Doxorubicin-based Chemotherapy Research Articles

Abstract PO2-12-05: Scalp Cooling with the Capelli System to Reduce Doxorubicin-induced Alopecia in Patients with Localized Breast Cancer: A Phase 2 Randomized Controlled Trial

Abstract Introduction: Chemotherapy-induced alopecia (CIA) is a distressing side effect of breast cancer (BC) treatment. Scalp cooling (SC) devices have shown promise in reducing the severity of CIA. However, the impact of reducing alopecia occurrence on the quality of life of Brazilian patients remains unclear. Objectives: This study aimed to assess the effectiveness of the Capelli System, a new SC device, in reducing CIA. Methods: This was a single-center, controlled, randomized phase 2 clinical trial involving women with TNM stage I to III BC undergoing neoadjuvant or adjuvant doxorubicin-based chemotherapy (AC regimen: doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m², i.v., q21 days), with or without a taxane (paclitaxel or docetaxel). Participants were randomized in a 1:3 ratio into the scalp cooling (n = 33) or control (n = 12) groups. All participants were advised to cut their hair short and avoid heat-inducing tools or processes throughout chemotherapy, using cold or lukewarm water and wide-toothed combs for hair washing. The primary efficacy endpoint was grade 2 alopecia (>50% hair loss or hair shaving due to alopecia) after 4 cycles of AC. Secondary endpoints included measures of hair loss distress (BRHL) and body image (BRBI) from the EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23), as well as symptoms of anxiety and depression from the Hospital Anxiety and Depression Scale (HADS). Fitzpatrick phototype and hair type were assessed. Statistical analyses utilized generalized linear models and Fisher's Exact test (p-value < 0.05). Results: Patients were enrolled from October 11, 2019, to January 17, 2022. Out of the 45 patients included, 8 were excluded: 2 due to intolerance, 1 with alopecia associated with COVID-19, and 5 who withdrew consent (2 with grade 2 headache, 3 without justification). The median age was 44.6 (min-max: 23-63) years, with 18 (40%) and 27 (60%) receiving adjuvant and neoadjuvant chemotherapy, respectively. Grade 2 alopecia or hair shaving occurred in 52% of scalp cooling patients and 100% of controls (p = 0.003), demonstrating a significant 48% reduction in alopecia. There were no significant differences in HADS-A, HADS-D, BRHL, or BRBI scores between the two groups. Alopecia occurrence did not show significant associations with skin or hair types. No serious adverse events related to the scalp cooling device were reported. Conclusions: SC with the Capelli System significantly reduced CIA by half. Some patients experienced discomfort or headaches and discontinued device use. Further research is needed to understand why reduced alopecia rates do not correlate with improvements in body image or reduced hair loss distress. Citation Format: Carlos Paiva, Fabiola Dias, Angelo Matthes, Bianca Paiva, Cristiano Souza, Domício Lacerda, Augusto Antoniazzi, Maria Fernanda Machado, Matheus Godinho, Crislaine de Lima, Cristiane Cárcano, Marina Zorzetto. Scalp Cooling with the Capelli System to Reduce Doxorubicin-induced Alopecia in Patients with Localized Breast Cancer: A Phase 2 Randomized Controlled Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-05.

Outcome of serial cardiac evaluations during doxorubicin-based chemotherapy in small- to medium-sized dogs with multicentric lymphoma

Doxorubicin is an anthracycline antitumor antibiotic with dose-dependent and cumulative cardiotoxicity. However, the necessity for serial cardiac evaluation is unknown in dogs without risk factors for dilated cardiomyopathy (DCM). This study aimed to investigate serial changes in echocardiographic and electrocardiographic measures in small- and medium-sized dogs after four doxorubicin doses. We included 17 dogs, weighting < 20 kg, with multicentric lymphoma. All dogs received doxorubicin over 30 min every 4 weeks as part of a multi-drug chemotherapy protocol. The average doxorubicin dose was 3.8 times per dog. Clinical cardiotoxicity was not observed during the monitoring period. The incidence of developing arrhythmia was not significantly associated with the number of doxorubicin doses received (P = 0.600). The development of valvular regurgitations and mitral regurgitation in these dogs was not significantly associated with the number of doxorubicin doses (P = 0.363 and P = 0.779, respectively). The other echocardiographic results were not significantly different between each evaluation. In conclusion, our results showed no significant cardiotoxicity under echocardiogram and electrocardiogram in small- and medium-sized dogs without risk factors for DCM after four doses of doxorubicin in a 30-minute infusion method.

