Molecular predictive factors in patients receiving trastuzumab-based chemotherapy for metastatic disease.
BACKGROUND
Trastuzumab-based chemotherapy can improve median survival in the metastatic setting when used in patients with cancer that overexpresses HER2/neu. In addition to HER2 expression, other molecular markers are needed to better predict outcomes after the initiation of trastuzumab-based chemotherapy and to elucidate potential mechanisms of resistance to trastuzumab.


METHODS
Patients with clinical documentation of HER2/neu-overexpressing metastatic breast cancer treated with trastuzumab between 1998 and 2004 were identified from the British Columbia Provincial Pharmacy Database. Tissues were obtained for microarray analysis of 153 of 306 patients who fit our clinical criteria. Tissue microarrays were constructed for the analysis of multiple molecular factors, and results were correlated to clinical outcomes. Immunohistochemistry was performed on the microarray specimens, and results were correlated with survival and time to progression.


RESULTS
Factors commonly associated with poor prognosis in the metastatic setting in general, including short disease-free intervals, high tumor grade, and low estrogen receptor status, were all associated with poor survival in this population with HER2 overexpression. Overexpression of HER3 was observed in 9% of specimens and was associated with a trend toward worse overall survival (P = 0.1). HER3 expression was not correlated with a significant difference in time to progression but did trend to predict for worse survival after progression (P = 0.06). In multivariate analysis, tumor grade and HER3 expression were significantly predictive of overall survival. Phosphatase and tensin homologue status did not appear to correlate with response or survival.


CONCLUSIONS
Our findings suggest that prognosis after initiation of trastuzumab-based chemotherapy depends, in part, on coexpression of HER3.
Robinson
Andrew G
AG
Division of Medical Oncology , BC Cancer Agency, Canada. arobinson@hrsrh.on.ca
Turbin
Dmitry
D
Thomson
Tom
T
Yorida
Erika
E
Ellard
Susan
S
Bajdik
Chris
C
Huntsman
David
D
Gelmon
Karen
K
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D001955:British Columbia / Q000453:epidemiology; D016208:Databases, Factual; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008499:Medical Records; D046228:Microarray Analysis; D009362:Neoplasm Metastasis; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab