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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

IMPORTANCE: Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)–positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. OBJECTIVE: To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. DESIGN, SETTING, AND PARTICIPANTS: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)–positive BC. INTERVENTIONS: Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m(2) weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m(2) (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). MAIN OUTCOMES AND MEASURES: The primary outcome was pCR rates between arms for each randomization. RESULTS: A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m(2) weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02682693

Purpose:Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial.Experimental Design:ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL).Results:After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68–1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41–4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis.Conclusions:Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs.See related commentary by Sharma, p. 4840

Supplementary Data from De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial

Supplementary Figure from De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial

Supplementary Table from De-escalated Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer (TNBC): Impact of Molecular Markers and Final Survival Analysis of the WSG-ADAPT-TN Trial

Background In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

AIM To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC. METHODS We compared negative oestrogen (ER) and progesterone receptor (PR) {\textless}1{\%}, low-positive (ER and/or PR 1-9{\%})~and strong-positive (ER or PR 10-100{\%}) HR-expression in neoadjuvant clinical trial cohorts (n~=~2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS)~and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n~=~38). RESULTS Ninety-four (3.4{\%}) patients had low HR-positive tumours, 1769 (64.0{\%}) had strong HR-positive tumours, and 902 (32.6{\%}) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7{\%}) and women with TNBC (35.5{\%}). DFS and DDFS were also not different for DFS, hazard ratio 1.26, 95{\%}-CI (confidence interval) : 0.87-1.83, log-rank test p~=~0.951; for DDFS, hazard ratio 1.17, 95{\%}-CI: 0.78-1.76, log-rank test p~=~0.774. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4{\%}; odds ratio 0.38, 95{\%}-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95{\%}-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95{\%}-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8{\%}). CONCLUSION Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.

Purpose: Although optimal treatment in early triple-negative breast cancer (TNBC) remains unclear, de-escalated chemotherapy appears to be an option in selected patients within this aggressive subtype. Previous studies have identified several pro-immune factors as prognostic markers in TNBC, but their predictive impact regarding different chemotherapy strategies is still controversial. Experimental Design: ADAPT-TN is a randomized neoadjuvant multicenter phase II trial in early patients with TNBC (n = 336) who were randomized to 12 weeks of nab-paclitaxel 125 mg/m2 + gemcitabine or carboplatin d 1,8 q3w. Omission of further (neo-) adjuvant chemotherapy was allowed only in patients with pathological complete response [pCR, primary endpoint (ypT0/is, ypN0)]. Secondary invasive/distant disease-free and overall survival (i/dDFS, OS) and translational research objectives included quantification of a predictive impact of markers regarding selection for chemotherapy de-escalation, measured by gene expression of 119 genes (including PAM50 subtype) by nCounter platform and stromal tumor-infiltrating lymphocytes (sTIL). Results: After 60 months of median follow-up, 12-week-pCR was favorably associated (HR, 0.24; P = 0.001) with 5y-iDFS of 90.6% versus 62.8%. No survival advantage of carboplatin use was observed, despite a higher pCR rate [HR, 1.04; 95% confidence interval (CI), 0.68–1.59]. Additional anthracycline-containing chemotherapy was not associated with a significant iDFS advantage in pCR patients (HR, 1.29; 95% CI, 0.41–4.02). Beyond pCR rate, nodal status and high sTILs were independently associated with better iDFS, dDFS, and OS by multivariable analysis. Conclusions: Short de-escalated neoadjuvant taxane/platinum-based combination therapy appears to be a promising strategy in early TNBC for using pCR rate as an early decision point for further therapy (de-) escalation together with node-negative status and high sTILs. See related commentary by Sharma, p. 4840

PURPOSENeoadjuvant systemic treatment (NST) elicits a pathologic complete response in 40%-70% of women with breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, nonsurgical approaches, including imaging or vacuum-assisted biopsy (VAB), were not able to accurately identify patients without residual cancer in the breast or axilla. We evaluated the feasibility of a machine learning algorithm (intelligent VAB) to identify exceptional responders to NST.METHODSWe trained, tested, and validated a machine learning algorithm using patient, imaging, tumor, and VAB variables to detect residual cancer after NST (ypT+ or in situ or ypN+) before surgery. We used data from 318 women with cT1-3, cN0 or +, human epidermal growth factor receptor 2–positive, triple-negative, or high-proliferative Luminal B–like breast cancer who underwent VAB before surgery (ClinicalTrials.gov identifier: NCT02948764 , RESPONDER trial). We used 10-fold cross-validation to train and test the algorithm, which was then externally validated using data of an independent trial (ClinicalTrials.gov identifier: NCT02575612 ). We compared findings with the histopathologic evaluation of the surgical specimen. We considered false-negative rate (FNR) and specificity to be the main outcomes.RESULTSIn the development set (n = 318) and external validation set (n = 45), the intelligent VAB showed an FNR of 0.0%-5.2%, a specificity of 37.5%-40.0%, and an area under the receiver operating characteristic curve of 0.91-0.92 to detect residual cancer (ypT+ or in situ or ypN+) after NST. Spiegelhalter's Z confirmed a well-calibrated model ( z score –0.746, P = .228). FNR of the intelligent VAB was lower compared with imaging after NST, VAB alone, or combinations of both.CONCLUSIONAn intelligent VAB algorithm can reliably exclude residual cancer after NST. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials.

Background: Currently, patients with breast cancer (BC) with hormone receptor (HR) immunohistochemical expression between 1-9% are eligible to receive endocrine therapy. However, recent data suggest that these tumors express a basal-like molecular phenotype associated with triple negative BC (TNBC) rather than luminal phenotype associated with HR positive BC. Here, we aimed to determine the differences between strong HR positive, low HR positive and negative HR BC, in regard to responsiveness to neoadjuvant chemotherapy (NACT) and disease free survival (DFS) in large cohorts from GBG clinical trials. Methods: In this retrospective analysis of data from women with BC treated in the neoadjuvant GeparQuinto (n=2572), GeparSixto (n=588) and GeparSepto (n=1206) clinical trials, we compared patients with three HR phenotypes: low positive (ER and/or PR= 1-9%), strong positive (ER or PR= 10-100%), and negative (ER and PR= Results: Patients median age was 49 years, the majority had clinical tumor stage 2 (54.1%), negative nodal status (54.7%), and Her2 negative tumors (72.4%). 85.1% of women had BC classified as no special histological type. The pCR rate across the studies was 26.2%. 145 (3.4%) patients had low HR positive, 2417 (57.3%) strong HR positive and 1658 (39.3%) HR negative tumors. After NACT, 16.3% of patients with strong HR positive BC achieved a pCR, while among those with HR negative and low HR positive tumors, pCR rates were 40.2% and 37.9%, respectively (p Conclusions: Similarly to patients with negative HR tumors, patients with low HR positive tumors have a better responsiveness to NACT and worse survival rates, compared to patients with strongly HR positive BC. We suggest that studies on treatment options for basal-like/TNBC, should also consider including patients with low HR positive tumors. Citation Format: Villegas SL, Lederer B, Untch M, Holms F, Ulmer H-U, Diebold K, Fasching PA, Weber K, Schmitt WD, Tesch H, Rezai M, Marmé F, Sinn B, Hackmann J, Schneeweiss A, Tannapfel A, Nekljudova V, Denkert C, Loibl S. Similarities between low hormone receptor positive and hormone receptor negative breast cancer: An analysis of 4366 patients from multicenter clinical trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-10.

OBJECTIVE We evaluated the ability of minimally invasive, image-guided vacuum-assisted biopsy (VAB) to reliably diagnose a pathologic complete response in the breast (pCR-B). SUMMARY BACKGROUND DATA Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in up to 80% of women with breast cancer. In such cases, breast surgery, the gold standard for confirming pCR-B, may be considered overtreatment. METHODS This multicenter, prospective trial enrolled 452 women presenting with initial stage 1-3 breast cancer of all biological subtypes. Fifty-four women dropped out; 398 were included in the full analysis. All participants had an imaging-confirmed partial or complete response to NST and underwent study-specific image-guided VAB before guideline-adherent breast surgery. The primary endpoint was the false-negative rate (FNR) of VAB-confirmed pCR-B. RESULTS Image-guided VAB alone did not detect surgically confirmed residual tumor in 37 of 208 women [FNR, 17.8%; 95% confidence interval (CI), 12.8-23.7%]. Of these 37 women, 12 (32.4%) had residual DCIS only, 20 (54.1%) had minimal residual tumor (

Background: Neoadjuvant systemic treatment (NST) elicits a pathologic complete response (pCR, ypT0, ypN0) in 40-70% of women with HER2 positive, triple-negative, and high-proliferative Luminal B breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, their safe identification prior to surgery is a major challenge: imaging after NST, minimally-invasive biopsies, or combinations of both using narrow patient selection criteria are not accurate enough either because they showed high rates of missed cancer or high rates of missed pCR. Recently, the concept of an intelligent, minimally-invasive, vacuum-assisted biopsy (intelligent VAB) was introduced to identify exceptional responders to NST. The intelligent VAB is a multivariate risk algorithm that uses artificial intelligence techniques to analyze conventional VAB results alongside contextualizing patient, imaging, and tumor information. It showed great potential to reliably identify patients with a pCR in the breast (ypT0). However, the absent integration of the axillary status impairs clinical applicability. In this study, we evaluated the feasibility of an intelligent VAB to identify exceptional responders to NST in the breast and axilla. Methods: We trained, tested, and validated a machine learning algorithm (Extreme Gradient Boosting Tree) using patient, imaging, tumor, and conventional VAB variables to detect residual cancer after NST (ypT+/is or ypN+) prior to surgery. We used data from 318 women with cT1-3, cN0/+, HER2 positive, triple-negative breast or high-proliferative Luminal B breast cancer who underwent VAB before surgery (NCT02948764). We used 10-fold cross-validation to train and test the algorithm which was externally validated using data of an independent, similar trial (NCT02575612). Findings were compared to the histopathologic evaluation of the surgical specimen. False-negative rate (FNR), specificity, and area under the ROC curve (AUROC) were the main outcome measures. Results: In the development set (n=318), mean patient age was 52.5 years and 45.3% (144 of 318) achieved a pCR (ypT0 and ypN0). Using resampling methods, the intelligent VAB showed an FNR of 5.2% (9 of 174, 95% CI 2.4-9.5), a specificity of 37.5% (54 of 144, 95% CI 29.6-45.9), and an AUROC of 0.92 (95% CI 0.90-0.94) in the development set to detect residual cancer (ypT+/is or ypN+) after NST. In the external validation set (n=45), mean patient age was 48.1 years and 44.4% (20 of 45) achieved a pCR. The intelligent VAB showed an FNR of 0% (0 of 25, 95% CI 0.0-13.7), a specificity of 40.0% (8 of 20, 95% CI 19.1-63.9) and an AUROC of 0.91 (95% CI 0.82-0.97). Spiegelhalter’s Z confirmed a well-calibrated model (z score -0.746, P 0.228). FNR of the intelligent VAB was lower compared to imaging after NST, conventional VAB, or combinations of both using narrow patient selection criteria. Conclusion: An intelligent VAB can reliably exclude residual cancer after NST for women with cT1-3, cN0/+, HER2 positive, triple-negative breast or high-proliferative Luminal B breast cancer. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials. Trial registration: NCT02948764 and NCT02575612. Funding: German Research Foundation (DFG) Diagnostic Performance ComparisonFalse-negative rate - % (95% CI); no.Specificity - % (95% CI); no.Negative predictive value - % (95% CI); no.Positive predictive value - % (95% CI); no.AUROC - value (95% CI)Development set (n=318)Imaging after NST24.4% (18.0-13.7); 40 of 16452.2% (43.4-61.0); 69 of 13263.3% (53.5-72.3); 69 of 10966.3% (59.1-73.0); 124 of 187-Conventional VAB32.8% (25.8-40.3); 57 of 174100% (97.5-100); 144 of 14471.6% (64.9-77.8); 144 of 201100% (96.9-100); 117 of 117-Imaging after NST + VAB16.7% (11.4-23.2); 28 of 16832.1% (24.4-40.6); 44 of 13761.1% (48.9-72.4); 44 of 7260.1% (56.1-69.1); 140 of 223-VAB + patient selection9.1% (5.0-14.1) 15 of 17036.3% (28.2-45.0); 49 of 13576.6% (64.3-86.2); 49 of 6464.3% (57.9-70.4); 155 of 241-Intelligent VAB (Extreme Gradient Boosting tree)5.2% (2.4-9.6); 9 of 17437.5% (29.6-45.9); 54 of 14485.7% (74.6-93.3); 54 of 6364.7% (58.5-70.6); 165 of 2550.92 (0.90-0.94)External validation (n=45)Imaging after NST24.0% (9.4-45.1%);6 of 2565.0% (40.8-84.6%);13 of 2068.4% (43.4-87.4%);13 of 1973.1% (52.2-88.4%);19 of 26-Conventional VAB28.0% (12.1-49.4%);7 of 25100% (83.2-100%);20 of 2074.1% (53.7-88.9%);20 of 27100% (81.5-100%);18 of 18-Imaging after NST + VAB12.0% (2.5-31.2); 3 of 2565.0% (40.8-84.6%);13 of 2081.3% (54.4-96.0%); 13 of 1675.9% (56.5-89.7%); 22 of 29-VAB + patient selection4.0% (1.0-2.4); 1 of 2530.0% (9.4-45.1%); 6 of 2085.7% (69.8-99.8); 6 of 763.2% (46.0-78.2); 24 of 38-Intelligent VAB (Extreme Gradient Boosting tree)0.0% (0.0-13.7%);0 of 2540.0% (19.1-63.9%);8 of 20100% (63.1-100%);8 of 867.8% (50.2-82.0%);25 of 370.91 (0.82 - 0.97)AUROC = Area under the receiver operating characteristic curve; CI = confidence interval Citation Format: André Pfob, Chris Sidey-Gibbons, Geraldine Rauch, Bettina Thomas, Benedikt Schaefgen, Sherko Kuemmel, Toralf Reimer, Markus Hahn, Marc Thill, Jens-Uwe Blohmer, John Hackmann, Wolfram Malter, Inga Bekes, Kay Friedrichs, Sebastian Wojcinski, Sylvie Joos, Stefan Paepke, Tom Degenhardt, Joachim Rom, Achim Rody, Regina Große, Marion van Mackelenbergh, Mattea Reinisch, Maria Karsten, Michael Golatta, Joerg Heil. Intelligent vacuum-assisted breast biopsy to identify breast cancer patients with pathologic complete response after neoadjuvant systemic treatment for omission of breast and axillary surgery [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-02.

The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m2 (nP150) weekly, after study amendment 125 mg/m2 (nP125) weekly or solvent-based paclitaxel 80 mg/m2 (P80) weekly followed by epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 for four 3-week cycles. 229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/m2 for nP was 103% with nP150, 95% with nP125, 99% with P80 before and 98% with P80 after the amendment. PSN grade 3–4 was observed in 14.5% of patients with nP150, 8.1% of patients with nP125 (p = 0.018), and 2.7% of patients with P80. Overall pCR before the amendment was 33.6% after nP150 and 23.5% after P80 (OR 1.65 [95% CI 1.10–2.50]; p = 0.022); pCR after the amendment was 41.4% after nP125, and 32.4% after P80 (1.48 [95% CI 1.10–1.99]; p = 0.013). Nab-paclitaxel 125 mg/m2 was associated with a better safety profile and compliance without compromising the efficacy compared to nab-paclitaxel 150 mg/m2.

Background Our recent randomized, multicenter phase III GeparSepto study (Untch M et al. Lancet Oncol 2016) found that substituting nab-paclitaxel for standard solvent-based paclitaxel significantly improved the pathologic complete response (pCR) rate in patients receiving a sequential regimen of taxane, epirubicin and cyclophosphamide as neoadjuvant treatment for high-risk primary breast cancer. Patients with HER2-positive tumors (32.8%; n=396) also received a combination of pertuzumab and trastuzumab: the present analysis focuses on efficacy and safety data from these HER2+ patients treated with the dual-blockade. Methods Patients with histologically confirmed early breast cancer (n = 1206) received either weekly paclitaxel 80mg/m2 or weekly nab-paclitaxel 150/125mg/m2, according to randomization), followed by four cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 q3w, with concurrent trastuzumab 6 mg/kg (loading (LD) dose 8 mg/kg) and pertuzumab 420 mg (LD 840 mg) q3w for those with HER2-positive tumors. The primary endpoint was pathologic complete response (pCR), defined as ypT0 ypN0. Results The GeparSEPTO trial included 396/1206 (32.8%) HER2+ primary breast cancer patients. 27.0% in the HER2-positive and 34.1% in the HER2-negative group had HR-negative disease. Baseline characteristics were otherwise comparable between HER2+ and HER2- patients. Higher rates of pCR were seen in HER2+, compared to HER2- tumors (57.8% vs 22.0%). The highest overall pCR rate was observed in the HER2+/HR- cohort with 71.0%; 66.7% with Pac and 74.6% with nab-Pac. In HER2+/HR+ pCR rate was 52.9% ; 49.4% with Pac and 56.4% with nab-Pac. Using the definition ypT0/is ypN0 for pCR; pCR rates were generally higher especially in the HER2+ cohort (66.2% (ypT0/is ypN0) vs 57.8% (ypT0 ypN0)) compared to 25.2% (ypT0/is ypN0) vs 22% (ypT0 ypN0)) in patients with HER2-negative tumors. The HER2+ patients experienced a significantly higher incidence of grade 3-4 adverse events 85.4% vs 78.0% in the HER2-cohort, p=0.003); grade 3-4 hematologic AEs 74.0% (HER2+) vs 69.5% (HER2-); p=0.120 with grade 3-4 anaemia 2.5% vs 0.9%; p=0.034); any grade thrombopenia 28.5% vs 21.8%; p=0.012) and febrile neutropenia 6.3 vs 3.3%; p=0.023. Any grade 3-4 non-haematological toxicities occurred in 38.4% vs 30.1%; p=0.005), with grade 3-4 diarrhea occurring in 7.6% vs 0.9%; p Conclusion This is the largest cohort of patients with HER2-positive early breast cancer receiving a dual HER2-targeted neoadjuvant therapy of pertuzumab and trastuzumab, together with nab-paclitaxel or paclitaxel followed by epirubicin and cyclophosphamide. HER2+ patients experienced more noteworthy toxicity. The pCR rate were higher in the HER2+ cohort receiving the dual blockade and was highest in patients with in HER+/HR- particularly if nab-paclitaxel was substituted for paclitaxel. The trial is financially supported by Celgene and Roche. Citation Format: Loibl S, Jackisch J, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Schem C, Wiebringhaus H, Kuemmel S, Luebbe K, Warm M, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Engels K, Nekljudova V, von Minckwitz G, Untch M. Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: A subanalysis of data from the randomized phase III GeparSepto trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-06.

Background: The GeparSepto (NCT01583426) study showed that nab-paclitaxel (nP) increases the pathological complete response (ypT0 ypN0) rate when it replaces paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for pts with early breast cancer (BC) (Untch Lancet Oncol 2016). After a safety analysis showed a higher rate of dose reductions, treatment discontinuations as well as peripheral sensory neuropathy (PSN) with nP 150 mg/m2 w (nP150) compared to P 80mg/m2 w, dose of nP was reduced to 125 mg/m2 w (nP125). The risk-benefit ratio of nP125 was improved over nP150 (von Minckwitz SABCS 2015). We reported follow-up (FU) data on PSN occurrence and resolution. Methods: Pts with untreated BC received P 80mg/m2 w or nP 150/125mg/m2 w followed by four cycles of E 90 mg/m2 plus C 600 mg/m2 q3w, with trastuzumab 6 mg/kg (loading (LD) dose 8 mg/kg) and pertuzumab 420 mg (LD 840 mg) q3w if HER2+. After the end of the study the protocol was amended in order to collect long-term data on PSN outcome as well as on treatment modalities. PSN will be reported according treatment and dose received on day 1. Results: Overall 601 pts received P80; 220 pts nP150 and 385 pts nP125 on day 1. PSN grade 2-4 was observed in 18.8% (n=113/601) of pts treated with P80 and in 41.8% (n=92/220) vs 39.2% (n=151/385) with nP150 and nP125 respectively (p=0.547). Grade 3-4 PSN was reported for 2.7% (n=16/601) of pts in the P80 group and 14.5% (n=32/220) vs 8.1% (n=31/385) in the nP150 vs nP125 group respectively (p=0.018). In 31.8% (36/113), 35.9% (33/92) and 27.2% (41/151), PSN was not resolved at the end of the treatment (EOT); PSN grade 3-4 was not resolved in 37.5% (6/16), 56.3% (18/32) and 58.1% (18/31). After a median FU of 110 weeks after EOT, data on PSN status for pts with unresolved PSN grade 2-4 were available from 30, 22 and 32 pts; 26 pts did not provide update information (n=7 died, n=5 data not yet available, n=14 status unknown). For 63.3% (n=19), 40.9% (n=9) and 56.2% (n=18) of pts, PSN grade 2-4 was resolved to grade 1. Time to resolve (TTR) of PSN grade 2-4 was significantly different between nP150 and nP125 (p Conclusions: nP125 is associated with a lower occurrence of PSN compared to nP150 but higher PSN than P80. If PSN occurred nP125 is associated with a more rapid resolution compared to nP150. Nearly 10.7% had no resolution of PSN so far. Further FU and markers for selecting pts at risk are needed. The trial is supported by Celgene. Table 1. Median time to resolution (mTTR) of PSN to grade 1comparison groupsmTTR n (weeks); [95% CI]P vs nPPnP150nP125grade 2-47 [6-9]8 [6-10]grade 3-49 [4-15]17 [5-123]nP150 vs nP125 grade 2-4 13 [9-15]6 [4-9]grade 3-4 56 [11-170]17 [10-nr]abbreviations: nP, nab-paclitaxel; P, paclitaxel; nr, not reached Citation Format: Furlanetto J, von Minckwitz G, Jackisch C, Schneeweiss A, Aktas B, Denkert C, Wiebringhaus H, Kuemmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Untch M, Loibl S. Peripheral sensory neuropathy occurrence and resolution: Results from the neoadjuvant randomized GeparSepto study (GBG 69) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-03.

Introduction The GeparSepto study showed that the substitution of paclitaxel (P) with nab-paclitaxel (nP) followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy increased the rate of pathological complete response (pCR) from 29% to 38% (p Patients and Methods In the GeparSepto trial (NCT01583426) patients were randomized in a 1:1 ratio to receive either nP 125mg/m2 or P 80 mg/m2 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w (Furlanetto et al. Annals Oncol 2016). Patients with HER2+ tumors received trastuzumab 6(8)mg/kg q3w and pertuzumab 420(840)mg q3w concomitantly to all chemotherapy cycles (Loibl et al. Annals Oncol 2016). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d breast carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Primary objective was pCR rate (ypT0 ypN0). Secondary objectives were invasive disease-free survival (IDFS), and overall survival (OS) overall and according to stratified subpopulations, amongst other time to event endpoints, quality of life focusing on peripheral sensory neuropathy (PNP), treatment of PNP, and cardiac toxicity, detection of circulating tumor (ct) DNA at the time of surgery and during follow up and correlation with pCR and early relapses. The IDFS analysis is planned after 248 events have occurred. The log-rank test will have 80% power to detect an improvement of the 5 year IDFS from 75% to 81.8% (HR=0.70) at a 2-sided significance level of α=0.05. Results In 69 German centers, 1229 patients were randomly assigned (07/2012 – 12/2013) to receive either nP (606) or P (600). nP was given for the majority of cycles at a dose of 150mg/m2 to 179 patients and at a dose of 125mg/m2 to 426 patients. Follow-up is still ongoing. The expected number of events will be awaited for October 2017. Conclusion Neoadjuvant GeparSepto study demonstrated a significantly higher pCR rate when patients received nP instead of P as part of an anthracycline/taxane based sequential chemotherapy. The expected long-term results will help to assess the overall benefit of nP in BC and the surrogate value of pCR for survival endpoints. Citation Format: Schneeweiss A, Jackisch C, Schmatloch S, Aktas B, Denkert C, Schem C, Wiebringhaus H, Kümmel S, Rhiem K, Warm M, Fasching PA, Just M, Hanusch C, Hackmann J, Blohmer JU, Gerber B, Furlanetto J, von Minckwitz G, Nekljudova V, Loibl S, Untch M. Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline/cyclophosphamide for patients with early breast cancer – GBG69 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-05.

PURPOSE The GeparSepto trial demonstrated that weekly nanoparticle albumin-bound (NAB)–paclitaxel significantly improves the pathologic complete remission rate compared with weekly solvent-based (sb) paclitaxel followed by epirubicin plus cyclophosphamide as neoadjuvant treatment in patients with primary breast cancer (BC). Here, we report data on long-term outcomes. METHODS Patients with histologically confirmed primary BC were randomly assigned in a 1:1 ratio to 12 times weekly NAB-paclitaxel 150 mg/m2 (after study amendment, 125 mg/m2) or weekly sb-paclitaxel 80 mg/m2 followed in both arms by four times epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks. Patients with human epidermal growth factor receptor 2 (HER2)-positive BC received dual antibody treatment with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) concurrently to chemotherapy and continued for 1 year. RESULTS A total of 1,206 patients started treatment, 606 with NAB-paclitaxel and 600 with sb-paclitaxel. After a median follow-up of 49.6 months (range, 0.5 to 64.0 months), 243 invasive disease–free survival (iDFS) events were reported (143 in the sb-paclitaxel and 100 in the NAB-paclitaxel arm). At 4 years, overall patients treated with NAB-paclitaxel had a significantly better iDFS compared with sb-paclitaxel (84.0% v 76.3%; hazard ratio, 0.66; 95% CI, 0.51 to 0.86; P = .002), whereas overall survival did not significantly differ between the two treatment arms (89.7% v 87.2%, respectively; hazard ratio, 0.82; 95% CI, 0.59 to 1.16; P = .260). Long-term follow-up of the treatment-related peripheral sensory neuropathy (PSN) showed a significant decrease of the median time to resolve PSN after NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2. CONCLUSION The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2.