Prognostic value of hemogram parameters in osteosarcoma: The French OS2006 experience.

Previous studies have shown that neutrophil-to-lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin-based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high-dose methotrexate and etoposide/ifosfamide (M-EI) chemotherapy. We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M-EI chemotherapy. A total of 164 patients were analyzed. The median age was 14.7years (interquartile range [IQR]: 11.7-17). Median follow-up was 5.6years (IQR: 3.3-7.7years). Three-year event-free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%-78%) and 86.4% (95% CI: 80%-91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR-W4) was associated with reduced OS in univariate (p=.0044) and multivariate analysis (hazards ratio [HR]=1.3, 95% CI: 1.1-1.5; p=.002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR-W4 of 1 was associated with an increased risk of death of 30%. We identified NLR-W4 as a potential early biomarker for survival in patients with OST treated with M-EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Cytoreductive Surgery with Bidirectional Intraoperative Chemotherapy (BDIC) Using Intravenous Ifosfamide Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients with Peritoneal Sarcomatosis: A Retrospective Cohort Study.

Peritoneal sarcomatosis (PS) is a rare tumor with limited therapeutic options. Bidirectional intraoperative chemotherapy (BDIC) using intravenous ifosfamide and doxorubicin-based hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) is an emerging treatment for peritoneal malignancies. Patients with PS who underwent CRS/BDIC using intravenous ifosfamide and HIPEC from January 2017 to July 2021 were retrospectively analyzed. The last follow-up date was May 2022. A total of 29 patients were included. Overall survival (OS) rates at 6, 12, 24, and 48 months after CRS/BDIC were 93.1%, 89.2%, 81.4%, and 73.3%, respectively. As of May 2022, 6 patients (20.6%) had died, including four (13.8%) with a proven recurrent tumor and two with incomplete tumor resection [completeness of cytoreduction (CC)-2 or CC-3]. Of the 20 patients (68.9%) with CC-0 or CC-1, 7 had locoregional tumor recurrence without distant metastasis, whereas the other 13 were alive with no evidence of recurrent tumor in May 2022. Disease recurrence rates were 15% at 6 months and 35% at 12, 24, and 48 months after CRS/BDIC. Clavien-Dindo class ≥ IIIa complications developed in 9 patients (31.0%) with no deaths. Leukopenia occurred in 5 patients (17.2%) and thrombocytopenia in 12 patients (41.3%); these hematologic abnormalities resolved. A total of 9 (31.0%) patients developed nephrotoxicity; all recovered except one, who progressed to chronic kidney disease. CRS/BDIC using intravenous ifosfamide and doxorubicin-based HIPEC is a potentially effective treatment for PS and has an acceptable rate of complications.

New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy.

Central Illustration : New Cardiovascular Biomarkers in Breast Cancer Patients Undergoing Doxorubicin-Based Chemotherapy. Cardiovascular diseases (CVDs) are relevant to the management of breast cancer treatment since a substantial number of patients develop these complications after chemotherapy. This study aims to evaluate new cardiovascular biomarkers, namely CXCL-16 (C-X-C motif ligand 16), FABP3 (fatty acid binding protein 3), FABP4 (fatty acid binding protein 4), LIGHT (tumor necrosis factor superfamily member 14/TNFS14), GDF-15 (Growth/differentiation factor 15), sCD4 (soluble form of CD14), and ucMGP (uncarboxylated Matrix Gla-Protein) in breast cancer patients treated with doxorubicin (DOXO). This case-control study was conducted in an oncology clinic that included 34 women diagnosed with breast cancer and chemotherapy with DOXO and 34 control women without cancer and CVD. The markers were determined immediately after the last cycle of chemotherapy. The statistical significance level adopted was 5%. The breast cancer group presented higher levels of GDF-15 (p<0.001), while control subjects had higher levels of FABP3 (p=0.038), FABP4 (p=0003), sCD14, and ucMGP (p<0.001 for both). Positive correlations were observed between FABPs and BMI in the cancer group. GDF15 is an emerging biomarker with potential clinical applicability in this scenario. FABPs are proteins related to adiposity, which are potentially involved in breast cancer biology. sCD14 and ucMGP engage in inflammatory and vascular calcification. The evaluation of these novel cardiovascular biomarkers could be useful in the management of breast cancer chemotherapy with DOXO.

Apatinib plus chemotherapy for non-metastatic osteosarcoma: a retrospective cohort study.

Effective adjuvant therapy for osteosarcoma is necessary for improved outcomes. Previous studies demonstrated that apatinib plus doxorubicin-based chemotherapy may improve the efficacy of neoadjuvant therapy. This study aimed to clarify the effectiveness and safety of apatinib plus doxorubicin and cisplatin (AP) as neoadjuvant therapy for osteosarcoma. The clinical data of osteosarcoma patients who underwent neoadjuvant therapy and surgery between August 2016 and April 2022 were retrospectively collected and analyzed. Patients were divided into two groups: the apatinib plus AP (apatinib + AP) group and the methotrexate, doxorubicin, and cisplatin (MAP) group. This study included 42 patients with nonmetastatic osteosarcoma (19 and 23 patients in the apatinib + AP and MAP groups, respectively). The 1- and 2-year disease-free survival rates in the apatinib + AP group were higher than those in the MAP group, but the difference was not significant (P=0.165 and 0.283, respectively). Some adverse events were significantly more common in the apatinib + AP group than in the MAP group, including oral mucositis (grades 3 and 4) (52.6% vs. 17.4%, respectively, P=0.023), limb edema (47.4% vs. 17.4%, respectively, P=0.049), hand-foot syndrome (31.6% vs. 0%, respectively, P=0.005), proteinuria (26.3% vs. 0%, respectively, P=0.014), hypertension (21.1% vs. 0%, respectively, P=0.035), and hypothyroidism (21.1% vs. 0%, respectively, P=0.035). No drug-related deaths occurred. There was no statistically significant difference in the incidence of postoperative complications between the groups (P>0.05). The present study suggests that apatinib + AP may be a promising candidate for neoadjuvant therapy for osteosarcoma, warranting further validation in prospective randomized controlled clinical trials with long-term follow-up.

Prognostic value of 6-minute walking test for early prediction of doxorubicin induced cardiotoxicity

Abstract BACKGROUND/OBJECTIVES The 6-minute walking test (6MWT) is an easily performed, widely available and well-tolerated test for assessing the functional capacity of patients with HF in everyday clinical practice. The measurement properties of the 6MWT, such as reliability and validity, have been studied in patients with chronic heart failure, coronary artery disease, and cancer. However, little is currently known about the 6MWT and cardiotoxicity. The study was aimed at assessing the incidence of cancer therapy-related cardiovascular toxicity, identified the role of 6MWT as early predictor of early onset cardiotoxicity. Methods We performed a prospective study of 85 patients with breast cancer, treated with doxorubicin-based chemotherapy in the Department of Oncology and Hematology. 2D echocardiography and speckle tracking echocardiography were performed before anticancer treatment was started and after the treatment. We defined anthracycline-induced subclinical cardiotoxicity if a decline in global longitudinal strain (GLS) by &amp;gt;15% from baseline was observed and based on that patients were divided into two groups– patients with subclinical cardiotoxicity and patients without subclinical cardiotoxicity. The 6MWT was developed by the American Thoracic Society comprehensive guidelines. The 6MWT was performed in a long straight hospital corridor, over a 30-m distance. Statistical analysis was performed with „IBM SPSS statistics 27.0" program. Statistical significance level p&amp;lt;0.05. Results In the study population statistically significant GLS reduction was detected before and after the anticancer treatment (-21±0.53 vs. -18.1± 1.18, p&amp;lt;0.01). Of 85 women (mean age, 54.5 (9.3) years) subclinical left ventricle dysfunction was identified in 51 (60%). We found a significant negative correlation between baseline 6MWT and cardiotoxicity (r = 0.3 and p = 0.02). The baseline 6MWT results were significantly lower among patients with subclinical cardiotoxicity (494.3 ± 40.5 m vs 629.8 ± 60.1 m, p&amp;lt;0.001). The diagnostic validity of 6 MWT as a cardiotoxicity biomarker was evaluated using the non-parametric ROC curve (Pic. 1). We obtained an optimal cut-off point of 6MWT of ≤540m. (AUC = 0.98; p &amp;lt; 0.001). Conclusions Baseline 6MWT may be used as independed prognostic predictor of subclinical anthracycline-induced cardiotoxicity.ROC curve for 6MWT and cardiotoxicity

