Dose-dense Anthracycline Research Articles

Abstract Mo025: Noninvasive cardiac phenotyping in patients treated with chemo- and immunotherapy for breast cancer

Current breast cancer diagnosis and treatment protocols achieve survival rates of>80% at 10 years.However, long-term cancer survivors have>4-fold higher incidence of cardiovascular complications, including heart failure.Early potentially reversible changes that may underlie downstream irreversible loss of mechanical function are unknown.Therefore, we aimed to test the feasibility of a noninvasive cardiac phenotyping protocol in patients undergoing treatment for breast cancer with doxorubicin, without or with immune checkpoint inhibitors, including multiparametric proton cardiac magnetic resonance(CMR) imaging and novel metabolic carbon13MR. A comprehensive set of studies included conventional 1HCMR,as well as metabolic 13CCMR using hyperpolarized(HP)[1-13C] pyruvate, following an oral glucose load. 13CCMR with HP[1-13C] pyruvate allows the detection of downstream metabolites of injected pyruvate within the myocardium: bicarbonate from mitochondrial oxidation and lactate from anaerobic cytosolic metabolism.HP[1-13C]pyruvate was prepared using dynamic nuclear polarization in a commercial polarizer.Imaging and spectroscopy(MRS) of hyperpolarized pyruvate was conducted using a 13C transmit/receive Helmholtz loop-pair coil on a 3Tscanner.13C data were acquired from a short-axis slice, ECG-triggered in end-systole. ProtonCMR images were analyzed using Circle, and 13CCMR images were analyzed using MATLAB. The left ventricular mid-myocardium and blood pool were segmented for metabolite quantitation. Baseline cardiac studies were performed in a consecutive series of 25 women treated for breast cancer. Of these 14(56%) were Caucasian, 3(12%) were Hispanic, 5(20%) Black, and 3(12%) Asian, with ages ranging 46±11 years.Patients received standard-of-care treatment plans based on the tumor type: 11 patients were treated with dose-dense anthracycline and cyclophosphamide, and 14 also received pembrolizumab. The comprehensive baseline phenotyping protocol is planned to be repeated after standard of care therapy in all patients. Baseline data are presented in Table1, with values reported as mean±standard deviation. Noninvasive cardiac phenotyping, including dynamic detection of metabolic substrate utilization is feasible,without showing significant adverse effects,and is well tolerated in a diverse group of patients.Completion of this protocol post-oncological therapy may allow to detect early changes in cardiac function due to chemo-and immunotherapy in susceptible patients.

Abstract GS01-03: Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial

Abstract Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane chemotherapy (arm A) versus chemotherapy alone (arm B) in early-stage TNBC. Methods: ALEXANDRA/IMpassion030 (NCT03498716) aimed to randomize (1:1) 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients were stratified by type of surgery (breast conserving versus mastectomy), nodal status (0 versus 1-3 versus >=4 nodes), and centrally assessed PD-L1 status (IC 0 vs >=1% ). Adjuvant chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab (Arm A) or the same chemotherapy regimen (T-EC/AC) alone (Arm B). The primary endpoint was invasive disease-free survival (iDFS); secondary endpoints included, iDFS in the PD-L1 positive and lymph node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). On the 14th of November 2022, following an IDMC recommendation, the study accrual was temporarily stopped. In February 2023, the protocol was amended in order for the IDMC to perform an early interim analysis of efficacy and futility, at approximately 62% of the planned (390) iDFS events. The futility boundary was set to a Hazard Ratio (HR) > 1. Results: The IDMC recommendations of 15th March 2023 reported that the primary endpoint crossed the futility boundary, accrual to the study was permanently stopped and the experimental treatment was discontinued. Between August 2018 and November 2022, the study enrolled 2199 patients, with 1101 randomised to the atezolizumab arm (A) and 1098 to the control arm (B). At a median follow-up of 25.3 months, 239 (10.9%) iDFS events were observed in the 2199 enrolled patients; 127 versus 112 iDFS events were observed (61.3% of 390) in the A versus B arms respectively, HR 1.12, (95% confidence interval, CI, 0.87, 1.45). In the PD-L1 positive subgroup, (1567/2199 patients, 71.3%), 77 versus 73 iDFS events were observed in the A versus B arms respectively, HR 1.03, (95% CI 0.75, 1.42). Among patients with lymph node positive tumors (1066/2199 patients, 48.5%), 86 versus 66 iDFS events were observed in the A versus B arm respectively, HR 1.41, (95% CI 1.02, 1.96). Incidence of adverse events grade >=3 was 58.01% versus 48.15% in the A versus B arms, including death in 1.01% (11) and 0.55% (6) of patients, respectively. Conclusions: Crossing the pre-specified futility boundary of HR > 1 provides evidence that adjuvant atezolizumab is very unlikely to improve invasive disease-free survival when added to adjuvant anthracycline and taxane based chemotherapy in patients with stage II-III triple-negative breast cancer. With longer treatment exposure in the atezolizumab arm (A), adverse events were more frequent but consistent with the atezolizumab safety profile. No new or unexpected safety issue was identified. Citation Format: Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Steve Chui, Max Dieterich, Thomas Perretti, Guenther Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, José Zarbá, Marcus Schmidt, Henry Gomez, Angel Guerrero-Zotano, Luca Moscetti, Joanne Win Yang Chiu, Carter DuFrane, Vanessa Honvault, Rosa Altarcheh, Luciana Molinero, Andrew Ellingson, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Gal-Yam, Xavier Gonzalez-Farré, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Ivan Sinielnikov, Zimina Anastasia, Aleksandr Vasiliev, Esther Shearer-Kang, Eric Winer, Diogo Martins-Branco, Shona Fielding, David Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-03.

Observation Effectiveness of Dose-Dense Neoadjuvant Anthracycline Sequential Weekly Paclitaxel for Triple-Negative Breast Cancer Patients

Introduction/BackgroundTo investigate the differences in pathological response and survival outcomes between dose-dense and conventional-interval neoadjuvant chemotherapy (NAC) in patients with triple-negative breast cancer (TNBC). Patients and MethodsPatients with TNBC who received NAC including epirubicin plus cyclophosphamide followed by weekly paclitaxel were included. A total of 494 patients were divided into either the dose-dense anthracycline (ddEC-wP) group or conventional interval anthracycline (EC-wP) group. ResultsThe breast pathological complete response (bpCR, ypT0/is) rate was 45.3% (n = 101) in the dose-dense group and 34.3% (n = 93) in the conventionally scheduled group, which was a significant difference (P = .013), and in the 251 pN+ cases, the lymph node pathological complete response (LNpCR, ypN0) rate was 57.9% (n = 62) in the dose-dense group and 43.7% (n = 63) in the conventionally scheduled group, which was a significant difference (P = .026) in the univariate analysis. In the multivariate logistic regression analysis, 3 variables were predictive of bpCR: pathological type, surgical methods and type of chemotherapy, with P values of .012, .001 and .021, respectively. Two variables were predictive of LNpCR: type of chemotherapy and Her-2 expression, with P values of .039 and .020, respectively. After a median follow-up of 54 months, there was no significant difference in survival for disease-free survival (DFS) (hazard ratio [HR], 0.788; 95% confidence interval [CI], 0.508 to 1.223; P = .288), distant disease-free survival (DDFS) (HR, 0. 709; 95% CI, 0.440 to 1.144; P = .159) or overall survival (OS) (HR, 0. 750; 95% CI, 0.420 to 1.338; P = .330) between the 2 groups. ConclusionOur study demonstrated that TNBC achieved a higher bpCR rate and LNpCR rate after dose-dense neoadjuvant chemotherapy than the conventional scheme. The survival benefit of the 2 groups did not reach statistical difference.

Impact of Aerobic Training on Cardiovascular Function, Fitness, and Patient Reported Outcomes During Anthracycline Chemotherapy: A Case Series in Women With Breast Cancer.

Chemotherapy for breast cancer can increase the risk of cancer therapy related cardiac dysfunction (CTRCD). Exercise has been proposed to prevent CTRCD, however, research to date has indicated high degrees of individual variability following exercise interventions in this population. This study aimed to explore the impact of regular, individualized aerobic exercise on CTRCD incidence (defined by global longitudinal strain [GLS]) during and immediately upon the completion of dose-dense anthracycline (DDAC) chemotherapy in 5 women with breast cancer. Five women receiving DDAC with stage I-III breast cancer enrolled. Participants underwent resting echocardiography and exercise testing before, during, upon the completion of, and 3 months after the completion of DDAC treatment to measure GLS and aerobic fitness (VO2peak). Participants opted-in to an individualized 8-week aerobic exercise intervention (3 sessions per week, 24 sessions total) or standard care for the duration of their DDAC treatment. Data for each participant were presented descriptively. Four of the 5 participants completed the exercise intervention during DDAC treatment (adherence 79.2%-91.7%). Mild asymptomatic CTRCD occurred in 2 of the 4 exercising participants, of whom both were at an increased risk (one was >65 years of age and diagnosed with hypertension, with the other receiving trastuzumab prior to DDAC treatment). Varied responses in VO2peak were observed and did not align with changes in GLS. The only participant not to complete the exercise intervention reported poorer health related quality of life and increased cancer related fatigue at all measurement timepoints. This study details the individual variability in cardiovascular responses to exercise that can occur during DDAC treatment in women with breast cancer, which can inform exercise professionals and researchers when designing individualized exercise programs for this population.

Changes in T-cell subsets and clonal repertoire during chemoimmunotherapy with pembrolizumab and paclitaxel or capecitabine for metastatic triple-negative breast cancer

BackgroundChemoimmunotherapy is a standard treatment for triple-negative breast cancer (TNBC), however, the impacts of different chemotherapies on T-cell populations, which could correlate with clinical activity, are not known. Quantifying T-cell...

ALEXANDRA/IMpassion030: A phase 3 study of standard adjuvant chemotherapy with or without atezolizumab in patients with early-stage triple-negative breast cancer.

TPS597 Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting, it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer. Atezolizumab (an anti–PD-L1 antibody), in combination with nab-paclitaxel has been approved in >70 countries for the treatment of PD-L1-positive unresectable locally advanced or metastatic TNBC based on the results of the randomized phase 3 IMpassion130 trial. The phase 3 IMpassion031 study, evaluating atezolizumab in combination with chemotherapy (nab-paclitaxel followed by doxorubicin and cyclophosphamide) in comparison to placebo plus chemotherapy as neoadjuvant treatment demonstrated a statistically significant and clinically meaningful improvement in pCR in both PD-L1 positive and PD-L1 negative tumors. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial currently investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane adjuvant chemotherapy versus chemotherapy alone in early stage TNBC. Methods: ALEXANDRA/IMpassion030 will randomize 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant chemotherapy consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary endpoint is invasive disease-free survival (iDFS) and secondary endpoints include, iDFS in the PD-L1 selected tumour status (IC1/2/3) and node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first site was activated on May 4 2018, and approximately 373 sites in 30 countries are currently participating in this trial. This trial is sponsored by F. Hoffmann-La Roche Ltd and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinical trial information: NCT03498716.

Abstract P2-16-30: Neoadjuvant therapy outcomes in non metastatic invasive breast carcinomas - Results from a large Brazilian cohort

Abstract Introduction: Neoadjuvant chemotherapy in addition to increasing the rate of breast conservation, offers a invaluable opportunity to monitor individual tumor response which may be related to survival outcomes. In view of this, neoadjuvant treatment has been increasingly used.However, several distinct strategies and protocols are employed in this scenario, depending on the histological subtype and local preferences, and there is no clear definition of which one is the best. Most of the published series are from developed countries. Here we describe results of neoadjuvant therapy for non metastaic breast cancer treated in a single Brazilian cancer center.Objective: To evaluate the clinical and pathological characteristics and survival outcomes of breast cancer patients treated with neoadjuvant chemotherapy diagnosed in a single specialized Brazilian institution. Method: This is an observational, retrospective cohort, which included patients diagnosed with invasive breast cancer (stage I to III) submitted to neoadjuvant chemotherapy between January 2007 and December 2018.Results: We evaluated 685 patients with a median age of 46 years, 23.9% were younger than 40 years of age, 64.2% were premenopausal, 24% had a mutation in the BRCA1/2 gene and 70% were treated in the private.Regarding staging, 2.2% had stage I disease, 33.9% stage II, and 63.9% stage III. Approximately 95% of patients received anthracycline-containing regimens. Among patients with ERBB2+ tumors, 97.1% received an anthracycline regimen and 30.3% received double anti-HER2 blockade. Eleven percent of patients with triple-negative triple tumors received carboplatin, and only 0.5% of the hormone receptor positive patients received neoadjuvant hormone therapy. Forty percent of the patients demonstrated complete clinical response and only 30% of thenderwent conservative surgery. Thirty-seven percent had complete pathological response (RCB-0), 13.1% had minimal residual disease (RCB-1,) 40% had moderate to extensive residual disease (RCB-2 and RCB-3), and 0, 8% presented disease progression. The RCB-0 rate was 45.7% for AC dense dose and 31.9% AC for conventional dose (p=0.001). Regardless of hormonal status, in the subgroup with ERBB2 + tumors, the rate of RCB-0 was 61% for those who received HER2 double-blockade versus 55.1% for those who received anti-HER2 monotherapy (p=0.049). Nineteen percent of the patients progressed during the follow-up, with 17% having locoregional progression. In the last follow-up, 70% of the patients were alive without disease, with a median cancer-specific survival (CSS) of 133 months. The median CSS was 129 months among luminal tumors, 116 months for triple-positive, 117 months for triple-negative, and 91 months for HER2 super-expressors (p=0.008). The median SCC of the patients that achieved RCB-0 was 116 months, 89 months for those who had RCB-III, and 27 months for those who presented disease progression (p=0.004). CSS was the same for patients who received or not anthracycline and for those who were treated or not with dense dose schedules. Twenty percent of patients with triple-negative tumors received carboplatin, 52% had RCB-0 versus 34% for those who did not receive carboplatin (p=0.002), however, we did not observe any difference in CSS between these groups (p=0.109). Patients with triple-negative tumors were the only ones in which we observed a direct association between achieving RCB-0 and better CSS and progression-free survival (PFS) (p=0.001 for both). Conclusion: The administration of dose-dense anthracycline, of carboplatin and of anti-HER2 double-blockade increased the rate of RCB-0, nevertheless, this did not translate into improved CSS. Achiving complete pathological response in the triple-negative subtype was was associated with improved CSS and PFS. Citation Format: Monique Celeste Tavares, Marcelle G Cesca, Fernanda A Oliveira, Poliana Andrade, Camilla A Fogassa, Rafaela Pirolli, Bruna R Mattos, Mariana P Xerfan, Sinara Figueiredo, Fernando AB Campos, Vinicius F Calsavara, Solange M Sanches, Fabiana B Makdissi, Cynthia A Bueno, Marina Sonagli, Marina Canal, Vladmir CC Lima. Neoadjuvant therapy outcomes in non metastatic invasive breast carcinomas - Results from a large Brazilian cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-30.

