Cardiotoxicity Research Articles

Abstract PO1-03-05: Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer

Abstract BACKGROUND AND PURPOSE: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiotherapy and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast radiotherapy has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab (P) with adjuvant radiotherapy (RT) in locally advanced TNBC patients. METHODS: This bicentric ambispective study included the first prospectively registered patients with non-metastatic TNBC treated with the KEYNOTE-522 regimen in our institution. They received P in combination with carboplatin and paclitaxel chemotherapy and a second chemotherapy with doxorubicin and cyclophosphamide, followed by surgery and locoregional RT with or without P as adjuvant treatment. RT was normo- or hypofractionated, for the breast or chest wall, with or without lymph node irradiation according to institutional guidelines. Adjuvant P was administered at a total dose of 1800 mg at 200 mg once every 3 weeks or 400 mg once every 6 weeks. The safety profile was evaluated during and after the end of RT (until the last contact) with CTCAE V.5 scale. RESULTS: A total of 55 patients (pts) were prospectively included between July 2021 and March 2023. The median age was 49 years (29-69). The median follow-up was 12 months ( range, 10-26). Of them, 27 (49%) did not receive P concomitantly with RT (RT-only group) because of neo-adjuvant treatment related toxicities, and 28 (51%) received P concomitantly with RT (P-RT group). There was no statistical difference in population and toxicity between the RT-only group and the P-RT group. Nine patients were diagnosed with cardiac toxicities before the beginning of the RT and did not receive P during the RT. No RT-induced grade ≥4 toxicities were observed. Early toxicities were mainly grade 1-2. Two grade 3 toxicities occurred (1 case of axillary pain in the P-RT group and 1 radiodermatitis in the RT-only group). No cardiac or pulmonary toxicities ≥grade 2 were observed with adjuvant therapy. The toxicity profile is given in table 1. DISCUSSION: In these series, the main cause of discontinuation of pembrolizumab was related to suspicion of cardiac adverse events occurring during the neoadjuvant treatment and related to the injection of pembrolizumab or of the chemotherapy. All myocarditis happened before radiotherapy and did not affect the administration of radiotherapy. In this context, the optimal radiotherapy technique and cardiac dose constraints after ICI-induced myocarditis is unknown and late cardiotoxicity studies will be needed to precise these points. Cardiac sparing techniques, such as deep-inspiration breath hold, proton therapy, or alternative positioning (such as isocentric lateral decubitus) could be considered. CONCLUSION: Adjuvant radiotherapy can be combined with pembrolizumab for TNBC patients without increasing the risk of radiation-induced adverse events, allowing maintaining a systemic treatment in these high-risk patients. Longer follow-up and prospective studies are needed to validate these results. Adjuvant treatment-related adverse events Citation Format: Youlia Kirova, Thaïs Tison, Pierre Loap, Emilie ARNAUD, Kim Cao, Solène Bringer, Manon Kissel, Safia Maaradji, Juliette Mainguene, Jean-Yves Pierga, Florence Lerebours, Anne Salomon, Mariana Mirabelle, Delphine Loirat, Francois-Clement Bidard. Tolerance of adjuvant radiotherapy combined with pembrolizumab for triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-05.

Abstract PO4-04-02: Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer

Abstract Background: HLX02 (Zercepac®) is the first manufactured trastuzumab biosimilar in China. Its similar efficacy, safety, and immunogenicity compared with Herceptin was confirmed in phase III clinical trials in patients with HER2-positive advanced breast cancer. Nevertheless, the real-world evidence of HLX02 combined with pertuzumab and chemotherapy in HER2-positive advanced breast cancer in China is still warranted. Methods: In this real world observational study, patients with HER2-positive advanced breast cancer who received HLX02, pertuzuamb and chemotherapy as first line treatment at Beijing Cancer Hospital from April 2020 to April 2023 were retrospectively and prospectively included. The primary outcome was progression-free survival (PFS), and secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: A total of 55 patients (including one male) were included in this study and analyzed. The median age was 57 (range: 49, 62) years. Nearly one-third of tumors were estrogen receptor-positive (n=20, 36.4%). Thirty patients (54.5%) had newly-diagnosed stage IV disease. Visceral metastasis was reported in 40 patients (72.7%), most commonly observed in liver (n=22, 40%) and lung (n=19, 34.5%). Seven patients received prior anti-HER2 therapy during (neo-) adjuvant therapy (n=7, 12.7%). Taxane was the most commonly administrated chemotherapy regimen (n=51, 92.7%), including 56.4% albumin-bound paclitaxel, 20% liposomal paclitaxel and 18.2% docetaxel. Objective response was observed in 44 patients, leading to an ORR of 80%, and the DCR achieved 100%. HLX02 and pertuzumab was continued as maintenance therapy in 50 patients (90.9%), among which 17 combined with endocrine therapy (30.9%) and 6 combined with oral chemotherapy (10.9%). With a median follow-up of 9.8 months (range: 0.6-38.2). Progressive disease (PD) occurred in 12 of 55 patients (21.8%) and no deaths occurred. The median PFS was 24.8 months (95% confidence interval [CI]: 16.9- not estimated). The 12-month and 18-month PFS rate was 84.0% (95%CI: 72.9-96.9) and 58.8% (95%CI: 41.5 ~ 83.2), respectively. OS cannot be estimated yet due to immature data. HLX02-related diarrhea and infusion-related reaction was reported in 2 (3.6%) and 1 (1.8%) patients, respectively. LVEF values were monitored before and after drug administration, no clinical significant decline in LVEF and cardiac toxicity was observed. Conclusions: The trastuzumab biosimilar HLX02 demonstrated comparable efficacy and safety to Herceptin when combined with pertuzumab and chemotherapy for Chinese patients with HER2-positive advanced breast cancer in real world first-line treatment, which suggested that HLX02 may provide another option of Her2-targeted therapy combined with pertuzumab for Chinese patients. The benefit regarding long-term survival need to be further verified. Table 1. Effectiveness Citation Format: Ruyan Zhang, Guohong Song, Xiaoran Liu, Hui-Ping Li. Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-02.

