1. Management of ER-Positive Postmenopausal Early Breast Cancer

2. Current Hormonal Therapy Strategies for ER-Positive Postmenopausal Breast Cancer

3. 3 Adjuvant hormone therapy (B) Postmenopausal GNRH agonists Breast carcinoma Breast carcinoma Antiestrogen Ovary LH FSH LH FSH Antiestrogen (A) Premenopausal Adrenal Estrogen Androstenedione Aromatase inhibitor Aromatase inhibitor Peripheral aromatization Peripheral aromatization Adapted with permission from Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777. GNRH = Gonadotropin-releasing hormone; LH = Luteinizing hormone; FSH = Follicle-stimulating hormone.

4. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer

5. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer

6. Androstenedione Steroidal Inactivators Androgen Substrate O CH 2 O Exemestane O O Nonsteroidal Inhibitors CH 3 NC CN Anastrozole Letrozole N NC CN N N N N N Third-Generation Aromatase Inhibitors/Inactivators

7. Selective inhibitors Nonselective inhibitors Multiple steps involving P-450 enzymes and production of steroid intermediates Cholesterol Cortisol Androstenedione Aldosterone Testosterone Estrone Estradiol Federman, DD. The adrenal. Scientific American Medicine. Dale DC, Federman DD, eds. Section 3. Subsection IV. ©1997 Scientific American Inc. All rights reserved. Selective vs Nonselective Aromatase Inhibition

8. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer

9.  Recruitment: July 1996 - March 2000  Median follow-up: 100 months  84% hormone receptor positive  61% node negative Anastrozole 1 mg/day + Tamoxifen 20 mg/day (n = 3215) Tamoxifen 20 mg/day (n = 3116) Surgery ± RT ± Chemotherapy Anastrozole 1 mg/day (n = 3125) 5-yr interim analysis Discontinued early ATAC Trialists' Group. Lancet. 2004. Published online, December 8, 2004. 10-yr analysis planned Postmenopausal women with invasive breast cancer (N = 9366) ATAC Trial

10. Patients (%) 30 25 20 15 10 5 0 2618 2598 2541 2516 2453 2400 2361 2306 2278 2196 2159 2075 1995 1896 1801 1711 1492 1396 608 547 At risk: Anastrozole Tamoxifen 13.9 16.4 25.8 29.9 0123456789 30 25 20 15 10 5 0 Tamoxifen Anastrozole Follow-up Time (Yrs) 2.54.1 Reprinted from The Lancet Oncology, 2008;9:45-53, Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Copyright (2008), with permission from Elsevier. DFS: Hormone Receptor–Positive Patients HR95% CI P Value Hormone Receptor-Positive 0.85 (0.76- 0.94).003 Absolute difference

11. 7.8 9.1 13.2 15.6 Absolute difference1.32.4 Patients (%) 30 25 20 15 10 5 0 2618 2598 2551 2533 2470 2440 2393 2363 2320 2263 2201 2151 2042 1982 1854 1809 1536 1484 636 591 At risk: Anastrozole Tamoxifen 0123456789 30 25 20 15 10 5 0 Tamoxifen Anastrozole Follow-up Time (Yrs) Reprinted from The Lancet Oncology, 2008;9:45-53, Forbes JF, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Copyright (2008), with permission from Elsevier. HR 95% CI P Value Hormone Receptor-Positive 0.84 (0.72- 0.97).022 Time to Distant Recurrence: Hormone Receptor–Positive Patients

12. ATAC: Endpoints HR+ Patients Disease Free Survival Time to Recurrence Contralateral Br Ca Time to Distant Recurrence Death After Recurrence Death: All Causes Favors Anastrozole Favors Tamoxifen Hazard Ratio (95%CI) P Value 0.85 (0.76-0.94)0.003 0.76 (0.67-0.87)0.0001 0.60 (0.42-0.85)0.004 0.84 (0.72-0.97)0.022 0.90 (0.75-1.07)0.2 0.97 (0.86-1.11)0.7 0.20.40.60.81.01.21.52.0 Hazard ratio (A/T) and 95% CI Forbes JF, et al. SABCS 2007. Abstract 41. Permission from author to print.

