bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic resistance and tumor-initiation: Molecular pathways involved in breast cancer stem cell self-renewal
Authors: Chang J. C. , Li X. , Wong H. , Creighton C. , Hilsenbeck S. G. , Osborne C. K. , Rosen J. M. , Lewis M. T. 
Published: March 2020

528 Background: Recent evidence supports the existance of a rare subpopulation of ‘cancer stem cells‘ (CSCs) which is chemoresistant and capable of self-renewal and tumor-initiation, resulting in relapse and metastases. We hypothesized that residual breast tumors after conventional chemotherapy (CTx) are enriched for CSCs bearing CD44+/CD24- markers, and show increased self-renewal as demonstrated by mammosphere (MS) forming assays. Molecular pathways like Notch, Wnt, and the polycomb family that regulate normal mammary self-renewal may be in aberrant in CSCs. Methods: Paired breast cancer biopsies from 35 patients were obtained before and after 12 weeks of neoadjuvant CTx (docetaxel 100 mg/m2 or Adriamycin/Cytoxan 60/600 mg/m2, 4 cycles, q3weeks), digested by collagenase, stained with CD24/CD44/lineage antibodies, and analyzed by flow cytometry. MS assays were performed to measure self-renewal ability. Gene expression, using the Affymetrix U133 GeneChip platform, of cancer cells bearing CD44+/CD24- markers vs. all other sorted cells, and between secondary cancer MS vs. the primary bulk invasive cancers were analyzed. Results: CD44+/CD24- cells increased from a median of 4.8% to 14.8% after CTx (p<0.005). Increased self-renewal was demonstrated by an increase in MS capacity after CTx (p=0.03), with a positive correlation between the number of CD44+/24- cells and MS assays (R=0.8, p<0.05). Common molecular pathways shared by CD44+/CD24- cells and MS show increased expression in normal self-renewal pathways - polycomb family (PCGF5), Notch (MAML2), FOXP1, and BBX. In addition, genes governing alternative splicing were increased, including a non-coding RNA (MALAT1) of unknown function, and RNA splicing factors (SFRS3, SFRS21P, SFRS4). Conclusions: Our results with an increase in cells bearing stem cell markers, and increased MS formation of residual tumors provide the first strong clinical evidence for the existance of therapy-resistant cancer stem cells. Post-transcriptional regulation may play a crucial role in modifying gene function involved in cancer stem cell self-renewal. Clinical trials targeting these newly identified pathways may eradicate residual disease and improved cure rates for many breast cancer patients. [Table: see text]
Body mass index and response to neoadjuvant chemotherapy in breast cancer patients
Authors: Litton J. K. , Gonzalez A. M. , Warneke C. L. , Kau S. , Buzdar A. U. , Bondy M. , Mahabir S. , Hortobagyi G. N. , Brewster A. 
Published: March 2020

531 Background: Obesity in breast cancer patients is associated with increased risk of poor outcome. One possible mechanism is that obesity may affect metabolism of chemotherapeutic agents, influencing tumor response to chemotherapy. To test this hypothesis, we evaluated the relationship between body mass index (BMI, weight kg/height m2) and response to neoadjuvant chemotherapy in women diagnosed with operable breast cancer. Methods: From May 1990 - July 2004, 1169 patients diagnosed with invasive breast cancer at our institution, received neoadjuvant chemotherapy (anthracycline and/or taxane) followed by definitive surgery. Based on BMI, patients were categorized as obese (BMI ≥30), overweight (BMI 25 to <30), normal weight (18.5 to <25) and underweight (BMI <18.5). We used logistic regression to examine associations between BMI and pathologic response to therapy (complete= no invasive carcinoma, and partial) as well as tumor characteristics. Kaplan-Meier survival curves for BMI groups were compared using the log-rank test. Results: Median patient age was 50 (range 23 - 84) years; 30% were obese, 32% overweight, 36% normal weight and 1% underweight. BMI was not significantly associated with pathologic response to neoadjuvant chemotherapy even after adjusting for relevant clinical factors (OR 1.00; 95% CI 0.96–1.03, p = 0.8). Compared to patients not overweight, obese patients had higher odds of having ER negative tumors (OR 1.5; 95% CI 1.1–2.0; p = 0.01) and T3 or T4 lesions (OR 1.7; 95% CI 1.3–2.4, p < 0.001) adjusting for age, race and menopausal status. At a median follow up of 4.1 (range 0.2–14.3) years, obesity was significantly associated with poorer overall survival (p = 0.006) but not progression-free survival. Conclusions: Obese patients presented with more aggressive tumor characteristics and had worse overall survival compared to patients not overweight. However, BMI was not related to lower tumor response to anthracycline and/or taxane based neoadjuvant chemotherapy suggesting a role for other co-morbidities in influencing outcome. Understanding specific components through which overweight and obesity contribute to breast cancer outcome is essential to individualize and improve care of overweight/obese breast cancer patients. No significant financial relationships to disclose.
Estrogen receptor expression and efficacy of docetaxel in early breast cancer: A pooled analysis of 3,490 patients included in two randomized trials
Authors: Andre F. , Broglio K. , Roche H. , Martin M. , Penault-Lorca F. , Hortobagyi G. N. , Berry D. A. , Pusztai L. 
Published: March 2020

537 Background: It has been suggested that estrogen receptor (ER) expression is associated with relative resistance to adjuvant chemotherapy. The efficacy of adjuvant chemotherapy is still matter of controversy in this subset of patients. The aim of the present study was to assess the efficacy of docetaxel according to ER expression in adjuvant treatment trials. Patients and Methods: The efficacy of docetaxel according to ER expression was assessed in a pooled analysis of two randomized studies (BCIRG001 and PACS01) that included overall 3,490 patients with axillary node positive breast cancer. These studies compared either 3 (PACS01) or 6 (BCIRG001) cycles of a docetaxel-containing regimen, to a chemotherapy that did not contain docetaxel. Hazard ratios (HR) for death were determined by a Cox model adjusted for clinical characteristics (age, T size and number of lymph node involved). Interaction between docetaxel efficacy and ER expression was tested. Results: ER status was assessable in 3,329 patients (95%). The median age was 49 years old (range, 23–70). ER was expressed in 2,493 tumors (74%). In patients with assessable ER status (n=3329), docetaxel was associated with a significant reduction in the risk of death (HR=0.69; 95%CI: 0.51–0.92, p=0.01). Docetaxel therapy was associated with a 30% reduction in the risk of death in ER-positive disease (HR=0.70; 95%CI: 0.54–0.91) and a 31% reduction in the risk of death in ER-negative disease (HR=0.69; 95% CI: 0.52–0.94). Test for interaction did not detect any statistically significant difference in the relative effect of docetaxel according to ER status (HR for interaction=1.03; p=0.87). Conclusion: In this pooled analysis of two randomized trials, the relative effect of docetaxel on overall survival in adjuvant setting was not different between ER-positive and ER-negative disease. Docetaxel was associated with a significant risk reduction of death in patients with ER-positive disease. No significant financial relationships to disclose.
Novel functional proteomics approach to defining ovarian cancer molecular heterogeneity
Authors: Carey M. S. , Hennessy B. T. , Gonzalez-Angulo A. M. , Liu W. , Coombes K. R. , Guan Y. , Kuo W. , Smith-McCune K. , Almeida J. , Mills G. B. 
Published: March 2020

5502 Background: A number of clinicopathologic risk factors are used for survival prediction and clinical decision-making in epithelial ovarian cancer (EOC). Information from novel technologies such as gene arrays has not had an impact on patient management. We studied EOC protein signaling profiles to determine if their addition to accepted clinicopathologic factors improves their accuracy in predicting individual patient outcomes. Methods: We applied a novel functional proteomics technology, reverse phase protein array (RPPA), to quantify expression and activation of 42 steroid and kinase signaling pathway proteins in 106 high-grade EOCs from patients with stages 1–4 tumors managed with surgery and platinum-based chemotherapy. Cox regression analysis and a novel committee modeling approach were used to study the impact of functional proteomics on patient outcomes. Results: In a Cox model using only clinical variables, stage and residual disease were significantly related to overall survival. By adding the proteins to the clinical Cox model, two proteins that were significantly associated with overall survival on univariate analysis (phosphorylated-MAPK (p-MAPK; log rank p = 0.0047) and progesterone receptor (PR; log rank p = 0.027)) remained significant at the alpha=0.10 level (z-test p-values 0.074 and 0.034, respectively, when treated as binary variables according to martingale residual plots); as a result, these two proteins added to the predictive accuracy of the clinical survival model. However, using the novel committee modeling approach in test and validation EOC sets, a closest neighbor metric was applied to successfully define distinct proteins groups, each composed of nine proteins, that are predictive of specific survival times in patients with EOC. This granular approach to modeling is particularly suited to defining the molecular heterogeneity of EOC. Conclusions: EOC is a complex process with significant individual variability. Using novel approaches to functional proteomic study and statistical modeling, our striking finding is that distinct combinations of steroid and kinase signaling proteins are predictive markers of specific survival times in EOC. No significant financial relationships to disclose.
A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991)
Authors: Hogberg T. , Rosenberg P. , Kristensen G. , de Oliveira C. F. , de Pont Christensen R. , Sorbe B. , Lundgren C. , Salmi T. , Andersson H. , Reed N. S. 
Published: March 2020

5503 Background: Adjuvant therapy for early stage high-risk endometrial cancer remains controversial. Methods: Patients with surgical stage I, II, IIIA (positive peritoneal fluid cytology only), or IIIC (positive pelvic lymph nodes only) were eligible if they, according to departmental guidelines, had a sufficiently high risk for micrometastatic disease to qualify for adjuvant therapy. Most patients had two or more of the risk factors: grade 3, deep myometrial invasion, or DNA non-diploidy, while some patients had only one of these. Patients with serous, clear cell, or anaplastic carcinomas were eligible regardless of risk factors. Patients with para-aortic metastases were not eligible. Lymph node exploration at staging surgery was optional. Pelvic RT ± vaginal brachytherapy was given to a dose =44 Gy. CT was given before or after RT. Before August 2004 CT consisted of four courses of cisplatin =50 mg/m2 + doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 (AP). Thereafter several CT regimens were allowed, of which AP, paclitaxel 175 mg/m2 + epirubicin 60 mg/m2 + carboplatin AUC 5, and paclitaxel 175 mg/m2 + carboplatin AUC 5–6 were used. Progression-free survival (PFS) was the primary end-point. The study was terminated before the aimed goal of 400 patients because of slow recruitment. We decided to make an early analysis since new studies on endometrial cancer are presently discussed. Results: 372 patients were entered between May 1996 and Oct 2006. Of 367 evaluable patients 190 were randomized to RT and 177 to RT+CT. Risk factors were well balanced between the randomization arms. The median follow-up time was 3.5 years. The hazard ratio for PFS was 0.58 in favor of RT+CT (95 % confidence interval (CI) 0.34 - 0.99; p=0.046). This translates to an estimated 7 % absolute difference in 5-year PFS from 75 % (95 % CI 67 % - 82 %) to 82 % (95 % CI 73 % - 88 %). Conclusion: RT+CT was better than RT alone. Next question is if RT+CT is better than CT alone. No significant financial relationships to disclose.
Overexpression of BRCA1-IRIS protein in familial ovarian cancers with no BRCA1 or BRCA2 germline mutation
Authors: Boustany R. , Pautier P. , Rey A. , Delaloge S. , Chompret A. , Bressac-De Paillerets B. , ElShamy W. M. , Livingston D. M. , Feunteun J. , Spatz A. 
Published: March 2020

5513 Background: Germline mutations of the BRCA1 and BRCA2 genes account for the majority of hereditary breast-ovarian carcinomas. Nevertheless, in some patients with family history of ovarian cancers, neither point mutations nor genomic alterations are identified. Recently, IRIS gene, an open reading frame that extended from codon 1 of BRCA1 to a termination point in intron 11, has been identified. The encoded protein has been reported to play a role in controlling the replication origins firing (ROF) pathway. The study presented here aims at characterizing whether ROF-related proteins are differentially expressed among familial ovarian cancers associated with a germline BRCA1 or 2 mutation, familial ovarian cancers with wild-type BRCA1/2 genes, and sporadic ovarian cancers. Methods: Tumor samples from 72 patients with ovarian cancer and screened for BRCA1 and BRCA2 mutation because of family history of breast/ovarian cancer were collected. These cases were matched with 134 sporadic ovarian cancers (controls) according to age, year of diagnosis, tumor stage, histological subtype, and grade. The cases distributed among 26 BRCA1-linked (BRCA1*) tumors, 9 BRCA2-linked (BRCA2*) tumors and 37 with no identified mutation (BRCA1wt/BRCA2wt). Tissue micro-arrays were prepared from the paraffin blocks. P53, MCM3, MCM4, Geminin, PTTG and BRCA1-IRIS immuno-expression were scored with no information on the sample group as follows: the final score was the product of the positive cells percentage by the staining intensity, the final result being used as a continuous variable. Differences between cases and controls were tested by a Wilcoxon test for paired samples. Results: IRIS expression was significantly higher in familial cancers than in controls (P=0.002). When BRCA1/2 genes status was taken into account, differences remained significant when BRCA1wt/BRCA2wt tumors (P=0.04), but not when BRCA1* tumors were compared with controls. However, the latter showed significant higher expression of Geminin than controls (P=0.04). Conclusions: BRCA-1 IRIS protein is overaccumulated in ovarian cancers developed by patients with family history. Our results suggest IRIS may play a role in the development of ovarian cancers and could be related with an ovarian susceptibility. No significant financial relationships to disclose.
Preliminary safety and efficacy results of a phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube
Authors: Herzog T. J. , Spirtos N. M. , Hines J. F. , Braly P. S. , Bell M. , Secord A. A. , Rose P. , Monk B. J. , Soltes-Rak E. , Childs B. H. 
Published: March 2020

5518 Background: Objectives: Determine safety and estimate efficacy of a novel taxane/platinum chemotherapy (CTX) doublet in conjunction with bevacizumab, as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube (FT), after initial debulking surgery. Methods: Treatment: 6 cycles of oxaliplatin (O) (85 mg/m2), docetaxel (D) (75 mg/m2) and bevacizumab (B) (15 mg/kg) Q3W, followed by maintenance B (15 mg/kg Q3W) to complete one year of therapy. Pts were treated until disease progression, unacceptable toxicity, prolonged treatment delay, death, or refusal to continue on study. The primary efficacy endpoint is PFS at 12 months. Results: As of 30 Nov 06, 59 pts (median age 58) were enrolled. Primary sites of disease included 47 ovary, 7 peritoneum, 4 FT. Tumors were mostly poorly differentiated (70%) with a serous adenocarcinoma initial pathology type (81%). Most pts were stage IIIC (40) or IV (17). 64% of pts. were optimally debulked. GOG PS was 0–1 in 56 pts. 58 pts were treated with at least one cycle of CTX. 22 pts. completed six cycles of CTX + B; 14 of these have begun B maintenance Rx. Safety data in available on a total of 283 patient-cycles. Of the 57 pts. with adverse event (AE) data available, 31 (54%) reported at least one grade 3–4 AE, 9 (16%) at least one serious AE (SAE), 54 at least one AE related to CTX (O or D), and 45 reported at least one AE related to B. There have been 8 SAEs related to CTX (O or D): febrile neutropenia (FN) (2), chest pain (1), dehydration (1), lymphopenia (1), neutropenia (1), peripheral sensory neuropathy (PSN) (1), palpitations (1). There have been 7 SAEs related to B: chest pain, colonic fistula, dehydration, FN, palpitations, PSN, vertigo (1 each). There were no B-associated colonic perforations. Of the 59 subjects, 31 (53%) had measurable disease at baseline. One of 31 patients has confirmed progression of disease. Conclusions: This preliminary data supports feasibility of this novel regimen, with an acceptable safety profile. As of December 2006, 75 patients have been enrolled. Updated safety and preliminary efficacy (RR) data will be presented. No significant financial relationships to disclose.
Prognostic significance of positive lymph nodes in carcinoma of the cervix following radical hysterectomy
Authors: Macdonald O. K. , Lee C. M. , Chen J. , Dodson M. , Gaffney D. K. 
Published: March 2020

5538 Background: Lymph node (LN) metastases portend a poor outcome in women with carcinoma of the uterine cervix, but little data quantitatively evaluate nodal metastasis in relation to prognosis. We queried a large population database to analyze the number of positive LN in relation to survival following radical hysterectomy and lymphadenectomy. Methods: Data were collected from the Surveillance, Epidemiology, and End Results (SEER) Program on women who had primary surgery for the years 1988–2003 (n = 4,559). Analyses using the chi-square test and Cox proportional hazards regression were performed. Exploratory analysis revealed equivalent statistical outcomes in each group for 0 (n = 3,715), 1–2 (n = 552), 3–9 (n = 261), and ≥10 (n = 31) positive LNs, respectively. Results: The median number of LNs removed per patient has significantly declined in recent years (median = 21 for 1988–1998, median = 18 1998–2003, p=.003). The 5-year rates of cause specific (CSS) and overall survival (OS) were 94% and 91%, 76% and 69%, 62% and 58%, and 41% and 35% for 0, 1–2, 3–9 and ≥10 positive LNs, respectively. Favorable stage and grade predicted for survival on multivariate analysis. Adenocarcinoma histology predicted significantly inferior CSS (p=.007) and OS (p=.01) compared to squamous histology in women with positive LNs, but predicted improved OS (p=.004) in women with LN negative disease. An increasing number of LNs removed significantly benefited OS (p=.001). The strongest predictors for both CSS and OS were ≥10 positive LN (HR 1.8 CI 1.2–2.7, p<.0001) a positive LN ratio >25% (HR 1.8 CI 1.5–2.2, p<.0001) and paraaortic LN metastasis (HR 2.1 CI 1.6–2.8, p<.0001). Conclusions: The extent of lympadenectomy has declined since 1988 within the SEER. LN positive disease in carcinoma of the cervix portends a prognosis that is inversely proportional to the number of involved nodes. Adenocarcinoma histology predicted for a more aggressive or benign phenotype depending on LN status. A positive LN ratio >25% demonstrated diminished survival suggesting that the quantitative LN burden is predictive of prognosis. Nodal involvement of the paraaortic region remains a strong indicator of mortality. No significant financial relationships to disclose.
International comparison of the cost-effectiveness of 5 years letrozole or anastrozole compared to 5 years tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: Belgium, Canada, UK, and US analyses
Authors: Kaura S. , Karnon J. , di Trapani F. 
Published: March 2020