289TiP - ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early stage triple negative breast cancer

BackgroundEarly stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer. On March 8th 2019, the Food and Drug Administration approved anti–PD-L1 antibody, atezolizumab, in combination with chemotherapy for the treatment of PD-L1-positive unresectable locally advanced or metastatic TNBC based on the results of the randomized phase 3 IMpassion130 trial. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial currently investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane adjuvant chemotherapy versus chemotherapy alone in early stage TNBC. Trial designALEXANDRA/IMpassion030 will randomize 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant chemotherapy consist of weekly paclitaxel 80mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90mg/m2 or doxorubicin 60mg/m2) and cyclophosphamide 600mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840mg every 2 weeks followed by maintenance atezolizumab 1200mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first site was activated May 4th 2018, and approximately 430 sites are expected to open globally in 30 countries. This trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinical trial identificationNCT03498716. Legal entity responsible for the studyThis trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. FundingRoche. DisclosureM. Ignatiadis: Advisory / Consultancy: Celgene, Novartis, Pfizer, Seattle Genetics, Tesaro; Research grant / Funding (institution): Roche, Menarini Silicon Biosystems, Janssen Diagnostics, Pfizer; Travel / Accommodation / Expenses: Pfizer,Bayer. H.L. McArthur: Advisory / Consultancy: LIlly, Amgen, Immunomedics, Pfizer, Genentech, BMS, Genomic Health, Merck, spectrum pharmaceuticals; Research grant / Funding (institution): BMS, Lilly, Merck, Ziopharm Oncology. J. Martinez: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.. C. Lai: Full / Part-time employment: Roche/Genentech; Shareholder / Stockholder / Stock options: Roche/Genentech. T. Goulioti: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.; Shareholder / Stockholder / Stock options: GlaxoSmithKline; Spouse / Financial dependant: GlaxoSmithKline, UCB. A. Bouhlel: Full / Part-time employment: Roche. V. Balta: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.. G. Viale: Honoraria (self): MSD Oncology; Advisory / Consultancy: Dako, Roche/genentech, Astellas Pharma, Novartis; Research grant / Funding (self): Roche/genentech; Research grant / Funding (institution): Ventana Medical Systems, Dako/Agilent Technologies; Travel / Accommodation / Expenses: Roche, Celgene. D.A. Nguyen: Shareholder / Stockholder / Stock options: Roche/Genentech; Full / Part-time employment: Roche/Genentech. R.D. Gelber: Research grant / Funding (institution): Roche, Novartis, Pfizer, Merck, Celgene, Ferring, Ipsen, AstraZeneca. M. Piccart: Officer / Board of Directors: Radius; Advisory / Consultancy: AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Camel-IDS, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics, Menarini, Seattle Genetics, Immunomedics, Oncolytics; Research grant / Funding (institution): AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, Servier. E.P. Winer: Honoraria (self): Genentech, Leap, Carrick Therapeutics, Lilly, Seattle Genetics, GSK. All other authors have declared no conflicts of interest.

ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early-stage triple-negative breast cancer.

TPS598 Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with the anti–PD-L1 antibody, atezolizumab, in Phase 1/1b metastatic TNBC trials. Furthermore, the randomized phase 3 IMpassion130 study demonstrated enhanced anti-tumor activity when atezolizumab was co-administered with chemotherapy in the first line metastatic setting, with benefit mainly observed in PD-L1+ cohort. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard anthracycline/taxane adjuvant chemotherapy in early TNBC patients. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients with operable stage II or III TNBC, confirmed by central pathology review, will be randomized. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on August 2nd 2018, and approximately 430 sites are expected to be opened globally in 30 countries. Clinical trial information: NCT03498716.

Abstract OT3-05-02: ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early triple negative breast cancer

Abstract Background: Triple negative breast cancer (TNBC) is a subtype with a high risk of relapse in the early disease setting. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. A growing body of evidence indicates that TNBC is more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with atezolizumab (an anti–PD-L1 antibody) in Phase 1/1b metastatic TNBC trials. Furthermore, the anti-tumor activity of PD-1/PD-L1 targeting drugs is hypothesized to be enhanced when co-administered with chemotherapy. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard adjuvant chemotherapy in early TNBC. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomised, open-label Phase 3 trial investigating the efficacy, safety and pharmacokinetic (PK) profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients diagnosed with non-metastatic operable stage II or III TNBC confirmed by central pathology review will be randomised. TumorPD-L1evaluationwill be performed centrally. Patients will be stratified by type of surgery, nodal status, and PD-L1 status. The adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. Primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumour tissue and blood samples will be collected for biomarker research. The first site was activated in May 4th, and approximately 430 sites are expected to be open globally in 30 countries. This trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinicaltrials.gov NCT03498716. Citation Format: Ignatiadis M, McArthur H, Bailey A, Martinez J-L, De Azambuja E, Metzger O, Lai C, Ponde N, Goulioti T, Daly F, Bouhlel A, Balta V, Van Dooren V, Viale G, Maetens M, Dufrane C, Nguyen Duc A, Winer E, Gelber R, Piccart M. ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early triple negative breast cancer [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 OT3-05-02.

