Prognostic and predictive value of HER2 extracellular domain in metastatic breast cancer treated with lapatinib and paclitaxel in a randomized phase III study.
OBJECTIVE
The HER2 extracellular domain (ECD) is enzymatically cleaved from the cell membrane. Shed ECD in serum has been studied as both prognostic and predictive markers. Lapatinib is a dual inhibitor of HER2 and epidermal growth factor receptor kinases. We examined the prognostic and predictive role of HER2 ECD in a randomized trial of paclitaxel with placebo or lapatinib in women with HER2-negative or -unknown breast cancer.


METHODS
Patients (n = 579) with newly diagnosed metastatic breast cancer (MBC) were randomly assigned to paclitaxel with placebo or lapatinib. HER2 status was determined centrally. ECD was centrally measured by enzyme linked immunoassay in available samples at baseline (b; n = 472), week 9, and every 12 weeks thereafter. Results were correlated to overall response rate (ORR) and progression-free survival (PFS).


RESULTS
Elevated baseline ECD (bECD) levels (>or= 16 ng/mL) did not predict HER2 tumor status (sensitivity, 62%; specificity, 75%). In HER2-negative tumors, elevated bECD was not correlated with improved efficacy for lapatinib plus paclitaxel versus placebo plus paclitaxel (ORR: odds ratio, 1.6; 95% CI, 0.1 to 3.8; P = .365; PFS: hazard ratio, 0.94; 95% CI, 0.60 to 1.47; P = .797). ECD levels tended to decrease over time when bECD was elevated. ECD conversion from low to high was associated with worse PFS. Converting from high to low was associated with a better PFS. A consistently low ECD level had better PFS than a consistently elevated ECD. All associations were found to be independent of lapatinib.


CONCLUSIONS
HER2 bECD does not predict lapatinib benefit in patients with HER2-negative MBC. Changes in ECD status correlates with patient outcome regardless of treatment given. Measuring HER2 ECD is not currently recommended for predicting benefit to lapatinib.
Finn
Richard S
RS
Geffen School of Medicine at UCLA, Norris Cancer Center, University of Southern California, Los Angeles, CA 90095, usa. Rfinn@mednet.ucla.edu
Gagnon
Robert
R
Di Leo
Angelo
A
Press
Michael F
MF
Arbushites
Michael
M
Koehler
Maria
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000556:secondary*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011237:Predictive Value of Tests; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077341:Lapatinib; D017239:Paclitaxel