This document summarizes hormonal treatment for breast cancer, including the history and mechanisms of various endocrine therapies. It discusses the timeline of developments in hormonal therapies from the late 19th century to present, covering areas like surgical oophorectomy, tamoxifen, aromatase inhibitors, and more. Key findings and mechanisms of different therapies like tamoxifen, aromatase inhibitors, and fulvestrant are summarized. The optimal use and duration of adjuvant tamoxifen therapy is discussed based on various clinical trials. The relationship between tamoxifen benefit and estrogen/progesterone receptor status is also covered.

1. Hormonal treatment of Breast Cancer Moderator: Dr. S C Sharma HOD, Department of Radiotherapy, PGIMER

4. 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. Endocrine pathways in cancer

23. Endocrine therapy in the adjuvant setting

26. 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.

33. 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

51. Results : 2004 EBCTSG review <3 ± 8 <2 ± 8 7 ± 7 40–49 <1 ± 11 <1 ± 11 7 ± 10 <40 Ovarian ablation + CCT vs CCT alone 25 ± 7 26 ± 7 25 ± 6 40–49 28 ± 12 32 ± 12 42 ± 10 <40 Ablation or LHRH agonist vs nil 13 ± 13 15 ± 13 16 ± 9 40–49 35 ± 17 45 ± 17 33 ± 12 <40 LHRH agonist vs nil 30 ± 8 32 ± 9 33 ± 8 40–49 22 ± 16 29 ± 16 30 ± 17 <40 Ovarian ablation vs nil Any death % Cancer death % Recurrence % Age group Reduction (SE) in annual odds

59. 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

61. Endocrine therapy in the neoadjuvant setup

66. Endocrine therapy in Metastatic Breast Cancer

68. Selection of patient & Rx 13% Neck nodes 15% Soft tissue 2% Brain 11% Liver 15% Lung 30% Bone (osteoblastic) 40% Bone (osteolytic) 10% Opposite axilla 10% Opposite breast 12% Local recurrence % OR Site Premenopausal Ovarian Ablation Postmenopausal Tamoxifen AIs Resistance Fulvestrant / Progestins High dose Estrogen ??

75. 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

87. Technique and results Circumscribed necrosis

89. Endocrine therapy in Preventive & other settings

97. Thank You