Hormone therapy for carcinoma breast

hormone for breast ca

1. HORMONAL THERAPY FOR BREAST CANCER Parag R oy Lok N ayak Hospital

2. INTRODUCTION Around 60-70% patients diagnosed to have breast cancer are Estrogen receptor-positive (65% of these are also positive for Progesterone receptors) Patients with Estrogen receptor-Positive (ER+) tumors have a better survival than tumors with no Estrogen receptors (ER- ) Five-year survival about 10 percent better for women with ER+ than for those with ER- tumors Patients with ER + tumors are candidates for hormonal therapy

3. TIMELINE OF DEVELOPMENT OF AGENTS IN BREAST CANCER

4. MOLECULAR BASIS Overexpression of Estrogen receptors is seen in a large number of breast cancer patients (~70%) Estrogen : Steroid hormone Profound proliferative effect on normal human mammary epithelium through its activation of ER-alpha, a classic nuclear hormone receptor Exerts its actions through both genomical and nongenomical mechanisms

5. C lassical genomic mechanism: Estrogen binds to an intracellular Estrogen receptor (ER ) ER dimerizes with another ER ER complex translocates to the nucleus and then binds to the Estrogen response element (ERE) leading to transcription Non Classical genomic mechanism: Estrogen binds to a membrane bound ER Second messenger systems are activated molecules from second messenger systems bind to DNA regulatory regions such as cAMP response element (CRE) and serum response element (SRE) regions to activate transcription

6. Non Genomic Mechanism : Believed to result from the hormone-dependent activation of membrane-bound and/or cytosolic ERs. These nonnuclear ER actions result in very rapid phosphorylation and activation of important growth regulatory kinases including EGFRs IGF-1R c- Src Shc p85 regulatory subunit of PI3-K

7. HORMONAL THERAPY

8. SITE OF ACTION OF HORMONAL DRUGS

9. HORMONE RECEPTOR STATUS AND PROBABILITY OF RESPONSE TO THERAPY Estrogen Receptor Status Progesterone Receptor Status Response Probability Positive Positive High (50-70%) Positive Negative Intermediate (33%) Negative Positive Intermediate (33%) Negative Negative Low (Less than 10%) At 10 yrs : The recurrence rates were reduced by 14% and 11% in node – ve and + ve patients respectively. Similarly, mortality reduced by 14.8% and 12% respectively.

10. AGENTS USED IN HORMONAL THERAPY Selective Estrogen Receptor Modulators (SERM) Tamoxifen Raloxifen Torimefene Anti Estrogens Fulvestrant Aromatase Inhibitors Letrozole Anastrazole Exemestane LHRH Agonists Leuprolide Goserlin Progestins Megestrol acetate Medroxyprogesterone acetate Gland ablation Ovary Pituitary Adrenals

11. SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) TAMOXIFEN 1 st hormonal drug approved by the FDA for usage in Breast Cancer Chemically : Triphenylethylene Mechanism of action : Competitive binding to the estrogen receptor resulting in reduction of transcription of estrogen regulated genes Blocks the cell cycle in G1 phase Cytostatic drug

12. ANCILLARY BENEFITS OF TAMOXIFEN Cardiovascular: Fewer non cancer related deaths due to cardiovascular events. Fewer hospitalizations for cardiac events Serum LDL / cholesterol reduced. Actual magnitude of benefit still unclear. Skeletal: Significant reduction in incidence of fractures of weight bearing bones. Estrogen agonist action on BMD Prevention of contralateral breast cancer

13. TOXICITY OF TAMOXIFEN Menopausal symptoms : MC in premenopausal Vaginal dryness and discharge may occur Depression Ocular toxicity : Keratopathy , maculopathy & cataract Reported with high doses Thromboembolism : Complication more common in elderly patients with metastatic breast cancer and who are receiving CCT Carcinogenesis : Increased risk of endometrial cancers Mostly low grade & stage I tumors. Other tumors : Hepatomas Clear cell sarcomas of ovary

14. ANTI ESTROGENS (SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR) Fulvestrant ANTI- ESTROGENS Fulvestrant

15. ANTI ESTROGENS FULVESTRANT Steroidal antiestrogen . Considerably higher affinity for Estrogen receptor than tamoxifen Promotes accelerated ER turnover, Suppression of ER protein levels, Inhibition of ER dimerization, Reduced shuttling of the ER from the cytoplasm to the nucleus Developed for clinical use as a 250-mg intramuscular monthly depot injection Developed to counter the estrogenic effects of Tamoxifen on uterus and the bone related effects of AIs.

16. AROMATASE INHIBITORS Letrozole Anastrazole Exemestane

17. AROMATASE INHIBITORS Work by inhibiting the action of the enzyme  aromatase Peripheral conversion of   androgens  into  estrogens  by a process called aromatization 2 types available (3 rd Generation) Steroidal Inhibitors : Exemestane Irreversible Inhibition P ermanent and deactivating bond with the aromatase enzyme Non steroidal Inhibitors : Letrozole , Anastrazole Reversible Inhibition inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme

18. Toxicity Hot Flushes: Usually self limiting HRT / SSRIs are not recommended Vaginal Bleeding: Watch out for an endometrial CA in post menopausal females. Myalgia / Arthalgia : Switching to Tamoxifen may be required. Osteoporosis: Calcium supplements, Vitamin D and bisphosphonates HRT / Raloxifen not recommended

19. LHRH AGONISTS Leuprolide Goserelin

20. LHRH ANALOGUES A nalogue that activates the GnRH receptor resulting in increased secretion of FSH and LH A fter their initial stimulating action – termed a “flare” effect - eventually causes a paradoxical and sustained drop in gonadotropin secretion This second effect i s termed “ downregulation ” and can be observed after about 10 days. While this phase is reversible upon stopping the medication, it can be maintained when GnRH agonists use is continued for a long time.

21. PROGESTINS Megestrol acetate Medroxyprogesterone acetate

22. PROGESTINS P owerful   antiandrogenic  and  antiestrogenic   effects S ignificantly lowers the  expression of the androgen receptor  (AR) and the  Estrogen receptor  (ER) in the body The antineoplastic action of progestins on carcinoma of the breast is effected by modifying the action of other steroid hormones and by exerting a direct cytotoxic effect on tumor cells

23. HORMONAL THERAPY IN ADJUVANT SETTING Tamoxifen is the agent of choice for all pre menopausal patients with Estrogen receptor positivity 5 years of adjuvant Tamoxifen reduced the risk of breast cancer recurrence and death at 15 years

24. Several trials have demonstrated that Tamoxifen adds significantly to the DFS in the adjuvant setting. Two major trials have also demonstrated a overall survival benefit Trial Dose Duration DFS OS NATO 20 2 P < 0.05 P < 0.05 Christie 20 1 P < 0.05 NS Stockholm 30 2 P < 0.05 NS CRC 20 2 P < 0.01 NS Scottish 20 5 P < 0.05 P < 0.05 NAL THERAPY HORMONAL THERAPY IN ADJUVANT SETTININ ADJUVANT SETTING HORMONAL THERAPY IN ADJUVANT SETTING

25. Reduction in Annual Odds * Recurrence Cancer Deaths Any Deaths Node negative 0 – 4 yrs 48% 33% 25% 5 + yrs 35% 30% 21% Node Positive 0 – 4 yrs 41% 40% 29% 5 + yrs 20% 38% 36% TAMOXIFEN AND NODAL STATUS Ref : Tamoxifen for early breast cancer: an overview of the randomised trials Early Breast Cancer Trialists ’ Collaborative Group Lancet 1998; 351: 1451–67

26. SOFT TRIAL N Engl J Med 2015;372:436-46

27. NO DIFFERENCE IN DFS AND FREEDOM FROM BREAST CANCER AT 5 YEARS

28. Exemestane  plus Ovarian Suppression had a higher rate of Freedom From Breast Cancer

29. TAMOXIFEN AND EXEMESTANE TRIAL(TEXT) 2 arms Triptorelin + exemestane Vs Triptorelin + tamoxifen 4690 women were included in the intention to treat population Median follow up period – 68months N Engl J Med 2014;371:107-18

30. DFS IS BETTER WITH EXEMESTANE AFTER 5 YEARS NO DIFFERENCE IN OVERALL SURVIVAL TREATMENT DISCONTINUE IS MORE WITH EXEMESTANE (16% Vs 11%)

31. HORMONAL THERAPY IN ADJUVANT SETTING Duration of therapy : Earlier 5 years of Tamoxifen was the recommendation 2 trials : ATLAS and aTTom have been done to see the advantage of giving Tamoxifen for more than 5 years Both the trials have confirmed benefits of giving the drug for 10 years in high risk paients ASCO 2014 Update on adjuvant Hormonal therapy in Breast Cancer recommends the use of Tamoxifen for 10 years in pre and peri menopausal females with Estrogen receptor positivity

32. ATLAS trail

33. RECURRENCE MORTALITY Significant reduction in the risk of recurrence and breast cancer mortality with 10yr of tamoxifen compared with a five-year treatment course

34. aTTom trial

35. aTTom trial (prelim result) Between 1991 and 2005, 6,934 women with ER+ (39%), or ER untested (61%) invasive breast cancer (53% node negative, 31% node positive, 16% node status unspecified) All completed 4+ years of adjuvant tamoxifen Randomized between continuing for another 5 years and stopping Median follow-up of 4.2 years, there were fewer recurrences those allocated to 10yrs than 5yrs tamoxifen . Breast cancer mortality was lower among those allocated 10yrs, Despite a doubling in the risk of endometrial cancer (76 vs 35) with 10yrs tamoxifen , there was no increase in deaths from endometrial cancer (10 vs 12) or from any other non-breast cancer cause. Results are consistent with preliminary findings from the atlas trial

36. HORMONAL THERAPY IN ADJUVANT SETTING Aromatase Inhibitors Have been proven beneficial in Post menopausal setting No benefit seen in Pre menopausal setting Presently considered the 1 st line hormonal therapy in Post menopausal setting

37. Ref : Perez and Brady’s Principles and Practice of Radiation Oncology, 6 th edition

38. ADJUVANT HORMONAL THERAPY IN POSTMENOPAUSAL

39. AI produce significantly lower recurrence rates compared with tamoxifen , either as initial monotherapy or after 2 to 3 years of tamoxifen .

40. MA -17 ATAC BIG IES Vaginal Complications - 1.7% - 14% - 3.3% - 1.5% Tamoxifen poorer Endometrial Cancer NA - 0.6% - 0.4% NA Thromboembolic events NA - 1.7% - 1.2% - .9% Cardiac complications 0.5% 0% 0.4% NA AI poorer Arthalgia /Myalgia 23% 7% NA 6% Osteoporotic fractures 2.3% 2.2% 1.7& 2% Hot flushes 6% 5% 4% 2% TOXICITY OF AROMATASE INHIBITORS VERSUS TAMOXIFEN

41. HORMONAL THERAPY IN ADJUVANT SETTING LHRH Agonists in Early breast Cancer Several trials have been done which have evaluated the role of LHRH agonists either alone or in combination with Tamoxifen or chemotherapy in adjuvant setting for Early breast cancer ZEBRA ABCSG 05 Trial GROTA 02 Trial ZIPP Trial INT 0101 Trial

42. CHEMOHORMONAL THERAPY median follow-up of 9.6 years, the addition of tamoxifen to CAF-Z improved TTR and DFS but not OS. There was no overall advantage for addition of goserelin to CAF

43. TIMING OF ENDOCRINE THERAPY  For women with hormone receptor-positive breast cancer who are not recommended to receive other adjuvant therapy ( eg , chemotherapy and/or radiotherapy), endocrine therapy is usually initiated four to six weeks after surgery.

44. WITH OR AFTER CHEMOTHERAPY North American Intergroup trial , 637 postmenopausal women with node-positive, hormone receptor-positive breast cancer were treated with chemotherapy and randomly assigned to treatment with tamoxifen  initiated during or following completion of chemotherapy. At 13 years of follow-up, sequential treatment resulted in: A trend towards improvement in DFS compared with concurrent treatment (HR 0.84, 95% CI 0.70-1.01) No improvement in OS (HR 0.90, 95% CI 0.73-1.10)

45. WITH OR FOLLOWING RADIATION THERAPY  Multiple studies show that the timing of endocrine therapy in relation to RT does not impact survival Some older studies suggest that concurrent treatment increases the risks of treatment complications (including pulmonary and/or breast fibrosis)

46. Women of childbearing potential  — Women who are of childbearing potential should be advised to use an effective means of contraception while on Tamoxifen  treatment because tamoxifen can induce ovulation. Following completion of  Tamoxifen  treatment, a waiting period of two months from drug discontinuation prior to attempting pregnancy is suggested to ensure that it has been cleared from the body Tamoxifen use is contraindicated during pregnancy as it can cause congenital anomaly

47. ENDOCRINE THERAPY IN METASTATIC BREAST CANCER Endocrine therapy should be started in all hormone receptor positive females with metastatic breast cancer. Hormone therapy may suitable as sole therapy with severe comorbid conditions or very old age. AI are standard 2 nd line agents after tamoxifen therapy. Recently evidence has emerged which highlights the superiority of AI in the 1 st 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.

48. OVERALL EFFECT OF ENDOCRINE RX Bone Mets: Significant and quick relief of pain Increased bone calcification and sclerosis Reduced hypercalcemia and calcium loss. Better benefit in osteolytic ( osteoclastic ) leisons . Skin / soft tissue mets : Nodular leisons respond better than lymphangitic leisons . Edema is rarely reduced. Choroidal metastasis: Regression and vision recovery may be seen in 10 - 20% Pleuropulmonary leisons : Significant number of patients have reduction in size of leisons and effusions. Systemic effects: Increased feeling of well being Reduced incapacitation due to pain Metastatic leisons that don’t respond: Hepatic Cerebral

49. Endocrine Rx in Metastatic CA Tamoxifen remains the gold standard. Been in use since 1970s Began to be used instead of high dose estrogens which were due to highly favourable side effect profile. Response rates range from 16% to 56% (Median 30%) – same as ovarian ablative techniques. Overall mean TTP for patients with metastatic disease treated with tamoxifen is about 6 months Duration of response is between 12 and 18 months

50. AI : 2 nd Line therapy 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.

51. AI : 1 st 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. Trial Drug N RR TTP (mo) Comment Nabholtz et al 1 Ana 353 21% 11.1* Retrospective analysis revealed longer TTP with Anastrazole after combining these two trials 3,4 Tmx 17.7% 5.6 TARGET trail 2 Ana 668 32.9% 8.2 Tmx 32.6% 8.3 Mouridsen et al 5 Let 907 30% 9.4 Tmx 20% 6.0

52. AI : 1 st line therapy Several trials have shown that the TTP is significantly improved in metastatic breast cancer when AI are used as 1 st line therapy instead of tamoxifen. The impact on OS not clear however. In the trail comparing Letrozole to Tamoxifen it was shown that OS improved in the first 2 yrs. However no benefit exists at 5yrs. However due to crossing over a significant impact on OS may have been lost. Crossing over to Tamoxifen after initial AI therapy may be theoretically unwise as: Estrogen deprived cancer cells may be become paradoxically sensitive to tamoxifen.

53. AI : 1 st line therapy Toxicity: Patients on AI therapy have experienced significantly lesser thromboembolic phenomenon. However the incidence of hot flashes is increased. There have been no trials which showed a benefit of one AI over another. One trial comparing Letrozole vs Anastrozole failed to show a difference in TTP or other parameters. Because intratumoral Aromatase inhibition is most important so it s unlikely any particular AI will be more beneficial over the other.

54. Treatment after progression on AI Progression after 1 st line AI therapy is difficult to tackle. A retrospective analysis has shown that objective response after tamoxifen therapy is of the order of 10% after AI failure. Another phase II trial has shown that Exemestane may be associated with a response rate of 6.6% after Letrozole / Anastrazole therapy. No endocrine therapy is thus available that can give promising results after AI failure.

55. Fulvestrant A potent inhibitor of estrogen-dependent transcription. In preclinical models, Fulvestrant was found to be effective against tamoxifen-resistant MCF7 cell xenografts. In a trial comparing 1 st line tamoxifen vs fulvestrant, no advantage was obtained in TTP or overall response over tamoxifen. Given easier use of AI / Tamoxifen place in therapy remains questionable. Trial N Response Rates (%) Stable Disease ≥ 24 wk (%) Time to Progression (mo) Osborne et al An 400 17.5 18.6 3.4 Ful 17.5 24.8 5.4 Howell et al Ana 451 15.7 45 5.1 Ful 20.7 44.6 5.4

56. Ovarian Ablation In a 2001 meta analysis by Klijn et al comparing adjuvant Tamoxifen + LHRH agonist vs LHRH agonist alone in advanced breast cancer: 22% reduction in the hazard of death for the combined treatment group 30% reduction in the hazard of progression/death for the combined treatment group. Median duration of response in patients receiving combined treatment was 602 days, compared with a median of 350 days in those receiving LHRH agonist alone Klijn, J. G. M. et al. J Natl Cancer Inst 2000;92:903-911 LHRH alone LHRH + Tmx TMX alone

57. High Dose Estrogens Considered only in postmenopausal women as ineffective before the menopause Activation of the FAS cell death receptor  therapeutic response Estrogen deprivation  upregulation of FAS receptor Estrogen  FAS ligand expression Reduction in serum IGF -1 and 2 levels. Reasonable alternative to chemotherapy in setting of failure to initial hormonal therapy (old age / poor GC) Doses: DES – 5 mg TDS Ethinyl Estradiaol: 30 mg in 3 – 4 divided doses Contraindication: DVT Cardiac problems Can produce objective responses in ~ 30 – 40% patients who have received endocrine therapy.

58. Progestins Useful in some selected patients who have developed resistance to SERM and AIs Megestrol acetate is used (160 mg /d) C/I include: Thromboembolic events Diabetes Needs evaluation in phase II trials for usefulness as 3 rd line agent. MOA: ? Aromatase inhibition ? Estrogen turnover increased (Estrogen deprivation) ? Separate action through PRs.

59. Other ablative procedures Adrenalectomy: Adrenals are source of estrogen in PM female. In large series ( 1950s – 60s) objective response rates varied from 28% - 59% (Mean 42%) Duration of benefit varied from 12 – 36 months. Necessity for life long hormone replacement and high operative mortality  obsolescence. Hypophysectomy: Another ablative procedure associated with response rates ranging from 40% - 50% Response duration ~ 18 months Better tolerance than adrenalectomy made this procedure a better choice.

60. Radiation Hypophysectomy Need to deliver doses in range of 100 Gy – 200 Gy to bring pituitary ablation. Investigators in the Berkley university have used proton beam therapy ( 50 Gy x 6 # = 300 Gy ) This dose ablated 90% of the pituitary glands with minimal morbidity. Growth Hormone  Thyroid hormones  Gonadotropin  Estrogen and Progesterone  Corticosteroid.

61. HORMONAL THERAPY IN NEO ADJUVANT SETTING Limited data Mostly used in patients with locally advanced breast cancer who are deemed unfit for systemic chemotherapy Responses are slower than neo adjuvant chemotherapy Rates of pathological complete response ( pCR ) are also less than neo adjuvant chemotherapy

62. IMPACT Trial : Immediate Pre operative Anastrazole , Tamoxifen or Combined with Tamoxifen Trial 330 Estrogen receptor positive post menopausal females randomised to 1:1:1 Response rates of 36% to 39 % Only 1% to 3% achieving a clinical complete response Rates of breast conservation after 3 months of neo adjuvant hormone treatment were highest in the anastrozole -alone arm HORMONAL THERAPY IN NEO ADJUVANT SETTING

63. PROACT Trial : Pre operative “ Arimidex ” compared to Tamoxifen Trial Objective responses for anastrozole and tamoxifen occurred in 39.5 % and 35.4% of patients, respectively (ultrasound measurements), and 50.0% and 46.2 % of patients respectively ( caliper measurements ). Anastrozole is an effective and well-tolerated preoperative therapy,producing clinically beneficial tumor downstaging and reductions in tumor volume Anastrozole appears to be at least as effective as tamoxifen HORMONAL THERAPY IN NEO ADJUVANT SETTING

64. HORMONAL THERAPY IN PREVENTION OF BREAST CANCER The BCPT trial ( NSABP P1 ) was designed to evaluate the efficacy of Tamoxifen given for 5yrs in high risk population 49 % reduction in invasive breast cancer 50 % reduction in non invasive cancers ER + ve tumors were much less frequent in women receiving tamoxifen Incidence of ER – ve tumors remained same Reduction in rates of occurrence of tumors of all sizes The FDA has now approved the use of tamoxifen in high risk women to reduce breast cancer incidence. STAR trial evaluated role of Raloxifen in prevention of breast cancer

65. CONCLUSIONS Endocrine therapy is a safe and well tolerated targeted treatment modality in majority of patients with breast cancer. In the adjuvant setting primary treatment with Tamoxifen should be considered in all receptor positive pre menopausal females. Ovarian ablation may have additive benefits with Tamoxifen in premenopausal females. Aromatase Inhibitors have a major role to play in hormone positive post menopausal females

66. CONCLUSIONS There is insufficient data on neo adjuvant hormonal therapy presently However, it can be considered in hormone positive females who have a poor general condition or have contraindications for systemic chemotherapy In the setting of metastatic breast cancer, hormone receptor positivity gives a lot of options to be utilised in cases of failure on one therapy or progression on one therapy Hormonal therapies have also been found useful in chemo prevention, however, sufficient data is lacking for routine usage

67. Thank you !!!