Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance.
BACKGROUND
Clinical data indicate that estrogen receptor-positive/progesterone receptor-negative (ER+/PR-) breast cancers are less sensitive to tamoxifen than are ER+/PR+ tumors. It has also been reported that tamoxifen may be less effective in tumors that overexpress either HER-2 or HER-1 (epidermal growth factor receptor) and that signaling through these receptors reduces PR expression in experimental models. We hypothesized that ER+/PR- breast tumors are more likely than ER+/PR+ breast tumors to have an aggressive phenotype, to express HER-1 and overexpress HER-2, and are less likely to benefit from tamoxifen adjuvant therapy.


METHODS
Clinical and biological features of 31 415 patients with ER+/PR+ tumors were compared with those of 13,404 patients with ER+/PR- tumors. Association between disease-free survival (DFS) and HER-1 and HER-2 status was analyzed in a subset of 11,399 patients receiving adjuvant tamoxifen therapy. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression or Kaplan-Meier analyses, and all statistical tests were two-sided.


RESULTS
ER+/PR- tumors were more frequent in older patients, were larger in size, had a higher S-phase fraction, and were more likely to be aneuploid than ER+/PR+ tumors. Furthermore, three times as many ER+/PR- tumors as ER+/PR+ tumors expressed HER-1 (25% versus 8%; P < .001) and 50% more overexpressed HER-2 (21% versus 14%; P < .001). Among all tamoxifen-treated women, recurrence was higher among women with HER-1-expressing tumors than with HER-1-negative tumors (HR = 1.9, 95% CI = 1.0 to 3.5; P = .05); a stronger association between worse DFS and HER-2 overexpression was observed (HR = 2.3, 95% CI = 1.2 to 4.3; P = .006). However, results varied by PR status. Among tamoxifen-treated women with ER+/PR+ tumors, HER-1 or HER-2 status was not associated with worse DFS. Among women with ER+/PR- tumors, however, both HER-1 expression (HR = 2.4, 95% CI = 1.0 to 5.4; P = .036) and HER-2 overexpression (HR = 2.6, 95% CI = 1.1 to 6.0; P = .022) were associated with a higher likelihood of recurrence.


CONCLUSIONS
ER+/PR- tumors express higher levels of HER-1 and HER-2 and display more aggressive features than ER+/PR+ tumors. As in laboratory models, lack of PR expression in ER+ tumors may be a surrogate marker of aberrant growth factor signaling that could contribute to the tamoxifen resistance observed in these tumors.
Arpino
Grazia
G
Breast Center, Baylor College of Medicine, The Methodist Hospital, Houston, TX, USA.
Weiss
Heidi
H
Lee
Adrian V
AV
Schiff
Rachel
R
De Placido
Sabino
S
Osborne
C Kent
CK
Elledge
Richard M
RM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D013629:Tamoxifen / Q000494:pharmacology*; D016896:Treatment Outcome; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen