Dose-dense AC Research Articles

Dose dense doxorubicin plus cyclophosphamide in a modified KEYNOTE522 regimen for triple negative breast cancer

The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

Abstract PO2-03-12: Dose-Dense Doxorubicin plus Cyclophosphamide (ddAC) and Impact of Chemotherapy Sequence in a Modified KEYNOTE-522 Regimen for Neoadjuvant Treatment of Triple Negative Breast Cancer: Real World Experience

Abstract Background: Standard of care systemic treatment for early stage triple negative breast cancer (TNBC) consists of neoadjuvant chemoimmunotherapy based upon the results of KEYNOTE 522 (KN-522). The KN522 regimen utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has shown superior OS compared to q3week AC in anthracycline and taxane-based regimens (per CALGB 9741 and EBCTCG analyses). We now present a retrospective study of patients treated with ddAC in a modified KN-522 regimen and report real world feasibility, safety, and efficacy endpoints, including exploration of whether sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab impacts outcome. Methods: Patients with TNBC treated at MSK from August 2021 to September 2022 with a preoperative KN-522 regimen were eligible for inclusion. Clinicopathological and demographic data were obtained from chart review. The primary goal of this study was to describe pathologic complete response (PCR) rate, incidence of treatment-related toxicities resulting in treatment delays, and type of toxicity. Treatment delays for toxicity were defined as a >1 week delay in treatment or discontinuation of a treatment regimen component due to a medical reason. Exploratory analysis was conducted to assess efficacy and toxicity of ddAC before or after CbT as well as rate of GCSF usage with CbT. Baseline characteristics, incidence and type of delays, and treatment outcomes were compared between ddAC first and CbT first using two sample non-parametric tests. Results: 129 TNBC patients met eligibility as defined above. Median age of diagnosis was 50. Clinical stage at diagnosis: Stage I 6%, Stage II 83%, and Stage III 11%. 128 patients received ddAC and 1 patient received AC q3week. Of the 128 patients, 54% received ddAC first while 46% received CbT first. Overall PCR rate of 56%. Treatment-related toxicity leading to chemotherapy delays was 61% and immunotherapy delays was 30%. Most chemotherapy delays were due to cytopenias (79%), with neutropenia (66%) most common. Adrenal insufficiency (4%) and hepatitis (5%) were the most common immune-related toxicities leading to delays. Overall, PCR rate was not affected by chemotherapy delays (No Delay 50% vs. Delay 60%, RR 0.83, 95%CI 0.60-1.15, p=0.25) or immunotherapy delays (No Delay 56% vs. Delay 58%, RR 0.96, 95%CI 0.69-1.33, p=0.81). Exploratory analysis comparing sequencing of ddAC vs CbT first showed incidence of CbT delays was 58% in patients treated with ddAC first and 27% in CbT first. Incidence of ddAC delays was 3% in patients treated with ddAC first and 7% in CbT first. Incidence of delays in both ddAC and CbT was 9% in ddAC first and 10% in CbT first. There was no difference in PCR rate (ddAC 55% vs. CbT 58%, RR 0.96, 95%CI 0.70-1.30, p=0.77) or rate of immunotherapy delays (ddAC 32% vs. CbT 34%, RR 0.93, 95%CI 0.55-1.57, p=0.79) based on sequence of chemotherapy. However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, RR 1.37, 95%CI 1.02-1.84, p=0.03), use of GCSF during CbT (ddAC 55% vs. CbT 34%, RR 1.60, 95%CI 1.06-2.45, p=0.02), and treatment-limiting cytopenias at any time point before surgery (ddAC 59% vs. CbT 31%, RR 1.95, 95%CI 1.26-3.00, p=0.001). Conclusions: These real world data support the feasibility and tolerability of ddAC in a modified KN522 regimen. Exploratory analysis on sequencing of ddAC vs. CbT first in this regimen suggests that efficacy is comparable, yet ddAC first is significantly associated with higher rates of treatment delays and cytopenias. Overall, our experience suggests ddAC is a safe and viable modification to KN-522, and sequencing ddAC after CbT may reduce the risk of treatment induced cytopenias. Citation Format: Nicholas Mai, Sara Myers, Sherry Shen, Stephanie Downs-Canner, Yuan Chen, Tiffany Traina, Nour Abuhadra. Dose-Dense Doxorubicin plus Cyclophosphamide (ddAC) and Impact of Chemotherapy Sequence in a Modified KEYNOTE-522 Regimen for Neoadjuvant Treatment of Triple Negative Breast Cancer: Real World Experience [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 PO2-03-12.

Abstract PO3-03-06: Real-world efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in Brazilian patients with early-stage triple-negative breast cancer

Abstract Background: Early-stage triple-negative breast cancer (TNBC) is associated with high risk of early recurrence and disease-specific mortality. Studies suggest a sustained clinical benefit in patients with TNBC who have a pathological complete response (PCR) after neoadjuvant chemotherapy (NACT). In TNBC, the combination of immunotherapy based on immune checkpoint inhibitors (anti-PD-1/PD-L1) combined with chemotherapy has been shown to be effective both in the advanced and early. In the early-stage setting, the addition of pembrolizumab to platinum-containing NACT significantly increased pathological complete response (pCR). Methods: We performed a retrospective observational cohort study of patients diagnosed with TNBC, stage II-III, who received NACT with chemotherapy based on paclitaxel and carboplatin (TC) followed by doxorubicin plus cyclophosphamide (AC) associated with pembrolizumab, treated from June 2022 to July 2023, at AC Camargo Cancer Center, São Paulo, Brazil. Objectives: To investigate the real-world pCR rate and safety profile of early-stage TNBC treated with neoadjuvant chemotherapy (weekly TC, ddAC/AC) associated with pembrolizumab and to describe the clinical-pathological characteristics of this population. Results: Eighty patients received neoadjuvant pembrolizumab plus chemotherapy. Around 50.6% of patients were premenopausal, with a median age of 47 years old at diagnosis. About 18% carried a germline mutation in the BRCA1 (50%) .Regarding the pathological characteristics of the tumor, 90.9% were invasive ductal carcinoma (IDC), 80% had histological grade (HG) III, and average Tumor Infiltrating Lymphocytes (TILs) was 18%. In 94.8% of cases, Ki67 was expressed in more 20% of tumor cells. The expression of HER2 was low in 14%, and 5% were ER-low. Regarding the clinical stage of the primary tumor, (64.9%)cT2, (18%) cT3, (10%) cT1c, and (2.5%) cT4. Regarding regional lymph node staging, 48%, 33.7%, 10.3%, and 6.4% were classified as cN0, cN1, cN2a, and cN, respectively. Clinical stage was IIA (42.8%), IIB (24.6%), IIIA (14.2%), IIIB ( 9%), and IIIC (5%). Regarding chemotherapy, 57.1% received dose dense AC, 54% percent had chemotherapy-related toxicity, 35.7% had neutropenic fever, 32.4% required hospitalization, and 31% used antibiotics. 31% received eight cycles of neoadjuvant pembrolizumab and 53.2% of patients completed all NACT, among these patients, 61% had complete .A cutoff date, about 61% of patients have undergone surgery, and 66.6% achieved a complete pathological response (ypT0ypN0). Patients that received eight cycles of neoadjuvant pembrolizumab had a higher chance of pathological complete response rate (61% vs. 45.2%) p=0.073. Immune-related toxicities (IRT) were observed in 16.8% patients, being the most common endocrinologic and cutaneous, being G3 or higher in 46%. About 15.5% used corticosteroids. Fifty percent had already started or completed adjuvant therapy, from which 66.6% received only adjuvant pembrolizumab, 28% had adjuvant pembrolizumab plus capecitabine, 1.2% received adjuvant capecitabine, and 1.2% had adjuvant olaparib. Eight percent of our patients have already completed nine cycles of adjuvant pembrolizumab, 12.7% did not receive adjuvant pembrolizumab due to prior toxicity. In our cohort, we observed greater intercurrences related to ddAC versus conventional AC 61.4% versus 52.4%, p=0.492, therefore, it did not impact whether or not the chemotherapy was completed. Conclusion: Our cohort is composed mostly of pre-menopausal with stage IIA tumors. Most patients received ddAC, Fifty-four percent had chemotherapy-related toxicity. We observed a high rate of pCR (61%) on our patients have already undergone surgery, 66.6% achieved a complete pathological response.Of those who received 8 cycles of neoadjuvant pembrolizumab had a higher chance of pathological complete response rate (61% vs. 45.2%) p=0.073 Citation Format: isadora sousa, Ana Carolina M. Comini, Italo BORGES, Flavia C. Balint, Livia alexandre Martins, Debora G. Sousa, Solange M. Sanches, Marcelle G. Cesca, Vladmir Cordeiro de Lima, Monique Tavares. Real-world efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy in Brazilian patients with early-stage triple-negative breast cancer [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 PO3-03-06.

Efficacy of dose-dense versus standard neoadjuvant chemotherapy regimensin luminal HER2-negative breast cancer: Interim results of single-centre study

Introduction. The efficacy of dose-dense AC in adjuvant chemotherapy of luminal breast cancer (ER+ BC) compared with the standard dosing regimen followed by switching to taxanes has been proven in numerous clinical trials and in a large meta-analysis of the EBCTCG group. However, no study about efficiency of this regimen in neoadjuvant setting has been published.The aim of the study. To assess the effectiveness of dose-dense regimens of neoadjuvant chemotherapy (NAC) of ER + HER2-BC (4 AC once every 2 weeks (dose dense, ddAC), then 4 courses of Docetaxel once every 3 weeks or 12 weekly injections of Paclitaxel [4D/12P]) and their comparison with the standard ones (AC once every 3 weeks [ACq3w], hereinafter 4D/12P). Primary end points are complete response rate (pCR) and RCB0–I.Methods. This retrospective study included patients with resectable or locally advanced luminal HER2-negative breast cancer who received NAC from Janu 2017 to Aug 2022. Statistical hypothesis – the dose-dense regimen AC increases the frequency of RCB0–I from 22 to 32% compared to the standard dosing regimen with subsequent switching to taxanes, with a study power of 80%, ά = 0.05, 138 patients should be included in the study. A total of 315 patients were included in the study, of which 147 and 168 patients received dose-dense (ddAC) and standard chemotherapy (ACq3w), respectively. After propensity matching analysis 138 patients in each group were included in the final analysis.Results. The pCR rate was 18.84% in the ddAC group versus 14.49% in the AC q3w group, the differences were not statistically significant (p = 0.379). The frequency of RCB0–I was higher in the ddAC – group 33.33% versus 21.74% in the AC q3w (p = 0.040). According to the subgroup analysis, rate of RCB0–I was significantly higher in patients younger 50 years, cN0, with the expression of progesterone receptors in ≥ 20%.Conclusions. This is the first study to compare the efficacy of a ddAC NAC with a standard regimen for ER + HER2-BC. NAC with ddAC is associated with an increase in RCB0–I rate.

32P Efficacy of olanzapine in the prophylaxis of delayed chemotherapy-induced nausea and vomiting in breast cancer patients receiving dose-dense AC with a steroid-sparing regimen: A single-center pilot study

32P Efficacy of olanzapine in the prophylaxis of delayed chemotherapy-induced nausea and vomiting in breast cancer patients receiving dose-dense AC with a steroid-sparing regimen: A single-center pilot study

An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer

PurposeBreast cancer is one of the most prevalent malignant diseases in women. The development of dose dense chemotherapy regimens has improved clinical outcomes but has been associated with increased hematological toxicity. Currently there is a paucity of data on the use of lipegfilgrastim in dose dense AC treatment in early breast cancer. The purpose of this study was to assess the use of lipegfilgrastim in the treatment of early breast cancer and to examine the incidence of treatment-related neutropenia during the dose dense AC phase and subsequent paclitaxel treatment.MethodsThis was a single arm, non-interventional, prospective study. The primary endpoint was to determine the rate of neutropenia defined as ANC of < 1.0 × 109/L, during four cycles of dose dense AC with lipegfilgrastim support. The secondary endpoints were the incidence of febrile neutropenia, (temperature > 38 °C and ANC < 1.0 × 109/L), treatment delays, premature treatment cessation and toxicity.ResultsForty-one participants were included in the study. Of the 160 planned dose dense AC treatments, 157 were administered, and 95% (152/160) of these were given on time. The rate of treatment delay was 5% (95% CI 2.2 to 9.9%) due to infection (4) and mucositis (1). Four (10%) patients developed febrile neutropenia. The most frequently occurring adverse event was grade 1 bone pain.ConclusionLipegfilgrastim is an effective option in the prophylaxis of chemotherapy-induced neutropenia, and its use in everyday anti-cancer treatment can be considered.

A phase 2 trial of talimogene laherparepvec (TVEC) in combination with neoadjuvant chemotherapy for the treatment of nonmetastatic triple-negative breast cancer.

578 Background: TVEC is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of unresectable cutaneous and nodal melanoma. TVEC is designed to preferentially lyse tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report results of a phase 2 trial combining NAC with TVEC in stage 2-3 TNBC. Methods: Stage II-III TNBC pts (N = 37) were to be enrolled into a single arm, optimal Simon 2 stage phase 2 trial with TVEC (10^6 PFU 1st dose then 10^8 PFU x 4 doses) weeks 1,4,6,8,10 + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone given preoperatively. Primary endpoint was residual cancer burden 0 rate (RCB0). Trial meets primary endpoint with ≥15 RCB0 responses out of 37 evaluable pts, assuming p1 = 45% vs. p0 = 30% with one sided type I error rate at 0.10 and power at 70%. Results: Forty pts were enrolled at Moffitt (5/2018 – 4/2020) and evaluable for safety with 3 pts non-evaluable for efficacy due to incomplete treatment. Study demographics: median age 49 (27-66), 67.5% White, 10% Black, 15% Hispanic, clinical stage II 83% and III 17%, node + 42%. The RCB0 rate = 16/37 (43%, 95% CI 27-61%) and additional 9 pts with RCB-1 (RCB0/1 rate 68%, 95% CI 50-82%). Toxicities did not differ significantly from expected NAC toxicities except for increased brief G1-2 fevers, chills, injection site pains. Four pts had G2-3 thromboembolic events (10%) slightly greater than expected 6% rate on NAC. Conclusions: Addition of TVEC to NAC increased RCB0 rates with manageable toxicities and warrants additional investigation in TNBC. Immune correlates and updated survival data will be presented at the meeting. Clinical trial information: NCT02779855.