Background: Breast cancer (BC) with a low hormone receptor (HR) expression (1-9%), although qualifying for endocrine therapy, very often have a molecular phenotype similar to triple-negative BC. In this study we evaluated the clinical behavior of low HR-expressing tumors in a multiparametric cohort of 9027 patients. Methods: We analyzed neoadjuvant clinical trial cohorts (n=4366) and a cancer registry cohort (n=5138). We compared patients with negative [oestrogen (ER) and progesterone receptor (PR)

BackgroundThe association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.MethodsMultiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression.ResultsCompared with no change in immune cell composition and functional markers, transition from ‘cold’ to ‘hot’ (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after ‘hot-to-cold’ transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with ‘altered’ distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14).ConclusionOur exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.

Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-11.

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.

Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response.Patients with TNBC (estrogen receptor/progesterone receptor1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease30% or 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided.A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P.001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01).This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR.

Background: Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery. Methods: This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%. Discussion: As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error). Trial registration: The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017.

BACKGROUND Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m2, methotrexate at a dose of 40 mg/m2, and 5-fluorouracil at a dose of 600 mg/m2 iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m2 iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m2 orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P

Background: Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in breast cancer. A reverse sequence of taxanes followed by anthracyclines was suggested to achieve higher pCR rates (H.Earl, Lancet Oncol 2014). Dual HER2 blockade was shown to be superior to trastuzumab alone increasing the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of paclitaxel (P) encapsulated in albumin which might further improve the pCR rate in breast cancer patients receiving neoadjuvant treatment and cause lower toxicity. Methods: In the GeparSepto study (NCT01583426) patients were randomized to either nP (125 mg/m2) q1w or P (80mg/m2) q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E, epirubicin 90mg/m2; C, cyclophosphamide 600 mg/m2) q3w. The primary objective is to compare the pathological complete response rate (pCR, ypT0 ypN0). Further objectives are to compare the pCR rate in predefined subgroups, pCR by other definitions, clinical response rate, rate of breast conserving surgery and toxicity and compliance. Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. HER2+ patients received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. HER2, estrogen receptor, progesterone receptor, Ki67 and SPARC status were centrally assessed prior to randomization for stratification. To increase the pCR rate from 33% with P to 41% with nP, corresponding to an odds ratio of 1.41 with an alpha of 0.05 and a power of 80%, 1200 patients would be needed. A window-of opportunity study was integrated to investigate response to anti-HER2 treatment without chemotherapy, HER2+ patients were randomized to receive 6 weeks of either trastuzumab, pertuzumab or the combination with biomaterial collection at the start and the end of the window. Results: A total of 1204/1229 (window study n=71) recruited patients (7/2012 - 12/2013) from 69 German centers were evaluable, 606 receiving nP. Baseline characteristics are well balanced; median age was 49/50 years (P/nP), 33/33% of the patients presented with HER2+ tumors, 23/23% triple negative breast cancer TNBC (ER and PR 20% 69/69%; SPARC positive 15.7/16%. 265 patients reported SAEs (119 P/146 nP) and 4 died on study (1 P: cardiac decompensation; 3 nP: accident at home, multiorgan failure, sepsis during EC). The pCR rate (ypT0 ypN0) is 29% with P and 38% with nP, OR 1.5; p Conclusions: GeparSepto showed that the pCR rate is significantly higher with nab-paclitaxel compared to solvent-based paclitaxel given weekly before anthracycline based chemotherapy. Subgroupanalyses and 2ndary endpoints will be presented at the meeting. The trial was financially supported by Roche and Celgene. The window-substudy was funded within the EU-FP7 project RESPONSIFY No 278659. Citation Format: Michael Untch, Christian Jackisch, Andreas Schneeweiß, Bettina Conrad, Bahriye Aktas, Carsten Denkert, Holger Eidtmann, Hermann Wiebringhaus, Sherko Kümmel, Jörn Hilfrich, Mathias Warm, Stefan Paepke, Marianne Just, Claus Hanusch, John Hackmann, Jens-Uwe Blohmer, Michael Clemens, Serban Dan Costa, Bernd Gerber, Valentina Nekljudova, Sibylle Loibl, Gunter von Minckwitz. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-07.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel.Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/mNab-paclitaxel 125 mg/m

