When all you have is a hammer…

1. When all you have is a hammer… Endocrine therapy Chemotherapy Targeted therapies Radiotherapy 1

5. Hormonal treatment of Breast Cancer

6. 1990’s Demonstration of the therapeutic efficacy of Tamoxifen 1970’s Development of Tamoxifen 1870 1st description of surgical oophorectomy 1980’s ER/PR detection and resurgence in interest in endocrine Rx Time Line

7. Endocrine pathways in cancer

8. Estrogen and Progesterone receptors • Several authors demonstrated the relationship of the cytosolic form ER to the efficacy of endocrine therapy. • The nuclear translocation and subsequent transcription are dependent on several co-repressors and activators. • The SRC co activator action is particularly important in this regard. • Recently ER-β has been identified.

9. Rationale for receptor based Rx • Response rates to endocrine manipulation in ER +ve patients was as high as 53% ( only 6% in ER –ve) – Whitliff et al. • Receptors correlate with other prognostic markers: • Cellular turnover rates, • Nuclear grade, and • Degree of histologic differentiation • Receptor positivity also correlates with: • Disease-free interval • Decreasing tumor size • Prolongation of DFS is independent of menopausal status, tumor size, and nodal status.

10. Mechanism of action • All endocrine therapies target the estrogen receptor at one level or other. • While the PR receptor doesn't act as a target directly it does indicate a functional ER pathway as it is a ER induced gene.

11. Selective Estrogen Receptor Modulators: Tamoxifen Torimefene Androgens Fluoxymesterone Progestins Megestrol acetate Medroxyprogesterone acetate High dose Estrogens Aromatase inhibitors: Letrozole Anastrazole Exemestane Steroidal Antiestrogens: Fulvestrant LHRH agonists Leuprolide Goserelin Gland ablation Ovary Pituitary Adrenals Endocrine therapies

12. SERM • The SERMs are chemically diverse compounds that lack the steroid structure of estrogens but possess a tertiary structure that allows them to bind to the estrogen receptor. • Examples: • Tamoxifen • Raloxifen • Toremifene • Selective modulation explained by: • Differential estrogen-receptor expression in a given target tissue • Differential estrogen-receptor conformation on ligand binding • Differential expression and binding to the estrogen receptor of coregulator proteins

13. Tamoxifen • Chemically a triphenylethylene. • The trans isomer is used as a citrate salt. • MOA: Competitive binding to the estrogen receptor resulting in reduction of transcription of estrogen regulated genes. • Dimethylaminoethoxy side chain and the trans configuration are crucial for the antiestrogenic activity of tamoxifen • The net result is a block in the G1 phase of the cell cycle and a slowing of cell proliferation. • Tamoxifen is thus, a cytostatic drug.

14. Pharmacokinetics • Long t1/2 : 7 -14 days. • OD dose can be used • Reduced bioavailability is not a cause for resistance. • False negative receptor assays for several months after stopping Rx in tumor tissue. • Metabolism in liver and excretion in feces ► Renal dysfunction not a contraindication. • Metabolized by CYP 450 3A4 enzyme: • Can reduce warfarin metabolism. • Careful INR monitoring needed in patients receiving warfarin with tamoxifen.

15. Aromatase Inhibitors • Include a class of drugs which prevent peripheral conversion of androgens to estrogen. • Also cause selective impairment of gonadal steroidogenesis. • Thus are capable of selective estrogen deprivation without impairment of adrenal androgen synthesis. • Two types exist: • Type I : Enzyme inactivators (Steroidal) • Type II : Competitive antagonists ( Non steroidal) • 3 generations exist: • 1st generation: Aminoglutethemide • 2nd generation: Formestane (Type I) , Fadrazole • 3rd generation: Exemestane (Type I) , Anastrazole , Letrozole, Vorozole

16. 3rd generation AI • These drugs inhibit the Aromatase enzyme selectively by blocking the heme moiety of the enzyme. • Active sites of other steroidogenic enzymes remain free. • 3rd generation AIs are 3 times more potent than aminoglutethemide. • Dose: • Letrozole (Femara) – 2.5 mg OD • Anastrazole (Arimidex) – 1 mg OD • Exemestane (Aromasin) – 25 mg OD Anastrazole Letrozole

17. Ovarian Ablation/ Suppression • Ovarian ablation classically includes techniques that cause permanent cessation of menstruation. • Techniques: • Surgical oophorectomy • Radiation induced oophorectomy • Ovarian suppression on the other hand refers to the suppression of ovarian function through the use of LHRH analogues. • Uses: • Treatment of breast cancer: • Adjuvant setting • Metastatic cancer • Prevention of hereditary breast cancer syndromes

18. Radiation oophorectomy • First series reported by Foveau de Courmelles in 1922 • Radiation oophorectomy: • Non invasive and cheap procedure. • Low dose carries little additional morbidity. • However takes time for effect to appear usually 2-3 months • For such reason best avoided when prompt relief is needed. • Also best reserved for the patient with slow progression of disease.

19. Technique • Position: Supine • Field selection: Parallel opposing two field technique • Energy : Co60 or 6 MV LINAC • Dose Schedules: • In a younger women 10 – 12 Gy in 5 -6 divided fractions is preferred. • In older women shorter course of radiation can give equivalent ovarian ablation. • Field borders: • The volume of interest is the entire true pelvis • 10 x 15 cm field is opened. • Lower border is placed just below the superior border of pubic symphysis.

20. Results • Treves in 1957 showed that following ovarian irradiation 10 yrs survival improved from 33.8% to 42.3%. • Benefit was greater in patients who had node negative disease as compared to patients with node positive disease. • Paterson and Russel (1959) also found that survival improved from 54.9% to 62.6% after addition of ovarian irradiation.

21. Endocrine therapy in the adjuvant setting

22. Ca Breast for adjuvant therapy Low risk*, node -ve Node +ve High risk, node -ve Receptor + ve Receptor - ve Receptor + ve Receptor - ve No Rx Chemotherapy Tamoxifen only Premenopausal Postmenopausal CCT + Tamoxifen# CCT + AI * 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.

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24. Adjuvant Tamoxifen alone • Several trials have demonstrated that tamoxifen adds significantly to the DFS in the adjuvant setting. • Two major trials have also demonstrated a OS benefit

25. Overall benefits of tamoxifen Rx • While the patients are on tamoxifen: • 1 of every 2 recurrences and • 1 of every 3 deaths are avoided by the tamoxifen therapy. • Tamoxifen continues to demonstrate further reductions in the odds of recurrence and death in years 5 through 9. • This is called the “carryover effect”

26. Optimal Duration of Tamoxifen Rx • In the EBCTSG meta-analysis 5 yr tamoxifen reduced the risk of recurrence and death twice as much as 2 yr tamoxifen therapy. • In two large European trials from Britain and Sweden, women treated with tamoxifen for 5 years, had fewer recurrences and deaths than those treated for only 2 years.

27. Dose of tamoxifen • 20 mg once daily dose of tamoxifen is the standard dose. • Higher doses are not more effective • Also lead to greater incidence of side effects.

28. Tamoxifen in Elderly patients • All meta-analyses have demonstrated a stastically significant benefit for addition of Tamoxifen in patients aged > 70 yrs. • ECOG evaluated the role of 2yr tamoxifen therapy vs placebo in 180 women aged > 65yrs • Drug was well tolerated • Significant reduction in recurrences • Borderline significant reduction in risk of death • Tamoxifen also reduced the incidence of contralateral breast cancers • Problems with adjuvant tamoxifen in elderly population: • High risk of death for unrelated cancer (22% in ECOG trial) • Poor adherence to prescribed treatment • Risk of thromboembolism increases with age.

29. Advantages of combining CCT with Tmx include: Elimination of both chemoresistant and tamoxifen resistant cell populations. Tamoxifen and progestins inhibit p-glycoprotein, an effect that could enhance sensitivity to drugs such as doxorubicin. The apoptosis inhibitor Bcl-2 is down-regulated by tamoxifen, possibly enhancing sensitivity to drugs using this cell death pathway. Disadvantages of combined approach: Cytostatic nature of tamoxifen may interfere with chemotherapy by locking cells in chemoresistant phases of cell cycle. It also antagonizes calmodulin and is an effective Ca2+ channel antagonist—effects that could alter drug uptake. Tamoxifen and chemotherapy

