Adjuvant TC Research Articles

The Omission of Anthracycline Chemotherapy in Women with Early HER2-Negative Breast Cancer-A Systematic Review and Meta-Analysis.

Anthracycline-taxane is the standard chemotherapy strategy for treating high-risk early breast cancer despite the potentially life-threatening adverse events caused by anthracyclines. Commonly, the combination of docetaxel and cyclophosphamide (TC) is considered an alternative option. However, the efficacy of TC compared to anthracycline-taxane chemotherapy is unclear. This study compares disease-free survival (DFS), overall survival (OS) and cardiotoxicity between adjuvant TC and anthracycline-taxane for stages I-III, HER2-negative breast cancer. A systematic search on MEDLINE, Embase and Cochrane CENTRAL for randomized-controlled trials published until 11 March 2024, yielded 203 studies with 11,803 patients, and seven trials were included. TC results in little to no difference in DFS (HR 1.09, 95% CI 0.98-1.20; moderate-certainty of evidence); OS (1.02, 95% CI 0.89-1.16; high-certainty of evidence); and cardiotoxicity (RR 0.54, 95% CI 0.16-1.76; high-certainty of evidence), compared to anthracycline-taxane. In the subgroup analysis, patients with ≥4 lymph nodes had improved DFS from anthracycline-taxane over TC. Overall, there was no difference between TC and anthracycline-taxane in DFS, OS and cardiotoxicity. In women with ≥4 nodes, anthracycline-taxane was associated with a substantial reduction in relapse events, compared to TC. Our study supports the current standard of practice, which is to use anthracycline-taxane and TC chemotherapy as a reasonable option in select cases.

Prediction of therapeutic response and cancer outcomes in solid tumours via in silico clinical trials.

e13603 Background: Oncology therapeutic development has high failure rates with substantial costs. Advances in technology, including molecular characterisations of cancer and computational power, provide the opportunity to better model therapeutic response for existing and emerging therapies. Methods: Concr adapted Bayesian statistical principles used by astrophysicists to effectively integrate multi-dimensional data (genomic & transcriptomic) for accurate modelling of cancer biology. Our proprietary computational framework was applied to predict clinical response and survival through construction of digital twins and in silico simulations of clinical trials. Predicted log odds ratios (LOR) were generated for drug response and compared to published data from 8 suitable historical clinical trials. Three distinct models underpin this framework: Drug Efficacy, Treatment Response & Overall Survival (OS). Three publicly available datasets were used for training: Cancer Therapeutic Response Portal ( in vitro dose-response data), Cancer Cell Line Encyclopaedia and TCGA. Results: For all 8 clinical studies, the digital twin model accurately simulated both trial arms, compared drug efficacy across arms and predicted which treatment was most active. Unblinded evaluation: Our model accurately predicted gemcitabine would have greater clinical benefit than 5-FU (LOR -0.10, P <0.0001) in metastatic pancreatic cancer. In advanced breast cancer, the model predicted docetaxel had a higher response rate than doxorubicin, and carboplatin response rates were similar to docetaxel in BRCA wild-type patients. In platinum-sensitive recurrent ovarian cancer, the model predicted cisplatin-based combination had a higher response rate than paclitaxel. Blinded evaluation: Using data for paclitaxel, the model correctly predicted that nab-paclitaxel+gemcitabine response rates were higher than gemcitabine in metastatic pancreatic cancer (predicted LOR -0.090, p = <0.001). In all 3 early breast cancer studies, predictions mirrored clinical trial results, adjuvant ECF > CMF, adjuvant TC > AC and adjuvant tamoxifen was superior to capecitabine. The underlying pan-tumour Overall Survival model used a Random Survival Forest approach, trained on 23 cancers with predictive accuracy of 0.78 AUC ROC and C-index 0.71. To enable cohort enrichment for drug response, the model segmented patient cohorts into treatment responder and non-responder. Using this approach, the log odds increased for drug response rate for 16 of the 19 different cancers and 14 of the different 17 drugs. Conclusions: Our digital twin model represents transformative technology for clinical trial simulation with strong potential for accelerating and de-risking clinical drug development, and utility for synthetic control arms.

Quantifying Chemotherapy Delivery in Older and Younger Women With Early-Stage Breast Cancer Using Longitudinal Cumulative Dose.

Delivery of cancer treatments, such as chemotherapy, requires a complex set of decisions that can change over time. Traditional measures of chemotherapy delivery, such as relative dose intensity, measure the amount of chemotherapy received by the end of treatment but mask the timing of dose reductions, delays, and discontinuation. These events may be important for delivering timely interventions to support adherence and lower the risk of recurrence. We used an institutional database to identify women diagnosed with stage I-III breast cancer receiving adjuvant chemotherapy with a standard 4-cycle regimen of docetaxel + cyclophosphamide (TC, every 21 days) from April 2014 to December 2019. LCD was calculated as the amount of a given chemotherapy agent delivered at a specified time, t, divided by the total planned standard chemotherapy dose at time t. We visualized LCD curves for each chemotherapy agent and reported the median LCD and interquartile range (IQR) at the end of the regimen, overall and by age group (<65 years vs. 65+ years). The study population included 80 women. At the end of treatment, overall median LCDs for both cyclophosphamide and docetaxel were 100% (IQR: 99.6%, 100%), suggesting that TC was well tolerated. However, the lower quartile LCD for cyclophosphamide was 98.7% in older women treated with TC compared with 99.7% in younger women. Within our cohort, adjuvant TC was well tolerated with LCD curves showing largely on-time and full-dose administration. Subgroup analyses showed only slight decreases in adjuvant TC LCD for patients aged 65+ versus <65 years.

Abstract P1-01-04: Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis

Abstract Background: Among women, breast cancer is the most common diagnosis of non-skin cancer and the fifth cause of oncological-related death worldwide. Adjuvant chemotherapy has been shown to extend overall survival (OS) and disease-free survival (DFS). Anthracyclines are cytotoxic regimens largely used in breast cancer, mainly in patients with risk factors or high burden of disease. The docetaxel and cyclophosphamide (TC) regimen is a Taxane-based treatment, and is an alternative option when anthracyclines are not indicated. However, anthracyclines have a myriad of adverse effects including alopecia, cardiac-related side effects and myelotoxicity. The question that remains is in which breast cancer population anthracycline chemotherapy should be omitted. Methods: A literature search was performed in Embase, Medline, and the Cochrane Libraries up to February 28 2022. We conducted an individual patient-level meta-analysis of 11,902 participants of 7 randomised controlled trials. The target population was adult women, with a histologically confirmed HER2 negative, stage I-III breast cancer who were treated with TC versus anthracycline-based chemotherapy in adjuvant setting under randomised-controlled trials. To analyse OS and DFS, we utilized the generic inverse variance method for time-to-event outcomes using hazard ratio (HR). A sensitivity analysis of risk of bias (ROB) was undertaken to examine the effects of high/moderate risk studies on each study endpoint. The assessment of certainty of evidence was conducted based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Results: With a median follow up of 60 months, the pooled analysis from 7 studies with available data on OS, and from 6 studies on DFS. From a total of 11,778 there was a total of 288 and 281 events of death in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of OS revealed HR 1.01, 95% CI (0.86 – 1.19), p = 0.88; high certainty of evidence. From a total of 11,902 participants, there were 639 and 595 recurrence events in the TC and in the anthracycline-based chemotherapy groups, respectively. The analysis of DFS revealed HR 1.07, 95% CI 0.95-1.22, p=0.26; moderate certainty of evidence. No relevant absolute risk of death or recurrence events were found between the two treatments. In the quality of evidence assessment, the heterogeneity across all the studies is likely not more than what is due to chance (i2&amp;lt; 14%). The risk of bias was not a serious concern, and the publication bias was undetected for the endpoints OS and DFS. Conclusion: In this study population, TC chemotherapy likely results little to no difference in OS or DFS compared to anthracyclines-based chemotherapies. Despite the large number of participants and minimum heterogeneity across all the studies, there was no evidence of significant benefit or harm between the treatments. Overall, there is a high to moderate quality of evidence that adjuvant TC chemotherapy does not increase OS or DFS when compared to anthracycline-based chemotherapy in patients with breast cancer HER2-negative. Albeit the choice between the two chemotherapies would need to be balanced considering the specific side-effects that each treatment is likely to cause. Citation Format: Danilo Giffoni M. M. Mata, Mary Smowton. Comparing the Effects of TC and Anthracycline-based Chemotherapy in Women with Breast Cancer HER2 Negative Treated in the Adjuvant Setting – An individual Patient Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-01-04.

The real-world experience of adjuvant docetaxel and cyclophosphamide (TC) chemotherapy in HER-2 negative breast cancer.

538 Background: Adjuvant chemotherapy in breast cancer (BC) substantially improves overall survival (OS) and the risk of recurrence. The short and long-term side effects of anthracycline, and its modest benefits in the adjuvant setting, led to controversy about its role in comparison with TC. We aim to compare the OS of TC with anthracycline-based regimens in Ontario, the most populous province in Canada. Methods: We conducted a retrospective population-based cohort study using the Institute for Clinical Evaluative Sciences (ICES) database, involving females with stage I-III BC HER2-negative. Patients were treated with adjuvant chemotherapy between January 2009 to December 2017. The anthracycline regimens for comparison were as follows, FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide, followed by Docetaxel; and ACT: Doxorubicin, Cyclophosphamide, followed by Docetaxel or Paclitaxel. Exclusion criteria included missing baseline characteristics, a prior history of malignancy or chemotherapy starting more than 120 days from breast surgery. The end of follow-up was March 31st, 2018. Adjusted analyses to compare OS by positive axillary lymph nodes (LN) and chemotherapy regimens were conducted with Cox proportional hazards models. Results: Of a total 10634 female patients with BC, 60% were ≥ 50 years-old, with 19.6% stage I, 61.1% stage II, and 19.3% stage III and 7130 (67%) women were classified as ER+ and 2379 (22.4%) as ER-. Among 5764 (54.2%) patients with positive LN, 4300 (40.4%) had LN 1-3 and 1464 (13.8%) had LN ≥ 4. There were 4945 (46.5%) high-grade cases. There were 2487 (23.5%) patients treated with TC, 2981 (28%) with ACT, and 5166 (48.5%) with FEC-D. With a median follow-up of 5.5 years, the OS comparison for the entire study population showed hazard ratio (HR) of TC vs ACT was 1.47 (95% CI 1.14 – 1.90), p = 0.0027 and TC vs FEC-D HR was 1.48 (95% CI 1.18 – 1.86), p = 0.0007. For ER+ patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.34 (95% CI 0.81 – 2.21), p = 0.26, and HR 4.29 (95% CI 2.09 – 8.79), p &lt; 0.0001, respectively. For ER+ LN 0 patients, the OS HR of TC vs. ACT was 1.15 (95% CI 0.58 – 2.35), p = 0.67, and TC vs. FEC-D HR was 1.38 (95% CI 0.81 – 2.33), p = 0.23. For ER- patients treated with TC, the OS comparison of LN 1-3 and LN ≥ 4 vs. LN 0 showed HR 1.12 (95% CI 0.42 – 3.01), p = 0.82 and HR 4.41 (95% CI 1.33 – 14.59), p = 0.015, respectively. For ER- LN 0 patients, the OS HR for TC vs. ACT was 2.04 (95% CI 1.09 – 3.81), p = 0.025, and TC vs. FEC-D HR was 2.05 (95% CI 1.08 – 3.90), p = 0.028. Conclusions: Patients treated with adjuvant TC who had four or more axillary LN had significantly lower OS when compared to patients with LN 0. For women with ER- disease, TC demonstrated a significant unfavourable survival outcome when compared to anthracycline-based treatments.

Underutilisation of prophylactic G-CSF in breast cancer patients receiving adjuvant docetaxel/cyclophosphamide chemotherapy

Docetaxel/cyclophosphamide (TC) is a widely used adjuvant chemotherapy regimen, especially in patients with node-negative or low-risk node-positive breast cancer. Guidelines recommend the use of prophylactic granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. In this study, we aimed to explore the use of G-CSF as a primary prophylactic and determine the factors influencing its use. This retrospective study used nationwide claims data from the National Inpatient Sample compiled by the Health Insurance Review and Assessment Service in South Korea from 2018. The claims data included 10% of inpatients admitted at least once in 2018 and 1% of outpatients who were not admitted. Female patients with breast cancer who received an adjuvant TC regimen after surgery were selected. Primary prophylactic G-CSF was defined as G-CSF prescribed within two days of the first cycle of TC. The factors influencing its utilisation were investigated using the chi-square test and a multiple logistic regression model. A total of 229 patients were included in the analysis. The proportion of patients who received primary prophylactic G-CSF treatment after the first cycle of TC was 55.5%. The factors positively influencing G-CSF utilization were patients’ age ≥65 years, location (i.e. metropolitan areas), and the type of healthcare facility (i.e. non-tertiary hospitals). The use of prophylactic G-CSF in patients with breast cancer who received the adjuvant TC regimen was insufficient. The use of primary G-CSF prophylaxis should be emphasised to reduce the risk of febrile neutropenia among patients receiving a myelosuppressive TC regimen.

Abstract OT-06-01: Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898)

Abstract Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day and 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC) administration, the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of Efla same-day (3 different dosing timepoints) in patients receiving TC for treatment of ESBC. Trial Design: This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla (3.6 mg G-CSF) following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Patients will be randomized 1:1:1 to Efla dose schedules of 0.5, 3, and 5 hours after TC. The primary endpoint is DSN (ANC &amp;lt;0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Eligibility Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are &amp;gt;18 years of age, are candidates for neoadjuvant or adjuvant TC chemotherapy, have an ECOG of &amp;lt;2, with adequate hematological, renal, and hepatic function. Patients will be excluded if they have a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant, or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters. The sample size produces a 2-sided 95% CI with a distance from the mean DSN to the limits that is equal to 0.554 using t-distribution when the estimated standard deviation is 1.0 days. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Citation Format: Lee S. Schwartzberg, Jawad Francis, Hlalah Osama, Manuel Modiano, Jayaram Bharadwaj, Shanta Chawla, Gajanan Bhat, Francois Lebel, Nishan Tchekmedyian. Open-label, phase 1 study to evaluate duration of severe neutropenia after same-day dosing of eflapegrastim in patients with breast cancer receiving docetaxel and cyclophosphamide (NCT04187898) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-06-01.

Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy.

PurposeTreatment with 4 cycles of docetaxel and cyclophosphamide (TC) in the adjuvant setting is associated with better outcomes than treatment with doxorubicin and cyclophosphamide (AC). However, Western guidelines have indicated that TC confers a high risk (>20%) of febrile neutropenia (FN), while AC confers an intermediate risk (10%–20%) of FN. Threrefore, we evaluated the incidence of FN and the clinical utilization of pegfilgrastim prophylaxis after adjuvant TC chemotherapy.MethodsWe categorized 201 patients who received adjuvant TC chemotherapy into 3 groups according to the method of prophylaxis and compared neutropenic events, other adverse events, and hospital care costs in the 3 groups.ResultsThe incidence of grade 4 neutropenia decreased from 93.0% in patients without prophylaxis to 82.4% in those who received secondary prophylaxis and 16.7% in those who received primary prophylaxis. Although the incidence of FN was not different between patients without prophylaxis and patients who received secondary prophylaxis (15.7% and 14.9%), none of the patients who received primary prophylaxis developed FN. Moreover, a decrease in neutropenic events resulted in a significant decrease in the mean duration of neutropenia (2.50 days to 0.08 days, P < 0.001), the risk of hospitalization (29.8% to 2.2%, P < 0.001), and the mean total hospital care cost for all chemotherapy cycles (790.80 to 486.00 US dollars, P < 0.001).ConclusionThe use of pegfilgrastim prophylaxis during adjuvant TC chemotherapy is associated with significant decreases in the incidence of neutropenic events, hospitalization, and hospital care cost compared to those seen in patients without prophylaxis.

Open-Label, Phase 1 Study to Evaluate Duration of Severe Neutropenia after Same-Day Dosing of Eflapegrastim in Patients with Breast Cancer Receiving Docetaxel and Cyclophosphamide (NCT04187898)

Background: Eflapegrastim (Rolontis®, Efla) is a long-acting granulocyte-colony stimulating factor (G-CSF), consisting of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. Efla is not a biosimilar and represents the first myeloid growth factor innovation in more than 15 years. In preclinical studies with chemotherapy-induced neutropenic rats, Efla showed ~3-fold higher exposure in serum and higher exposure in bone marrow at similar doses compared to pegfilgrastim (Peg). The duration of neutropenia (DN) was shown to be significantly shorter with Efla vs Peg when administered on the same day or 24-hours post-chemotherapy. Additionally, the DN after Efla administered on the same day as chemotherapy was similar to the DN 24 hours post-chemotherapy. Moreover, in two Phase 3 studies that randomized a total of 643 patients with early-stage breast cancer (ESBC) to either Efla (3.6 mg G-CSF n=314) or Peg (6 mg G-CSF n=329) given ~ 24 hours after docetaxel and cyclophosphamide (TC), the duration of severe neutropenia (DSN) was statistically noninferior in patients treated with Efla compared to Peg. As a standard of practice, G-CSF products require administration 24 hours after chemotherapy. Since Efla preclinical and clinical results suggest that the increased activity of Efla may provide effective prophylaxis against chemotherapy-induced neutropenia when administered on the same day as chemotherapy, the purpose of this study is to assess the feasibility of giving Efla same-day (at 3 different dosing timepoints) in patients receiving TC for the treatment of ESBC. Study Design and Methods : This is a randomized, schedule finding, multicenter, Phase 1, open-label study evaluating the same-day administration of 13.2 mg/0.6 mL Efla following IV infusion of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) in patients with ESBC. Treatment: On Cycle 1, Day 1, patients will be randomized 1:1:1 to Efla dose administration schedules of 0.5, 3, and 5 hours after TC. In Cycles 2-4, Efla will be administered ~ 24 hours following the administration of TC for all treatment arms. Clinical Endpoints: The primary endpoint is DSN (ANC &amp;lt;0.5×109/L) in Cycle 1. The secondary endpoints for Cycle 1 administration include the incidence of SN, time to recovery from SN, incidence of Grade 3 febrile neutropenia, incidence of neutropenic complications, and pharmacokinetics (PK) of Efla. Blood for hematology will be drawn daily for the first 10 days and then on Day 1 of Cycles 2-4. Inclusion Criteria: This study is enrolling histologically confirmed (operable stage I-IIIA) patients with ESBC, who are &amp;gt;18 years of age, are candidates for neoadjuvant or adjuvant TC, have an ECOG of &amp;lt;2, with adequate hematological, renal, and hepatic function. Exclusion Criteria: Patients will be excluded if they have an active or concurrent malignancy, or locally recurrent/metastatic or bilateral breast cancer, a life-threatening disease, a known sensitivity or previous reaction to E. coli derived products, exposure to a G-CSF agent within 3 months, history of bone marrow or hematopoietic stem cell transplant, radiotherapy or surgery within 30 days, are pregnant or are breast-feeding. Statistical Methods: A sample size of 15 patients per dosing schedule arm was determined to provide adequate precision for the 95% CI of the DSN and secondary endpoints, including PK parameters, assuming a standard deviation of 1.0 days based on the prior studies. A safety evaluation will be performed once the first three patients in each arm have completed Cycle 1. Target Accrual: 45 patients (15 subjects/arm). Enrollment began in April 2020. Disclosures Schwartzberg: Spectrum Pharmaceuticals, Inc.: Consultancy, Other: clinical investigator for trial. Francis:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Osama:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Modiano:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Bharadwaj:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial. Chawla:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bhat:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Lebel:Spectrum Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Tchekmedyian:Spectrum Pharmaceuticals, Inc.: Other: clinical investigator for trial.

Value of adjuvant chemotherapy using paclitaxel plus carboplatin after radical surgery with or without radiotherapy in stage IB-iia cervical adenocarcinoma with risk factors.

e17016 Background: The aim of this study was to evaluate the efficacy and safety of paclitaxel/carboplatin as an adjuvant systemic chemotherapy for stage IB-IIA cervical adenocarcinoma patients after radical hysterectomy and pelvic lymphadenectomy with or without radiotherapy(RT). Methods: The cases of all patients (n = 152) with FIGO IB-IIA cervical adenocarcinoma who were treated by radical hysterectomy and pelvic lymphadenectomy with or without RT at Chinese academy of medical sciences cancer institute and hospital between January 2008 and January 2017 were reviewed. Of these, 35 patients displayed high-risk prognostic factors (high-risk group), 65 displayed intermediate-risk prognostic factors meeting sedlis criteria(intermediate-risk group),and 54 cases presented poorly differentiated status or LVSI, without other risk factors. In the high-risk group,18 patients received adjuvant radiotherapy and concurrent cisplatin chemoradiotherapy(RT-CCRT ) and 17 received adjuvant radiotherapy plus systemic chemotherapy using Paclitaxel Plus Carboplatin (RT-CT ). In the intermediate-risk group, 47 patients were treated with RT-CCRT and 16 were treated with RT-CT ,among the patients with poorly differentiated status or LVSI ,20 were treated with adjuvant chemotherapy using Paclitaxel Plus Carboplatin (CT ) and 34 received no further treatment (NFT). Results: In the high-risk group, adjuvant RT-CT was significantly superior to RT-CCRT with regard to median PFS and 2-year PFS rate(93.07months vs 52,44months, 94.1% vs 72.2%), but the recurrence rate and survival rate showed no significantly difference(11.8% vs 33.3%,100% vs 83.3%) . In the intermediate-risk group, Patients receiving RT-CT showed a better 2-year PFS rate and recurrence rate compared to those with RT-CCRT (100% vs 90.7%, 6.3% vs 12.6%), but the differences were not statistically significant. Among the patients with poorly differentiated status or LVSI, addition of adjuvant systemic chemotherapy resulted in significantly improved 2-year PFS rate compared with the NFT group (95% vs. 75.2%,p = 0.032). Conclusions: Adjuvant systemic chemotherapy using Paclitaxel Plus Carboplatin improved the prognosis of FIGO stage IB-IIA cervical adenocarcinoma patients in the high-risk group and patients who presented 2 or more intermediate-risk factors. Early cervical adenocarcinoma patients with low differentiation or LVSI can also benefit from postoperative adjuvant TC chemotherapy.

