Use Of Anthracyclines Research Articles

Effects of a structured intervention program to improve physical activity (PA) of adolescents and young adult cancer survivors (AYAs): Final results of the randomized Motivate AYA–MAYA trial.

11518 Background: Major cardiovascular (CV) events are the most common late toxicities among AYAs. Although regular PA of vigorous intensity (≥ 9 metabolic equivalent [MET]-hours/week) lowers the risk for CV events and mortality, no larger randomized controlled trials on interventions are available. Our aim was to assess whether a 12-week structured intervention increases the vigorous PA of AYAs. Methods: AYAs aged 15 to 39 years, after curative intent cancer treatment with at least one CV risk factor, were randomized to usual-care control group (CG) and to intervention group (IG). The CG received standard recommendations, and the IG participated at a semi-structured interview and phone consulting focusing on PA and behavioral change. At baseline, post-intervention (12 wks), and at follow-up (52 wks), participants completed the International Physical Activity Questionnaire (IPAQ) and quality of life assessment (EORTC QLQ-C30). Primary endpoint was the rate of AYAs with ≥ 9 MET-hours/week of vigorous activity (IPAQ) at 12 weeks. This single center trial was registered (DRKS00009453). Results: Among 115 screened AYA 89 eligible patients were randomized; 69 (77.5%) completed the intervention and the endpoint assessment; 36 (52.2%) were in the IG and 33 (47.8%) in the CG. Median age was 24.3 years (range, 18 to 39). CV risk factors were use of anthracyclines (94.2%), chest radiation (47.8%), or both (44.9%). At baseline 49.2% of all AYAs reported to perform vigorous PA with at least 9 MET-hours/week, although reporting was individually biased. Post-intervention this rate significantly increased in the IG from 45.7% to 69.7% (p = 0.007), whereas in the CG only a modest non-significant increase was noted (53.3% to 65.6%, p = 0.134). Notably, upon long-term follow up (52 wks) AYAs did not keep their increased vigorous PA, whereas improved moderate PA was achieved (MET score in IG p = 0,044). Also, both groups reduced significantly the time they spent sitting from 6.5 (SD, 2.9) to 5.4 (SD, 2.7) hours/day (p = 0.001). Conclusions: Intensified PA counseling improves short term vigorous PA and long term moderate PA of AYAs and, should thus be part of survivorship programs. Further studies with AYAs will be required to establish reliable PA screening methods and to confirm the results in larger cohorts. Clinical trial information: DRKS00009453.

Genomic correlates of response to adjuvant trastuzumab (H) and pertuzumab (P) in HER2+ breast cancer (BC): Biomarker analysis of the APHINITY trial.

1012 Background: We conducted a comprehensive genomic and immune-marker based analysis to identify prognostic and predictive biomarkers beyond clinical parameters (eg nodal status) in the setting of HP-based therapy. Methods: APHINITY, a phase III study, randomized 4805 pt with HER2+ BC to adjuvant chemo/H, plus P or placebo. Tumor Infiltrating Lymphocytes (TILs) were analysed using published methods. A nested case-control design with 1023 pt samples (3 controls matched to 1 distant relapse) underwent DNA (targeted) and RNA sequencing. Inverse probability weighting with Kaplan-Meier estimator weights, and models adjusted for treatment, hormone receptor, nodal status, age and chemotherapy type were used. Results are reported descriptively with 95% CIs. Interaction p-values are unadjusted for multiplicity. Results: DNA-seq, RNA-seq and TIL analyses were successful in 940/1023 (92%), 974/1023 (95%), and 4313/4804 (90%) samples, respectively. Prognosis (arms pooled): PI3K/PTEN/AKT alterations (HR 1.35; CI 1.01-1.79), MYC (HR 1.61; CI 1.16-2.23) or ZNF703 amplification (HR 1.62; CI 1.07-2.47) suggest poorer prognosis while TOP2A amplification (HR 0.49; CI, 0.32-0.74) suggests better prognosis independent of anthracycline use. Higher mRNA expression of an immune signature (IFNG, PD-L1, CXCL9 (HR 0.68; CI 0.52-0.89)) and TILs (HR 0.91; CI 0.86-0.96) also suggest better outcomes. Predictive effects: Table shows the HR for H+P benefit versus H for selected markers. PAM50 subtype did not predict benefit. Conclusions: In this comprehensive biomarker analysis, higher levels of immune markers and HER2 appeared to be associated with better prognosis and greater H+P benefit. Clinical trial information: NCT01358877. [Table: see text]

A META-ANALYSIS OF CARDIOPROTECTIVE AGENTS IN PREVENTING CANCER THERAPY-RELATED CARDIOTOXICITY

Cardiotoxicity is a well-known adverse effect of anthracyclines and trastuzumab. The roles of statins, beta blockers (BBs), and ACEI/ARBs in the context of anthracycline and trastuzumab use are unsettled, mostly due to variability in study findings. Primary studies on use of statins, BBs, and ACEI/

