bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in operable breast cancer: Results of Intergroup Trial E1199
Authors: Sparano J. A. , Wang M. , Martino S. , Jones V. , Perez E. , Saphner T. , Wolff A. C. , Sledge G. W. , Wood W. C. , Davidson N. E. 
Published: March 2020

516 Background: Evidence suggests that docetaxel is more effective than paclitaxel, and paclitaxel is more effective when given weekly than every 3 weeks in metastatic breast cancer (BC). Methods: Eligibility included axillary lymph node positive or high-risk (tumor at least 2 cm) node-negative BC. All patients received 4 cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) every 3 weeks, followed by either: (1) paclitaxel 175 mg/m2 every 3 weeks × 4 (P3), (2) paclitaxel 80 mg/m2 weekly × 12 (P1), (3) docetaxel 100 mg/m2 every 3 weeks × 4 (D3), or (4) docetaxel 35 mg/m2 weekly × 12 (D1). The primary comparisons included taxane (P vs. D) and schedule (every 3 weeks vs. weekly), and secondary comparisons included P3 vs. other arms. The trial had 86% power to detect a 17.5% decrease in disease-free survival (DFS) for either primary comparison, and 80% power to detect a 22% decrease for the secondary comparisons (2-sided nomimal 5% level tests corrected for multiple comparisons). Results: A total of 4,950 eligible patients were accrued. There was no difference in the primary comparisons afer 856 DFS events and 483 deaths after a median follow-up of 46.5 months at the 4th interim analysis ( www.sabcs.org , abstract 48). This is the final pre-specified analysis for the primary comparisons after 1,042 DFS events and 650 deaths (with 1,020 DFS events at this time, to be updated at the meeting). After a median followup of 60.2 months, there remains no significant difference in the hazard ratio (HR) for the taxane (1.02; p=0.73) or schedule (1.07; p=0.30) (as in the first analysis). In secondary comparisons of the standard arm (P3) with the other arms (HR > 1 favoring the experimental arms), the HRs were 1.30 (p = 0.003) for arm P1, 1.24 (p=0.02) for arm D3, and 1.09 (p=0.33) for arm D1. Analysis of interaction by hormone-receptor status will be presented. The incidence of worst grade toxicity (grade 3/4) was 24%/6% for arm P3, 24%/3% for arm P1, 21%/50% for arm D3, and 38%/6% for arm D1. Conclusions: There were no differences in DFS when comparing taxane or schedule overall. DFS was significantly improved in the weekly paclitaxel and every 3-week docetaxel arms compared with the every 3-week paclitaxel arm. [Table: see text]
Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Updated safety analysis of trial BIG 1–98
Authors: Coates A. S. , Mouridsen H. , Sun Z. , Rabaglio M. , Castiglione-Gertsch M. , Thürlimann B. , Mauriac L. , Price K. N. , Colleoni M. , Smith I. 
Published: March 2020

521 Background: Studies of aromatase inhibitors (AI) vs. tamoxifen (T) including the BIG 1–98 study have suggested a small numerical excess of cardiac adverse events (AEs) and increased incidence of hypercholesterolemia on AIs, and significantly higher incidence of thromboembolic AEs on T. Methods: 8,028 postmenopausal women with receptor-positive early breast cancer were randomized (double-blind) between March 1998 and May 2003 to receive 5 years letrozole (L), T, or a sequence of these agents. 7,963 patients who actually received therapy are included. AEs were recorded through 30 days after therapy completion or after switch on the sequential arms. Cardiovascular AEs were prospectively collected and graded. Cholesterol measurements were analyzed for percent change in total cholesterol from baseline by follow-up visit. Cox proportional hazards models were used to compare T and L according to time to first cardiovascular AE, adjusting for hypercholesterolemia at baseline or prior to the event, age, BMI, and history of smoking, hypertension, diabetes, and cardiac morbidity. The median follow-up was 30.1 months. Results: Baseline co-morbidities were balanced. Cox model results for time to first grade 3–5 cardiovascular AE are below. Cholesterol values decreased over time on both treatments, but to a greater extent and earlier on T. Conclusion: Taken together, cardiovascular AEs were relatively rare, and any excess of cardiac events on L seems to be outweighed by the superior control of recurrence afforded by L compared to T. An understanding of the nature, frequency and mechanism of such AEs is important to the optimization of the therapeutic ratio in adjuvant endocrine therapy with AIs. [Table: see text] No significant financial relationships to disclose.
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). [Table: see text] [Table: see text]
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. [Table: see text] [Table: see text]
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. [Table: see text] [Table: see text]
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. [Table: see text] [Table: see text]
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. [Table: see text] [Table: see text]