Abstract P1-13-05: Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second Phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial)

Abstract Background: Eflapegrastim is a novel investigational biologic comprised of recombinant human G-CSF covalently linked to the human immunoglobulin G4FC fragment using proprietary LAPSCOVERY™ technology with potentially unique distribution to areas rich in FcRn receptors. RECOVER is the second Phase 3 study to investigate the non-inferiority (NI) of eflapegrastim to pegfilgrastim in patients receiving chemotherapy for breast cancer. The first Phase 3 study, ADVANCE, has demonstrated the non-inferiority of eflapegrastim comparing to pegfilgrastim in the duration of severe neutropenia (DSN) in breast cancer patients receiving docetaxel and cyclophosphamide (TC) and was previously published at ASCO 2018 meeting. TrialDesign: Patients with Stage I to Stage IIIA breast cancer from centers in the USA, Canada, Poland, Hungary, South Korea and India were treated on Day 1 of each of four 21-day cycles with adjuvant or neo-adjuvant TC. On Day 2 of each cycle, patients received a single subcutaneous dose of either eflapegrastim 13.2 mg/0.6 mL (equivalent to 3.6 mg G-CSF) or pegfilgrastim (6 mg) in a 1:1 ratio. Patients had CBCs drawn on Day 1 prior to chemotherapy and Days 4-15 daily or until recovery of neutropenia in Cycle 1. CBC was also collected on Days 1, 4, 7, 10 and 15 in Cycles 2-4. The primary endpoint was to demonstrate the non-inferiority of eflapegrastim comparing to pegfilgrastim as measured by the mean DSN in Cycle 1 with NI margin of &amp;lt;0.62 day. Results: In a total of 237 intent-to-treat patients (randomized to 118 eflapegrastim; 119 pegfilgrastim), median age was 59 years (range 29 to 88 years); mean (SD) DSN was 0.31 (0.688) days for eflapegrastim and 0.39 (0.949) days for pegfilgrastim, demonstrating the non-inferiority (95% CI of ΔDSN: [-0.292, 0.129]; p&amp;lt;0.0001). Non-inferiority of eflapegrastim for DSN was maintained across all 4 cycles. There were no statistically significant differences in secondary endpoints: time to ANC recovery, depth of ANC nadir and incidence of FN at Cycle 1. The common Grade 3/4 adverse events observed in≥5%of patients were similar across both arms and were mainly hematologic including neutropenia, lymphopenia, anemia and leukopenia. Grade 3/4 bone pain and febrile neutropenia rates were similar across both arms and were less than 5%. Conclusions: Eflapegrastim, a novel long acting G-CSF demonstrated non-inferiority to pegfilgrastim in the reduction of DSN in breast cancer patients treated with TC and has validated the results from the first Phase 3 ADVANCE study. Eflapegrastim was safe and well-tolerated with a similar safety profile to pegfilgrastim. Citation Format: Schwartzberg L, Bhat G, Mezei K, Lang I, Moon YW, Senviratne L, Chawla S, Cobb P, Yang Z. Efficacy and safety of eflapegrastim confirmed in reducing severe neutropenia in breast cancer patients treated with myelosuppressive chemotherapy in the second Phase 3 randomized controlled multinational trial compared to pegfilgrastim (RECOVER trial) [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 P1-13-05.

Age-related microRNAs in older breast cancer patients: biomarker potential and evolution during adjuvant chemotherapy

BackgroundMicroRNAs (miRNAs) are important regulators of cellular function and have been associated with both aging and cancer, but the impact of chemotherapy on age-related miRNAs has barely been studied.Our aim was to examine whether chemotherapy accelerates the aging process in elderly breast cancer patients using miRNA expression profiling.MethodsWe monitored age-related miRNAs in blood of women, aged 70 or older, receiving adjuvant chemotherapy (docetaxel and cyclophosphamide, TC) for invasive breast cancer (chemo group, CTG, n = 46). A control group of older breast cancer patients without chemotherapy was included for comparison (control group, CG, n = 43). All patients underwent geriatric assessment at inclusion (T0), after 3 months (T1) and 1 year (T2). Moreover, we analysed the serum expression of nine age-related miRNAs (miR-20a, miR-30b, miR-34a, miR-106b, miR-191, miR-301a, miR-320b, miR-374a, miR-378a) at each timepoint.ResultsExcept for miR-106b, which behaved slightly different in CTG compared to CG, all miRNAs showed moderate fluctuations during the study course with no significant differences between groups. Several age-related miRNAs correlated with clinical frailty (miR-106b, miR-191, miR-301a, miR-320b, miR-374a), as well as with other biomarkers of aging, particularly Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein-1 (MCP-1) (miR-106b, miR-301a, miR-374a-5p, miR-378a-3p). Moreover, based on their ‘aging miRNA’ profiles, patients clustered into two distinct groups exhibiting significantly different results for several biological/clinical aging parameters.ConclusionsThese results further corroborate our earlier report, stating that adjuvant TC chemotherapy does not significantly boost aging progression in elderly breast cancer patients. Our findings also endorsed specific age-related miRNAs as promising aging/frailty biomarkers in oncogeriatric populations.Trial registrationClinicalTrials.gov, NCT00849758. Registered on 20 February 2009. This clinical trial was registered prospectively.

The effect of adjuvant chemotherapy on symptom burden and quality of life over time; a preliminary prospective observational study using individual data of patients aged ≥70 with early stage invasive breast cancer.

We aim to assess short and long term effects of chemotherapy on patient-reported quality of life (QOL) and patient versus clinician symptom reporting in older patients with breast cancer adjusted for tumour and aging parameters. In this prospective, multicentre, non-interventional, observational study, women aged ≥70years were enrolled after surgery and assigned to a TC chemotherapy (docetaxel and cyclophosphamide) group or a control group depending on their planned adjuvant treatment. Longitudinal multivariate models were used to assess the statistical and minimal clinically important difference (MCID) in the impact of TC chemotherapy over time on QOL and symptom burden adjusted for baseline aging and tumour parameters. Statistical significance was set at 5% and MCID at 10 points. In total, 57 patients were enrolled in the chemotherapy and 52 patients in the control group. Within the chemotherapy group, clinical deterioration was reported at 3months for Fatigue (17.73), Dyspnoea (17.05), Diarrhoea (12.06) and Appetite Loss (17.05) scores (all p<0.001). However, the scores had returned to baseline (or even better for Role Functioning) at year 1. No clinical deterioration was reported in the control group. Symptom scores as reported by patients were significantly (p<0.05) higher than those reported by the clinicians, even more so for Fatigue, Dyspnoea, and Pain. Our results show that symptom burden and diminished QOL in an older breast cancer population receiving adjuvant TC chemotherapy are short-lived and disappear after a while with no long-term differences compared to a similar population not receiving chemotherapy.

Incidence of febrile neutropenia with use of docetaxel plus cyclophosphamide (TC) for breast cancer.

e12073 Background: Incidence of febrile neutropenia (FN) is reported as 5% in breast cancer patients receiving TC (Jones et al., JCO 2006), which would not justify the usage of prophylactic granulocyte colony stimulating factors (G-CSF). We previously showed that the incidence of FN may be as high as 23% in a small study. (N = 130, Soni et al., ASCO 2011). In the current study, we determined the incidence of FN in a larger cohort (N = 415), and evaluated the usage of G-CSF and its relation to FN, age, stage, and hormonal status. Methods: We retrospectively reviewed the electronic medical records from patients diagnosed with breast cancer who received at least one standard dose cycle of adjuvant TC between 2010-2016 at a university-based breast oncology practice. Chi-square or Fisher’s exact tests were used to assess differences between groups. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multiple logistic regression models. Results: We identified in total 415 patients who received adjuvant TC. Median age at diagnosis was 58 (range: 25-86), the majority had stage I or II (N = 382; 92.1%) disease, and 315 (75.9%) were ER+, 277 (66.8%) PR+, 42 (10.1%) HER2+, 22 (5.3%) triple-positive, and 81 (19.5%) triple-negative. Prophylactic G-CSF was utilized in 247 patients (59.5%), and unknown for 43 (10.4%). Overall 39 (9.4%) patients experienced febrile neutropenia. Incidence of FN among those receiving G-CSF was 4.5% versus 17.6% among those who did not (p &lt; 0.001). Use of G-CSF significantly lowered risk of FN, OR (95%CI): 0.20 (0.10-0.43) adjusted for age at diagnosis and stage. Use of G-CSF on incidence of FN did not differ significantly by age, stage, or hormonal status. Conclusions: Our data confirms a high rate of FN in patients receiving TC without G-CSF prophylaxis. Our institutional high rate of G-CSF use ( &gt; 50%) reduced the incidence of FN to 4.5% and the observed significant difference in FN incidence between the non G-CSF group and G-CSF group suggests that prophylaxis may be considered when administering TC. Age, stage, and hormonal status do not seem to affect the usage of G-CSF or incidence of FN in our population.

Toxicity profile differences of adjuvant docetaxel/cyclophosphamide (TC) between Asian and Caucasian breast cancer patients.

For early-stage breast cancer, four cycles of docetaxel and cyclophosphamide (TC) was proven superior to doxorubicin plus cyclophosphamide in the US Oncology 9375 trial. Given primary prophylactic antibiotics, 5% febrile neutropenia was recorded in a population comprising 75.5% Caucasians. Smaller trials and retrospective studies reviewing TC use in Asian patients did not produce similar incidence rates. This study aims to discover the variable hematological toxicities with TC use in Caucasian and Asian patients. Breast cancer data was retrospectively reviewed for patients receiving adjuvant docetaxel 60-75 mg/m2 plus cyclophosphamide 600 mg/m2 from six countries (China, Hong Kong, Japan, Taiwan, Italy, and United States). Similar number of patients with relatively balanced baseline characteristics were chosen for analysis of hematological and nonhematological toxicities and survival data. From March 2004 to July 2013, data of 227 patients (127 Asians and 100 Caucasian) patients were analyzed for treatment-related toxicities. During the four cycles of TC, Asians had a significantly higher rate of grade ≥2 neutropenia than Caucasians (45.7% vs 6.0%; P <0.001) and significantly more grade ≥3 neutropenia events were documented (respectively 30.7% vs 4.0%, P <0.001). The prophylactic use of G-CSF was similar; 26.0% in Asians and 28.0% in Caucasian (P = 0.764). There were no differences in nonhematological toxicities. No significant difference in disease-free survival was observed between Asians and Caucasians (log-rank P = 0.910). Ethnic differences in toxicity profile exist between Asian and Caucasian patients given adjuvant TC. Over 30% Asians but less than 5% Caucasians experienced grade ≥3 neutropenia.

Abstract OT1-01-11: Randomized phase 3 study of a novel, long-acting G-CSF (eflapegrastim) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study)

Abstract Background: Eflapegrastim is a distinct biologic that uses an innovative, proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™). Eflapegrastim consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors including its site of action in the bone marrow. A successful dose-finding Phase 2 trial including a pegfilgrastim control arm established the dose for a Phase 3 non-inferiority trial. Trial Design: This is a randomized, open-label, active-controlled, multinational, multicenter, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim. Patients (n=580) will be randomized in a 1:1 ratio to receive either eflapegrastim (equivalent to 3.6 mg G-CSF) or pegfilgrastim (equivalent to 6.0 mg G-CSF) once per chemotherapy cycle (up to 4 cycles), approximately 24 hours after chemotherapy. The primary endpoint is to compare the efficacy of a single dose of eflapegrastim with pegfilgrastim in patients with ESBC receiving TC, as measured by the Duration of Severe Neutropenia (DSN) in Cycle 1. Key secondary objectives include Time to Absolute Neutrophil Count (ANC) Recovery in Cycle 1; Depth of ANC Nadir in Cycle 1; incidence of Febrile Neutropenia. Safety and pharmacokinetics will also be assessed. Eligibility Criteria: This study is enrolling histologically confirmed ESBC patients who are: eligible to receive adjuvant or neoadjuvant TC chemotherapy; at least 18 years of age, with adequate hematologic, renal and hepatic function. Patients will be excluded if they have: active concurrent malignancy or life-threatening disease; a known sensitivity or previous reaction to E. coli derived products or any of the products to be administered during study participation; concurrent adjuvant cancer therapy; locally recurrent/metastatic or contralateral breast cancer; previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development prior to the administration of study drug; bone marrow or hematopoietic stem cell transplant or radiation therapy prior to enrollment, or are pregnant or breast-feeding. Statistical Methods: The goal of this study is to demonstrate non-inferiority. For the Primary Efficacy Analysis, the mean DSN in Cycle 1 will be compared between the eflapegrastim and pegfilgrastim treatment arms. A 2-sided 95% confidence interval (CI) of the difference between the mean DSN of the eflapegrastim arm and the mean DSN of the pegfilgrastim arm will be calculated using bootstrap resampling with treatment as the only stratification factor. For the Secondary Efficacy Analyses, the results will each be summarized by treatment arm and cycle. The two-sided 95% CI for the difference between the treatment arms will be calculated. Target Accrual: Approximately 580 patients. Enrollment began January 2016. Contact Information: Spectrum Pharmaceuticals. advance@sppirx.com. Citation Format: Schwartzberg LS, Bharadwaj J, Peguero JA, Vacirca JL, Ibrahim EN, Bhat G, Choi MR, McGregor K, Agajanian R. Randomized phase 3 study of a novel, long-acting G-CSF (eflapegrastim) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study) [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 OT1-01-11.

Febrile Neutropenia Risk with Adjuvant Docetaxel and Cyclophosphamide (TC) Chemotherapy Regimen in Two Brazilians Cancer Centers

Introduction: In selected patients diagnosed with Breast Cancer (BC), adjuvant chemotherapy might reduce local and systemic recurrence risk, as well as cancer death rate. The combination of Docetaxel and Cyclophosphamide (TC) is a well-recognized effective adjuvant chemotherapy regimen. Nonetheless, a considerable high rate of febrile neutropenia (FN) is associated with this regimen. We sought to investigate hematologic toxicity associated with adjuvant TC in a non-selected, “real world” cohort of BC patients. Methods: We reviewed the electronic medical records of patients who presented to the Oncology Center from Hospital Sirio-Libanes (HSL) and Instituto do Câncer do Estado de Sao Paulo (ICESP). Patients included in the analysis received adjuvant chemotherapy with TC regimen after definitive breast surgery. Results: 95 patients with were included in our analysis. Median age was 55.5 years. All patients had a good performance status (either ECOG 0 or 1), and the great majority had no comorbidities. Most patients received 4 cycles of chemotherapy (80%). Data on granulocyte colony stimulating factor (G-CSF) administration was available in 85 patients from our cohort. G-CSF was used as primary prophylaxis in 31 patients, and as secondary prophylaxis in 13 patients, following a prior episode of febrile neutropenia. Overall, fifteen women (15.8%) had a documented FN episode. Among women who received G-CSF as primary prophylaxis, the rate of FN was 6.45% (2 patients). In contrast, among patients who did not receive primary prophylaxis with G-CSF, FN rate was considerably higher, namely 24.07% (13 patients). Patients who received primary prophylaxis with G-CSF had a statistically significant lower risk of experiencing a FN episode (p=0.049). Conclusion: Febrile Neutropenia rate in this group of non-selected BC patients was higher than previous reported on randomized controlled trials that evaluated adjuvant TC regimen in the same dosing and schedule as used in our cohort. Primary prophylaxis with G-CSF was associated with a statistically significant lower risk of FN and should be considered in the management of patients who receive this chemotherapy combination.

Systematic Review of Emerging Models of Cancer Care: Implications for the Health Industry

In selected patients diagnosed with Breast Cancer (BC), adjuvant chemotherapy might reduce local and systemic recurrence risk, as well as cancer death rate. The combination of Docetaxel and Cyclophosphamide (TC) is a wellrecognized effective adjuvant chemotherapy regimen. Nonetheless, a considerable high rate of febrile neutropenia (FN) is associated with this regimen. We sought to investigate hematologic toxicity associated with adjuvant TC in a non-selected, “real world” cohort of BC patients. Methods: We reviewed the electronic medical records of patients who presented to the Oncology Center from Hospital Sirio-Libanes (HSL) and Instituto do Câncer do Estado de Sao Paulo (ICESP). Patients included in the analysis received adjuvant chemotherapy with TC regimen after definitive breast surgery. Results: 95 patients with were included in our analysis. Median age was 55.5 years. All patients had a good performance status (either ECOG 0 or 1), and the great majority had no comorbidities. Most patients received 4 cycles of chemotherapy (80%). Data on granulocyte colony stimulating factor (G-CSF) administration was available in 85 patients from our cohort. G-CSF was used as primary prophylaxis in 31 patients, and as secondary prophylaxis in 13 patients, following a prior episode of febrile neutropenia. Overall, fifteen women (15.8%) had a documented FN episode. Among women who received G-CSF as primary prophylaxis, the rate of FN was 6.45% (2 patients). In contrast, among patients who did not receive primary prophylaxis with G-CSF, FN rate was considerably higher, namely 24.07% (13 patients). Patients who received primary prophylaxis with G-CSF had a statistically significant lower risk of experiencing a FN episode (p=0.049). Conclusion: Febrile Neutropenia rate in this group of non-selected BC patients was higher than previous reported on randomized controlled trials that evaluated adjuvant TC regimen in the same dosing and schedule as used in our cohort. Primary prophylaxis with G-CSF was associated with a statistically significant lower risk of FN and should be considered in the management of patients who receive this chemotherapy combination.

Impact of an electronic tool in prescribing primary prophylaxis with ciprofloxacin or granulocyte colony-stimulating factor for breast cancer patients receiving TC chemotherapy

The US Oncology Trial 9735 (doxorubicin and cyclophosphamide (AC) versus docetaxel and cyclophosphamide (TC)) reported febrile neutropenia (FN) in 5% of patients receiving TC chemotherapy, in the absence of routine primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) or antibiotics. In contrast, higher rates of FNhave been reported in the 'real world' setting. This retrospective study compares the incidence and severity of FN and other TC-related toxicities before and after implementation of a primary prophylaxis computerized prescribing tool. Medical records of 207 patients receiving adjuvant TC between May 1, 2006, and November 1, 2011, were reviewed for toxicity. The incidence for each TC adverse event was measured by an incident rate ratio (IRR), and chi-square analysis was used to compare the differences in severity of TC toxicities before and after use of a primary prophylaxis computerized prescribing tool, and to compare G-CSF and ciprofloxacin groups. The implementation of a computerized prescribing tool significantly increased the proportion of patients prescribed primary prophylaxis (18.2 vs. 97.4%; p<0.001). Prior to the change in practice, the incidence of FN (incidence rate ratio 3.87; 95% CI [1.3, 11.5]) and neutropenia (OR 4.8; 95% CI [2.0, 11.7]) was significantly higher. Primary prophylaxis significantly reduced the rate of febrile neutropenia (20 vs. 5.3%, p=0.003). No significant differences were found in incidence and severity of other TC-related toxicities. Patients who did not receive G-CSF were at a greater risk for neutropenia (OR 5.1, 95% CI [1.06, 24.3]). There were insufficient patients treated with antibiotics alone to compare to those treated with G-CSF. Implementation of a computerized prescribing tool significantly increased the use of primary prophylaxis by treating physicians in patients receiving TC chemotherapy, which was associated with reduced incidence of febrile neutropenia.Further research efforts should focus on the incorporation and routine use of evidence-based practices using tools such as alerts and prompts, in order to optimize patient care and improve outcomes.

Abstract OT3-02-13: Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study)

Abstract Background: SPI-2012 is a distinct biologic that uses the innovative, proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™) to enhance the activity of G-CSF. SPI-2012 consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, more potent, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors. The primary endpoint of this Phase 3 study is to compare the efficacy of a single dose of SPI-2012 with pegfilgrastim in patients with early-stage breast cancer (ESBC) receiving TC chemotherapy, as measured by the Duration of Severe Neutropenia (DSN) in Cycle 1. Key secondary objectives include the comparison of SPI-2012 with pegfilgrastim during Cycle 1 in: Time to Absolute Neutrophil Count (ANC) Recovery; Depth of ANC Nadir and Incidence of Febrile Neutropenia. Safety and pharmacokinetics will also be assessed. Trial Design: This is a randomized, open-label, active-controlled, multicenter study comparing the efficacy and safety of SPI-2012 to pegfilgrastim. Patients (n=506) will be randomized in a 1:1 ratio to receive either SPI-2012 (equivalent to 3.6 mg G-CSF) or pegfilgrastim (equivalent to 6.0 mg G-CSF) once per chemotherapy cycle (up to 4 cycles), approximately 24 hrs after chemotherapy. Eligibility Criteria: This study will enroll histologically confirmed ESBC patients who are eligible to receive adjuvant or neoadjuvant TC chemotherapy and at least 18 years of age, with adequate hematologic, renal and hepatic function. Patients will be excluded if they have active concurrent malignancy or life-threatening disease; a known sensitivity or previous reaction to E. coli derived products or any of the products to be administered during study participation; concurrent adjuvant cancer therapy; locally recurrent/metastatic or contralateral breast cancer; previous exposure to filgrastim, pegfilgrastim, or other G-CSF products in clinical development prior to the administration of study drug; bone marrow or hematopoietic stem cell transplant or radiation therapy prior to enrollment or are pregnant or breast-feeding. Statistical Methods: The goal of the study is to demonstrate non-inferiority of SPI-2012 to pegfilgrastim. For the Primary Efficacy Analysis, the mean DSN in Cycle 1 will be compared between the SPI-2012 and pegfilgrastim treatment arms. A 2-sided 95% confidence interval (CI) of the difference between the mean DSN of the SPI-2012 arm and the mean DSN of the pegfilgrastim arm will be calculated using bootstrap resampling with treatment as the only stratification factor. For the Secondary Efficacy Analyses, the results will each be summarized by treatment arm and Cycle. The two-sided 95% CI for the difference between the treatment arms will be calculated. Target Accrual: Approximately 506 pts. Citation Format: Schwartzberg L, Vacirca JL, Hager SJ, Adoo CS, Ibrahim EN, Bhat G, Choi MR, Allen LF, Tedesco KL, Agajanian R. Randomized phase 3 study of a novel, long-acting G-CSF (SPI-2012) versus pegfilgrastim in the management of chemotherapy-induced neutropenia in early-stage breast cancer patients receiving docetaxel and cyclophosphamide (TC) (ADVANCE study). [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 OT3-02-13.