Abstract P1-11-02: Meta-regression and meta-analysis of dexrazoxane for cardioprotection in all breast cancer stages in patients treated with anthracyclines

Abstract Background: Anthracyclines continue to be a valuable option in chemotherapy for breast cancer (BC), in spite of their well-documented cardiotoxicity. Anthracycline-induced cardiotoxicity depends on cumulative dose, and it actually begins with the first dose. Clinical studies have suggested that dexrazoxane could reduce this toxicity. Dexrazoxane is frequently used when higher anthracycline cumulative doses are needed, but is often omitted in the adjuvant setting. We aimed to analyse by an updated meta-analysis the cardioprotective effect of dexrazoxane in all BC stages in patients receiving anthracycline-based chemotherapy. In addition, we perfomed subgroup analyses and meta-regression to assess if the average anthracycline dose and the studies publication date would interfere in the cardiac event outcome. Methods: We performed a systematic review and meta-analysis. The review was registered in PROSPERO database (CRD42017077462). We searched data from 1990 to August 2017 in Cochrane Central Register of Controlled Trials, Google Scholar, MEDLINE/Pubmed, LILACS, Web of Science, articles references and ASCO proceedings. Studies assessing congestive heart failure and cardiac event (cardiac function alterations without cardiac symptoms or hospitalization for cardiac reasons) as primary endpoints were included. Two reviewers independently performed the studies selection, risk of bias assessment and data extraction. Meta-analysis was done using random effect model for estimation of treatment effect. Heterogeneity was assessed by visual inspection of forest plots and by Q test. Subgroup analyses were carried out, according with the chemotherapy regimen (use of anthracycline in previous chemotherapy). In the meta-regression we used the random effects model. Results: Our search resulted in 1603 articles, from which we included 7 studies providing 1545 participants. Meta-analysis showed an overall beneficial effect of dexrazoxane on reducing the risk of cardiac events (OR 0.262, CI 95%:0.169-0.407, p < 0.0001). In two of the seven studies which evaluated the cardiac event outcome, the patients were previously exposed to anthracyclines. In this patients' subgroup, we found an odds ratio of 0,244 (CI 95%, 0,102 to 0,584). In the study subgroup that the patients didn't report previous exposure to anthracycline, the odds ratio was 0,266 (CI 95%, 0,149 to 0,478). The Q test to evaluate the difference between the subgroups showed a value of 0,026 with p = 0,871 suggesting there was no difference between the subgroups. The multiple meta-regression was performed, adding to the model the average dose and studies age variables, for a combined analysis. The statistical analysis of the impact of the two combined cofactors didn't show significative association (Q test = 2,36, df = 2 and p = 0,30). Conclusions: Dexrazoxane reduced the occurrence of cardiac events when added to anthracycline based chemotherapy regimen. There was no evidence that the benefit of the reduction of cardiac events with the use of dexrazoxane was different according to the use of anthracycline in previous chemotherapy or by the used average dose of anthracycline. These findings may have significant implications for clinical practice. Citation Format: Macedo AV, Rodrigues AN, Brant RC, Ribeiro AL. Meta-regression and meta-analysis of dexrazoxane for cardioprotection in all breast cancer stages in patients treated with anthracyclines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-02.

Abstract P5-03-11: Sensitivity to cell cycle inhibitors in taxane resistant breast cancer models

Abstract Background: The use of anthracycline and taxane chemotherapy has improved overall and disease-free survival in breast cancer. However these agents have significant toxicity. In addition, breast cancers can acquire or possess intrinsic chemoresistance. It is imperative to identify patients who will benefit most from adjuvant taxane treatment and those with resistant tumours who could be spared unnecessary toxicity. Methods: A panel of in vitro derived cell lines models of taxane resistance were generated by serial culture in escalating doses of either paclitaxel or docetaxel until resistance was achieved. Taxane resistant cells were characterised by 2D growth, cell cycle and apoptosis analyses. Genomic profiling using the NanoString® platform was performed to identify differentially expressed genes. The identification of kinases which target the chemoresistant models was achieved through a small molecule kinase inhibitor screen. Effects of selected target kinases on cell proliferation, cell cycle, apoptosis and protein expression were assessed. Results: Resistant cell lines exhibited an IC50 at least 40-fold higher than that of the parental cells and displayed cross-resistance to the non-establishing taxane. Cell cycle analysis revealed taxane treatment failed to induce G2/M arrest in the resistant models. A reduced apoptotic response was demonstrated. Genomic profiling identified pathways associated with the cell cycle as being significantly altered. Dinaciclib, a CDK inhibitor of CDK1, CDK2, CDK5 and CDK9, inhibited taxane resistant cell growth with IC50s comparable to the parental lines. Upon exposure to dinaciclib, cell cycle arrest at G2/M was induced and marked apoptosis demonstrated. A reduction in cyclin B1, PLK1 and pRB was observed by western blotting. Table 1:Sensitivity of taxane resistant cell lines models to paclitaxel and docetaxelCell line modelPaclitaxel (μM)Docetaxel (μM)MDA-MB-231 Parent0.004 ± 0.0030.002 ± 0.003MDA-MB-231 PACR0.184 ± 0.030.017 ± 0.02MDA-MB-231 DOCR0.414 ± 0.0470.262 ± 0.058MCF7 Parent0.004 ± 0.00050.005 ± 0.001MCF PACR0.769 ± 0.1050.07 ± 0.02 Table 2:Gene ontology enrichment analysis of biological process terms significantly over-represented in MDA-MB-231 PACR cell line modelGO TermP-valueFDRpositive regulation of transcription from RNA polymerase II promoter1.11E-162.44E-13positive regulation of cell proliferation9.99E-161.10E-12activation of cysteine-type endopeptidase activity involved in apoptotic process1.43E-106.27E-08negative regulation of apoptotic process2.13E-095.83E-07extrinsic apoptotic signaling pathway8.33E-091.62E-06cell cycle arrest8.89E-091.62E-06positive regulation of cell migration2.83E-084.42E-06 Conclusion: In this study we identified candidate resistance-associated pathways which were differentially expressed between in vitro derived taxane resistant cell line models and the sensitive parental line. The CDK inhibitor, dinaciclib, demonstrated potent activity against the taxane resistant cell line models. Clinical validation to ascertain the role of dinaciclib as a novel therapeutic in the treatment of chemorefractory breast cancer is required. Citation Format: Taylor KJ, Lyttle N, Liao L, Gourley C, Cameron DA, Bartlett JM, Spears M. Sensitivity to cell cycle inhibitors in taxane resistant breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-03-11.

Abstract GS5-01: A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab

Abstract Background: Exposure to trastuzumab for one year is an integral part of therapy for patients with early stage HER2-positive breast cancer. Yet, cardiac side effects, particularly in patients who also receive anthracyclines require frequent monitoring and result in dose interruptions and discontinuation of trastuzumab. Prophylactic use of angiotensin converting enzyme (ACE) nhibitors or beta blockers (BB) may prevent cardiotoxicity associated with chemotherapy and trastuzumab. Methods A large community-based prospective double-blind, placebo-controlled trial, evaluated the rates of pre-specified cardiotoxicity in patients with early stage breast cancer treated with one year of trastuzumab. Cardiac events were followed for two years. Patients were randomized to simultaneously receive either the ACE inhibitor, lisinopril, or the BB, carvedilol, or placebo and were further stratified by anthracycline use to determine whether ACE inhibitors or BB can prevent trastuzumab-induced decrease in left ventricular ejection fraction (LVEF) and trastuzumab interruptions. Results: The study included 468 eligible patients (median age:51, BMI:27 kg/m2, baseline systolic BP: 126mmHg and LVEF :63 ± 6.29%) from 127 community-based practices, 189 patients received an anthracycline. For the entire study population and the non-anthracycline group, no difference in number of trastuzumab interruptions were seen. For patients receiving an anthracycline, cardiac event rates were higher in the placebo group (47%), and reduced in both the lisinopril (37%), and the carvedilol (31%) groups. Interruptions of trastuzumab were required in 23% patients on lisinopril and 20% on carvedilol compared to 40% on placebo (p=0.007). Changes in LVEF from baseline (least square means, SE) were significantly reduced with both carvedilol (-4.5 (0.8), p=0.008, and lisinopril (-4.0 (0.8), p=0.002) than placebo, (-7.7 (0.8). Cardiotoxicity-free survival was longer on both carvedilol (hazard ratio 0.49, 95% confidence intervals 0.27, 0.89, p=0.009) or lisinopril (HR 0.53, CI 0.30, 0.94, p=0.015). Conclusions In patients with HER2-positive breast cancer receiving trastuzumab and an anthracycline, both lisinopril and carvedilol during treatment reduced cardiotoxicity in patients, but not in those with non-anthracyline containing regimens. The use of lisinopril or carvedilol may allow the use of an anthracycline without compromising trastuzumab treatment in those who might benefit from an anthracycline. Citation Format: Munster P, Krischer J, Tamura R, Fink A, Bello-Matricaria L, Guilin M. A randomized community-based trial of an angiotensin converting enzyme inhibitor, lisinopril or a beta blocker, carvedilol for the prevention of cardiotoxicity in patients with early stage HER2-positive breast cancer receiving adjuvant trastuzumab [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-01.