Subtractive Nanopore Engineered MXene Photonic Nanomedicine with Enhanced Capability of Photothermia and Drug Delivery for Synergistic Treatment of Osteosarcoma.

Two-dimensional (2D) nanomaterials as drug carriers and photosensitizers have emerged as a promising antitumor strategy. However, our understanding of 2D antitumor nanomaterials is limited to intrinsic properties or additive modification of different materials. Subtractive structural engineering of 2D nanomaterials for better antitumor efficacy is largely overlooked. Here, subtractively engineered 2D MXenes with uniformly distributed nanopores are synthesized. The nanoporous defects endowed MXene with enhanced surface plasmon resonance effect for better optical absorbance performance and strong exciton-phonon coupling for higher photothermal conversion efficiency. In addition, porous structure improves the binding ability between drug and unsaturated bonds, thus promoting drug-loading capacity and reducing uncontrolled drug release. Furthermore, the porous structure provides adhesion sites for filopodia, thereby promoting the cellular internalization of the drug. Clinically, osteosarcoma is the most common bone malignancy routinely treated with doxorubicin-based chemotherapy. There have been no significant treatment advances in the past decade. As a proof-of-concept, nanoporous MXene loaded with doxorubicin is developed for treating human osteosarcoma cells. The porous MXene platform results in a higher amount of doxorubicin-loading, faster near-infrared (NIR)-controlled doxorubicin release, higher photothermal efficacy under NIR irradiation, and increased cell adhesion and internalization. This facile method pioneers a new paradigm for enhancing 2D material functions and is attractive for tumor treatment.

Microparticles and cardiotoxicity secondary to doxorubicin-based chemotherapy in breast cancer patients

Doxorubicin (DOXO)-cardiotoxicity is a limiting factor for breast cancer chemotherapy. The relationship between microparticles (MPs) and cardiotoxicity remains unclear. MPs can be released under varying pathophysiological conditions. Thereby, this study aimed to assess MPs derived from cardiomyocytes (CardioMPs), platelets (PMPs) and those that expresses tissue factor (TFMPs) in 80 women with breast cancer undergoing DOXO-based chemotherapy, with or without cardiotoxicity in a one-year follow-up. We observed in the cardiotoxicity group higher count of total-MPs at T0 (prior chemotherapy) (p = 0.034), CardioMPs at T0 and T1 (just after chemotherapy) (p = 0.009 and p = 0.0034) and TFMPs at T0 (p = 0.011) compared to non-cardiotoxicity group. The results suggest that MPs could be associated to cardiotoxicity due to DOXO treatment in breast cancer patients.

Gold Nanomaterial System That Enables Dual Photothermal and Chemotherapy for Breast Cancer.

This study involves the fabrication and characterization of a multifunctional therapeutic nanocomposite system, as well as an assessment of its in vitro efficacy for breast cancer treatment. The nanocomposite system combines gold nanorods (GNRs) and gold nanoclusters (GNCs) to enable a combination of photothermal therapy and doxorubicin-based chemotherapy. GNRs of various sizes but exhibiting similar absorbance spectra were synthesized and screened for photothermal efficiency. GNRs exhibiting the highest photothermal efficiency were selected for further experiments. GNCs were synthesized in bovine serum albumin (BSA) and integrated into citrate-capped GNRs using layer-by-layer assembly. Glutaraldehyde crosslinking with the lysine residues in BSA was employed to immobilize the GNCs onto the GNRs, forming a stable "soft gel-like" structure. This structure provided binding sites for doxorubicin through electrostatic interactions and enhanced the overall structural stability of the nanocomposite. Additionally, the presence of GNCs allowed the nanocomposite system to emit robust fluorescence in the range of ~520 nm to 700 nm for self-detection. Hyaluronic acid was functionalized on the exterior surface of the nanocomposite as a targeting moiety for CD44 to improve the cellular internalization and specificity for breast cancer cells. The developed nanocomposite system demonstrated good stability in vitro and exhibited a pH- and near-infrared-responsive drug release behavior. In vitro studies showed the efficient internalization of the nanocomposite system and reduced cellular viability following NIR irradiation in MDA-MB-231 breast cancer cells. Together, these results highlight the potential of this nanocomposite system for targeted breast cancer therapy.

Advances in treatment of alveolar soft part sarcoma: an updated review.

Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.

The Impact of Polymorphisms in ATP-Binding Cassette Transporter Genes on Anthracycline-Induced Early Cardiotoxicity in Patients with Breast Cancer.

Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p < 0.001; global longitudinal strain: -17.03 ± 0.52% vs. -18.40 ± 0.88%, p < 0.001). The ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405-45.547, p = 0.019). The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Modelling cardiac mechanics in doxorubicin-induced cardiotoxicity following childhood acute lymphoblastic leukemia using a combination of cardiac magnetic resonance imaging, cardiopulmonary exercise testing and the CircAdapt model

Children with acute lymphoblastic leukemia (ALL) are treated with doxorubicin-based chemotherapy that can lead to cardiotoxicity which is a well-known cause of mortality. This study aims to characterize myocardial subtle changes induced by doxorubicin-related cardiotoxicity. We used the combination of cardiac magnetic resonance (CMR) imaging, cardiopulmonary exercise testing and the CircAdapt model to explore hemodynamics and intraventricular mechanisms at rest and during exercise in 53 childhood ALL survivors. A sensitivity analysis of the CircAdapt model identified the most influencing parameters on the left ventricle volume. ANOVA were performed to explore significant differences between left ventricle stiffness, contractility, and arteriovenous pressure drop, as well as survivors’ prognostic risk groups. No significant differences were observed between prognostic risk groups. The left ventricle stiffness and left ventricle contractility were non-significantly higher in survivors receiving cardioprotective agents (94.3 %), compared to those at standard and high prognostic risk (77 % and 86 %, respectively). In both left ventricle stiffness and left ventricle contractility, we observed that survivors receiving cardioprotective agents were close to the nominal value of CircAdapt (healthy reference group value is 100 %). This study allowed to improve our knowledge of potential subtle myocardial changes induced by doxorubicin-related cardiotoxicity in childhood ALL survivors. This study confirms that survivors exposed to a high cumulative dose of doxorubicin during treatments are at potential risk of myocardial changes many years after the end of their cancer, while cardio-protective agents may prevent changes in cardiac mechanical properties.

Topoisomerase II alpha immunoexpression as a potential predictor of doxorubicin-based chemotherapy in dogs with visceral haemangiosarcoma

Topoisomerase II alpha immunoexpression as a potential predictor of doxorubicin-based chemotherapy in dogs with visceral haemangiosarcoma

Evaluation of the RDW Index (Red Cell Distribution Width) in Women with Breast Cancer Treated with Doxorubicin in a One-Year Follow-Up Study.

