Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors

Dunbar, Andrew; Bolton, Kelly L.; Devlin, Sean M.; Sanchez‐Vega, Francisco; Gao, Jianjiong; Mones, Jodi V.; Wills, Jonathan; Kelly, Daniel; Farina, Mirko; Cordner, Keith B.; Park, Young; Kishore, Sirish; Juluru, Krishna; Iyengar, Neil M.; Levine, Ross L.; Zehir, Ahmet; Park, Wungki; Khorana, Alok A.; Soff, Gerald A.; Mantha, Simon

doi:10.1182/blood.2020007488

Cited by 70 publications

(47 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Her tumor had wild‐type KRAS , but exhibited ALK‐EML4 fusion and MET amplification, both associated with a significant increase in VTE rates. 20 , 21 Her platelet count was 23 × 10 9 /L at the time of the splenic and renal infarct and 210 × 10 9 /L and 21 × 10 9 /L at the time of the two cerebral vascular events. The subject and her oncologist decided to continue romiplostim, as her cancer was responding well to ongoing chemotherapy, and without romiplostim, thrombocytopenia precluded her from receiving optimal anticoagulation.…”

Section: Resultsmentioning

confidence: 98%

Romiplostim for chemotherapy‐induced thrombocytopenia: Efficacy and safety of extended use

Wilkins

Ortiz²,

Gilbert³

et al. 2022

Research and Practice in Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

Background Chemotherapy‐induced thrombocytopenia (CIT) is common during treatment with antineoplastic therapies and may adversely impact chemotherapy dose intensity. There is no approved therapy for CIT. In our recent phase II randomized study, romiplostim led to correction of platelet counts in 85% of treated patients and allowed resumption of chemotherapy, with low rates of recurrent CIT in the first two cycles or 8 weeks of chemotherapy. However, there is a lack of long‐term data on the efficacy and safety of romiplostim in CIT. Objectives To analyze efficacy and safety of romiplostim in the patients in the phase 2 study, who received romiplostim for ≥1 year. Patients/Methods Twenty‐one patients remained on romiplostim for ≥1 year. We analyzed the effect of romiplostim on platelet counts, absolute neutrophil counts, and hemoglobin, as well as impact on ongoing chemotherapy. We also tracked venous or arterial thrombotic events. Results During the study period, romiplostim was effective in preventing reduction of chemotherapy dose intensity due to CIT. Fourteen of the 20 (70%) analyzable patients experienced no episode of CIT, 4 subjects experienced a single chemotherapy dose delay due CIT, and 2 patients required a chemotherapy dose reduction. Platelet counts were preserved throughout the duration of the extension analysis. One patient experienced a proximal deep vein thrombosis, and one patient experienced multiple tumor‐related ischemic events. Conclusions Long‐term use of romiplostim for treatment of CIT was effective and safe, with no evidence of resistance or increased risk of thrombosis.

show abstract

Section: Resultsmentioning

confidence: 98%

Romiplostim for chemotherapy‐induced thrombocytopenia: Efficacy and safety of extended use

Wilkins

Ortiz²,

Gilbert³

et al. 2022

Research and Practice in Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

show abstract

“…The search identified the gene amplifications of PLAT and SERPINE1 as the most frequent genomic events in OSCC, albeit at a low frequency of 2.2% ( Table S2 ). Somatic tumor mutations in STK11 , KRAS , CTNNB1 , KEAP1 , CDKN2B and MET , which were reported to be associated with cancer-induced venous thromboembolism in an independent study [ 12 ], were infrequent in OSCC. We found no statistically significant association of any of the corresponding mutations with the expression of the coagulome in TCGA (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…The concept of the tumor coagulome refers to the equilibrium that exists between coagulation and fibrinolysis within tumors, and the contribution of multiple genes and proteins to this equilibrium [ 9 ]. Over the past decade, systems biology approaches, especially using genomics, have been applied to study the «core» components of the tumor coagulome, i.e., the local regulation of the main effectors of coagulation [ 10 , 11 , 12 , 13 ]. Clot formation is induced by the polymerization of fibrin resulting from thrombin activity, and it is initiated by the Tissue Factor (TF) encoded by the gene F3 [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Lottin

