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Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor tyrosine kinase HER2/ErbB2. This agent has shown a highly significant antitumour effect for patients with HER2-positive breast cancer, and is now considered part of the standard regimens for the treatment of this disease in both the metastatic and adjuvant setting. Cardiotoxicity has been associated with trastuzumab, and this issue has now been studied and documented in a number of adjuvant trials for which data have now been released. Cardiotoxicity has been shown to be potentiated when the agent is used concurrently or sequentially with an anthracycline, and this has limited the use of trastuzumab in some patients. Determining the overall impact of trastuzumab is further complicated by the administration of other cardiotoxic agents such as the taxanes and cyclophosphamide as well as by pre-existing cardiac disease. The incidence of severe congestive heart failure (New York Heart Association class III or IV) was 0-3.9% in the trastuzumab arms versus 0-1.3% in the control arms in the five major randomized adjuvant trials. Only one cardiac death was related to trastuzumab whereas two cardiac deaths occurred in the control arms. Ejection fraction decline of >or=10% or 15% was reported in 3-34% of trastuzumab recipients in these trials. Patients affected by trastuzumab-related cardiotoxicity do not exhibit the cellular death and distinctive ultrastructural myocardial changes seen on electron microscopy with anthracycline-induced cardiotoxicity. The cardiotoxicity of trastuzumab also differs from traditional chemotherapy-induced cardiotoxicity in that it appears to be at least partially reversible, not related to the cumulative dose, and re-challenge is generally tolerated. There remain a number of uncertainties regarding the diagnosis and management of trastuzumab-related cardiotoxicity. While no formal guidelines or consensus statements exist at present regarding cardiac monitoring during use of trastuzumab, proposed recommendations include a careful assessment of ejection fraction prior to initiating trastuzumab, avoidance of concurrent administration of trastuzumab with anthracyclines, and regular monitoring of symptoms and cardiac function during and for several years after therapy. Increased vigilance is appropriate for higher risk patients. [ABSTRACT FROM AUTHOR]

The pivotal trial by Slamon and colleagues of trastuzumab combined with chemotherapy in metastatic breast cancer showed a high incidence of congestive heart failure (CHF) among patients who had received trastuzumab and anthracycline-based therapy simultaneously. As a result, the development of nonanthracyclinebased treatment options for patients with HER2-overexpressing breast cancer has garnered significant attention. This review discusses the cardiac toxic effects of trastuzumab and trastuzumab-related regimens and how their mechanisms of action and physiologic effects differ from cardiac toxicity typically associated with anthracycline use. An overview of cardiac safety data from selected trials of trastuzumab in combination with a taxane after anthracyclines for HER2-overexpressing early-stage breast cancer shows rates of symptomatic or severe CHF of < 4% and asymptomatic declines in left ventricular ejection fractions of > 10 points in ≤ 30% of patients. For metastatic breast cancer, severe CHF has been reported in 2% of patients and ejection fraction declines in 6%-18% of patients. However, interstudy comparisons of chemotherapy-induced cardiac dysfunction are difficult because of the use of different definitions of cardiac dysfunction and different parameters for assessing cardiac safety. Recent data on cardiac safety of taxane/trastuzumab–based combination regimens demonstrate that the docetaxel/carboplatin/trastuzumab triple combination can offer clinical efficacy with a low risk of cardiac dysfunction in patients with HER2-overexpressing early-stage breast cancer as well as in patients with metastatic breast cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze the cardiac safety of lapatinib, an oral, reversible, tyrosine kinase EGFR (ERBB1) and HER2 inhibitor, using prospective data collected in 44 clinical studies. PATIENTS AND METHODS: Lapatinib (as monotherapy or in combination) was administered to 3689 patients in studies conducted between January 5, 2001, and September 30, 2006. Left ventricular ejection fraction (LVEF) was prospectively evaluated via multiple-gated acquisition scan or echocardiography at screening, every 8 weeks during therapy, and at withdrawal. We analyzed cardiac events defined as symptomatic (grade 3 or 4 left ventricular systolic dysfunction according to the National Cancer Institute Common Terminology Criteria for Adverse Events) or asymptomatic (LVEF decreases > or = 20% relative to baseline and below the institution's lower limit of normal; no symptoms). RESULTS: A study-defined cardiac event was reported in 60 patients (1.6%) previously treated with anthracyclines (n=12), trastuzumab (n=14), or neither (n=34). These prior treatments were associated with a 2.2%, 1.7%, and 1.5% incidence of cardiac events, respectively. In most patients (53 patients, 83%), events were not preceded by symptoms. Mean times to onset and duration of LVEF decrease were 13.0 and 7.3 weeks, respectively. The decrease in LVEF was rarely severe; the mean nadir was 43%. In 40 patients for whom outcome was determined, 35 (88%) had a partial or full recovery regardless of continuation or discontinuation of lapatinib. No cardiac deaths occurred among patients treated with lapatinib. CONCLUSION: Our review of data from 44 clinical studies revealed low levels of cardiotoxicity for lapatinib. Cardiac events were usually asymptomatic, caused reversible decreases in LVEF, and occurred at similar rates in patients who were and were not pretreated with anthracyclines or trastuzumab. [ABSTRACT FROM AUTHOR]

Concerns regarding cardiac adverse events during and after cancer care include contractile dysfunction, dysrhythmia, and inflammation. Clinical trials and practice guidelines may require or recommend sequential ejection fraction determinations for early recognition of contractile dysfunction, bio-marker screening where inflammation or contractile dysfunction could be anticipated, and multiple electrocardiograms with timings of cardiac intervals. In some instances, surveillance schedules used in clinical trial protocols have been incorporated in recommendations without revision or critical scrutiny. When adverse events are rare and interpretative parameters imperfect, false positive results may lead to delay or interruption of vital cancer treatment, may suggest that further cardiac testing be undertaken, and may add to patient anxiety. The risks of excessive monitoring also include inconvenience and increased cost. This paper looks at areas where surveillance recommendations may be problematic, specifically, ejection fractions, cardiac biomarkers, and electrocardiographic monitoring are considered. Changes reported following surveillance monitoring of cancer patients using these parameters may reflect true adverse events or clinically relevant future risk, but interpretative uncertainty or true physiologic change that is unrelated to the drug in question should be considered. Clinicians may not be sufficiently aware of the degree to which reported changes may reflect surveillance artifacts. A balance that incorporates both the likelihood of an event that could be prevented along with clinical implications is suggested. The authors recognize that differentiating among these variables is not always possible yet advocate for modifying surveillance schedules to balance the frequency and severity of events that can be mitigated, based on reliable data. SIGNIFICANCE STATEMENT: The authors' concerns regarding the predictive value of surveillance initiatives are explored. Confounding factors and false-positive results may add to the expense of cancer care and/or compromise optimal therapeutic initiatives., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial., Patients and Methods: Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board., Results: The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m 2 , baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%)., Conclusions: Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors., Competing Interests: Disclosure EdA: Honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs, and Pierre Fabre. Travel grants from Roche/GNE, and GSK/Novartis. Research grant to his institution from Roche/GNE, AstraZeneca, GSK/Novartis, and Servier. EA: Consultancy fees/honoraria: Eli Lilly, Sandoz, and AstraZeneca. Support for attending medical conferences from: Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, and Daiichi Sankyo (all outside the submitted work). MP: Her institution received funding from Roche in respect to the APHINITY trial. DE: Employment: Roche. Stock and Other Ownership Interests: Roche; Research Funding: Novartis. NP is an employee of IQVIA Biotech. ML: Honoraria and/or advisory board from Roche, Novartis, Lilly, Pfizer, AstraZeneca, Gilead, Seagen, MSD, Exact Sciences, Takeda, Ipsen, Sandoz, Libbs, and Knight. CC: Her institution received research funding from: AstraZeneca, Roche/Genentech, Tesaro, Novartis, Pfizer, SERVIER, Biovica, GlaxoSmithKline, and Sanofi/Aventis. Her institution receives royalties from Agendia for MammaPrint. CA: Full-time employment, Medical Director for F. Hoffmann-La Roche Ltd, and own stock in F. Hoffmann-La Roche Ltd. GJ: Honoraria and/or advisory board Novartis, Roche, Amgen, Pfizer, Bristol-Myers Squibb, Lilly AstraZeneca, Seagen, Daiichi Sankyo, and Abbvie. Research grant to the institution Novartis, Roche, and Pfizer. JMW: Honoraria and/or advisory board from Roche/GNE, Novartis, and AstraZeneca. JB: Honoraria and/or advisory board from AstraZeneca, Daiichi Sankyo, Eli Lilly, Genomic Health, Libbs, MSD, Novartis, Pfizer, and Roche. SL: Grants, non-financial support and other from Roche, during the conduct of the study; grants and other from Abbvie, other from Amgen, grants and other from AstraZeneca, other from Bayer, other from BMS, grants and other from Celgene, other from Eirgenix, other from GSK, grants, non-financial support and other from Immunomedics/Gilead, other from Lilly, other from Merck, grants, non-financial support and other from Novartis, grants, non-financial support and other from Pfizer, other from Pierre Fabre, other from Prime/Medscape, non-financial support and other from Puma, other from Samsung, non-financial support and other from Seagen, grants, non-financial support and other from Daiichi Sankyo, outside the submitted work; In addition, SL has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent EP15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid. MP-G: Consultant honoraria: Oncolytics (Scientific Board), AstraZeneca, Camel-IDS/Precirix, Gilead, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Seattle Genetics, Immutep, Seagen, NBE Therapeutics, Frame Therapeutics; Research grants to my Institute: AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon. MSE: Consultant for Boehringer Ingelheim and Beyer. Receives book royalties for Cancer and the Heart.SD: Honoraria/advisory boards from Novartis and AstraZeneca; research grant Novartis. CP: Honoraria and/or advisory board from Amgen, Celgene, Incyte, Ipsen, and Novartis. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

(No abstract allowed for commentary)., (© 2023 S. Karger AG, Basel.)

Reports of cardiac adverse events from oncology clinical trials often are at variance with reports derived from clinical observations or data-base reviews. These differences may lead to confusion, as different levels of risks abound in the literature, and the true cardiac risk of using some agents is uncertain. Additionally, such discrepancies may lead to the creation of over-cautious surveillance algorithms. Reasons for these reported differences are complex and often reflect subtleties in the criteria for individual patient evaluation. Both clinical trial data and real-world data have potential flaws that make reconciliation problematic. Importantly, however, both provide crucial information regarding the risk of adverse events. Major factors contribute to these differences including different tools used to diagnose events, and how those tools are interpreted. Additionally, differences in the populations of clinical trial participants and real-world populations play a crucial role. This paper looks at these differences and provides a perspective intended to help clinicians interpret reported variations in event rates derived from highly scrutinized clinical trials and broader real-world data., (© 2022. The Author(s).)

BERENICE (NCT02132949) assessed the cardiac safety of the neoadjuvant−adjuvant pertuzumab−trastuzumab-based therapy for high-risk, HER2-positive early breast cancer (EBC). We describe key secondary objectives at final analysis. Eligible patients received dose-dense doxorubicin and cyclophosphamide q2w × 4 ➝ paclitaxel qw × 12 (Cohort A) or 5-fluorouracil, epirubicin, cyclophosphamide q3w × 4 ➝ docetaxel q3w × 4 (B) as per physician’s choice. Pertuzumab−trastuzumab (q3w) was initiated from the taxane start and continued post-surgery to complete 1 year. Median follow-up: 64.5 months. There were no new cardiac issues and a low incidence of Class III/IV heart failure (Cohort B only: one patient (0.5%) in the adjuvant and treatment-free follow-up (TFFU) periods). Fourteen patients (7.7%) had LVEF declines of ≥10% points from baseline to <50% in Cohort A, as did 20 (10.5%) in B during the adjuvant period (12 (6.2%) in A and 7 (3.6%) in B during TFFU). The five-year event-free survival rates in Cohorts A and B were 90.8% (95% CI: 86.5, 95.2) and 89.2% (84.8, 93.6), respectively. The five-year overall survival rates were 96.1% (95% CI: 93.3, 98.9) and 93.8% (90.3, 97.2), respectively. The final analysis of BERENICE further supports pertuzumab−trastuzumab-based therapies as standard of care for high-risk, HER2-positive EBC.

