Mechanisms of Exercise Intolerance Across the Breast Cancer Continuum: A Pooled Analysis of Individual Patient Data.

PURPOSE: The purpose of this study is to evaluate the prevalence of abnormal cardiopulmonary responses to exercise and pathophysiological mechanism(s) underpinning exercise intolerance across the continuum of breast cancer (BC) care from diagnosis to metastatic disease. METHODS: Individual participant data from four randomized trials spanning the BC continuum ([1] prechemotherapy [n = 146], [2] immediately postchemotherapy [n = 48], [3] survivorship [n = 138], and [4] metastatic [n = 47]) were pooled and compared with women at high-risk of BC (BC risk; n = 64). Identical treadmill-based peak cardiopulmonary exercise testing protocols evaluated exercise intolerance (peak oxygen consumption; V̇O2peak) and other resting, submaximal, and peak cardiopulmonary responses. The prevalence of 12 abnormal exercise responses was evaluated. Graphical plots of exercise responses were used to identify oxygen delivery and/or uptake mechanisms contributing to exercise intolerance. Unsupervised, hierarchical cluster analysis was conducted to explore exercise response phenogroups. RESULTS: Mean V̇O2peak was 2.78 ml O2.kg-1·min-1 (95% confidence interval [CI], -3.94, -1.62 mL O2.kg-1·min-1; P < 0.001) lower in the pooled BC cohort (52 ± 11 yr) than BC risk (55 ± 10 yr). Compared with BC risk, the pooled BC cohort had a 2.5-fold increased risk of any abnormal cardiopulmonary response (odds ratio, 2.5; 95% confidence interval, 1.2, 5.3; P = 0.014). Distinct exercise responses in BC reflected impaired oxygen delivery and uptake relative to control, although considerable inter-individual heterogeneity within cohorts was observed. In unsupervised, hierarchical cluster analysis, six phenogroups were identified with marked differences in cardiopulmonary response patterns and unique clinical characteristics. CONCLUSIONS: Abnormal cardiopulmonary response to exercise is common in BC and is related to impairments in oxygen delivery and uptake. The identification of exercise response phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions.

Nomogram for Predicting Risk of Cancer Therapy-Related Cardiac Dysfunction in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

BACKGROUND: Cancer therapy-related cardiac dysfunction (CTRCD) is an important treatment-limiting toxicity for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that adversely affects cancer and cardiovascular outcomes. Easy-to-use tools that incorporate readily accessible clinical variables for individual estimation of CTRCD risk are needed. METHODS AND RESULTS: From 2004 to 2013, 1440 patients with stage I to III HER2-positive breast cancer treated with trastuzumab-based therapy were identified. A multivariable Cox proportional hazards model was constructed to identify risk factors for CTRCD and included the 1377 patients in whom data were complete. Nine clinical variables, including age, race, body mass index, left ventricular ejection fraction, systolic blood pressure, coronary artery disease, diabetes, arrhythmia, and anthracycline exposure were built into a nomogram estimating risk of CTRCD at 1 year. The nomogram was validated for calibration and discrimination using bootstrap resampling. A total of 177 CTRCD events occurred within 1 year of HER2-targeted treatment. The nomogram for prediction of 1-year CTRCD probability demonstrated good discrimination, with a concordance index of 0.687. The predicted and observed probabilities of CTRCD were similar, demonstrating good model calibration. CONCLUSIONS: A nomogram composed of 9 readily accessible clinical variables provides an individualized 1-year risk estimate of CTRCD among women with HER2-positive breast cancer receiving HER2-targeted therapy. This nomogram represents a simple-to-use tool for clinicians and patients that can inform clinical decision-making on breast cancer treatment options, optimal frequency of cardiac surveillance, and role of cardioprotective strategies.

Association of Circulating Cardiomyocyte Cell-Free DNA With Cancer Therapy-Related Cardiac Dysfunction in Patients Undergoing Treatment for ERBB2-Positive Breast Cancer.

Importance: Cancer 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. Objective: To 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 Participants: A 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 Measures: The 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. Results: Of 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 Relevance: This 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 Registration: ClinicalTrials.gov Identifier: NCT02177175.

Rationale and design of a cardiac safety study for reduced cardiotoxicity surveillance during HER2-targeted therapy.

BACKGROUND: Echocardiograms are recommended every 3 months in patients receiving human epidermal growth factor 2 (HER2)-targeted therapy for surveillance of left ventricular ejection fraction (LVEF). Efforts to tailor treatment for HER2-positive breast cancer have led to greater use of non-anthracycline regimens that are associated with lower cardiotoxicity risk, raising into question the need for frequent cardiotoxicity surveillance for these patients. This study seeks to evaluate whether less frequent cardiotoxicity surveillance (every 6 months) is safe for patients receiving a non-anthracycline HER2-targeted treatment regimen. METHODS/DESIGN: We will enroll 190 women with histologically confirmed HER2-positive breast cancer scheduled to receive a non-anthracycline HER2-targeted treatment regimen for a minimum of 12 months. All participants will undergo echocardiograms before and 6-, 12-, and 18-months after initiation of HER2-targeted treatment. The primary composite outcome is symptomatic heart failure (New York Heart Association class III or IV) or death from cardiovascular causes. Secondary outcomes include: 1) echocardiographic indices of left ventricular systolic function; 2) incidence of cardiotoxicity, defined by a ≥ 10% absolute reduction in left ventricular ejection fraction (LVEF) from baseline to < 53%; and 3) incidence of early interruption of HER2-targeted therapy. CONCLUSIONS: To our knowledge, this will be the first prospective study of a risk-based approach to cardiotoxicity surveillance. We expect findings from this study will inform the development of updated clinical practice guidelines to improve cardiotoxicity surveillance practices during HER2-positive breast cancer treatment. TRIAL REGISTRATION: The trial was registered in the ClinicalTrials.gov registry (identifier NCT03983382) on June 12, 2019.

Timing of exercise therapy when initiating adjuvant chemotherapy for breast cancer: a randomized trial.

AIMS: The 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 RESULTS: Using 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). CONCLUSION: There 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.

Association of cardiac calcium burden with overall survival after radiotherapy for non-small cell lung cancer.

Background and purpose: Coronary calcifications are associated with coronary artery disease in patients undergoing radiotherapy (RT) for non-small cell lung cancer (NSCLC). We quantified calcifications in the coronary arteries and aorta and investigated their relationship with overall survival (OS) in patients treated with definitive RT (Def-RT) or post-operative RT (PORT). Materials and methods: We analyzed 263 NSCLC patients treated from 2004 to 2017. Calcium burden was ascertained with a Hounsfield unit (HU) cutoff of > 130 in addition to a deep learning (DL) plaque estimator. The HU cutoff volumes were defined for coronary arteries (PlaqueCoro) and coronary arteries and aorta combined (PlaqueCoro+Ao), while the DL estimator ranged from 0 (no plaque) to 3 (high plaque). Patient and treatment characteristics were explored for association with OS. Results: The median PlaqueCoro and PlaqueCoro+Ao was 0.75 cm3 and 0.87 cm3 in the Def-RT group and 0.03 cm3 and 0.52 cm3 in the PORT group. The median DL estimator was 2 in both cohorts. In Def-RT, large PlaqueCoro (HR:1.11 (95%CI:1.04-1.19); p = 0.008), and PlaqueCoro+Ao (HR:1.06 (95%CI:1.02-1.11); p = 0.03), and poor Karnofsky Performance Status (HR: 0.97 (95%CI: 0.94-0.99); p = 0.03) were associated with worse OS. No relationship was identified between the plaque volumes and OS in PORT, or between the DL plaque estimator and OS in either Def-RT or PORT. Conclusions: Coronary artery calcification assessed from RT planning CT scans was significantly associated with OS in patients who underwent Def-RT for NSCLC. This HU thresholding method can be straightforwardly implemented such that the role of calcifications can be further explored.

Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

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 inducing 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 cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Effects and tolerability of exercise therapy modality on cardiorespiratory fitness in lung cancer: a randomized controlled trial.

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 < 0.05). No between-group changes were observed for any patient-reported outcomes. Relative dose intensity of exercise was lower in RT and CT compared with AT (Ps < 0.05). CONCLUSIONS: In the context of a smaller than planned sample size, AT and CT significantly improved VO2 peak in lung cancer survivors; however, the tolerability-to-benefit ratio was superior for AT and hence may be the preferred modality to target impaired CRF in post-treatment lung cancer survivors.

Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer: The WECARE Study.

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 <55 years of age when diagnosed with breast cancer between 1985 and 2008 completed a cardiovascular health questionnaire. Risk of radiation-associated CAD was evaluated by comparing women treated with left-sided RT with women treated with right-sided RT using multivariable Cox proportional hazards models. Effect modification by treatment and cardiovascular risk factors was examined. RESULTS: In total, 517 women who did not receive RT and 94 women who had a pre-existing cardiovascular disease diagnosis were excluded, leaving 972 women eligible for analysis. Their median follow-up time was 14 years (range 1-29 years). The 27.5-year cumulative incidences of CAD for women receiving left- vs right-sided RT were 10.5% and 5.8%, respectively (P = 0.010). The corresponding HR of CAD for left- vs right-sided RT in the multivariable Cox model was 2.5 (95% CI: 1.3-4.7). There was no statistically significant effect modification by any factor evaluated. CONCLUSIONS: Young women treated with RT for left-sided breast cancer had over twice the risk of CAD compared with women treated with RT for right-sided breast cancer. Laterality of RT is independently associated with an increased risk of CAD and should be considered in survivorship care of younger breast cancer patients.

Increasing Heart Dose Reduces Overall Survival in Patients Undergoing Postoperative Radiation Therapy for NSCLC.

INTRODUCTION: Given the concern for cardiopulmonary toxicity in patients with NSCLC undergoing postoperative radiation therapy (PORT), the purpose of this study was to evaluate the association between heart dose and overall survival (OS) in patients undergoing PORT with modern techniques. METHODS: This is a retrospective study of consecutive patients with NSCLC treated with PORT between May 2004 and January 2017. Clinical records were reviewed and radiation dose distributions were analyzed for association with OS. RESULTS: A total of 284 patients were analyzed. At the time of surgery, most patients had pathologic American Joint Committee on Cancer seventh edition stage III disease (91.2 %) and received either preoperative or adjuvant chemotherapy (92.3 %). Most patients underwent a lobectomy (81.3 %) and had R0 (80.6 %) or R1 (19.4 %) resection. PORT was delivered with a median radiation dose of 54 Gy, and 70.4 % of patients were treated with intensity-modulated radiation therapy. Dosimetric variables across a large range of doses to the heart were highly significant (p < 0.05) for OS. The volume of the heart receiving 8 Gy (HV8) was the most significant dosimetric variable (p < 0.001), and the median HV8 was 35.5 %. The median OS was 33.2 versus 53.6 months (p < 0.005) for patients with HV8 above or below 35.5 %, respectively. On multivariable analysis accounting for other potential prognostic confounders, HV8 remained highly significant (p < 0.001). CONCLUSIONS: The data reveal a strong correlation between increasing heart dose and OS in patients with NSCLC undergoing PORT. Taken together with the recently presented LungART trial, lowering heart dose in PORT patients may help to decrease the risk of morbidity and mortality and improve the therapeutic ratio of PORT.

Racial and Socioeconomic Disparities in Cardiotoxicity Among Women With HER2-Positive Breast Cancer.

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.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

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.

Cardiotoxicity Surveillance and Risk of Heart Failure During HER2 Targeted Therapy.

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 <55% at any surveillance timepoint was identified in 49% of cases and 3% of controls, and an LVEF <55% during the final surveillance timepoint before developing HF was identified in 54% of cases and 4% of controls. In multivariable-adjusted analyses, LVEF <55% at any timepoint or during the final surveillance timepoint (odds ratio: 27.0; 95% confidence interval: 9.3 to 78.8 and odds ratio: 25.6; 95% confidence interval: 7.3 to 90.3, respectively) was associated with HF. CONCLUSIONS: Patients with LVEF <55% on routine surveillance during HER2 targeted therapy are at increased risk for HF. Additional studies to define their optimal management are warranted.

Incremental Value of Global Longitudinal Strain for Predicting Survival in Patients With Advanced AL Amyloidosis.

BACKGROUND: Advanced light-chain (AL) amyloidosis is associated with poor prognosis, with a 5-year survival rate of <25%. Prognostication is based on the revised Mayo (rMayo) staging according to serum cardiac biomarkers. OBJECTIVES: This study sought to determine whether global longitudinal strain (GLS) can provide incremental prognostic value in patients with advanced disease. METHODS: Baseline (pre-treatment) clinical, 2-dimensional echocardiogram with GLS and laboratory data were collected prospectively in 94 patients with newly diagnosed AL amyloidosis with rMayo stage III or IV disease. Overall survival (OS) was defined as time from baseline echocardiography to death. RESULTS: Of 94 patients, 60% (n = 56) had rMayo stage III and 40% (n = 38) had stage IV disease. Ninety of the 94 patients underwent plasma cell-directed therapy. The median left ventricular ejection fraction (LVEF) was 60%, and the median GLS was 13.2%. Of 94 patients, 64 died during follow-up. The median OS was 11.2 months, with an estimated 5-year OS of 21%. In univariable analysis, brain natriuretic peptides, GLS, LVEF, E/e' ratio, and rMayo stage were significantly associated with OS. In Cox regression, GLS provided incremental value over brain natriuretic peptide, troponin, and LVEF for predicting OS. Patients with GLS < -14.2% had a corresponding median OS and 5-year OS rate of 33.2 months and 39%, respectively, versus 7.7 months and 6% for those with GLS ≥ -14.2%. This difference was maintained despite further stratification by rMayo stage. CONCLUSIONS: Baseline GLS is an independent predictor of OS beyond the circulating biomarkers and can identify groups with different survival outcomes beyond the Mayo Staging.

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

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 (VO2peak) 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 VO2peak (mL O2·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, VO2peak increased 0.6±1.7 mL O2·kg-1·min-1 (P=0.05) and 0.8±1.8 mL O2·kg-1·min-1 (P=0.07) in LET and NLET, respectively, compared with attention control. Change in VO2peak ranged from -2.7 to 4.1 mL O2·kg-1·min-1 and from -3.6 to 5.1 mL O2·kg-1·min-1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO2peak responders (ie, Δ ≥1.32 mL O2·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.

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer.

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 <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019. Main Outcomes and Measures: Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2). Results: A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (ß coefficient, -0.75; 95% CI, -1.32 to -0.18). Conclusions and Relevance: Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.