Abstract PS15-09: Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study

Abstract Background: Imlunestrant is an oral, brain-penetrant selective estrogen receptor degrader, designed to deliver continuous ER target inhibition, including in ESR1-mutant breast cancer. In the first-in-human dose escalation/expansion (Phase 1a/1b) study of the EMBER trial (NCT04188548), imlunestrant showed favorable safety, pharmacokinetics, and clinical benefit in pre-treated patients with ER+, HER2- aBC when administered as monotherapy (Jhaveri, ASCO 2022) or with abemaciclib ± aromatase inhibitor (AI) (Jhaveri, SABCS 2022). Here, we report updated data from Phase 1a/1b of imlunestrant monotherapy as well as from Phase 1b of imlunestrant with abemaciclib ± AI in EMBER. Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior endocrine therapy (ET) sensitivity or untreated de novo aBC). Prior aBC therapy allowance was ≤3 (no restrictions on the type of prior therapies) in Phase 1a and ≤2 (only 1 prior ET) in Phase 1b for patients receiving imlunestrant monotherapy; and ≤1 (no prior CDK4/6 inhibitors) in Phase 1b for patients randomized to receive imlunestrant + abemaciclib ± AI. Key endpoints included safety and tolerability, objective response rate (ORR: complete response (CR) or partial response (PR) in patients with measurable disease), clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) per RECIST v1.1, and progression-free survival (PFS). Results: As of March 2023, 114 patients received imlunestrant monotherapy (200mg n=21; 400mg (RP2D) n= 51; ≥600mg n=42), and 85 patients received imlunestrant (400mg n=80; 800 mg n=5) in combination with abemaciclib ± AI (both at labeled doses). At the RP2D, the most common all-grade/Grade 3 treatment-emergent adverse events (TEAEs) with imlunestrant monotherapy were fatigue (39%/4%), nausea (39%/2%), and diarrhea (29%/2%). With the combination of imlunestrant + abemaciclib ± AI, the most common all-grade/Grade 3 TEAEs were diarrhea (88%/9%), nausea (61%/0%), fatigue (51%/5%), and neutropenia (44%/16%). No safety signals of ocular or cardiac toxicity (bradycardia/QTc prolongation) were observed. Baseline characteristics, safety, and preliminary efficacy are presented in Table 1. Combination therapy of imlunestrant and abemaciclib ± AI improved ORR and CBR. Conclusion: With longer follow-up, imlunestrant alone or in combination with abemaciclib ± AI continues to demonstrate a tolerable safety profile along with favorable preliminary efficacy in patients with ER+, HER2- aBC. Further data will be presented at the meeting. The Phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant plus abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table. Baseline characteristics, safety and preliminary efficacy a, in patients with available ctDNA data. Citation Format: Komal Jhaveri, Elgene Lim, Rinath Jeselsohn, Cynthia Ma, Erika Hamilton, Cynthia Osborne, Manali Bhave, Peter Kaufman, J. Thaddeus Beck, Luis Manso, Ritesh Parajuli, Hwei-Chung Wang, Jessica Tao, Ajay Dhakal, Jean-Yves Pierga, Yen-Shen Lu, Tim Larson, Yolanda Jerez Gilarranz, Roohi Ismail-Khan, Francesca Bacchion, Claudia Karacsonyi, Yujia Li, Shawn T. Estrem, Bastien Nguyen, Muralidhar Beeram. Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-09.

Abstract GS03-12: Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis

Abstract Background: Patients with HER2-positive early breast cancer (EBC) who have residual invasive disease after neoadjuvant chemotherapy + HER2-targeted therapy have a high risk of recurrence and death. The standard of care when KATHERINE was designed was continuation of the same HER2-targeted therapy in the adjuvant setting for 1 year. The primary analysis of KATHERINE in 2018 showed that the risk of recurrence of invasive BC or death was 50% lower with adjuvant ado-trastuzumab emtansine (T-DM1) than with trastuzumab. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed, HER2-positive (immunohistochemistry 3+ or in situ hybridization-positive) primary BC (T1–4, N0–3, M0) who received neoadjuvant chemotherapy + HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg intravenously [IV] every 3 weeks [q3w]) or trastuzumab (6 mg/kg IV q3w) for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single vs dual neoadjuvant HER2-targeted therapy, and pathologic nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS). We report the final IDFS analysis, which was to occur after ~384 events had been reported, and the preplanned second interim analysis of overall survival (OS); specified to occur at the same time. Results: With a median follow-up of 8.4 years (101 months), T-DM1 sustained the improvement in IDFS over trastuzumab (unstratified hazard ratio [HR] 0.54; 95% confidence interval [CI] = 0.44, 0.66; p < 0.0001). Landmark 7-year IDFS rates were increased from 67.1% with trastuzumab to 80.8% with T-DM1; a difference of 13.7%. At clinical cutoff for the final IDFS analysis, 215 deaths had been reported. T-DM1 significantly reduced the risk of death by 34% compared with trastuzumab (unstratified HR 0.66; 95% CI = 0.51, 0.87; p = 0.0027). Deaths had occurred in 89/743 patients (12.0%) in the T-DM1 arm and 126/743 (17.0%) in the trastuzumab arm. Landmark 7-year OS rates were increased from 84.4% with trastuzumab to 89.1% with T-DM1; a difference of 4.7%. OS and IDFS benefits were seen across key subgroups. A low incidence of adverse events (AEs) related to study treatment or to study procedures was observed during the post-treatment period: Grade ≥3 related AEs occurred in 3/740 patients (0.4%) in the T-DM1 arm and 3/720 (0.4%) in the trastuzumab arm; serious related AEs, in 2/740 (0.3%) and 4/720 (0.6%), respectively. Related AEs classed as “cardiac disorders” were rare in both arms with extended follow-up. Conclusions: After 8.4 years (101 months) median follow-up, T-DM1 significantly improved OS in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. The IDFS benefit of T-DM1 was sustained in the intention-to-treat population with longer follow-up, and no new safety issues emerged. Cardiac toxicity was rare in both arms. T-DM1 is the first therapy to show improved survival post-surgery in patients with HER2-positive EBC with residual invasive disease after neoadjuvant therapy. Follow-up is ongoing for the final OS analysis. Citation Format: Sibylle Loibl, Max Mano, Michael Untch, Chiun-Shen Huang, Eleftherios Mamounas, Norman Wolmark, Adam Knott, Asna Siddiqui, Thomas Boulet, Beatrice Nyawira, Eleonora Restuccia, Charles Geyer. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-12.

