title: High-sensitivity C-reactive protein (hs-CRP) as a biomarker for trastuzumab-induced cardiotoxicity in HER2-positive early-stage breast cancer: a pilot study.
abstract: Monitoring of left ventricular ejection fraction (LVEF) is the current standard for detection of trastuzumab-induced cardiotoxicity; however, time-to-diagnosis and cost of assessment are suboptimal in women with early-stage breast cancer. We assessed the utility of B-type natriuretic peptide (BNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin I (cTnI) as serum biomarkers for early detection of trastuzumab-induced cardiotoxicity. Fifty-four women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were prospectively enrolled, and the relationship between elevated serum BNP, hs-CRP, and cTnI levels and clinically significant decreases in LVEF was examined. LVEF was monitored at 3-4 month intervals during trastuzumab treatment. Laboratory testing for candidate biomarkers was repeated every 3 weeks with each cycle of trastuzumab. Trastuzumab-induced cardiotoxicity was defined as a decrease in LVEF of ≥15% or to a value below 50%. A clinically significant decrease in LVEF was observed in 28.6% of women. Abnormal hs-CRP (≥3 mg/L) predicted decreased LVEF with a sensitivity of 92.9% (95% CI 66.1-99.8) and specificity of 45.7% (95% CI 28.8-63.4), and subjects with normal hs-CRP levels (<3 mg/L) have 94.1% negative predictive 94.1% (95% CI 70.3-99.9) suggesting that normal hs-CRP levels may be associated with low future risk for decreased LVEF; however, no association with BNP or cTnI was observed. A false positive would have a relatively low associated cost in breast cancer patients undergoing adjuvant trastuzumab therapy and would indicate continuation of routine observation during treatment through traditional means. The maximum hs-CRP value was observed a median of 78 days prior to detection of cardiotoxicity by decreased LVEF, and those with normal levels were at lower risk for cardiotoxicity. Regular monitoring of hs-CRP holds promise as a biomarker for identifying women with early-stage breast cancer at low risk for asymptomatic trastuzumab-induced cardiotoxicity. To our knowledge, this is the first study documenting the utility of a less expensive, reproducible, easily obtainable biomarker with rapid results for evaluating cardiotoxicity related to trastuzumab therapy.
authors.affiliation: Department of Hematology/Oncology, Marshfield Clinic Weston Center, 3501 Cranberry Boulevard, Weston, WI 54476, USA. onitilo.adedayo@marshfieldclinic.org
authors.forename: Adedayo A
authors.initials: AA
authors.lastname: Onitilo
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Engel
authors.forename: Rachel V
authors.initials: RV
authors.lastname: Stankowski
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Berg
authors.forename: Suhail A R
authors.initials: SA
authors.lastname: Doi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002097:C-Reactive Protein / Q000378:metabolism*; D005260:Female; D006331:Heart Diseases / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis*; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D015999:Multivariate Analysis; D010865:Pilot Projects; D011446:Prospective Studies; D012372:ROC Curve; D013318:Stroke Volume / Q000187:drug effects; D000068878:Trastuzumab; D019210:Troponin I / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D019210:Troponin I; D002097:C-Reactive Protein; D000068878:Trastuzumab