Search

ImportanceCancer therapy–related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD.ObjectiveTo determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy.Design, Setting, and ParticipantsA prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/− pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022.Main Outcomes and MeasuresThe outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression.ResultsOf 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046).Conclusions and RelevanceThis study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation.Trial RegistrationClinicalTrials.gov Identifier: NCT02177175

AimsThe most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer.Methods and resultsUsing a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens—concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20–50 min at 55%–100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, −0.88 mL O2·kg−1·min−1; 95% confidence interval (CI): −3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg−1·min−1, P < 0.001).ConclusionThere was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

BACKGROUND Poor cardiorespiratory fitness (CRF) is a cardinal feature of post-treatment primary lung cancer. The most effective exercise therapy regimen to improve CRF has not been determined. METHODS In this parallel-group factorial randomized controlled trial, lung cancer survivors with poor CRF (below age-sex sedentary values) were randomly allocated to receive 48 consecutive supervised sessions thrice weekly of (i) aerobic training (AT)-cycle ergometry at 55% to >95% of peak oxygen consumption (VO2 peak); (ii) resistance training (RT)-lower and upper extremity exercises at 50-85% of maximal strength; (iii) combination training (CT)-AT plus RT; or (iv) stretching attention control (AC) for 16 weeks. The primary endpoint was change in CRF (VO2 peak, mL O2 ·kg-1 ·min-1 ). Secondary endpoints were body composition, muscle strength, patient-reported outcomes, tolerability (relative dose intensity of exercise), and safety. Analysis of covariance determined change in primary and secondary endpoints from baseline to post-intervention (Week 17) with adjustment for baseline values of the endpoint and other relevant clinical covariates. RESULTS Ninety patients (65 ± 9 years; 66% female) were randomized (AT, n = 24; RT, n = 23; CT, n = 20; and AC, n = 23) of the planned n = 160. No serious adverse events were observed. For the overall cohort, the lost-to-follow-up rate was 10%. Mean attendance was ≥75% in all groups. In intention-to-treat analysis, VO2 peak increased 1.1 mL O2 ·kg-1 ·min-1 [95% confidence interval (CI): 0.0, 2.2, P = 0.04] and 1.4 mL O2 ·kg-1 ·min-1 (95% CI: 0.2, 2.5, P = 0.02) in AT and CT, respectively, compared with AC. There was no difference in VO2 peak change between RT and AC (-0.1 mL O2 ·kg-1 ·min-1 , 95% CI: -1.2, 1.0, P = 0.88). Favourable improvements in maximal strength and body composition were observed in RT and CT groups compared with AT and AC groups (Ps

Background Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined. Objectives The purpose of this study was to report CAD risk among participants in the Women’s Environmental Cancer and Radiation Epidemiology Study. Methods A total of 1,583 women who were, Central Illustration

Objective (1) Assess the feasibility of 13 N-ammonia cardiac PET (13 N-ammonia-PET) imaging in radiotherapy (RT) treatment position in locally-advanced breast cancer (LABC) patients. (2) Correlate pre−/post-RT changes in myocardial flow reserve (MFR) with the corresponding radiation heart dose. Methods Ten left-sided LABC patients undergoing Volumetric Modulated-Arc-Therapy (VMAT) to chest wall and regional lymph nodes underwent a rest/stress 13 N-ammonia-PET at baseline and (median) 13 months post-RT. Changes in cardiac functions and coronary artery Ca2+ scoring between baseline and follow-up were correlated with average RT dose to the myocardium,3 coronary territories, and 17 myocardial segments. Results Eight (of 10) patients successfully completed the study. The average rest (stress) global MBF (ml.g-1.min-1) for baseline (follow-up) were 0.83 ± 0.25 (2.4 ± 0.79) and 0.92 ± 0.30 (2.76 ± 0.71), respectively. Differences in MBF, heart rate, blood pressure, and rate-pressure product (RPP) between baseline and follow-up were insignificant (P > 0.1).Strong (R = 0.79; P 50) for all patients in both studies. Conclusion The feasibility of 13 N-ammonia-PET imaging in treatment position of LABC patients was demonstrated. MFR at 1-year post-irradiation of the heart decreased in 50% of the patients. MFR may be a potential index for early detection of cardiotoxicity in BC patients receiving RT to the chest wall.

