DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is    current as of August...
DISCLAIMERParticipants have an implied responsibility to use the newly acquired information    to enhance patient outcomes...
Disclosure of Conflicts of InterestEleni Andreopoulou, MD, reported a financial interest/relationshipor affiliation in the...
Community Oncology Clinical  Debates in Breast Cancer:Advanced ER-Positive Disease  Harold J. Burstein, MD, PhD  Dana-Farb...
Learning Objectives                           Upon completion of this activity,                          participants sho...
Activity Agenda   Activity Overview (5 mins)   Interdisciplinary Debates and Interactive Discussion (50 mins)    – Can w...
Outline   Overview of approach for advanced breast cancer   Predictors of outcome with endocrine therapy   Premenopausa...
Can We Predict Response orResistance Patterns to Endocrine Therapy in ER+ Breast Cancer?
Case Study 1       A 57-yr-old woman has recently been diagnosed with        ER+ MBC. She had been diagnosed with node+ b...
Question 1     Which of the following are predictors of outcome     for endocrine therapy for advanced breast cancer?     ...
Advanced Breast Cancer Is TreatedBased on the Biology of the Tumor             Advanced Breast Cancer                Requi...
Interdisciplinary Debatesand Interactive Discussion
Clinical Predictors of Outcome                     for ER+ Breast Cancer          Disease-free interval          Prior e...
Time Dependence of Breast Cancer Recurrence            in Subsets Defined by Genomic Assays                               ...
ER+ Metastatic Breast Cancer                          Goals of Therapy      Individual Goals                              ...
Response/Benefit Rates                       Over Time                                                R                   ...
How Important Is Response in ER+ MBC?                                                                                     ...
Metastatic Breast Cancer:                                Chemo or Endocrine                                             Tr...
NCCN Database: Univariate Logistic      Regression for Site of First Recurrence*                                          ...
Sites of Recurrence by Subset           British Columbia Registry 1986–1992                                               ...
ER Status and Response     to Tamoxifen
Relationship of ER to Response to Endocrine     Therapy in Advanced Breast Cancer                                   Early ...
Quantitative Estrogen Receptor Analysis:              The Response to Endocrine and Cytotoxic             Chemotherapy in ...
Value of Estrogen and Progesterone Receptors         in the Treatment of Breast Cancer                                 Qua...
ER Status and Response to Tamoxifen                  in Advanced Breast Cancer               Clinical Correlation Between ...
Quantitative ER and PR as Predictors of Response       to Tamoxifen in Advanced Breast Cancer                      Correla...
Significant Rate of Discordancy                   Between Primary and Metastases                                          ...
Key Takeaways:Can We Predict Response or Resistance Patterns to    Endocrine Therapy in ER+ Breast Cancer?     Familiar c...
What Is the Optimal Frontline  Therapy for a Patient WithAdvanced ER+ Breast Cancer?
Case Study 2             A 47-yr-old premenopausal woman has been diagnosed with MBC.              She had non-specific c...
Question 2   The appropriate initial endocrine treatment is:         1) Tamoxifen         2) Ovarian suppression         3...
Shifting Landscape of Therapy for               ER+ Metastatic Breast Cancer       Decade                                 ...
Treatment Options forPremenopausal Women WithER+ Advanced Breast Cancer
Endocrine Therapy of Breast Cancer        in the 19th Century
Randomized Trial of Single Vs.                     Combination Endocrine Therapy                                          ...
Treatment Options forPostmenopausal Women WithER+ Advanced Breast Cancer
Endocrine Agents for    Postmenopausal Breast Cancer   SERMs                  Aromatase Inhibitors    – Tamoxifen       ...
Megesterol Acetate Vs. Tamoxifen                                            for Advanced Breast Cancer                    ...
Summary: First-Line Randomized           Studies AI Vs. Tamoxifen                               Anastrozole        Letrozo...
Fulvestrant Vs. Anastrozole: Trial Design                   Postmenopausal women with advanced breast cancer receiving pri...
Fulvestrant Vs. Anastrozole            Proportion Without Progression (%)          After SERMs                            ...
Duration of Response:                            Without or With Visceral Metastases Without Visceral Metastases          ...
CONFIRM: Fulvestrant 500 Vs. 250           PFS Curves by Treatment Arm                                         1.0        ...
FIRST Trial: Fulvestrant Vs. Anastrozole        in Endocrine-Naïve Breast Cancer                                          ...
Combined Letrozole and Fulvestrant Delays           Emergence of Resistance to LTED in MCF-7Ca                          Xe...
FACT Trial: AI +/- Fulvestrant                     Kaplan-Meier TTP and Median TTP in Mos (full analysis set)             ...
SWOG 0226:          Anastrozole +/- Fulvestrant for MBCMehta et al, 2012.
Progression-Free Survival, According to Subgroups    Subgroup                                Hazard Ratio for Progression ...
SoFEA        Partially-Blind Phase III Randomized Trial        Postmenopausal Women With ER+        Advanced Breast Cancer...
Comparison of AI ± F Trials                                        FACT    SWOG 0226       No. Patients                   ...
CALGB 40503                                                                        Stratification:         Women With Adva...
Key Takeaways:    What Is the Optimal Frontline Therapy for a    Patient With Advanced ER+ Breast Cancer?            Vari...
What Is the Optimal Therapy for Patients  With Advanced or Metastatic ER+Endocrine-Resistance Who Progressed  After Previo...
Case Study 3        A 64-yr-old woman is being treated for advanced ER+ breast         cancer. 14 yrs ago, she received A...
Case Study 3 (cont.)      You are discussing treatment options with her.      In comparison to exemestane alone, treatment...
Summary: Second-Line Randomized Studies                       AI Vs. MA                                             Anastr...
NCCTG Study: Efficacy of Fulvestrant         Following Failure of an AI and Tamoxifen          *Overall CBR: 35.0%, PR: 1...
EFECT: Evaluation of Fulvestrant                     and Exemestane Clinical Trial      500 mg Day 1,     250 mg Day 14,  ...
EFECT: EXE Vs. Fulvestrant Following                                          Nonsteroidal AI Therapy                     ...
Sir Alexander Haddow 1944                                   “The oestrogens thus provide a further                        ...
BJ Kennedy, 1957        “The findings suggest that some advanced primary breast cancers not        originally thought to b...
Basil Stoll 1973                          “When the tumor reactivated a                          hormone therapy was reins...
Tamoxifen Vs. Diethylstilbestrol                                       Event        DES        TAM                        ...
Estradiol Induced Apoptosis                                                                                            1.2...
Estradiol After AI                                                                  RR CBR               Postmenopausal   ...
ER and mTOR / PI3K:     Crosstalk
Schematic of the PI3K/AKT/mTOR PathwayPI3K = phosphatidyl inositol 3-kinase; AKT = protein kinase B.Rugo et al, 2012.
BOLERO-2: Phase 3 RCT Study                                             Kaplan-Meier Plot of PFS           Exemestane ±   ...
BOLERO-2: Phase 3 RCT Study           AEs Irrespective of Relationship to Study Treatment*      AE                        ...
BOLERO-2: Phase 3 RCT Study                     Efficacy Analysis Local/Central Assessment                  Central Assess...
TAMRAD Trial                             TTP in the ITT population for (I) the overall patient population and patients wi...
Temsirolimus in Heavily Pretreated MBC                                  1.0                                  0.9          ...
Letrozole +/- Temsirolimus     Estratification by:                  R     Geographic Regions                   A          ...
Letrozole +/- Temsirolimus EfficacyTEMSR + LET: LET = comparisons for stratified log-rank p value and HR.Chow, 2006.
ER and EGFR: Crosstalk
Reciprocal Crosstalk Between ERα and              Growth Factor Receptor Signaling PathwaysMiller et al, 2011.
Tamoxifen ± Gefitinib for ER+ MBC                                            Stratum 1. Tam-Sensitive                     ...
Anastrozole ± Gefitinib for ER+ MBC  Probability of PFS (%)                                                               ...
ER and HER2: Crosstalk
Crosstalk Between Signal Transduction Pathways and         ER Signaling in Endocrine-Resistant Breast Cancer,            W...
HER2 Upregulation in. Tamoxifen-Resistant                 Breast Cancers                 3 Cases From 30 That Were ER+ and...
TANDEM: Anastrozole +/- Trastuzumab                       PFS (probability)                       TTP (probability)       ...
Letrozole +/- Lapatinib                                 100                                                               ...
Letrozole +/- Lapatinib:                                     Clinical Efficacy in Human EGFR2+ Population     Alive Withou...
Optimizing Chemotherapy-Free Survival          The 2 most prominent biological targets in breast cancer that           ar...
CALGB 40302               Postmenopausal women                                              Stratification:               ...
CALGB 40302 (cont.)                                         Median PFS                                         Lapatinib  ...
CALGB 40302 (cont.)                                                    PFS: HER2-negativ e Tumors                         ...
Key Takeaways:What Is the Optimal Therapy for Patients With  Advanced or Metastatic ER+ Endocrine- Resistance Who Progress...
Key Takeaways (cont.)   Management of ER+ breast cancer is the art of oncology   A variety of endocrine options availabl...
Community Oncology Clinical Debates in Breast Cancer: Advanced ER-Positive Disease
Community Oncology Clinical Debates in Breast Cancer: Advanced ER-Positive Disease
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Community Oncology Clinical Debates in Breast Cancer: Advanced ER-Positive Disease

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Despite remarkable progress in the treatment of breast cancer in recent years, management of estrogen receptor (ER)-positive disease remains a challenge. Through didactic and case presentations, expert faculty will address clinical debates regarding optimal treatment selection and the incorporation of new classes of targeted therapies into practice to improve outcomes and overcome resistance in the management of ER-positive breast cancer

Target Audience
This activity has been designed to meet the educational needs of medical oncologists and other healthcare providers who are involved in the care and treatment of patients with advanced estrogen receptor (ER)-positive breast cancer.

Purpose
The goal is to optimize the clinical decision-making of clinicians involved in the treatment of advanced ER-positive breast cancer by providing updates on emerging data.

Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.

Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply.

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Community Oncology Clinical Debates in Breast Cancer: Advanced ER-Positive Disease

  1. 1. DISCLAIMER This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of thefaculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice,diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity. Usage Rights This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
  2. 2. DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Albert Einstein College ofMedicine and IMER do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Albert Einstein College of Medicine and IMER. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
  3. 3. Disclosure of Conflicts of InterestEleni Andreopoulou, MD, reported a financial interest/relationshipor affiliation in the form of: Speakers Bureau, Amgen, Inc.Harold J. Burstein, MD, PhD, has no real or apparent conflicts ofinterest to report. Dr. Burstein has disclosed that he will discuss orpresent information that is related to an off-label or investigationaluse of fulvestrant, aromatase inhibitors (Als), estradiol, andtamoxifen.
  4. 4. Community Oncology Clinical Debates in Breast Cancer:Advanced ER-Positive Disease Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute
  5. 5. Learning Objectives Upon completion of this activity, participants should be better able to:  Identify predictive factors and markers associated with response or resistance to endocrine therapy  Examine current data regarding the mechanisms of endocrine resistance and the rationale for therapeutic strategies to overcome resistance  Apply optimal sequencing of current and novel agents used in the treatment of advanced ER+ breast cancer  Identify current, emerging, and investigational therapeutic approaches for frontline and refractory ER+ breast cancer, including endocrine therapies and combination strategies using targeted agents  Explain common crosstalks between ER and growth factor signaling pathways and the rationale for targeting these pathways in advanced ER+ breast cancer  Describe the efficacy, safety, and tolerability of novel and emerging therapies demonstrated in recent clinical trials, including their clinical implicationsER = estrogen receptor.
  6. 6. Activity Agenda Activity Overview (5 mins) Interdisciplinary Debates and Interactive Discussion (50 mins) – Can we predict response or resistance patterns to endocrine therapy in ER+ breast cancer? – What is the optimal frontline therapy for a patient with advanced ER+ breast cancer? – What is the optimal therapy for patients with advanced or metastatic ER+ endocrine-resistance who progressed after previous lines of therapies? Questions & Answers (5 mins)
  7. 7. Outline Overview of approach for advanced breast cancer Predictors of outcome with endocrine therapy Premenopausal and postmenopausal women Role of AIs, fulvestrant, progestins, estradiol mTOR inhibitors ER+/HER2+ tumors PI3K mutations
  8. 8. Can We Predict Response orResistance Patterns to Endocrine Therapy in ER+ Breast Cancer?
  9. 9. Case Study 1  A 57-yr-old woman has recently been diagnosed with ER+ MBC. She had been diagnosed with node+ breast cancer 6 yrs ago, and after her surgery, received adjuvant AC/T chemotherapy, radiation, and 5 yrs of an aromatase inhibitor.  She developed lower back discomfort and an MRI showed lesions suspicious for metastatic disease  A CT-guided bone biopsy confirmed metastatic carcinoma, ER+, PR-, HER2-, consistent with advanced breast cancer. Staging studies showed multiple bone abnormalities throughout the axial skeleton, borderline enlarged mediastinal lymph nodes, and no evidence for visceral metastases.AC/T = doxorubicin, cyclophosphamide, paclitaxel; MBC = metastatic breast cancer;MRI = magnetic resonance imaging; CT = computed tomography; PR = progesteronereceptor; HER2 = human epidermal growth factor receptor 2.NCCN, 2012.
  10. 10. Question 1 Which of the following are predictors of outcome for endocrine therapy for advanced breast cancer? 1) Extent of prior endocrine therapy 2) Disease-free interval 3) Overexpression of HER2 4) Quantitative levels of ER 5) PR negativity 6) All of the above 7) 1, 3, 4NCCN, 2012.
  11. 11. Advanced Breast Cancer Is TreatedBased on the Biology of the Tumor Advanced Breast Cancer Requiring TherapyER and/or PR Positive ER and/or PR Negative Hormonal Treatment ChemotherapyRefractory to Hormonal HER2+ HER2- Therapy Chemotherapy Chemotherapy + Anti-HER2 Agents
  12. 12. Interdisciplinary Debatesand Interactive Discussion
  13. 13. Clinical Predictors of Outcome for ER+ Breast Cancer  Disease-free interval  Prior endocrine therapy – Clinical history radically different now than 20+ yrs ago with widespread use of adjuvant therapy  Quantitative ER expression  Bone-only vs. visceral metastases  HER2 expression  PR negativityOh et al, 2006; Rakha et al, 2007; Sainsbury et al, 1987; Loi et al, 2008; Ross et al, 2008;Weigel et al, 2010; Taneja et al, 2010; Niikura et al, 2011; Kurebayashi et al, 2000.
  14. 14. Time Dependence of Breast Cancer Recurrence in Subsets Defined by Genomic Assays Intrinsic/ PAM50 Relapse-Free Survival MammaPrint (%) OncotypeDX Time After Diagnosis (yrs)Jatoi et al, 2011.
  15. 15. ER+ Metastatic Breast Cancer Goals of Therapy Individual Goals Clinical Trial Outcomes  Extend survival  Response rate  Improve or maintain QOL  Response duration  Clinical trial end points have  TTP only some relationship to these goals  TTF  OS Clinician Goals  QOL  Maximize QOL  Minimize treatment related symptoms and impact on patient lifestyle  Practice the “art” of oncologyQOL = quality of life; TTP = time to disease progression; TTF = time to treatment failure;OS = overall survival.
  16. 16. Response/Benefit Rates Over Time R E S I S 40% 30% 25% 15% T A N C First Second Third Fourth E Line Line Line LineHarvey, 2000.
  17. 17. How Important Is Response in ER+ MBC? At 2-Yr Risk Deaths Estimate CR or PR 33 10 85% 100 Stable ≥ 24 wks78 23 86% Other 152 118 35% 80 Survival (%) 60 40 20 0 0 1 2 3 4 Time (yrs from randomization)CR = complete response; PR = partial response.Robertson et al, 1999.
  18. 18. Metastatic Breast Cancer: Chemo or Endocrine Trials Included ER- Patients ANZBCTG* Taylor Tam AC Tam CMF N 339 181 CR + PR (%) 22 45 45 38 TTP (mos) 3 11 6.2 6.2 OS (mos) 23 20 23 21*The Australian and New Zealand Breast Cancer Trials Group (ANZBCTG).AC = doxorubicin, cyclophosphamide; TAM = tamoxifen; CMF =cyclophosphamide, methotrexate, fluorouracil.ANZBCTG, 1986; Taylor et al, 1986.
  19. 19. NCCN Database: Univariate Logistic Regression for Site of First Recurrence* Triple Negative vs. ER+ HER2+ vs. ER+ Site OR (95% CI)** p Value OR (95% CI) p Value Distant vs. Locoregional 1.32 (1.01, 1.74) .045 1.12 (0.83, 1.51) .45 Lung vs. Other 2.17 (1.47, 3.21) < .001 1.73 (1.13, 2.66) .012 Brain vs. Other 3.50 (2.10, 5.85) < .001 3.97 (2.35, 6.72) < .001 Bone vs. Other 0.26 (0.19, 0.36) < .001 0.39 (0.29, 0.54) < .001 Liver vs. Other 1.09 (0.74, 1.61) .67 1.48 (1.07, 2.33) .021 *Analysis based on cohort of 1,389 patients with documented recurrence (TN, n = 480; HER+, n = 373; Luminal, n = 536) ER+ cohort used as the referent group for all analyses. **OR; CI; Other refers to any/all distant/locoregional site.NCCN = National Comprehensive Cancer Network; TN = triple negative; OR = odds ratio;CI = confidence interval.Lin et al, 2012.
  20. 20. Sites of Recurrence by Subset British Columbia Registry 1986–1992 Pleura / Brain (%) Liver (%) Lung (%) Bone (%) LN (%) Peritoneum (%) A 8 29 24 67 16 28 Luminal B 11 32 30 71 23 35 ER+ 15 44 37 65 22 34 HER2+ ER- 29 46 47 60 25 32 Basal 25 21 43 39 40 30 TN Non- Basal 22 32 36 43 36 28Kennecke et al, 2010.
  21. 21. ER Status and Response to Tamoxifen
  22. 22. Relationship of ER to Response to Endocrine Therapy in Advanced Breast Cancer Early Clinical Correlations Objective Remissions Investigator Year Patients Positive Borderline and Negative Jensen et al. 1970 26 4/6 1/20 1971 42 10/13 1/29 1973 54 13/17 2/37 Maass et al. 1972 21 6/7 0/14 1973 59 13/24 2/35 Englesman et al. 1973 37 14/17 2/20 Leung et al. 1973 20 10/10 2/10 Savlov et al. 1974 11 3/5 0/6 Total (through 1974) 181 53/73 8/108Jensen, 1980.
  23. 23. Quantitative Estrogen Receptor Analysis: The Response to Endocrine and Cytotoxic Chemotherapy in Human Breast Cancer and Disease-Free Interval Response Rate to Endocrine Therapy as a Function of ER Correlation Response Rate ER (fmol/mg cytoplasmic protein) 0 ≤ ER < 10 3/33 (9%) ---- 10 ≤ ER < 20 3/10 (30%) p > .05 20 < ER < 50 7/11 (63%) p < .001 ER ≥ 50 24/31 (77%) p < .00001Lippman et al, 1980.
  24. 24. Value of Estrogen and Progesterone Receptors in the Treatment of Breast Cancer Quantitative ER and the Response to Endocrine Therapy Objective Response Primary Biopsy Metastatic Biopsy ER fm/mg 0–3 1/6 (17%) 4/47 (8%) 3–100 17/38 (45%) 26/65 (40%) > 100 5/6 (83%) 22/36 (61%) Response to Endocrine Therapy as a Function of ER and PgR ER- PgR- ER- PgR+ ER+ PgR- ER+ PgR+ San Antonio 3/20 --- 14/45 16/20 Other Series 9/91 6/13 19/76 71/93 Total 12/111 (11%) 6/13 (46%) 33/121 (27%) 87/113 (77%)PgR = progesterone receptor.Osborne et al, 1980.
  25. 25. ER Status and Response to Tamoxifen in Advanced Breast Cancer Clinical Correlation Between ER Measurements and Response to Tamoxifen Remissions No Change Failures No. (%) No. (%) No. (%) Status No. A. ER (Assay Not 80 34 43 13 16 33 41 Done) B. ER+ 77 43 56* 5 6 29 38 C. ER- 6 0 0 0 0 6 100 D. ER+/-** 3 0 0 0 0 3 100*p = .04; A vs. B.**ER measurements were low positive in 1 biopsy, and negative in another takensimultaneously.Manni et al, 1980.
  26. 26. Quantitative ER and PR as Predictors of Response to Tamoxifen in Advanced Breast Cancer Correlation Between ER, PR, and Response to Tamoxifen PR Level and Response to Tamoxifen ER Level No. Percent (fmol/mg of Patients 0–10 10.1–30 30.1–300 > 300 Total Response protein) <3 22* 1/20 0/1 0/1 --- 1/22 5 3.0–10 76 10/66 3/8 1/2 --- 14/76 18 10.1–30 219 24/86 43/107 10/20 3/6 80/219 37 30.1–300 63 6/11 25/31 14/17 3/4 48/63 78 > 300 35 4/6 12/15 7/8 4/6 27/35 77 Total 415 45/189 83/162 32/48 10/16 170/416 Percent 14 51 68 63 46*Includes 9 patients with ER concentration < 3 fmol/mg of protein and 13 patients withER of 3 fmol/mf of protein.Bezwoda et al, 1991.
  27. 27. Significant Rate of Discordancy Between Primary and Metastases Amir Curigliano 2010 Studies Karlsson Lindstrom (n ~ 270) (n ~ 250) Comparing Primary (n ~ 470) (n ~ 118–459) Prospective Retrospective to Metastasis Retrospective Retrospective Reanalyzed Liver Only ER+  ER- 12% 11% 36% 26% ER-  ER+ 14% 25% 22% 7% HER2-  HER2+ 5% 6% nd 7% HER2+  HER2- 12% 32% nd 3%Amir et al, 2010; Curigliano et al, 2011; Karlsson et al, 2010; Lindstrom et al, 2010.
  28. 28. Key Takeaways:Can We Predict Response or Resistance Patterns to Endocrine Therapy in ER+ Breast Cancer?  Familiar clinical factors predict likelihood of benefit from endocrine treatments  To date, other molecular diagnostics have not proven value in clinical management of advanced, ER+ breast cancer  Clinical history governs much of likely outcome
  29. 29. What Is the Optimal Frontline Therapy for a Patient WithAdvanced ER+ Breast Cancer?
  30. 30. Case Study 2  A 47-yr-old premenopausal woman has been diagnosed with MBC. She had non-specific changes in the right breast which prompted MRI evaluation.  Extensive architectural abnormalities were noted in an area exceeding 5 cm in size, and a biopsy revealed invasive lobular carcinoma, grade 2, that was ER+, PR+, and HER2-  She underwent a mastectomy and axillary node dissection, and was found to have metastatic lobular cancer in 5 of 13 axillary lymph nodes with extranodal extension  Staging CT scan showed suspicious lesions in the bone, multiple, subcentimeter pulmonary nodules, and enlarged mediastinal lymph nodes  A bronchosopic biopsy of a hilar lymph node showed MBC consistent with her lobular tumorNCCN, 2012.
  31. 31. Question 2 The appropriate initial endocrine treatment is: 1) Tamoxifen 2) Ovarian suppression 3) Ovarian suppression and tamoxifen 4) Ovarian suppression and an aromatase inhibitor 5) Ovarian suppression and fulvestrantNCCN, 2012.
  32. 32. Shifting Landscape of Therapy for ER+ Metastatic Breast Cancer Decade Adjuvant Metastatic 1980s None OA, Tamoxifen 1990s Tamoxifen AI [AI, Tamoxifen] 2000s AI, Tamoxifen Fulvestrant [AI, Tamoxifen] Fulvestrant, mTOR 2010s AI, Tamoxifen InhibitionOA = ovarian ablation; AI = aromatase inhibitors; mTOR = mammalian target of rapamycin.
  33. 33. Treatment Options forPremenopausal Women WithER+ Advanced Breast Cancer
  34. 34. Endocrine Therapy of Breast Cancer in the 19th Century
  35. 35. Randomized Trial of Single Vs. Combination Endocrine Therapy 100 LHRH-A + TAM Premenopausal LHRH-A Women With ER+ 80 TAM Advanced Breast Percent (%) Cancer 60 Tamoxifen 40 Vs. 20 Buserelin Vs. 0 Combination 0 2 4 6 8 10 Time (yrs) O N No. Patients At Risk Treatment 43 54 29 11 2 1 LHRH-A 35 53 39 23 11 4 LHRH-A+TAM 44 54 34 16 6 0 TAMKlijn et al, 2000.
  36. 36. Treatment Options forPostmenopausal Women WithER+ Advanced Breast Cancer
  37. 37. Endocrine Agents for Postmenopausal Breast Cancer SERMs  Aromatase Inhibitors – Tamoxifen – Anastrozole – Toremifene – Letrozole – Raloxifene – Exemestane Estrogens  Progestins – Estradiol – Megestrol Acetate – DES, EE2 – MPA ER-Down Regulator  Androgens – Fulvestrant – Fluoxymesterone
  38. 38. Megesterol Acetate Vs. Tamoxifen for Advanced Breast Cancer Phase III Study of the Piedmont Oncology Association Cumulative Proportion Survival (%) Proportion Progression Free (%) 90 100 80 60 70 50 40 20 30 0 10 0 6 12 18 24 30 36 0 12 24 36 48 60 Time (mos) Time (mos)Muss et al, 1988.
  39. 39. Summary: First-Line Randomized Studies AI Vs. Tamoxifen Anastrozole Letrozole Exemestane (2 studies) 60% ER+ 66% ER+No. Patients 1,021 907 371Daily Dosage 1 2.5 25Significant Survival Not Yet vs.Advantage vs. TAM (mos) None 35 vs. 32 ns 123 wks (.039) 10.7 vs. 6.4TTP (mos) vs. TAM (ER+ only, not ITT) 9.4 vs. 6.0 9.9 vs. 5.8Clinical Benefit(CR + PR + SD ≥ 24 wks)vs. TAM (%) 56.8 vs. 50.0 50.0 vs. 38 NRResponse Rates**(CR + PR) vs. % 29 vs. 27.1 32 vs. 21 46 vs. 31Survival Impact No +/- No
  40. 40. Fulvestrant Vs. Anastrozole: Trial Design Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trials 0020 and 0021: Recruitment between May 1997 and August 1999 Trial 0020: International, randomized 1:1, open, parallel-group Trial 0021: North American, randomized 1:1, double-blind, double-dummy, parallel-group Fulvestrant 250 mg im qm Anastrozole 1 mg qdo Trial 0020: 1 x 5 mL (n = 222) Trial 0020 (n = 229) Trial 0021: 2 x 2.5 mL (n = 206) Trial 0021 (n = 194) Median TTP: Fulvestrant = 5.5 mos Anastrozole = 4.1 mosRobertson et al, 2003.
  41. 41. Fulvestrant Vs. Anastrozole Proportion Without Progression (%) After SERMs Time to Progression (mos)Howell et al, 2002.
  42. 42. Duration of Response: Without or With Visceral Metastases Without Visceral Metastases With Visceral Metastases Fulvestrant 250 mg (n = 52) Fulvestrant 250 mg (n = 30) Anastrozole 1 mg (n = 45) Anastrozole 1 mg (n = 25) 1.0 1.0 Objective Response Proportion With 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 200 400 600 800 1,000 0 200 400 600 800 1,000 Duration of Objective Response (days)Mauriac et al, 2003.
  43. 43. CONFIRM: Fulvestrant 500 Vs. 250 PFS Curves by Treatment Arm 1.0 Proportion of Patients 0.8 Progression Free (%) 0.6 0.4 0.2 4 12 20 28 36 44 Time (mos) No. Patients At Risk Fulvestrant 500 mg 362 216 163 113 90 54 37 19 12 7 3 2 0 Fulvestrant 250 mg 374 199 144 85 60 35 25 12 4 3 1 1 0PFS = progression-free survival.Di Leo et al, 2010.
  44. 44. FIRST Trial: Fulvestrant Vs. Anastrozole in Endocrine-Naïve Breast Cancer 1.0 Progressed (%) Proportion Not 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 Time to Progression (mos) No. Patients At Risk: Fulvestrant HD 102 96 76 46 31 17 7 5 Anastrozole 1 mg 103 90 68 38 23 13 6 5Robertson et al, 2009.
  45. 45. Combined Letrozole and Fulvestrant Delays Emergence of Resistance to LTED in MCF-7Ca Xenografts The Effect of the Letrozole and Fulvestrant Alone or in Combination on the Growth of MCF-7Ca Aromatase Xenograft 800 600 400 200 0 4 8 12 16 20 24 28 32 36 Treatment Time (wks)LTED = long term extrogen deprived.Brodie et al, 2005.
  46. 46. FACT Trial: AI +/- Fulvestrant Kaplan-Meier TTP and Median TTP in Mos (full analysis set) 1.0 0.8 PFS (%) 0.6 0.4 0.2 0 6 18 30 42 54 Time (mos) No. Patients At Risk: Anastrozole 256 148 108 57 31 16 10 5 4 1 Anastrozole 258 149 107 55 40 20 6 2 1 0 + Fulvestrant Fulvestrant + Anastrozole Anastrozole (n = 258) (n = 256) No. Patients With Progression (%) 200 (77.5) 200 (78.1) Median TTP (mos) 10.8 10.2 Primary TTP Analysis (log-rank test): 0.99 HR* (95% CI) (0.81–1.20) p Value .91Bergh et al, 2012.
  47. 47. SWOG 0226: Anastrozole +/- Fulvestrant for MBCMehta et al, 2012.
  48. 48. Progression-Free Survival, According to Subgroups Subgroup Hazard Ratio for Progression of Death (95% CI) P value for interaction Age .95 ≥65 yr 0.79 (0.62-1.01) <65 yr 0.79 (0.63-1.00) HER2 status .22 positive 0.58 (0.33-1.03) negative 0.81 (0.67-0.98) Disease site .96 nonvisceral 0.84 (0.61-1.14) visceral 0.79 (0.62-0.99) bone only 0.77 (0.54-1.11) Measurable disease .08 No 0.93 (0.73-1.19) Yes 0.69 (0.55-0.86) Time between diagnosis of primary and .22 metastatic disease ≥10 yr 0.59 (0.42-0.83) 5 to <10 yr 1.03 (0.70-1.48) 3 mo to <5 yr 0.84 (0.54-1.31) none 0.84 (0.65-1.10) Previous chemotherapy .80 No 0.81 (0.66-1.00) Yes 0.75 (0.56-1.00) Previous Tamoxifen .22 No 0.74 (0.59-0.92) Yes 0.89 (0.69-1.15) Overall 0.80 (0.68-0.94) 0.4 0.6 0.8 1.0 1.2 1.4 Combination Anastrozole Better Alone BetterMehta RS et al, 2012
  49. 49. SoFEA Partially-Blind Phase III Randomized Trial Postmenopausal Women With ER+ Advanced Breast Cancer Following Progression on Non-Steroidal AIs PFS OS CBR Fulvestrant + Anastrozole 4.4 mos 20.2 mos 33.7 N = 241 p = .98 p = .61 % RANDOMIZED Fulvestrant + Placebo N = 230 4.8 mos 19.4 mos p = .98 p = .61 31.6 % Exemestane 3.4 mos 21.6 mos N = 247 p = .56 p = .68 26.9 %  Only study of fulvestrant in the setting of acquired AI resistance None of the differences in RR, CBR, PFS or OS were statistically significant.Johnston et al, 2012; Moser, 2012.US NIH, NCT00253422.
  50. 50. Comparison of AI ± F Trials FACT SWOG 0226 No. Patients 514 707 De Novo Metastatic 13% 39% Disease Prior Adjuvant 45% 33% Chemotherapy Prior Adjuvant Endocrine 68% 40% Therapy (TAM) Mean PFS Range (m) 10–11 13–15 PFS Benefit No YesMehta et al, 2012; Bergh et al, 2012.
  51. 51. CALGB 40503 Stratification: Women With Advanced Planned Endocrine Tx Breast Cancer Letrozole / Tamoxifen ER and/or PgR + Tumors Disease Measurability Yes / No Disease-Free Interval ≤ 24 Mos / > 24 Mos R Endocrine Therapy* po Daily + A Bevacizumab 15 mg/kg IVPB q21days N D Restage q3cycles for first O 18 cycles, then q4cycles M until first disease progression I Cycle = 21 days Z Endocrine Therapy* po Daily + Placebo E (for bevacizumab) 15 mg/kg IVPB q21days Choice of endocrine therapy is tamoxifen or the aromatase inhibitor letrozole Ovarian suppression is required, if premenopausal Ovarian suppression can be initiated at startCALGB = Cancer and Leukemia Group B.US NIH, NCT00601900.
  52. 52. Key Takeaways: What Is the Optimal Frontline Therapy for a Patient With Advanced ER+ Breast Cancer?  Variety of treatment options for such patients  Premenopausal: OFS + TAM  Postmenopausal: AI, F, TAM  Role of combination anti-estrogen therapy unclear – Maybe modest benefit in absolutely endocrine naïve populations*OFS = ovarian function suppresion.NCCN, 2012.
  53. 53. What Is the Optimal Therapy for Patients With Advanced or Metastatic ER+Endocrine-Resistance Who Progressed After Previous Lines of Therapies?
  54. 54. Case Study 3  A 64-yr-old woman is being treated for advanced ER+ breast cancer. 14 yrs ago, she received AC chemotherapy for node- negative breast cancer.  She experienced chemotherapy-induced amenorrhea, and received 5 yrs of tamoxifen  3 yrs ago, she was diagnosed with recurrent breast cancer to bone and lymph node. She began treatment with bisphosphonates and aromatase inhibitor.  After 2 yrs, she had progression and began fulvestrant therapy. 10 mos later, she has again progressed with increased bone disease and enlarged axillary, chest, and abdominal lymph nodes.  She has mild bone pain in multiple locations and is fatigued but otherwise wellNCCN, 2012.
  55. 55. Case Study 3 (cont.) You are discussing treatment options with her. In comparison to exemestane alone, treatment with everolimus and exemestane is associated with an increased risk of all of the following, except: 1) Hyperglycemia 2) Stomatitis 3) Fatigue 4) Arthralgias 5) Pneumonitis / DyspneaBaselga et al, 2012; NCCN, 2012.
  56. 56. Summary: Second-Line Randomized Studies AI Vs. MA Anastrozole Letrozole Letrozole Exemestane No. Patients 263 vs. 253 199 vs. 201 174 vs. 189 366 vs. 403 Daily Dosage 1 mg 2.5 mg 2.5 mg 25 mg Significant Yes No No Yes Survival 26.7 vs. 22.5 28.6 vs. 26.2 25.8 vs. 21.5 vs. 28.4 Advantage vs. MA (p < .025) (NS) (p = .15) (p = .039) (mos) Median FU +33 mos +37 mos 45 mos 11 mos TTP (mos) vs. MA 4.8 vs. 4.6 3.2 vs. 3.4 5.6 vs. 5.5 4.7 vs. 3.9 (NS) (p = .99) (p = .07) (p = .037) Clinical Benefit 42 vs. 40 26.7% vs. 23.4 35 vs. 32 37 vs. 35 (CR + PR + SD ≥ (NS) (NS) (NS) (NS) 24 wks) vs. MA (%) Response Rates 12.6 vs. 12.2 16.11 vs. 14.9 15 vs. 12.4 15 vs. 12.4 (CR + PR) vs. MA (NS) (NS) (p = .04) (NS) (%)*MA = megestrol acetate.Buzdar et al, 1996, 2001; Dombernowsky et al, 1998; Kaufmann et al, 2000.
  57. 57. NCCTG Study: Efficacy of Fulvestrant Following Failure of an AI and Tamoxifen  *Overall CBR: 35.0%, PR: 14.3%  Median duration of response: 11.4 mos  Median survival: 20.2 mos – 1-yr survival rate: 70.5% Adjuvant Advanced AI Tamoxifen Tamoxifen AI Fulvestrant AI Tamoxifen N = 56 CBR 28.6% *Tamoxifen AI PR 8.9% AI Fulvestrant CBR 52.4% PR 28.6%CBR = clinical benefit rate.Ingle et al, 2006.
  58. 58. EFECT: Evaluation of Fulvestrant and Exemestane Clinical Trial 500 mg Day 1, 250 mg Day 14, Prior Nonsteroidal AI Failure 28, and Monthly Fulvestrant Loading Exemestane 25 mg Orally Dose + Placebo for Daily + Placebo for Exemestane Fulvestrant (n = 330) (n = 330) Progression Progression Survival Survival Analysis After 580 Events (progression or death)Chia et al, 2008.
  59. 59. EFECT: EXE Vs. Fulvestrant Following Nonsteroidal AI Therapy Kaplan-Meier Estimates for TTP 1.0 Proportion of Patients Progression-Free (%) 0.8 0.6 0.4 0.2 0 100 200 300 400 500 600 700 800 Time to Progression (days) Days 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 Fulvestrant At Risk 351 301 191 127 89 67 46 29 23 13 10 4 4 2 0 Exemestane At Risk 342 305 184 130 86 56 37 24 21 13 10 8 8 6 2Chia et al, 2008.
  60. 60. Sir Alexander Haddow 1944 “The oestrogens thus provide a further example of the relation (only apparently paradoxical) that compounds possessing growth-retarding properties in certain circumstances may also have either with the physiological stimulation of growth or with the induction of tumors.”Haddow et al, 1944.
  61. 61. BJ Kennedy, 1957 “The findings suggest that some advanced primary breast cancers not originally thought to be susceptible to palliative operative attack may be so rendered after significant regression under hormonal therapy.”Kennedy et al, 1957.
  62. 62. Basil Stoll 1973 “When the tumor reactivated a hormone therapy was reinstituted and eight months of therapy lead to a further tumor regression for 18 months.”Stoll, 1973.
  63. 63. Tamoxifen Vs. Diethylstilbestrol Event DES TAM N = 74 N = 69 Emesis 18 (25%) 8 (12%) Edema 39 (53%) 8 (12%) Phlebitis 2 (3%) 0 Vag Bleed 11 (15%) 1 (1%) CCF 2 (4%) 0 Hot 2 (3%) 20 (29%) FlashesIngle et al, 1981.
  64. 64. Estradiol Induced Apoptosis 1.2 Cross Sectional Tumor Area (cm2) Cell Number (x106/well) 0.8 0.4 0 1 2 3 4 5 6 7 8 9 Time (wks) E2 Concentration (nM) Estradiol deprivation sensitizes MCF7 cells Tamoxifen resistant MCF7 cells are to estradiol induced apoptosis in vitro sensitive to estradiol induced apoptosis in vivoImages courtesy of Matthew Ellis.Song et al, 2001; Liu et al, 2003.
  65. 65. Estradiol After AI RR CBR Postmenopausal ER+ and/or PR+ 30 mg estradiol 3% 28% R (10 mg tid) A Acquired AI Resistance N D O M Response to AI I 6 mg estradiol 9% 29% CR, PR, or SD* Z (2 mg tid) or E 2 yrs before relapse on AI*Progression-free at 24 wks.Ellis et al, 2009.
  66. 66. ER and mTOR / PI3K: Crosstalk
  67. 67. Schematic of the PI3K/AKT/mTOR PathwayPI3K = phosphatidyl inositol 3-kinase; AKT = protein kinase B.Rugo et al, 2012.
  68. 68. BOLERO-2: Phase 3 RCT Study Kaplan-Meier Plot of PFS Exemestane ± Everolimus 10 mg Day ER+ and HER2- AI Refractory ECOG 0–2ECOG = Eastern Cooperative Oncology Group.Baselga et al, 2012.
  69. 69. BOLERO-2: Phase 3 RCT Study AEs Irrespective of Relationship to Study Treatment* AE Everolimus and Exemestane Placebo and Exemestane (N = 482) (N = 238) Toxicity % (any event) Stomatitis 56 11 Rash 36 6 Diarrhea 30 16 Decreased Appetite 29 10 Dysgeusia 21 5 AEs with most Weight Loss 19 5 relevant toxicity Dyspnea 18 9 difference between Anemia 16 4 both groups Epistaxis 15 1 Edema 14 6 Pyrexia 14 6 Hyperglycemia 13 2 Pneumonitis 12 0 Thrombocytopenia 12 <1 Asthenia 12 3 Pruritus 11 3*With at least 10% incidence in the everolimus-exemestane group.AE = adverse event.Baselga et al, 2012.
  70. 70. BOLERO-2: Phase 3 RCT Study Efficacy Analysis Local/Central Assessment Central Assessment Everolimus and Placebo and p Value HR Exemestane (N = 485) Exemestane (N = 239) (95% CI) Best Overall Response (%) CR 0.0 0.0 PR 7.0 0.4 SD 74.6 64.4 PD 5.6 21.8 Unknown or Too Early 12.8 13.4 Objective Response (%; 95% CI) 7.0 (4.9–9.7) 0.4 (0.0–2.3) < .001 PFS Events (No.; %) 114 (24) 104 (44) < .001 0.36 (0.27-0.47) Duration (Mos Median) 10.6 4.1 95% CI 9.5–NR 2.8–5.8 Local Assessment Everolimus and Placebo and p Value HR Exemestane (N = 485) Exemestane (N = 239) (95% CI) Best Overall Response (%) CR 0.4 0.0 PR 9.1 0.4 SD 70.1 58.6 PD 9.9 31.4 Unknown or Too Early 10.5 9.6 Objective response (%; 95% CI) 9.5 (7.0–12.4) 0.4 (0.0–2.3) < .001 PFS Events (No.; %) 202 (42) 157 (66) < .001 0.43 (0.35- Duration (Mos Median) 6.9 2.8 0.54) 95% CI 6.4–8.1 2.8–4.1SD = stable disease; PD = progressive disease.Baselga et al, 2012.
  71. 71. TAMRAD Trial  TTP in the ITT population for (I) the overall patient population and patients with (II) primary and (III) secondary hormone resistance I Probability of Survival (%) TTP Probability (%) II III Time (mos) Time (mos)ITT = intent-to-treat.Bachelot et al, 2012.
  72. 72. Temsirolimus in Heavily Pretreated MBC 1.0 0.9 0.8 Probability of PFS (%) 0.7 0.6 0.5 Overall Response Rate: 9% 0.4 Clinical Benefit Rate: 14% 0.3 0.2 0.1 0 8 16 24 32 40 48 56 Time (wks from first dose)Chan et al, 2005.
  73. 73. Letrozole +/- Temsirolimus Estratification by: R Geographic Regions A Temsirolimus, 30 mg VOQD N for 5 days q2wks  United States D  Western Europe, O + Australia, New Zealand, India, M Letrozole, 2.5 mg VOQD Canada I (n = 556)  Asia-Pacific, Z Eastern Europe, E Africa, South America Letrozole, 2.5 mg VOQD (n = 556)  Enrollment open from May 2004 to March 2006  1,112 patients randomly assigned  Patients treated until evidence of PD or as long as toleratedChow, 2006.
  74. 74. Letrozole +/- Temsirolimus EfficacyTEMSR + LET: LET = comparisons for stratified log-rank p value and HR.Chow, 2006.
  75. 75. ER and EGFR: Crosstalk
  76. 76. Reciprocal Crosstalk Between ERα and Growth Factor Receptor Signaling PathwaysMiller et al, 2011.
  77. 77. Tamoxifen ± Gefitinib for ER+ MBC Stratum 1. Tam-Sensitive Tam ± Gefitinib RR: T, 15%; T+G, 12% Stratum 1. HER2+ Cases Proportion PFS (%) Stratum 1, By Prior Endocrine Rx Stratum 2. AI-Resistant RR: T, 0%; T+G, 0% PFS: T, 7.0 m; T+G, 5.7 m Time (yrs)Osborne et al, 2011.
  78. 78. Anastrozole ± Gefitinib for ER+ MBC Probability of PFS (%) Probability of PFS (%) PFS – Overall Time (mos) Time (mos) RR: A, 12%; A+G, PFS: Endocrine-Treated 2% Median PFS: A, Probability of PFS (%) 8.4 m; A+G 14.7 m PFS: Endocrine-NaïveCristofanilli et al, 2010. Time (mos)
  79. 79. ER and HER2: Crosstalk
  80. 80. Crosstalk Between Signal Transduction Pathways and ER Signaling in Endocrine-Resistant Breast Cancer, With Opportunities for Targeted Intervention Growth Factor IGFR Estrogen EGFR/HER2 Plasma P P Membrane P P P P SOS PI3-K RAS RAF Cell Survival P Akt MEK P ER mTOR p90RSK MAPK P P Cytoplasm Cell P P P Basal P Transcription Growth ER p160 CBP Machinery ER Nucleus ERE ER Target Gene TranscriptionAdapted from Johnston, 2010.
  81. 81. HER2 Upregulation in. Tamoxifen-Resistant Breast Cancers 3 Cases From 30 That Were ER+ and HER2- at BaselineGutierrez et al, 2005.
  82. 82. TANDEM: Anastrozole +/- Trastuzumab PFS (probability) TTP (probability) OS (probability) Time (mos)Kaufman et al, 2009.
  83. 83. Letrozole +/- Lapatinib 100 70 Alive Without Progression (%) 80 50 Patients (%) 60 30 40 20 10 0 0 10 20 30 40 50 CR PR SD > 6 mos ORR CBR Time Since Random Assignment (mos) Patients At Risk: Letrozole 642 438 294 208 120 78 51 26 11 2 + Lapatinib Letrozole 644 403 291 212 140 80 53 23 13 7Johnston et al, 2009.
  84. 84. Letrozole +/- Lapatinib: Clinical Efficacy in Human EGFR2+ Population Alive Without Progression (%) Surviving (%) Time Since Random Assignment (mos) Time Since Random Assignment (mos) Patients At Risk: Patients At Risk: Letrozole 110 69 33 20 12 8 4 1 1 Letrozole 111 104 89 80 64 48 32 19 9 4 + Lapatinib + Lapatinib Letrozole 108 43 26 18 12 7 5 2 2 Letrozole 108 93 76 69 59 38 31 15 8 2 Patients (%)Johnston et al, 2009.
  85. 85. Optimizing Chemotherapy-Free Survival  The 2 most prominent biological targets in breast cancer that are used for therapy and research are ER and HER2  50% of all HER2+ breast cancer cases also express ER, so 10% of all breast cancer  ER and HER2 pathways crosstalk and thereby synergize in tumor progression  Therefore, targeting both at the same time, potentially with other compounds and dual HER2 targeting, may increase clinical efficacy and improve long-term outcomes of patients with MBC  Several clinical trials are supporting this preclinical hypothesisGluck et al, 2011.
  86. 86. CALGB 40302 Postmenopausal women Stratification: ER and/or PgR + tumors Prior tamoxifen Tx Prior Tx with AI Yes/no Bone disease only Double-Blinded Yes/no R Fulvestrant D1, 15 (Cycle 1 only) A Lapatinib D1-28 N Restage q2cycles D O Continue study Tx until M PD or undue toxicity I Z Fulvestrant D1, 15 (Cycle 1 only) E Placebo D1-28 Cycle duration = 28 days Follow -up: Follow all patients registered to this study, including those who do not receive any protocol treatment, for first PD, any new primaries and survival for 5 yrs from study entry or until death, whichever comes firstBurstein et al, 2010.
  87. 87. CALGB 40302 (cont.) Median PFS Lapatinib 5.2 m Placebo 4.0 m Logrank p Value .94Burstein et al, 2010.
  88. 88. CALGB 40302 (cont.) PFS: HER2-negativ e Tumors PFS: HER2-positiv e Tumors 1.0 1.0 Lapatinib Lapatinib Placebo Prob. Alive & Progression-Free Placebo Prob. Alive & Progression-Free 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 6 12 18 24 30 0 6 12 18 24 30 Months from Study Entry Months from Study Entry Number of Patients at Risk Number of Patients at Risk Lapatinib 93 52 24 13 10 5 4 1 0 0 0 Lapatinib 23 16 9 6 3 3 3 3 2 1 1 Placebo 85 46 24 13 5 3 1 1 1 0 0 Placebo 28 12 8 Median PFS 4 3 2 5 5 2 1 0 Median PFS Lapatinib 5.9 m Lapatinib 4.1 m Placebo 2.8 m Placebo 4.0 m Interaction test: HER2 status and treatment in Cox proportional hazard model 2-sided p value = .23Burstein et al, 2010.
  89. 89. Key Takeaways:What Is the Optimal Therapy for Patients With Advanced or Metastatic ER+ Endocrine- Resistance Who Progressed After Previous Lines of Therapies? Variety of options for endocrine-refractory breast cancer including AIs, fulvestrant, progestins, estrogens, treatment withdrawal Strategies to overcome resistance – Anti-EGFR shows no clinical benefit – Anti-HER2 shows modest gains – Anti-mTOR improves PFS but with side effects
  90. 90. Key Takeaways (cont.) Management of ER+ breast cancer is the art of oncology A variety of endocrine options available After more than 100 yrs, new options still emerging

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