Aim: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial., Patients and Methods: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (T→L), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac)., Results: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for T→L versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, T→L, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for T→L versus T. The 6-year OS were 93%, 92%, and 91% for L+T, T→L, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups., Conclusion: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer., Trial Registration: clinicaltrials.gov Identifier NCT00490139., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests:, (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease-free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)-negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up., Methods: After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab., Results: This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance ( P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen., Conclusion: This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit., Competing Interests: Martine PiccartConsulting or Advisory Role: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, ImmutepResearch Funding: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche/Genentech, Radius Health, Synthon, ServierOther Relationship: Oncolytics, EU Cancer Mission Board Marion ProcterResearch Funding: Roche/GenentechOther Relationship: Roche/Genentech Debora FumagalliResearch Funding: Roche/Genentech, AstraZeneca, Novartis, GlaxoSmithKline, Servier, Pfizer, Tesaro Evandro de AzambujaHonoraria: Roche/Genentech, Seattle Genetics, Zodiac PharmaConsulting or Advisory Role: Roche/Genentech, NovartisResearch Funding: Roche/Genentech, AstraZeneca, Servier/Pfizer, GlaxoSmithKline/NovartisTravel, Accommodations, Expenses: Roche/Genentech, GlaxoSmithKline Emma ClarkEmployment: RochePatents, Royalties, Other Intellectual Property: Issued patent: Uses for and article of manufacture including HER2 dimerization inhibitor pertuzumab, 13/649591 Michael S. EwerConsulting or Advisory Role: Bayer, AstraZeneca, Boehringer IngelheimPatents, Royalties, Other Intellectual Property: Author of the book Cancer and the Heart Eleonora RestucciaEmployment: Hoffmann LaRoche LtdLeadership: VectivBio AGStock and Other Ownership Interests: Hoffmann LaRoche Ltd, VectivBio AGTravel, Accommodations, Expenses: Hoffmann LaRoche Ltd, VectivBio Guy JerusalemHonoraria: Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbvieConsulting or Advisory Role: Novartis, Roche, Amgen, Pfizer, Bristol-Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, AbbvieResearch Funding: Novartis, Roche, PfizerTravel, Accommodations, Expenses: Novartis, Roche, Pfizer, Lilly, Amgen, Bristol-Myers Squibb, AstraZeneca, Medimmune, Merck Susan DentHonoraria: Novartis Canada Pharmaceuticals IncResearch Funding: NovartisTravel, Accommodations, Expenses: Novartis Linda ReabyTravel, Accommodations, Expenses: Roche Hervé BonnefoiHonoraria: RocheResearch Funding: BayerTravel, Accommodations, Expenses: Roche, Pfizer Ian KropEmployment: AMAG Pharmaceuticals, Freeline TherapeuticsLeadership: AMAG Pharmaceuticals, Freeline TherapeuticsStock and Other Ownership Interests: AMAG Pharmaceuticals, Freeline Therapeutics, VertexHonoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, ION Pharma, Bristol-Myers SquibbResearch Funding: Genentech, Pfizer Tadeusz PieńkowskiHonoraria: Novartis, RocheConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Roche, AstraZeneca, Novartis, PfizerTravel, Accommodations, Expenses: Roche Masakazu ToiHonoraria: Novartis, Takeda, AstraZeneca, Eisai, Genomic Health, Chugai Pharma, Taiho Pharmaceutical, Daiichi Sankyo, Yakult Pharmaceutical, Shimadzu, Pfizer, Konica Minolta, Lilly, Kyowa Hakko Kirin, Devicore medical JapanConsulting or Advisory Role: Daiichi Sankyo, Kyowa Hakko Kirin, Konica Minolta, Bertis, Athenex, Bristol-Myers SquibbSpeakers' Bureau: Pfizer, AstraZeneca, LillyResearch Funding: Taiho Pharmaceutical, Chugai Pharma, Shimadzu, Astellas Pharma, AFI technology, Japan Breast Cancer Research Group, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca, Ono Pharmaceutical, Nippon Kayaku, Kyoto Breast cancer Research NetworkPatents, Royalties, Other Intellectual Property: JP 2017-143763, PCT/JP2016/004374Travel, Accommodations, Expenses: Eisai, TakedaOther Relationship: Japan Breast Cancer Research Group, Kyoto Breast Cancer Research Network, Organization for Oncology and Translational Research Nicholas WilckenHonoraria: Roche/GenentechTravel, Accommodations, Expenses: Amgen Hans-Joachim LueckConsulting or Advisory Role: AstraZeneca, GlaxoSmithKline, Lilly, Seagen, MSD OncologySpeakers' Bureau: Roche, Pfizer, Amgen, Novartis Estefania MonturusEmployment: RocheStock and Other Ownership Interests: RocheOther Relationship: F. Hoffmann-La Roche Ltd (support for third-party writing assistance) Mihaela SicoeResearch Funding: Roche, Pfizer/EMD Serono, Novartis Sébastien GuillaumeResearch Funding: Roche, AstraZeneca, NovartisTravel, Accommodations, Expenses: Roche José BinesHonoraria: Roche, Lilly, Novartis, MSD, PfizerConsulting or Advisory Role: Roche, Lilly, MSDTravel, Accommodations, Expenses: Roche Richard D. GelberResearch Funding: AstraZeneca, Novartis, Roche, Celgene, Merck, Pfizer, Ipsen, FerringTravel, Accommodations, Expenses: Roche, AstraZeneca, Novartis Giuseppe VialeHonoraria: MSD Oncology, Pfizer, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: Dako, Roche/Genentech, Novartis, Bayer, Daiichi Sankyo, MSD Oncology, MenariniSpeakers' Bureau: Roche/GenentechResearch Funding: Roche/Genentech, Ventana Medical Systems, Dako/Agilent Technologies, CepheidTravel, Accommodations, Expenses: Roche Christoph ThomssenHonoraria: AstraZeneca, Celgene, Daiichi Sankyo Europe GmbH, Eisai Germany, Lilly, Pfizer, Roche, Pierre Fabre, MSD, Vifor PharmaConsulting or Advisory Role: Amgen, AstraZeneca, Celgene, Daiichi Sankyo Europe GmbH, MSD, Pfizer, RocheResearch Funding: AstraZeneca, Daiichi Sankyo Europe GmbH, Novartis, Pfizer, RocheTravel, Accommodations, Expenses: Daiichi Sankyo Europe GmbH, Pfizer, RocheNo other potential conflicts of interest were reported.

