Myocardial infarction accelerates breast cancer via innate immune reprogramming

Koelwyn, Graeme J.; Newman, Alexandra A C; Afonso, Milessa Silva; Solingen, Coen van; Corr, Emma M.; Brown, Emily J.; Albers, Kathleen; Yamaguchi, Naoko; Narke, Deven; Schlegel, P. Martin; Sharma, Monika; Shanley, Lianne C.; Barrett, Tessa J.; Rahman, Karishma; Mezzano, Valeria; Fisher, Edward A.; Park, David; Newman, Jonathan; Quail, Daniela F.; Nelson, Erik R.; Caan, Bette J.; Jones, Lee W.; Moore, Kathryn J.

doi:10.1038/s41591-020-0964-7

Cited by 159 publications

(168 citation statements)

References 41 publications

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“…A recent preclinical study in breast cancer demonstrated that MI causes reprogramming of monocytes in the bone marrow to an immunosuppressive phenotype that was maintained in circulation and recruited to the tumor, resulting in accelerated breast cancer growth. 38 Similarly, another study has demonstrated that activation of coagulation by tissue factor-thrombin-proteaseactivated receptor-1 signaling in pancreatic cancer alters the immune regulation pathway by suppressing CD8+ T cells in the tumor microenvironment, and potentially evading the immune system. 39 Analysis of multiple cancer cell types, including melanoma, has demonstrated that increased activity of tissue factor, thrombin, or prothrombin increases metastatic disease burden.…”

Section: Discussionmentioning

confidence: 99%

Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

Sussman

Hobbs

et al. 2021

J Immunother Cancer

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BackgroundThromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Little is known about the incidence of arterial TE (ATE) and venous TE (VTE) in patients with melanoma on immune checkpoint inhibitor (ICI) therapy.MethodsWe conducted a retrospective cohort study of patients with melanoma receiving ICI from July 2015 through December 2017 at the Cleveland Clinic. TE, including VTE events of deep venous thrombosis, pulmonary embolism, visceral vein thrombosis, and ATE events of myocardial infarction, stroke, peripheral arterial embolism, or transient ischemic attack after ICI initiation were identified. Overall survival (OS) from ICI initiation was estimated by Kaplan-Meier and Cox hazard models; associations between TE, ICI regimen, and clinical risk factors were evaluated using log-rank test.ResultsThe study population comprised 228 patients with median age of 65 years (23–91 years), 67% male, and median follow-up of 27.3 months. Pembrolizumab was most commonly used (38.7%), followed by combination of ipilimumab plus nivolumab (29.4%), ipilimumab (20%), and nivolumab (12.3%). Most had stage IV disease (81.1%) and 11% had brain metastases (BM) at treatment initiation. Fifty-one TE events occurred in 47 patients (20.6%), including 37 (16.2%) VTE and 14 (6.1%) ATE. Cumulative incidence of TE after ICI initiation was 9.3% (95% CI: 6.0% to 13.6%) at 6 months, and 16.0% (95% CI: 11.6% to 21.2%) at 12 months. The 6-month and 12-month VTE cumulative incidence rates were higher with combination ICI than single agent (16.7% vs 5.0% and 21.3% vs 9.5%, respectively; p=0.02). Risk factors significantly associated with VTE in multivariate analysis included combination ICI (HR 2.70; 95% CI: 1.28 to 5.70; p=0.009), Khorana Score ≥1 (HR 2.24; 95% CI: 1.06 to 4.74; p=0.03), history of coronary artery disease (HR 2.71; 95% CI: 1.16 to 6.29); p=0.02), and anticoagulation at treatment start (HR 4.14; 95% CI: 1.60 to 10.7; p=0.003). Of patients without BM, OS was worse in patients with TE compared with those without (2-year OS 50.8% vs 71.3%; HR 2.27; 95% CI: 1.36 to 3.79; p=0.002), when adjusted for age and stage.ConclusionsICI is associated with a high incidence of TE in patients with melanoma, with higher rates with combination therapy; TE is associated with substantial worsening of survival. Further studies are needed to identify pathophysiology, biomarkers, and preventive approaches.

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Section: Discussionmentioning

confidence: 99%

Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

Sussman

Hobbs

et al. 2021

J Immunother Cancer

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“…The investigators reported increased circulating Ly6Chi monocyte levels and recruitment to tumours in MI mice compared to sham mice. Interestingly, the depletion of these cells abrogated MI‐induced tumour growth 77 …”

Section: Heart Failure Driving Cancermentioning

confidence: 99%

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

Boer

Hulot

Tocchetti

et al. 2020

European J of Heart Fail

103

109

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The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

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“…Furthermore, perturbation of the immune system resulting from surgical wounding may impact residual disease progression. Recent studies have shown that altered myloid cell differentiation resulting in an immunosuppressive state can result from surgery (36) or myocardial infarction (37) to promote the outgrowth of breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

A mouse model of neoadjuvant chemotherapy followed by interval cytoreductive surgery indicates impaired efficacy of perioperative cisplatin

Clark

Kollara

Brown

et al. 2021

Preprint

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Background Investigate the impact of interval cytoreductive surgery (ICS) on progression in an orthotopic mouse model of ovarian cancer and the impact of chemotherapy delivered at various timelines following surgery. Methods Luciferase-expressing ID8 murine ovarian cancer cells were implanted intra-bursally and IP to C57BL/7 mice. Once disease was established by bioluminescence, 2 cycles of neoadjuvant cisplatin were administered, and animals received either ICS (removal of the injected bursa/primary tumor) or anesthesia alone. Postsurgical chemotherapy was administered on the same day as the intervention (ICS/anesthesia), or on day 7 or day 28 following the intervention. Progression was quantified serially with in vivo bioluminescence imaging. Volume of ascitic fluid volume collected at necropsy was measured. Results Animals were matched for tumor burden at stratification. There was no accelerated growth of residual tumor after interval cytoreduction compared to controls. Animals who received chemotherapy on postoperative day (POD) 7 had better disease control compared to standard-of-care POD 28. Animals who underwent surgery had less ascites at necropsy compared to those who had anesthesia alone. Conclusions In this animal model, surgical wounding with suboptimal cytoreduction after neoadjuvant chemotherapy did not cause accelerated expansion of residual disease. Surgical wounding appears to impair cisplatin activity when given at time of surgery.

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Myocardial infarction accelerates breast cancer via innate immune reprogramming

Cited by 159 publications

References 41 publications

Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

A mouse model of neoadjuvant chemotherapy followed by interval cytoreductive surgery indicates impaired efficacy of perioperative cisplatin

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