BACKGROUND Brain metastases constitute a major clinical concern occurring in 28–43% of women treated for HER2+ metastatic breast cancer (MBC). The initial diagnosis of Central Nervous System (CNS) lesion is commonly based upon development of neurological symptoms. Data to address incidence of CNS lesions in asymptomatic patients are rare and not generally reported. EGF111438/CEREBEL study requires systematic screening for brain metastases by brain MRI and the ineligible patients due to detection of asymptomatic brain metastases are reported here. METHODS The patients screened for CEREBEL have consented to a multi-centre, open-label Phase III study in subjects with HER2+ metastatic breast cancer who received prior treatment with anthracyclines or taxanes and trastuzumab in the adjuvant or metastatic setting. Eligible subjects must not have any history of CNS metastases (including leptomeningeal involvement) or have evidence of benign or malignant brain tumours and/or clinical evidence of spinal cord metastases at baseline. In order to confirm this, subjects must have negative brain MRI at baseline as confirmed by independent review (IR). All MRI scans of the brain had to be acquired with gadolinium contrast agent (T1 only) and 3mm slice thickness without gaps. The primary endpoint of CEREBEL is the incidence of CNS lesions as first site of relapse. A total of 650 subjects (325 per group) are expected to be randomized between capecitabine + trastuzumab versus capecitabine + lapatinib. RESULTS The study is currently recruiting with 322 patients enrolled as of 15.06.2011. At this date, the total number of patients screened were 492 and 170 of these patients were screen failures. There are 15 patients in screening. The percentage of screen failures due to asymptomatic brain metastases assessed by investigators was 13.5% (23/170). The overall incidence of clinically asymptomatic brain metastases assessed by investigators for this study is 4.7% (23/492). CONCLUSIONS Around 5% of all screened patients (14% of screen failures) in this study who were clinically thought to be free of brain lesions actually had brain metastases verified by brain MRI. We therefore conclude that screening for occult brain metastases by MRI is important for trials with defined CNS endpoints. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-03.

573Background: Optimal chemotherapy in TNBC EBC is unclear. ADAPT TN demonstrated higher pCR (46% vs. 29%) and better safety for only 12 weeks nab-paclitaxel/carboplatin vs nab-paclitaxel/gemcitabine (JNCI 2017). Methods: Patients with centrally confirmed TNBC (ER/PR < 1%, HER2-, cT1c-cT4c, cN0/+) were randomized to neoadjuvant A: 4x nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 q3w vs. B: 4x nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1/8 3-weekly (q3w). Primary endpoint was pCR (ypT0/is/ypN0) after 12 weeks of therapy. Event-free (EFS) -- defined as time from registration to any invasive relapse, secondary malignancy or death of any cause -- and overall survival (OS) were secondary endpoints. Adjuvant anthracycline-based chemotherapy (4xEC) was optional in patients with pCR. Here, we report the per-protocol interim survival analysis recommended by the DSMB after a median follow-up of 3 years. Results: 336 patients were enrolled (48 centers, arms A/B: n = 182/154). Median age was 50 years. At ba...

Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age>50 years, and low cellularity ( Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-07.

573 Background: In the ADAPT-TN neoadjuvant trial, 12-week nab-paclitaxel (nab- pac)+carboplatin (carbo) was highly effective and superior to nab-pac+gemcitabine (gem). However, within TNBC, reliable predictive markers for carbo use have yet to be identified. Methods: Patients with early TNBC (centrally confirmed) were treated by nab-pac 125 mg/m2 with either carbo AUC2 or gem 1000 mg/m2 d 1,8 q21 given for 4 cycles. Genomic data (80 genes) and Prosigna (PAM-50) scores were available in 306 pre-therapeutic samples of 331 treated patients. Fisher’s exact test was performed for pCR differences; associations of continuous measurements or scores with pCR were analyzed by the Mann-Whitney statistic. Results: pCR was 44.5% to 28.4% (p=.004) in favor of nab-pac - carbo. Specifically within the carbo- containing arm, immunological (CD8, PD1, PFDL1) genes and proliferation markers (proliferation score and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3, TYMS) were positively associated with pCR (p

Background: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). Patients and methods: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500\textgreekmg q3w) was started at hemoglobin (Hb) levels \15g/dl were reported in 0.8\% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3\%, DA-: 87.5\%; Plog-rank = 0.55) or OS (DA+: 95.5\%, DA-: 95.4\%; Plog-rank = 0.77). Conclusions: DA treatment did not impact EFS or OS in routine adjuvant BC treatment. \copyright The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

1032 Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Neoadjuvant weekly nab-paclitaxel (Nab-Pac) has higher...

TPS1141 Background: Anthracyclines (A) followed by taxanes (T) are standard of care for neoadjuvant therapy in breast cancer (BC). A reverse sequence of T followed by A was suggested to achieve higher pCR rates. Previous studies have shown that dual anti-HER2 blockade is superior to trastuzumab (H) alone and thus can increase the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of P encapsulated in albumin and might also improve the pCR rate with eventually lower toxicity. Methods: The GeparSepto study (NCT01583426) will randomize 1200 patients to either nP (150 mg/m²) q1w or P (80mg/m²) q1w for 12 weeks followed by 4 cycles conventionally dosed EC (E 90mg/m², C 600 mg/m²) q3w for 4 cycles. Primary objective is to compare the pCR rate (ypT0+ ypN0). Patients with untreated, histologically confirmed cT2- cT4d BC can be included. HER2+ patients receive H (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. Biomaterial including FFPE from core biopsy, serum, plasma and full blood is collected. HER2, ER, PgR, Ki67 and SPARC status will be centrally assessed prior to randomization for stratification. P was assumed to achieve a pCR rate of 33% which will be increased to 41% when using nP, corresponding to an odds ratio of 1.41. To investigate resistance to anti-HER2 treatment, patients with HER2+ BC are randomized prior to start of chemotherapy to receive either 6 weeks H, pertuzumab or the combination as biological window with biomaterial collection prior to start of therapy and after week 6 prior to start of chemotherapy. Results: After been approved by ethics committees and authorities recruitment started in 7/2012 in 56 sites. 293 patients were recruited (53 HER2+; 240 HER2-) by 1st Feb 2013. A first safety interim analysis is planned after 60 patients have finished therapy. Conclusions: GeparSepto investigates the efficacy of neoadjuvant nP compared to solvent-based P given weekly with a dual blockade of the HER2 receptor in HER2-pos BC. Interim safety results for nP will be presented. The window-substudy is funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01583426.

Background: Darbepoetin alpha (ARA) is currently used to reduce chemotherapy-associated anemia (CAA) rates in various solid tumors. A possible negative impact of ARA on patient survival has been suggested in some clinical trials. The objective of the prospective randomized phase III ARA Plus trial is to compare the survival effect of darbepoetin alpha use (ARA+/ARA-) in combination with modern standard adjuvant chemotherapy targeting guideline-recommended Hb-levels in high-risk breast cancer (BC). Methods: ARA Plus compared 6 cycles T75A50C500 q3w or 6 cycles F500E100C500 q3w (at discretion of each center) in patients with node positive BC (aged 18–65 years). Patients were randomized to darbepoetin (ARA+) 500 μg q3w until completion of radiotherapy or to standard supportive care (ARA-). ARA was started at Hb-levels ≤13 g/dL (amendment 01/2008: Hb ≤12 g/dL) and stopped at >14 g/dL (>12 g/dL). Primary endpoint is event-free survival (EFS: relapses, death without disease evidence, second malignancy). Overall survival (OS), toxicity, Hb-levels and quality of life are secondary endpoints. Survival analysis was planned after 7 years of study duration. EFS was tested using χ2-test (α=0.05) with a statistical power of β=80% and log-rank test. Quality of life was measured using FACT questionnaires at beginning of therapy, mid, end of therapy, and at 1 year afterwards. Results: 1234 pts (616 ARA+/618 ARA-) from 70 centres in Germany were randomized between 01/04 and 06/08. 1198 intent to treat patients (ITT) were analysed (1096 TAC; 102 CEF). Baseline characteristics were well balanced in ARA+ and ARA- arms: median age 53/53 years; tumor size 2.4/2.4cm; number of + LN 3/3; HR+ 80%/ 83.5%, G3 40.7%/36.7%. Toxicity data have been reported earlier (SABCS 2008). At median follow up of 40 months, 168 events (81 ARA+, 83 ARA-) and 134 relapses (65 ARA+, 69 ARA-) were reported. There was no significant difference in 3-year EFS between ARA+ and ARA- arms (89.2% vs. 87.6%, p=0.97, χ2-test). 37 deaths were reported in the ARA- and 36 in the ARA+ arm. 3-year OS was 95.4% and 95.1% for ARA+ and ARA-, respectively (p=0.85). Only nodal involvement (≥4 vs. 1–3), negative HR, tumor size >2 cm and G3 were significant survival predictors by multivariate analysis. Unplanned retrospective analysis revealed better EFS for ARA+ vs. ARA- in HR- (p=0.05), and no difference in HR+ group (p=0.6). In ARA+ patients, Hb-levels were stable over the whole treatment period with rare overstimulation. In ARA- patients, Hb-levels decreased during therapy (median of all cycles ARA+/ARA-: 12.5/11.6 g/dL). There was no correlation between mean Hb-levels and survival in either study arm. There were no significant differences in mean FACT scores changes (general, anemia, cognitive) from begin to end of therapy in either study arm. More detailed analyses are ongoing. Conclusions: To date, the WSG ARA plus trial is the only prospectively randomized trial in early high-risk BC exclusively focusing on the impact of adjuvant ARA on patient outcome. Supportive administration of ARA appears to be safe and to have no significant survival effect when used in combination with TAC or CEF according to current guidelines. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-06.

Abstract #4100 Background: Modern adjuvant chemotherapy regimens may cause considerable anemia. Epoetins are currently used to reduce chemotherapy-associated anemia (CAA) rates in a variety of solid tumors. The discussion of potential effects on survival rates is highly controversial. The ARA Plus trial is a prospective randomized trial comparing adjuvant chemotherapy +- darbepoetin (ARA+ / ARA-) in node-positive breast cancer patients. Methods: Inclusions criteria were: age of 18 to 65 years, positive lymph nodes (LN) after resection of >10 LN, free margins , M0 status confirmed by conventional staging. At the discretion of the investigating centre patients could receive 6 cycles T75A50C500 or 6 cycles F500E100C500) q3w. They were randomized to darbepoetin (ARA+) 500μg q3w until completion of radiotherapy or to standard supportive care. Darbepoetin was started at Hb level Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4100.