Metastatic Breast Cancer Research and Treatment

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Join Dr. Erica Mayer, medical oncologist at Dana-Farber/Brigham and Women's Cancer Center, to learn about exciting metastatic breast cancer developments from the past year. Dr. Mayer presents an overview on metastatic breast cancer and the subgroups, including Hormone Receptive, HER2+, and Triple Negative, and highlights recent advances for each of these subgroups. She also discusses the importance of clinical trials and what it means to participate in a clinical trial.

For more information on the Breast Cancer Treatment Center at Dana-Farber Cancer Institute, please visit:

http://www.dana-farber.org/Adult-Care/Treatment-and-Support/Treatment-Centers-and-Clinical-Services/Breast-Cancer-Treatment-Center.aspx

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Metastatic Breast Cancer Research and Treatment

  1. 1. Progress Against Metastatic Breast Cancer: 2012 Erica L. Mayer MD MPH DFCI Susan F. Smith Center for Women’s Cancers October 2012
  2. 2. We are Making Progress Against Metastatic Breast Cancer!• 2 new chemotherapies for breast cancer recently approved• 2-3 new biologics for breast cancer approved in 2012• Greater understanding of the categories of breast cancer, with identification of new targets• MULTIPLE trials ongoing for every subtype of breast cancer These advances will translate into real improvements for patients today and in the future fighting metastatic disease!
  3. 3. Clinical Breast Cancer Subsets Hormone Receptor + 65%-75% All Breast Cancers HER2+ 15%-20% Triple negative 15%Burstein, Goldhirsch. St Gallen 2007. 3
  4. 4. Available Endocrine Medications for ER+ Breast CancerTrade Name Generic Name Pre-or Post FormNovaldex tamoxifen either pillArimidex anastrozole post pillFemara letrozole post pillAromasin exemestane post pillFaslodex fulvestrant post injectionLupron leuprolide pre injectionZoladex goserelin pre injectionMegace megestrol acetate post pill
  5. 5. A Model of Endocrine Resistance Estrogen Receptor Cell Nucleus
  6. 6. A Model of Endocrine Resistance Estrogen Receptor Endocrine agents Cell Nucleus
  7. 7. A Model of Endocrine Resistance Estrogen Growth Factor Receptor Receptor PI3K AKT Endocrine agents mTOR Cell Nucleus
  8. 8. A Model of Endocrine Resistance Estrogen Growth Factor Receptor Receptor PI3K AKT Targeted Inhibitors Endocrine agents mTOR Cell Nucleus
  9. 9. A Model of Endocrine Resistance Estrogen Growth Factor Receptor Receptor PI3K AKT Targeted Inhibitors Endocrine agents mTOR Cell Nucleus Resistance to endocrine therapy may be inhibited by targeting ER and growth factor pathways
  10. 10. Everolimus (Affinitor)• Oral inhibitor of mTOR, taken daily• Approved in 2009 for advanced kidney cancer, pancreatic cancer• Side effects include: rash, diarrhea, mouth sores
  11. 11. BOLERO-2: A Trial of Everolimus in HR+ Breast Cancer Everolimus 10 mg/day +724 women with 2 Exemestane 25 mg/day ER+ HER2- (N = 485) 1 Survival andmetastatic breast Safety cancer, with Placebo + Endpointsexposure to prior Exemestane 25 mg/day AI (N = 239) Baselga et al, NEJM 2012
  12. 12. BOLERO-2: A Trial of Everolimus in HR+ Breast Cancer Everolimus 10 mg/day +724 women with 2 Exemestane 25 mg/day ER+ HER2- (N = 485)metastatic breast 1 Survival and cancer, with Safety Placebo + Endpointsexposure to prior Exemestane 25 mg/day AI (N = 239) • Results: – Improvement in cancer control with combination – Some increased toxicity – Preserved quality of life Baselga et al, NEJM 2012
  13. 13. BOLERO-2: A Trial of Everolimus in HR+ Breast Cancer Everolimus 10 mg/day +724 women with 2 Exemestane 25 mg/day ER+ HER2- (N = 485) Survival andmetastatic breast 1 Safety cancer, with Endpoints Placebo +exposure to prior Exemestane 25 mg/day AI (N = 239) • Results: – Significant improvement in time on therapy vs AI alone – Some increased toxicity with combination vs AI alone – No reported decrease in quality of life Baselga et al, NEJM 2012
  14. 14. Future for Targeted Inhibitors in HR+ Breast Cancer• Many inhibitors in development targeting mTOR, PI3K, AKT• Multiple ongoing trials of new inhibitors – With endocrine medicines – With chemotherapy – With other biologics• Inhibitors may work even better in tumors with alterations in PI3K; tumor testing ongoing at DFCI to identify best candidates for trials
  15. 15. HER2-Positive Breast Cancer Protein ReceptorHER2Gene Normal Cell HER2+ Cell
  16. 16. HER2-Positive Breast Cancer Protein ReceptorHER2Gene Normal Cell HER2+ Cell
  17. 17. HER2-Positive Breast Cancer HERCEPTIN Protein ReceptorHER2Gene LAPATINIB Normal Cell HER2+ Cell
  18. 18. Timeline1985HER2 amplification 2001 2005described in breast 1st trials of Demonstration that Herceptincancer lapatinib begun reduces the risk of recurrence in HER2+ early-stage patients 1998 2007 Herceptin approved by FDA Lapatinib approved by FDA for treatment of metastatic for treatment of metastatic HER2+ breast cancer HER2+ breast cancer 1992 following Herceptin Herceptin developed1984HER2 geneidentified
  19. 19. Pertuzumab• Inhibitors HER receptor interactions• Prevents activation of cell growth• Synergistic with Herceptin
  20. 20. CLEOPATRA: Adding Pertuzumab forFirst Line Therapy HER2+ Breast Cancer Taxotere + herceptin +HER2+ metastatic placebobreast cancer, noprior therapy Taxotere + herceptin+N = 808 pertuzumab
  21. 21. CLEOPATRA: Adding Pertuzumab forFirst Line Therapy HER2+ Breast Cancer Taxotere + herceptin +HER2+ metastatic placebobreast cancer, noprior therapy Taxotere + herceptin+N = 808 pertuzumab• Results: – Significant improvements in survival – No additional toxicity
  22. 22. What is TDM-1?• Antibody-drug Conjugate
  23. 23. T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release P Inhibition of P microtubule P polymerization Lysosome Internalization Nucleus 23Adapted from LoRusso PM, et al. Clin Cancer Res 2011.
  24. 24. 2012 Was a Big Year for TDM1!• 2012: presentation of data from a large trial comparing TDM1 vs oral regimen of capecitabine + lapatinib – Patients who received TDM1 did much better – TDM1 had remarkably less toxicity (no rash or diarrhea)• FDA approval TDM1 expected early 2013• Multiple other trials of TDM1 ongoing
  25. 25. TDM1 at DFCI• We have had 9 clinical trials offering TDM1 to DFCI patients – 06-046 - TRASTUZUMAB-MCC-DM1 FOR HER2+ MET BREAST – 08-058 - TRASTUZUMAB-MCC-DM1 FOR MET HER2+ BREAST – 08-194 - TRASTUZUMAB-MCC-DM1 FOR HER2+ BREAST – 09-096 - TRASTUZUMAB-MCC-DM1 EXTENSION STUDY – 09-130 - T-DM1/PACLITAXEL/PERTUZUMAB FOR HER2+ BREAST – 09-148 - TRASTUZUMAB-MCC-DM1/GDC-0941 FOR HER2+ BREAST – 10-305 - T-DM1 W/CT FOR HER2+ BREAST – 10-442 - EMILIA: T-DM1 VS CAPECITABINE/LAPATINIB FOR BREAST – 11-309 - THERESA: T-DM1 VS. SOC FOR HER2+ BREAST CANCER• 109 DFCI patients so far have participated in clinical trials of TDM1, and have played an important role in development of this medication
  26. 26. Timeline1985HER2 amplification 2001 2005 2012:described in breast 1st trials of Demonstration that Herceptin Pertuzumabcancer lapatinib begun reduces the risk of recurrence first-line in HER2+ early-stage patients metastatic 1998 2007 2013: Herceptin approved by FDA Lapatinib approved by FDA TDM-1 for for treatment of metastatic for treatment of metastatic metastatic HER2+ breast cancer HER2+ breast cancer disease 1992 following Herceptin Herceptin developed1984HER2 geneidentified
  27. 27. Timeline1985HER2 amplification 2001 2005 2012:described in breast 1st trials of Demonstration that Herceptin Pertuzumabcancer lapatinib begun reduces the risk of recurrence first-line in HER2+ early-stage patients metastatic 1998 2007 2013 Herceptin approved by FDA Lapatinib approved by FDA TDM-1 for for treatment of metastatic for treatment of metastatic metastatic HER2+ breast cancer HER2+ breast cancer disease 1992 following Herceptin Herceptin developed1984HER2 geneidentified Many exciting agents in trials!!
  28. 28. “Triple Negative” Breast Cancer (TNBC)• Defined as negative for estrogen, progesterone, and HER2 receptors• Represents about 15% of all breast cancer• Although endocrine and HER2 directed therapies not used, chemotherapy works the best against TNBC• Large number of targeted agents in trials
  29. 29. Whats New in TNBC? Heterogeneity • Gene profile analysis from over 500 TNBC tumor samples • 6 TNBC subgroups were identified with unique profilesLehmann et al, JCI 2011
  30. 30. Heterogeneity of TNBC TNBC
  31. 31. Heterogeneity of TNBC EGFR PARP VEGF AR BRCA1- Src
  32. 32. Heterogeneity of TNBC EGFR PARP VEGF AR BRCA1- Src• “A disease defined by negatives is not one disease!” – Andrew Tutt, MD
  33. 33. Many Agents Under Evaluation for TNBC in Clinical Trials! Targeted Agent Target PARP inhibitors DNA repair pathways Tivozanib VEGFR, angiogenesis dasatinib Src CDK inhibitors Cell cycle control MetMab, ARQ197 Met Tigatuzumab Death receptor PI3K inhibitors PI3K mTOR inhibitors mTOR FGF inhibitors FGF Ruxolitinib JAK-1 Bicalutamide AR, androgen receptor
  34. 34. TNBC: Conclusions• Chemotherapy works and has gotten better• No single best target has been identified; novel biologic agents may have activity for some subgroups• TNBC is an area of very active research; in the past 2 months, 4 new trials opened at DFCI• Speak to you provider about entering a trial!
  35. 35. How Can We Do Better? Participate in Trials!• Clinical trials exist for patients at any step of their breast cancer journey; trials are a part of the continuum of care• There are benefits to being on a trial! – a larger treatment team – possible exposure to cutting edge new medications – helping other patients with breast cancer• None of the advances in breast cancer could have happened without patients volunteering to be in trials
  36. 36. What are clinical trial phases?Clinical trials are conducted in a series of steps (phases) - each phase is designed toanswer a separate research question.• Phase I: Testing a new treatment in a small group of people to evaluate safety, dose, and side effects.• Phase II: Evaluating within a larger group the efficacy and safety of a new treatment• Phase III: A comparison study in a large group to determine if a new treatment works better than standard therapy. These trials typically involve randomization and may have a placebo; the data from a phase 3 trial can be used for FDA drug approval. nlm.nih.gov/services/ctphases.html
  37. 37. How to learn about trials? Or ask your provider…
  38. 38. How Do I Enter a Trial?• Your provider will discuss with you trials of interest, review rationale, as well as risks and benefits• A research RN will review a consent form with you, which describes the structure and details of the trial• After a consent is signed, there is a “screening” period to determine if you are eligible• When eligibility is confirmed, then you register and can begin trial therapy
  39. 39. FAQs• If I consent to a trial, do I have to stay on it? – You can leave a trial at any time if either you or your provider thinks being on the trial is no longer in your best interest• Will I have to pay more to be on a trial? – All normal procedures are billed to insurance; anything beyond normal care is paid for by the trial. There should be no “upcharge” for being in a trial• Is being on a trial busy? – Each trial is different and has a different schedule• Will I know what medicine I am getting? I don’t want a placebo. – In most trials, both patient and provider know exactly what treatment is being given. – Some larger trials use randomization and placebos, and in some cases neither patient nor provider know identity of study drug. – But in almost every trial with placebo, at minimum a patient receives best standard of care.
  40. 40. How Can We Do Better? “Tissue is the Issue”• Sources of breast cancer tissue – Blood samples: Circulating tumor cells – Archived samples from initial diagnosis – Biopsies while receiving treatment before surgery – Biopsies of breast cancer after relapse• 5 ongoing DFCI breast cancer studies collect and bank tissue for ongoing and future analyses• Many recent advances have been developed from tissue samples; please consider contributing if a biopsy is needed
  41. 41. Conclusions• 2012 has brought great new advances in the treatment of metastatic breast cancer• Many exciting new drugs in the pipeline• Involvement in clinical trials is encouraged; speak to your provider about how you can get involved• Future progress depends on.....Making every woman count!

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