Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data

Grana, Generosa

doi:10.1002/jso.20564

Cited by 15 publications

(7 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The major toxicity associated with AIs including exemestane is joint pain and bone loss, the propensity for bone fractures, and increased risk for osteoporosis [11–13], a pattern consistent with the lower hip and lumbar spine bone mineral density observed in patients on AIs [14]. Although not as severe as tamoxifen, other toxicities reported for AIs include a variety of gynecological events including vaginal bleeding or discharge and hot flashes [15,16]. Variability in changes to lipid profiles, manifestation of osteoporosis, and time of recurrence, were observed in patients in many AI clinical trials [9] and the mechanism underlying this variability in response to AIs and to their toxicities remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

Sun¹,

Chen²,

Dellinger³

et al. 2010

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Objective Exemestane is a third-generation aromatase inhibitor used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to exemestane-17-O-glucuronide is a major pathway for exemestane metabolism. The goal of this study was to analyze 17-dihydroexemestane anti-aromatase activity, characterize the 17-dihydroexemestane glucuronidation pathway, and determine whether the functional polymorphisms in active UGTs could play a role in altered 17-dihydroexemestane glucuronidation. Methods Homogenates from a HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine exemestane versus 17-dihydroexemestane anti-aromatase activities. UGT-overexpressing cell lines and a panel (n = 110) of human liver microsome (HLM) were screened for glucuronidation activity against 17-dihydroexemestane. UGT2B17 genotyping and liver mRNA expression were performed by real-time PCR. Results The inhibition of estrone formation from androst-4-ene-3,17-dione in HEK293-aro cell homogenates was similar for 17-dihydroexemestane (IC50 = 2.3 ± 0.83 μmol/l) and exemestane (IC50 = 1.4 ± 0.42 μmol/l). UGTs 2B17 and 1A4 were high-expression hepatic UGTs that exhibited activity against 17-dihydroexemestane, with UGT2B17 exhibiting a 17-fold higher Vmax/KM than UGT1A4. The rate of exemestane-17-O-glucuronide formation was shown to be significantly (P < 0.001) decreased (14-fold) in HLMs exhibiting the UGT2B17(*2/*2) deletion genotype versus wild-type UGT2B17(*1/*1) HLMs; a 36-fold lower Vmax/KM (P = 0.023) was observed in UGT2B17(*2/*2) versus UGT2B17(*1/*1) HLMs. A significant (P < 0.0001, R2 = 0.72) correlation was observed between HLM exemestane-17-O-glucuronide formation and liver UGT2B17 expression. Conclusion These data suggest that 17-dihydroexemestane is an active metabolite of exemestane and that the UGT2B17 deletion polymorphism could play an important role in determining levels of excretion of 17-dihydroexemestane and overall exemestane metabolism.

show abstract

Section: Introductionmentioning

confidence: 99%

Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

Sun¹,

Chen²,

Dellinger³

et al. 2010

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…ER positive status is generally associated with a more favorable prognosis (1,2), but more importantly, it is a predictive marker of response to hormonal therapies such as tamoxifen and aromatase inhibitors (3,4). However, ER-positive tumors represent a large and heterogeneous subgroup, and treatment decisions are most often based on clinicopathologic features such as tumor grade and lymph node status.…”

Section: Introductionmentioning

confidence: 99%

GATA-3 Expression in Breast Cancer Has a Strong Association with Estrogen Receptor but Lacks Independent Prognostic Value

David

Cheang

Nielsen

2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

141

131

View full text Add to dashboard Cite

Background: GATA-3 is a transcription factor involved in human growth and differentiation. Gene expression profiling has shown that GATA-3 is highly expressed in the Luminal A subtype of breast cancer. A recent study found GATA-3 to be associated with favorable breast cancer pathologic features, including negative lymph node and positive estrogen receptor (ER) status. GATA-3 levels were also found to be an independent prognostic marker, with low expression predicting for breast cancer recurrence. Materials and Methods: Our case series consists of 3,119 cases of invasive breast cancer in which GATA-3 expression was assessed by immunohistochemistry on tissue microarrays. We considered >5% nuclear staining to be a positive result for GATA-3. Results: Thirty-two percent of cases were GATA-3 positive. GATA-3 is almost exclusively expressed in ER+ patients and is also associated with lower tumor

show abstract

“…The use of AIs has been very successful in combating hormone sensitive breast cancer in postmenopausal women [19,95,96,[108][109][110]. However, the risk of these cancers developing resistance to the available therapeutics cannot be ignored.…”

Section: Resultsmentioning

confidence: 99%

Aromatase inhibitors: past, present and future in breast cancer therapy

Dutta

Pant

2007

Med Oncol

View full text Add to dashboard Cite

Estrogen has been implicated in promoting breast cancer in a majority of women. Endocrine therapy controlling estrogen production has been the guiding principle in treating breast cancer for more than a century. A greater understanding of this disease at a molecular level has led to the development of molecules that inhibit estrogen production by inhibiting the aromatase enzyme, that is the primary source of estrogen in postmenopausal women. This review examines the evolution of aromatase inhibitor (AI) based therapies over the past three decades. The third generation aromatase inhibitors (anastrozole, letrozole and exemestane), which have been found to be extremely specific and effective in an adjuvant/neoadjuvant/extended adjuvant setting are discussed from a biochemical and clinical perspective. A comprehensive discussion of the past, present, and future of aromatase inhibitors is conducted in this review.

show abstract

Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data

Cited by 15 publications

References 25 publications

Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

GATA-3 Expression in Breast Cancer Has a Strong Association with Estrogen Receptor but Lacks Independent Prognostic Value

Aromatase inhibitors: past, present and future in breast cancer therapy

Contact Info

Product

Resources

About