Use Of Anthracyclines Research Articles

The use of anthracyclines in the treatment of endemic Burkitt lymphoma.

Burkitt lymphoma is the most common malignancy in children in Malawi, the world's poorest country, where there is a long history of treating this disease using a 28-day cyclophosphamide-based protocol. Stage III/IV disease has had poor outcomes. In an attempt to improve the outcome for higher stage disease, anthracyclines were added to the existing protocol. The disease-free (DFS) and overall survival (OS) of 58 children with cytologically confirmed Burkitt lymphoma admitted during 2012-2014 and treated using this protocol were calculated. Six (10%) children had stage I disease, ten (17%) stage II and 42 stage III or IV (73%). Overall 12-month DFS (OS) was 68·5% (72·9%); for stage I disease 100% (100%), stage II 56·2% (60%), stage III/IV 66·3% (72·2%). The DFS was significantly improved from the previous protocol (P=8×10-4 ). The addition of doxorubicin to stage III and IV disease resulted in a markedly improved DFS. Anthracyclines are deliverable in resource-poor settings and possibly improve the survival of children with Burkitt lymphoma.

Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511).

We examined acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) events among 9679 women treated for breast cancer on four adjuvant Alliance for Clinical Trials in Oncology trials with >90months of follow-up in order to better characterize the risk for AML/MDS in older patients receiving anthracyclines. We used multivariable Cox regression to examine factors associated with AML/MDS, adjusting for age (≥65 vs. <65years; separately for ≥70 vs. <70years), race/ethnicity, insurance, performance status, and anthracycline receipt. We also examined the effect of cyclophosphamide, the interaction of anthracycline and age, and outcomes for those developing AML/MDS. On Cancer and Leukemia Group B (CALGB) 40101, 49907, 9344, and 9741, 7290 received anthracyclines; 15% were in the age ≥65 and 7% were ≥70. Overall, 47 patients developed AML/MDS (30 AML [0.3%], 17 MDS [0.2%]); 83% of events occurred within 5years of study registration. Among those age ≥65 and ≥70, 0.8 and 1.0% developed AML/MDS (vs. 0.4% for age <65), respectively. In adjusted analyses, older age and anthracycline receipt were significantly associated with AML/MDS (adjusted hazard ratio [HR] for age ≥65 [vs. <65]=3.13, 95% confidence interval [CI] 1.18-8.33; HR for anthracycline receipt [vs. no anthracycline]=5.16, 95% CI 1.47-18.19). There was no interaction between age and anthracycline use. Deaths occurred in 70% of those developing AML/MDS. We observed an increased risk for AML/MDS for older patients and those receiving anthracyclines, though these events were rare. Our results help inform discussions surrounding anticipated toxicities of adjuvant chemotherapy in older patients.

Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis.

Background:Trastuzumab targets the human epidermal growth factor receptor 2 oncogene and in combination with first-line therapy results in significantly improved survival outcomes and has thus become standard of care in both adjuvant and metastatic settings. While it is estimated that 1% to 4% of patients treated with trastuzumab will develop heart failure and ∼10% will experience a reduction in left ventricular ejection fraction (LVEF), the patient risk factors associated with trastuzumab-induced cardiotoxicity (TIC) are unclear. This meta-analysis aims to consolidate previously published data to identify the risk factors most likely leading to TIC.Methods:A search of the MEDLINE literature database using the keywords trastuzumab/Herceptin, risk factors, outcomes, cardiac, cardiotoxicity, cardiomyopathy, LVEF, and chemotherapy was performed. Only prospective/retrospective human studies were included, with additional studies excluded if they reported baseline LVEF > 68%, a cohort of <50 patients, or results that were not stratified based on cardiotoxic events. Pooled odds ratio (OR) and 95% confidence interval (CI) for each potential risk factor were calculated, with heterogeneity of data and samples explored using random-effects modeling.Results:Data were collected from 17 articles, capturing 6527 patients. Hypertension (OR 1.61, 95% CI 1.14–2.26; P < 0.01), diabetes (OR 1.62; 95% CI 1.10–2.38; P < 0.02), previous anthracycline use (OR 2.14; 95% CI 1.17–3.92; P < 0.02), and older age (P = 0.013) were all shown to be associated with TIC.Conclusion:Cardiac performance should be closely monitored in women treated with trastuzumab. Recognizing potential risk factors along with careful attention to symptoms/LVEF measurements could minimize the occurrence of TIC in this population.

Transcriptional regulation of the canine carbonyl reductase 1 gene (cbr1) by the specificity protein 1 (Sp1)

The clinical use of anthracyclines to treat various canine cancers is limited by the development of cardiotoxicity. The intra-cardiac synthesis of anthracycline C-13 alcohol metabolites (e.g. daunorubicinol) contributes to the development of cardiotoxicity. Canine carbonyl reductase 1 (cbr1) catalyzes the reduction of daunorubicin into daunorubicinol. Recent mapping of the cbr1 locus by sequencing DNA samples from dogs from various breeds revealed a cluster of conserved motifs for the transcription factor Sp1 in the putative promoter region of cbr1. We hypothesized that the variable number of Sp1 motifs could impact the transcription of canine cbr1. In this study, we report the functional characterization of the canine cbr1 promoter. Experiments with reporter constructs and chromatin immunoprecipitation show that cbr1 transcription depends on the binding of Sp1 to the proximal promoter. Site-directed mutagenesis experiments suggest that the variable number of Sp1 motifs impacts the transcription of canine cbr1. Inhibition of Sp1-DNA binding decreased canine cbr1 mRNA levels by 54% in comparison to controls, and also decreased enzymatic carbonyl reductase activity for the substrates daunorubicin (16%) and menadione (23%). The transactivation of Sp1 increased the expression of cbr1 mRNA (67%), and increased carbonyl reductase activity for daunorubicin (35%) and menadione (27%). These data suggest that the variable number of Sp1 motifs in the canine cbr1 promoter may impact the pharmacodynamics of anthracyclines in canine cancer patients.

Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional Portuguese cohort study

BackgroundA contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. MethodsRetrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. ResultsAmong patients with stage I–III breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2− tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2− received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. ConclusionsOverall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions.

Pediatric quality of life in long-term survivors of childhood cancer treated with anthracyclines.

Anthracyclines are a common class of drugs used to treat pediatric cancer. While much attention is given to their cardiotoxicity, little is known about the relationship between the use of anthracyclines and health-related quality-of-life (HRQoL) outcomes. This study examines the association of anthracycline cardiotoxicity risk status and Pediatric Quality-of-Life (PedsQL) InventoryTM scores in childhood cancer METHODS: Pediatric cancer survivors aged 8-21 who were at least 5 years posttreatment were recruited from a Cancer Survivor Clinic. Participants completed the PedsQL 4.0 Generic Core Scales and a health behavior survey. Linear regression was used to evaluate the association between PedsQL scores and anthracycline cardiotoxicity risk status and to assess whether self-reported physical activity modified the association. Eighty survivors participated and were characterized by cardiotoxicity risk status (high: 12; moderate: 23, low: 24, no risk: 21) as defined by the Children's Oncology Group (COG). Measures in all PedsQL domains tended to be slightly lower for survivors exposed to anthracyclines as compared to the unexposed. The largest difference in unadjusted mean scores was for social functioning (96.0% for unexposed vs. 91.3% for exposed, P = 0.0068). There was also an inverse dose-response relation between adjusted PedsQL scores and increasing anthracycline cardiotoxicity risk; this association was not modified by physical activity level. These data indicate that regular psychosocial assessments, such as those currently recommended by the COG, may be especially important for survivors treated with anthracyclines.

Anthracycline- and trastuzumab-induced cardiotoxicity: a retrospective study.

Some chemotherapeutic agents cause cardiotoxic effects including reduction in left ventricular ejection fraction (LVEF) and occasionally congestive heart failure. Anthracyclines and HER2 monoclonal antibodies are common offenders, but clinical practice data on LVEF changes, risk factors and acute recovery is lacking. We retrospectively examined the electronic medical record at an academic medical center for receipt of anthracyclines and/or trastuzumab from 2000 to 2013 in cancer patients. Patient characteristics and serial LVEF assessments were collected. Patients with and without LVEF decline were analyzed by univariate and multivariate analysis. A total of 549 patients were identified with anthracycline/trastuzumab use and 216 had multiple LVEF assessments. Only 27 of the 216 patients who had multiple LVEF assessments at multiple occasions suffered a clinically significant LVEF fall (12.5%), and symptomatic CHF was rare (0.5%). Compared to unaffected patients, those with a fall in LVEF were more likely to have hypertension, hyperlipidemia or coronary artery disease (CAD). Concomitant trastuzumab and anthracycline use was a risk factor (36 vs 9.5% for anthracycline alone, p<0.001). The median time from start of chemotherapy to reduced LVEF was 202days (5-3008). On multivariate analysis, hypertension and use of trastuzumab remained independent predictors of LVEF fall. Acute recovery in LVEF was observed in 44% of patients. LVEF changes from cancer therapies are frequent and hard to predict. Hypertension, hyperlipidemia and CAD are associated with LVEF decline. Acute recovery of LVEF is observed in those experiencing treatment-related cardiotoxicity. Attention to timely interruption of cardiotoxic chemo is recommended.

Loss of ataxia-telangiectasia-mutated protein expression correlates with poor prognosis but benefits from anthracycline-containing adjuvant chemotherapy in breast cancer

We investigated the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors. ATM loss was observed in 126/407 evaluable cases (31.0%), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival rates than those in patients with intact ATM (5-year disease-free survival rate 81.2 vs. 90.7%, p=0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter disease-free survival [hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.48-8.17, p=0.004]. A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached (HR 1.74; 95% CI 0.95-3.20; p=0.075). In subgroup analysis, ATM loss was associated with shorter disease-free survival in patients who did not receive adjuvant anthracycline chemotherapy (5-year disease-free survival rate 92.7% in intact ATM group vs. 68.1% in ATM loss group, p=0.002), but this poor prognosis was overcome in patients who did (5-year disease-free survival rate 89.8 vs. 84.4%, p=0.243), suggesting more benefit from anthracycline-based chemotherapy. Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy.

Cardiotoxicity in anthracycline therapy: Prevention strategies

The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline-induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non-pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline-induced cardiotoxicity.

Cardiotoxicidade na terapêutica com antraciclinas: estratégias de prevenção

The increasing use of anthracyclines, together with the longer survival of cancer patients, means the toxic effects of these drugs need to be monitored. In order to detect, prevent or mitigate anthracycline‐induced cardiomyopathy, it is essential that all patients undergo a rigorous initial cardiovascular assessment, followed by close monitoring. Several clinical trials have shown the cardioprotective effect of non‐pharmacological measures such as exercise, healthy lifestyles, control of risk factors and treatment of comorbidities; a cardioprotective effect has also been observed with pharmacological measures such as beta‐blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor antagonists, statins, dexrazoxane and liposomal formulations. However, there are currently no guidelines for managing prevention in these patients. In this review the authors discuss the state of the art of the assessment, monitoring, and, above all, the prevention of anthracycline‐induced cardiotoxicity.

OOTR-N006: mTOR inhibition with everolimus in invasive breast cancer patients after pre-operative use of anthracycline and/or taxane-based chemotherapy.

e12507Background: Inhibition of mTOR, a downstream mediator of the PI3K/AKT signaling pathway, is a significant anti-cancer approach in response to PI3K/AKT activation, as demonstrated clinically w...

Evaluation and management of chemotherapy-induced cardiotoxicity in breast cancer: a Delphi study

PurposeWhile much progress has been made in the treatment of breast cancer, cardiac complications resulting from therapy remain a significant concern. Both anthracyclines and novel targeted agents can inflict cardiac damage. The present study aimed to evaluate the difference between what it is currently done and what standards of care should be used to minimizing and managing cardiac toxicity in breast cancer survivors.MethodsA two-round multicenter Delphi study was carried out. The panel consisted of 100 oncologists who were asked to define the elected therapies for breast cancer patients, the clinical definition and patterns of cancer drug-derived cardiac toxicity, and those protocols focused on early detection and monitoring of cardiovascular outcomes.ResultsExperts agreed a more recent definition of cardiotoxicity. Around 38 % of patients with early-stage disease, and 51.3 % cases with advanced metastatic breast cancer had preexisting risk factors for cardiotoxicity. Among risk factors, cumulative dose of anthracycline ≥450 mg/m2 and its combination with other anticancer drugs, and a preexisting cardiovascular disease were considered the best predictors of cardiotoxicity. Echocardiography and radionuclide ventriculography have been the proposed methods for monitoring changes in cardiac structure and function. Breast cancer is generally treated with anthracyclines (80 %), so that the panel strongly stated about the need to plan a strategy to managing cardiotoxicity. A decline of left ventricular ejection fraction (LVEF) >10 %, to an LVEF value <53 % was suggested as a criterion for changing the dose schedule of anthracyclines, or suspending the treatment of chemotherapy plus trastuzumab until the normalization of the left ventricular function. The use of liposomal anthracyclines was strongly suggested as a treatment option for breast cancer patients.ConclusionsThe present report is the first to produce a set of statements on the prevention, evaluation and monitoring of chemotherapy-induced cardiac toxicity in breast cancer patients.

Esophagogastric Adenocarcinoma: Is More Chemotherapy Better?

Two cycles of neoadjuvant cisplatin and fluoropyrimidine (CF) and 6 cycles of perioperative CF with or without epirubicin are an evidence-based approach in operable esophageal and esophagogastric junctional adenocarcinomas. Three-drug regimens with anthracycline or taxane are associated with significantly higher tumor regression rates, with an expected increase in toxicity. In order to achieve an R0 resection and consequently a survival advantage, in selected patients having a risk of a threatened margin or incomplete resection, chemotherapy might be continued beyond 2 cycles if a response has been demonstrated. In metastatic setting, multidrug combination regimens have demonstrated a significant survival benefit when compared to single-agent regimes. A three-drug regimen should be considered for fit patients and/or when a response is required for symptom control. The expected increase in toxicity needs to be carefully considered and discussed with patients. The choice to use a taxane in first-line setting may limit the options of second-line treatment to irinotecan-containing regimens and also precludes the use of anthracyclines in the first line. For this reason, we prefer to reserve taxane-based therapy for the second-line setting.

Assessment of brachial artery reactivity, carotid intima-media thickness, and adhesion molecules in pediatric solid tumor patients treated with anthracyclines

ABSTRACTThe aim of this study was to determine subclinical atherosclerosis and endothelial functional disturbance with measurement of carotid intima-media thickness (IMT), brachial artery reactivity (BAR), and levels of serum adhesion molecules in children with solid tumors who were treated with anthracyclines and are actually in complete remission. Fifty patients who were in remission and 30 healthy children were included in the study. Mean ages of patient and control groups were 13.5 ± 4.7 years (range: 3–23 years) and 12.00 ± 4.3 years (range: 4–21 years), respectively. The patients were divided into 3 groups according to cumulative doxorubicin dose: Group 1, ≤100 mg/m2; Group 2, 101–299 mg/m2; Group 3, ≥300 mg/m2. The BAR and carotid IMT were measured in order to determine the endothelial function. The serum adhesion molecule levels in our patients and controls were also measured. The BAR of the patients with cumulative anthracycline dose ≥300 mg/m2 was significantly lower than the patients with cumulative anthracycline dose ≤100 mg/m2 and healthy controls (P =.005 and P =.003, respectively). Also, there was a negative correlation between brachial artery reactivity and increasing cumulative anthracycline dose (r = −.287, P =.044). We also found significant difference between the mean carotid IMT of the patients and the healthy children (P =.041). No statistically significant difference was detected between the serum levels of sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), sE-selectin of the patients and controls. The use of anthracyclines in pediatric patients with cancer could result in increase of the carotid IMT and endothelial dysfunction.

Trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel in the neoadjuvant setting of HER-2 positive breast cancer.

Neoadjuvant treatment based on the combination of trastuzumab plus chemotherapy is the standard of care in patients with HER2-positive early or locally advanced breast cancer. The concurrent use of trastuzumab, anthracyclines and taxanes is frequently used in this setting despite the potential cardiotoxicity of both anthracyclines and trastuzumab. However, not much information is available about this chemotherapy scheme. We wanted to evaluate the efficacy and safety profile of the combination of trastuzumab, liposome-encapsulated doxorubicin and paclitaxel as neoadjuvant scheme. We also tried to establish predictive factors of pathologic complete response. The study was carried out in a tertiary University Hospital of Spain. This is a descriptive study of the clinical practice performed in our hospital. Efficacy was measured in terms of pathologic complete response, which was defined as the absence of invasive cancer cells in the breast and the axilla after neoadjuvant treatment. Thirty patients were included, the median age was 48. Seventeen (56.7 %) were hormonal receptor (HR) positive, 14 (46.6 %) had IIIa-b clinical stage and one of them had inflammatory breast cancer. 12 patients (40 %) achieved pCR. Patients with HR-negative BC achieved a higher pCR rate than those ones with HR-positive BC (61.5 % and 23.5 %, respectively; p value = 0.035). 21 patients (70 %) underwent breast conservative surgery. The treatment was in general well tolerated, most frequent grade 3-4 adverse events were neutropenia (20 %), asthenia and liver enzyme alteration (10 %) and febrile neutropenia (6.7 %). No patient developed heart failure, but one (3.3 %) presented a 10 % asymptomatic absolute reduction in left ventricular fraction ejection. The studied treatment for the neoadjuvant setting of HER2 positive breast cancer seems to be an effective therapeutic option. Despite the expected high rate of cardiotoxicity of this regimen, the study results shows that this treatment regimen appears to be safe. The combination of trastuzumab, non-pegylated liposomal-encapsulated doxorubicin and paclitaxel should be considered for the treatment of HER2-overexpressing breast cancer.

Sarcome à cellules claires du rein chez l’enfant

Clear cell sarcoma of the kidney (CCSK) is a rare tumor that is diagnosed most often in children between 2- and 4-years-old of age. Usually, patients with CCSK are treated in international study for intrarenal tumors, preferentially Wilms tumor, according to bad histopronostic group. The purpose of this paper is to review the most important features in 2015about epidemiology, radiology, anatomopathology and genetic of CCSK, and above all a synthesis about successive treatment strategies with their results. Second most common pediatric renal tumor in children less than 5-years-old, its prognosis has improved dramatically in recent years with the use of anthracyclines.

Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management.

Answer questions and earn CME/CNE Cancer and heart disease are the leading causes of morbidity and mortality in the industrialized world. Modern treatment strategies have led to an improvement in the chances of surviving a diagnosis of cancer; however, these gains can come at a cost. Patients may experience adverse cardiovascular events related to their cancer treatment or as a result of an exacerbation of underlying cardiovascular disease. With longer periods of survival, late effects of cancer treatment may become clinically evident years or decades after completion of therapy. Current cancer therapy incorporates multiple agents whose deleterious cardiac effects may be additive or synergistic. Cardiac dysfunction may result from agents that can result in myocyte destruction, such as with anthracycline use, or from agents that appear to transiently affect left ventricular contractility. In addition, cancer treatment may be associated with other cardiac events, such as severe treatment-induced hypertension and vasospastic and thromboembolic ischemia, as well as rhythm disturbances, including QTc prolongation, that may be rarely life-threatening. Early and late effects of chest radiation can lead to radiation-induced heart disease, including pericardial disease, myocardial fibrosis, cardiomyopathy, coronary artery disease, valvular disease, and arrhythmias, in the setting of myocardial fibrosis. The discipline of cardio-oncology has developed in response to the combined decision making necessary to optimize the care of cancer patients, whether they are receiving active treatment or are long-term survivors. Strategies to prevent or mitigate cardiovascular damage from cancer treatment are needed to provide the best cancer care. This review will focus on the common cardiovascular issues that may arise during or after cancer therapy, the detection and monitoring of cardiovascular injury, and the best management principles to protect against or minimize cardiotoxicity during the spectrum of cancer treatment strategies. CA Cancer J Clin 2016;66:309-325. © 2016 American Cancer Society.

Abstract OT3-01-04: An open-label, single-arm, phase II study of pertuzumab with high-dose trastuzumab for the treatment of central nervous system progression post-radiotherapy in patients with HER2-positive metastatic breast cancer (PATRICIA)

Abstract Background: Central nervous system (CNS) metastases are observed in up to half of patients with HER2-positive metastatic breast cancer (MBC), with incidence likely to continue to rise due to longer survival through improved systemic treatments. While radiotherapy-based approaches can be effective, there are potential short- and long-term toxicities, and patients frequently progress. CNS response to existing systemic therapies has been generally poor, and there is a high unmet need with no approved treatment for CNS metastases in HER2-positive MBC. Combination of the HER2-targeted monoclonal antibodies trastuzumab and pertuzumab provides a more comprehensive blockade of HER2 than either antibody alone, and data from the phase III CLEOPATRA trial suggest that adding pertuzumab to trastuzumab and docetaxel may delay onset of CNS disease. Trastuzumab concentrations in the CNS are increased under conditions of an impaired blood–brain barrier (BBB) and subtherapeutic levels in the CNS may be related to insufficient dosing rather than inability to cross the BBB. The PATRICIA trial is evaluating the addition of pertuzumab with high-dose trastuzumab to a patient's current systemic treatment for HER2-positive MBC patients with CNS progression post-radiotherapy and stable systemic disease. Study design: In this US-based, phase II, open-label, single-arm study, patients will receive intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) in combination with intravenous high-dose trastuzumab (6 mg/kg weekly) in addition to their current systemic therapy (except for ado-trastuzumab emtansine or lapatinib) until disease progression or unacceptable toxicity. Eligibility criteria: Patients aged ≥18 years with confirmed HER2-positive MBC with new and/or progressive CNS lesions &amp;gt;60 days after whole-brain radiotherapy or stereotactic radiosurgery for CNS metastases, performance status 0–1, and stable systemic disease will be eligible. Patients must have a baseline left ventricular ejection fraction (LVEF) ≥50%, no significant history of cardiac disease or current use of anthracyclines, life expectancy &amp;gt;12 weeks, and not be pregnant or lactating. Aims: The primary efficacy endpoint will be objective response rate (ORR) in the CNS, assessed by the investigator using RANO–BM criteria. Secondary endpoints will include duration of CNS response, progression-free survival (CNS and/or non-CNS), overall survival, and safety. Pharmacokinetic and patient-reported outcomes will also be evaluated. LVEF will be assessed throughout treatment and follow-up. An interim analysis will be performed when 15 patients have completed 2 cycles, and the study will be stopped if no clinical benefit (complete response, partial response, or stable disease in the CNS) is seen or if two or more patients have congestive heart failure events related to trastuzumab or pertuzumab. Statistical methods: The recruitment target is 40 patients; with 35 evaluable, the 95% confidence interval around an estimated ORR of 20% will be 8.4–36.9%. The trial opens for accrual in Q3 2015. Citation Format: Lin NU, Pegram MD, Lai C, Lacasia A, Stein A, Yoo B, Perez EA. An open-label, single-arm, phase II study of pertuzumab with high-dose trastuzumab for the treatment of central nervous system progression post-radiotherapy in patients with HER2-positive metastatic breast cancer (PATRICIA). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-04.

Abstract P1-15-01: Adjuvant trastuzumab +/- anthracycline and cardiotoxicity in a community cohort of 962 HER2+ breast cancers from 2005-2011: Comparison of incidence by risk factors and by diagnostic codes vs clinical chart review

Abstract Background: Prospective clinical trials using clinical criteria and observational studies using diagnostic codes from electronic health records have reported seemingly contradictory cardiotoxicity risk for adjuvant trastuzumab (T). Accurate estimates of individualized patient specific cardiotoxicity risk are essential for treatment decisions in early HER2+ breast cancer (BC). Methods: 1,109 consecutive non-metastatic HER2+ invasive BC's diagnosed 5/1/2005 to 12/31/2011 at Kaiser Permanente Northern California receiving adjuvant T were reviewed for symptomatic congestive heart failure (SxCHF), baseline and post-T cardiac ejection fraction (EF), anthracycline (A) use, and CHF risk factors (RF) including age, race, hypertension (HTN), diabetes (DM), obesity, smoking. Records of patients with CHF ICD9 codes or an EF drop to &amp;lt;50% were reviewed by a RN, a cardiologist, and an oncologist. Primary outcomes were SxCHF (NYHA Class II or higher), EF fall to &amp;lt;50%, and &amp;lt; 38 weeks of T (75% of prescribed). Results: Median age of 962 eligible patients was 54 years (range 24-95). 305 (31.7%) were &amp;gt; 60 years old. During a median follow-up of 4.1 years, 4.6% of patients had CHF ICD9 codes, but only 2.5% had SxCHF or cardiac death confirmed by clinical review. At 1 year, cumulative incidence of an EF fall to &amp;lt;50% was 5.7% with T alone and 17.7% with T+ A. A total of 15.3% finished &amp;lt;38 weeks of T, 9.4% with T alone and 20.6% with T+A. The overall 2- and 5-year cumulative incidence of SxCHF/cardiac death was low: 1.3% and 2.7% with T alone and 2.2% and 3.1% with T + A. These rates were lower than reports based solely on diagnostic or billing codes, and varied substantially by RF (see table). The rates were similar to those predicted by the NSABP B-31 Cardiac Risk Score. Clinical heart failure based on diagnostic codes was not confirmed at chart review 48% of the time. Results from multivariable analyses will be presented. Predictors of Trastuzumab Cardiotoxicity Cumulative Incidence (%)PredictorsNFall EF to&amp;lt;50%Symptomatic CHF 1-year2-year5-yearAll96212.01.82.8Anthracycline50517.72.23.1Non-anthracycline4575.71.32.7Age&amp;lt;6065711.71.11.1Age 60-6922212.61.43.8Age 70-797112.77.111.0Baseline EF 50-55%9230.78.88.8HTN dx39212.63.44.7BMI 30+31516.32.64.5DM Dx10315.55.06.9Smoking (ever)33314.23.76.1HTN and BMI 30+18215.53.96.0HTN, BMI 30+, DM5016.08.212.2Age&amp;lt;50, BMI&amp;lt;30, No HTN/DM2197.30.00.0Age&amp;gt;60, 2+ RF(HTN, DM, BMI 30+)10114.95.08.9 Conclusions: Risk of clinically confirmed CHF/cardiac death was substantially lower than risk based on ICD codes alone. Risk was consistent with prior clinical trials and differed substantially by age, baseline EF, use of A, and other CHF risk factors. Greatest risk was with age of 70+, borderline baseline EF, and comorbidities known to increase CHF risk. Quite low risk (1.1% at 5 years) was seen in patients under 60 years old. Citation Format: Fehrenbacher L, Capra A, Krishnaswami A, Quesenberry C, Habel L. Adjuvant trastuzumab +/- anthracycline and cardiotoxicity in a community cohort of 962 HER2+ breast cancers from 2005-2011: Comparison of incidence by risk factors and by diagnostic codes vs clinical chart review. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-15-01.

Chemotherapy-Induced Cardiotoxicity in Breast Cancer Patients

Chemotherapy-induced cardiotoxicity (CIC) is a well-documented side effect of breast cancer treatment. Nearly all chemotherapeutic agents can cause CIC with the highest occurrence found in anthracycline and trastuzumab use. Treatment- and patient-related risk factors contribute to the development of CIC making risk modification an important consideration during breast cancer treatment. Prevention and early detection of cardiotoxicity are key to minimizing permanent and devastating cardiac damage; therefore, early involvement of a cardiologist including periodic cardiac monitoring during and after chemotherapy exposure is recommended.