30. AI in adjuvant setting • 7 trials have been reported all of which involve post menopausal females with HR +ve disease. • A theoretical priming benefit initial tamoxifen made many trials use tamoxifen in initial 2-3 yrs prior to witching over to tamoxifen. * Placebo controlled

31. Menopausal symptoms: 50% - 60% ( N.B. 40% - 50% in placebo) MC in premenopausal Vaginal dryness and discharge may occur in excess. Depression: Maybe seen in as high as 10% of patients. But no randomized comparisons available. Ocular toxicity: Keratopathy, maculopathy & cataract Reported with high doses However NSABP studies have found no increase in vision threatening ocular toxicity. Thromboembolism: Severe thromboembolism seen in ~ 1% patients in the preventive setting. Risk up to 10 times that experienced by healthy women Complication more common in elderly patients with metastatic breast cancer and who are receiving CCT Carcinogenesis: Increased risk of endometrial cancers (hazard rate of 1.7 per 1000 – NSABP B 14 data) Mostly low grade & stage I tumors. Other tumors: Hepatomas Clear cell sarcomas of ovary Tamoxifen Toxicity

32. 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.

33. Endocrine therapy in the neoadjuvant setup

34. Use of hormone therapy • Best suited for a hormone receptor positive, postmenopausal woman • Presence of +ve HR strongly influences response to preoperative endocrine therapy • Complete and partial response rates of the order of 40 - 70% • Majority of patients will have evidence of tumor shrinkage by 3 months. • Progression of disease is uncommon in hormone-sensitive patients receiving preoperative therapy (<5%)

35. Summary • The strategy of preoperative endocrine therapy will require more studies. • Exciting area for further translational research: • The therapeutic target is known and can, therefore, be measured • The biologic pathways arising from the therapeutic target have been extensively studied • Slower response to therapy gives a greater window of opportunity for assessing changes in tumor tissue. • Caution: 2nd generation taxane based CCT regimes have clinical response rates ranging from 80 -90%.

36. Endocrine therapy in Metastatic Breast Cancer

37. Guidelines • Endocrine therapy should be started in all hormone receptor positive females with metastatic breast cancer. • Hormone therapy may be suitable as a sole therapy in patients with severe comorbid conditions or very old age. • AI are standard 2nd line agents after tamoxifen therapy. • Recently evidence has emerged which highlights the superiority of AI in the 1st line setting too. • In premenopausal females ovarian ablation may be another alternative. It also allows use of AI in this population. • Selection of the appropriate initial management depends on: • Tempo of the disease (Slower progress, fewer symptoms) • Vital organ involvement ( Bone & Soft tissue) • General condition of the patient (Older age, poorer GC) • Socio economic conditions.

38. Premenopausal Ovarian Ablation Postmenopausal Tamoxifen AIs Resistance Fulvestrant / Progestins ?? High dose Estrogen Selection of patient & Rx

39. Tumor Flare • Tumor Flare: • Incidence: • 4% to 7% with high-dose estrogen • 3% to 13% with tamoxifen • Dramatic  in bone pain, an  in size & number of metastatic skin nodules, and erythema. • Within days to several weeks after starting treatment • Hypercalcemia in 5% • Tumor regression may occur as the flare reaction subsides • Look for objective evidence of disease progression if the patient's symptoms have not resolved by 4 to 6 weeks as flare is transient

40. AI : 1st line therapy • 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.

42. Taxanes — Taxanes are among the most active agents for metastatic breast cancer – Docetaxel, Paclitaxel, NabPaclitaxel. Anthracyclines – Doxorubicin, Epirubicin, Caelyx. Capecitabine / 5 FU Eribulin Vinorelbine Gemcitabine Ixabepilone Etoposide Cyclophosphamide Methotrexate Platinum agents Combination Chemotherapy High Dose Chemotherapy and Stem Cell Transplant – no benefit.

43. Common Adjuvant Regimens 20% 20%

44. Doxorubicin 60 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles RANDOMIZE Docetaxel 75 mg/m2 IV Day 1 Cyclophosphamide 600 mg/m2 IV Day 1 Every 21 days x 4 cycles

45. 2nd Generation Adjuvant Chemo Trials

49. What’s the Goal? • Select patients who will require systemic therapy • Find predictive factors (either before or early in treatment) that allow for accurate tailoring of therapy