patient demographics and clinico-pathologic data were abstracted from the medical records. Biomarker expression results were evaluated for mutation of p53 (m-p53), DNA profiling, multi-drug resistance gene-1 (MDR-1), estrogen receptor, and progesterone receptor. In-vitro drug resistance assay results were compared among platinum, taxane, cyclophosphamide, doxil, etoposide, gemcitabin, and topotecan (EDR Assay, Oncotech, Inc.). Results: There were 19 cases of USC and 185 cases of OSC identified. USC and OSC showed similar biomarker expressions except for the DNA index and expression of progesterone receptor. Biomarker expressions were: m-p53, 83.3% vs 68.7%, p = 0.28; DNA aneuploidity, 88.8% vs 80.8%, p = 0.53; DNA index, 1.7 (1.0–2.7) vs 1.5 (0.8–3.2), p = 0.044; S-phase fraction, 8.1% (3.1–19) vs 8.6% (0.3–19.2), p = 0.5; MDR-1, 33.3% vs 19.1%, p = 0.21; and estrogen receptor, 82.3% vs 82.9%, p = 1.0. Increased progesterone receptor expression was seen in USC compared to OSC (29.4% vs 9.2%, odds ratio 4.1, 95%CI 1.25–13.7, p = 0.028). In the in-vitro drug resistance assay, proportions of extreme drug resistance were similar in all tested drugs, including: cisplatin, 7.7% vs 7.2%, p = 0.5; carboplatin, 11.1% vs 9.5%, p = 0.3; paclitaxel 26.7% vs 23.5%, p = 1.0; doxil, 44.4% vs 33.9%, p = 0.69; and topotecan, 15.4% vs 18.5%, p = 1.0. Conclusions: Advanced uterine serous carcinoma was associated with increased expression of progesterone receptor compared to advanced ovarian serous carcinoma. The different expression potentially could be used to differentiate the two conditions and as a target in treatment therapies for uterine serous carcinoma. No significant financial relationships to disclose.
DNA mismatch repair protein defects and endometrial cancer in women age 40 and younger
Authors: Shih K. K. , Garg K. , Levine D. A. , Kauff N. , Abu-Rustum N. R. , Soslow R. A. , Barakat R. R. 
Published: August 2020

5579 Background: The significance of the hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to describe the incidence and prognostic implications of DNA mismatch repair protein defects in a series of patients age 40 years and younger with endometrial cancer. Methods: We performed a retrospective cohort study of patients age 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry (IHC) was performed. Cases were analyzed according to presence of DNA MMR protein defects. Standard two-sided statistical tests were performed. Results: Of the 71 identified patients, the median age was 37 years (range, 24–40), with a median follow-up of 47 months (range, 1–178). The majority were of endometrioid histology (94%), stage I (73%), and FIGO grade 1 (61%). IHC was performed with available blocks (n = 56), and loss of DNA MMR was found in 9 cases (16%). Cases with loss of DNA MMR were more likely to have high-grade (FIGO 2 or 3) tumors (p < 0.001), be advanced stage (III or IV) at the time of diagnosis (p < 0.001), and have a family history suggestive of hereditary non-polyposis colorectal cancer (p = 0.01). There was no difference between the groups in histology, obesity (BMI>30), parity, or history of infertility. Analysis of clinical outcomes revealed that cases with loss of DNA MMR had significantly worse overall survival (median survival not reached, log rank p = 0.018). At the time of last follow-up, 2 (22%) patients with loss of DNA MMR were dead of disease compared with 2 (4%) patients with retained DNA MMR. Conclusions: Endometrial cancer is rare in young women age 40 years or less. In these patients, loss of DNA MMR was associated with worse clinicopathologic factors (high-grade and advanced-stage tumors) and worse outcome. Other clinical risk factors associated with endometrial cancer were not associated with loss of DNA MMR. The data suggest that MMR testing in women 40 years of age or younger with endometrial cancer may have clinically useful prognostic information. No significant financial relationships to disclose.
A survival comparison between women with uterine serous and/or clear cell carcinoma with and without a history of breast cancer
Authors: Mendivil A. , Vogel T. J. , Bae-Jump V. L. , Gehrig P. A. 
Published: August 2020

5580 Background: The association between breast and uterine is well known. However, the effect that a prior breast cancer diagnosis may have on women with a new endometrial cancer diagnosis is less well described. The goal of our study was to determine the effect that a prior history of breast cancer would have on the outcome for women with type II uterine cancer. Methods: After obtaining IRB exemption, a retrospective chart review was performed. All women treated for uterine carcinoma between 1994 and 2007 were identified and we identified women with either uterine serous (UPSC) or clear cell carcinoma (UCCC) as the study group. The patients were then divided between those with and those without a prior breast cancer diagnosis. Patient demographics, cancer histologies, and stage of disease data were collected. Fisher's exact test and unpaired t test were used as appropriate. Progression-free (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Results: Approximately 1,083 patients were treated for uterine carcinoma during the study period of which 74 had pre-existing breast carcinoma (6.9%). One hundred and fifty women had USC and/or UCCC (13.8%) of whom 23 also had pre-existing breast carcinoma (13.3%). The women with breast cancer where older at the time of their uterine cancer diagnosis (77 y.o.) compared to those without breast cancer (68 y.o.) (p = 0.0089); were more likely to develop USC/UCCC (OR 2.56; 95% CI 1.47–4.44); and were more likely to be white compared to black (OR 4.6; 95% CI 1.74–11.99). At five years, there was no significant difference in PFS or OS between those women with and without a prior history of breast cancer. Conclusions: Women with a history of breast cancer have more the twice the likelihood of developing USC and/or UCCC. While having two primary malignancies can be devastating, our study indicated that women who developed a type II uterine cancer and also had a history of a prior breast cancer had the same outcomes as those women without a prior cancer diagnosis. This finding may help to allay patients’ fears about developing another malignancy and its impact on their prognosis. No significant financial relationships to disclose.
Comparison of the outcome between cervical adenocarcinoma and squamous cell carcinoma patients with adjuvant radiotherapy after radical surgery: SGSG/TGCU Intergroup Surveillance
Authors: Shimada M. , Kigawa J. , Nishimura R. , Hiura M. , Hatae M. , Takehara K. , Sato A. , Kurachi H. , Mizunuma H. , Sugiyama T. 
Published: August 2020

5585 Background: We conducted the present surveillance to clarify the significance of adjuvant radiotherapy and the cause of poor outcome of adenocarcinoma (AC). Methods: A total of 825 patients with FIGO stage Ib-IIb cervical cancer, who underwent type III radical hysterectomy in 10 institutes of SGSG/ TGCU Intergroup between April 1997 and March 2003, were enrolled in this study. There were 543 patients with squamous cell carcinoma (SCC) (261 in stage Ib1, 67 in Ib2, 83 in IIa, 132 in IIb) and 282 with AC (186 in stage Ib1, 39 in Ib2, 11 in IIa, 46 in IIb). Mean age of patients was 49.0 yrs (range: 19–84 yrs) in SCC and 46.6 yrs (range: 18–84) in AC. Two hundred and fifty-five patient with SCC and 69 with AC received adjuvant radiotherapy including CCRT. Results: The 5-year overall survival rate (OS) for patients with SCC and AC were 87.4% and 83.4%. The OS for stage I patients did not differ between SCC and AC. Stage II patients with AC showed significantly worse prognosis compared with SCC (54.5% vs. 87.4% in IIa, 63.3% vs. 78.8% in IIb). There was a significant difference in OS for patients receiving adjuvant treatment between SCC and AC (83.0% vs. 73.9%). Although the OS for stage I patients did not differ between SCC and AC, the OS for stage II patients with AC was significantly lower (86.9% vs. 50.0% in IIa, 75.5% vs. 61.1% in stage IIb). In patients with stage I, SCC showed significantly higher lymphnode involvement compared with AC (16.5% vs. 9.7% in Ib1, 46.3% vs. 20.1% in Ib2). The incidence of lymphnode involvement did not differ between SCC and AC in patients with stage II (36.4% vs.34.9% in IIa and 39.1% vs.45.5% in IIb). When patients had lymphnode involvement, the outcome of patients with AC showed significantly worse than those with SCC (46.4% vs. 72.3%). The local failure defined as recurrence in stump and pelvis was more frequent in patients with AC compared with SCC (24.6% vs.10.7%). Conclusions: Although the incidence of lymphnode involvement did not differ between AC and SCC, AC patients with lymphnode involvement showed significantly worse outcome. The present study indicates that lower sensitivity to radiotherapy might be an important cause for the poorer prognosis in AC. No significant financial relationships to disclose.
A double-blind randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin hydrochloride-related palmar-plantar erythrodysesthesia
Authors: Von Gruenigen V. E. , Frasure H. , Fusco N. , Eldermire E. , Eaton S. , Waggoner S. 
Published: August 2020

5594 Background: To compare the efficacy of pyridoxine versus placebo in the prevention of palmar-plantar erythrodysesthesia (PPE) and on quality of life (QOL) in patients treated with pegylated liposomal doxorubicin hydrochloride for ovarian, breast, or endometrial cancer. Methods: All patients received pegylated liposomal doxorubicin hydrochloride 40 mg/m2 IV q 4 weeks over 1 hour every 28 days for a maximum of 6 cycles. Patients received pyridoxine 100 mg (group A) by mouth or placebo (group B) twice daily. Nurses conducted standard PPE education for all patients. Patients with Grade 2 or 3 PPE that persisted despite dose reductions/delays were unblinded, and were given pyridoxine if taking placebo. Patients completed the Functional Assessment of Cancer Therapy (FACT) assessment tool. Analyses were conducted by group and comparisons were also made between patients who experienced grade 2/3 PPE versus grade 0/1. Chi-square or Fisher's exact test were used. Results: Thirty-four patients were enrolled with 18 randomized to group A and 16 to group B. Mean age was 64 years (SD=9.6; range 45–81 years). Five patients (group A, 3; group B, 2) were unevaluable (due to pegylated liposomal doxorubicin hydrochloride reaction during first chemotherapy cycle). Overall 15/29 (52%) patients had incidence of PPE (all grades), with 10/29 (34%) having grade 2/3 events (no grade 4 events observed). In group A, 8/15 (53%) patients had a PPE event and 7/14 (50%) in group B; p=0.857. For grade 2/3 events, there was no difference as 6/15 (40%) occurred in group A and 4/14 (29%) in group B; p=0.70. There were no differences in global or domain QOL scores between those patients with Grade 2/3 PPE versus Grade 0/1. Less than half [4/10 (40%)] of patients with Grade 2/3 PPE reported being bothered by side effects of pegylated liposomal doxorubicin hydrochloride treatment. Conclusions: As administered in this study, pyridoxine did not prevent PPE in patients treated with pegylated liposomal doxorubicin hydrochloride. Quality of life differences were not observed; however, not all patients with PPE reported being bothered by side effects of pegylated liposomal doxorubicin hydrochloride treatment. Pyridoxine is not indicated for prevention of PPE during chemotherapy. [Table: see text] [Table: see text]
Evaluation of the false-negative rate of standardized and quantitative measurement of estrogen receptor (ER) in tissue using AQUA technology
Authors: Gustavson M. D. , Welsh A. , Jones C. , Mayotte J. , Tu J. , Hopkins J. , Rimm D. , Christiansen J. 