Local and Systemic Inflammatory Markers as Prognostic and Predictive Markers In Locally Advanced Triple Negative Breast Cancer

Local inflammatory markers have been defined as prognostic and predictive markers in triple negative markers as proved by many studies. The prognostic and predictive value of systemic inflammatory markers such as neutrophil lymphocyte ratio (NLR) and lymphocyte monocyte ratio (LMR) remain to be elucidated. Aim of study: To evaluate pathological complete response (PCR) to neoadjuvant chemotherapy in locally advanced cancer breast in relation to tumor infiltrating lymphocytes(TILs), neutrophil lymphocyte ratio and lymphocyte monocyte ratio as well as overall survival and disease free survival. Patients and methods: In Tanta university Hospital, oncology department form January 2012 to December 2013, 67 patients with locally advanced TNBC stage IIB, IIIB 0r IIIC using TNM 8t h edition . All patients received neoadjuvant chemotherapy in the form of dose dense AC followed by paclitaxel (adriamycin &amp; cyclophosphamide 60 mgm/m2 &amp; 600 mgm/m2 respectively the cycle is repeated every 2 weeks for 4 cycles followed by paclitaxel 175mgm/m2 every 2 weeks for 4 cycles). All cycles with G-CSF support. Pre treatment TILs, NLR and LMR were evaluated with PCR and as prognostic factor of survival. Results: Low NLR has been detected in 74.6% of cases and has been associated with high TILs and this was statistically significant (p value=0.03). High LMR was observed in 80.6% of cases and correlated significantly with TILs (p value =0.003). Pathological CR was found to be associated with high TILs, low NLR and high LMR. In our study we evaluated the pre neoadjuvant systemic and local inflammatory markers as prognostic marker we found that in multivariate analysis, the lymphocyte monocyte ratio maintained their statistical significance with overall survival. While tumor infiltrating lymphocyte maintained their statistical significance as prognostic factors with overall survival and disease free survival. Conclusion: Systemic inflammatory markers can be used as marker of pathological complete response in locally advanced triple negative breast6 cancer with neoadjuvant chemotherapy.

Abstract OT1-01-02: Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer

Abstract Background: Higher levels of tumor-infiltrating lymphocytes (TIL) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy and improved outcomes. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers by upregulating tumor antigen expression, increasing MHC Class I expression and antigen presentation, decreasing numbers and activity of myeloid derived suppressor cells (MDSC) and increasing responsiveness of T lymphocytes. We have shown that decitabine augments the effectiveness of immunotherapy against murine triple negative breast cancer (TNBC). Trial design: Patients with HER-2-negative breast cancer who are candidates for neoadjuvant chemotherapy will receive decitabine (15 mg/kg x 4 doses over 5 days) followed by 2 doses of pembrolizumab (200 mg, 2 weeks apart) prior to starting neoadjuvant chemotherapy. Two research biopsies are obtained - 1 prior to the window immunotherapy and 1 afterwards, prior to starting chemotherapy. Chemotherapy regimens: TNBC - ddAC X 4 followed by weekly Taxol + Carboplatin X 12; HR+ - ddAC X 4 followed by weekly Taxol X 12. After the safely lead-in, the sequence of regimens can be reversed, per treating physician preference. Safety Lead-In: During immunotherapy and dose-dense AC in the first 11 patients enrolled and who have received at least 3 doses of decitabine and at least 1 dose of pembrolizumab, clinically significant immune related adverse events (irAEs) will be reported in an expedited manner. Accrual was halted until the safety lead-in phase was completed. Brief Eligibility criteria: Primary breast cancer, candidates for neoadjuvant chemotherapy Cohort A: TNBC (ER&amp;lt;10%, PR&amp;lt;10%, Her-2 negative) cT2, N1 or N2 cT2, 3-5 cm, N0 Any T3 or T4 Cohort B: ER+ or PR+, Her-2 negative cT2, N1 or N2 Any T3 or T4ECOG status 0-1 No Active autoimmune diseases Absence of metastatic disease too extensive to consider surgery for the primary Specific aims: Primary endpoint: Changes in Lymphocyte infiltration - by 10-15% Tumor area Stromal area Secondary endpoints: Gene expression (Nanostring) Multiplex Cell Markers (DAPI/CD4/CD8/FOXP3/CK/PDL1/PDL2, and MDSCs) pCR Percentage of patients with lymphocyte-predominant breast cancer Correlation of PD-L1 expression with pCR MDSC in blood samples pre- and post- window portion Sample Size and Statistical methods: Cohort A (TNBC) is the primary target group in this trial. When Cohort A has achieved its required sample size of 28 evaluable patients, Cohort B (HR+) will be closed to accrual irrespective of accrual to that cohort. However, in the unlikely event that accrual to Cohort B occurs at a faster rate than in Cohort A, Cohort B will be capped at 18 patients. Therefore, the projected sample size for this study is 32-50 patients. A one-sided paired t-test will be used to compare baseline and post-treatment percentage of tumor and stromal areas with infiltrating lymphocytes. The paired t-test will be applied separately to Cohorts A and B. Present accrual and target accrual: 12 subjects have been accrued; 1 withdrew prior to any protocol therapy. The 11 patient safety lead-in has been completed. As described above, the projected total sample size is 32-50 patients. Citation Format: Harry Douglas Bear, Michael O. Idowu, Andrew Poklepovic, Adam Sima, Maciej Kmieciak. Neoadjuvant pembrolizumab + decitabine followed by standard neoadjuvant chemotherapy for locally advanced HER2-breast cancer [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 OT1-01-02.

Abstract CT040: A Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer

Abstract BACKGROUND: Talimogene laherparepvec (TVEC) is a modified oncolytic herpes simplex 1 (HSV1) virus currently FDA approved for the treatment of melanoma. TVEC preferentially lyses tumor cells over normal tissue to release tumor associated antigens, produces GM-CSF to activate dendritic cells, and stimulates T cells to infiltrate the tumor (TILs). TILs in breast cancer are associated with better response to neoadjuvant chemotherapy (NAC), so we hypothesized that intratumoral TVEC may enhance response to NAC. We report safety and outcomes of a Phase I trial combining NAC with TVEC in stage 2-3 TNBC. METHODS: Stage 2-3 TNBC patients were enrolled into a 3+3 Phase I trial with 2 TVEC dose levels [DL1=106 PFU x 5 doses, DL2=106 PFU 1st dose then 108 PFU x 4 doses] q2week + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone. Patients then had surgery and were assessed for pathologic complete response (pCR). Primary endpoint is safety by CTCAE 4.03 and maximum tolerated dose (MTD), secondary is pCR rate and immune correlates. Dose limiting toxicity (DLT) rule was grade 3-5 adverse event due to TVEC during 1st 6 weeks. RESULTS: Nine patients (DL1 [n=3], DL2 [n=6]) were enrolled. Six pts were stage II, three were stage III (6 clinically N+). No DLTs were encountered and MTD dose was DL2. Most common toxicities due to TVEC were fevers (n=8), chills (n=3), hematomas (n=3), injection site pain (n=3). One genital wild type HSV1 reactivation event occurred. Common NAC related toxicities included anemia, nausea, fatigue, neuropathy, infusion reactions, lymphopenia as expected. Thromboembolic events (n=2) and severe bradycardia (n=1) occurred during or after AC chemo. Five pts (55%) had pCR, 2 had microscopic residual disease (22%), 2 had gross residual disease (22%). Preliminary immune correlates show heavy immune infiltration in analyzed tumors, full results will be presented. CONCLUSION: Addition of TVEC to NAC was feasible at full FDA approved dose with manageable toxicity. The combination is highly active in TNBC with an increase in pCR rate (55%) over expected rate of 30% with NAC alone. Preliminary evidence of robust immune activation was observed. This combination will continue to be evaluated in an ongoing phase II trial. Citation Format: Hatem Soliman, Deanna Hogue, Hyo Han, Blaise Mooney, Ricardo Costa, Marie C. Lee, Bethany Niell, Nazanin Khakapour, Robert J. Weinfurtner, Susan Hoover, Marilin Rosa, Hung Khong, Brian Czerniecki. A Phase I trial of talimogene laherparepvec combined with neoadjuvant chemotherapy for non-metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT040.

Relation between dexamethasone (DEX) usage, preventive trimetprim/sulfametoxazole (ST), and pneumocystis pneumonia (PCP) for patients with breast cancer receiving dose-dense AC followed by dose-dense paclitaxel (ddAC-ddP): Preplanned analysis of WJOG9016B.

e12022 Background: PCP is rare complication of ddAC-ddP. DEX is plausible risk factor for PCP. Dose and duration of DEX against CINV is changing over time as other anti-emetic drugs (5HT3 RA, NK1 RA, and olanzapin) became available. Then DEX usage varies widely in each hospitals. ASCO/IDSA guideline recommends preventive ST for patients receiving 20 mg or more predonisone equivalents daily for more than one month, although evidence is lacking in patients receiving ddAC-ddP. This study is to investigate relation between DEX usage, preventive ST, and risk of PCP for patients receiving ddAC-ddP. Methods: This study is preplanned analysis of WJOG9016B (UMIN000024992) which investigated relative dose intensity of ddAC-ddP supported by 3.6 mg (approved dose in Japan) of pegfilgrastim. Eligible pts were HER2 negative PBC with stage I to IIIc, going to start ddAC-ddP and younger than 65 y.o.. DEX usage and preventive ST usage were discrete to treating physicians. Results: From Jan. 2017 to Jan. 2018, 92 pts were registered and 91 pts were in the FAS set, because one patients turned out be ineligible after registration. All patients received DEX for prevention of delayed CINV. Median total dose of DEX during ddAC was 112 mg (range; 80 to 212 mg), which was equal to 13.3 mg (9.52 mg–24.76 mg) predonisone equivalents daily. Only five of them (5.4%) received more than 20 mg predonisone equivalents daily. Twenty patients received preventive ST. Three patients developed PCP. None of them with preventive ST developed PCP (0%), whereas three of patients without ST developed PCP (4.2%). These three patients received total DEX dose during ddAC at 80 mg, 112 mg, and 112 mg, respectively. Conclusions: ST was highly effective for PCP prevention for patients receiving ddAC-ddP, if DEX used against delayed CINV. Without ST prevention, the risk of PCP was 4.2 %, which was higher than threshold (3.5%) proposed in ASCO/ IDSA guidelines. The threshold of steroid dose leading to the risk of PCP might be lower than 20 mg or more predonisone equivalents daily in patients receiving ddAC-ddP. Clinical trial information: UMIN000024992.

P002 - A phase 2 study evaluating dose dense AC (ddAC) followed by dose dense paclitaxel (ddP) supported by 3.6 mg peg-filgrastim (ddAC-ddP3.6) for patients (pts) with primary breast cancer (PBC) in Japan -WJOG9016B-

P002 - A phase 2 study evaluating dose dense AC (ddAC) followed by dose dense paclitaxel (ddP) supported by 3.6 mg peg-filgrastim (ddAC-ddP3.6) for patients (pts) with primary breast cancer (PBC) in Japan -WJOG9016B-

1792P - Comparison of palonosetron and granisetron in triplet antiemetic therapy in nonmetastatic breast cancer patients receiving high emetogenic chemotherapy. A multicenter, prospective, and observational study

We aimed to investigate the efficacy of 0.25 mg dose of palonosetron and granisetron in triplet antiemetic prophylaxis in breast cancer patients receiving HEC. Patients with nonmetastatic breast cancer who received HEC [doxorubicin or epirubicin plus cyclophosphamide (AC/EC)] were enrolled in the study. The prophylactic triplet antiemetic regimens were used according to the doctor’s preference during the first cycle of HEC as intravenous dexamethasone and palonosetron 0.25 mg or granisetron 3 mg on day 1 as well as oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3).The primary endpoint was complete response rate (CR) on acute and delayed chemotherapy-induced nausea and vomiting (CINV), separately. A total of 118 female patients were included in the study. Patients received AC (83%), EC (3%), and dose-dense AC (14%) as adjuvant (88%) or neoadjuvant (12%). The majority of patients received palonosetron (59%) containing antiemetic treatment. The CR rate on acute and delayed vomiting was very high and not statistically different in both of the arms (acute 87% vs. 96%, p = 0.089; delayed 90% vs. 92%, p = 0.489), respectively. Nevertheless, the CR rate on either acute or delayed nausea was lower than vomiting (acute 51% vs. 51%; delayed 38% vs. 29%, p = 0.203; respectively). This is the second study that compared a 0.25 mg dose of palonosetron with first-generation setron in triplet antiemetic prophylaxis in cancer patients receiving HEC. We could not find meaningful statistical differences between two arms, regarding CR rate on acute and delayed CINV.

A Phase II Study to Evaluate the Safety and Efficacy of Pegteograstim in Korean Breast Cancer Patients Receiving Dose-Dense Doxorubicin/Cyclophosphamide

PurposeDose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT.Materials and MethodsPatients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability.ResultsOf 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%).ConclusionDose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.

Abstract OT2-07-01: Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative breast cancer

Abstract Background: The host anti-tumor immune response plays an important role in determining natural history and therapy response for early stage breast cancer. Tumors with high levels of lymphocytic infiltration appear to have a superior prognosis and response rate to neoadjuvant chemotherapy. However, these tumors are in the minority so methods to enhance tumor lymphocyte infiltration should be identified. The oncolytic virus, talimogene laherparpvec (TVEC) is a genetically modified HSV1 virus which selectively replicates in transformed cells while sparing normal tissue. This leads to lysis of infected tumor cells along with co-expression of GM-CSF to elicit an enhanced anti-tumor immune response. Prior data has shown TVEC can be safely combined with chemotherapy in other indications, so we launched an investigator initiated study to determine the safety and efficacy of combining TVEC with neoadjuvant dose dense chemotherapy in stage II-III TNBC. Study design: The study is a phase 1 (2 dose levels of TVEC, 3+3 design) and phase 2 single arm Simon two stage combination trial. Primary endpoints of phase 1 is safety of intratumoral TVEC (DL1=106 PFU x 5 injections, DL2=106 PFU x 1 then 108 PFU x 4 injections) administered q2-3 weeks concurrently with weekly paclitaxel followed by standard dose dense AC x 4 and local therapy as indicated. Phase 2 primary endpoint is pCR rate of the study treatment, secondary endpoints include DFS, OS, immune correlates in resected tumor specimens. Eligibility criteria includes females &amp;gt;17 years old, newly diagnosed T2-3N0-3 TNBC, adequate organ function, primary tumor amenable to injection with TVEC, no immunosuppressive or autoimmune conditions, no inflammatory or bilateral/multifocal disease. Sample size is up to 49 patients (12 phase 1, 37 phase 2) with 80% power to detect increase in pCR rate from 30% to 50% with one sided p=.1 in phase 2. Study status: This novel Amgen supported investigator initiated study activated to accrual 3/2017 and first patient on study was on 5/2017. The study is currently open only at the Moffitt Cancer Center. Target study completion date 8/2021. (NCT02779855) Citation Format: Soliman HH, Hogue D, Han H, Lee C, Ismail-Khan R, Khong H, Niell B, Czerniecki B. Phase 1/2 trial of the oncolytic virus, talimogene laherparpvec, in combination with neoadjuvant chemotherapy in stage II/III triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-01.

O1-10-1 - Feasibility study of Dose-dense AC or EC followed by PTX for Japanese breast cancer patients

The feasibility study of Dose-Dense chemotherapy for operable Japanese breast cancer patients(SBP 09) Dose-dense(D-D) chemotherapy for operable breast cancer revealed significant survival benefit compared to the standard chemotherapy. In western countries, it has become a standard of care. Whereas in Japan, owing to the unapproval of G-CSF primary prophylactic administration, Dose-dense chemotherapy has not been defined for a long time in spite of its efficacy. Although in recent years, the number of reports regarding D-D therapy is slightly increasing in this country, prospective feasibility study is still uncommon. To verify of the feasibility of D-D chemotherapy, we conducted a multicenter phaseII study. We enrolled patients aged under 70years, with HER2 negative and operable node-positive primary breast cancer from 10centers. The primary end point was pCR rate, and the secondary end points were safety(FN rate, completion rate),overall response rate, toxicity profile and RDI. Neoadjuvant chemotherapy with D-D AC or EC followed by PTX was administrated to eligible patients every 2weeks with Pegfilgrastim support. 50 patients were scheduled to be enrolled. 41/50 patients have been enrolled to this point. In analysis of 14/41 patients, median age was 48years(34-66), Histological subtypes were 57% Triple negative, 21% Luminal A Like, 21% LuminalB like. Clinical stageII and III were 64%, 36% respectively, and of them, StageIIIC was included at 21%. pCR rate showed 25% and, all were TN patients. Overall response rate was 100%, Grade3 or worse adverse events occurred in 33% of the patients (febrile neutropenia, pneumonia and so on). 20% of the patients were converted from q2w PTX to wPTX because of Grade3 adverse event. At the present, 80% accrual enrollment has been achieved. We plan to report the result of 50 patients full analysis.

Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P<0.001) in the dexrazoxane group, but no significant difference in the incidence of treatment delays or cancellations. The incidence of cardiac events was the same in both treatment groups with and without dexrazoxane. There was a nonsignificantly lower mortality rate in the dexrazoxane group (9.6%) compared with the nondexrazoxane group (15.0%) at data lock. Adding dexrazoxane to doxorubicin in adjuvant therapy patients leads to higher rates of bone marrow suppression in all blood components, as well as more febrile neutropenia events, and dose reductions. No differences in events defined as cardiac toxicities were detected. Dexrazoxane had no detrimental effect on survival, despite the higher hematological toxicity, the older median age, and the higher prevalence of HER2-positive disease in the dexrazoxane group.

ISY-23-2 - The vision of Japanese guidelines for the proper use of G-CSF and future perspective

The Japanese guidelines for the proper use of G-CSF were drastically revised in 2013, in which primary prophylactic use of G-CSF was recommended for the prevention of febrile neutropenia (FN) in cancer patients treated with chemotherapy when the risk of FN is 20% or higher. However, in most solid tumors, prophylactic use of G-CSF had not been covered by health insurance until pegfilgrastim was approved in Japan in 2014. Before the approval of pegfilgrastim, we could not use G-CSFs in line with guidelines and could not use many global standard chemotherapy regimens such as TAC (docetaxel + doxorubicin + cyclophosphamide) and dose-dense AC (doxorubicin + cyclophosphamide) followed by dose-dense paclitaxel as adjuvant or neo-adjuvant chemotherapy for breast cancer.Now, we can use prophylactic G-CSF and global standard chemotherapy. We should promote the appropriate use of G-CSF, ensure the safety in Japanese patients, and conduct well-designed clinical trials to provide evidence to answer clinical questions. The Japanese guidelines for the proper use of G-CSF were drastically revised in 2013, in which primary prophylactic use of G-CSF was recommended for the prevention of febrile neutropenia (FN) in cancer patients treated with chemotherapy when the risk of FN is 20% or higher. However, in most solid tumors, prophylactic use of G-CSF had not been covered by health insurance until pegfilgrastim was approved in Japan in 2014. Before the approval of pegfilgrastim, we could not use G-CSFs in line with guidelines and could not use many global standard chemotherapy regimens such as TAC (docetaxel + doxorubicin + cyclophosphamide) and dose-dense AC (doxorubicin + cyclophosphamide) followed by dose-dense paclitaxel as adjuvant or neo-adjuvant chemotherapy for breast cancer. Now, we can use prophylactic G-CSF and global standard chemotherapy. We should promote the appropriate use of G-CSF, ensure the safety in Japanese patients, and conduct well-designed clinical trials to provide evidence to answer clinical questions.

Abstract OT3-02-03: An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer

Abstract Background: The combination of the anthracycline, doxorubicin with cyclophosphamide (AC) is a widely used chemotherapy regimen in early stage breast cancer. Studies have shown that dose dense chemotherapy (incorporating AC) improved both disease-free survival and overall survival compared to once every 3 week treatment with daily subcutaneous G-CSF support. An important advance in the use of dose dense chemotherapy regimens was the development of pegylated forms of G-CSF, which offered the convenience of a single subcutaneous injection, rather than multiple daily injections. Lipegfilgrastim is a pegylated long-acting covalent conjugate of filgrastim (G-CSF). In a pivotal randomised phase III study in breast cancer lipegfilgrastim was shown to be non-inferior to pegfilgrastim. Although lipegfilgrastim is licensed in Europe and can facilitate every 2 week (dose dense) scheduling of chemotherapy there are a lack of prospective data about its efficacy in this setting. In this prospective, non-interventional, study we are investigating the incidence of treatment-related neutropaenia following four cycles of dose dense AC with lipegfilgrastim support. Methods: The primary end point of this prospective, single arm study is to determine the incidence of treatment-related neutropaenia, defined as an absolute neutrophil count (ANC) of &amp;lt;1.0 x 109/L, following four cycles of dose dense AC with lipegfilgrastim support. The secondary end points are to (1) determine the incidence of febrile neutropaenia, defined as temperature &amp;gt; 38°C and ANC &amp;lt;1.0 x 109/L, during 4 cycles of dose dense AC with lipegfilgrastim and (2) examine the incidence of treatment-related neutropaenia during subsequent intravenous chemotherapy post completion of AC. Eligibility criteria include, patients with stage I-III breast cancer, planned treatment with dose dense AC in the adjuvant or neoadjuvant setting, age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and adequate bone marrow function. Patients with prior exposure to chemotherapy and/or G-CSF, who are pregnant, have a cardiac or other concurrent illness, which at the investigator's discretion contraindicates the use of AC will be excluded. We will enrol 40 consecutive patients who are planned to undergo dose dense AC. Based on previous clinical trials, we expect that the incidence of treatment-related neutropaenia will be &amp;lt;12%. However, it is likely that the current study will more closely resemble real-world practice and a higher incidence of treatment-related neutropaenia may be observed. This study has been approved by the Instituational Review Board and 9 patients have been consented to date. (registered with clinicaltrials.gov). Citation Format: Lyons T, Mallet V, Collins D, Malone E, Milewski M, Egan K, Hennessy B, Grogan L, Breathnach O, Morris P. An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer. [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 OT3-02-03.

Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Abstract Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons &amp;lt;0.0001: Table 1 pCR BreastpCR Br/AxpCR Br/Ax or RCB IYes/No N (%)231 (52%)/212 (48%)207 (47%)/236 (53%)266 (60%)/177 (40%)EFS-HR0.33 (0.22-0.50)0.30 (0.19-0.46)0.29 (0.20-0.43)OS-HR0.28 (0.17-0.46)0.20 (0.11-0.36)0.21 (0.13-0.34) Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Table 2 CbBevN (Yes/No)225/218222/221EFS - HR0.84 (0.58-1.22) p=0.360.80 (0.55-1.17) p=0.25OS - HR1.15 (0.74-1.79) p=0.530.76 (0.49-1.19) p=0.23 Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [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 S2-05.