1 / 85

Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer. Current Considerations in the Management of Patients with Hormonally Sensitive Early-stage Breast Cancer. Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA. Overview.

snowy
Download Presentation

Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer Current Considerations in the Management of Patients with Hormonally Sensitive Early-stage Breast Cancer Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

  2. Overview • Case 1: Optimizing Therapy in Postmenopausal Women • ER+, PR+, HER2 negative stage I breast cancer • Case 2: Optimizing Therapy in Premenopausal Women • Which patients with ER+ tumors should receive adjuvant chemotherapy?

  3. Case 1 • Postmenopausal Women • T = 0.8 cm • ER+ • PR+ • HER2 negative • Stage I breast cancer • What issues should be considered to optimize endocrine therapy for postmenopausal women?

  4. Key Issues in Adjuvant Endocrine Therapy for Postmenopausal Women • When to start an AI • When to stop an AI • Whether and how to use tamoxifen • Tumor features (ER, PR, HER2) • Clinical factors (patient preference, comorbidities) • Pharmacogenomic factors • Concurrent medication factors • Minimizing side effects, esp. bones • Late sequelae – good or bad – of AI therapy

  5. Importance of Endocrine Therapy • 2/3 of breast cancers are ER/PR+ • 3/4 of post-menopausal women have ER/PR+ tumors • Overall little toxicity from endocrine treatment • Significant benefit from optimizing use of endocrine agents in the post-menopausal population

  6. Adjuvant Endocrine Agents: Tamoxifen • Useful regardless of menopausal status • In postmenopausal women: • Reduces recurrence by 37 – 54% • Reduces death by 11 – 33% • Long-term side effects characterized • Carryover effect documented • Utility in sequence with AIs in post-menopausal women Early Breast Cancer Trialists, Lancet 2005.

  7. Adjuvant Endocrine Agents: Aromatase Inhibitors • Inhibit peripheral conversion of androgens to estrogens by the aromatase enzyme • 3 agents: anastrazole, letrozole, exemestane • Utility of adjuvant AIs established through 3 trial designs • Upfront comparison with tamoxifen • ATAC, BIG 1-98 • Sequential therapy after 2-3 years tamoxifen • IES, ARNO/ABCSG, ITA • Extended therapy after 5 years tamoxifen • MA.17

  8. Adjuvant Trials AIs in Postmenopausal Women Tamoxifen x 5 years Upfront vs Tamoxifen AI x 5 years Tamoxifen x 5 years Sequential vs Tamoxifen Tamoxifen AI Placebo x 5 years Tamoxifen x 5 years AI x 5 years Extended Rx, AI vs Placebo

  9. ATAC: 100 month follow-up Lower recurrence rate after 5 years, suggests carry-over effect No new toxicity signals No OS benefits 5 years of AI is Established Forbes et al, Lancet 2008

  10. ATAC: 100 Month Follow-up Forbes et al, Lancet 2008

  11. DFS OS Big 1-98: 5-year Analysis Coates et al, J Clin Oncol 2007;25:486-92 Coates, A. S. et al. J Clin Oncol; 25:486-492 2007

  12. IES Update 2007 Coombes, et al. Lancet 2007;369:559

  13. ARNO 95 / ABCSG 8 / ITA Pooled Outcomes Jonat, et al. Lancet Oncology 2006;7:991

  14. MA.17 DFS OS Goss, P. E. et al. J. Natl. Cancer Inst. 2005 97:1262-1271; doi:10.1093/jnci/dji250

  15. ASCO Guidelines “The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.” Winer, et al JCO 2004

  16. The DebateWhat is the Optimal Approach to the Use of an AI in the Adjuvant Setting? • Upfront AI x 5 years • Proponents of an upfront AI cite early benefit and seek to minimize risk of early relapse, hoping this will lead to long-term benefit • Tamoxifen x 2 years followed by AI x 3-5 years • Proponents of cross-over approach seek to minimize risk of late recurrence by using two effective agents, hoping that short-term losses will be more than compensated by long-term gains

  17. BIG 1-98: Design RANDOMI ZE RANDOMI ZE 2-Arm Option N=1,828 Enrolled 1998-2000 A N=911 Tamoxifen B N=917 Letrozole SURGERY Stratify • Institution • CT (Adjuvant/ Neoadjuvant) -Prior -None -Concurrent 4-Arm Option N=8,010* A RANDOMI ZE N=1548 Tamoxifen B *ITT: excludes 18 patients who withdrew consent and did not receive study treatment N=1546 N=6,182 Enrolled 1999-2003 Letrozole C N=1548 Tamoxifen Letrozole D N=1540 Letrozole Tamoxifen 0 2 5 Years • Previous Analyses: • Is 5 years Let superior to 5 years Tam as initial therapy? • Primary Core Analysis (PCA), Median follow-up 26 months • Monotherapy Arm Analysis, Median follow-up 51 months

  18. Summary of Previous Analyses The PCA and monotherapy analyses showed that 5 years upfront letrozole is significantly superior to 5 years of upfront tamoxifen in terms of: • Disease-free survival • Time to distant recurrence BIG 1-98 Collaborative Group, N Engl J Med 2005;353:2747-57 Coates et al, J Clin Oncol 2007;25:486-92

  19. *Let:Tam: breast cancer events, 321:363 second (non breast) malignancy, 101:115 deaths without prior cancer event, 87:87 BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months Mouridsen HT, et al: SABCS 2008, Abstr. 13

  20. BIG 1-98 Sequential Treatment Disease-Free Survival Mouridsen HT, et al: SABCS 2008, Abstr. 13

  21. Tam→Let vs.Let Let→Tamvs. Let Sequential Treatment ComparisonsMedian Follow-up 71 months Mouridsen HT, et al: SABCS 2008, Abstr. 13

  22. Breast Cancer EventsTamLet vs. Let Overall By Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen HT, et al: SABCS 2008, Abstr. 13

  23. Overall By Nodal Status* *42% of the population is node positive; 58% node negative Breast Cancer EventsLetTam vs. Let Mouridsen HT, et al: SABCS 2008, Abstr. 13

  24. Conclusions For postmenopausal women with endocrine-responsive breast cancer • Updated results of BIG 1-98 suggest superior overall survival with letrozole compared with tamoxifen • Adjuvant endocrine therapy should start with letrozole especially for patients at higher risk for early recurrence • Patients commenced on letrozole can be switched after 2 years to tamoxifen, if required • Safety is consistent with known safety profiles of each agent (data not shown) • Improved therapeutic approaches beyond five years are required to control late relapses Mouridsen HT, et al: SABCS 2008, Abstr. 13

  25. Duration of Therapy

  26. ER+ tumors demonstrate a relatively constant hazard of regression over time After TAM x 5 years, over half of all recurrences occur in years 6-15 (EBCTCG, Lancet 2005) MA-17: risk of recurrence was approx 2-3% each year on placebo arm (Ingle, SABCS 2005) With 5-8 years follow-up, none of the AI trials are truly mature The Natural History of HR+ Breast Cancer is Very Long Saphner et al, JCO 1996

  27. ATTom Results 2008 Gray et al, ASCO 2008

  28. How Long Should AI Be Administered If Started After Tamoxifen? • No direct evidence for more than 2-3 years of an AI after a 2-3 years of tamoxifen, BUT… • In MA-17, a 5 year course of an AI is safe and data through 4 years of follow-up demonstrate ongoing effectiveness • In IES, benefit of E over T appears to be largely while patients are on treatment • Given these data, a 5 year course of AI treatment is reasonable when switching to AI after 2-3 years of tamoxifen

  29. Ongoing Studies to Establish Optimal Duration of AI Therapy: MA.17R AI x 5y Letrozole x 5y Tam x 2y AI x 5y Placebo x 5y Tamoxifen x 5y Letrozole x 5y

  30. NSABP B42 Letrozole vs placebo; N = 3,800 SALSA Anastrazole 2y vs 5y; N = 3,500 SOLE 5y continuous vs intermittent letrozole Dutch Anastrazole 3y vs 6y, N = 1,800 GIM4 Letrozole 2y vs letrozole 5y; N = 4,000 Ongoing Studies to Establish Optimal Duration of AI Therapy > 10,000 pts will be studied

  31. Can we identify which tumors and which patients will benefit most from the different strategies at our disposal?

  32. Tumors HER2 status PR status Grade Luminal A vs B, or other genetic signature …and more Patients Variability in drug metabolism CYP2D6 Risk of toxicity …and more Heterogeneity of ER+ Breast Cancer And the lists will grow much longer in the years ahead

  33. Risk of Distant Recurrence Using Oncotype DX (21-Gene RS) in Patients Treated with Anastrozole or Tamoxifen: ATTAC Study • Objective was to evaluate the prognostic ability of 21-gene RS assay in patients treated in ATAC study • RS score was predictive of risk of recurrence in postmenopausal patients with ER+ with either node negative or node positive disease being treated with either tamoxifen or anastrozole Dowsett et al. SABCS 2008, Abstract 53

  34. CYP2D6 and Tamoxifen Pharmacogenetics

  35. CYP2D6 and Tamoxifen Metabolism Goetz, M. P. et al. J Clin Oncol; 23:9312-9318 2005

  36. CYP2D6 and Tamoxifen MetabolismCYP2D6 Polymorphism Jin, JNCI 2005

  37. Concomitant Drug Use and CYP2D6 Jin, JNCI 2005

  38. DFS OS Clinical Evidence Tamoxifen Pharmacogenetics and Clinical Outcomes Goetz, et al JCO 2005

  39. Clinical EvidenceTamoxifen Pharmacogenetics and Clinical Outcomes Goetz, et al JCO 2005

  40. AI Toxicities • Arthralgias • Sexual Dysfunction • Osteoporosis

  41. AI Toxicities TEAM Trial Jones, S. E. et al. J Clin Oncol; 25:4765-4771 2007

  42. AI Trials Summary From Whalen, 2006

  43. Vaginal Estrogens for Genitourinary Symptoms Related to AI Therapy • Common complaint in postmenopausal women; aggravated by estrogen deprivation of AI • Topical / intravaginal estrogens may alleviate sx • Are they safe? • Kendall, SABCS 2005: E2 levels in women receiving concurrent AI treatment and Vagifem 25 mg PV BIW Estradiol Levels AI BL Day 14 Day 28 LET < 3 220 40 LET < 3 232 31 LET 3.5 77 16 ANA < 3 46 2.4

  44. AI Arthralgia Syndrome Common complaint • Symmetric • Hands, feet, pelvis/hip, arms • Pathognomonic criteria: • “I aged overnight.” “I feel like an old lady.” • Squeezing hands/joints gesture • Etiology unclear

  45. ATAC Arthralgia Incidence over Time Sestak, et al. Lancet Oncology 2008

  46. Diagnosis: AI-associated Joint SymptomsPts referred to rheumatology at Michigan and Hopkins

  47. AI Arthralgia Syndrome Practical Suggestions • Alert patients to this side effect 2. Reassure patients that this is not associated with destructive arthritis and that most cases are mild and abate over time 3. Encourage weight reduction and regular exercise 4. For more severely affected patients, suggest AI withdrawal to gauge relationship to treatment 5. Options: tamoxifen, other AIs, none

  48. Fracture Rates in Adjuvant AI Trials

  49. 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 x x x x ATAC IES MA-17 % change In BMD from baseline x 0 1 2 3 4 5 6 7 Years x x Placebo (MA-17) Exemestane (IES) Anastrazole (ATAC) x x Tamoxifen (IES) Tamoxifen (ATAC) Letrozole (MA-17) Influence of Different AI Strategies on BMD Coleman et al Lancet Oncology 2007

  50. ATAC: Annual Bone Fracture Rates ATAC Trialists, Lancet Oncology 2008;9:45

More Related