Background: Advanced light-chain (AL) amyloidosis is associated with poor prognosis, with a 5-year survival rate of

Background: Guidelines recommend left ventricular ejection fraction (LVEF) assessments every 3 months for cardiotoxicity monitoring during human epidermal growth factor receptor 2 (HER2) targeted therapy. Evidence in support of this practice is lacking. Objectives: This study examines the association between adherence to cardiotoxicity surveillance guidelines and heart failure (HF) in HER2-positive breast cancer patients. Methods: A case-control study was performed in 53 patients who developed cardiotoxicity during HER2 targeted therapy, and 159 controls matched by age, anthracycline exposure, and year of treatment. Cardiotoxicity was defined as HF (New York Heart Association functional class III or IV) or cardiac death. Adherence to cardiotoxicity surveillance guidelines was ascertained from the beginning of HER2 targeted therapy to the diagnosis date of HF for cases or the corresponding timepoint for matched controls. Conditional logistic regression was used for case-control comparisons. Results: Eighty-one percent of cases and controls were previously treated with an anthracycline. Adherence to cardiotoxicity surveillance guidelines during the entire observation period or during the first 6 months of treatment was not associated with lower risk of HF. An LVEF

Background: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40–50 minutes per session), and volume (120–160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer. Methods: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO 2 peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO 2 peak (mL O 2 ·kg −1 ·min −1 ) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety. Results: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO 2 peak increased 0.6±1.7 mL O 2 ·kg −1 ·min −1 ( P =0.05) and 0.8±1.8 mL O 2 ·kg −1 ·min −1 ( P =0.07) in LET and NLET, respectively, compared with attention control. Change in VO 2 peak ranged from −2.7 to 4.1 mL O 2 ·kg −1 ·min −1 and from −3.6 to 5.1 mL O 2 ·kg −1 ·min −1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO 2 peak responders (ie, Δ ≥1.32 mL O 2 ·kg −1 ·min −1 ). NLET improved all patient-reported outcomes compared with attention control. Conclusions: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01186367.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA damaging agents such as radiation and anthracycline chemotherapies induce delayed cardiac inflammation following therapy due to activation of cGAS and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING-signaling in mice inhibits DNA damage induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA damaging therapies and effectively mitigates cardiotoxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Purpose of review Cardiotoxicity is a well recognized adverse effect of human epidermal growth factor receptor 2 (HER2)-targeted therapies. The goal of this review is to highlight recent studies that have advanced our knowledge of the diagnosis, prevention, and management of cardiotoxicity associated with HER2-targeted agents. Recent findings Several clinical risk factors for cardiotoxicity associated with HER2-targeted therapies have been identified including age, low-baseline left ventricular ejection fraction, and treatment with anthracyclines; however, these remain insufficient to identify all patients at risk for cardiotoxicity. Routine cardiac monitoring remains the standard for cardiotoxicity surveillance, although the optimal frequency and modality of monitoring remains uncertain. Global longitudinal strain, T1/T2 weighted CMR imaging protocols, and circulating biomarkers can detect early signs of cardiotoxicity, but studies are needed to investigate whether use of these markers in clinical practice improves patient outcomes. Cardioprotective medications (e.g. beta-blockers or ACE-inhibitors) may be of benefit to patients at increased risk for cardiotoxicity from HER2-taregeted therapies, particularly those who are treated with an anthracycline-containing regimen. Summary Improved risk stratification of patients during HER2-targeted therapy and effective prevention and management strategies for cardiotoxicity are needed to enhance the value of longitudinal cardiac monitoring and increase cardiac safety so that optimal breast cancer treatment can be delivered.

Purpose HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. Methods Patients with stage I–IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40–49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. Results Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. Conclusion This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population. Electronic supplementary material The online version of this article (10.1007/s10549-019-05191-2) contains supplementary material, which is available to authorized users.

Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.Patients with HER2-positive breast cancer and asymptomatic LVEF decline to 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death.Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29).Continuation of trastuzumab after an asymptomatic LVEF decline to 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.

Purpose/Objective(s) Heart dose in patients receiving thoracic radiotherapy (RT) correlates with cardiovascular events (CVE) and outcomes, but there are currently no established cardiac biomarkers predictive of RT-induced cardiotoxicity. A cardiac risk score (CRS) (10-point score: 0- Materials/Methods Patients with NSCLC were treated with SBRT on an IRB-approved prospective phase II study on dose escalation in patients with large (T1b-T4N0-N1M0) primary NSCLC. Consecutive patients treated from 2013 to 2018 with a history of a prior CVE, a CVE after SBRT, or a mean heart dose (MHD) > 5 Gy were selected for CRS analysis. Patient samples were obtained pre-treatment, on the last day of SBRT and in follow-up (1, 3 and 6 months after SBRT). Two-sample t-tests were performed to compare CRS over time. Subset analyses were performed in patients with or without MHD > 5 Gy and in patients with or without a CVE during follow-up. Results A total of 62 samples from 17 patients were analyzed for CRS. The median age was 79 years and 53% were male. Patients were AJCC 8th edition stage IB (29%), IIA (12%), IIB (41%) and IIIA (18%). RT doses were 40 to 45 Gy in 5 fractions (18%), 50 Gy in 5 fractions (70%) or 60 Gy in 8 fractions (12%). Eight (47%) patients had a MHD > 5 Gy. At a median follow-up of 21 months, 11 (65%) patients experienced a CVE after RT. Baseline CRS were LR (41%), IR (41%), HR (12%) or not evaluable (6%). CRS increased from baseline to the last day of SBRT (mean difference (MD) in score was +0.52, P = 0.06). On subgroup analysis, patients who experienced a CVE in follow-up had a greater increase in CRS (MD: +1.101, P = 0.008). There was also a trend of increase in CRS in patients with MHD > 5 Gy (MD: +0.592, P = 0.1). There were no significant changes in the CRS during the follow-up period. Conclusion Our results from this exploratory prospective analysis demonstrate a significant correlation between an increase in CRS during SBRT and the development of CVE in follow-up after SBRT. Additionally, a trend in association between an increase in CRS during SBRT and MHD was identified, which could indicate an underlying relationship between CRS change during RT and MHD. These findings should be further explored in a larger patient population.

Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.

A 41-year-old woman was diagnosed with CML and treated in the first-line setting with dasatinib, a second-generation BCR-ABL TKI. After 2 years of treatment, she achieved a major molecular response but reported new dyspnea on exertion.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40–49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

Cardiac dysfunction is the major determinant of survival in patients with advanced light chain (AL) amyloidosis. Whether monoclonal light chain suppression therapy, the mainstay of AL amyloidosis, can improve cardiac function remains uncertain. 94 patients with newly diagnosed AL amyloidosis from

Prognostication of light chain (AL) amyloidosis is based on the revised Mayo (rMayo) staging according to baseline troponin, N terminal pro brain natriuretic peptides and free light chains. Whether global longitudinal strain (GLS) can provide incremental prognostic value in advanced AL amyloidosis

Background The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. Methods Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had ≥ 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate ( Results One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% ± 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention-to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity ≥ 70%), and this led to improvements in VO2peak and functional capacity (P values Conclusions Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. © 2018 American Cancer Society.

Background Autologous hematopoietic cell transplantation (HCT) is a first-line therapy for prolonging survival in patients with light-chain (AL) amyloidosis. Cardiac involvement is the most important determinant of survival. However, patients with advanced cardiac involvement have often been excluded from HCT because of high risk for transplantation-related mortality and poor overall survival. Whether baseline left ventricular global longitudinal strain (GLS) can provide additional risk stratification and predict survival after HCT in this high-risk population remains unclear. The aim of this study was to evaluate the prognostic implication of baseline GLS and the added value of GLS beyond circulating cardiac biomarkers for risk stratification in patients with AL amyloidosis undergoing HCT. Methods Eighty-two patients with newly diagnosed AL amyloidosis who underwent upfront HCT between January 2007 and April 2014 were included in the study. Clinical, echocardiographic, and serum cardiac biomarker data were collected at baseline and 12 months following HCT. GLS measurements were performed using a vendor-independent offline system. The median follow-up time for survivors was 58 months. Results Sixty-four percent of patients were in biomarker-based Mayo stage II or III. GLS, brain natriuretic peptide, troponin, and mitral E/A ratio were identified as the strongest predictors of survival ( P Conclusions GLS is a strong predictor of survival in patients with AL amyloidosis undergoing HCT, potentially providing incremental value over serum cardiac biomarkers for risk stratification. GLS should be considered as a standard parameter along with serum cardiac biomarkers when evaluating eligibility for HCT or other investigational therapies.

Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting.A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF (10% to 55% or 16% from baseline).A total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF 50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to 50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy.The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines.

Aims The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events. Methods and results Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups. Conclusion A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.

Background: Trastuzumab and pertuzumab are approved for the treatment of HER2-postiive breast cancer in the neoadjuvant setting. However, limited cardiac safety data is available when used in combination with doxorubicin-based chemotherapy. At a single center we retrospectively report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. Methods: Patients treated with neoadjuvant dose dense AC followed by THP from September 1, 2014 to March 1, 2015 were retrospectively identified. Patients then had breast surgery and completion of anti-HER2 therapy for 1 year. The primary outcome was cardiac event rate, defined by New York Heart Association (NYHA) class III/IV or cardiac death. The secondary outcome was significant asymptomatic decline in left ventricular ejection fraction (LVEF) of 10%-15% from baseline to below the lower limit of normal, or > 16% from baseline. Patients underwent LVEF monitoring at baseline prior to AC, prior to initiation of THP, and serially during 1 year of anti-HER2 therapy (neoadjuvant to adjuvant phases). Results: Fifty-seven patients were included in the study. The median age was 46 years (range 26-68 years). The median number of cycles of trastuzumab and pertuzumab in the neoadjvuvant setting was 6 (range 3-8) and 6 (range 2-8), respectively. In the adjuvant setting, 56 (98%) patients received trastuzumab with pertuzumab with a median cycle number of 12 (range 1-13). Two of 57 (3.5%) patients developed NYHA class III/IV heart failure after 5 and 9 months of trastuzumab, leading to permanent discontinuation of anti-HER2 treatment. Additionally, 7 (12.3%) patients developed a significant LVEF decline (without severe HF symptoms). The median LVEF was 65% (range 55-75%) at baseline and 64% (range 53-72%) after AC. There was a reduction in median LVEF to 60% (range 35-70%), 60% (range 23- 73%), 61% (range 25-73%), and 58% (range 28-66%) at 3, 6, 9, and 12 months (+/- 6 weeks) of trastuzumab-based therapy. Conclusion: In patients with HER2-positive breast cancer treated with neoadjuvant dose-dense AC and THP followed by completion of anti-HER2 therapy in adjuvant setting, the overall rate of NYHA Class III/IV heart failure was comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity when pertuzumab is added to trastuzumab following a doxorubicin-based regimen. Citation Format: Yu AF, Wang R, Singh J, Liu JE, Eaton A, Jones L, Oeffinger K, Steingart RM, Hudis CA, Dang CT. Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-38.

Objectives Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. Methods An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). Results Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. Conclusion At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Treatment-related cardiotoxicity remains a significant concern for breast cancer patients undergoing cancer treatment and extends into the survivorship period, with adverse cardiovascular (CV) outcomes further compounded by the presence of pre-existing CV disease or traditional CV risk factors. Awareness of the cardiotoxicity profiles of contemporary breast cancer treatments and optimization of CV risk factors are crucial in mitigating cardiotoxicity risk. Assessment of patient- and treatment-specific risk with appropriate CV surveillance is another key component of care. Mismatch between baseline cardiotoxicity risk and intensity of cardiotoxicity surveillance can lead to unnecessary downstream testing, increased healthcare expenditure, and interruption or discontinuation of potentially life-saving treatment. Efforts to identify early imaging and/or circulating biomarkers of cardiotoxicity and develop effective management strategies are needed to optimize the CV and cancer outcomes of breast cancer survivors.

This cohort study evaluates the association of early trastuzumab interruption with clinical outcomes in patients with ERBB2-positive breast cancer.

Background: Trastuzumab (H) improves disease-free survival and overall survival in HER2+ early breast cancer (EBC) but is associated with risk of treatment-induced cardiotoxicity especially when administered after an anthracycline. We performed a single center retrospective study to assess the cardiac safety of adjuvant trastuzumab therapy without anthracyclines in a real-world clinical setting. Methods: Patients (pts) with HER2+ early breast cancer (EBC) who received H without anthracycline-based chemotherapy between January 2010 and June 2014 were studied. Patients enrolled in a clinical trial were excluded. Tumor characteristics, chemotherapy regimen, cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. A cardiac event (C.E.) was defined as New York Heart Association class III or IV heart failure with LVEF decline of > 10% to < 55% or possible/probable cardiac death, as previously defined by the NSABP B-31 trial. Results: In total, 174 pts with HER2+ EBC treated with H-based therapy without anthracyclines were identified. Median age was 59 years (range, 32 to 85 years), 72 (41%) had hypertension, 55 (32%) had hyperlipidemia, 29 (16%) had diabetes, and 5 (3%) had coronary artery disease. At baseline, all pts had a LVEF > 50% (median, 66%; range, 50% to 81%). Two (1.1%) pts developed a C.E. Both pts had risks factors for C.E. (1 - age > 60 years, hypertension, and prior history of anthracycline exposure; 1- age > 60 years, hypertension, hyperlipidemia, and baseline LVEF of 50-55%). After discontinuation of H, both patients had recovery of LVEF to > 50% and resolution of heart failure symptoms. Twelve (6.9%) pts developed asymptomatic LVEF decline of > 10% points to < 55% during H therapy. Of the 14 patients who developed cardiotoxicity, H was prematurely interrupted or discontinued in 8 patients. Conclusion: In our single center experience of patients being treated off study, the incidence of C.E.s and asymptomatic LVEF decline during H therapy without an anthracycline was 1.1% and 6.9%, respectively. These appeared higher than events reported in clinical trials possibly due to the inclusion of an older group of women with a higher prevalence of cardiovascular risk factors. Overall, the incidence of symptomatic heart failure is low for H without an anthracycline even in this older group. Citation Format: Mukku RB, Verma S, Liu J, Steingart R, Hudis C, Yu AF, Dang C. Cardiac safety of trastuzumab without an anthracycline in patients with HER2-positive early stage breast cancer: A single center experience. [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 P4-14-09.

Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting. Here we report the pathologic complete response (pCR) rate. Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2015. Charts were analyzed for pt demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy. Results: Charts from 66 pts were reviewed; 60 pts were evaluable for pCR defined as absence of invasive disease in the breast, and 6 were not (3-no anthracycline, 1-incomplete chart, 1-no surgery yet, 1-metastatic). Median age was 47 years (range 28-68 years). Of 60 pts, 52 (86%) had operable breast cancer (T1-3, N0-1, M0) of which 7 had clinical stage I disease (T1N0)]; 7 (12%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (2%) had inflammatory breast cancer (T4d, any N, M0). 49 (82%) and 11 (18%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of > 2.0. 30 pts (50%) underwent mastectomy and lumpectomy, respectively. Out of 60 evaluable pts, 41 (68%) had pCR; 32/49 (65%) with HR-positive and 9/11 (82%) with HR-negative diseases had pCR, respectively. Overall 58/60 (97%) pts completed neoadjuvant therapy; 2 did not (1 developed Steven Johnson Syndrome after one cycle of AC and 1 developed pneumonitis after third weekly dose of T with HP). Conclusions: At our single center experience the pCR rate of dose dense AC→THP is high at 68 %. These data are similar to results seen in the TRYPHAENA study, and we await the results from the BERENICE trial evaluating pCR as a secondary endpoint. Patient Demographics Age, years 5516 (26%) ECOG Performace Status 031 (52%)129 (48%) Hormone receptor (HR) status HR+ Her2+49 (82%)HR- Her2+11 (18%) Status of Her-2 Positivity IHC positive52 (86%)FISH positive8 (14%) Median tumor size2.6cm (range: 1-8.4cm) Stage Operable (T1-2, N0-1, M0)52 (86%)Operable Stage I7 (12%)Operable Stage II/III45 (74%)Locally advanced (T2-3, N2-3, M0 or T4a-c, any N, M0))7 (12%)Inflammatory (T4d, any N, M0)1 (2%) Type of surgery Lumpectomy30 (50%)Mastectomy30 (50%) Citation Format: Singh JC, Sugarman S, Jones L, Boafo C, Patil S, Schweber S, Yu A, Argolo D, Modi S, Iyengar N, Smyth L, Norton L, Baselga J, Hudis C, Dang C. Pathologic complete response rate with doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2-positive early stage breast cancer: A single institution experience. [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 P1-14-17.

IMPORTANCE: Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer. OBJECTIVE: To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to

Trastuzumab (T) improves outcomes in patients (pts) with HER2 (+) breast cancer (BCA) but is associated with risk of cardiotoxicity (CTOX). CTOX is the most common reason for early T interruption, but the impact of this practice on BCA outcomes is unknown. All pts with stage I-III HER2 (+) BCA