Aromatase inhibitors (AIs) are considered the gold standard for endocrine
therapy of
estrogen receptor (ER) positive postmenopausal
breast cancer patients. The
therapy may enhance therapeutic response and stabilize disease but resistance and
disease progression inevitably occur in the patients. These are considered at least partly due to an emergence of alternative intratumoral
estrogen production pathways. Therefore, in this study we evaluated effects of
exemestane (EXE) upon the
enzymes involved in intratumoral
estrogen production including
estrogen sulfatase (STS),
17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), and
estrogen sulfotransferase (EST) and correlated the findings with therapeutic responses including Ki67 labeling index (Ki67). 116 postmenopausal patients with invasive
ductal carcinoma, stage II/IIIa, were enrolled in JFMC34-0601 clinical trials between March, 2006 and January, 2008. EXE of 25 mg/day was administered according to the protocol. Pre- and posttreatment specimens of 49 cases were available for this study. Status of STS, EST, 17beta-HSD1, ER,
progesterone receptor (PgR), human
epidermal growth factor receptor type 2 (Her2), and Ki67 in pre- and post-specimens were evaluated. Specimens examined before the
therapy demonstrated following features; ER+ (100%), PgR+ (85.7%), and Her2+ (77.6%).
After treatment, the number of Ki67, PgR, and ER positive
carcinoma cells demonstrated significant decrement in clinical response (CliR) and pathological response (PaR) groups. Significant increment of 17beta-HSD1 and STS immunoreactivity was detected in all groups examined except for STS in PaR. EST showed significant increment in nonresponsive groups. Alterations of Ki67 of
carcinoma cells before and after
therapy were subclassified into three groups according to its degrees. Significant alterations of intratumoral
enzymes, especially 17beta-HSD1 and STS, were correlated with Ki67 reduction after neoadjuvant EXE
therapy. This is the first study demonstrating significant increment of STS and 17beta-HSD1 following AI
neoadjuvant therapy of postmenopausal ER positive
breast carcinoma patients. This increment may represent the compensatory response of
breast carcinoma tissues to
estrogen depletion.