bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration of topoisomerase II-alpha gene in human breast cancer and its association with responsiveness to anthracycline- based chemotherapy
Authors: Press M. F. , Sauter G. , Buyse M. , Bernstein L. , Eiermann W. , Pienkowski T. , Bee V. , Taupin H. , Seelig S. , Slamon D. J.
Published: March 2020

524

Background: Topoisomerase II-alpha (TOP2A) gene amplification, and not HER2 amplification, may be the predictive marker for responsiveness to anthracycline chemotherapy. Methods: To address this issue we performed a test set-validation set series of analyses. Amplification of TOP2A and HER2 was evaluated by fluorescence in situ hybridization (FISH) in patients with metastatic breast cancer who participated in a randomized trial (H0648g, n = 469) of anthracycline-based chemotherapy with or without trastuzumab. This group represented the test set. To validate our observations in the H0648g test set we analyzed breast cancers from two other, large, randomized clinical studies of anthracycline-based chemotherapy; one with HER-2 amplification and trastuzumab-based therapy (BCIRG006, n = 3,222) and one without HER-2 amplification and combination-based chemotherapy (BCIRG005, n = 3,298), comparing TOP2A status with clinical outcome. Both of the latter trials were adjuvant trials. Results: In the H0648g test set patients whose breast cancers had TOP2A gene co- amplification and who were treated with doxorubicin, cyclophosphamide (AC) and trastuzumab had a longer progression-free survival compared to those who were treated with AC alone (p = 0.03). Patients treated solely with AC, whose breast cancers had TOP2A gene co-amplification had a statistically significant improvement in duration of survival compared to those without TOP2A gene amplification (p = 0.004). Among all women entered in the HER2-positive BCIRG 006 clinical trial, as well as among women who were treated with anthracycline-containing chemotherapy alone, women whose breast cancers showed TOP2A gene co-amplification had a significantly longer disease-free (p <0.001), recurrence-free (p <0.001) and overall survival (p = 0.01) compared to women whose breast cancers lacked TOP2A amplification. Unexpectedly, the added beneficial effect of trastuzumab was not seen among TOP2A co-amplified breast cancer patients in the larger BCIRG006 trial. Conclusions: In patients treated with chemotherapy alone the findings demonstrate that TOP2A gene co-amplification is a useful predictive marker of responsiveness to anthracycline-containing chemotherapy.

No significant financial relationships to disclose.
Abstract Submission
Authors: Goldstein L. J. , Gray R. , Childs B. H. , Watson D. , Rowley S. G. , Shak S. , Badve S. , Davidson N. E. , Sledge G. W. , Sparano J. A.
Published: March 2020

526

Background: Evidence suggests modern chemotherapy (CT) regimens are only marginally more effective in HR-pos breast cancer (Berry et al. JAMA 2006: 295: 1658). Genomic classifiers may be useful for selection of high-risk subjects for more aggressive CHT. Methods: A case-cohort sample of 776 patients enrolled on E2197 who did (N=179) or did not have a recurrence after CT (if HR-neg) or CHT (if HR-pos) and had available tissue were evaluated for Oncotype DX™ Recurrence Score (RS). E2197 included 2885 evaluable patients with 0–3 positive nodes treated with four 3-week cycles of doxorubicin (60 mg/m2) plus cyclophosphamide 600 mg/m2 (AC) or docetaxel 60 mg/m2 (AT) and hormonal therapy (if HR-pos). Median follow-up was 76 months. Results: There was no difference in DFS between treatment arms. In multivariate analysis, RS was a significant predictor of recurrence in HR-pos disease (p=0.0007, recurrence risk 21% lower for each 10 point drop in RS, 95% confidence intervals 9% to 31%). Recurrence risk was significantly elevated for an intermediate RS 18–30 (n=138, hazard ratio [HR] 2.96 [p=0.0002]) or a high RS ≥ 31 (n=108, HR 4.00, p=0.0001) compared with low RS < 18(n=196), but not for high compared with intermediate RS (HR 1.34, [p=0.32]); results were similar if only HER2-neg disease was included. The 5-year relapse free interval(RFI), breast cancer free survival (BCFS), disease-free survival (DFS), and overall survival (OS) for patients with HR-pos, HER2-neg disease are shown below (%); patients with both node-neg or node-pos breast cancers whose RS was < 18 had excellent outcomes. Conclusions: Oncotype DX™ RS identifies individuals with HR-pos, HER2-neg breast cancer with 0–3 positive axillary lymph nodes at 3–4-fold increased risk of relapse despite standard CHT, and may serve as a means to distinguish between those who do well with standard CHT (RS <18) from those who may be suitable candidates for clinical trials evaluating alternative CT regimens or other strategies (RS ≥ 18).

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The impact of hormone receptor status on pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy with or without trastuzumab
Authors: Peintinger F. , Buzdar A. , Kuerer H. , Gonzalez-Angulo A. , Hatzis C. , Pusztai L. , Esteva F. , Green M. , Hortobagyi G. , Symmans W.
Published: March 2020

533

Background: The aim of this study was to compare the extent of pathologic response in HER2-positive patients treated with standard neoadjuvant chemotherapy with or without trastuzumab according to hormone receptor (HR) status. Methods: The study included 199 patients with HER2-positive disease treated in clinical trials of neoadjuvant chemotherapy. Eighty-nine patients treated with 3- weekly paclitaxel and concurrent trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) were compared with 110 patients treated with weekly or 3-weekly paclitaxel followed by FEC or FAC. Residual cancer burden (RCB), a measurement of residual disease (RD) from pathologic review of the primary tumor and lymph nodes, was classified as pathologic complete response (pCR), RCB-I (near-pCR, minimal RD), RCB-II (moderate RD), or RCB-III (extensive RD). RCB was compared between treatment groups according to HR status. Results: In HR-negative patients, similar pCR rates were achieved with weekly T/FAC as with 3-weekly T/FEC and trastuzumab (61% and 65%, respectively). However, in HR-positive patients, higher pCR rates were achieved with 3-weekly T/FEC and trastuzumab (47%) than with the weekly T/FAC (25%; p=0.04) or 3-weekly T/FAC (19%; p=0.01) ( Table 1 ). Near pCR (RCB-I) was slightly higher in HR-positive (26%) than in HR-negative patients treated with 3-weekly T/FEC and trastuzumab (11%; p=0.07). Conclusions: Patients with HR- negative/HER2-positive breast cancer had similar pathologic response rates from addition of trastuzumab to 3-weekly T/FEC or from weekly T/FAC chemotherapy. Patients with HR-positive/HER2-positive breast cancer obtained significant benefit from addition of trastuzumab to 3- weekly T/FEC, compared to 3-weekly T/FAC or weekly T/FAC. The combination of weekly T/FEC with trastuzumab as neoadjuvant chemotherapy should be evaluated.

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Clinical validation of in vitro drug sensitivity microarray data: Regimen-specific signatures predict pathological complete response to neo-adjuvant chemotherapy for breast cancer in a randomized trial (EORTC 10994/BIG 00–01)
Authors: Bonnefoi H. R. , Potti A. , Piccart M. , Mauriac L. , Tubiana-Hulin M. , Cameron D. , Bergh J. , Delorenzi M. , Nevins J. R. , Iggo R.
Published: March 2020

544

Background: We previously described gene expression signatures that predict sensitivity to common chemotherapeutic agents and published promising results of their applicability in patients (Nature Med 2006). The goal of this study was to confirm their validity in a larger series of breast cancer patients with hormone-receptor negative (HR negative) since these tumours are more sensitive to chemotherapy. We used pathological complete response as a surrogate for chemosensitivity. We analyzed samples from a subset of patients included in a recently completed large neoadjuvant phase III trial. The trial compares a non-taxane regimen (fluorouracil + epirubicin + cyclophosphamide × 6; FEC arm) with a taxane regimen (docetaxel × 3 then epirubicin + docetaxel × 3; T->ET arm). Methods: RNA prepared from frozen samples obtained at diagnosis were hybridized to Affymetrix arrays. In vitro single agent signatures generated using a metagene approach were combined to obtain a FEC and a T->ET regimen-specific signatures. Predictions were blinded to patient outcome. With both signatures we calculated the receiver operating curve, its AUC, and the cut-point with maximal Youden index- accuracy, positive predictive value (PPV), sensitivity (Sens), negative predictive value (NPV) and specificity (Spec). Results: Samples from 124 patients (55 pCR) with HR negative tumours underwent a successful gene-expression array: 65 patients were treated in FEC arm and 59 patients in T->ET arm. The results are summarized below. Conclusions: We have validated the approach of using regimen-specific genomic signatures developed in vitro, in the context of a multicenter randomized trial. These results support the activation of a prospective trial comparing the conventional random choice of chemotherapy versus a specific array based approach.

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A meta-analysis of taxanes in adjuvant chemotherapy (ACT) of early breast cancer (EBC)
Authors: Nowak A. K. , Ferguson T. , Wilcken N. R. , Ghersi D.
Published: March 2020

545

Background: Taxanes (docetaxel and paclitaxel) are highly active against breast cancer. Recent trials have examined taxanes as ACT for EBC. The objective of this meta-analysis is to compare taxane containing ACT regimens with ACT not containing a taxane in women with operable EBC. Methods: Eligible studies were properly randomized controlled trials in women with operable EBC receiving ACT (neoadjuvant CT was excluded) that compared taxane containing ACT regimens to ACT without a taxane. Studies were identified by a specifically designed search performed of the Cochrane Breast Cancer Group specialized register (to January 2007), Medline (to November 2006), and relevant conference proceedings (to November 2006). The primary outcome measure was overall survival (OS); secondary outcome measures included disease free survival (DFS) and toxicity. Two reviewers independently assessed eligibility, quality, and time-to-event (TTE) outcomes. Hazard ratios were derived for TTE outcomes where possible, and a fixed effect model was used for meta-analysis. Results: 20 studies were identified, 11 (4 abstracts; 7 full publications) with sufficient data published for inclusion (10 for OS, 11 for DFS). The average median follow-up was 54.6 months. All studies fulfilled quality criteria (allocation concealment, outcome measures, balance between arms, follow-up and intention to treat analysis) adequately or well. Amongst 17056 women with 2397 deaths, the HR for OS was 0.81, (95%CI=0.75–0.88, p<0.00001) favoring taxane-containing ACT. 19943 women were included in analysis of DFS with a HR=0.81 (95%CI=0.75- 0.86, p<0.00001) favoring taxane-containing ACT. There was no statistically significant heterogeneity for either OS or DFS. The effects were consistent in studies of node positive or node negative/positive patients, and with the same or longer duration of ACT in the taxane arm. Further analyses of taxane type (docetaxel or paclitaxel), sequential or concurrent taxane-anthracycline, and toxicity will be presented. Conclusions: This is the first meta-analysis quantifying the statistically significant OS and DFS benefit for the use of taxanes as ACT in operable EBC. Additional relevant studies remain unreported. Ongoing studies will define the optimal use of taxanes in EBC.

No significant financial relationships to disclose.
Tamoxifen (T) compared to placebo (P), after adjuvant chemotherapy (CT), in premenopausal women with early breast cancer (EBC): Interim results of NCIC-CTG MA.12
Authors: Bramwell V. H. , Pritchard K. I. , Tu D. , Tonkin K. , Vachhrajani H. , Robert J. , Arnold A. , Vandenberg T. , Graham B. , Shepherd L.
Published: March 2020

547

Background: In the early 1990’s, the role of adjuvant T in premenopausal women with EBC had not been clearly established. The efficacy of adjuvant T in hormone receptor (H) negative EBC was unclear. Methods: Eligible premenopausal women with node (N) +ve/high risk N -ve EBC, any H status, post surgery, received standard adjuvant CT (AC ×4, CMF ×6, CEF x6) then were randomized to T (20 mg/day) or P for 5 yrs. Overall survival (OS), disease-free survival (DFS) and toxicity/compliance were evaluated. Original sample size was 800 pts but based on slow accrual was reduced to 660. Mortality rate is lower than anticipated, and Data Safety Monitoring Committee approved reporting results after second interim analysis (152 deaths). Results: 1993–2000, 672 women randomized, median follow-up 8.4 yrs. For T vs P, 5 yr OS 87% vs 82% [Hazard Ratio HR 0.81 (95% CI 0.58–1.12), p = 0.19] and 5 yr DFS 78% vs 71% [HR 0.79 (95% CI 0.61–1.03), p = 0.09]. HR for OS (0.87 vs 0.78, p = 0.71) and DFS (0.79 vs 0.77, p = 0.87) were not significantly different for H +ve and H -ve tumors respectively. Compliance with T/P was suboptimal, 29% women stopping treatment within 2 yrs, and only 53% completing 5 yrs. Conclusions: Current results show only a trend towards improved DFS for premenopausal women with EBC who receive T after adjuvant CT. Other studies of similar design have shown improved DFS, but not OS, and meta-analysis may be more informative. Issues affecting results (slow accrual, improved outcomes for EBC, poor compliance, additional therapies) will be discussed.

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HER2 expression and efficacy of preoperative paclitaxel and 5-fluorouracil, cyclophosphamide, doxorubicin chemotherapy in breast cancer
Authors: Pusztai L. , Andre F. , Mazouni C. , Liedtke C. , Kau S. , Frye D. , Green M. , Gonzalez-Angulo A. M. , Symmans W. F. , Hortobagyi G. N.
Published: March 2020

548

Purpose: We examined the correlation between HER2 expression and pathologic complete response (pCR) to paclitaxel/FAC (T/FAC) preoperative chemotherapy in stage II-III breast cancer. Patients and Methods: Retrospective analysis of data including 534 patients treated with preoperative T/FAC was performed. Gene expression results were available from a subset of 132 patients and were used to examine the co-expression of HER2 and topoisomerase II a (TOP2A) and microtubule associated protein tau (MAP-Tau). Results: Of the 534 patients, 105 (20%) had HER2 overexpressing (HER2+) breast cancer. The pCR rates were 33% and 15% for patients with HER2+ and HER2- tumors (P<0.001). The 5-year relapse-free survival rates were 94% and 70% in HER2+ tumors with and without pCR (P=0.009). In multivariate analysis ER-negative status (OR 3.1, 95% CI 1.7–5.5, P < 0.001), high nuclear grade (OR 6.7, 95% CI 3.1–14.2, P < 0.001), weekly paclitaxel regimen (OR 2.6, 95% CI 1.5–4.5, P <0.001), and HER2 overexpression (OR 2.4, 95% CI 1.3–4.2, P = 0.003) were significant predictors of pCR. Among ER- cancers, the pCR rates were 50% (95%CI: 36–64%) in HER2+ (n=24/48) and 30% (95%CI: 23–37%) in HER2- disease (n=48/159), P = 0.02. Among ER+ cancers, the pCR rate was 19% (95% CI: 9–29%) in HER2+ (n=11/57) and 6% (95% CI: 3–9%) in HER2- disease (n=17/270), P = 0.003. In the gene expression data, HER2 overexpression was associated with lower expression of MAP-tau (mean 303 vs 500, p=0.001) and higher expression of TOP2A mRNAs (mean 398 vs 274, p=0.048) in patients with ER+ disease. All ER- cancers had low MAP-Tau expression (compared to ER+ cancers) regardless of HER2 status. Conclusion: HER2 overexpression is associated with higher rate of pCR to preoperative T/FAC chemotherapy in both ER- and ER+ cancers. HER2 overexpression correlates with increased TOP2A and decreased MAP-Tau expression in ER+ cancers which could explain increased anthracycline and taxane sensitivity of these tumors.

No significant financial relationships to disclose.
Long-term follow-up of women enrolled in a randomized trial of adjuvant chemotherapy for early stage ovarian cancer (ICON1)
Authors: Swart A. C.
Published: March 2020

5509

Background: ICON1 and a meta-analysis of all relevant trials demonstrated an improvement in 5 year recurrence-free and overall survival (RFS and OS) for women with early-stage epithelial ovarian cancer (ES EOC) treated with adjuvant chemotherapy compared to no adjuvant chemotherapy. We aimed to determine if this initial benefit is maintained long-term and whether benefit is different with different risk groups of patients defined by stage, grade and histology. Method: 477 women with ES EOC were recruited from centres in Italy (271 women) UK (195) Switzerland (11) between August 1991 and January 2000. 5-year results were presented at ASCO 2001. Systematic long-term follow up was planned and completed in May 2006. Results: With a median follow-up of 9.2 years, 168 women have developed recurrent disease or died and 144 women have died. The Hazard Ratio (HR) for RFS of 0.70 in favour of adjuvant chemotherapy (95% CI 0.52–0.95 p= 0.023) translated into an improvement of 10-year absolute RFS of 10% from 57 to 67%. For OS, HR was 0.74 (95% CI 0.53–1.02 p= 0.066), a corresponding improvement in 10-year absolute OS of 8% from 64% to 72%. 26% of patients died from causes other than ovarian cancer. Stage I patients were grouped as low (Ia, grade 1), medium (Ia grade 2, Ib or Ic grade 1) and high risk (Ia, grade 3, Ib or IC grade 2 or 3, any clear cell). The test of interaction between risk groups and adjuvant treatment for RFS and OS was 0.055 and 0.13, respectively. The HR, 95%CI and p value are summarised in the table . Conclusions The long-term benefit of adjuvant treatment on RFS is confirmed. There is clear evidence that adjuvant chemotherapy reduces the risk of recurrence/death or death alone in high-risk patients but not in the low-risk group.

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Oral uracil-tegafur (UFT) compared to classical cyclophosphamide/methotrexate/5-fluorouracil (CMF) as postoperative chemotherapy in patients with node-negative, high-risk breast cancer (BC): Results of the national surgical adjuvant study for breast cancer
Authors: Watanabe T. , Sano M. , Takashima S. , Kitaya T. , Tokuda Y. , Yoshimoto M. , Kono N. , Nakagami K. , Iwata H. , Ohashi Y.
Published: March 2020

551

Background: Oral UFT and classical (c-) CMF provide similar response rates in patients (pts) with metastatic BC (CMF: 36.1%, UFT: 39.3%). In a postoperative setting, these regimens showed comparable effectiveness in terms of odds reductions in relapse-free survival (RFS) (CMF: 23.5%, UFT: 21.0%), but data fromrandomized controlled trials (RCT) is not sufficient. Methods: We conducted a RCT to study the efficacy and toxicity of 2-year oral UFT as compared with c-CMF in pts with Stage I - IIIA node-negative, pathologically high-risk BC in a postoperative setting. In the CMF arm, pts received 6 cycles of c-CMF (C: 100 mg po, days 1 to 14, M: 40 mg/m2 iv, days 1 and 8, F: 500 mg/m2 iv, days 1 and 8). In the UFT arm, pts received UFT at 300 mg/m2/day po for 2 years. Tamoxifen (20 mg/day) was administered for 5 years if ER or PgR was positive or unknown. The primary endpoint was RFS. Overall survival (OS), toxicity, and quality of life were secondary endpoints. The statistical hypothesis was non- inferiority of UFT in terms of RFS (95% CI of HR: <1.30). Results: From October 1996 through March 2001, a total of 733 pts were enrolled of whom 707 pts were analyzed. Patients’ characteristics were well balanced between the two arms. Median follow-up time was 6.1 years. At 5 years the RFS rate was 88.2% in the CMF arm and 87.7% in the UFT arm, and OS rates were 96.0% and 96.1%, respectively. Hazard ratios of the UFT arm to the CMF arm were 1.05 (95% CI: 0.69–1.57) for RFS and 0.88 (95% CI: 0.48–1.63) for OS. The toxicity profile differed between the groups. Major grade 3 or higher adverse events were as follows: leukopenia (CMF: 3.1%, UFT: 0.3%, p=0.006), neutropenia (CMF: 5.5%, UFT: 3.5%, p=0.27), elevation of total bilirubin (CMF: 0.3%, UFT: 5.5%, p=0.00001), elevation of GOT (CMF: 1.4%, UFT: 5.7%, p=0.004), elevation of GPT (CMF: 5.1%, UFT: 8.9%, p=0.08), nausea/vomiting (CMF: 2.8%, UFT: 1.1%, p=0.18) and diarrhea, (CMF: 0.3%, UFT: 2.0%, p=0.04). Conclusions: Our results suggest that UFT is a promising alternative to CMF as postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

No significant financial relationships to disclose.
A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer
Authors: Colombo N. , McMeekin S. , Schwartz P. , Kostka J. , Sessa C. , Gehrig P. , Holloway R. , Braly P. , Matei D. , Einstein M.
Published: March 2020

5516

Background: There are few effective therapies for women with advanced or recurrent endometrial cancer. Targeted therapies such as AP23573, a novel mTOR inhibitor, may result in clinical benefit with fewer side effects. Preliminary results of a trial of single agent AP23573 in patients with progressive endometrial cancer who may have had up to 2 prior regimens of cytotoxic chemotherapy are reported. Methods: The trial is an open-label, Simon 2-stage, single-arm study enrolling patients who have advanced endometrial cancer with documented progression in the 3 months prior to entry. Patients receive 12.5mg AP23573 QDx5 as a 30-min. intravenous infusion every other week for 28-day cycles. The primary efficacy endpoint is Clinical Benefit Response (CBR), defined as a complete or partial response or prolonged stable disease (= 16 weeks) by modified RECIST guidelines. Results: Seven of the first 19 patients achieved CBR, allowing expansion to the second stage. Enrollment is now complete (45 patients). Demographic data are available for 35 (median 66 yrs.; range 46–89) patients who received treatment: 23 adenocarcinomas, 5 carcinosarcomas, 6 papillary serous carcinomas (UPSC) and 1 clear cell carcinoma. Thirty-four patients had prior chemotherapy including doxorubicin, taxanes or platinum agents. Fourteen of the 26 patients with available history had prior pelvic radiotherapy. Nine of 27 (33%) patients evaluable for response had CBRs, including 2 partial responses (PRs). One CBR had UPSC, the remaining patients, including the PRs, had adenocarcinomas. Seven of the patients achieving CBR are still on treatment. Eighteen of the 27 patients discontinued treatment before 4 cycles because of progressive disease (14), consent withdrawal (1) or unrelated adverse events (3). Adverse event data are available for 27 patients. The most common adverse events are fatigue, anemia (33% each), mouth sores and nausea/vomiting (30% each). There have been 16 grade 3/ 4 treatment related adverse events (2 hyperglycemia, 14 separate events similar to those reported in other AP23573 trials). Conclusions: AP23573 shows encouraging single-agent activity in pretreated patients with advanced, progressive endometrial cancer and is well tolerated.

No significant financial relationships to disclose.
CA-125 response as a marker of clinical benefit in patients with recurrent ovarian cancer treated with gemcitabine and sorafenib—A trial of the PMH Phase II Consortium
Authors: Welch S. , Hirte H. , Elit L. , Schilder R. J. , Pond G. , Kovacs J. , Wright J. , Oza A. M.
Published: March 2020

5519

Background: Molecularly targeted agents are expected to have a cytostatic effect on cancers, thus traditional radiographic criteria for objective response may not be optimal in evaluating these agents. There is considerable preclinical rationale for the use of angiogenesis inhibitors in ovarian cancer (OC), and early phase trials of these agents have suggested activity. We have completed a phase II trial evaluating the efficacy of the combination of gemcitabine (GEM), a cytotoxic agent with activity in OC, and sorafenib (SOR), a novel mutitargeted kinase inhibitor with antiangiogenic activity, in patients (pts) with recurrent OC. Methods: Eligible pts had recurrent OC after platinum-based therapy and received up to 2 prior lines of chemotherapy for recurrence. All pts were gemcitabine-naive. GEM (1,000 mg/m2 i.v.) was given weekly for 7 weeks out of 8 weeks in the first cycle, then weekly for the first 3 weeks of each subsequent 4-week cycle. SOR (400 mg p.o. bid) was given continuously. The primary endpoint was objective response rate by RECIST criteria. Secondary endpoints included CA-125 response, time to progression (TTP), overall survival (OS) and toxicity. Results: 43 pts were accrued to this study. 137 (median 3; range: 1–19) cycles of treatment were given to 38 evaluable pts. 26 were evaluable for CA-125 response. Median age was 60 (range: 37–78). 44% of pts were ECOG PS 0 and 56% were PS 1. Using RECIST criteria, 2 pts (4.7%) had a confirmed partial response and 26 pts (60.4%) had a best response of stable disease. 9/26 pts (36.6%) with abnormal baseline CA-125 level achieved a CA-125 response using GCIG criteria. The median TTP was 5.4 months (95% CI: 3.5–9.5) and the median OS was 13.3 months (95% CI: 9.0-NR). The most frequent grade 3 or 4 adverse events were lymphopenia (32%), neutropenia (21%), thrombocytopenia (21%), hand-foot syndrome (21%), fatigue (16%), and hypokalemia (16%). Conclusions: The combination of GEM and SOR is well tolerated and associated with encouraging rates of disease stability. This trial illustrates the need for novel clinical trial design and response endpoints in order to more clearly identify the activity of targeted therapies in recurrent OC.

No significant financial relationships to disclose.
Treatment of ovarian cancer patients with malignant ascites using the trifunctional antibody catumaxomab: Results of a phase II/III study
Authors: Parsons S. L. , Kutarska E. , Koralewski P. , Gore M. , Wimberger P. , Burges A. , Stroehlein M. A. , Lahr A. , Jaeger M. , Heiss M. M.
Published: March 2020

5520

Background: Malignant ascites in ovarian carcinoma patients (pts.) is associated with a poor prognosis and reduced quality of life. Catumaxomab (anti-EpCAM × anti-CD3) is known to effectively eliminate tumor cells within ascites by simultaneously activating T cells and Fc gamma-receptor positive cells and redirecting them against the tumor. Methods: A total of 129 ovarian cancer pts. with recurrent symptomatic malignant ascites containing EpCAM+ tumor cells were enrolled in the study; 85 were randomized to treatment with catumaxomab (paracentesis plus intraperitoneal infusions of 10, 20, 50 and 150 μg for 11 days), and 44 to the control arm (paracentesis alone). The primary endpoint was puncture free survival (time to first need for paracentesis after treatment or time to death, which ever occurred first). Results: Pts. characteristics were well balanced in both arms. Median puncture free survival was 52 days for catumaxomab vs. 11 days for control (p<0.0001) whereas the median time to first need for paracentesis was 71 days vs. 11 days l (p<0.0001). There was a pronounced decrease of tumor cell load accompanied by a distinct increase of leukocyte count during catumaxomab treatment within the ascites fluid. Overall and progression free survival data suggest longer survival for catumaxomab-treated pts. compared to control. Follow-up data will be presented. The most frequent AEs were symptoms related to cytokine release (pyrexia, nausea, vomiting). These were generally mild to moderate in intensity, and fully reversible. Transient increases in liver enzymes and bilirubin, and transient WBC abnormalities such as leukocytosis, neutrophilia and a decrease in peripheral lymphocyte were regularly observed as abnormal laboratory values but rarely considered clinically significant. Conclusions: Intraperitoneal therapy with catumaxomab resulted in a significant and clinically relevant improvement of puncture-free survival time, tumor cell load, and time to first need for puncture compared to the control group of best available treatment. The safety profile reflects catumaxomabs mode of action and reveals a low and acceptable toxicity.

No significant financial relationships to disclose.
Randomized trials of combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian carcinoma (ROC): A meta-analysis of published data
Authors: Orlando M. , Costanzo M. V. , Chacon R. D. , Tajer C. D.
Published: March 2020

5524

Background: Results of recent randomized clinical trials (RCTs) support the use of combination chemotherapy in the management of ROC, more specifically in the platinum-sensitive setting. We performed a literature-based meta-analysis of RCTs comparing combination versus monotherapy in previously treated ROC to validate or refute conclusions of individual trials. Methods: This was a systematic review of the available literature identified from multiple databases using the terms ‘combination chemotherapy‘, ‘advanced ovarian cancer‘ and ‘randomized trial‘. Data were pooled for Meta-analysis using the Mantel Hanzsel Peto model. Event-based relative odds ratios (OR) with 95% confidence intervals (CI) were derived. Heterogeneity test was applied. Results: We identified and included 8 RCTs trials fulfilling the selection criteria, 6 phase III and 2 Phase II. Seven published trials and one ASCO poster presentation. One study was conducted exclusively in patients with platinum-resistant disease, five in platinum-sensitive disease only, and 2 in a mixed population. A total of 2312 patients were included in those 8 trials. Relevant endpoints of interest for this meta-analysis were: Overall Response Rate (ORR), Progression-Free Survival (PFS) at 2 years and Overall Survival (OS) at 2 years. Results are summarized in the table : Conclusion: Acknowledging all the drawbacks related to literature-based meta-analyses, combination chemotherapy seems to improve ORR, PFS and OS when compared to monotherapy in the mangement of ROC. References: Bolis G et al Gynecol Oncol 1999, 72:60; Bolis G et al Gynecol Oncol 2001, 81:3; Cantu M et al J Clin Oncol 2002, 20:1232; ICON and AGO collaborators Lancet 2003, 361:2099; Buda et al Br J Cancer 2004, 90:2112; Gonzalez-Martin AJ et al Ann Oncol 2005, 16:749; Pfisterer J et al J Clin Oncol 2006, 24:4699; Sehouli et al Proceedings ASCO 2006, Abstract 5030

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No significant financial relationships to disclose.
Topotecan weekly versus routine 5-day schedule in patients with platinum-resistant ovarian cancer (TOWER): A randomized, two-stage phase-II study of the North-Eastern German Society of Gynaecological Oncology (NOGGO)
Authors: Sehouli J. , Oskay-Oezcelik G. , Stengel D. , du Bois A. , Markmann S. , Loibl S. , Wilke J. , Nugent A. , Belau A. , Lichtenegger W.
Published: March 2020

5526

Background: Optimizing the therapeutic index (that is, maintaining drug effectiveness while reducing toxicity) is a major goal in chemotherapy for platinum-resistant ovarian cancer. Early phase-I/II studies suggest that weekly topotecan (T) might be effective and apparently better tolerated than the established 5-day regimen. As yet, no randomized comparison of both regimes was attempted. To prove the hypothesis of an improved therapeutic index with weekly T, we conducted a randomized, multicenter, two-stage phase-II trial, and herein present the data of the planned interim analysis. Methods: Pts with platinresistent ovarian and fallopian tube cancers or primary peritoneal carcinoma, measurable or assessable disease (GCIG-CA-125 response criteria), were eligible. Pts were randomized to receive either weekly T (d1,8,15/q28d, 4 mg/m2) or T from d1–5/q21d at a dose of 1.25 mg/m2. According to Gehan’s two-stage-design, both arms were handled as independent studies. Overall response rate (CR + PR) was defined as primary study endpoint, secondary endpoints of the interim analysis were toxicity and safety. Results: 28 pts in the weekly and 21 pts in the conventional group, enrolled at 38 centers form the basis of this report. 230 cycles of chemotherapy were evaluated for toxicity analyses. Median age was 61 years (range, 36 - 82 years). Demographic baseline characteristics, including tumor stage and grade were well balanced between treatment arms. There were 2/28 and 5/21 responses in weekly and the conventional arm, respectively (Risk Ratio [RR] 0.30, 95% confidence interval [CI] 0.06 - 1.40, p=0.122). The risk of early treatment termination due to tumor progression (RR 1.39, 95%CI 0.75 - 2.56), haematological (RR 0.20, 95% CI 0.01 - 3.97) or non- hematological toxicities (RR 1.96, 95% CI 0.18 - 20.83) did not differ significantly between groups. The only three events of neutropenic fever occurred in the conventional arm (RR 1.70, 95% CI 0.99 - 1.16). Conclusions: Weekly T is well tolerated and potentially active. The second stage of this study will require additional 46 patients each arm. Complete enrolment is expected to be accomplished in May 2007.

No significant financial relationships to disclose.
Factors predictive of response to cisplatin-based chemotherapy in stage IVB persistent or recurrent cervical carcinoma: A multivariate analysis of three Gynecologic Oncology Group trials
Authors: Moore D. H. , Tian C. , Monk B. J. , Long H. J. , Omura G.
Published: March 2020

5534

Purpose: A number of patients with advanced/recurrent cervical cancer do not respond to cisplatin-based chemotherapy. A pool analysis of three published phase III GOG studies was undertaken to identify the predictive factors and develop a model predictive of (non-) response to chemotherapy. Methods: The study population consisted of patients who received single-agent cisplatin or a cisplatin-containing combination in GOG protocols 110, 169 and 179. Prognostic variables (age, race, performance status, stage, histology, grade, disease site, prior chemotherapy—with primary radiation, time to recurrence, single-agent versus combination) were analyzed and multivariate analysis was conducted to identify factors independently predictive of response and survival. These analyses were used to establish a predictive model. Results: 816 patients were evaluable for response. In addition to single-agent treatment, multivariate analysis identified six factors (age, African-American, PS > 0, pelvic disease, prior radiosensitizer, recurrence ≤ one year) independently predictive of poor response. Those factors, but not age and African-American, were also independently associated with increased risk of death. 428 patients treated with a cisplatin- containing combination were classified into three risk groups based on the total number of risk factors (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors). Patients with 4–5 of risk factors were predicted to have a treatment response of only 13% (observed 10%), and median progression-free and overall survival of PFS of 2.8 months and 5.5 months, respectively. This subgroup of patients consist ∼14% of the target population in clinical practice. The predictive model was externally validated using GOG protocol 149 data that were not used for model development and further supported the predictive accuracy. Conclusions: High risk patients should be directed to non-cisplatin chemotherapy or investigational trials.

No significant financial relationships to disclose.
The 50-month results of the four non-platinum concurrent chemoradiation regimens for locally advanced cervical cancer
Authors: Kamnerdsupaphon P. , Chitapanarux I. , Sukthomya V. , Lorvidhaya V.
Published: March 2020

5540

Objectives: To determine the efficacy, disease free and overall survivals of radiation therapy in combination with four non-platinum chemotherapy regimens for locally advanced cervical cancer. Materials and Methods: Eligible patients were those with a diagnosis of locally advanced cervical cancer, under 70 years of age, and undergone the necessary prestudy investigations. All patients received external-beam pelvic irradiation to a minimum dose of 5,000 cGy, and brachytherapy delivered to bring the minimum total dose at point A to 7,500 cGy. Patients were randomized to receive one of four chemotherapy regimens: Arm1: oral 5FU 250 mg/m2/day, Arm2: mitomycin 12 mg/m2 on days 1 and 28 + oral 5FU 200 mg/m2/day, Arm3: mitomycin 12 mg/m2 on days 1 and 28 followed by 5FU 1,000 mg/m2/day on days 1 through 4 and 28 through 31, Arm4: oral hydroxyurea 25 mg/kg/day. Results: From September 1995 to October 2001, the study include 921 women; 226 in arm 1, 229 in arm 2, 234 in arm 3, and 232 in arm 4. The median follow-up time was 51.69 months. More than 89% of the patients achieved complete response. Disease free survival rates were 62.4% among arm 1, 63.8% among arm 2, 66.2% among arm 3, and 68.5% among arm 4. Overall survival rates were 77.4%, 79.5%, 80.8%, and 84.5% respectively. Conclusion: The efficacy of these regimens were not inferior to the standard platinum based regimen for locally advanced cervical cancer. This study demonstrates the results of large randomized clinical study of radiochemotherapy and requires the longer follow up time for the late complications.

No significant financial relationships to disclose.
A phase I study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer
Authors: Rischin D. , Narayan K. , Oza A. , Mileshkin L. , Bernshaw D. , Hanlon K. , McClure B. , Fyles A.
Published: March 2020

5543

Background and Purpose: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. GOG are currently studying the hypoxic cytotoxin, tirapazamine (TPZ) in combination with biweekly intermediate dose cisplatin (CIS) and radiation in a large phase III trial. The aim of this phase I study was to develop a better tolerated regimen that added TPZ to the standard regimen of radiation and weekly low dose CIS. Methods: Eligible patients had previously untreated carcinoma of the cervix, Stages IB2 - IVA. The starting schedule was radiotherapy (45 to 50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly CIS 40 mg/m2 weeks 1–6 and weekly TPZ 290 mg/m2 (prior to CIS) in weeks 1–5. Results: Between 3/05 and 7/06 eleven patients were enrolled, median age (range) 52 (31–65), squamous cell carcinoma 10, adenocarcinoma 1, 1B2–5, IIA-1, IIB-3, IIIB- 1, IVA-1. The first 2 patients on dose level 1 experienced a dose limiting toxicity (DLT), one grade 3 ALT (SGPT) elevation and grade 4 pulmonary embolism and one grade 3 ototoxicity. Doses were decreased to dose level -1 CIS 30 mg/m2 and TPZ 260 mg/m2. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a, CIS 35 mg/m2 and TPZ 260 mg/m2, with 2 DLTs: grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. The sixth patient on dose level -1a withdrew from the trial in week 2 after being advised about the DLTs observed on this dose level. 3 additional patients will be accrued on dose level -1 to confirm safety of this dose level. One patient has relapsed in pelvic nodes, all other patients remain disease-free with a median followup of 10 months (range 5 - 21) Conclusions: The combination of weekly TPZ and CIS with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being TPZ 260 mg/m2, CIS 30 mg/m2.

No significant financial relationships to disclose.
Cervix cancer regression measured using weekly MR imaging during fractionated radiotherapy: Radiobiologic modeling and correlation with tumor hypoxia
Authors: Lim K. S. , Chan P. , Dinniwell R. , Fyles A. , Haider M. , Cho Y. , Jaffray D. , Manchul L. , Levin W. , Hill R. P. , Milosevic M.
Published: March 2020

5547

Background: To utilize cervix cancer volumetry, as measured with MR imaging during definitive chemoirradiation (RT-CT), to derive radiobiological parameters using a mathematical model of tumor regression, and compare them to pre-treatment measurements of tumor hypoxia. Methods: Twenty-eight patients receiving RT-CT for cervix cancer underwent weekly magnetic resonance imaging (MRI) scans. Tumor volume was assessed on each of these scans and the rate of regression plotted. A mathematical model of tumor regression was formulated to simulate the relationship between three independent radiobiological parameters, 1) surviving fraction of cells after 2 Gy, SF2, 2) the cell clearance constant Tc, and 3) the cellular proliferation constant Tp. Non-linear regression analysis was applied to fit the MR-derived tumor volumes to the mathematical model and to derive SF2 and Tc values for each patient. These were compared to pre-treatment hypoxia measurements. Results: Initial tumor volume ranged between 8 and 209 cm3. Relative reduction in volume during treatment was 0.02 to 0.79. Simulations using representative values of the independent biologic variables derived from the literature showed SF2 and Tc to strongly influence the shape of the volume response curves. Non-linear regression analysis yielded a median SF2 of 0.71 and median Tc of 10 days. Radioresistant tumors (SF2 >0.71) were significantly more hypoxic at diagnosis (p=0.02). Conclusion: Based on serial MR imaging during treatment, a marked variation in cervix tumor regression is seen from patient to patient. Through our radiobiological model, tumors can be classified as radioresistant or radiosensitive, which correlates with hypoxia

[Table: see text]

No significant financial relationships to disclose.
Assessment of gynecological malignancies based on pathologic reports in five general hospitals in Tehran (1995–2005)
Authors: Momtahen S. , Sadreddin Kazzazi A. , Kadivar M.
Published: March 2020

5550

Background: Various histological types of gynecological tumors may develop from different etiological aspects. The observed differences in cancer incidence are mainly due to different individual and social risk factors. Step toward establishing a nation wide registry is being taken in this study. Methods: To give a relative frequency of female genital tract malignant tumors in Iran we designed a cross-sectional study included 450 women with definite diagnosis of gynecological cancer based on pathologic reports in five pathologic centers, Iran University of Medical sciences, Tehran, 1995–2005. WHO classification of gynecological tumors and International Federation of Gynecology and Obstetrics (FIGO) were used as basis of study. Spss 14 and correlation test was used for data analysis. Results: The average age of diagnosis was (50±0.7). 49.6% were menopausal. 82.7% were multipar. 89.8% were nonsmoker. 9.3% had history of using OCP. Ovarian cancers (55.5%), uterus cancers (24.9%) and cervical cancers (19.6%) were diagnosed. Surface epithelial-stromal tumor was the most frequent type of ovarian tumors (78.4%). Endometrial adenocarcinoma (70.5%) and squamous cell carcinoma (83%) were most frequent types of uterus and cervical cancers respectively.Well differentiated tumors were seen in 45%, 37% and 36% of uterus, cervical and ovarian tumors. In tumors of uterus and cervix the most frequent stage of diagnosis was stage IIA. The most metastatic diagnosed cases were seen between ovarian tumors (39.7%). Conclusions: Comparison with data published as review articles in NEJM till 2006, the most frequent gynecologic cancer in our study (ovarian cancer) is different to them; also the median age of our patients is lower than them.

[Table: see text]

No significant financial relationships to disclose.
A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets
Authors: Landen C. N. , Coleman R. , Milam M. R. , Johnston T. , Iyer R. , Gershenson D. M. , Ramirez P.
Published: March 2020

5558

Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease.

No significant financial relationships to disclose.
HER2 overexpression and amplification in advanced ovarian cancer (AOC): Treatment with trastuzumab—A GINECO study
Authors: Guastalla J. P. , Allouache D. , Combe M. , Weber B. , Cretin J. , Curé H. , Mousseau M. , Paraiso D. , Camilleri-Broët S. , Pujade-Lauraine E.
Published: March 2020

5559

Background: Variable rates of HER2 protein overexpression and gene amplification have been reported in AOC. Trastuzumab (Herceptin [H]) has been tested only as single agent and has shown a 7% response rate (RR) in heavily pre-treated AOC patients (pts) with 3+ and 2+ HER2 immunostaining (IHC) (Bookman MA et al, J Clin Oncol 2003). GINECO has explored the combination of H with paclitaxel (T) and carboplatin (C) in pts with resistant AOC (< 6 months) and HER2 gene amplification. Methods: 321 AOC pts were centrally screened for HER2 status (243 pts in first-line and 78 relapsing pts). All positive (3+) and doubtful (2+) cases were screened by fluorescence in-situ hybridisation (FISH). Pts with HER2 gene amplification, normal left ventricular ejection fraction (LVEF) and resistant relapse after first or second line of chemotherapy including TC were treated with T (175mg/m2, 3h), C (AUC 5) and H (9mg/kg first course, 6mg/kg subsequent courses) every 3 weeks. Results: Of the 321 cases tested, 22 (6,7%) were HER2+ by IHC and FISH. Only 7 pts (32%) with a median age of 56 (range: 48–70) met the eligibility criteria of the trial. Pts had measurable lesions (n=4) or elevated CA 125 level + non-measurable lesions (n=3). Three pts had complete response (6, 7+ and 24+ months) and 2 had stable disease (3 months). Toxicity was moderate: febrile neutropenia, Gr3 infection, Gr2 neurotoxicity and decrease of LVEF after 23 cycles of H were observed in one patient respectively. Conclusions: HER2 overexpression/amplification is low in advanced ovarian carcinoma (6,7 %). In this small prospective cohort of resistant patients, 3 of 7 have achieved complete remission when adding Trastuzumab to conventional chemotherapy.

No significant financial relationships to disclose.