Purpose: Osimertinib is a third-generation, CNS-active, irreversible, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits both EGFR-TKI-sensitizing and T790M resistance mutations. We assess the cardiac failure risk in patients receiving osimertinib by evaluating the available data., Methods: Post hoc analyses of cardiac data from (1) studies in patients with advanced non-small-cell lung cancer, FLAURA (osimertinib, n = 279; comparator EGFR-TKI, n = 277) and AURA3 (osimertinib, n = 279; chemotherapy, n = 140), and (2) a pooled data set of patients treated with osimertinib 80 mg from across the clinical trial program (n = 1,142), including cardiac failure-related adverse events and left ventricular ejection fraction (LVEF) reductions. An LVEF pharmacokinetic or pharmacodynamic analysis of the pooled data set was performed. The sponsor's global safety database was analyzed for cardiac failure-related adverse events, and a literature search was conducted., Results: Decreases in LVEF from a baseline of ≥ 10 percentage points to an absolute value of < 50% following osimertinib treatment were observed in 8 (3.1%) and 14 (5.5%) patients in FLAURA and AURA3, respectively, and in 35 (3.9%) patients in the pooled population. Most events were asymptomatic and resolved without treatment of the event or osimertinib discontinuation. The pharmacokinetic or pharmacodynamic analysis did not indicate a relationship between exposure to osimertinib and decreases in LVEF from baseline. The database and literature search showed no specific trend or pattern that was suggestive of a safety issue in patients receiving osimertinib., Conclusion: These data do not suggest a causal relationship between osimertinib and cardiac failure. However, because of LVEF decreases that were observed in patients with cardiac risk factors before osimertinib treatment, cardiac monitoring, including an assessment of LVEF at baseline and during osimertinib treatment, is advised.

An innovative Cardio-Oncology meeting was held in Houston, Texas in January of 2020. This gathering was intended to broaden the scope of Cardio-Oncology to include major presentations by clinicians and researchers beyond physicians, as well as to provide comprehensive reviews by established experts aimed at a variety of levels of professional practitioners. The unique perspective of this meeting is presented in the overview that follows. This overview is intended to contribute to a broader view of Cardio-Oncology, and to provide perspective for the expanding group of providers relative to their individual areas of expertise. These perspectives can and should be incorporated in cardio-oncology centers., Competing Interests: Competing interestsNone of the authors have disclosed any competing interests., (© The Author(s) 2020.)

Background: Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting., Methods: This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm., Results: With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68-1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4-11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54-6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25-2.75]), BMI > 30 kg/m 2 (vs < 25 mg/kg 2 , OR 2.21 [95% CI 1.40-3.49]), cumulative dose of doxorubicin ≥240 mg/m 2 (OR 1.36 [95% CI 1.01-1.82]) and of epirubicin≥ 480 mg/m 2 (OR 2.33 [95% CI 1.55-3.51])., Conclusions: Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial., Trial Registration Number: ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006-000562-36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2-06 /EGF106708/N063D.

: Cancer patients are increasingly referred for cardiology evaluations. These patients differ from those routinely seen in cardiology clinics because of their psychological burden and because the therapies and cancer itself can cause cardiac symptoms. A humane approach is critical to managing these patients. Cardiologists may see patients who are newly diagnosed with cancer or are in various phases of treatment; these patients may or may not have preexisting cardiac disease, and may develop cardiotoxicity from chemoimmunotherapy or radiotherapy. Each of these situations presents unique communication challenges for cardiologists. Although some oncology centers provide training in communication skills for their personnel, including cardiologists, this training is not widely available to physicians in general hospitals or private practice. This article examines the psychological aspects of cardio-oncology. It offers practical suggestions on how to best communicate with cancer patients in different phases of oncology care, and discusses when professional psychological help is needed.

Guidelines for the diagnosis, management, and surveillance of cancer patients have evolved with the single goal of improving patient care based on established data when available, or in the absence of firm data, on the standard practices of those with broad experience in actual hands-on patient care. Two initiatives intended to disseminate information to cardio-oncologists, were discussed in this session: the first, from the American Society of Clinical Oncology was focused on available data and the confidence level of that data; the second, from The European Society of Cardiology was a position paper. Interestingly, notwithstanding the somewhat different focus, there is considerable agreement between these two initiatives. Nevertheless, guidelines my not be applicable to all afflicted patients, and may raise questions as to when deviations from published standards should be considered. Such deviations may result in allegations of failure to meet standards of care or legal liability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The opening session of Second International Colloquium on Cardio-Oncology addressed two areas of vital interest. The first reviewed new thoughts related to established agents. While anthracycline cardiotoxicity has been studied and reviewed extensively, ongoing research attempting to understand why it appears the mechanism(s) of toxicity differs from that of oncologic efficacy continue to evoke comment and intriguing speculation. Better understanding of the role of β-topoisomerase II in toxicity has advanced our understanding of the cascade of events that lead to heart failure. Additionally, the cardioprotective role of dexrazoxane fits well with our new understanding of how β-topoisomerase II works. Beyond the anthracyclines, new insight is providing us insight to better understand the impact on cardiac function seen with other agents including those targeting HER2 and several tyrosine-kinase inhibitors. Unlike the anthracyclines, these agents affect cardiac function in ways that are less direct, and therefore have different characteristics and should be thought of in alternate ways. This new knowledge regarding established agents furthers our understanding of the spectrum of cardiotoxicity and cardiac dysfunction in the cancer patient. The session also addressed cardiovascular toxicities of newer and established agents beyond myocardial dysfunction including effects on the vasculature. These agents cause changes that may be temporary or permanent, and that range from subclinical to life-threatening. The session ended with a discussion of the cardiac effects of immune checkpoint inhibitors. These agents can cause rare and sometimes fatal cardiac inflammation, for which long-term follow up may be required., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity., Materials and Methods: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment., Results: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care., Conclusion: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies., (© 2018 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer., Patients and Methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive., Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively)., Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab., Clinical Trial Information: NCT02132949.

Purpose: Cardiac ultrasound provides important structural and functional information that makes identification of cardiac abnormalities possible. Left ventricular ejection fraction (LVEF) provides the most commonly used parameter for recognition of treatment-related cardiac dysfunction. Random reading variance and physiologic factors influence LVEF and make the reported value imperfect. We attempt to quantitate the likelihood of false positive events by computer simulation., Methods: We simulated four visits on hypothetical trials. We assumed a baseline LVEF of 55% and normal distribution with regard to reading error and physiologic variation. 1,000 trials of sample size 1,500 were simulated. In a separate simulation, 1,000 patients entered with LVEFs of 45, 43, and 41% to estimate true positive incidence., Results: At each examination, less than 1.0% of false positives were noted. The cumulative false positive rate over four visits was 3.60%. True cardiotoxicity identification is satisfactory only when LVEF declines substantially., Conclusion: A 3.60% false positive rate in trials where the expected level of toxicity is low suggests that false positives are troubling and may exceed true positive results. Strategies to reduce the number of false positive results include making confirmatory studies mandatory. Evaluating increases along with decreases obtains some estimation of variance., (© 2019 S. Karger AG, Basel.)

Takotsubo syndrome, also known as stress-induced cardiomyopathy (SC), is underrecognized in cancer patients. This study aims to investigate the incidence, natural history, and triggers of SC in cancer patients and its impact on cancer therapy and overall survival. A total of 30 subjects fulfilled the diagnostic criteria for SC at MD Anderson Cancer Center over a 6-year period. Clinical presentation, electrocardiogram, laboratory data, and transthoracic echocardiogram results registered during the acute phase and follow-up were collected. All patients underwent coronary angiography. The most frequent presenting symptoms were chest pain in 63.3% of the patients and shortness of breath/dyspnea on exertion in 27% of the patients. T-wave inversion was a more common electrocardiographic presentation (60%) than ST elevation (13.3%). The median and interquartile range of peak creatine kinase MB fraction, troponin I, and brain natriuretic peptide were creatine kinase MB fraction 8.9, 4.6 to 21.1; troponin I 1.31, 0.7 to 3.3; and brain natriuretic peptide 1,124, 453.5 to 2,369.5. The most common complication of SC was cardiogenic shock requiring inotropic agents (20%). Of the 21 patients who required ongoing cancer treatment, 16 were able to resume chemotherapy, 5 underwent surgery, and 4 received radiation treatment. Median time to resume cancer treatment was 20 days after SC. None of the patients experienced recurrence of SC and other cardiac events. In conclusion, SC should be considered in the differential diagnosis of cancer patients who present with chest pain and ECG findings characteristic of acute coronary syndrome. Most of these patients normalize ejection fraction and may resume cancer therapy early., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Afatinib is an oral irreversible ErbB family blocker that targets epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and HER4 (ErbB4) and is approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) with certain sensitizing EGFR mutations. As anti-HER2 therapies have been associated with cardiac dysfunction, we report cardiac safety data for afatinib., Methods: Cardiac data were analyzed from phase III trials of afatinib 40 mg in treatment-naive patients with EGFR mutation-positive NSCLC (LUX-Lung 3 [LL3]; n = 229 afatinib, n = 111 chemotherapy) and afatinib 50 mg in EGFR tyrosine kinase inhibitor-pretreated NSCLC patients (LUX-Lung 1 [LL1]; n = 390 afatinib, n = 195 placebo). Additional pooled data from 49 trials (n = 3865 afatinib-treated patients) is reported. Cardiac failure adverse events (CF-AEs), including symptomatic cardiac failure and depressed left ventricular ejection fraction (LVEF), were analyzed., Results: Time at risk-adjusted CF-AE rates (events/100 patient-years) were similar for afatinib versus placebo in LL1 (2.40 vs 2.23) and versus chemotherapy in LL3 (2.28 vs 2.92); the pooled afatinib CF-AE rate (2.88) was consistent with that for both trials. The frequency of clinically significant LVEF reductions was higher for chemotherapy in LL3 (2/15 [13.3 %], afatinib 13/208 [6.3 %]; p = 0.267) and similar to placebo in LL1 (5/122 [4.1 %], afatinib 14/304 [4.6 %]; p = 1.000)., Conclusion: Afatinib was not associated with cardiac failure or LVEF reductions in the afatinib clinical trial program.

Background: The present multicenter phase II trial evaluated the safety and efficacy of pegylated liposomal doxorubicin (PLD) instead of conventional doxorubicin in standard R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine [Oncovin], and prednisone) therapy for elderly patients with diffuse large B-cell lymphoma., Materials and Methods: Patients aged > 60 years who had stage II to IV disease were included. Treatment consisted of rituximab 375 mg/m(2) intravenously (I.V.); cyclophosphamide 750 mg/m(2) IV; PLD 40 mg/m(2) (maximum, 90 mg) I.V. over 1 hour; and vincristine 2.0 mg I.V., all on day 1. Additionally prednisone, 40 mg/m(2), was given orally on days 1 to 1 to 5 (DRCOP [rituximab, cyclophosphamide, PLD, vincristine, and prednisone]). The cycles were repeated every 3 weeks for 6 to 8 cycles., Results: Eighty patients were enrolled and were evaluable for toxicity. The median age was 69 years. All except 1 had additional cardiac risk factors for anthracycline-induced cardiac toxicity beyond advanced age. From the intent-to-treat analysis of 79 eligible patients, the overall response rate was 86%, and the complete response rate was 78%. Cardiac events greater than grade 3 were identified in 3 patients (4%); grade 1 to 2 events, mostly asymptomatic declines in ejection fraction, were noted in another 16 patients. One death was attributed to cardiac failure. The estimated 5-year event-free and overall survival rate was 52% and 70%, respectively., Conclusion: DRCOP represents an effective strategy for potentially mitigating cardiotoxicity in elderly patients with aggressive B-cell lymphoma. Future studies incorporating baseline cardiac risk assessments, long-term follow-up data, and biospecimen collection for correlative science should be undertaken., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cancer survivorship has been greatly impacted with the development of modern cancer treatments. While significant strides have been made in managing many types of cancer, now physicians face new challenges. Over the past decades, cardiovascular events in cancer survivors have increased in prevalence, driving the development of multidisciplinary cardio-oncology programs. Additionally, as cancer patients live longer, their risk of developing secondary cardiovascular events increases. The rapid development of novel cancer therapies will continue to generate questions of cardiac risk and cardiac protection in cancer patients over time. We wish to outline the development of cardio-oncology in its present state, and provide future perspectives for the discipline.