Breast cancer is the most common cancer and the most frequent cause of death in women. Doxorubicin, an anthracycline, is an important drug due to its efficacy in treating solid cancers, especially breast cancer. However, this drug is often responsible for cardiotoxicity that may affect more than 25% of patients. This study aimed to evaluate the red cell distribution width (RDW) in women with breast cancer to monitor adverse events associated with the use of doxorubicin. A prospective study of 80 women with breast malignancy undergoing neoadjuvant doxorubicin-based chemotherapy was conducted. The patients were evaluated at baseline (T0), just after the last cycle of chemotherapy with doxorubicin (T1), and 1 year after the treatment (T2). There was a significant increase over the time points for the RDW (p < 0.001). There was a negative correlation between the RDW and C-reactive protein (CRP) levels at T1. The RDW did not show a significant difference between the groups classified according to cardiotoxicity. Based on these results, the RDW is a cost-effective test that shows a relationship with the doxorubicin response, but not with cardiotoxicity. It is a potential biomarker to evaluate patients with breast cancer after they receive chemotherapy with doxorubicin.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib

BackgroundSoft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS.MethodsThe JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial.DiscussionThis is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD.Trial registrationThis study was registered with the Japan Registry of Clinical Trials (jRCTs031190152) on December 5, 2019.

Abstract P1-13-02: The Aberrant Activity of Retrotransposon Elements Mediates the Chemo-tolerant Persister Cells Relapse in TNBC

Abstract The emergence of acquired drug resistance through therapeutic treatment remains a critical threat to efficient chemotherapy, target therapy, or immune therapy. These resistant cancer cells most often lead to relapse or metastasis. The development of drug resistance is a multi-step evolutionary adaptation for cancer cells. Tumor heterogeneity, cancer cells’ plasticity, and microenvironment contribute to the resistant clone’s formation. Therefore, a time-lapse adaptation model is critical to define the mechanism of drug resistance evolution. Recently, several studies have revealed that the initial acquired drug resistance might be conferred by transient events, such as drug-tolerant persisters (DTP) that might occur in a subpopulation of the cancer cells at the early stage of the treatment, which were then followed by the transcriptomic reprogramming and secondary-wave genetic mutations in the progression of resistance development. In the clinic, chemotherapy is still the mainstream treatment for TNBC, and one of the primary chemo agents is doxorubicin. Although the initial responsive rate of doxorubicin-based chemotherapy is up to 70%, it is well recognized that TNBC cells usually generate an evolutionary adaptive response that can result in the acquired drug-resistance and multi-drug resistant phenotypes. To date, numerous different mechanisms of acquired chemo-resistance have been reported, but the vast majority of these results have been derived from the continuous-high-dose-exposure acquired resistant cell line models. Since the chemo-treatment dosage in these artificial models is well above what is physiologically achievable in patients, few of them can mimic the actual situation of resistance development or improve the clinical trial outcomes. Moreover, most of these studies only characterized the terminal resistant cells, which are challenging to be resensitized because of their dominant genetic mutations. In this study, we hypothesize that the TNBC chemo-resistant cells may derive from the early-stage reversible chemo-tolerant “DTP-like” (CTP) cells, and early-stage epigenetic landscape perturbation might determine the progression of chemo-resistance development. To test the hypothesis and overcome the previous model limitations, based on the clinical drug exposure kinetics for doxorubicin, we developed an in vitro “pulsing-treatment CTPs regrowth” model (referred to as CTP model), which could mimic the clinical treatment and provide therapeutically relevant insights into the initial drug-induced stress response and resistance development. Leveraging this CTP model, we are able to define the early event for drug response, in which the doxorubicin-treated cells showed a senescence-like phenotype, and the interferon alpha (type I) pathway was activated. Furthermore, unexpectedly, we found that the expression of HERVs was significantly activated but LINE1s not. To further explore the TEs reactivation, we did the single cell RNA-seq for 0h, 2h, and 4 days samples. With a novel bioinformatic workflow, we integrated the TE expression information with coding genes mRNA profiling from the same single cell RNA-seq dataset and identified the IFN-enriched cluster had higher expression of HERVs. Herein, a subpopulation of HERVhigh cells with IFN activation was identified as a “hot-cluster” which might be the early determinant in the resistance evolution. Citation Format: Zijian Zhang, Yiyang Wang, Xinluo Luo, Xuwen Li, Xiaomei Zhan, Yumin Zheng, Jun Ding, Tao Wu. The Aberrant Activity of Retrotransposon Elements Mediates the Chemo-tolerant Persister Cells Relapse in TNBC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-02.