13.  Significant long-term carryover effect for anastrozole –Absolute difference in recurrence increased from 2.8% after 5 years to 4.8% after 9 years –HR of anastrozole vs tamoxifen for Years 5-9: 0.75 (P =.01) 9-Yr Follow-up, % AnastrozoleTamoxifen Recurrence 17.021.8 HR: 0.76; P =.0001 Distant Recurrence 13.215.6 HR: 0.84; P =.022 Contralateral Breast Cancer 2.54.2 HR: 0.60; P =.004 DFS HR: 0.85; P =.003 Death After Recurrence HR: 0.90; P =.20 Forbes JF, et al. SABCS 2007. Abstract 41. ATAC: Efficacy of Anastrozole vs Tamoxifen in HR+ Population

14. Tamoxifen Letrozole TamoxifenLetrozole Tamoxifen RANDOMIZERANDOMIZE 025 YEARS A B C D 2-arm option 3/98 - 3/00 1835 patients 4-arm option 9/99 - 5/03 6193 patients BIG 1-98: Study Design

15. T 0 20 40 60 80 100 012345 Alive and Disease Free (%) Years From Randomization 97.7 97.6 Let Tam 95.1 93.4 90.5 89.0 86.8 84.6 84.0 81.4 NHR (95% CI)P Value 80100.81 (0.70-0.93).003 No. at Risk 3892 3896 2964 2926 1261 1238 892 866 4003 4007 567 544 Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757. Copyright @ 2005 Massachusetts Medical Society. All rights reserved. Let Tam Letrozole vs Tamoxifen: DFS

16. Years from Randomization Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757. Copyright @ 2005 Massachusetts Medical Society. All rights reserved. 023451 0 10 5 15 20 Failure (%) Letrozole Tamoxifen 13.6 10.2 8.1 6.2 5-year difference (Letrozole-Tamoxifen): -3.4% (SE: 1.2%) Cumulative incidence: P =.0002 Cumulative Incidence: Breast Cancer Relapse Year

17. BIG 1-98 (BIG FEMTA) TEAM EXE ATAC Tamoxifen Anastrozole Letrozole Exemestane Ongoing First-Generation Aromatase Inhibitor Adjuvant Trials

18. Exemestane (5162*) Tamoxifen (5294*) Tamoxifen (N = 4724) Posttherapy follow-up 2-3 years 5-yr total duration of endocrine therapy Start of study *Total women-years. Postmenopausal women with completely resected ER-positive or unknown status early-stage breast cancer Intergroup Exemestane Study: Trial Design

19. Intent-to-treat ER+/Unknown Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta- analysis. Copyright (2008), with permission from Elsevier. Year Abs diff, % (95% CI) 2.55.0 3.2 (1.6-4.9) 3.4 (0.1-6.8) 2.55.0 3.4 (1.8-5.1) 3.5 (0.1-6.9) End of treatment End of treatment HR: 0.75 (95% CI: 0.65-0.87) Log rank test: P =.0001 E = 339/2296 T = 438/2306 HR: 0.76 (95% CI: 0.66-0.88) Log rank test: P =.0001 E = 354/2352 T = 454/2372 Intent to treatER+/Unknown 0 10 20 30 40 50 60 70 80 90 100 012345 DFS (%) 0 10 20 30 40 50 60 70 80 90 100 012345 DFS (%) Exemestane After Tamoxifen: DFS Time Since Randomization (Yrs)

20. End of treatment Year Abs diff, % (95% CI) 2.55.0 0.8 (-0.4 to 1.9) 1.2 (-1.5 to 3.9) 2.55.0 0.7 (-0.4 to 1.9) 1.6 (-1.2 to 4.3) Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta- analysis. Copyright (2008), with permission from Elsevier. End of treatment HR: 0.83 (95% CI: 0.69-1.00) Log-rank test: P =.05 E = 210/2296 T = 251/2306 HR: 0.85 (95% CI: 0.71-1.02) Log-rank test: P =.08 E = 222/2352 T = 261/2372 Intent-to-treatER+/Unknown 0 10 20 30 40 50 60 70 80 90 100 012345 Time Since Randomization (Yrs) Women Alive (%) 0 10 20 30 40 50 60 70 80 90 100 012345 Time Since Randomization (Yrs) Women Alive (%) Exemestane After Tamoxifen: OS

21. ARNO 95 2 years of previous tamoxifen (N = 979) Jonat W, et al. Lancet Oncol. 2006;7:991-996. Tamoxifen (n = 490) Anastrozole (n = 489) Year 5 ABCSG 8 2 years of previous tamoxifen (N = 2579) Tamoxifen (n = 1282) Anastrozole (n = 1297) ITA 2-3 years of previous tamoxifen (N = 448) Tamoxifen 2-3 years (n = 225) Anastrozole 2-3 years (n = 223) Meta-analysis of Anastrozole Sequencing Studies

22. Time to DFS Event (Yrs) 2009 1522 1161792509256999 1997 1492 1109764460241789 Anastrozole Tamoxifen Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta- analysis. Copyright (2008), with permission from Elsevier. Anastrozole Tamoxifen At risk: 0124567 0 60 70 80 90 100 Event Free (%) HR: 0.59 (95% CI: 0.48-0.74) P <.0001 38 DFS: Anastrozole vs Tamoxifen (ITT Population)

23. 0.20.40.60.81.0 ARNO 95 ITA Meta-analysis ABCSG 8 1.21.41.6.726.026.094.038 P value 2579 979 448 4006 Patients 0.93 0.48 0.50 0.71 HR Favors anastrozoleFavors tamoxifen Hazard ratios and 95% confidence intervals Reprinted from The Lancet Oncology, 2006;7:991-996, Jonat W, et al. Effectiveness of switching from adjuvant tamoxifen to anastrozole in postmenopausal women with hormone-sensitive early-stage breast cancer: a meta- analysis. Copyright (2008), with permission from Elsevier. OS: Anastrozole vs Tamoxifen (ITT Population)

24. Tamoxifen Letrozole 2.5 mg daily (n = 2575) Placebo (n = 2582) 5 years of early adjuvant5 years of extended adjuvant Node negative: n = 2581 Node positive: n = 2370 30 months of follow-up Extended Adjuvant Therapy MA.17: Trial Design

25. DFS* Distant* DFS OS Node- Negative Patients Node- Positive Patients HR: 0.61* (0.45-0.84) HR: 0.45* (0.27-0.73) HR: 0.63 (0.31-1.27) HR: 0.53* (0.36-0.78) HR: 1.52 (0.76-3.06) HR: 0.61* (0.38-0.98) *Statistically significant benefit of letrozole. Goss PE, et al. J Natl Cancer Inst. 2005;17:1262-1271. Extended Adjuvant Therapy: Letrozole After 5 Years of Tamoxifen  A similar reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patients

26. Placebo (n = 2594) 5 years Letrozole (n = 1655) 19982003 Unblinding2005 Letrozole (n = 2457) No Letrozole (n = 613) 30 months54 (16-86) months Median follow-up Goss PE, et al. SABCS 2005. Abstract 16. Letrozole After Unblinding of MA.17 Tamoxifen (N = 5187) Letrozole (n= 2593)

27. Goss PE, et al. SABCS 2005. Abstract 16. DFS Distant DFS OS Contralateral breast cancer HR 0.31 0.28 0.53 0.23 0 0.1 0.2 0.3 0.4 0.5 0.6 PLAC-LET to PLAC P <.0001 P <.002 P <.05 P <.012 Significant Advantage for PLAC-LET in Efficacy Outcomes

28. BIG 1-98 (BIG FEMTA) IES Trial ITA NSABP B33 Tamoxifen Anastrozole Placebo Letrozole Exemestane MA-17 Ongoing First-Generation Aromatase Inhibitor Adjuvant Trials

29. Summary  Aromatase inhibitors offer a modest but significant benefit over tamoxifen in both the metastatic and adjuvant settings  In the adjuvant setting, it remains unclear whether upfront aromatase inhibitor therapy is superior to sequencing approach  High-risk premenopausal patients should receive an aromatase inhibitor as part of their adjuvant therapy (after 2 years, 5 years, or when off tamoxifen)

30. Endocrine Therapy for Metastatic Breast Cancer

31. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer Initial Treatment of HR-Positive Advanced Breast Cancer  AIs are the current standard of care for initial treatment of postmenopausal women with HR-positive advanced breast cancer  AIs have demonstrated improved efficacy compared with tamoxifen –TTP, anastrozole vs tamoxifen: 10.7 vs 6.4 mos [6] –TTP, letrozole vs tamoxifen: 9.4 vs 6.0 mos [5] –PFS, exemestane vs tamoxifen: 9.9 vs 5.8 mos [7]  Fulvestrant has demonstrated improved efficacy compared with anastrozole –TTP, fulvestrant vs anastrozole: 23.4 vs 13.1 mos [8] –Fulvestrant has demonstrated similar efficacy compared with tamoxifen [9] –Combination fulvestrant and anastrozole was more efficacious than anastrozole alone [10] 6. Bonneterre J, et al. Cancer. 2001;92:2247-2258. 5. Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109. 7. Paridaens RJ, et al. J Clin Oncol. 2008;26:4883-4890. 8. Robertson FJ, et al. Breast Cancer Res Treat. 2012;136:503-511. 9. Howell A, et al. J Clin Oncol. 2004;22:1605-1613. 10. Mehta RS, et al. N Engl J Med 2012;367:435-444.