Published: August 2020

567 Background: The discovery of an astoundingly high false negative rate for estrogen receptor (ER) testing in Canada has raised questions about the accuracy and reproducibility of ER testing. One solution would be the introduction of a standardized and reproducible diagnostic test that is easily adaptable in the clinical setting. Here, we have tested the AQUA method of quantitative immunofluorescence for the standardized and reproducible quantification of ER protein expression in tissue. Methods: Quantitative Western blotting was used in conjunction with AQUA analysis to create standard curves for assessment of absolute ER protein concentration in tissue (n = 118). We used standard scoring methods and AQUA analysis to quantify ER protein expression in a large cohort of breast cancer samples (n =669). Results: Using a series of standard curves, we determined that the range of the ER AQUA assay is between 100 pg/μg and 1500 pg/μg total protein. ER protein concentration in breast cancer samples showed an expected unimodal distribution for quantitative assessment of ER. Reproducibility studies of AQUA analysis demonstrated significant instrument-to-instrument (laboratory-to-laboratory) reproducibility for 3 instruments across the range of AQUA scores (average %CV = 1.34; R2>0.99; ANOVA p = 0.67). The same cases were then read and classified by 3 pathologists using the Allred scoring system. Although their concordance is similar to that seen in the literature (Kappa = 0.81, 0.88, and 0.89), pathologist concordance rate is lower than for that observed with AQUA analysis (Kappa = 0.95, 0.96, and 0.97). Importantly, 9.0% of cases showed a change of diagnosis (positive/negative) across 3 pathologists whereas only 2.8% of cases changed classification using AQUA analysis. Additionally, misclassified cases occurred across the entire range of Allred scores, but were restricted to a narrow region defined by the cut-point for AQUA scoring. Conclusions: We have demonstrated that AQUA technology can provide for the standardized and reproducible quantification of ER with a 3 fold reduction in misclassification. This approach has the potential to decrease the problem of false negative tests for ER. [Table: see text]
Functional pathways analyses to identify candidate therapeutic targets in triple-negative breast cancer
Authors: Andre F. , Dessen P. , Job B. , Delaloge S. , Pusztai L. , Lazar V. 
Published: August 2020

569 Background: In the present study, we have analyzed dysregulated pathways in triple-negative breast cancers. Methods: Two datasets of cDNA arrays were used to identify differentially expressed genes between triple negative breast cancer and either normal/benign breast tissue or other molecular classes. The first dataset (I) was included 165 samples. The second data set (II) included 148 samples. Pathway analyses (gene set) were done based using BRB array tool and a software developed in house (SBIME). Results: Fifteen and 27 patients presented a triple negative breast cancer in the dataset I and II respectively. Ten and eleven pathways were significantly different between triple negative and other molecular classes in dataset I and II respectively (LS permutation p value<0.01). Six pathways were common between the two datasets (p53, cyclin E, E2F1, p27 phosphorylation, Ran, cycle regulation). We then focused the analyses on differential pathways between triple negative and normal/benign tissue. In the dataset I, targetable pathways were identified (hotelling t-test <10–7) including VEGF signalling pathway, proteasome, Hedgehog and Notch pathway. In addition, an enrichment of histone overexpression was observed in triple negative breast cancer (3% of overexpressed genes, ratio expression >2). In the dataset II, histone (p = 2x10–6), chromosome organization (p = 2x10–4) gene sets were enriched in triple negative breast cancer. We then assessed whether such pathway dysregulations could be linked to genomic aberration enriched in triple negative breast cancer. Using high resolution CGH arrays (Agilent, 4*44K) on 53 triple negative breast cancers, we detected that 31% of triple negative tumors presented a gene gain in 6p21 and 6p22, two regions that contain VEGFA gene (6p21) and a cluster of histones (6p22). Conclusions: Triple negative breast cancers present dysregulation of targetable pathways, including VEGF signaling and chromosome organization. Dysregulation of these two pathways could be related to gene gains in 6p21–22 regions observed in 30% of triple negative breast cancer. No significant financial relationships to disclose.