Abstract PO5-12-03: Cardiovascular Toxicities in Breast Cancer Survivors

Abstract Background: Chemotherapy, despite its effectiveness, presents drawbacks in breast cancer patients due to its side effects. Fatigue, hair loss, nausea, and anemia are among the many symptoms associated with chemotherapy. Moreover, chemotherapy can lead to cardiovascular diseases, including cardiac arrhythmias, hypertension, heart failure, heart attacks, and cardiomyopathy, particularly with the use of anthracyclines and HER-2-targeted agents. Risk factors such as weight, age, race, comorbidities (e.g., obesity, diabetes, hyperlipidemia), and radiation exposure further increase these risks. Despite these potential complications, guidelines are just emerging aiming to prevent these cardiovascular complications in breast cancer patients. Untreated cardiovascular abnormalities can have long-term effects on breast cancer survivors. Our aim is to analyze the relationships between breast cancer treatment and cardiovascular abnormalities, examining associations with various factors, including race, BMI, and age in a majority Hispanic cohort of breast cancer survivors. Methods: retrospective, single institution study data from a total of 53 patients treated with chemotherapy with either anthracyclines and/or HER 2 directed therapy with curative intent between 2018-2020. Our analysis included basic demographic information, menopausal status, breast cancer type, treatment types, use of cardio-protective medications, and cardiovascular effects (both pre-existing and developed during treatment). Results: Our sample of 50 women primarily comprised Hispanic individuals (73%), most of whom were postmenopausal (86%), with an average age of 63 years (range 35-86). Among the breast cancer types identified, 35 were hormone-positive, 8 were HER-2 positive, and 10 were triple negative. 72% of the patients received adjuvant hormonal therapy. 18% of the population received anthracycline-based treatment, 8% received Her 2 directed therapy and 2 % received Immune check point inhibitors. Radiation therapy was administered to 50% of the patients. The most prevalent cardiovascular disease observed was hypertension, affecting 62% of patients, followed by type 2 diabetes (38%), hyperlipidemia (34%), stroke (8%), and heart attack (6%). The predominant cardioprotective medications used were ACE inhibitors/ARBs (48%), followed by statins (46%), beta-blockers (20%), aspirin (16%), and GLP-1 agonists (14%). Conclusion: Our analysis revealed a high prevalence of cardiovascular conditions among breast cancer survivors treated with chemotherapy in a majority Hispanic cohort of patients. This population has been linked to higher risk of developing comorbidities such as diabetes, obesity and hypertension. Further analysis evaluating risk factors and implementation of treatment strategies to minimize adverse effects is needed in this population. Citation Format: Victoria Ayodele, Emily Sherry, Marcela Mazo-Canola. Cardiovascular Toxicities in Breast Cancer Survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-03.

Abstract PO5-18-09: Anthracycline-free neoadjuvant therapy with nab-paclitaxel and carboplatin in non-luminal breast cancer: a single-arm phase II trial

Abstract Background Anthracycline and taxane-based chemotherapy are the corner stone of neoadjuvant therapy in early breast cancer. Anthracycline-free regimens have been addressed widely because of cardiac toxicity especially in HER2-positive breast cancer when combining trastuzumab and pertuzumab. Aim of this trial was to assess the efficacy and safety of nab-paclitaxel combined with carboplatin in the neoadjuvant therapy of non-luminal breast cancer. Methods The Neopath trial was a prospective, single-arm phase II trial conducted in Comprehensive Breast Health Center, Ruijin Hospital between April 2019 and October 2021. Patients who had cT2-4NanyM0 or cTanyN1-3M0 triple negative breast cancer (TNBC) or HER2-positive breast cancer were enrolled. Patients were treated with neoadjuvant nab-paclitaxel (100 mg/m2) and carboplatin (area under the curve 2) on days 1, 8, and 15, for four 4-week cycles. Concurrent trastuzumab at 2 mg/kg (loading dose 4 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) were given in patients with HER2-positive tumors. Surgery was performed after 4-6 cycles of neoadjuvant therapy. Trastuzumab and pertuzumab after surgery was continued every 3 weeks for a total duration of 1 year. The primary endpoint was pathological complete response (pCR) rate, defined as no invasive tumor in breast and axillary lymph nodes (ypT0/Tis N0) after neoadjuvant therapy. Secondary endpoints were pCR rate in predefined subgroups, pCR (ypT0 N0), objective response rate (ORR); event-free survival (EFS), breast conservation rate and toxicity. Results A total of 106 patients were enrolled in the study and 99 of them proceeded to surgery. The pCR (ypT0/is N0) rate was 41.41% in total, 33.78% in TNBC and 64.00% in HER2-positive breast cancer. Proportion of patients achieving pCR (ypT0 N0) was 38.38% in total, 31.08% in TNBC and 60.00% in HER2-positive tumors. In the ITT population, 93 patients were event-free at a median follow-up of 24 months, while 5 in TNBC group and 1 in HER2-positive group had relapse or distant metastasis. EFS in patients achieving pCR was higher than patients without pCR (HR=7.328, 95%CI=1.453-36.96, p=0.0158). ORR was 72.49% in total, 67.12% in TNBC and 88.00% in HER2-positive breast cancer. Total breast conservation rate was 10.1% and 12.2% in TNBC, 4.0% in HER2-positive subgroup. The most frequent grade 3 or higher adverse events were neutropenia (57%), vomiting (11%) and thrombocytopenia (8%). Conclusion Neoadjuvant anthracycline-free regimen of nab-paclitaxel combined with carboplatin in non-luminal breast cancer was an effective and well-tolerated regimen. Citation Format: Deyue Liu, Li Zhu, Jiayi Wu, Wei Wang, Shuning Ding. Anthracycline-free neoadjuvant therapy with nab-paclitaxel and carboplatin in non-luminal breast cancer: a single-arm phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-09.

Abstract PO2-04-12: From Clinical Trials to Clinical Practice; Real World Clinical Outcomes of Patients Treated with Ribociclib in Combination with Aromatase Inhibitors or Fulvestrant for HR-Positive, HER2- Negative Metastatic Breast Cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer (MBC), with an impressive efficacy and safety profile. Here we report real-world clinical outcomes and toxicity data in patients treated at a tertiary care cancer center. Methods: The study is a retrospective analysis of individual patients’ data. All consecutive patients with HR+ and HER2-negative MBC, treated at our institution with ribociclib plus aromatase inhibitors (AI) or fulvestrant, between June 2017 and May 2020 were reviewed. Data were collected from patients’ electronic medical records. Progression free survival (PFS) was defined as the time from treatment initiation with CDK4/6i until the first documented progression, death from any cause or last follow-up, whichever occurred first. The Overall survival (OS) was defined as the time from treatment initiation with CDK4/6i until the date of death from any cause, or last follow-up. Results: A total of 305 patients, median age 49 (22-87) years were enrolled. Although bone metastasis was reported in 241 (79.0%) patients, bone-only metastasis was identified in 64 (20.9%). Visceral metastasis in the liver and lungs were reported in 22.0% and 25.9 % of patients, respectively. CDK4/6i combined with AI were used in first-line setting in 195 (63.9%) patients and with fulvestrant as a second line (20.7%) or beyond (15.4%). Dose reduction was required in 44 (14.14%) patients, mostly because of neutropenia (n=38, 12.5%) and abnormal liver enzymes (n=12, 3.9%), while 11 (3.6%) discontinued treatment, mostly due cardiac toxicities. Nevertheless, there were no deaths due to toxicity. Patients were followed up for a median of 31.1 months. Overall response rate (ORR) was 51.4% and median PFS, irrespective of the line of therapy, was 19.3 (17.6-23.3) months. PFS was longer in first-line setting; 23.1 (19.7-NR) months compared to 13.9 (10.2-17.6) months in second-line or beyond, p< 0 .0001, and when combined with AI compared to fulvestrant; 28.6 (17.8-23.1) months versus 9.1 (4.4-NR) months, p=0.0001, and in those with bone-only metastasis; 23.1 (19.5-NR) months versus 17.3 (12.2-18.9) months for patients with visceral metastasis, p=0.0008. The median OS was not reached. Conclusions: Despite enrolling sicker patients, and outside the stringent clinical trials settings, our treatment outcomes, in real world settings, are comparable to those reported in major clinical trials, including MONALEESA-2, MONALEESA-3 and MONALEESA-7. Citation Format: Baha' Sharaf, Faris Tamimi, Sarah Edaily, Osama Salama, Hazem Abdulelah, Anas Zayed, Mahmoud Abunasser, Hala Abu-Fares, Hikmat Abdel-Razeq. From Clinical Trials to Clinical Practice; Real World Clinical Outcomes of Patients Treated with Ribociclib in Combination with Aromatase Inhibitors or Fulvestrant for HR-Positive, HER2- Negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-12.

Abstract PO1-17-03: Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan

Abstract Purpose Biosimilars have emerged as a promising alternative to reference biologic products for the treatment of cancers and immunological diseases. With regard to breast cancer, trastuzumab, a reference monoclonal antibody biologic, has been the standard of care for early and advanced HER2-positive breast cancer since 1998. Trastuzumab biosimilars, which provide comparable efficacy at a lower cost, have the potential to reduce financial burden on patients and healthcare systems and improve patient access to HER2-targeted therapy. This study aimed to evaluate the utilization, efficacy, and safety of trastuzumab biosimilars in HER2-positive breast cancer patients at Kaohsiung Veterans General Hospital. Methods A total of 113 HER2-positive breast cancer patients were enrolled between February 2020 and December 2022 and treated with trastuzumab biosimilars (OGIVRI®, trastuzumab-dkst). Of these, 44 were in the neoadjuvant group, 27 in the adjuvant group, and 42 in the metastatic group. Clinical outcomes were evaluated, including pathological complete response (pCR) rate in the neoadjuvant group, objective response rate (ORR) and clinical benefit rate (CBR) in the metastatic group, and safety profile in all groups. Results In the neoadjuvant group, 18 out of 44 evaluable patients achieved pathological complete response after surgery, resulting in a pCR rate of 40.90%. In the metastatic group , the ORR was 57.14% and the CBR was 90.47%. Furthermore, in the metastatic group, treatment with dual blockade using biosimilars resulted in an better ORR of 62.96%. No adverse events of cardiac toxicity were reported in any group. In the adjuvant group, longer follow-up is needed to assess efficacy. Conclusions Our real-world experience suggests that trastuzumab biosimilars are a safe and cost-effective alternative to reference trastuzumab in the treatment of HER2-positive breast cancer. Biosimilar trastuzumab demonstrated efficacy in the neoadjuvant setting, while dual blockade with biosimilars resulted in better disease control in the metastatic setting. Further follow-up is necessary to evaluate the efficacy of trastuzumab biosimilars in the adjuvant setting. Citation Format: Yi-Hung Lo, Yen-Dun Tzeng. Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-03.

Antioxidant, anti-inflammatory, and anti-DNA damage effects of carnosic acid against aflatoxin B1-induced hepatic, renal, and cardiac toxicities in rats

Abstract Background Aflatoxin B1 (AFB1) food contamination is a global health hazard that has detrimental effects on both human and animal health. The objective of the current study is to assess the protective impact of carnosic acid against AFB1-induced toxicities in the liver, kidneys, and heart. Methods Forty male Wistar Albino rats (weighting 180 ~ 200 g) were allocated into 5 groups (8 rats each); the 1st group received saline as served as a control, the 2nd group received carnosic acid (CA100) at a dose of 100 mg/kg bw/day by gavage for 14 days, the 3rd group received AFB1 at a dose of 2.5 mg/kg bw, orally twice on days 12 and 14, the 4th group (AFB1-CA50) received AFB1 as in the 3rd group and CA at a dose of 50 mg/kg bw/day, and the 5th group (AFB1-CA100) received AFB1 as in the 3rd group and CA as in the 2nd group. Results CA significantly decreased the liver enzymes (ALT, AST. ALP), renal function products (LDH, BUN, creatinine), and cardiac enzymes (CK and CK-MB) to control levels after the high increment by AFB1 exposure. Moreover, CA significantly decreased the oxidative stress (MDA, NO, 8-OHdG) and increased the antioxidant enzyme activities (CAT, GSH, GSH-Px, and SOD) after severe disruption of oxidant/antioxidant balance by AFB1 exposure. Interestingly, CA significantly decreased the proinflammatory mediators (IL-6, IL-1β, and TNF-α) to the control levels after severe inflammation induced by AFB1 exposure. Conclusions Conclusively, CA had antioxidant, anti-inflammatory, and anti-DNA damage effects against hepatic, renal, and cardiac AFB1-induced toxicities.

ПОТЕНЦИАЛ ИСПОЛЬЗОВАНИЯ ДИНАМИКИ ЭЛЕКТРОКАРДИОГРАФИЧЕСКИХ ПОКАЗАТЕЛЕЙ ПРИ ВЫЯВЛЕНИИ КАРДИОТОКСИЧНОСТИ ЧЕРЕЗ 12 МЕСЯЦЕВ ПОСЛЕ ОКОНЧАНИЯ ХИМИОТЕРАПИИ РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ ДОКСОРУБИЦИНОМ

Background. Changes in electrocardiographic parameters of the heart, reflecting the processes of depolarization and repolarization of the myocardium, can be signs of early cardiotoxicity (CT). Aim. To study changes in electrocardiographic parameters of the myocardium in patients with verified breast cancer 12 months after the end of chemotherapy with doxorubicin. Material and methods. The study included 100 patients with a confirmed diagnosis of breast cancer who were treated at the health care institution “Grodno University Clinic” (Grodno, Belarus). A number of electrocardiographic parameters of the myocardium were measured in patients before and 12 months after the end of chemotherapy using electrocardiography and 24-hour Holter monitoring. Results. A statistically significant increase in electrocardiographic parameters of depolarization and repolarization was revealed (P, P-Q, Tpeak-Tend, Q-Tc / QRS, Q-Tc - p<0.007; p<0.001; p=0.042; p=0.009; p<0.001, respectively) before and 12 months after the end of chemotherapy. A change in the time and total number of episodes of sinus tachycardia and supraventricular extrasystoles was also noted (p=0.029, p=0.026 and p=0.002). The Tpeak-Tend indicator changed statistically significantly in the CT+ subgroup (p=0.032) after 12 months. The dynamics of the Q-Tc indicator before and 12 months after the end of chemotherapy was observed in almost all patients. However, in the CT+ subgroup, an increase in Q-Tc was recorded statistically significantly more often compared to the CT- subgroup (p <0.005). Conclusion. During chemotherapy with doxorubicin, an increase in Tpeak-Tend and Q-Tc was observed. An especially significant increase in these indicators was noted in the CT+ subgroup. The number and duration of sinus tachycardia episodes as well as the number of supraventricular extrasystoles also increased. This may correlate with the relationship between chemotherapy with doxorubicin and the dynamics of electrocardiographic parameters.

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study.

Over the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune-related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate. We conducted a multicenter retrospective study to characterize ICI-associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer-Lemeshow test. Forty-four patients were identified, including thirty-five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin-I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme-MB (CK-MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty-one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N-terminal pro-B-type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK-MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non-severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK-MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055-2.984, p = 0.031) was the independent risk factor of the development of ICI-associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002-1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026-3.483, p = 0.041) were the independent risk factors of ICI-associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK-MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016). Elevated CK-MB after ICI treatment is the independent risk factor for the incidence of ICI-associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI-associated severe myocarditis. CK-MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI-associated myocarditis and severe myocarditis.

(-)-Epicatechin gallate ameliorates cyprodinil-induced cardiac developmental defects through inhibiting aryl hydrocarbon receptor in zebrafish.

Cyprodinil is a widely used fungicide with broad-spectrum activity, but it has been associated with cardiac abnormalities. (-)-Epicatechin gallate (ECG), a natural polyphenolic compound, has been shown to possess protective properties in cardiac development. In this study, we investigated whether ECG could mitigate cyprodinil-induced heart defects using zebrafish embryos as a model. Zebrafish embryos were exposed to cyprodinil with or without ECG. Our results demonstrated that ECG significantly improved the survival rate, embryo movement, and hatching delay induced by cyprodinil. Furthermore, ECG effectively ameliorated cyprodinil-induced cardiac developmental toxicity, including pericardial anomaly and impairment of cardiac function. Mechanistically, ECG attenuated the cyprodinil-induced alterations in mRNA expression related to cardiac development, such as amhc, vmhc, tbx5, and gata4, as well as calcium ion channels, such as ncx1h, atp2a2a, and cdh2. Additionally, ECG was found to inhibit the activity of the aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In conclusion, our findings provide evidence for the protective effects of ECG against cyprodinil-induced cardiac developmental toxicity, mediated through the inhibition of AhR activity. These findings contribute to a better understanding of the regulatory mechanisms and safe utilization of pesticide, such as cyprodinil.

Targeting Cardiomyocytes with Adeno Associated Viruses to Protect Hearts from Trastuzumab-induced Cardiotoxicity

