Adriamycin And Cyclophosphamide Research Articles

Abstract PO1-11-12: Factors associated with treatment failure for chemotherapy-induced nausea and vomiting (CINV) among breast cancer patients receiving adjuvant chemotherapy

Abstract Background Cancer patients often consider CINV as one of the most disturbing side effects of cytotoxic chemotherapy. Adriamycin and cyclophosphamide (AC), considered by many to be part of the standard adjuvant regimen for breast cancer patients, is highly emetogenic. Despite adopting optimal antiemetic prophylaxis, the control of CINV remains modest for some patients. Among Chinese breast cancer patients receiving adjuvant AC chemotherapy, the present analysis aims to determine the association of the number of risk factors for CINV with (i) likelihood of antiemetic treatment failure; (ii) time to first vomiting in 1st AC cycle. Methods: We retrieved data from three previously reported prospective antiemetic studies on patients who received AC, in whom different antiemetic regimens were administered. Treatment failure was defined as (i) not achieving CR (CR= no vomiting and no use of rescue medication over 120 hours after start of AC), or (ii) experiencing nausea (nausea VAS >/= 5mm during the 120 hours). Multivariate logistic regression models were applied to identify potential factors associated with the development of CINV. The Cochran–Armitage trend test was utilized to assess possible trends in the relationship between treatment failure and number of identified risk factors. The time-to-treatment failure curves, as classified by the number of identified factors in each subgroup, were evaluated using the Kaplan–Meier method. Results: Based on multivariate analysis of 303 breast cancer patients, not achieving CR was more likely among non-obese patients, not receiving guideline recommended prophylactic antiemetic regimens, history of motion sickness and history of vomiting in pregnancy. Experience of nausea was more likely in non-obese patients, not receiving guideline recommended prophylactic antiemetic regimens, and history of motion sickness. Treatment failure in terms of ‘no CR’ was associated with increased number of risk factors that an individual patient displayed; the figures increased from 18.8% for those with 0 risk factor to 94.1% for those with 4 risk factors (p < 0.0001). Treatment failure in terms of nausea was associated also with increased number of risk factors; the figures increased from 25.9% for those with 0 risk factor to 83.3% for patients with 3 risk factors (p < 0.0001). Time to first vomiting was significantly related to number of identified factors (p < 0.0001). Among patients who had 0, 1, 2 and 3 risk factors, the 24-hour rate of ‘no vomiting’ were 81.3%, 80.3%, 66.7%, 53.7% and 17.7%, respectively; similar trends were observed for analyses on 48-hour and 72-hour rates. Conclusions: The present study confirmed that reported risk factors for CINV in the literature were important in Chinese breast cancer patients receiving AC chemotherapy. Furthermore, patients who had more risk factors had increased likelihood of treatment failure and shorter time to first vomiting. Funding: Madam Diana Hon Fun Kong Donation for Cancer Research Citation Format: Winnie Yeo, Nicole Ngai, Horatio Yeo, Dong Lai, Elizabeth Pang, Carol Kwok, Thomas Lau, Frankie Mo. Factors associated with treatment failure for chemotherapy-induced nausea and vomiting (CINV) among breast cancer patients receiving adjuvant chemotherapy [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 PO1-11-12.

Abstract PO2-28-08: A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy

Abstract TNBC is one of the most aggressive subtypes of breast cancer. Combating chemotherapy resistance is critical to improving quality of care and reducing fatality among TNBC patients. In order to understand the mechanisms of chemoresistance in TNBC tumors, it has been proposed that the spatial interactions between cell types in the tumor microenvironment (TME) could offer insights into the differential response to therapy among tumors, and metastatic potential of certain tumors over others. Thus, this study utilizes spatially resolved transcriptomic (SRT) technology to profile the spatial interactions in the TNBC TME. With the goal of better understanding chemoresistance in TNBC and providing a proof-of-concept for new technology, we have launched a longitudinal SRT study of a TNBC PDX of residual disease before, during, and after adriamycin and cyclophosphamide (AC) treatment (Tx). SRT by 10X Genomics Visium was performed on vehicle, AC-treated residual tumor (21 days post-Tx), and AC-treated regrown tumor (50 days post-Tx when tumors regrew to starting tumor volume). This study is divided into two parts: 1) development of a computational pipeline; 2) spatial colocalization analysis of residual and regrown tumors to understand chemoresistance. PART 1: Due to the lack of specialized tools for processing and sorting xenograft reads from SRT data, we developed the Xenomake pipeline, which combines a xenograft sorting algorithm (Xengsort) and spatial barcode demultiplexing pipeline to assign reads into the host and graft organisms for each spatial spot. RESULTS: Xenomake permits clustering the spatial spots into stroma-rich (enriched for mouse mRNAs), and epithelial-rich (enriched for human mRNAs) regions. We show that Xenomake can find differential cytokine production in the stroma and epithelium. Since PDX data separate the tumor into stroma and epithelium by organism, the pipeline enables fine-tuned downstream analysis such as stromal-stromal and stromal-epithelial interactions. Xenomake is thus generally applicable for SRT involving PDX samples. PART 2: Previously we detailed patterns of tumor regression into a residual tumor state, followed by uncontrolled regrowth in the absence of treatment in multiple PDX models of TNBC. Although using PDX models necessitates immune-compromised mice, several types of stromal populations are present and analyzable in these models. Thus, using organism-assigned reads processed by Xenomake, we computationally inferred the localization pattern of stromal cell types in Visium spots including cancer associated fibroblasts (CAF), macrophages (MP), endothelial cells (ENDO), monocytes, and perivascular-like cells. We compared the spatial localization profiles (SLP) of stromal cell types across samples. With human reads, we computed the spatial pathway activity map (SPAM) for the ~30 HALLMARK pathways across samples. We correlated the patterns of SPAM with stroma cell-type SLP to survey the stroma-epithelial interactions across samples. RESULTS: Stroma cells are generally distributed in the tumor periphery in vehicle and AC50, while in AC21 there is a notable increase in stroma abundance and stroma infiltration within tumor mass. SLP of MP (Cd68+ and Csf1r+) is correlated with ENDO (Pecam1+), and with CAF (Acta2+ and Pdgfrb+). Additionally, all 3 cell types are correlated with Vim and Cd44 expression. Although all samples show enrichment of MP, ENDO, and CAF, they interact differently with pathway activities of adjacent epithelial cells. In vehicle and AC50, the 3 cell types are colocalized with OXPHOS, MYC targets, E2F pathway, while in AC21, a switch to colocalization with EMT is observed. Furthermore, hypoxia response and glycolysis display anti-correlation with stroma cell types, meaning that these pathway activities are further away from stroma and occupy distinct territories. The results suggest stroma-tumor metabolic crosstalk and ways of targeting residual disease. Citation Format: Benjamin Strope, Katherine Pendleton, William Bowie, Gloria Echeverria, Qian Zhu. A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy [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 PO2-28-08.

Abstract 3876: A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy

Abstract Combating chemotherapy resistance in TNBC is critical to improving quality of care and reducing fatality. To understand chemoresistance, it has been proposed that the spatial interactions between cell types in the tumor microenvironment (TME) could offer insights into the differential response to therapy and metastatic potential. Thus, this study utilizes spatially resolved transcriptomics (SRT) to profile the spatial interactions in TNBC TME. With the goal of understanding chemoresistance and providing a proof-of-concept for new technology, we launched a longitudinal SRT study of a TNBC PDX of residual disease before, during, and after adriamycin and cyclophosphamide (AC) treatment (Tx). SRT by 10X Visium was performed on Veh, AC-residual tumor (21 d post-Tx), and AC-regrown tumor (50 d post-Tx when tumors regrew). This study is divided into two parts. 1. Due to the lack of specialized tools for processing xenograft reads from SRT, we developed the Xenomake pipeline, which combines xenograft sorting and spatial barcode demultiplexing to assign reads into the host and graft organisms per spatial spot. It permits clustering the spots into stroma-rich (mouse), and epithelial-rich (human) regions. We show that it can find differential cytokines in the stroma (S) and epithelium (E), and finding SS, EE, and SE interactions. 2. Although using PDX necessitates immune-compromised mice, several types of stromal populations are present and analyzable. Thus, using Xenomake, we inferred the localization of stromal cell types in Visium spots including cancer associated fibroblasts (CAF), macrophages (MP), endothelial (ENDO), monocytes, and perivascular cells. We compared the spatial localization profiles (SLP) of stromal cell types across samples. With human reads, we computed the spatial pathway activity map (SPAM) for HALLMARK pathways. We correlated SPAM with stroma cell type SLP to survey stroma-epithelial interactions. Stroma cells are distributed in the tumor periphery in vehicle and AC50, while in AC21 there is a notable increase in stroma abundance and stroma infiltration within tumor mass. SLP of MP (Cd68+ and Csf1r+) is correlated with ENDO (Pecam1+), and CAF (Acta2+ and Pdgfrb+). Additionally, all 3 cell types are correlated with Vim and Cd44 expression. Although all samples show enrichment of MP, ENDO, and CAF, they interact differently with pathway activities of adjacent epithelial cells. In vehicle and AC50, the 3 cell types are colocalized with OXPHOS, MYC targets, E2F pathway, while in AC21, a switch to colocalization with EMT is observed. Further, hypoxia response and glycolysis display anti-correlation with stroma cell types, meaning that these pathway activities are further away from stroma and occupy distinct territories. The results suggest stroma-tumor metabolic crosstalk and ways of targeting residual disease. Citation Format: Benjamin Strope, Katherine Pendleton, William Bowie, Gloria Echeverria, Qian Zhu. A spatial transcriptomic study of a triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model of residual disease refractory to conventional chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3876.

Abstract 14569: Chemotherapy in Pregnancy: Assessing the Safety of Adriamycin Administration in Pregnancy Complicated by Breast Cancer

Introduction: Treatment of Pregnancy Associated Breast Cancer (PABC) with radiation and endocrine therapy is challenging due to potential risks to the fetus. Surgical treatment is safe throughout pregnancy, and chemotherapy agents such as anthracyclines are safe during 2 nd and 3 rd trimesters. Case Presentation: A 39-year-old G4P3 female presented at 8 weeks gestation with a twin pregnancy and a right breast mass with bloody nipple discharge. Past medical history was significant for obesity and chronic hypertension. Biopsy of the mass confirmed weakly ER+/PR-/HER2-, node+, stage IIb PABC. After radical mastectomy and axillary lymph node dissection, 4 Adriamycin and Cyclophosphamide (AC) based adjuvant chemotherapy cycles q3 weeks were started at 12 weeks of gestation with a maternal and fetal echocardiogram, brain natriuretic peptide and troponin measurements after each cycle. A baseline echocardiogram revealed cardiomyopathy with an LVEF of 45% and a severely dilated left ventricle. She was New York Heart Association class II at baseline. Carvedilol 6.25 mg BID was started prior to beginning AC and titrated to 12.5 mg BID due to palpitations after 1 st AC cycle. She tolerated 4 AC cycles with no change in EF from baseline, no symptoms of heart failure, and a normal fetal echocardiogram. Weekly Paclitaxel was resumed to complete 12 cycles prior to radiation treatment. She delivered healthy male and female infants at 32 weeks with no complications (M: APGAR 5 and 7; F: APGAR 8 and 7). Postpartum EF decreased to 40%, necessitating titration of carvedilol to 25mg BID and the addition of Sacubitril/Valsartan 24/26 mg BID. Chest pain complaint after delivery prompted evaluation with computed tomography-based angiogram and cardiac magnetic resonance imaging (CMR), ruling out coronary artery disease. Despite this, no evidence of microvascular disease on CMR symptomatic relief was reported on long-acting nitrates. Discussion: This case demonstrates the importance of multidisciplinary patient management, particularly for those with low LVEF who are at higher risk of decompensation. Despite not knowing the etiology of PABC, she could be suffering from thrombotic microangiopathy of small coronary vessels, which explains relief from nitrates.

Abstract P5-07-03: The Association Between Symptom Severity and Physical Function among Participants in I-SPY2

Abstract Background. Patient-reported outcomes (PROs) are increasingly recognized as a valuable component to understand treatment tolerability and toxicity among patients on clinical trials. We have implemented a system for monitoring patient reported outcomes (PROs), symptoms, and quality of life (QOL) using electronic PRO (ePRO) instruments for patients enrolled in the I-SPY2 trial. I-SPY2 is a phase II multi-site clinical trial evaluating the effect of novel neoadjuvant therapies for locally advanced breast cancer. We correlated patient demographic factors with symptoms, investigated the trajectory of symptoms throughout treatment, and sought to characterize symptoms associated with decline in physical function (PF). Methods. Our study population included 259 I-SPY2 patients that completed surveys on one of 9 study arms (including novel oral taxane/immunotherapy combinations, IV paclitaxel, checkpoint inhibitor+/- LAG3 inhibitor, and control IV paclitaxel +/- trastuzumab/pertuzumab). After the 12 week period of investigational agents, most patients received standard adriamycin and cyclophosphamide (AC). Symptom severity, frequency, and interference was assessed weekly using 33 items from the PRO-CTCAE item bank. PF was assessed using the NIH PROMIS instrument and was evaluated at baseline, inter-regimen (after 12 weeks of treatment), pre-surgery, and 1 and 6 months at follow-up. An odds ratio was used to assess univariate associations between age and race, and symptoms. Regularized multi-variate regression was used to evaluate early symptoms (prior to week 6) predictive of a clinically significant (>5 point T-score) decline in PF from baseline to post-treatment follow-up among all races and age groups. Results. Of 259 patients (mean age (SD) = 46.8 (13.6)), 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), 25 (9.3%) were Hispanic, and 35 (13.5%) self-reported “Other”. At baseline, AA patients had a higher severity of joint pain than White patients (OR = 14.9, P < 0.05). During study treatment with paclitaxel and/or novel agent within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P< 0.05 and P< 0.03 respectively). During treatment with AC, NW patients were more likely to report higher severity of neuropathy than White patients (OR = 5.43, P< 0.03). Among all patients, in analysis of early symptoms predictive of a clinically significant decline in PF between baseline and 1 month post treatment, predictors included high frequency of diarrhea, severity of itching, and severity of joint pain. Further analysis of symptom trajectories revealed that frequency of diarrhea reported rose sharply between baseline and Cycle 2 with 9 patients (7%) reporting occasional or frequent diarrhea to 39 patients (28%) reporting occasional to almost constant diarrhea and remained stable at that proportion for the remainder of treatment. Frequency of diarrhea declined slightly during AC (17%) and dropped to baseline levels by follow-up. In contrast, severity of joint pain persisted post-treatment, rising consistently from baseline through follow- up with 3 patients (2%) reporting moderate to severe joint pain at baseline to 18 patients (35%) reporting moderate to severe joint pain at follow-up. Conclusion. Among I-SPY2 participants, when higher grade of diarrhea is persistent (or uncontrolled), it impacts physical function even after end of therapy. In some cases, race was also a determinant in symptom trajectory, although a higher enrollment of AA and NW patients will enable more robust estimates to be computed. While some of these early symptom predictors are transient and resolve by the time of follow-up, others persist long-term and contribute more directly towards impaired physical function at follow-up. Citation Format: Amrita Basu, Saumya Umashankar, Kaylee Blevins, Anna Northrop, Anika Christofferson, Ebunoluwa Olunuga, Jaeyoon Cha, Ananya Mittal, Julissa Molina-Vega, Laura Sit, Thelma Brown, Bev Parker, Diane Heditsian, Susie Brain, Carol Simmons, Alessandra Taboada, Tina J. Hieken, Kathryn Ruddy, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene M. Kang, Jane Perlmutter, Hope Rugo, Sai Kanaparthi, Garry Peterson, Lisa T. Weiss, Adam Asare, Laura J. Esserman, Michelle Melisko, Dawn Hershman. The Association Between Symptom Severity and Physical Function among Participants in I-SPY2 [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 P5-07-03.

Additional effect of anthracycline in preoperative chemotherapy with a sequential anthracycline‑containing regimen preceded by pertuzumab, trastuzumab and docetaxel combination therapy.

The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021.

Abstract 1595: Analysis of spatiotemporal phenotypic heterogeneity in chemoresistant triple negative breast cancer using imaging mass cytometry

Abstract Shifts in tumor cell phenotype in response to selective pressures (i.e. changing microenvironments, drug treatments) pose one of the biggest obstacles to successful breast cancer therapies. Phenotypically diverse breast tumor and stroma subpopulations, and interactions between them that alter tumor cell biology, represent unique and spatially distinct niches. We hypothesize that localized neighborhoods of breast tumor cells possess specialized phenotypes that mediate chemoresistance and represent novel therapeutic vulnerabilities. In order to assess these potential phenotypes, we utilized imaging mass cytometry (IMC), a highly multiplexed imaging modality that allows simultaneous measurement of 30-40 antigens while retaining the spatial architecture of the cancer tissue. We constructed an IMC antibody panel that combines markers for tissue architecture, tumor and stromal cell phenotyping, and signaling pathway activation. IMC was applied to patient-derived xenograft (PDX) models of triple negative breast cancer (TNBC).Our TNBC PDX collection was established from tumors obtained before and after neoadjuvant Adriamycin and cyclophosphamide (AC). IMC analysis of 18 PDX models representing eight patients revealed that stromal cell phenotypes were generally shared between all models, but tumor cell phenotypes were largely patient-specific. While every model was comprised primarily of a few major tumor cell phenotypes, we noted that each case also harbored several minor, unique populations, suggesting that specialized neighborhoods may exist within the tumor mass. Comparison of paired PDX models showed a wide range of phenotypic responses to chemotherapy, ranging from stable tumor composition to widespread changes in tumor phenotypes. These phenotypic changes arose despite relatively consistent genomic architecture. Vimentinhi fibroblasts were present more often in post-AC models, while SMAhi fibroblasts were unchanged after treatment. Comparison of pre-/post-AC PDX pairs revealed spatially constrained MAPK activation emerged after treatment. To capture acute changes in tumor phenotype, we treated treatment-naïve PDX models with AC and evaluated tumors by IMC. As tumors regressed and then regrew, we identified novel phenotypic shifts, again including increased MAPK signaling localized to discrete neighborhoods, suggesting this property may be a common feature of chemoresistant TNBC. Analysis of adjacent cells revealed seven distinct neighborhoods, and ongoing work is aimed at determining whether these neighborhoods are altered in response to chemotherapy treatment. Taken together, our findings suggest that distinct tumor phenotypes arise following treatment. Our goal is to determine whether these unique phenotypic niches functionally contribute to chemoresistance and if disruption of these niches enhances chemosensitivity. Citation Format: Amanda L. Rinkenbaugh, Vidya C. Sinha, Pankaj Singh, Yuan Qi, Jiansu Shao, Xiaomei Zhang, Gloria V. Echeverria, W. Fraser Symmans, Stacy L. Moulder, Helen Piwnica-Worms. Analysis of spatiotemporal phenotypic heterogeneity in chemoresistant triple negative breast cancer using imaging mass cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1595.

Outcome of neoadjuvant treatment in triple-negative breast cancer in a rural underserved community.

e12608 Background: Complete pathological response (pCR) is a surrogate of successful neoadjuvant treatment of triple-negative breast cancer (TNBC). We extended our study from 2016, where we discussed unusually high pCR employing taxane/platinum (T/P) without the use of adriamycin and cyclophosphamide (AC). Methods: This is a retrospective observational study of an underserved, low income, rural population in Oroville, California over 10 years (2011-2021). Neoadjuvant chemotherapy was offered to eighteen women with ages ranging from 36 to 77 years old (mean age is 56). Minimum requirements for evaluation was three cycles administered within 90 days of starting treatment. The primary end point of this study was pCR. We analyzed the relationship between pCR, chemotherapy regimen, proliferation rate of original tumor by Ki-67 and the ratio of neutrophil and lymphocyte (NLR). The two regimens of chemotherapy included both standard AC+T or the alternative treatment with T/P. We grouped Ki-67 to above and below 50% pre-treatment. NLR was grouped between those above and below 3.2. Results: Our study produced a respectable response rate with 12/18 (67%) achieving pCR. There was no difference with or without exposure to anthracyclines. Out of the twelve who achieved pCR, eight (67%) received T/P and four (33%) got AC+T. Ki-67 in all eighteen patients ranged from 2% to 97% with a median of 75%. Ki-67 was >50% in 10/12 (83%) patients who achieved pCR and 3/6 (50%) in those who did not have a response. NLR was a significant predictor for pCR. 8/12 (67%) of patients who experienced pCR had a NLR of <3.2 compared to the 1/6 ( 17%) with no response. The p-value is .0455. Conclusions: Treatment with the alternative regimen of T/P didn’t affect pCR in our population. We hypothesize that some of the beneficial effects of cytotoxics affected the patient’s immunological milieu on top of the direct effect of the malignant clone.

The significance of Serum Vitamin D Levels on Changes in Hematological Parameters After Chemotherapy in Patients with Breast Cancer

Objective: To investigate the relationship between serum Vitamin D (VD) level and the change of hematological parameters after chemotherapy in patients with breast cancer (BC) who received adjuvant Adriamycin and Cyclophosphamide (AC).
 Material and Methods: A total of 74 BC patients who were treated with adjuvant 60 mg/m2 Adriamycin and 600 mg/m2 Cyclophosphamide (AC) were included in the study. VD levels, complete blood count (CBC) findings after 1st cycle AC were retrospectively recorded. The relationship between changes in CBC parameters according to VD levels and the presence of hematological toxicity was examined.
 Results: The mean age was 55.11±9.97 years and the median VD level was 12.78 (4-53.40) ng/mL. In all patient groups, there was a significant decrease in the values of lymphocytes and monocytes after chemotherapy (p=0.030, p=0.024 respectively). In the correlation analysis, there was no correlation between VD levels and hemoglobin levels, the number of cells in CBC-1, and the amount of change in the number of cells in after chemotherapy. However, there was a negative correlation between VD level and platelet/lymphocyte ratio-1 (PLR-1), monocyte/lymphocyte ratio-1 (MLR-1) (p=0.025, r:-0.237; p=0.001, r:-0.370, respectively), but there was no correlation with PLR-2 and MLR-2 (p>0.05 all).
 Conclusion: There was no relationship between VD levels and changes in hematological parameters and hematological toxicity related to AC chemotherapy in the patient with BC. VD level was inversely correlated with PLR-1 and MLR-1, which is generally accepted as inflammatory markers. This result showed that the levels of VD do not have a significant role in the development of hematological toxicity after AC chemotherapy in BC.

A Study on Clinical and Pathological Responses to Neoadjuvant Chemotherapy in Breast Carcinoma.

Aim and objectivesTo assess the effectiveness of neo-adjuvant chemotherapy and its impact on the clinical and pathological response in locally advanced breast cancer. To compare molecular subtypes of breast cancer with response to neo-adjuvant chemotherapy.Patients and methodsThis was a prospective study on patients who received neoadjuvant chemotherapy for breast carcinoma for a 3-year period. A total of 60 patients who presented with locally advanced breast cancer (LABC) were treated with neoadjuvant chemotherapy. Forty patients were treated with the 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) schedule, 16 patients were treated with Adriamycin and cyclophosphamide (AC), and four patients were treated with oral cyclophosphamide, intravenous methotrexate, and fluorouracil (CMF). Taxol was added in all node-positive cases, triple negative breast cancer (TNBC), and Her 2 positive cases. The clinical response was assessed with RECIST criteria after neoadjuvant chemotherapy. The response was compared with molecular subtypes of carcinoma breast and receptor status individually.ResultsA total of 60 female patients receiving primary chemotherapy for locally advanced breast malignancy were studied. The median age of the patients at the time of diagnosis was 44 years (range=24–73). In terms of menopausal status, 25 (42%) patients were pre-menopausal and 35 (58%) patients were post-menopausal. Histological classification showed invasive ductal carcinoma in 72% of patients, invasive lobular carcinoma in 15% of patients, and other types including mixed patterns in 13% of patients. Among 60 patients, 16 patients (26.6%) had clinically complete remission (cCR), 30 patients (50%) had partial remission, eight patients (13.3%) had stable disease, and six patients (10%) had progressive disease. Following neoadjuvant chemotherapy, 46 (76.6%) patient underwent Modified radical mastectomy surgery. Target therapy was given for Her2 neu patients after surgery. Hormonal therapy was added to hormone ER PR positive cases postoperatively. Eight patients (13.3%) among this operated cases attained complete pathological response.ConclusionPreoperative chemotherapy downstages the primary tumors and axillary metastasis in patients with locally advanced breast carcinoma. Comparison of molecular subtypes with chemotherapy response is a better way to find out the predictors of response to chemotherapy.

Abstract P3-02-08: Comparison of metabolic changes after neoadjuvant endocrine and chemotherapy in ER positive, HER2 negative premenopausal women with breast cancer

Abstract Background Survival of breast cancer has improved and treatments related changes and long term effect regarding weight gain and metabolic profile deterioration after neoadjuvant systemic treatment (NST) become important issues in cancer survivor especially young women. We sought to compare changes in body mass index (BMI), metabolic profiles and neutrophil lymphocyte ratio (NLR) in patients who underwent 6 months of neoadjuvant chemotherapy (NCT) and neoadjuvant endocrine therapy (NET) before/ after NST and 3 years after treatment. Methods Prospective, randomized, phase III trial (NEST) which compared 24 weeks of response of NCT with Adriamycin and cyclophosphamide(AC) followed by docetaxel (T) and NET with goserelin and tamoxifen. Among them, 123 patients from NEST trial in Asan Medical Center were retrospectively reviewed to evaluate metabolic changes such as BMI, blood pressure (BP), total cholesterol (TC), fasting glucose, and NLR.BP was classified according to 2017 AHA guideline such as normal, elevated, HTN stage I and HTN stage II. NLR was calculated from the differential leukocyte count by dividing neutrophil percentage by lymphocyte percentage in routine blood cell counts. Results The mean age of patients was 42 years old. BMI were significantly increased during NCT (22.6 to 23.7, p<0.05), and recovered after 3 year follow up. BMI change were not observed before and after NET and 3 year follow up (23.2, 22.0 and 23.2 respectively p>0.05, all) In the NCT group, the normal group of BP increased from 35 (58%) patients to 40(67%) patients and the elevated group decreased from 12 patients (20%) to 2 patients (3.3%). HTN stage I group was increased from 8 (13%) to 12 (20%) and HTN stage II group increased from 5 (8%) to 6 (10%) after NCT (p=0.001). There were no significant changes of BP during NET. The mean value of initial total cholesterol before NCT was 184.6mg/dL, 215.98 mg/dL after NCT (p<0.05, before vs after), 179 mg/dL after 3 years of treatment (p<0.05, after vs 3 yrs.). In the NET group, the mean initial cholesterol before NET was 185mg/dL, 176.3 mg/dL (p=0.04, before vs after) after NET, and 179.4 mg/dL after 3 yrs. follow up (p=0.23, before vs after 3years). In the NCT group, the mean fasting glucose were significantly increased while NCT (95.75mg/dL to 111.61mg/dL, p<0.05), and recovered after 3 year follow up (95.78 mg/dL, p<0.05). In the NET group, the mean fasting glucose changes were not observed before and after NET and 3 year follow up (97.78mg/dL, 99.04mg/dL and 99.06mg/dL respectively p>0.05, all). NLR was increased from 2.02 to 4.43 after NCT (p<0.05) and decreased from 2.13 to 1.57(p<0.05) after NET. Conclusion NCT causes worsening of metabolic profiles such as BMI, blood pressure, TG, and fasting glucose, which is recovered over 3 years. In the NET group, there were no significant changes in BMI, BP and fasting glucose but total cholesterol was significantly decreased after NET treatment. NLR was increased after NCT but decreased after NET. Citation Format: Ho-Hyun Ryu, Ji-Seon Kim, Il-Yong Chung, Jong-Won Lee, Beom-Seok Ko, Byung-Ho Son, Sei-Hyun Ahn, Hee-Jeong Kim. Comparison of metabolic changes after neoadjuvant endocrine and chemotherapy in ER positive, HER2 negative premenopausal women with 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 P3-02-08.

Survival outcome of combined GnRH agonist and tamoxifen is comparable to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal patients with early breast cancer.

Survival outcome of ovarian suppression plus tamoxifen has been shown to be comparable with chemotherapy in premenopausal women; however, there are a few previous studies that compared this treatment to the current standard adriamycin and cyclophosphamide (AC) regimen. The aim of the present study was to compare the survival outcome of gonadotropin-releasing hormone (GnRH) agonist plus tamoxifen (GnRH-TAM) and chemotherapy AC plus tamoxifen (AC-TAM) in premenopausal patients with early breast cancer who were hormone receptor-positive. Premenopausal patients with early breast cancer who were treated at The Siriraj Hospital between January 2005 and December 2015 were retrospectively recruited. The inclusion criteria included newly diagnosed breast cancer, size ≤3 cm, node-negative and hormone receptor-positive. All patients received adjuvant systemic therapy and were divided into two groups. In the GnRH-TAM group, the patients received subcutaneous injection of 10.8 mg of goserelin every 3 months for 2-3 years and TAM (20 mg/day) for 5 years. In the AC-TAM group, AC was administered every 3 weeks for 4 cycles followed by TAM (20 mg/day) for 5 years. In total, 40 patients received GnRH-TAM and 130 patients received AC-TAM. The mean age at diagnosis was 44.4±6.3 years while the median follow up time was 77 (36-167) months. There was no mortality in either group and no significant difference in disease-free survival between the two groups. No adverse effect occurred and good compliance was observed in all patients who received GnRH-TAM. Treatment with GnRH-TAM resulted in a comparable survival outcome and better quality of life compared with AC-TAM.

Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation.

Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy-induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis-related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy.

Pattern of management of febrile neutropenia among breast cancer patients treated with different chemotherapeutic regimens

Background: Breast cancer is one of the common malignancies in females. Chemotherapy with Adriamycin and Cyclophosphamide (AC) followed by the Docetaxel (AC-T, Regimen-I), AC followed by Docetaxel and Carboplatin (AC-T+Cr, Regimen-II) and AC followed by Docetaxel and Trastuzumab (AC-T+Tr, Regimen-III) are commonly given for treatment. These cause myelosuppression and febrile neutropenia and need necessary interventions.Methods: This is a prospective open labelled observational comparative study to evaluate the antibiotic usage needed to treat sepsis following febrile neutropenia among breast cancer patients undergoing chemotherapy with regimen I, II and III. All patients received prophylactic Pegfilgrastim / Filgrastim. Antibiotics used and days in intensive care unit (ICU) in all the 8 cycles of chemotherapy were recorded. 38 patients in Regimen I, 40 patients in Regimen II and 46 patients in Regimen III completed the study and were included in the statistical analysis.Results: In regimen II, following cycle 2 of chemotherapy, none of the patients needed antibiotic therapy. Antibiotic use was maximum, following cycle 1of chemotherapy in regimen I and III, maximum number of antibiotics prescribed were 7. Number of days of ICU care needed for regimen II patients following 3rd cycle of chemotherapy was 3.5±3.5 days. No ICU care was needed for regimen III patients, following cycles 2, 3 and for regimen II following cycle 7.Conclusions: Febrile neutropenia produced by chemotherapy were effectively treated with intravenous antibiotics in ICU for an average of 2-3 days. No mortality was associated with febrile neutropenia and all patients were recovered.

Abstract OT3-06-04: A randomized phase II study of neoadjuvant panitumumab /carboplatin/paclitaxel (PaCT) versus carboplatin/paclitaxel (CT) followed by adriamycin and cyclophosphamide (AC) for newly diagnosed primary triple-negative inflammatory breast cancer (TNIBC)

Abstract Primary Objective: To determine pathological complete response (pCR) rate in patients with primary TNIBC treated with PaCT in comparison with CT, followed by AC. To explore if the pCR rate correlates with reduced nodal expression status; and with arginine methylation status of epidermal growth factor receptor (EGFR). We will identify molecular biomarkers predictive of the pCR rate by analysis of multiplexed immunohistochemical (IHC) staining, identify molecular biomarkers predictive of the pCR rate by genomic and proteomic analysis, and determine whether the inhibition of the EGFR pathway down regulates the COX-2 pathway and mesenchymal marker. Background: EGFR is overexpressed in triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC). Therefore, EGFR targeted therapy may have a promising role in TNBC and IBC. A study showed that EGFR-targeted therapy may enhance the initial chemosensitivity of TNBC cells. Panitumumab blocks epidermal growth factor ligands and transforming growth factor EGFá (TGFá) binding to EGFR, inhibits tumor growth, and elicits both tumor regression and eradication of established tumors in murine xenograft tumor models. Panitumumab, a fully humanized anti-EGFR antibody, has been shown to be active in a breast cancer preclinical model using human breast cancer cell line MDA-MB-468, which has been shown to overexpress EGFR by both IHC and fluorescence in situ hybridization (FISH). Furthermore, EGFR tyrosine kinase inhibitors such as erlotinib have antitumor activity against human IBC cell lines. Thus, EGFR targeted therapy may have a promising role in TNBC and IBC. Study Design: In this open label randomized phase II trial, up to 72 patients with primary IBC, have no HER2 overexpression, and have <10% expression of ER and PgR, who also meet other criteria will be randomized to PaCT arm - receiving panitumumab single agent in window study and 4 cycles PaCT, or CT arm - receiving 4 cycles of CT. All patients will receive 4 cycles of AC before surgery. Statistical Considerations: A sample size of 36 patients per arm will achieve 84% power to detect a difference of 0.24 in pCR rate between 0.2 in the CT arm and 0.44 in the PaCT arm with a type I error rate of 10% using one-sided Z test. Based on historical data, we expect that the pCR rate of a PaCT regimen to achieve 24% additional efficacy compared with the CT regimen. Status of the study: Activation date: Oct. 2016. So far 6 patients have been enrolled. Enrollment continues. Sponsor: Amgen. State of Texas appropriation for rare and aggressive breast cancer research. NIH grant 1R01CA205043-01A1 Citation Format: Willey JS, Parker CA, Lim B, Valero V, Le-Petross HT, Krishnamurthy S, Woodward WA, Lucci A, Wood AL, Sun H, Babiera GV, Song J, Shen Y, Valero V, Wang X, Ueno NT. A randomized phase II study of neoadjuvant panitumumab /carboplatin/paclitaxel (PaCT) versus carboplatin/paclitaxel (CT) followed by adriamycin and cyclophosphamide (AC) for newly diagnosed primary triple-negative inflammatory breast cancer (TNIBC) [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 OT3-06-04.

The cost-effectiveness of neoadjuvant chemotherapy in women with locally advanced breast cancer: Adriamycin and cyclophosphamide in comparison with paclitaxel and gemcitabine.

Background:A decision analysis model was developed to assess the cost-effectiveness of adriamycin and cyclophosphamide (AC) in comparison with paclitaxel and gemcitabine (PG) in women with advanced breast cancer in Iran.Materials and Methods:This is a cost-effectiveness analysis performed as a cross-sectional study in Namazi Hospital in Shiraz, Iran. Patients were divided into two groups by random numbers, 32 women in the AC group and 32 women in the PG group. The costs were measured using the societal perspective and effectiveness of 2 regimens were assessed using tumor response. By a decision tree, the incremental cost-effectiveness ratio was calculated. In addition, the robustness of results was examined by sensitivity analysis.Results:The estimated total cost of AC and PG per patient was 1565.23 ± 765.31 and 2099.08 ± 926.99, respectively. Response to treatment in AC and PG arm were 84% versus 75% respectively. The incremental cost-effectiveness ratio results showed AC is a dominate alternative.Conclusion:Overall, AC was a simple dominate strategy. In other words, AC was estimated to have a lower cost and greater effectiveness than PG.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5days of each cycle. The primary outcome was reduction in nausea score. Thirty-four subjects (68cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97%) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95% confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. Ginger (500mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.

Abstract P3-06-04: Investigating clonal dynamics in triple negative breast cancer chemoresistance

Abstract Approximately 50% of triple-negative breast cancer (TNBC) patients have extensive residual disease following neoadjuvant chemotherapy (NAC). These patients have a four-fold increase in mortality risk and an increased risk of distant metastases within three years (1). Understanding the molecular basis of resistance to NAC is expected to provide opportunities to better treat patients in the primary setting. Extensive intratumoral subclonal heterogeneity has been well documented in primary, treatment-naïve TNBC (2). Subclonal populations harboring distinct molecular profiles may confound targeted therapy strategies, yet the functional impact of subclonal heterogeneity in TNBC resistance to therapy is unknown. We are implementing DNA barcoding to quantitatively track changes in subclonal architecture pre- and post-treatment in patient-derived xenograft (PDX) models of TNBC in order to design novel combination therapies. Such barcoding strategies have been used to monitor clonal dynamics in breast cancer PDXs with great sensitivity (3). We have established an orthotopic PDX from a treatment-naïve TNBC patient (PIM1, procured from a patient later found to have chemoresistant disease). In order to model chemoresistance, we treated PIM1 with Adriamycin and cyclophosphamide (AC), standard of care NAC for TNBC patients, which resulted in partial response but left residual disease. To characterize subclonal dynamics in response to NAC, we transduced freshly isolated PIM1 cells with a lentiviral library expressing 25 million unique DNA barcodes (Cellecta) using conditions to ensure each transduced cell contained a single unique barcode. Transduced cells were selected with puromycin, then orthotopically implanted into immuno-compromised mice. High-throughput barcode sequencing revealed reproducible maintenance of greater than 60,000 unique barcodes in PDX tumors. Comparison of barcode distribution in tumors treated with vehicle or NAC will reveal whether NAC selects for a subpopulation of cells during the development of resistance. Future directions will include whole-exome and RNA sequencing to characterize genomic changes associated with alterations in barcode distribution in response to NAC treatment. Our ultimate goal is to identify novel combination therapies to eliminate subclones that contribute to chemoresistance in primary TNBC.

Comparison of survival outcome of concurrent GnRH agonist plus tamoxifen to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal, lymph node-negative, hormone-responsive, HER2-negative, T1-2 breast cancer patients.

137 Background: The purpose of this study was to compare treatment outcomes between gonadotropin-releasing hormone (GnRH) agonist plus tamoxifen and adriamycin and cyclophosphamide (AC)-containing chemotherapy plus tamoxifen in hormone-responsive, premenopausal, node-negative, breast cancer patients. Methods: Among 7278 breast cancer patients who were diagnosed as breast cancer at Asan medical center, Seoul, Korea, 994 premenopausal women with node-negative, hormone receptor-positive, HER2-negative, T1-2 breast cancers were included in this retrospective cohort study: A median follow-up was 7.4 years (range, 0.5-11.4 years). 608 patients (61.2%) were treated with GnRH agonist together with tamoxifen, and 386 patients (38.8%) were treated with AC-containing chemotherapy with tamoxifen. The propensity score matching and inverse probability weighting was applied to original cohort based on patients’ age, operation method, nuclear and histologic grade, estrogen receptor and progesterone receptor positivity, T stage, Her2 positivity, and p53 positivity. In final analysis, 260 patients for each treatment arm were included. Results: In propensity matched cohorts (n = 520), a total of 34 patients had recurrence. There were 5 cancer-specific deaths and 12 overall deaths among total 520 patients. There were no survival differences for recurrence-free survival (p= 0.306), cancer-specific survival (p= 0.212), and overall survival (p= 0.102) between the two treatment groups. After applying inverse probability weighting, there were no survival differences for recurrence-free survival (p = 0.522), cancer-specific survival (p= 0.154). However, GnRH agonist with tamoxifen arm showed better overall survival than AC chemotherapy with tamoxifen arm (p= 0.021). Conclusions: Adding GnRH agonist to tamoxifen is a reasonable alternative to adding AC chemotherapy to tamoxifen in premenopausal, hormone-responsive, HER2-negative, lymph node-negative, T1-2, breast cancer patients.

Comparison of neoadjuvant chemotherapy (NACT) with 5-flurouracil, epirubicin (100mg), cyclophosphamide (FEC100) followed by docetaxel (D) (75mg) versus adriamycin and cyclophosphamide (AC) followed by docetaxel (100mg) in locally advanced breast cancer (LABC): A randomized clinical study.

e12002 Background: NACT in LABC improves the rate of breast conservation and pathological complete response (pCR), which could be a surrogate marker for chemo responsiveness and survival. In this s...