bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, multicenter phase III trial comparing doxorubicin + cyclophosphamide followed by paclitaxel or doxorubicin + paclitaxel followed by weekly paclitaxel as adjuvant therapy for high-risk breast cancer
Authors: Loesch D. M. , Greco F. , O’Shaughnessy J. , Hainsworth J. D. , Vukelja S. J. , Sandbach J. , Boehm K. A. , Ilegbodu D. , Asmar L. , Robert N. J.
Published: March 2020

517

Background: This study compared the disease-free survival (DFS) obtained with 2 regimens of adjuvant therapy for patients (pts) with high-risk breast cancer Methods: Women PS 0–1 with local, operable, confirmed stage I-III adenocarcinoma were eligible. Pts may have had primary surgery, with no residual tumor. Therapy was as follows:Arm 1 (AC→T) - doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 repeated every 3 weeks for 4 cycles → paclitaxel 175 mg/m2 repeated every 3 weeks for 4 cycles; Arm 2 (AT→T) - doxorubicin 50 mg/m2 plus paclitaxel 200 mg/m2 repeated every 3 weeks for 4 cycles → paclitaxel 80 mg/m2 weekly ×12. Results: 1,830 pts were enrolled and treated; n=915 Arm 1 (AC→T) and n=915 Arm 2 (AT→T). Pts were: PS=0 (70%/Arm), ER+/PR+ (54% and 50%, Arms 1 and 2 respectively), ER-/PR- (35% and 34%) with 0 positive nodes (N+) (28% and 27%), 1–3 (N+) (44% and 46%), 4–9 (N+) (21% and 18%) and 10+ (N+) (7% and 8.5%). Most were postmenopausal (57%/Arm); median age was 52 years/Arm. To date 1,655 pts (90%) are alive. 5-year DFS was 80% vs 81% for Arms 1 and 2 Overall 5-year survival was 86% vs 89%, in Arms 1 and 2. Cause of death was recurrence for 76 pts in Arm 1 and 56 pts in Arm 2. The main reasons for pts being taken off study treatment were toxicity (85 pts Arm 1 vs 128 pts Arm 2), recurrence (79 pts Arm 1 vs 52 pts Arm 2), and consent withdrawal (18 pts Arm 1 vs 30 pts Arm 2). The most frequent toxicities were neutropenia, leukopenia, neuropathy, febrile neutropenia, nausea, vomiting, arthralgia, and myalgia. GI toxicities were more frequent in Arm 1. Alopecia occurred in both Arms (77%). Conclusions: At 5-years, the AT→T produced significantly better OS (p=0.054) and improved DFS (p=0.19). Clinically important toxicities were more frequent with AC→T. Given this, AT→T in the adjuvant treatment of breast cancer is well tolerated and warranted in place of AC→T in these pts. Research support provided by Bristol-Myers Squibb (Princeton, NJ).

No significant financial relationships to disclose.
Comparison of survival rates in carcinoma in situ of the breast treated with total mastectomy to breast-conserving surgery and radiotherapy
Authors: Ibrahim M. N. , Abdullah Z. , Healy L. , Murphy C. , Yousif I. Y. , Martin M. J.
Published: March 2020

519

Background: Carcinoma in situ (CIS) of the breast is a precancerous lesion with the potential to progress to invasive cancer. In 2003, CIS accounted for 19% of all newly diagnosed invasive and non-invasive breast lesions combined in the United States. Current treatment options are mastectomy ± tamoxifen, and breast-conserving surgery with radiotherapy ± tamoxifen. As there are no randomized comparisons of these 2 treatments, data from the Surveillance Epidemiology and End Results (SEER) database was used to compare their survival rates. Methods: 88,285 patients were identified with CIS from 1988 - 2003. Of these, 27,728 patients were treated with a total mastectomy, and 25,240 patients received breast-conserving surgery with radiotherapy. Kaplan-Meier survival analyses and Cox proportional hazards regression were used to compare overall survival and disease specific survival at 5 and 10 years. Results: Kaplan-Meier analyses demonstrated 5 year overall survival rates for total mastectomy vs. breast conserving surgery with radiotherapy of 95.46% vs. 97.59% respectively (Log-rank P < 0.0001). The 5 year rates for disease specific survival were 99.16% vs. 99.72% respectively (Log-rank P < 0.0001). At 10 years the overall survival rates had fallen to 91.96% vs. 96.09% respectively (Log-rank P < 0.0001). The 10 year disease specific survival rates were 98.61% vs. 99.50% respectively (Log-rank P < 0.0001). Cox proportional hazards regression demonstrated a relative risk of 0.847 (95% confidence interval (CI) 0.790 - 0.907) and 1.110 (95% CI 0.931 - 1.324) for 5 year overall survival and disease specific survival respectively, when total mastectomy was compared with breast conserving surgery and radiotherapy. At 10 years, the relative risks were 0.865 (95% CI 0.820 - 0.913) and 1.035 (95% CI 0.900 - 1.190) for overall survival and disease specific survival respectively. Conclusions: Overall, when looking at disease-specific survival rates by multi-variate analysis, there does not appear to be a significant difference between total mastectomy and breast-conserving surgery with radiotherapy in the treatment of CIS.

No significant financial relationships to disclose.
Long-term outcomes after invasive breast tumor recurrence (IBTR) in women with DCIS in NSABP B-17 and B-24
Authors: Wapnir I. , Dignam J. , Julian T. B. , Land S. , Mamounas E. P. , Anderson S. , Fourchotte V. , Costantino J. , Wolmark N.
Published: March 2020

520

Background: DCIS patients treated with lumpectomy have a very favorable outcome but are at risk for IBTR. Local control is improved by radiotherapy (RT) and adjuvant tamoxifen (TAM). Local failures, specifically invasive IBTRs (I-IBTR), may impact on long-term outcome. We present long-term outcome results from a cohort of DCIS patients from two NSABP randomized trials. Patients and Methods: A total of 2,615 women with primary DCIS from NSABP B-17 and B-24 (randomized from 1985 to 1994) were included. Median follow-up was > 12 yrs. In B-17 treatment was lumpectomy (LO, 403) or lumpectomy with whole breast irradiation (LRT, 410). In B-24 patients received LRT (901) or LRT plus TAM [901]. Hazard ratio and cumulative incidence of IBTR were examined by treatment. Mortality hazard was evaluated in relation to prior IBTR. Results: IBTR was a first failure in 465 patients (243 invasive, 222 noninvasive). The 12 year cumulative incidence of all IBTRs was 32.9% for LO, 15.8% LRT, and 12.5% LRT+TAM. RT significantly reduced I-IBTR (LRT/LO hazard ratio (HR) = 0.39; 95% confidence interval (CI) =0.26 to 0.59). TAM conferred additional benefit on I-IBTR (LRT+TAM/LRT HR=0.68; 95% CI= 0.48 to 0.97). Overall mortality was low. Women with I-IBTR had a two-fold greater mortality risk relative to those without I-IBTR (HR=2.08; 95% CI = 1.46 to 2.98). The effect was greater for LRT patients (HR=3.04; 95% CI= 1.92 to 4.84) than for LO patients (HR=1.17; 95% CI = 0.57 to 2.39). For LRT+TAM patients, the effect was similar to that for LRT patients HR=1.91; 95% CI= 0.76 to 4.78). Conclusions: As in cases of I- IBTR after an invasive index tumor, the occurrence of an I-IBTR with a DCIS index tumor, particularly after RT, confers increased risk for subsequent mortality.

No significant financial relationships to disclose.
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.
Ki67 expression as a predictor for suboptimally debulked patients with advanced epithelial ovarian cancer
Authors: Adams S. F. , Levine D. A. , Zhang L. , Barakat R. , Boyd J. , Gimotty P. , Coukos G.
Published: March 2020

5563

Objective: The death rate from ovarian cancer has not changed significantly in several decades. Additional prognostic biomarkers may allow for more tailored chemotherapy and an improved response rate. Our aim was to clarify the utility of Ki67, a nuclear protein expressed by mitotic cells, as a prognostic marker in cases of advanced epithelial ovarian cancer (EOC). Methods: We conducted a retrospective cohort study of patients undergoing primary surgery for advanced EOC between 1989 and 2003 at one institution. All were diagnosed with serous or poorly differentiated ovarian adenocarcinoma, and received platinum/paclitaxel chemotherapy. Snap-frozen surgical specimens were subjected to immunohistochemical analysis using a monoclonal antibody against human Ki67. Cases were stratified into those wtih high (>25%) or low expression (<25%) of Ki67 based on the percentage of postively-staining tumor cells. Kaplan-Meier curves were used to estimate five-year survival rates, and were compared using a log-rank statistic. Results: 134 cases (106 stage III; 28 stage IV) were analyzed. Average age at diagnosis was 62 (range 26–84 years); average duration of follow-up was 42 months (range 0.7 - 128.8). 61 (45%) patients were optimally debulked. The 5-year survival rates were 24.7% and 41.4% (p=0.0421) for patients with high and low Ki67 expression, respectively. Patients in these two groups did not differ significantly with regard to age, tumor grade, debulking status, histotype, or stage. Sub-group analysis indicated that the differential effect of Ki67 expression existed exclusively among patients who were suboptimally debulked, with a 5-year survival of 16% vs. 39% (p=0.027) for cases with high vs. low Ki67 expression. There was no difference in survival among optimally debulked patients based on Ki67 expression (43% vs. 48%, p=0.890). Conclusion: Ki67 immunostaining provides robust prognostic information for patients with advanced EOC who are incompletely debulked at primary surgery. This biomarker may define subgroups of patients who would be more likely to benefit from cell-cycle dependent chemotherapy regimens, and may guide the development of future therapeutic strategies.

No significant financial relationships to disclose.
Mature results of a phase II study of intraperitoneal topotecan as consolidation therapy in ovarian cancer
Authors: Malpass T. W. , McGonigle K. , Roberston M. , Weiden P. , Muntz H. G.
Published: March 2020

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Background: Previous studies with intraperitoneal (IP) topotecan have shown 20 mg/m2 to be well tolerated. This study evaluated the feasibility, safety, and effectiveness of IP topotecan as consolidation therapy for ovarian cancer. Methods: Patients with stage III/IV ovarian (or primary peritoneal) cancer in clinical complete response after cytoreduction and IV chemotherapy with carboplatin and paclitaxel who had benign findings or minimal persistent disease (<= 1 cm diameter) documented at second-look surgery were eligible. IP topotecan 20 mg/m2 was administered once every 21 days for 4 to 6 cycles. Dose reduction was based on grade 3–4 toxicities. Hematopoietic growth factors were used at the discretion of the treating physician. Results: Twenty patients were enrolled (18 ovarian and 2 peritoneal cancers). Sixteen patients received 4 cycles, 3 patients received 6 cycles, and 1 patient withdrew by personal request after 1 cycle. Of the total 83 cycles, 10 (12%) were delayed due to slow recovery of neutropenia, and 22 (27%) were administered with does reductions due to prior grade 3–4 myelosuppression. Mean delivered dose was 18 mg/m2. Major toxicities included episodes of neutropenia (6 grade 3; 3 grade 4) and thrombocytopenia (7 grade 3; 2 grade 4). Filgrastim was administered to 75% of patients in 51 (61%) cycles, and epoetin alfa was administered to 30% of patients in 20 (24%) cycles. Other adverse events (grade 1 or 2) that occurred in approximately half of patients included nausea and abdominal distension. Median progression-free survival was 24 months from second-look surgery (Kaplan-Meier, 95% CI 14–34 months). Sixteen patients (80%) are alive after median of 42 months from second look surgery (range, 29 to 62 months), with 4.5 year estimated overall survival of 84% (95% CI 68–100%) measured from original diagnosis. Conclusion: Consolidation IP topotecan 20 mg/m2 every 3 weeks for 4–6 cycles is feasible and well tolerated. Progression-free and overall survival in this pilot study compare favorably with results expected for advanced ovarian cancer. Future investigation of IP topotecan is warranted, both as consolidation therapy and salvage therapy for advanced ovarian cancer.

No significant financial relationships to disclose.
Influence of sequencing of chemotherapy and radiotherapy regarding adverse effects of the cytostatic treatment: Results of the ADEBAR trial
Authors: Sommer H. L. , Jueckstock J. K. , Genss E. , Annecke K. , Rack B. , Steinfeld-Birg D. , Harbeck N. , Kiechle-Bahat M. , Janni W. J. , Friese K.
Published: March 2020

559

Background: The ADEBAR-trial was designed as a multicenter randomised phase III study for high risk primary breast cancer (BC) pts., i.e. with more than 3 axillary lymph node metastases. Primary objective of the trial was to evaluate the benefit of a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline- containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). Patients and Methods: The study started in 2001 and was closed in 2005. By this time 200 actively participating sites had recruited a total number of 1,502 patients. One of the stratification issues was the sequencing of chemotherapy and radiotherapy. All patients were required to receive adjuvant radiotherapy. However the timing of irradiation, either in a sandwich setting after the first half of chemotherapy cycles or after completion of the entire cytostatic treatment was at the discretion of the study sites. In a toxicity-analysis in December 2006, the influence of sequencing of chemotherapy and radiotherapy was analyzed in 980 patients. Results: In 223 pts. radiotherapy was performed midtime after the first half of chemotherapy cycles, 757 pts. received radiotherapy only after completing the entire cytostatic treatment and before starting endocrine treatment, if applicable. Hospitalisation occurred in 32.7 % (73 pts.) of the sandwich group and in 27.9% (211 pts.) of the sequential group (p-value = 0.160). Interval prolongation was necessary in 37.7% (84 pts.) versus 31.6% (239 pts.) in the sequential group, (p-value = 0.089). The target dose was reduced in 15.7% (35 pts.) in the sandwich group and in 20.2% (153 pts.) of the sequential group, (p-value = 0.132). SAEs occurred in 29.6% (66 pts.) in the sandwich group versus 23.1% (175 pts.), (p-value = 0.048). Conclusion: No consistent association between treatment toxicity and the timing of chemotherapy and radiotherapy was observed. Because in this high risk patient group, the prevention of systemic relapse is most important, chemotherapy should be completed before the start of radiotherapy.

No significant financial relationships to disclose.
A phase II trial of the use of 4,4’-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone (A-007) topical gel in the treatment of high-grade squamous intraepithelial lesions (HSIL) of the cervix
Authors: Muñoz D. , Cantu D. , Gonzalez A. , Meneses A. , Mohar A. , Astudillo-de la Vega H. , Nguyen B.
Published: March 2020

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Background: The incidence of cervical cancer is highly correlated with cervical high grade squamous intraepithelial lesions (HSIL [CIN2/3]) and human papillomavirus (HPV) infection in men and women. Approximately 70 - 80% of sexually active adolescents and adults will become infected with HPV during their lifetime. In 2003 alone, there were 50 million cases of HPV infections in the United States. Our main objective is to determine the pathological response (complete and partial, based on independent review panel of two patho the uterine cervix of women with HSIL [CIN 2/3]. Materials and Methods: Following colposcopy, pap smear and biopsy confirmation of HSIL (CIN 2/3) and HPV infection status, women are treated with gel applied to the cervix via an intravaginal applicator once daily for 5 consecutive days of a 28-day cycle for 2 cycles. At month 4 post enrollment into the trial, all women undergo the loop electrosurgical excision procedure (LEEP) procedure and repeated virology assessment. Results: 65 patients were enrolled at 2 centers and completed treatment with A-007 and 100% (65/65) were HPV positive (81.5% by Hibrid Capture II for High Risk and 100% PCR positive). All baseline and LEEP pathological specimens will be blinded read by a panel of two independent expert pathologists. A subject will be considered a complete pathological responder (CR) when the patient has regression of HSIL (CIN 2/3) without pathological evidence of HSIL, and a partial pathological responder (PR) when she has regression of HSIL (CIN 2/3) to LSIL (CIN 1). Overall response rate is defined as the percentage of patients with CR and PR. To date, no serious adverse events (SAE) has been reported during treatment in all enrolled patients, only has been reported a moderate local and transitory itching/burning sensation during the first 5–20 minutes after application in 18% (12/65) of the cases. At this moment LEEP procedures are being scheduled for all patients and the pathological response rate as well as the HPV response rate will be available and presented at the conference.

[Table: see text]
Retrospective analysis of two modes of lymphadenectomy (para-aortic + pelvic vs. pelvic alone) with regard to survival in endometrial cancer: A comparative study of two gynecologic units
Authors: Handa Y. , Kato H. , Hareyama H. , Hada K. , Kaneuchi M. , Oikawa M. , Mitamura T. , Aono A. , Saitoh Y. , Okuyama K. , Yamashita K.
Published: March 2020

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Background: Patients with endometrial cancer are at high risk of severe post-operative complications because of obesity, diabetes mellitus, and hypertension. The purpose of this study is, for minimizing surgical injury, to determine whether para-aortic lymph nodes dissection is dispensable. Methods: 295 patients received hysterectomy and lymphadenectomy during 1995 - 2005 in two gynecologic units of hospitals, one of where para-aortic lymph nodes (to the level of renal vein) and pelvic lymph node (PAN+PLN) dissection were routinely performed and the other only pelvic lymph node (PLN) were dissected, were enrolled. Their overall survival was retrospectively compared between these units. Results: Mean lymph node count was 58.9±19.7 in 99 patients with PAN+PLN lymphadenectomy, and 36.8±14.6 in 196 patients with PLN alone. 5-year survival was 93.3% in PAN+PLN cases and 92.9% in PLN, with no significant difference. Cases who died of the disease (DD) were 6.1% in PAN+PLN and 9.2% in PLN (relative risk = 0.660). Distribution in each stage was ignorable between two units; however, specific histology types, such as serous, clear cell, and carcinosarcoma, were highly counted in DD of the PLN unit. 5-year survival of only endometrioid type, excluding specific histology types, was 92.9% in PAN+PLN and 95.1% in PLN, and DD were 6.6% in PAN+PLN and 6.0% in PLN (RR = 1.095). Lymph node metastases were found 13.1% in PAN+PLN and 4.1% in PLN. One case was observed PAN-alone metastsis, where histology was serous type. Conclusions: Overall survival in patients received PAN+PLN and PLN dissection is not significantly different in endometrial cancer. It is supposed that only PLN dissection is sufficient and PAN dissection is omittable especially in endometrioid type, however, PAN+PLN lymphadenectomy might be suggestive to reduce death in specific histology types.

No significant financial relationships to disclose.
Are BRCA1 mutations a predictive factor for anthracycline-based neoadjuvant chemotherapy response in triple-negative breast cancers?
Authors: Petit T. , Wilt M. , Rodier J. , Muller D. , Ghnassia J. , Dufour P. , Fricker J.
Published: March 2020

580

Background: BRCA1 being involved in DNA repair and apoptosis, its mutations may influence response to chemotherapy. In vitro studies demonstrated that loss of BRCA1 function increased sensitivity to platinum compounds and induced resistance to anthracyclines. BRCA1-related breast cancers tend to be ductal carcinomas with high tumor grade, absence of hormonal receptors and no HER2 overexpression, so called triple-negative. We retrospectively analyzed anthracycline-based neoadjuvant chemotherapy efficacy in triple- negative tumors according to BRCA1 status. Methods: 393 breast cancer pts were treated with FEC100 neoadjuvant chemotherapy (FU 500 mg/m2, epirubicine 100 mg/m2, cyclophosphamide 500 mg/m2) between 1/2000 and 12/2006. Out of them, 14% had a triple-negative phenotype (55 pts). Patients with young age at diagnosis or family history of breast cancer were offered genetic testing for BRCA1 and BRCA2 mutations. Twelve of these patients had a BRCA1 deleterious mutation with a triple-negative tumor. Characteristics of these 12 pts at diagnosis were: median age = 38, tumor stage = 7 T2N0, 2 T2N1, 2 T3N0, 1 T3N1. Results: Pathological complete response was defined as absence of invasive tumor in breast and axillary nodes. After 6 cycles of FEC100, 42% of patients with triple-negative tumors (23/55) had a pathological complete response, compared to 17% (2/12) with a BRCA1 mutation. Only one of the 12 BRCA1 patients had an axillary node involvement. Conclusions: In our series, BRCA1 deleterious mutations decreased anthracycline-based chemotherapy efficacy in triple- negative breast cancers. Platinum compounds should be evaluated in these BRCA1-related tumors.

No significant financial relationships to disclose.
The ADEBAR trial: Final toxicity analysis of a phase III study evaluating the role of docetaxel in the adjuvant therapy of breast cancer patients with extensive lymph node involvement
Authors: Janni J. W. , Sommer H. , Rack B. , Augustin D. , Simon W. , Steinfeld D. , Annecke K. , Harbeck N. , Friese K. , Kiechle-Bahat M.
Published: March 2020

585

Background: Taxane based adjuvant chemotherapy has been established as standard treatment in node-positive breast cancer. However, toxicity concerns of combined anthracycline-taxane regimens have compromised its acceptance. We analyzed the toxicity of a sequential anthracycline-taxane chemotherapy compared to a conventional anthracycline regimen. Patients and Methods: ADEBAR was a multicenter phase III trial (n=1,502) to evaluate whether breast cancer (BC) pts with > 3 axillary lymph metastases benefit from a sequential anthracycline-docetaxel regimen (E90C-D: 4 cycles epirubicin [E] 90 mg/m2 plus cyclophosphamide [C] 600 mg/m2 q21 days followed by 4 cycles docetaxel [D] 100mg/m2 q21 days) compared to dose-intensive anthracycline-containing polychemotherapy (FE120C: 6 cycles E 60 mg/m2 d 1+8, 5-FU 500mg/m2 d 1+8 and C 75 mg/m2 d 1–14, q4 weeks). We present the final toxicity analysis. Results: Complete toxicity data were available from 1,338 pts. Treatment was stopped prematurely in 3.7% of the pts in the E90C-D arm and in 8.0% in the FE120C arm due to toxicity (p=0.0009). Antibiotic treatment was given in 10.4% (E90C-D) vs. 19.7% (FE120C), G-CSF support in 39.2% vs 61.4 % and erythropoietin stimulation in 8.7% vs. 20.0%, respectively (p<0.0001). Hematologic and non-hematological grade 3–4 toxicities are summarized in the table . In summary, haematological toxicity (leucopenia, infection thrombocytopenia, anemia) was significantly greater in the FE120C-arm. Skin toxicity, edema and vomiting occurred significantly more often in pts treated with E90C-D. Conclusion: Different toxicity profiles given, overall toxicity of a sequential anthracycline-taxane regimen is not necessarily greater than that of an adequately dosed anthracycline chemotherapy, which needed to be interrupted more frequently due to toxicity.

[Table: see text]

No significant financial relationships to disclose.