Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer?
OBJECTIVE
Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)-negative patients. We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)-positive tamoxifen-treated breast cancer patients.


METHODS
Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer-related relapse on tamoxifen) was done.


RESULTS
HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P= 0.017). HER1-3-positive and/or PR-negative patients combined as a "high-risk" group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status.


CONCLUSIONS
We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.
Tovey
Sian
S
Endocrine Cancer Group, Section of Surgical and Translational Research, Glasgow University, United Kingdom.
Dunne
Barbara
B
Witton
Caroline J
CJ
Forsyth
Amanda
A
Cooke
Timothy G
TG
Bartlett
John M S
JM
D000970:Antineoplastic Agents / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D020893:Receptor, ErbB-3 / Q000032:analysis; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D046888:Tissue Array Analysis / Q000379:methods
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C587689:ERBB4 protein, human