Amplification of HER2 occurs in 20% of breast cancers. HER2 (known as ErbB2 in mouse) belongs to the Epidermal Growth Factor Receptor (EGFR) family that is responsible for cell growth and survival. While HER2 does not bind ligands, it forms heterodimers with HER1 (also known as EGFR) in the presence of its ligand EGF, and HER4 following stimulation with Neuregulin. In HER2-positive breast cancer where HER2 expression is high, HER2 homodimerizes leading to excessive activation of downstream signalling and cell proliferation. Current HER2-positive breast cancer treatment involves chemotherapy with drugs called anthracyclines, such as Doxorubicin, and an antibody targeting HER2 called Trastuzumab. This combination is effective in killing HER2-positive breast tumours, however, Trastuzumab alone or in combination with anthracyclines leads to severe cardiotoxicity and heart failure in 2.6-11% of cases, making it a dose-limiting side effect. We hypothesise that cardiac toxicity can be mitigated by targeting cardiomyocytes exclusively to express a mutated (but functional) version of HER2 that is not recognised by trastuzumab. We designed 3 HER2 variants wherein the trastuzumab binding domain was mutated to disrupt binding. These HER2 mutants were transfected into HEK293T cells, and we confirmed that all 3 successfully localised to the cell membrane, and did not bind trastuzumab. We have used bioluminescence resonance energy transfer to examine the capacity of all 3 mutants to activate recruitment of Grb2 to the HER2 as part of HER1/HER2 and HER4/HER2 heterodimers; Western blotting also confirming mutants were capable of stimulating ERK and Akt phosphorylation. Future studies will evaluate the effcacy of using AAVs to instruct cardiomyocytes to express these HER2 mutants in a murine model of breast cancer. We predict that this new therapy would not only mitigate cardiac toxicity, but would also permit higher doses of trastuzumab to be used to treat breast cancer. This work is supported by Australia's National Health and Medical Research Council and the Australian Research Council. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exercise may be a Novel Strategy to Reduce Vascular Toxicity of Immune Checkpoint Inhibitors in a Mouse Melanoma Model

Background: Immune checkpoint inhibitors (ICIs) are a cornerstone in advanced melanoma treatment. Unfortunately, ICI-associated cardiovascular toxicity, particularly atherosclerotic events, poses a significant challenge. Identifying interventions to mitigate the cardiovascular toxicity of ICI is critical for enhancing the quality and duration of life in cancer survivors. Given the established benefits of exercise in atherosclerosis prevention, this study explores its potential to reduce ICI-induced vascular toxicity in the context of melanoma. We hypothesized that aerobic exercise would decrease ICI's vascular toxicity in a mouse melanoma model. The primary experimental outcome was endothelial mesenchymal transition (EndMT), an early atherosclerosis indicator. Methods: C57BL/6 mice were subcutaneously injected with 0.8 x 106 BP melanoma cells ( BrafV600E/WT and Pten−/−). Upon tumor palpability, mice were assigned into four groups: IgG, Exercise, anti-PD-1, and anti-PD-1+Exercise. Mice were treated with bi-weekly administration of anti-PD-1 or IgG antibody (150 μg) for three weeks, combined with or without treadmill exercise (12 meters/minute for 45 min per day, five days/week). Body weight was monitored weekly. Following the final treatment, aortic tissues were collected and en face immunofluorescence staining for endothelial marker VE-cadherin (VE-Cad) and vimentin was performed to assess EndMT, then analyzed via confocal microscopy. Results: No significant weight differences were observed between groups. Notably, the EndMT marker vimentin expression was significantly higher in anti-PD-1 treated tumor-bearing mice compared to IgG controls (3.8% vs 0.6%, p=.03) in the atheroprotective laminar flow area. This was reduced by exercise; the anti-PD-1+Exercise group showed significantly reduced endothelial vimentin levels relative to the anti-PD-1 alone (0.8% vs 3.8%, p=.04). Disturbed flow areas did not exhibit notable differences between any group. Conclusions: Aerobic exercise may be protective against vascular toxicity in mice treated with ICIs by promoting atheroprotective flow and potentially inhibiting EndMT. Although these initial results are promising, comprehensive studies are required to ascertain the impact of exercise on preventing ICI-induced EndMT and subsequent atherosclerosis in this mouse melanoma model. Future research will aim to more deeply characterize the process of EndMT following ICI treatment and evaluate the preventive capacity of exercise against atherosclerosis in this context. MD Anderson Cancer Center Melanoma SPORE grant (NCI P50CA221703-05). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MitoQ Treatment Mitigates Senescence Burden in DOXO-Induced Senescent Endothelial Cells Through Reductions in mtROS and DNA Damage

Cardiovascular toxicity is one of the adverse consequences of chemotherapy that limits treatment. Specifically, chemotherapeutics such as doxorubicin (DOXO) can lead to endothelial dysfunction through the induction of reactive oxygen species (ROS) and mitochondrial ROS (mtROS) production. MtROS are chemically reactive molecules generated as byproducts of oxidative phosphorylation during mitochondrial respiration. DOXO exacerbates its cardiotoxic effects by amplifying mtROS production, leading to an increase in DNA damage and cell senescence, particularly in endothelial cells (ECs). MitoQ is a mitochondria-targeted antioxidant designed to accumulate within the mitochondria and mitigate oxidative damage by neutralizing mtROS. However, whether MitoQ can rescue mtROS-induced DNA damage and senescence remains elusive. Here, we tested the hypothesis that MitoQ will attenuate DOXO-induced mtROS thus blunting DNA damage and subsequent EC senescence. Human umbilical vein endothelial cells (HUVECs) were simultaneously subjected to 24-hour treatments with DOXO (250nM) and MitoQ (250nM). To evaluate the antioxidative effect of the MitoQ, we examined mitochondrial superoxide using MitoSOX. The results demonstrated that DOXO increases mitochondrial superoxide by 40% (Fig1, p=0.019), whereas addition of MitoQ (MitoQ+DOXO) attenuated mitochondrial superoxide significantly compared to the DOXO group (Fig1, p=0.033). Gene expression of senescence markers, p16 and p21, and Senescence Associated Secretory Phenotypes (SASPs) factors were also examined to assess the effect of MitoQ on senescent endothelial cells. p16 was significantly reduced in the MitoQ+DOXO treatment group compared to the DOXO alone (Fig2, p=0.0090). MitoQ+DOXO lowered p21 expression by 35%, although this difference did not reach significance (Fig2, p=0.340). Moreover, MitoQ+DOXO reduced the SASP factors, IL-8, IL-6 and MCP-1, by more than 54% in comparison to the DOXO group (Fig2, all p≤0.027). Senescent endothelial cells were examined for 53BP1, a double-stranded DNA break marker, using an immunofluorescence (IF) assay. MitoQ+DOXO reduced 53BP1 by 32.6% compared to the DOXO-treated group (Fig3, p=0.011). We also assessed cell proliferation using Bromodeoxyuridine (BrdU) assay. In line with other results, the BrdU assay indicates that the proliferative capability of MitoQ+DOXO-treated cells was improved by more than 20% compared to DOXO-induced senescent cells (Fig4, p=0.008). Our findings suggest that MitoQ can mitigate DOXO-induced mtROS, attenuate DNA damage, and ameliorate senescence in endothelial cells. This provides mechanistic insight suggesting that mtROS may be a driver of cellular senescence in ECs via an increase in DNA damage and MitoQ may be an effcacious therapeutic to treat chemotherapy-induced cardiovascular toxicity. Funded in part by awards from National Institutes of Health Awards R01 AG060395, R01 AG048366, T32 HL139451, F31 AG076312, R01 AG077751, R01 AG076748, Nora Eccles Treadwell foundation (NETF), and Veteran's Affairs Merit Review Award I01 BX004492. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Characteristics and outcomes of gemcitabine-associated pulmonary hypertension.

Despite its known cardiac and lung toxicities, the chemotherapy drug gemcitabine has only rarely been associated with pulmonary hypertension (PH), and the underlying mechanism remains unclear. The objective of the present study was to assess the association between gemcitabine and PH. We identified incident cases of precapillary PH confirmed by right heart catheterisation in patients treated with gemcitabine from the French PH Registry between January 2007 and December 2022. The aetiology, clinical, functional, radiological and haemodynamic characteristics of PH were reviewed at baseline and during follow-up. A pharmacovigilance disproportionality analysis was conducted using the World Health Organization (WHO) pharmacovigilance database. We identified nine cases of pulmonary arterial hypertension, either induced (in eight patients) or exacerbated (in one patient) by gemcitabine. Patients exhibited severe precapillary PH, with a median mean pulmonary arterial pressure of 40 (range 26-47) mmHg, a cardiac index of 2.4 (1.6-3.9) L·min-1·m-2 and a pulmonary vascular resistance of 6.3 (3.1-12.6) Wood units. The median time from the initiation of gemcitabine to the onset of PH was 7 (4-50) months, with patients receiving a median of 16 (6-24) gemcitabine injections. Six patients showed clinical improvement upon discontinuation of gemcitabine. In the WHO pharmacovigilance database, we identified a significant signal with 109 cases reporting at least one adverse event related to PH with gemcitabine. Both clinical cases and pharmacovigilance data substantiate a significant association between gemcitabine use and the onset or worsening of precapillary PH. The observed improvement following the discontinuation of treatment underscores the importance of PH screening in gemcitabine-exposed patients experiencing unexplained dyspnoea.

Bed Bug Infestation: An Updated Review.

In the past decade, there has been a global resurgence of bed bug infestations, especially in developed countries. Proper awareness and identification of bed bug infestations are essential to guide treatment and eradication. The purpose of this article is to familiarize physicians with bed bug bites so that they can effectively diagnose, treat, and address questions about bed bug bites and infestations. Bed bug bites are often painless. Typical reactions include pruritic, erythematous maculopapules occurring in clusters or in a linear or curvilinear distribution in exposed areas of the body. A small red punctum may be visualized at the center of the bite mark. Lesions that appear three in a row and papules on the upper eyelid associated with erythema and edema are highly suggestive of bites from bed bugs. Exaggerated local reactions such as vesicles, urticarial wheals, urticarial perilesional plaques, diffuse urticaria, bullae, and nodules may occur in previously sensitized individuals. Reactions to bed bug bites are self-limited. As such, treatment is mainly symptomatic. Topical pramoxine and oral antihistamines can be used to alleviate pruritus. Topical corticosteroids can be used for significant eruptions to control inflammation and pruritus, and to hasten resolution of the lesions. Integrated pest management, an approach for the eradication of bed bugs, includes monitoring devices (active monitors include the use of heat or carbon dioxide attractants and passive monitors include the use of sticky pads for trapping), and judicious use of nonchemical and chemical treatments known to be effective. Nonchemical interventions include keeping affected areas clean and free of clutter, vacuuming, washing linens with hot water, caulking wall holes and cracks where bugs can hide, proper disposal of highly infested items, and placement of bed bug traps/interceptors at the base of beds and furniture. Chemical interventions involve the use of insecticides such as synthetic pyrethroids, silicates, insect growth disruptors, carbamates, organophosphates, neonicotinoids, diethyl-meta-toluamide, chlorfenapyr, fipronil and plant essential oils. Insecticides should be used with caution to prevent over-exposure and toxicity (in particular, cardiovascular and neurologic toxicity), especially if there are young children around. It is important to note that multiple mechanisms of insecticide resistance exist and as such, chemical treatment should only be undertaken by trained professionals who understand the current literature on resistance. Both nonchemical and chemical technologies should be combined for optimal results. Bed bug infestations may cause diverse dermal reactions, stigmatization, poor self-esteem, emotional stress, anxiety, significant adverse effect on quality of life, and substantial socioeconomic burden to society. As such, their rapid detection and eradication are of paramount importance. Consultation with a professional exterminator is recommended to fully eradicate an infestation.

IF1 Knockout Protects Against Doxorubicin-Induced Cardiac Dysfunction by Improving Cardiomyocyte Energetics

