Schinzinger was the first person to propose that oophorectomy might be of benefit in breast cancer:
Post menopausal breast atrophy
More virulent tumor growth in premenopausal
The first reported series of surgical oophorectomy for breast cancer was reported by Thomas Beatson (1896)
Showed significant tumor regression by castration
Better sense of well being
Regression of cutaneous metastasis
Best above age of 40
No effect on osseous metastatsis
Time Line 1870 1 st description of surgical oophorectomy 1940’s Full range of ablative hormonal therapy developed 1950’s Era of Additive hormonal therapy 1980’s ER/PR detection and resurgence in interest in endocrine Rx 1990’s Demonstration of the therapeutic efficacy of Tamoxifen 1970’s Development of Tamoxifen
5 yrs of tamoxifen is the standard therapy in all hormone receptor +ve patients.
5 yrs of tamoxifen therapy is also standard in post menopausal females.
In females with unknown receptor status tamoxifen is usually added specially if patient is post menopausal.
Adjuvant endocrine Rx is of little benefit in ER -ve females.
Except selected stage I patients without significant risk factors all most all can be considered for adjuvant hormone therapy.
Present evidence doesn't support 1 st line use of AI in adjuvant setting.
However it can be used after 3 -5 yrs of Tmx therapy after careful consideration of the cost benefit ratio.
Ca Breast for adjuvant therapy Low risk*, node -ve High risk, node -ve Node +ve Receptor - ve Chemotherapy Receptor - ve No Rx Receptor + ve Receptor + ve Premenopausal Postmenopausal Tamoxifen only CCT + Tamoxifen CCT + Tamoxifen # * Low risk defined as -ve axillary lymph nodes and tumor size ±1 cm, nuclear grade 1, special histologic type or 1-2 cm tumor with positive steroid receptor and special histologic type. # Ovarian suppression may be considered in those who remain premenopausal after chemotherapy.
ER receptor –ve tumors in tissue cultures are non responsive to tamoxifen therapy.
However problems interpreting the results of tamoxifen therapy in ER –ve tumors are:
Variable assay quality and reference values
Variable assay sensitivity
Possible paracrine loop action of tamoxifen (Few ER +ve tumors affecting surrounding ER –ve tumors)
Systemic effects of Tamoxifen (e.g. IGF -1 concentrations)
The low response rates observed with tamoxifen in ER -ve metastatic disease (5% to 10%) argue that these ancillary effects of tamoxifen are clinically unimportant
Tamoxifen & ER status Results of tamoxifen therapy for 5 years in patients with ER +ve or –ve tumors. Adapted from Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast Cancer Trialists’ Collaborative Group Lancet 1998; 351: 1451–67 Reduction (SE) in Annual Odds 14 (8%) 20 (9%) 31 (7%) Unknown 33 (5%) 45 (6%) 49 (5%) Positive (≥100 fmol/mg) 22 (5%) 27 (5%) 36 (4%) Positive (≥10, <100 fmol/mg) <3 (7%) <4 (8%) <4 (7%) Poor (<10 fmol/mg) Any Death Cancer Death Recurrence ER Level
Tmx has been evaluated against Tmx + CCT in a NSABP trial in ER +ve, node negative tumor
Women < 50 yrs who received concurrent CCT and tamoxifen compared with tamoxifen alone had a 35% reduction in annual odds of recurrence.
Initial trials had failed to show a benefit for addition of tamoxifen to chemotherapy in premenopausal women.
Addition of different CCT may explain the variable results as it is now known Tmx may inhibit the action of some CCT agents e.g. Melphalan (Used in NSABP B09 where premenopausal women had a poorer DFS and OS)
A recent SOFT trial is evaluating the question whether the addition of ovarian ablation to tamoxifen is better than tamoxifen in premenopausal females after CCT who are hormone receptor +ve.
FAC + G + Tam > FAC + G (HR = 0.73 , p = 0.01) FAC + G + Tam x 5 yrs FAC + G x 5 yrs G + Tam x 2yrs Tam x 2 yrs G x 3 years + Tam x 5 years FAC + G = FAC alone (HR = 0.93 , p = 0.25) FAC INT - 0101 Davidson G > no G ( HR 0.9; p= 0.001) G x 2 yrs ZIPP Rutqvist CMF < G +Tam for DFS [HR = 1.40; P = .017] CMF x 6 ABCSG Jakesz Comments Design Author
History of benign or malignant liver tumor secondary to oral contraceptives
Other hormonal therapy (estrogens, oral contraceptives)
History of thrombophlebitis, particularly hormone related
History of depression, particularly hormone related
Drugs: Chlorpromazine, chloroquine, thioridazine, amiodarone, other
Severe vasomotor symptoms
Toxicity of AIs vs Tamoxifen Since the absolute benefit of using a AI in adjuvant setting over tamoxifen is ~ 2% reduction in recurrence rates and 1.5% reduction in mortality this excess toxicity needs to be balanced against the bone damage produced by AIs in this setting. AI poorer Tmx poorer 2% 4% 5% 6% Hot flushes 2% 1.7& 2.2% 2.3% Osteoporotic fractures 6% NA 7% 23% Arthalgia /Myalgia NA 0.4% 0% 0.5% Cardiac complications - .9% - 1.2% - 1.7% NA Thromboembolic events NA - 0.4% - 0.6% NA Endometrial Cancer - 1.5% - 3.3% - 14% - 1.7% Vaginal Complications IES BIG ATAC MA -17
Initially used instead of high dose steroid in tamoxifen resistant patients.
Showed a small but significant benefit in 5 RCTs in terms of survival and better side effect profile
However overall the response rates were in the 10% to 20% range
Significant clinical benefit from Aromatase inhibitors often occurs in the absence of dramatic disease regression.
Therefore now the standard 2 nd line endocrine therapy in tamoxifen resistant metastatic breast cancer.
Results: AIs as 2 nd line Rx 26 3 15 Meg (40 mg) 33* 6* 21 Let (0.5 mg) 29 3 16 602 Let (2.5 mg) Letrozole vs Megestrol acetate 21.5 5.5 16 Meg (40 mg) 21.5 5.1 13 Let (0.5 mg) 25.3* 5.6* 24 551 Let (2.5 mg) Letrozole vs Megestrol acetate 22.5 7.9 Meg (40 mg) 26.7 * 10.3 Ana (1 mg) 25.5 < 21 8.9 764 Ana (10 mg) Anastrazole vs Megestrol acetate OS (mo) TTP (mo) RR N Drug Trial
3 major pahse III trials have directly compared tamoxifen against AI.
All have shown an improvement in time to progression (TTP)
The study by the International Letrozole Breast Cancer Group is the largest in the series.
6.0 20% Tmx 9.4 30% 907 Let Mouridsen et al 5 8.3 32.6% Tmx Retrospective analysis revealed longer TTP with Anastrazole after combining these two trials 3,4 8.2 32.9% 668 Ana TARGET trail 2 5.6 17.7% Tmx 11.1* 21% 353 Ana Nabholtz et al 1 Comment TTP (mo) RR N Drug Trial
Women with early disease benefit more from adjuvant therapy
Benefit in DFS and OS in most trials with adjuvant tamoxifen
Several trials have demonstrated a reduction in the incidence of contralateral breast cancer in women receiving tamoxifen.
Preclinical studies have demonstrated a preventive effect in animal populations.
Pre / post meno Pre / post meno Post meno Post meno Comment 29 (1326) 13 (1318) NSABP (1989) 14 (651 ) 8 (661) Scottish (1987) 32 (696) 18 (711) Stockholm (1989) 3(91) 1 (90) ECOG (1993) Placebo Tamoxifen Trial