Abstract P1-13-08: A prospective non-randomized clinical trial of adjuvant carboplatin chemotherapy in triple negative breast cancer

Abstract Background: The addition of carboplatin in the neoadjuvant setting has demonstrated improved outcomes in patients with triple negative breast cancer (TNBC). Carboplatin in the adjuvant setting has not been demonstrated to be an accepted regimen to date. This trial addresses this issue. Methods: The primary objectives of this study were to assess the toxicity of an adjuvant carboplatin-containing regimen for early stage TNBC patients, and to correlate outcomes with molecular markers including Spy-1. Secondary objectives included determination of progression free (PFS) and overall survival (OS), and comparing these to our institutional historical controls. Patients received the backbone of a dose dense anthracycline, taxane, cyclophosphamide (DD ACT), with the addition of carboplatin. Results: Ninety patients with stage I to III patients with triple negative breast cancer were accrued to this trial between Jan 2011 and June 2017. We discovered that DD ACT with carboplatin with an AUC of 5 given on the second and last paclitaxel was well tolerated. Chemotherapy delays were minimized when the parameters for administration of the carboplatin was to allow chemotherapy to proceed if the platelet count was >/= 70,000 x10^9/L and dose adjustment of paclitaxel was allowed based on neuropathy. There were no grade 4 adverse events. 4% of patients had grade 3 peripheral neuropathy (PN), 28% had grade 2 PN and 45% had grade 1 PN. Results of molecular profiles will be reported. Univariate analysis are reported, and were found to be very promising. Using log-rank statistic, a trend to improvement in overall survival was found when compared to historical controls (p=0.089). Median follow-up is 24 months. Longer follow-up is necessary to determine PFS and overall survival benefit. Conclusion: If considering an adjuvant regimen for triple negative breast cancer patients DDAC/TC with the carboplatin administered with an AUC of 5 on the second and fourth taxol of DDACT is a well-tolerated regimen. Univariate Analysis Comparing Carboplatin vs Historical Controls that did not receive CarboplatinVariableHistorical (no carbo)Carbo containing chemop overall n = 179n = 82 Age56.3 (13.1)49.8 (11.0)< 0.001Stage0.188Stage I47 (26.3%)15 (18.3%) Stage II88 (49.2%)50 (61.0%) Stage III44 (24.6%)17 (20.7%) Grade0.011Grade 18 (4.5%)0 (0.0%) Grade 233 (18.4%)7 (8.8%) Grade 3138 (77.1%)73 (91.2%) Remission Status0.009In Remission126 (70.4%)70 (86.4%) Relapsed53 (29.6%)11 (13.6%) Survival< 0.001Alive121 (67.6%)73 (90.1%) Deceased58 (32.4%)8 (9.9%) Citation Format: Hamm C, Kulkarni S, Gupta R, Mathews J, Amin K, Hussein A, Porter L. A prospective non-randomized clinical trial of adjuvant carboplatin chemotherapy in triple negative breast cancer [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 P1-13-08.

Abstract P5-17-05: Outcome of triple negative inflammatory breast cancer (TNIBC) treated with dose-dense dose intense neoadjuvant chemotherapy (NAC), prognostic impact of post NAC lymphovascular invasion and tumor infiltrating lymphocytes (TIL)

Abstract Background Inflammatory breast cancers (IBC) particularly triple negative (TN) subtype have poor prognosis. There are few series reporting IBC outcome according to their immunohistochemical profile. We have already shown the efficiency of dose dense dose intense chemotherapy in triple negative breast cancer (1). We report a series of TNIBC treated with dose dense anthracycline cyclophosphamide followed with taxane and analyzed the correlation between pathological complete response (pCR), pre and post NAC TIL, post NAC LVI and disease free survival (DFS). Methods Between January 2010 and December 2016, all patients with TNIBC seen at breast cancer disease center, St Louis hospital, Paris, France, were treated with neoadjuvant dose dense dose intense Cyclophophamide (1.2g/m2 d1) - Epirubicin (75mg/m2 d1) q2w (SIM regimen) followed with 12 injections of paclitaxel (80 mg/m2) qw or 4 injections of docetaxel (100 mg/m2) q3w. All patients have histologically proven TN tumors and no evidence of metastases assessed by initial FDG PET Scanner. Mastectomy and axillary clearance was performed after chemotherapy. pCR was defined as no residual invasive tumor in breast and lymph nodes. TIL and lymphovascular invasion were evaluated pre and post NAC by 2 independent anatomopathologists dedicated to breast cancer. Delta TILS was defined as the difference between post chemotherapy and pre chemotherapy TIL. Results Thirty TNIBC pts were treated, 28 underwent surgery and 2 progressed during chemotherapy. Median follow-up was 39 months (8 – 86). 9/30 patients (30%) achieved pCR. Median disease free survival (DFS) was 41 months (2 – 86). Median TIL infiltration at diagnosis was 11% (0-60) and dropped to 1% after chemotherapy (0 – 80). Median delta TIL was - 9% (-50% – +40%). TIL increase after chemotherapy was associated with a decrease of DFS (14 months vs not reached ; p = 0,0009). LVI was present on surgical specimens in 12 cases (12/30, 43%; 12/21 non pCR pts 57 %). Presence of LVI after chemotherapy was significantly associated with a decrease of DFS in the whole population (21 months vs not reached ; p = 0.008) and no significantly among the patients without pCR (23 months vs not reached; p = 0.07). Conclusion To the best of our knowledge, it is the best pCR rate reported in TNIBC (2). We showed in this retrospective series of 30 TNIBC that dose dense dose intense chemotherapy is efficient in this population. Presence of lymphovascular invasion and TIL after neoadjuvant chemotherapy in TNIBC are strong prognostic factors associated with DFS. Systematic determination of post NAC TIL and LIV could be a surrogate to propose adjuvant treatment after NAC in TNIBC.

Evaluation of tolerability and efficacy of incorporating carboplatin in neoadjuvant anthracycline and taxane based therapy in a BRCA1 enriched triple-negative breast cancer cohort

PurposeThe addition of carboplatin (Cb) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) has been demonstrated to improve pathologic complete response (pCR) at the expense of increased toxicity. We aimed to evaluate the effectiveness and tolerability of dose-dense anthracycline & cyclophosphamide (ddAC) followed by weekly paclitaxel (wT) in combination with weekly Cb. MethodsRetrospective data was collected on patients with clinical stage I-III TNBC treated with neoadjuvant ddAC-wTCb (four cycles of ddA 60 mg/m2 and ddC 600 mg/m2 every 2 weeks followed by 12 cycles of wT 80 mg/m2 with Cb AUC 1.5). Indices of tolerability and pCR were evaluated and compared to a historical cohort (n = 76) treated with ddAC-T. A secondary objective was to evaluate the rates of pCR by BRCA status. ResultsFor 43 eligible patients, mean age was 41.5 years, 51% had clinical stage II disease, 81.4% were clinically node positive and 32.6% carried a deleterious BRCA1 mutation. Only 35% completed all scheduled doses of chemotherapy. Grade 3/4 neutropenia was observed in 42.5% of patients. Overall pCR was 51.2%; 44.8% in BRCA wild-type compared to 64.3% in BRCA–associated TNBC (p = 0.232). pCR rates with ddAC-wTCb were similar to historic institutional rates with ddAC-T (51.2% vs. 51.3%, p = 0.987) and were comparable when stratified by BRCA status. In pooled multivariate analysis, only BRCA status (HR 4.00, 95%CI 1.65–9.75, p = 0.002) was significantly associated with pCR. ConclusionNeoadjuvant ddAC-wTCb is less tolerable in clinical practice compared to most clinical trials, with a pCR comparable to historic rates using non-platinum regimen. The role of Cb in neoadjuvant chemotherapy for BRCA mutated TNBC remains uncertain.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG)

Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. NCT01985724.

Abstract P1-14-08: Prediction of pathological response (pCR) to neoadjuvant dose dense and intense cyclophosphamide and anthracycline in a prospective series of triple negative locally advanced breast cancers (TNLABC)

Abstract Background: Stage II-III TNBC retains a poor outcome despite high chemosensitivity. Patients (pts) with pCR after neoadjuvant chemotherapy have a good prognosis whereas non-responding pts have a 25-40% risk of distant relapse at 5 years. pCR is thus a major goal in TNBC. We previously reported that TNLABC benefit the most of dose dense dose intense cyclophosphamide (C)-epirubicin (E) (S.Giacchetti; BJC, 2014) Aim: To confirm these results prospectively and analyze the predictive factors of response to high dose chemotherapy in TNBC. Patients and methods: From january 2009 to april 2015 non inflammatory TNLABC received high dose C (1200 mg/m2 d1 qw 2) with E (75 mg/m2/ d1 qw2) for 6 cycles. The pts had a breast biopsy with frozen tissue. We performed molecular studies: qRT-PCR for AR, FOXA1, PI3K and FASAY technic for p53 mutation.The percentage of stromal Tumor-infiltrating lymphocytes (TILs) was also evaluated by two independent pathologists and assessed as a continuous variable. A18F-FDG PET/CT was performed initially and after 2 courses of chemotherapy and the metabolic answer assessed as a variation of the tumor uptake (ΔSUVmax). We report here the pathological complete response (pCR) (absence of infiltrative carcinomas in the breast and in the lymph nodes) and the factors associated with pCR. Results: The characteristics of the 74 pts are listed in table 1. The median age is 48 years old, 48 pts (65.8%) are premenopausal and 79% did not have any family history of breast cancers. TIL was divided in 3 groups &amp;lt; 10 % (26 pts, 40 %); 10-50 % (30 pts, 46 %) &amp;gt; 50% (9 pts, 14 %). Pathological response was assessed in 66 pts, one pt progressed during chemotherapy and 6 pts did not undergo surgery yet. 28 pts were in pCR (42.4 %). With a median follow up of 25 months, 13 pts (17.8 %) progressed and 8 (11%) died. Table 1: Patients characteristics and pCR according to tumor features and metabolic responseCharacteristicsNumber of pts (%)N of pts evaluated for pCRpCR (%)OR [IC 95%]p-valueTumor size T2363519 (54)10.04T337319 (29)0.34 [0.12 ; 0.96]Nodal status N0363315 (46)10.62N1/N2/N3 24/11/33313 (39)0.78 [0.29 ; 2.07]Histological grade: 2660 (0) 0.04*3676028 (47)TILs &amp;lt;10 %26 (40)2510 (40)10.02610-50 %30 (46)267 (27)0.55 [0.17 ; 1.80]≥ 509 (14)9 7 (78)5.25 [0.90 ; 30.62]P53 Mutated54 (89)5121 (41)10.43WT7 (12)53 (60)2.14 [0.33; 13.96]AR Negative43 (83)4318 (42)10.46Positive 9 (17)95 (56)1.74 [0.41 ; 7.38]FOXA1 Negative40 (77)4015 (38)10.08Positive 12 (23)128 (60) 3.33 [0.86 ; 12.99]Molecular Apocrine8 (17)85 (63)10.19TN38 (83)3814 (37)0.35 [0.07 ; 1.69]PI3K Non mutated44 (88)4419 (43)10.75Mutated6 (12)63 (50)1.31 [0.24 ; 7.26]SUVmax at 2 courses0.0001&amp;lt; 70 %27 (53)221 (5)1≥ 70 %24 (47)2318 (78)79.2 [8.48 ; 739.82]* Measured with a Fisher Test Tumor size, tumor grade, percentage of TILs, the change in 18F-fluorodeoxyglucose tumor uptake (ΔSUVmax) were significantly associated with pCR at univariate analysis. Only one factor remained significant at multivariate analysis, the ΔSUVmax, OR: 0.04 [0.007- 0.27], p = 0.0008. Conclusion: In this prospective phase III trial we confirm the efficacy of a dose dense EC in TNBC. The metabolic response evaluated with 18 F-FDG PET/CT is a strong and reliable predictor of pCR and could allow an early change of treatment for the non responders. A clinical trial is planned to test this strategy. Citation Format: Giacchetti S, De Roquancourt A, Groheux D, Piron P, Lehmann-che J, Cuvier C, Resche-rigon M, Albiter M, Roche B, Frank S, Hamy A-S, Teixeira L, Marty M, Lalloum M, Espié M. Prediction of pathological response (pCR) to neoadjuvant dose dense and intense cyclophosphamide and anthracycline in a prospective series of triple negative locally advanced breast cancers (TNLABC). [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 P1-14-08.

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance).

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha=0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio=1.20; 95% confidence interval=0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P<0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P=0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P<0.0001), but no association with treatment benefit was seen (P=0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Pegfilgrastim (P) administration after 24, 72, or 96 hours (h) to allow dose-dense (DD) anthracycline- and taxane-based chemotherapy (CT) in breast cancer (BC) patients (pts): A single-center experience within the GIM2 randomized phase III study.

9632 Background: The GIM2 study (ClinicalTrials.gov number, NCT00433420) compared two different schedules of CT (DD versus standard duration) as adjuvant treatment of 2,091 node positive BC pts. DD...

Abstract P6-12-13: Synchronous metastases are highly prevalent in HER2 positive inflammatory breast carcinomas evaluated by 18F-FDG PET/CT

Abstract Background: Inflammatory breast carcinomas have poor prognosis even in the absence of evident synchronous metastases. 18F-FDG PET/CT is not recommended in initial staging but could improve the sensibility of synchronous metastases detection and the management of the patients. Objective: To assess factors associated with synchronous metastases in inflammatory breast carcinomas when evaluated by 18F-FDG PET/CT. Methods: Since 2006, initial staging of locally advanced breast carcinomas in our center consisted of 18F-FDG PET/CT in addition to standard laboratory and radiological tests. We reviewed data of patients with inflammatory breast carcinomas treated from 2006 to 2013 who had an initial evaluable18F-FDG PET/CT. Fisher's exact test and logistic model were used to assess factors associated with synchronous metastases. Overall survival was estimated with the method of Kaplan-Meier. Results: Among 353 locally advanced breast carcinomas seen at the breast disease unit, hospital Saint Louis from 04/2006 to 04/2013, we identified 40 inflammatory breast carcinomas. Initial 18F-FDG PET/CT was available for review in 32 inflammatory breast carcinomas. Median age was 57 years (range 38-78), 39% had pre-menopausal status (n = 12), clinical node involvement was found in 87.5% (n = 28). Histological features on biopsy were: ductal invasive carcinoma 91% (n = 29), SBR grade III 72% (n = 23), negative hormonal receptor 75% (n = 24), positive HER2 37.5% (n = 12), triple negative 44% (n = 14). Synchronous metastases were found in 41% of inflammatory breast carcinomas (n = 13), bone (n = 7), liver (n = 6) and mediastinum (n = 4). Synchronous metastases seemed more common in HER2 positive than in HER2 negative inflammatory breast carcinomas (58% vs 30%, p = 0.15). In multivariate analysis, no factor was associated with synchronous metastases. All patients with inflammatory breast carcinomas received neoadjuvant chemotherapy with sequential anthracycline and taxane (16 patients), dose-dense anthracycline and alkylating agent (8 patients), taxane with or without bevacizumab (7 patients) and anthracycline in 1 patient. Trastuzumab was given in all HER2 positive inflammatory breast carcinomas. Clinical response to neoadjuvant chemotherapy was complete in 16.5% (n = 5), partial in 67% (n = 20), stable or progressive in 16.5% (n = 5) and missing for 1 patient. One patient died before response assessment. Thirty patients (94%) underwent radical mastectomy with axillary node dissection. Pathologic complete response in breast and nodes was found in 27.5% (n = 8). Axillary node invasion was found in 45% (n = 13). All positive hormonal receptors patients received endocrine therapy after surgery. With a median follow-up of 33 months, 10 patients died. Median overall survival was 38.8 months (95%CI: 30.3-NA) with no difference between HER2 positive and HER2 negative patients. Conclusion: Synchronous metastases are common in inflammatory breast carcinomas especially in case of HER2 positive tumors. Complete initial staging with 18F-FDG PET/CT could be useful to detect synchronous metastases mainly in bone and liver and thus allowed to adapt further treatment. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-13.

Feasibility and safety of dose-dense docetaxel after conventional epirubicin and cyclophosphamide as adjuvant treatment for early breast cancer patients

BackgroundAlthough dose-dense chemotherapy may reduce breast cancer recurrence and death, phase II studies show that dose-dense docetaxel is poorly tolerated following administration of dose-dense anthracycline-based chemotherapy mainly because of cutaneous toxicity. Material and methodsThis pilot study was designed to explore feasibility and safety of dose-dense docetaxel after conventional anthracycline-based therapy.Treatment consisted of sequential administration of 4 cycles of 3-weekly epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2), followed by 4 cycles of bi-weekly docetaxel with pelfilgrastim on day 2 of each docetaxel cycle. Two docetaxel dose levels were planned: 75 mg/m2 (D75) and 100 mg/m2 (D100). Patients could only be assigned to the higher docetaxel dose if no early treatment discontinuations due to toxicity were seen, and a median relative dose intensity of docetaxel >90% among the first 5 evaluable patients was achieved. ResultsFifty three patients received 4 cycles of epirubicin/cyclophosphamide (EC). Six patients withdrew from study before commencing docetaxel: four for toxicity, and two who declined further study participation.Eight patients, 2 in the first dose level and 6 in the second dose level, stopped treatment for toxicity after the first cycle of docetaxel and before densification. Therefore these events were not considered early treatment discontinuations. No patients required dose interruption after the second docetaxel administration. Overall 5 patients in the first dose level and 34 patients in the second dose level received 4 cycles of accelerated (dose-dense) docetaxel. No grade 3 or grade 4 toxicities occurred at the first dose level. No grade 4 toxicities occurred at the second dose level, while grade 3 toxicities occurring in >2 patients were myalgia and bone pain (5 and 8 patients respectively, 13% and 20%) and skin-nail toxicity (7 patients, 21%). No dose-reductions or significant treatment delays were required, translating to median relative dose intensity of 100% for docetaxel 75 mg/m2, and 99% for 100 mg/m2. ConclusionsAdministration of docetaxel 100 mg/m2 bi-weekly after conventional EC is feasible in selected early breast cancer patients. Lack of prior exposure to dose-dense anthracycline, as well as the use of stringent criteria implemented in the treatment protocol, might explain the improved safety profile and high treatment compliance observed in this study.

Abstract P1-17-03: Comparison of Long Term Outcome of Locally Advanced and Inflammatory Breast Cancers Treated with Dose Dense Neoadjuvant Chemotherapy

Abstract Background: Inflammatory breast cancers (IBC) have a worse prognosis than locally advanced breast cancer (LABC) (KW Hance, JNCI 2005; 97:966-75). We report a series of LABC and IBC treated with dose dense anthracycline and cyclophosphamide and report the correlation between phenotypic features, pathological complete response (pCR) and disease free survival (DFS). Materials and methods: Between 1990 and 2003, 196 patients (pts) with LABC (105 pts) and IBC (91 pts) treated at St Louis hospital received 6 cycles (c) of dose dense Cyclophophamid (1.2g/m2 d1)-Epirubicin (E) (75mg/m2d1) q2w (SIM regimen). 133 patients had frozen biopsy allowing p53 determination. Surgery was done after chemotherapy. pCR was defined as no residual invasive tumor in breast and lymph nodes. Results: Median follow-up was 110 months. IBC were more often ER negative than LABC(52 % vs 34%), more often triple negative (33 % vs 22 %) and more often TP53 mutations .(60% vs 39 %). pCR in breast and lymph nodes was identical in LABC (17 pts,16%) and in IBC (14 pts, 16 %). Table I Pathological response and factors associated with pCR Negative ER and presence of TP53 mutations were strong predictive factors of chemotherapy efficacy in LABC and less in IBCS. histologically grade 3 was not predictive in IBC. Median disease free survival (DFS) was higher in LABC [103 months (m)] than in IBC (54 m), p=.031. Median Overall survival (OS) was not reached in LABC and was of 134 m in IBC (p = .015). A significant effect of ER status on DFS was found in LABC and IBC. When adjusting for ER, IBC still had a significantly shorter DFS (HR 1.64, 95%CI 1.12 to 2.39, P=.011). Similar results were found for OS. For TP 53, a significant interaction was found with LABC/IBC (p=0.017) with a risk for mutated patients in LABC (p=0.004) and a slight and nonsignificant increased risk in IBC patients (p=0.62). Estimated disease free survival at 15 years Conclusion: High risk patients treated with dose dense cyclophosphamide and anthracyclin have very long survival rate. Negativity of ER and p53 mutations are strong predictive factors of good outcome in LABC but less in IBC. This approach in ER-LABC should be prospectively studied.. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-17-03.