Doxorubicin (DOX), a member of the Anthracycline antibiotics class, has been used as a potent chemotherapy agent against solid tumors. However, its use is limited by its cardiotoxicity. It is well-documented that mitochondrial dysfunction is one of the main mechanisms of DOX-induced cardiotoxicity. ATP synthase inhibitory subunit 1 (ATPIF1, or IF1) is an endogenous inhibitor of mitochondrial ATP synthase. Recent studies indicate that IF1 may suppress mitochondrial respiration via inhibiting ATP synthase. Others and our previous studies demonstrated that IF1 inactivation exerts hepatic and cardiac protective effects. We hypothesize that the absence of IF1 protects the heart from DOX-induced cardiotoxicity by improving mitochondrial energy metabolism. We first investigate the impact of IF1 KO on mitochondrial respiration using the high-resolution respirometer (OROBOROS) on freshly isolated cardiac mitochondria from IF1 KO and WT mice. IF1 KO mitochondria did show substantially increased state 2, state 3, and state 4 respiration rates compared with those of WT. We then investigated if WT and IF1 KO mice respond differently to DOX treatment. WT and IF1 KO mice at the ages of 12-16 weeks either received DOX 3mg/kg/every other day or vehicle intraperitoneally for two weeks. In vivo, cardiac function was evaluated using the VEVO F2 Echocardiographic system (Visual Sonic) 4 and 6 weeks after initiation of DOX and vehicle administration. Compared with the vehicle-treated WT mice, left ventricular ejection fraction (LVEF) was substantially decreased in DOX-treated WT mice compared with vehicle-treated WT mice. In contrast, LVEF in DOX-IF1 KO mice was substantially less reduced compared with vehicle-treated IF1 KO mice. We next investigated if improving cellular energetics is the critical mechanism underlying the protective effects of IF1 KO. Mouse neonatal cardiomyocyte (NMCM) isolated from WT and IF1 KO mice were cultured and treated with 0.5 and 1mM Dox for 24 hours. Cellular energetics were measured with the Mito stress assay using the Seahorse Bioanalyzer (96Xpro, Agilent). Basal, maximal, and ATP production-linked oxygen consumption rates were markedly decreased in DOX-treated-NMCM but not in DOX-treated IF1 KO NMCM compared with Vehicle-treated NMCM. In summary, the above in vivo and in vitro investigations support that IF1 inactivation is protective against DOX cardiac toxicity, at least partly, via improving cellular energetics; therefore, inactivating IF1 may be a potential therapeutic target to prevent and mitigate DOX-induced cardiomyopathy in patients. This research was supported by project number 5R01HL160969 from the National Heart Lung and Blood Institute at the NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessment of Chemotherapy-Induced Cardiac Dysfunction in Breast Cancer Patients: A Prospective Study.

Background Advances in cancer treatment have markedly improved survival rates but have also heightened morbidity due to treatment-related side effects. Despite this, the literature remains scarce on predicting the incidence of acute cardiac toxicity resulting from chemotherapy. We conducted a prospective evaluation to assess the incidence, timing, clinical correlates, global longitudinal strain (GLS), and response to heart failure (HF) therapy in patients experiencing cardiotoxicity. Aims and objectives Our study aimed to assess the cardiovascular complications of cancer therapy in breast cancer patients, with particular emphasis on therapy-related cardiac dysfunction. Materials and methods We conducted a prospective observational study to detect chemotherapy-related cardiac dysfunction (CTRCD) in breast cancer patients attending the outpatient department (OPD) or admitted to Dayanand Medical College and Hospital (DMCH), Ludhiana, Punjab, between March 1, 2020, and October 31, 2021. We assessed left ventricular ejection fraction (LVEF) at baseline, mid-chemotherapy, and post-chemotherapy. Patients who developed left ventricular dysfunction (LVD) had their chemotherapy regimen modified and were initiated on HF therapy. Results Ninety-seven patients (mean age: 50.74±10.30 years) were enrolled and categorized into the LVD group (n=13) and non-LVD group (n=84). CTRCD developed in 13 patients (13.4%). Patients with estrogen receptor (ER) positive, progesterone receptor (PR) positive, and human epidermal growth factor receptor 2 (HER2) positive status, as well as those in cancer stages III and IV, are at higher risk of developing LV dysfunction. Among the 13 patients, 10 (77%) experienced complete recovery, while three (23%) had partial recovery. Markers for partial recovery included cancer stages III-IV, younger age, lower body mass index (BMI), lower radiotherapy dosage, lower mean chemotherapy dosage, and left breast involvement. Conclusion Our findings suggest that acute cardiotoxicity is not linked to the cumulative dose of anthracyclines. Early detection, modification of chemotherapy regimens, and prompt initiation of CTRCD therapy can lead to substantial recovery of cardiac dysfunction.

BLOOD PRESSURE VARIABILITY AS PREDICTOR OF CANCER THERAPY-RELATED CARDIOVASCULAR TOXICITY IN PATIENTS WITH MULTIPLE MYELOMA

Objective: Blood pressure variability (BPV) is an independent predictor of cardiovascular (CV) events and overall mortality. The potential role of BPV in defining CV risk of patients undergoing anticancer therapy with a potential cancer therapy-related cardiovascular toxicity (CTR-CVT) is currently unknown. The aims of this study were: (i) to assess the predictive value of BPV indexes for CTR-CVT development and defining the corresponding cut-off values; (ii) to identify subgroups of subjects based on BPV, through clustering analysis. Design and method: Patients with Multiple Myeloma, who were eligible to anticancer therapy with Carfilzomib, were consecutively enrolled and underwent a baseline evaluation, including office blood pressure (BP) measurement, 24h-Ambulatory Blood pressure Monitoring (ABPM), PWV, and Echocardiography. Short-term BPV was assessed through standard deviation (SD), weighted standard deviation (wSD), coefficient of variation (CoV), average real variability (ARV), and variability independent of the mean (VIM), evaluated on ABPM measurements. Results: The study population included 124 patients (50% female). During follow-up, CTR-CVT occurred in 70 subjects (56.5% of the total population), including both BP and CV events. Night-time BPV was associated to CTR-CVT, independently by BP, age, smoking, and comorbidities as diabetes and renal dysfunction (night-time systolic CoV: adjusted OR 1.11 [1.01-1.22]; night-time systolic VIM adjusted OR 1.17 [1.03-1.35]; night-time diastolic VIM adjusted OR 1.18 [1.01-1.40]). Cut-off for these BPV parameters were identified as predictor of CTR-CVT occurrence: 10.5 for night-time systolic CoV (sensibility 73%, specificity 47%); 7.8 and 6.4 for systolic and diastolic night-time VIM (sensibility 85% for both; specificity 35% and 39%, respectively). Clustering analysis identified a subgroup of subjects characterized by the highest BPV, who had a greater prevalence of events during follow-up, but no differences in other conventional CV risk factors, as BP, dyslipidaemia, diabetes, renal function, and smoking habit, as well as left ventricular mass and global longitudinal strain. Conclusions: Short-term BPV is an independent predictor of CTR-CVT in patients with Multiple Myeloma undergoing therapy with Carfilzomib. The inclusion of these indexes improves CV risk prediction in these subjects and higher BPV is a distinctive feature predicting adverse events, on top of conventional CV risk factors.