2. Aromatase Inhibitors
Aromatase inhibitors block the final enzymatic biosynthetic pathway
In premenopausal women, androgens are synthesized from cholesterol predominantly in the ovaries, with lesser production occurring in the adrenals. In postmenopausal women, ovarian production of estrogen ceases and the majority of the circulating estrogen is derived from the peripheral conversion of adrenal androgens in such sites as muscles and adipose tissues.
Aromatase inhibitors block the final enzymatic biosynthetic pathway
In premenopausal women, androgens are synthesized from cholesterol predominantly in the ovaries, with lesser production occurring in the adrenals. In postmenopausal women, ovarian production of estrogen ceases and the majority of the circulating estrogen is derived from the peripheral conversion of adrenal androgens in such sites as muscles and adipose tissues.
3. Aromatase Inhibitors
Geisler J, Haynes B, Anker G, Dowsett M, Lnning PE (2002) Influence of
letrozole and anastrozole on plasma estrogen levels in postmenopausal
breast cancer patients evaluated in a randomized, cross-over study. J Clin
Oncol 20: 7511757
Geisler J, Haynes B, Anker G, Dowsett M, Lnning PE (2002) Influence of
letrozole and anastrozole on plasma estrogen levels in postmenopausal
breast cancer patients evaluated in a randomized, cross-over study. J Clin
Oncol 20: 7511757
4. Use of Aromatase Inhibitors in Breast Cancer Patients
Aromatase activity is present in the bone microenvironment.
Aromatase activity is present in the bone microenvironment.
8. Effects of Letrozole on Bone
4% of patients had BSO
60% had adjuvant radiotherapy previously and 46% had previous adjuvant chemotherapy
Early termination of trial
4% of patients had BSO
60% had adjuvant radiotherapy previously and 46% had previous adjuvant chemotherapy
Early termination of trial
9. Effects of Letrozole on Bone
4% of patients had BSO
60% had adjuvant radiotherapy previously and 46% had previous adjuvant chemotherapy
Early termination of trial
4% of patients had BSO
60% had adjuvant radiotherapy previously and 46% had previous adjuvant chemotherapy
Early termination of trial
10. Effects of Letrozole on Bone
Randomized controlled double-blinded double-dummy phase III trial with optional crossover AFTER progression of disease
N = 916 postmenopausal women with stage IIIB locally advanced breast cancer or locoregioinally recurrent or metastatic hormone receptor-positive or unknown tumors
Letrozole 2.5mg vs TAM 20mg until progression of disease
Median follow-up = 32 months (up to 57 months)
Superiority of letrozole to tamoxifen was confirmed for the time to progression (9.4 vs 6.0 months; p<0.0001), time to treatment failure (9 vs 5.7; p<0.0001) and overall objective response rate (32% vs 21%; p<0.0002).
Median OS was slightly prolonged for the randomized letrozole arm (34 vs 30 months)
Randomized controlled double-blinded double-dummy phase III trial with optional crossover AFTER progression of disease
N = 916 postmenopausal women with stage IIIB locally advanced breast cancer or locoregioinally recurrent or metastatic hormone receptor-positive or unknown tumors
Letrozole 2.5mg vs TAM 20mg until progression of disease
Median follow-up = 32 months (up to 57 months)
Superiority of letrozole to tamoxifen was confirmed for the time to progression (9.4 vs 6.0 months; p<0.0001), time to treatment failure (9 vs 5.7; p<0.0001) and overall objective response rate (32% vs 21%; p<0.0002).
Median OS was slightly prolonged for the randomized letrozole arm (34 vs 30 months)
11. Effects of Letrozole on Bone
Randomized controlled double-blinded double-dummy phase III trial with optional crossover AFTER progression of disease
N = 916 postmenopausal women with stage IIIB locally advanced breast cancer or locoregioinally recurrent or metastatic hormone receptor-positive or unknown tumors
Letrozole 2.5mg vs TAM 20mg until progression of disease
Median follow-up = 32 months (up to 57 months)
Superiority of letrozole to tamoxifen was confirmed for the time to progression (9.4 vs 6.0 months; p<0.0001), time to treatment failure (9 vs 5.7; p<0.0001) and overall objective response rate (32% vs 21%; p<0.0002).
Median OS was slightly prolonged for the randomized letrozole arm (34 vs 30 months)
Randomized controlled double-blinded double-dummy phase III trial with optional crossover AFTER progression of disease
N = 916 postmenopausal women with stage IIIB locally advanced breast cancer or locoregioinally recurrent or metastatic hormone receptor-positive or unknown tumors
Letrozole 2.5mg vs TAM 20mg until progression of disease
Median follow-up = 32 months (up to 57 months)
Superiority of letrozole to tamoxifen was confirmed for the time to progression (9.4 vs 6.0 months; p<0.0001), time to treatment failure (9 vs 5.7; p<0.0001) and overall objective response rate (32% vs 21%; p<0.0002).
Median OS was slightly prolonged for the randomized letrozole arm (34 vs 30 months)
12. Effects of Anastrozole on Bone
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
musculoskeletal disorders and
fractures were significantly more common with
anastrozole than with tamoxifen. The greatest increase in
fractures on anastrozole treatment seemed to be in the
spine, and no increase in hip fractures was seen.
13. Effects of Anastrozole on Bone
Musculoskeletal disorders and fractures were significantly more common with anastrozole than with tamoxifen.
The greatest increase in fractures on anastrozole treatment seemed to be in the spine, and no increase in hip fractures was seen.
Musculoskeletal disorders and fractures were significantly more common with anastrozole than with tamoxifen.
The greatest increase in fractures on anastrozole treatment seemed to be in the spine, and no increase in hip fractures was seen.
18. Effects of Exemestane & Letrozole on Bone
Randomized placebo-controlled explorative study
12-week treatment with exemestane or letrozole
Randomized placebo-controlled explorative study
12-week treatment with exemestane or letrozole
21. Tissue-specific Promoters of CYP19 Gene
Aromatase cytochrome P450 is the product of human CYP19 gene.
The protein coding region spans 9 exons beginning with exon II. Upstream of exon II are several alternative exons I, which are spliced into the 55-UTR of the transcript in a tissue-specific fashion.
Transcripts in adipose tissue contain yet another distal exon located 20kb downstream of exon I.1 promoter I.4
Bone utilizes promoter I.6
Splicing of all these untranslated exons to form the mature transcript occurs at a common 33-splice junction that is upstream of the translational start site. Although transcripts in different tissues have different 55-termini, the coding region and thus the protein expressed in these various tissue sites is always the same.
Aromatase cytochrome P450 is the product of human CYP19 gene.
The protein coding region spans 9 exons beginning with exon II. Upstream of exon II are several alternative exons I, which are spliced into the 55-UTR of the transcript in a tissue-specific fashion.
Transcripts in adipose tissue contain yet another distal exon located 20kb downstream of exon I.1 promoter I.4
Bone utilizes promoter I.6
Splicing of all these untranslated exons to form the mature transcript occurs at a common 33-splice junction that is upstream of the translational start site. Although transcripts in different tissues have different 55-termini, the coding region and thus the protein expressed in these various tissue sites is always the same.