Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer—results from the randomized phase III SUCCESS-A trial

Abstract Background When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. Methods A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. Results No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. Conclusion Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. Trial registration Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005-000490-21. Registered September 2005.

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Frühes Mammakarzinom: Hinzunahme von Gemcitabin zur adjuvanten Chemotherapie ohne Vorteil

Karger Kompass Onkologie ◽

10.1159/000516882 ◽

2021 ◽

pp. 1-3

Author(s):

Maggie Banys-Paluchowski ◽

Natalia Krawczyk

Keyword(s):

Breast Cancer ◽

High Risk ◽

Early Breast Cancer ◽

Disease Free Survival ◽

Metastatic Breast ◽

Tumor Grade ◽

Primary Study ◽

Breast Cancer Patients ◽

Standard Chemotherapy ◽

Frühes Mammakarzinom

Background: When chemotherapy is indicated in patients with early breast cancer, regimens that contain anthracyclines and taxanes are established standard treatments. Gemcitabine has shown promising effects on the response and prognosis in patients with metastatic breast cancer. The SUCCESS-A trial (NCT02181101) examined the addition of gemcitabine to a standard chemotherapy regimen in high-risk early breast cancer patients. Methods: A total of 3754 patients with at least one of the following characteristics were randomly assigned to one of the two treatment arms: nodal positivity, tumor grade 3, age ≤ 35 years, tumor larger than 2 cm, or negative hormone receptor status. The treatment arms received either three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by three cycles of docetaxel (FEC → Doc); or three cycles of FEC followed by three cycles of docetaxel and gemcitabine (FEC → Doc/Gem). The primary study aim was disease-free survival (DFS), and the main secondary objectives were overall survival (OS) and safety. Results: No differences were observed in the 5-year DFS or OS between FEC → Doc and FEC → Doc/Gem. The hazard ratio was 0.93 (95% CI, 0.78 to 1.12; P = 0.47) for DFS and 0.94 (95% CI, 0.74 to 1.19; P = 0.60) for OS. For patients treated with FEC → Doc and FEC → Doc/Gem, the 5-year probabilities of DFS were 86.6% and 87.2%, and the 5-year probabilities of OS were 92.8% and 92.5%, respectively. Conclusion: Adding gemcitabine to a standard chemotherapy does not improve the outcomes in patients with high-risk early breast cancer and should therefore not be included in the adjuvant treatment setting. Trial registration: Clinicaltrials.gov NCT02181101 and EU Clinical Trials Register EudraCT 2005–000490–21. Registered September 2005.

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Subgroup efficacy evaluation of the AE37 HER2 vaccine in breast cancer patients in the adjuvant setting.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3088 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3088-3088 ◽

Cited By ~ 4

Author(s):

Kaitlin M. Peace ◽

Elizabeth Ann Mittendorf ◽

Sonia A. Perez ◽

Panagiotis Tzonis ◽

Nikolaos Fragkiskos Pistamaltzian ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Disease Free Survival ◽

Phase Iii ◽

Her2 Expression ◽

Breast Cancer Patients ◽

Adjuvant Setting ◽

Gm Csf ◽

Significant Difference ◽

Disease Free

3088 Background: AE37 is a Ii-Key hybrid of the HER2 peptide AE36 (HER2776-790), which stimulates peptide-specific T cells. We have completed the active phase of a prospective, randomized, multi-center, phase II trial of the AE37 vaccine in the adjuvant setting. The primary analysis, performed after a median follow up (f/u) of 25 months (mo), did not show a significant difference in disease free survival (DFS) between vaccinated and control patients (pts). However, demonstrating the efficacy of cancer vaccines may require more time than other therapies, especially in malignancies with relatively late recurrences like breast cancer. Here, we present updated efficacy data after extended f/u in subgroups of pts stratified by clinicopathologic characteristics. Methods: Clinically disease-free, node positive or high-risk node negative pts with any level of HER2 expression were randomized to receive AE37 + GM-CSF (VG) or GM-CSF alone (CG) following standard of care therapy. Pts received 6 monthly intradermal inoculations during the primary vaccine series (PVS) followed by 4 boosters administered every 6 mo. Kaplan Meier and log rank analyses were performed from the time of the first inoculation in pts who completed at least the PVS, according to stage, node status, tumor size, HER2 expression and ER/PR status. Results: There were no clinicopathologic differences between groups in the 298 enrolled pts (VG = 153, CG = 145). The vaccine is safe and well tolerated. After a median f/u of 55 mo, there was a trend toward improved DFS in the VG among stage IIB/III pts (VG, n = 73, DFS 82% vs CG, n = 61, 67%, HR = 0.48, p = 0.06) and those with low HER2 expression (HER2 LE, VG, n = 68, 89% vs CG, n = 66, 51%, HR = 0.47, p = 0.1). Improved DFS in the VG was documented in patients with both stage IIB/III disease and HER2 LE (VG, n = 39, 90% vs CG, n = 38, 32%, HR 0.3, p = 0.02) and triple negative (TNBC) pts (VG, n = 21, 89% vs CG, n = 21, 0%, HR 0.26, p = 0.05). Conclusions: The AE37 vaccine is safe and well tolerated and has statistically significant efficacy in stage IIB/III pts with HER2 LE and in TNBC pts. This justifies further evaluation in a phase III study enrolling stage IIb/III pts not eligible for trastuzumab treatment and the very high risk TNBC group. Clinical trial information: NCT00524277.

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Adjuvant phase III trial to compare intense dose-dense adjuvant treatment with EnPC to dose dense, tailored therapy with dtEC-dtD for patients with high-risk early breast cancer (GAIN-2).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps1137 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS1137-TPS1137 ◽

Cited By ~ 1

Author(s):

Volker Moebus ◽

Helmut Forstbauer ◽

Grischa Wachsmann ◽

Andreas Schneeweiss ◽

Angelika Ober ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Safety Data ◽

Disease Free Survival ◽

Phase Iii ◽

Breast Cancer Patients ◽

Luminal A ◽

Ki 67 ◽

Phase Iii Trial ◽

Dose Dense

TPS1137 Background: Intense dose-dense (idd) chemotherapy (CT) significantly improves overall survival in breast cancer patients. Two preceding trials explored iddETC vs a dd combination of EC-TX (GAIN) and dtEC-dtD vs conventional dosed FEC-D (Panther). Nab-paclitaxel (nP) provides a better toxicity profile and higher efficacy compared to solvent based taxanes and might be preferred in an idd regimen. Methods: This is a multicenter, prospective, randomized, open-label phase III trial comparing iddEnPC or dtEC-dtD as adjuvant CT. Pts with uni- or bilateral primary high risk node-positive (N+) breast cancer (BC) and centrally confirmed ER/PR/HER2 and Ki-67 status can be included. Luminal A pts are only recruited with N+ ≥4. Randomization to iddEnPC or dtEC-dtD will be stratified by biological subtype defined by hormone receptor, HER2 and Ki-67. The iddEnPC arm will receive epirubicin (150mg/m2) q2w x3 followed by nP (260-330mg/m2, dose to be determined in run-in phase) q2w x3, followed by cyclophosphamide (2g/m2) q2w x3. The dtEC-dtD arm will receive EC (38-120/450-1200 mg/m2) q2w x4 followed after 1 wk rest by docetaxel (60-100mg/m2) q2w x4. GAIN-2 will compare toxicity and efficacy of an idd regimen (EnPC) vs a dd regimen with modification of single doses depending on individual hematological and non-hematological toxicities. Primary objective is invasive disease-free survival (IDFS). Secondary objectives are survival by other definitions, compliance, safety, side effects of taxanes and subgroup analyses (by 0-3, 4-9 or 10+ involved nodes and Ki-67). Efficacy analyses are planned 60 mths after end of accrual, safety interim analyses after 200 and 900 pts have completed CT. It was assumed that dtEC-dtD will achieve a 5-yr IDFS of 75% and ddEnPC will improve IDFS to 79% (HR 0.819) with a power of 80% (α=0.05, ß= 0.2).GAIN-2 is registered under NCT01690702 Results: 75pts were recruited since 1stOct 2012. Recruitment (in total 2886 pts) is planned for 36 mths in 80-100 sites in Germany. Run-in safety data to be presented. Conclusion: GAIN-2 will compare the efficacy of adjuvant iddEnPC and dtEC-dtD in pts with early N+ BC. Clinical trial information: NCT01690702.

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Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313)

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.0847 ◽

2007 ◽

Vol 25 (6) ◽

pp. 656-661 ◽

Cited By ~ 29

Author(s):

Hannah M. Linden ◽

Charles M. Haskell ◽

Stephanie J. Green ◽

C. Kent Osborne ◽

George W. Sledge ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Total Dose ◽

Early Stage ◽

Randomized Study ◽

Disease Free Survival ◽

Phase Iii ◽

Hematologic Toxicity ◽

Breast Cancer Patients ◽

Node Negative

Purpose We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A → C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC). Patients and Methods High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A → C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cyles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A → C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy. Results Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor–positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A → C. Grade 4 hematologic toxicity was greater on A → C, but nonhematological grade 4 was similar. Conclusion The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.

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OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.lba1 ◽

2021 ◽

Vol 39 (18_suppl) ◽

pp. LBA1-LBA1

Author(s):

Andrew Tutt ◽

Judy Ellen Garber ◽

Bella Kaufman ◽

Giuseppe Viale ◽

Debora Fumagalli ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Early Breast Cancer ◽

Synthetic Lethality ◽

Local Treatment ◽

Disease Free Survival ◽

Phase Iii ◽

Multiple Testing Procedure ◽

Neo Adjuvant Chemotherapy

LBA1 Background: PARP inhibitors (PARPi) target cancers with homologous recombination repair defects by synthetic lethality. The PARPi olaparib (OL) is licensed for metastatic HER2-negative breast cancer with BRCA1/2 germline mutation (gBRCAm). Despite (neo)adjuvant chemotherapy ([N]ACT), recurrence rates in patients (pts) with gBRCAm early breast cancer (EBC) can be high. Novel adjuvant treatments are needed. Methods: OlympiA (NCT02032823), a randomized, double-blind, phase III study, enrolled pts with gBRCAm and HER2-negative (TNBC or hormone-receptor+ [HR+]) high-risk EBC after primary local treatment and ACT/NACT. Eligible pts with TNBC had ≥pT2 or ≥pN1 disease prior to ACT or non-pCR after NACT; those with HR+ BC had ≥4 positive nodes prior to ACT or non-pCR and CPS&EG score ≥3 after NACT. Pts were randomized 1:1 to 1 year of continuous oral OL (300 mg BID) or placebo (PL). Endocrine therapy and bisphosphonates were allowed. The primary endpoint was invasive disease-free survival (IDFS) in the ITT population. Secondary endpoints included distant DFS (DDFS), overall survival (OS) and safety. Safety analysis included adverse events of special interest (AESI) (myelodysplastic syndrome/ acute myeloid leukemia, new primary malignancy, pneumonitis). Per protocol IDMC interim analysis (IA) review was triggered at 165 IDFS events in the first 900 pts, with superiority boundaries based on a hierarchical multiple testing procedure: P < 0.005 for IDFS, followed by P < 0.005 for DDFS and p<0.01 for OS. Results: 1836 pts were enrolled between 06/14–05/19; 49.9% had ACT, 50.1% NACT. Baseline demographics and tumor characteristics were balanced between arms. 82.2% had TNBC; 26.5% received a platinum agent. The IDMC recommended data unblinding as IA showed a significant benefit of OL vs PL for IDFS (hazard ratio [HR] 0.58; 99.5% CI 0.41, 0.82; P < 0.0001) at 2.5 yrs median follow-up. IDFS events occurred in 106/921 and 178/915 pts assigned to OL and PL, respectively. 3-yr IDFS was 85.9% vs 77.1% (diff. 8.8%; 95% CI 4.5%, 13.0%). DDFS was significantly improved with OL (HR 0.57; 99.5% CI 0.39, 0.83; P< 0.0001); 3-yr DDFS was 87.5% vs 80.4% (diff. 7.1%; 95% CI 3.0%, 11.1%). OS was greater for OL than PL but was not statistically significant at IA (HR 0.68; 99.0% CI 0.44, 1.05; P = 0.024); 3-yr OS% 92.0% vs 88.3% (diff. 3.7%; 95% CI 0.3%, 7.1%). Median intended OL exposure was 94.8%. AEs were consistent with the label. G3+ AEs in >1% of OL pts were; anemia (8.7%), neutropenia (4.8%), leukopenia (3.0%), fatigue (1.8%), and lymphocytopenia (1.2%). SAEs and AESI were not increased by OL, SAE 8.7% vs 8.4% and AESI 3.3% vs 5.1%, OL vs PL respectively. Conclusions: Adjuvant OL following ACT or NACT significantly improved IDFS and DDFS with acceptable toxicity in pts with gBRCAm and high-risk HER2-negative EBC. Clinical trial information: NCT02032823.

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Evaluation of the prognostic significance of RACGAP1, Ki67, and TOP2A mRNA expression in high-risk early breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.582 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 582-582

Author(s):

Kyriaki Pliarchopoulou ◽

Helen Gogas ◽

Christos A. Papadimitriou ◽

Ralph M Wirtz ◽

George Kouvatseas ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Mrna Expression ◽

Cancer Patients ◽

Early Breast Cancer ◽

Prognostic Significance ◽

Phase Iii ◽

Breast Cancer Patients

582 Background: Proliferation is a major process in carcinogenesis. RACGAP1 is a protein involved in cell growth regulation and metastasis, Ki67 is a known proliferation marker and TOP2A has a key role in DNA replication and remodeling. The aim of the present study was to explore the prognostic significance of a signature of proliferation markers, such as RACGAP1, Ki67 and TOP2A on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients. Methods: A total of 1681high-risk breast cancer patients, enrolled in two consecutive phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded tumor tissue samples from 963 of these patients were extracted using a standardized fully automated isolation method for total RNA based on silica-coated magnetic beads, followed by multiplex RT-qPCR for assessing RACGAP1, Ki67 and TOP2A mRNA expression. CALM2 was included in the same reaction, as a reference gene. Results: After a median follow-up of 107 months, 289 patients (30.0%) demonstrated disease progression and 261 (27.1%) patients died. Univariate analysis revealed that poor OS was associated with high RACGAP1 mRNA expression (p=0.0185, log-rank), high Ki67 (p=0.0219), as well as high TOP2A (p=0.0019) mRNA expression, while in multivariate analysis only TOP2A retained significance (Wald’s p=0.008). In an effort to improve prognostic significance, combinations of the expression of two or all three genes were tested, with low mRNA expression of the three genes being associated with improved DFS (HR=0.74, CI=0.56-0.98, p=0.035) and OS (HR=0.60, CI=0.42-0.85, p=0.004). However, in multivariate analysis, none of the combinations retained prognostic significance, except the combination of high RACGAP1 and TOP2A mRNA expression, which was found to be associated with decreased DFS (HR=1.26, CI=0.96-1.63, p=0.092) and OS (HR=1.49, CI=1.10-2.03, p=0.009). Conclusions: High RACGAP1 and TOP2A mRNA expression was found, in multivariate analysis, to be of adverse prognostic significance in high-risk early breast cancer patients treated with anthracycline-containing adjuvant chemotherapy.

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German Adjuvant Intergroup Node-Positive Study: A Phase III Trial to Compare Oral Ibandronate Versus Observation in Patients With High-Risk Early Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2012.47.2167 ◽

2013 ◽

Vol 31 (28) ◽

pp. 3531-3539 ◽

Cited By ~ 58

Author(s):

Gunter von Minckwitz ◽

Volker Möbus ◽

Andreas Schneeweiss ◽

Jens Huober ◽

Christoph Thomssen ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Early Breast Cancer ◽

Data Monitoring Committee ◽

Disease Free Survival ◽

Phase Iii ◽

Phase Iii Trial ◽

Positive Study ◽

Node Positive ◽

Dose Dense

Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

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