Soudet

Fercot

et al. 2022

Cancers

View full text Add to dashboard Cite

Background: Hemostatic complications, ranging from thromboembolism to bleeding, are a significant source of morbidity and mortality in cancer patients. The tumor coagulome represents the multiple genes and proteins that locally contribute to the equilibrium between coagulation and fibrinolysis. We aimed to study the coagulome of Oral Squamous Cell Carcinoma (OSCC) and examine its link to the tumor microenvironment (TME). Methods: We used data from bulk tumor DNA/RNA-seq (The Cancer Genome Atlas), single-cell RNA-seq data and OSCC cells in culture. Results: Among all tumor types, OSCC was identified as the tumor with the highest mRNA expression levels of F3 (Tissue Factor, TF) and PLAU (urokinase type-plasminogen activator, uPA). Great inter- and intra-tumor heterogeneity were observed. Single-cell analyses showed the coexistence of subpopulations of pro-coagulant and pro-fibrinolytic cancer cells within individual tumors. Interestingly, OSCC with high F3 expressed higher levels of the key immune checkpoint molecules CD274/PD-L1, PDCD1LG2/PD-L2 and CD80, especially in tumor dendritic cells. In vitro studies confirmed the particularity of the OSCC coagulome and suggested that thrombin exerts indirect effects on OSCC cells. Conclusions: OSCC presents a specific coagulome. Further studies examining a possible negative modulation of the tumor’s adaptive immune response by the coagulation process are warranted.

show abstract

“…The Khorana score was not a useful tool to predict thrombosis in our mostly HR + HER2 negative breast cancer population while on CDK4/6 inhibitors. Increasingly, the role of the tumor mutational profile as an independent predictor of cancer‐associated thrombosis is being described 29‐32 . For example, non‐small cell lung cancers (NSCLCs) driven by aberrant anaplastic lymphoma kinase (ALK) rearrangements have been shown to be at increased risk for arterial and venous thrombosis compared to non‐ALK rearranged NSCLC 29,31 .…”

Section: Discussionmentioning

confidence: 99%

“…Another recent publication that evaluated over 14 000 pooled solid tumor samples, including 14% from breast tumors, identified seven somatic tumor mutations independently associated with VTE risk. Mutations including CDKN2B, CDK4, and CDKN2A were associated with thrombosis 30 . This is of interest, as the HR + HER2‐ breast cancers often have overexpression of cyclin D1 and CDK4, in addition to mutations within the CDK 4/6 pathway including CDKN2A loss 3,4,6 .…”

Section: Discussionmentioning

confidence: 99%

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real‐world practice

West

Smith

Kaempf

et al. 2021

European J of Haematology

View full text Add to dashboard Cite

Purpose Cyclin‐dependent kinase (CDK) 4/6 inhibitors are integral treatment for advanced hormone receptor positive breast cancer; however, venous thromboembolic events (VTE) occurred in 1%‐5% of clinical trial patients. Thrombosis rates in the real‐world setting remain unclear. We aimed to define the rate of thromboembolic events, risk factors for thrombosis on CDK 4/6 inhibitors and evaluate the Khorana VTE risk score as a predictive tool for VTE in patients on CDK 4/6 therapy. Methods Multicenter retrospective analysis of adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib. The primary endpoint was thrombosis during treatment or within 30 days of CDK inhibitor discontinuation. Cox regression was used to model time‐to‐thrombosis, starting from a patient's initiation of CDK 4/6 therapy. The extended Kaplan‐Meier method and Cox modeling were used to assess the effect of time‐varying thrombosis status on overall survival. Results Two hundred and sixty‐six patients were included (89% on palbociclib, 14% on abemaciclib, 7% on ribociclib). Twenty‐nine thrombotic events occurred in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1‐year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib. Hemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014). Khorana score ranged from 0‐3, with the majority between 0 and 1 and was not predictive of VTE. Thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK‐associated clot (median 35.7 months). Discussion VTE in our analysis is higher than reported in clinical trials and arterial thrombosis comprised over one‐third of events. The highest incidence was with palbociclib, followed by ribociclib. Khorana score did not predict VTE risk. Larger, real‐world studies are needed. The role for prophylactic anticoagulation is yet to be defined in this patient population.

show abstract

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors

Cited by 70 publications

References 58 publications

Romiplostim for chemotherapy‐induced thrombocytopenia: Efficacy and safety of extended use

Romiplostim for chemotherapy‐induced thrombocytopenia: Efficacy and safety of extended use

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real‐world practice

Contact Info

Product

Resources

About