Single-center study of different treatment for advanced or unresectable angiosarcoma patients

Objective: To evaluate the efficacy and safety of different medical treatment in advanced or unresectable angiosarcoma. Methods: This study was a single-center retrospective clinical study. Fifty-five advanced or unresectable angiosarcoma patients treated in Sun-Yat Sen University Cancer Center from January 2005 to August 2020 were enrolled. There were 34 patients who received first-line doxorubicin-based chemotherapy (doxorubicin group), 12 patients received first-line doxorubicin or liposome doxorubicin plus paclitaxel or albumin bound paclitaxel chemotherapy (combination therapy group), and 4 patients received first-line paclitaxel-based treatment (paclitaxel group). There were 6 patients who received anti-angiogenesis targeted therapy, another 2 patients received anti-PD-1 antibody plus anti-angiogenesis targeted therapy. Targeted therapy and immunotherapy plus targeted therapy included 5 cases of first-line therapy and 3 cases of second-line therapy. The therapeutic effect was evaluated by RECIST 1.1 standard. The adverse reactions were evaluated by CTCAE4.0 standard. Kaplan-Meier survival analysis was evaluated with Log rank test. Cox proportional hazard model was used to analyze the influencing factors. Results: There were 18 patients achieved partial response (PR) in 34 patients in the doxorubicin group, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 15 months. Four patients achieved PR in 12 patients in the combination therapy group, mPFS and mOS were 4 months and 19 months. Two patients achieved PR in 4 patients in the paclitaxel group, mPFS and mOS were 3 months and 9 months. However, only 1 in 6 patients achieved PR for anti-angiogenesis targeted therapy, mPFS and mOS were 3 months and 16 months. Two patients who received anti-PD-1 immunotherapy combined with anti-angiogenesis targeted therapy acquired PR for 17 months and more than 16 months. Median PFS (7.5 months) were longer in those with primary liver, lung and spleen angiosarcoma than in those with other primary site (3.0 months, P=0.028). The mOS (20 months) was longer in females than that in males (12 months, P=0.045). Primary tumor site, sex, age and treatment were not independent prognostic factors for angiosarcoma patients (P>0.05). Grade 3-4 cardiac toxicity was found in 2 patients in the combination therapy group. Conclusions: Doxorubicin-based and paclitaxel-based chemotherapy are the most important treatment for advanced angiosarcoma. Potential efficacy for targeted therapy combined with anti-PD-1 immunotherapy are showed in some patients with long duration of response and moderate adverse event.

Predictive value of topoisomerase IIα immunoreactivity in canine diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) treated with a doxorubicin-based chemotherapy protocol

Topoisomerase IIα (TOPIIα) plays a key role in DNA replication and is a molecular target for TOPIIα inhibitor chemotherapy. A doxorubicin-based chemotherapy remains the most effective treatment for canine lymphoma, but there are no clear indications for its use in individual patients. The aim of this study was to assess the predictive value of TOPIIα expression in the treatment of canine lymphomas with TOPIIα inhibitors. Samples of formalin-fixed paraffin-embedded lymph nodes from 14 dogs with diffuse large B-cell lymphoma (DLBCL) and 5 dogs with peripheral T-cell lymphoma (PTCL) treated with a CHOP protocol were immunohistochemically labelled with anti-TOPIIα. Progression-free survival time (PFS) and overall survival time (OS) were estimated and compared with TOPIIα expression. Dogs with DLBCL had a higher level of TOPIIα expression compared to dogs with PTCL. The median PFS for dogs with DLBCL was significantly longer (260 days) than it was for dogs with PTCL (60 days). In DLBCL dogs with a high TOPIIα expression level, the median PFS was significantly longer (310 days) then it was in dogs with week or medium TOPIIα expression (51 days). The results of the study indicate that the immunohistochemical assessment of TOPIIα expression may be a valuable predictive indicator for anthracycline-based treatment of dogs with malignant lymphoma.