556 Background: The BIG1–98 and ATAC trials have proven the effectiveness of 5 years letrozole (LET) and anastrozole (ANA), respectively, compared to 5 years tamoxifen (TAM) for the treatment of postmenopausal women with hormone receptor positive (HR+) early stage breast cancer. This analysis uses similar assumptions to those used in the NICE appraisal in the UK, and country specific input data to estimate the cost-effectiveness of LET vs TAM and ANA vs. TAM from the Belgian, Canadian, UK, and US health care perspective (8 analyses). Methods: The same Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained (ICQ) across the 8 analyses in postmenopausal women with HR+ early stage breast cancer. Model events and assumptions were based on the analysis undertaken by the NICE appraisal team in the UK. Probabilities of breast cancer events (contralateral; locoregional; and metastases) were based on the latest early breast cancer (Lancet) overview. Country-specific cost, utility, and adverse event parameter values were informed by relevant population-based studies. LET and ANA effects were informed by published results of the BIG 1–98 and ATAC trials, which were assumed to cease after therapy discontinuation (other than fracture risk that continued for 5 further years). Costs and QALYs were estimated over the remaining lifetime of a cohort of HR+ women aged 60 yrs, discounted at 3.5% annually. Conclusion: Compared to TAM, adjuvant treatment of postmenopausal HR+ women with LET or ANA for 5 years is a cost-effective use of resources in all of the countries included in this analysis. Based on the model assumptions used by the NICE appraisal team in the UK, the mean results indicate that LET is more cost-effective than ANA, though the confidence intervals are wide. [Table: see text] No significant financial relationships to disclose.
A phase II, open-label study of ispinesib (SB-715992) in patients with platinum/taxane refractory or resistant relapsed ovarian cancer
Authors: Shahin M. S. , Braly P. , Rose P. , Malpass T. , Bailey H. , Alvarez R. D. , Hodge J. , Bowen C. , Buller R. 
Published: March 2020

5562 Background: Kinesin spindle protein (KSP) is required for mitotic spindle bipolarity and cell cycle progression. Ispinesib (ISP), a selective KSP inhibitor, blocks assembly of the mitotic spindle leading to cell cycle arrest and cell death. Methods: This was a phase II study to determine the effectiveness of ISP in patients (pts) with platinum/taxane resistant or refractory ovarian cancer. Pts with progression during, or recurrence < 6 months after prior platinum/taxane therapy, ECOG status 0–2, and CA-125 > 40 U/ml were eligible. ISP was given as a 1 hr IV infusion of 18 mg/m2 Q 21 days. A 2-stage Green-Dahlberg design was employed. In Stage I, 20 evaluable pts were enrolled. If there were no CA-125 responses (Rustin criteria), the study was to be stopped. If > 1 CA-125 responses were seen, 15 more pts were to be enrolled in Stage 2. Overall response was defined by pts who achieved both CA-125 and RECIST criteria. Results: 22 pts with carboplatin/taxane resistant (9) or refractory disease (13) were enrolled: median age = 63 (43–80); 21 were Caucasian; median no. of cycles = 2 (1 - >16). All pts were evaluable for CA-125 assessment. The best CA-125 response was SD in 10 pts (45%); 12 pts had PD (55%). The best radiographic response was a confirmed PR lasting > 30 weeks in one pt who also met CA-125 progression criteria (5%); 5 pts (26%) had SD; and 13 pts (68%) had PD. The most common AEs, in decreasing order, were neutropenia, fatigue, anemia, leukopenia, thrombocytopenia, diarrhea, nausea, vomiting, and decreased appetite. The most frequent Gr 3/4 AE was neutropenia. Conclusions: This study was terminated after Stage I as the CA-125 response criterion to progress to Stage II was not met. One confirmed radiographic partial response was observed. ISP was well tolerated with an acceptable safety profile. No significant financial relationships to disclose.