32. First-line Letrozole vs Tamoxifen, Then Crossover Median OS Letrozole: 34 mos Tamoxifen: 30 mos Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos Mouridsen H, et al. J Clin Oncol. 2003;21:2101-2109. P =.53 (long-rank test) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 06121824303642485460 Mos Proportion Alive Letrozole 1stTamoxifen 1st

33. In the CONFIRM trial, 500 mg of monthly fulvestrant was superior to 250 mg for which survival endpoints? A.PFS, but not OS B.Both PFS and OS C.Neither PFS nor OS

34. In the CONFIRM trial, 500 mg of monthly fulvestrant was superior to 250 mg for which survival endpoints? A.PFS, but not OS B.Both PFS and OS C.Neither PFS nor OS

35. CONFIRM: Fulvestrant 500 mg vs 250 mg in Postmenopausal Women With ER+ MBC Fulvestrant 250 mg* (n = 374) Fulvestrant 500 mg † (n = 362) Postmenopausal women with ER-positive advanced breast cancer (N = 736) *Fulvestrant 250 mg: 1 injection of fulvestrant 250 mg IM + 1 placebo injection on Day 0; 2 placebo injections on Day 14; 1 injection of fulvestrant 250 IM + 1 placebo injection on Day 28, then every 28 days thereafter. † Fulvestrant 500 mg: 2 injections of fulvestrant 250 mg IM on Days 0, 14, 28, then every 28 days thereafter. DiLeo A, et al. SABCS 2012. Abstract S1-4.

36. CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women  Baseline characteristics appeared well balanced between treatment arms –Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy Outcome Timing of Analysis Fulvestrant 500 mg Fulvestrant 250 mgHR (95% CI) Median PFSFirst*6.5 mos5.5 mos0.80 ‡ (0.68-0.94) Median OSFirst*25.1 mos22.8 mos0.84 § (0.69-1.03) Median OSFinal † 26.4 mos22.3 mos0.81 ¶ (0.69-0.96) *First analysis was performed at 50% maturity. † Final analysis was performed at 75% maturity. ‡ P =.006 § P =.001 ¶ P =.016 DiLeo A, et al. SABCS 2012. Abstract S1-4.

37. FIRST Study Design Robertson JF, et al. Clin Oncol. 2009;27:4530-4535. Endpoints at primary data cutoff Primary endpoint  Clinical benefit rate Secondary endpoints  ORR  TTP  Duration of response  Duration of clinical benefit  Safety Exploratory endpoint  Best response to subsequent therapy Open-label first-line ER+ postmenopausal patients with advanced breast cancer (target, N = 200; actual, N = 205) Fulvestrant 500 mg IM on Days 0, 14, 28, and every 28 days thereafter Anastrozole 1 mg/day PO Progression Follow-up Progression Follow-up

38. 0 0.2 0.4 0.6 0.8 1.0 06121824 Mos 30364248 Fulvestrant 500 mg Anastrozole 1 mg Proportion of Patients Alive and Progression Free HR: 0.66 (95% CI: 0.47-0.92; P =.01) Pts at Risk, n Fulvestrant 500 mg Anastrozole 1 mg 102 103 74 69 65 55 52 39 45 30 34 21 20 8 62620 Robertson JF, et al. Breast Cancer Res Treat. 2012;136:503-511. FIRST: TTP at Follow-up Analysis

39. Postmenopausal women with hormone receptor– positive MBC (N = 707) Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg every 28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Treatment until disease progression Stratified by previous adjuvant tamoxifen Women with progression encouraged to cross over to receive fulvestrant Mehta RS, et al. N Engl J Med. 2012;367:435-444. SWOG S0226: Study Design  Primary endpoint: PFS  Secondary endpoints: OS, safety

40. SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen EndpointAnastrozole + Fulvestrant AnastrozoleHR (95% CI)P Value Median PFS (n = 694), mos 15.013.50.80 (0.68-0.94).007  No previous adjuvant tamoxifen (n = 414) 17.012.60.74 (0.59-0.92).0055  Previous adjuvant tamoxifen (n = 280) 13.514.10.89 (0.69-1.15).37 Median OS (n = 694), mos 47.741.30.81 (0.65-1.00).049  No previous adjuvant tamoxifen (n = 414) 47.739.70.74 (0.56-0.98).0362  Previous adjuvant tamoxifen (n = 280) 49.644.50.91 (0.65-1.28).59 Mehta RS, et al. N Engl J Med. 2012;367:435-444.

41. Finn RS, et al. SABCS 2012. Abstract S1-6. Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC 0 0.2 0.4 0.6 0.8 1.0 06121014 Mos 16202228 PD 991 + LET (n = 84) 21 (25) 26.1 (12.7-26.1) PFS Probability Pts at Risk, n PD 991 + LET LET 84 81 75 57 60 38 53 29 43 22 35 17 25 11 31311 2426 18 8 2 4 0.3 0.5 0.7 0.9 0.1 LET (n = 81) 40 (49) 7.5 (5.6-12.6) 18 6 15 5 14 4 9393 5353 Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value 0.37 (0.21-0.63) <.001

42. EFFECT: Fulvestrant vs Exemestane After Progression of Nonsteroidal AI PFS Probability Mos Pts at Risk, n Fulvestrant Exemestane 3.7 Median, mos HR: 0.963 (95% CI: 0.819-1.133; P =.6531) Cox analysis, P =.7021 ExemestaneFulvestrant Exemestane 0369121518212427 0.0 0.2 0.4 0.6 0.8 1.0 3511959650251242 3421909841211286 0 1 0 0 Chia S, et al. J Clin Oncol. 2008;26:1664-1670.

43. Patients with which site of metastatic disease had the longest PFS with exemestane + everolimus vs exemestane in the BOLERO-2 trial? A.Bone only B.Liver only C.Lung only D.Any visceral disease E.No visceral disease

44. Patients with which site of metastatic disease had the longest PFS with exemestane + everolimus vs exemestane in the BOLERO-2 trial? A.Bone only B.Liver only C.Lung only D.Any visceral disease E.No visceral disease

45. Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889s-899s. ER target gene transcription SOS PP PP PI3-K akt P P RAS RAF MEK MAPK p90 RSK ER P p160 Basal transcription machinery CBP ER P P P ERE Plasma membrane Cytoplasm Nucleus E2 SERD AI T IGF1R EGFR/HER2 Increased signaling through PI3-K pathway Increased signaling through EGFR and/or IGF1-R VEGFR Mechanisms of Hormone Resistance

46. BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC Baselga J, et al. N Engl J Med. 2012;366:520-529. 06121824303642485460667278 Wks Probability of Event (%) Everolimus + exemestane (median PFS: 10.6 mos) Placebo + exemestane (median PFS: 4.1 mos) HR: 0.36 (95% CI: 0.27-0.47; log-rank P <.001) Patients at Risk, n Everolimus Placebo 485 239 385 168 281 94 201 55 132 33 102 20 67 11 43 11 28 6 18 3 9393 3131 2020 0000 100 90 80 70 60 50 40 30 20 10 0 Central Assessment

47. BOLERO-2: Final PFS Analysis (18-Mo Follow-up) PFS, MosEVE + EXEPBO + EXEHR (95% CI)P Value Local review7.83.20.45 (0.38-0.54) <.0001 Central review11.04.10.38 (0.31-0.48) <.0001 With visceral mets6.832.760.47 (0.37-0.60) -- Without visceral mets9.864.210.41 (0.31-0.55) -- Bone-only mets12.885.290.33 (0.21-0.53) -- Progression after neo/adj therapy 11.504.070.39 (0.25-0.62) --  OS data still not mature (HR: 0.77; 95% CI: 0.57-1.04)  Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%) Piccart, M, et al. SABCS 2012. Abstract P6-04-02.

48. Case  A 68-yr-old woman presents with a T4N2 left breast mass with associated contraction and fibrosis that had been developing over 3-4 yrs  Breast biopsy shows ER+/PgR+, HER2- IDC, grade 2  Staging evaluation shows bone metastases and multiple pulmonary nodules  The patient has mild DOE but no bone pain

49. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer An IV bisphosphonate or SC denosumab is recommended for this patient, but which of the following endocrine therapies is NOT recommended? A.Fulvestrant 500 mg B.Letrozole C.Exemestane + everolimus D.Fulvestrant + a nonsteroidal AI

50. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer An IV bisphosphonate or SC denosumab is recommended for this patient, but which of the following endocrine therapies is NOT recommended? A.Fulvestrant 500 mg B.Letrozole C.Exemestane + everolimus D.Fulvestrant + a nonsteroidal AI

51. clinicaloptions.com/oncology Management of ER+ Postmenopausal Early Breast Cancer Endocrine Therapy Sequencing in MBC: Which Order Is Best?  AI or fulvestrant are most effective first-line single agents; fulvestrant ± AI reasonable choice for endocrine therapy– naive patients with MBC  Continue endocrine therapies until resistance  mTOR inhibition with everolimus + exemestane is best second-line therapy after progression on nonsteroidal AI  After everolimus, back to anti-ER therapy alone or enhanced blockade of PI3K pathway  Addition of CDK4/6 inhibitor to first-line letrozole may become a new SOC; phase III trial under way