Abstract GS5-06: No survival benefit of chemotherapy escalation in patients with pCR and “high-immune” triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial

Abstract Background:Immune markers such as tumor infiltrating lymphocytes (TILs), CD8, PDL1, PD1 and other protein or mRNA-based genomic markers have been identified as prognostic / predictive in TNBC regarding survival / chemotherapy (CTx) efficacy. In the adjuvant WSG-PlanB trial, patients with high TILs and/or CD8 by mRNA had excellent outcome, irrespective of anthracycline use; in the neoadjuvant ADAPT-TN trial, high PDL1, PD1 and CD8 and/or TILs were predictive for pCR. Still, optimal markers for potential treatment de-escalation have yet to be determined. Here, we analyse for the first time impact of immune mRNA-based markers and TIL's as prognostic and predictive survival markers. Methods: TNBC patients (ER/PR<1%, HER2-,) were randomized to neoadjuvant 4x nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1/8 q3w (gem arm) or 4x nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1/8 3-weekly (q3w) (carbo arm). Primary endpoint of WSG-ADAPT-TN was pCR (ypT0/is/ypN0); secondary endpoints included translational analyses, e.g., TILs or expression of 119 genes by nCounter platform. Standard adjuvant chemotherapy (4xEC) was optional (not randomized) in patients achieving pCR after 12 weeks. According to protocol, 1st safety survival analysis was performed after 3y median follow-up. Results: Present translational analysis included 306 of 336 TNBC patients (36 months median FU). pCR was associated with significantly better survival (3y EFS: 92% vs. 71%, p<.001), but despite substantially higher pCR in the carbo arm (46% vs. 29%), no significant EFS advantage was seen (p=.6) (gem: 78%; carbo: 80%; 3y-EFS). Bivariate Spearman correlations among CD8, PD1, and PDL1 were strongly positive; their correlations with TILs were moderately positive. Preliminary Cox analysis of EFS was performed with clinical variables (cN, cT, menopausal status); neoadjuvant study arm; pCR; TILs; proliferation markers (baseline Ki67 by IHC, scores derived from PAM50); baseline immune markers; risk scores; and individual gene expression scores previously identified as prognostic for pCR in one or both neoadjuvant arms. Independent prognostic factors included pCR, cN, Ki67, PD1, and CD8; these were entered into (prognostic) interaction analysis. The resulting model contained cN, high Ki67 and low TILs as (unfavorable) main effects and the interaction of (higher) PD1*pCR (favorable). Among pCR patients, the groups with/without additional adjuvant CTX were similar with respect to explanatory factors. Baseline TILs, Ki67, cN, and PD1 were entered into exploratory predictive analysis; the model retained only the interaction [adjuvant CTx * (fractionally ranked) PD1]. In patients with pCR, those with low PD1 benefited from standard anthracycline-containing adjuvant CTx, whereas patients high PD1 did not with an 98% 3y-EFS. Conclusions: Our exploratory results suggest independent prognostic impact of mRNA markers and TIL's in early TNBC. Patients with both pCR (after 12 weeks) and “high-immune” signature (defined here by PD1) had excellent 3y-EFS and may be candidates for treatment de-escalation (e.g. omission of anthracyclines), whereas “low-immune” pCR patients may benefit from standard adjuvant poly-chemotherapy. Citation Format: Gluz O, Nitz U, Liedtke C, Prat A, Christgen M, Feuerhake F, Garke M, Grischke E-M, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Kuemmel S, Pelz E, Gebauer D, Paré L, Kates R, Wuerstlein R, Kreipe HH, Harbeck N. No survival benefit of chemotherapy escalation in patients with pCR and “high-immune” triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-06.

Factors Determining Anthracycline Use in Hormone Receptor Positive, Early-Stage Breast Cancer

BackgroundAnthracyclines are associated with significant toxicities whereas nonanthracyclines have proven to be better tolerated. A 21-gene assay allows clinicians to predict who will not benefit from adjuvant chemotherapy and avoid systemic toxicities. Physicians are using the recurrence score to guide chemotherapy selection, despite the lack of evidence. In this study we examined factors associated with prescribing patterns for an anthracycline-based chemotherapy in hormone receptor-positive stage I to III breast cancer. Materials and MethodsThis was a retrospective study using the Michigan Breast Oncology Quality Initiative data set (February 1, 2006 to December 31, 2015). Women with histologically confirmed stage I to III invasive breast cancer with estrogen receptor and/or progesterone receptor-positive, HER2/neu-negative receptor status were included. We used χ2 analysis to determine associations of these characteristics with the 21-gene assay score and anthracycline use. ResultsA total of 17,788 patients were evaluated. Most tumors were stage I (60%). Most procedures were lumpectomy with radiation (66%). Anthracyclines were used more often in stage III patients (69%), younger patients (40% for patients younger than 65 years), and those with higher 21-gene recurrence scores. Patients with low recurrence scores were more likely to receive anthracyclines if lymph node-positive (10%) than if lymph node-negative (1%; P < .001). Patients with high recurrence scores and lymph node-positive status were just as likely to receive an anthracycline-based as a nonanthracycline-based regimen (47.5% vs. 49.2%; P = .89). ConclusionThese data indicate that medical oncologists might be anticipating the results of Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer study (TAILORx) and the Clinical Outcomes in ER+HER2-node-positive Breast Cancer Patients Who Were Treated According to the Recurrence Score Results: Evidence From a Large Prospectively Designed Registry (RxPonder) trials and are avoiding the potential serious complications associated with anthracycline treatment in patients least likely to receive benefit.

A Case of Azacitidine-Induced Toxic Erythema of Chemotherapy

Toxic Erythema of Chemotherapy (TEC) is a well-described spectrum of overlapping toxic reactions to chemotherapy, clinically characterized by painful erythematous, violaceous, and/or edematous plaques of the hands, feet, and intertriginous regions that may have a dusky appearance and develop bullae with subsequent erosions. TEC is most often associated with use of cytarabine, anthracyclines, 5‐fluorouracil, capecitabine, taxanes, and methotrexate. however, no prior occurrence of TEC following azacitidine therapy has been reported. Here we present a rare case of azacitidine-induced TEC in an 83-year-old female patient.

Cardiotoxicity with sequential use of Anthracycline and Trastuzumab in carcinoma breast patients in a North Indian tertiary care centre

Background: Anthracycline and Trastuzumab containing regimens demonstrate significant efficacy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. The utility of this strategy is limited by significant cardiotoxicity associated with these drugs. This study was conducted to study the cardiotoxicity with sequential use of Anthracyclines and Trastuzumab to identify early signs of carditoxicity and tailor therapy for these patients. Materials and Methods: A total of 45 cases of breast cancer patients who expressed HER 2 by immunohistochemistry (IHC) (3+) or fluorescent in situ hybridisation (FISH) were included in this study. The patients were evaluated for cardiotoxicity by clinical examination, echocardiography and Multigated acquisition (MUGA) scan at periodic intervals. Results: Fall in ejection fraction was noticed in 20% of patients. Most of these patients were asymptomatic. Two dimensional echocardiography (2 D Echo) and MUGA scans were complimentary to each other. The fall of ejection fraction was reversible in 89% of these patients on stopping Trastuzumab for median of 6 weeks duration. All these patients completed planned treatment on reintroduction of Trastuzumab. Conclusion: The sequential use of Anthracyclines and Trastuzumab has cardiotoxic potential. Detecting early signs of cardiotoxicity and monitoring asymptomatic fall in ejection fraction can prevent long term cardiotoxic side effects. Due to reversible nature of cardiotoxicity of Trastuzumab, it can be reintroduced in most of the patients. Benefits of Trastuzumab therapy can be achieved by keeping close observation on cardiotoxicity and tailor treatment accordingly.

Economic assessment of dexrazoxane in prophylaxis of cardiotoxicity in children undergoing chemotherapy with anthracyclines

Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors recorded in Brazil. The use of anthracyclines is frequently associated with cardiotoxicity, and these drugs are part of approximately 60% of treatment protocols in pediatric oncology. Among the existing strategies for the prevention of cardiotoxicity, dexrazoxane obtained favorable results based on intermediate outcomes (biochemical markers and echocardiographic parameters). This study was based on a cost-effectiveness assessment comparing the use of dexrazoxane in different populations, besides an assessment of the budget impact from the technology's potential incorporation. The patient's lifetime was used as the timeline, and the analysis was performed from the perspective of the Brazilian Unified National Health System (SUS). A budget impact analysis was also performed for each technology. After a literature search, a Markov model was developed, capable of comparing the use of dexrazoxane in six profiles of patients at risk of developing cardiotoxicity. Use of the drug in children under 5 years of age proved to be the most cost-effective alternative (incremental cost effectiveness ratio - ICER of BRL 6,156.96), followed by use in all patients (ICER of BRL 58,968.70). If the price decreased to less than BRL 250.00 per vial, the alternative of using the drug in all children would become the most cost-effective. The budget impact at 5 years was BRL 30,622,404.81 for use only in children under 5 years of age. Using the technology in all the children could produce an incremental impact of BRL 94,352,898.77.

First-Line Therapy for Metastatic Soft Tissue Sarcoma

Soft tissue sarcomas are rare cancers with an expected incidence of about 14,000 new cases in 2018, and account for less than 1% of all cancers. It includes in excess of 75 heterogeneous subtypes with varying biology, molecular aberrations, and variable response to treatment. Because of the rarity of these tumors and the many different subtypes, there is no large-scale data to guide treatment, and hence the need for a multidisciplinary individualized approach to treatment, preferably at a high-volume tertiary referral center. For localized disease, surgery with or without radiation is the preferred treatment. In metastatic disease, the longest track record is with use of anthracyclines, either alone or in combination with ifosfamide, but the median overall survival even with combination was just over a year. There have been recent advances in understanding the heterogeneity of these tumors and the need for an individualized approach. With that new knowledge, recent approvals of trabectedin, eribulin, and pazopanib have been limited to some select histologic subtypes with improved outcomes. More recently, immunotherapy has been tested in select histotypes of sarcoma with encouraging activity and has led to further evaluation in combination with immunotherapeutic agents, as well as with chemotherapy and radiation treatments. Here, in this article, we summarize the data of the currently approved therapies in metastatic soft tissue sarcoma, with the principal focus on first-line therapies. We also review the recent encouraging data with PDGFR-targeted antibody (olaratumab) with doxorubicin which showed an impressive improvement in overall survival in phase II study. Molecular characterization of sarcoma subtypes will likely improve understanding of these very diverse tumors and improve target characterization. The ongoing efforts in better understanding these rare tumors hold the key to make a difference in the outcome of these patients.

MiR-15b-5p is Involved in Doxorubicin-Induced Cardiotoxicity via Inhibiting Bmpr1a Signal in H9c2 Cardiomyocyte.

The wide use of anthracyclines represented by doxorubicin (DOX) has benefited cancer patients, yet the clinical application is limited due to its cardiotoxicity. Although numerous evidences have supported a role of microRNAs (miRNAs) in DOX-induced myocardial damage, the exact etiology and pathogenesis remain largely obscure. In this study, we focused on the role of miR-15b-5p in DOX-induced cardiotoxicity. We employed a public miRNA and gene microarray to screen differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) in rat cardiomyocytes, and 33 DEMs including miR-15b-5p and 237 DEGs including Bmpr1a and Gata4 were identified. The Gene ontology (GO) and pathway enrichment analysis of 237 DEGs indicated that the DEGs were mainly enriched in heart development and ALK pathway in cardiomyocyte which included the main receptor Bmpr1a and transcription factor Gata4. The up-regulated miR-15b-5p and down-regulated Bmpr1a and Gata4 mRNA expressions were further validated in H9c2 cardiomyocytes exposed to DOX. Moreover, the results showed overexpression of miR-15b-5p or inhibition of Bmpr1a may enhance the DOX-induced apoptosis, oxidative stress and mitochondria damage in H9c2 cardiomyocytes. The Bmpr1a was suggested as a potential target of miR-15b-5p by bioinformatics prediction. We further verified the negatively regulatory effect of miR-15b-5p on Bmpr1a signaling. Moreover, we also confirmed that overexpression of miR-15b-5p may exacerbate the DOX-induced apoptosis of H9c2 cardiomyocytes by affecting the protein expression ratio of Bcl-2/Bax and Akt activation, while this pro-apoptotic effect was able to be suppressed by Bmpr1a agonist. Collectively, the results suggest that miR-15b-5p is likely involved in doxorubicin-induced cardiotoxicity via inhibiting Bmpr1a signaling in H9c2 cardiomyocytes. Our study provides a novel insight for investigating DOX-induced cardiotoxicity.

Cardio-toxicity in childhood cancer survivors "Cure is not enough".

The number of pediatric cancer survivors is growing, and they are getting older. Therapy-induced cardiotoxicity therefore is debated as an ongoing problem. Recognition of the side effects in the use of anthracyclines and radiation as well as the patients' clinical condition and comorbidities leads back as far as the beginning of systematic cancer treatment in children in the 1980s. Since, numerous case reports, meta-analyses and retrospective surveys were published worldwide. However, randomized clinical trials with standardized protocols yet fail to be designed. This article gives an overview of the recent reports and emphasizes on the heterogeneity of the different approaches. A standardized work-up which may identify the patient at risk-including the patient's history and condition, individual genetic dispositions, dosage and method of drug application, consideration of co-medication, radiation therapy and dose, standardized imaging methods-is the main proposition of our report. The fusion of already established sources, e.g., data of different registries or study centers, might help to create preventive strategies for and a better understanding of patients with therapy induced cardiomyopathy.

The association between early-onset cardiac events caused by neoadjuvant or adjuvant chemotherapy in triple-negative breast cancer patients and some novel autophagy-related polymorphisms in their genomic DNA: a real-world study

BackgroundAn increasing number of cancer patients die of cardiovascular diseases. The cardiotoxicity of chemotherapy is particularly important in triple-negative breast cancer (TNBC) with limited therapeutic options. Cardiac autophagy is an important mechanism of cardiotoxicity. This research was aimed to investigate the cardiotoxicity of chemotherapy in TNBC, screen the susceptible population, and determine the relationship between cardiotoxicity and autophagy-related polymorphisms.MethodsFrom a total of 2450 stage I-III TNBC patients, 147 met the inclusion criteria and finally recruited. Electrocardiography (ECG) was performed before most chemotherapy cycles, and echocardiography (UCG) was performed according to clinical needs. All ECG and UCG records were re-interpreted by cardiologists at the National Center for Cardiovascular Disease, Fuwai Hospital. According to the National Center for Biotechnology Information and the Catalog of Somatic Mutations in Cancer database, we selected 25 single nucleotide polymorphisms (SNPs) related to autophagy and genotyped the 147 TNBC patients. Paired-sample T tests, Chi squared tests, and logistic regression models were employed for the analysis.ResultsOnly 46 (31.3%) patients had normal ECG records after every chemotherapy cycle. Among the 16 patients who underwent UCG, 2 (12.5%) had a reversible decrease of left ventricular ejection fraction. The use of anthracyclines and excessive alcohol consumption were risk factors of ECG abnormalities. With the continuation of chemotherapy, heart rate gradually increased. Anthracyclines were associated with QRS duration abnormalities (P = 0.043). After genotyping for 25 autophagy-related SNPs, we found that the G allele of autophagy-related 13 (ATG13) rs10838611 was significantly associated with ECG abnormalities (odds ratio = 2.258, 95% confidence interval = 1.318–3.869; P = 0.003).ConclusionECG abnormalities caused by chemotherapy are common in the real world. Autophagy-related SNPs are associated with chemotherapy-induced cardiotoxicity, thereby providing new evidence for autophagy as a cause of chemotherapy-induced cardiac damage.

Leukocyte Subtypes As Predictors for Venous Thromboembolism in Diffuse Large B-Cell Lymphoma

Introduction: Venous thromboembolic events (VTE) are a frequent complication of patients diagnosed with diffuse large B -cell lymphoma (DLBCL). Development of VTE portends poor prognosis. Previous studies have identified use of anthracyclines, advanced stage at presentation, obesity, and development of neutropenia and anemia after first cycle of chemotherapy as risk factors for VTE. Recent studies suggest leukocyte subpopulations may affect the risk of VTE; elevated neutrophil and monocyte counts have been associated with increased risk of VTE in solid malignancy patients. The role of leukocyte subpopulations in VTE risk in DLBCL patients has not yet been evaluated. We conducted a retrospective study to identify risk factors for VTE and specifically address the role of leukocytes and their subtypes in VTE risk assessment in DLBCL.Methods: We accessed the Stem Cell Transplant and Hematologic Malignancies database of University Hospitals Seidman Cancer Center for DLBCL patients diagnosed between 2000 and 2016. Information collected included demographic characteristics, baseline laboratory and disease information, as well as treatment details. Patient records were reviewed for the presence of VTE, including radiographic confirmation. Progression free survival and overall survival were calculated from time of diagnosis using Kaplan Meier methodology, comparisons were done with log rank. Cumulative incidence of VTE was calculated considering death as competing risk. Univariate Cox regression analysis was conducted for baseline characteristics, risk factors and baseline laboratory parameters. Variables with a univariate p value lower than 0.1 were included in multivariate Cox regression. All analyses were performed using XLSTAT (Addinsoft, NY).Results: A total of 542 patients were included in the study. Baseline characteristics are described in Table 1. At a median follow up of 48 months, 93 patients developed VTE, with 1 and 2 -year cumulative incidence of VTE of 13.5% (95% CI 10.9-16.8) and 20.5% (95% CI 17.3-24.3). In subsequent years, VTE risk increased more modestly, reaching 23.6% at 4 years (95% CI 20.2-27.7). Eighty percent of VTE occurred in patients with active disease. Sixteen percent of VTE were pulmonary embolism (PE), 53% were lower extremity deep vein thrombosis (DVT), and 31% upper extremity DVTs. Approximately 55% of upper extremity DVTs were line - related.On univariate analysis (table 2), the risk factors with statistically significant odds for increased hazard of VTE included previous history of VTE, albumin less than 3 gm/dl, leukocyte count greater than 11,000/mcl, hemoglobin less than 12 gm/dl, absolute neutrophil count (ANC), ANC to absolute lymphocyte ratio (ANC: ALC) higher than 2.5 and presence of bulky disease at the time of diagnosis. In multivariate analysis, BMI > 35, bulky disease and ANC/ALC ratio ≥ 2.5 remained statistically significant risk factors for development of VTE.Presence of VTE at any time after DLBCL diagnosis was also associated with worse overall survival (OS) and progression free survival (PFS) rates. Patients with VTE after diagnosis had an estimated 4 - year OS of 50.6 % (95% CI 39.7-61.6) vs. 71.3% (95% CI 66.9-75.7) in patients without VTE (p<0.0001) (figure 1). Four-year PFS estimates were 37.5% (95 % CI 27.1-48) and 60% (95 % CI 55.3-64.7), respectively (p<0.0001) (figure 2).Conclusion: VTE is a frequent complication in DLBCL patients and is associated with increased mortality and risk of progressive disease. The first 24 months after DLBCL diagnosis appear to be the time of highest VTE risk, likely a consequence of active disease, treatment and other risk factors such as indwelling catheters. Leukocyte subpopulations appear to have a correlation with VTE risk; the ANC: ALC ratio is a measure of systemic inflammatory response, and in DLBCL patients, a ratio above 2.5 is correlated with increased risk of VTE. Incorporation of this laboratory measurement to currently available VTE risk assessment tools may help more precisely identify the at highest risk of VTE. DisclosuresMalek:Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Tomlinson:Foundation Medicine: Consultancy. Caimi:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees.

Efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy for HER2-positive breast cancer: a systematic review and meta-analysis.

The concurrent use of trastuzumab and anthracycline-based neoadjuvant chemotherapy (NAC) has been proposed to improve the pathologic complete response (pCR) rate, although there are conflicting views about its efficacy and safety. The purpose of this study was to evaluate the efficacy and cardiac safety of the concurrent use of trastuzumab and anthracycline-based NAC for human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer. We systematically searched PubMed, Embase, and Cochrane databases from inception until July 1, 2017, for relevant articles. A total of 13 studies were included in the meta-analysis. The results showed that the pCR rate was significantly higher in the concurrent use of trastuzumab and anthracycline group (45%) than that in the nonconcurrent use group (32%) (OR: 2.36, 95% CI: 1.69–3.30, P<0.0001). Besides, the pooled absolute rate of breast conservation surgery (BCS) was 48% (95% CI: 0.35–0.61) and 38% (95% CI: 0.14–0.62) in the experimental and control groups, respectively (OR: 1.10, 95% CI: 0.64–1.90, P=0.73). No significant differences were found in the left ventricular ejection fraction (LVEF), which decreased by >10% (OR: 1.26, 95% CI: 0.55–2.88, P=0.59), and in terms of cardiac failure (OR: 2.17, 95% CI: 0.24–19.84, P=0.49), when comparing the concurrent use of trastuzumab and anthracyclines with their nonconcurrent use. In conclusion, the concurrent use of trastuzumab and anthracycline-based NAC for certain HER2-positive locally advanced breast cancers significantly improves the pCR rates without obvious increases in the cardiotoxicity.

Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers.

This study aimed at assessing the role of beta-blockers on preventing anthracycline-induced cardiotoxicity in adults. A systematic review was performed on electronic databases, including relevant studies that analysed beta-blockers as cardioprotective agents before the use of anthracyclines by adult oncologic patients. After application of eligibility and selection criteria, eight articles were considered as high quality, complying with the proposed theme; all eight clinical trials, four of them placebo-controlled, with a total number of 655 patients included. From this sample, 281 (42.9%) used beta-blocker as intervention, and carvedilol was the most frequent (167 patients - 25.5%). Six studies were considered positive regarding the cardioprotection role played by beta-blockers, although only four demonstrated significant difference on left ventricle ejection fraction after chemotherapy on groups that used beta-blockers compared to control groups. Carvedilol and nebivolol, but not metoprolol, had positive results regarding cardioprotection. Other beta-blockers were not analysed in the selected studies. Despite the potential cardioprotective effect of beta-blockers, as demonstrated in small and unicentric clinical trials, its routine use on prevention of anthracycline-associated cardiotoxicity demands greater scientific evidence.

Results of program acute myeloid leukemia therapy use in National Medical Research Center for Hematology of the Ministry of Health of Russian Federation.

To analyze treatment results of 172 patients with acute myeloid leukemia (AML) aged 18-60 years in National Medical Research Center for Hematology of MHRF. Inductive and consolidation program for 139 (80%) patients was based on a standardized protocol: 4 courses "7+3" with different anthracycline use (2 courses of daunorubicin, idarubicin, mitoxantrone) and continuous use of cytarabine on the second inductive course. In 20% of patients cytarabine courses at the dose of 1 g/m2 2 times a day for 1-3 days combined with idarubicin and mitoxantrone were used as two consolidation courses. Allogenic bone marrow transplantation was performed in the first complete remission (CR) period in 40% of patients. The frequency of CR achievement in all patients was 78.6%, refractory forms were observed in 13.9% of patients, early mortality - in 7.5% of patients. Seven-year overall survival (OS) rate was 40.7%, relapse free survival (RFS) - 43.2%. When estimating effectiveness depending on cytogenetic risk group it was demonstrated that 5-year OS and RFS in patients with translocation (8; 21) cannot be considered as satisfying, it accounted for 50 and 34%, respectively. At the same time in patients with 16th chromosome inversion (inv16) these characteristics accounted for 68.6 and 63.5%. Acquired results forced reconsidering of the consolidation program in AML patients of this subgroup. The median time to allogenic blood stem cells transplantation (allo-BSCT) in patients with first CR was 6.5 months that was taken as a reference point in landmark analysis of patients in whom allo-BSCT was not performed. Landmark analysis showed that in AML patients of favorable prognosis group allo-BSCT does not significantly reduce the probability of relapse (0 and 36%) and does not influence RFS (33 and 64%). In patients of border-line and poor prognosis allo-BSCT significantly reduces relapse probability (26 and 66%; 20 and 100%) and significantly increases a 7-year RFS (68.7 and 30%; 45.6 and 0%). Allo-BSCT also results in significant RFS increase and reduces the probability of relapse (25 и 78%) in patients in whom CR was achieved only after the second induction course. At the same time allo-BSCT does not influence patients who achieved CR after the first treatment course: 55 and 50%. Multivariate analysis showed that cytogenetic risk group (HR=2.3), time of CR achievement (HR=2.9), and allo-BSCT transplantation (HR=0.16) are independent factors for disease relapse prognosis after achieving CR.

Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma

BackgroundThe treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes.MethodsEchocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989–2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs.ResultsOur results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76–27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98–67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5–10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5–10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5–10 years after the diagnosis.ConclusionsGenetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy.