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Making Progress in the Treatment of Estrogen Receptor Positive Metastatic Breast Cancer

Patients with ER+ breast cancer have many treatment options, and a better understanding of mechanisms of resistance to therapy is leading to new treatments.

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Making Progress in the Treatment of Estrogen Receptor Positive Metastatic Breast Cancer

  1. 1. Ian Krop Dana-Farber Cancer Institute Harvard Medical School September 2016 Making progress in the treatment of estrogen receptor positive metastatic breast cancer
  2. 2. The Old Approach A little treatment A lot of treatment
  3. 3. Invasive Breast Cancer Subsets Defined by IHC All Breast Cancers Triple negative 15% Burstein, Goldhirsch. St Gallen 2007. ER+ 65%-75% HER2+ 15%-20% 3
  4. 4. HER2+ Estrogen receptor + Triple Negative GENES TUMORS Breast cancer is family of different cancers
  5. 5. “Targeted” therapy • Drug which inhibits a protein or molecule that is only expressed in cancer or which only the cancer is dependent • Offer the promise of reduced side effects compared to less targeted drugs
  6. 6. Estrogen Receptor Function: The Basics Estrogen Estrogen Receptor Cancer cell
  7. 7. Estrogen Receptor Function: The Basics Estrogen Estrogen Receptor Cancer cell
  8. 8. Estrogen Receptor Function: The Basics Estrogen Estrogen Receptor DNA Cancer cell
  9. 9. Estrogen Receptor Function: The Basics Estrogen Estrogen Receptor DNA Cancer cell Cell Growth
  10. 10. Hormonal therapy • The original targeted therapy • Several types: – Tamoxifen • Blocks estrogen from binding to ER – Aromatase inhibitors (anastrozole, letrozole, exemestane) • Blocks production of estrogen – Fulvestrant (Faslodex) • Blocks estrogen from binding to ER and helps degrade ER
  11. 11. Endocrine Therapy Side Effects Good (tam) • Bone Strengthening Bad • More common – Hot Flashes – Vaginal discharge/dryness – Arthralgias (AIs) – Osteopenia/Osteoporosis (AI) • Rare – Blood Clots (tam) – Endometrial cancer (tam) – Cataracts (tam) – ?stroke (tam)
  12. 12. Blocking cancer cell growth: Cyclin Dependent Kinase (CDK 4/6) inhibition • A classic feature of breast cancer is uncontrolled growth • In ER+ breast cancer, out-of-control growth may be due to a failure in the braking system: overactive CDK4/6
  13. 13. CDK 4/6 inhibition blocks cancer cell division • CDK 4/6 Inhibition: – puts the brakes on cell growth – pushes cancer cells towards cell death
  14. 14. Palbociclib (Ibrance) • Palbociclib: oral inhibitor of CDK 4/6 • Taken daily, 3 weeks on, 1 week off • Most common toxicities: low white blood cell count (but no infections), fatigue, mild hair thinning
  15. 15. PALOMA-1 Trial: Schema • First randomized trial of palbociclib in breast cancer (phase II) • Women with newly diagnosed metastatic breast cancer were randomized to first-line therapy with letrozole alone, or letrozole + palbociclib Letrozole Palbociclib + Letrozole • Metastatic breast cancer • ER+/HER2- • First line
  16. 16. Time PercentageofwomenWITHOUT progression100- Kaplan Meier plots allow comparison of clinical outcome over time
  17. 17. 17 PALOMA-1: Progression-Free Survival (ITT Population) Finn RS et al. Presented at AACR 2014; San Diego, California, USA PAL + LET (N=84) LET (N=81) Number of Events (%) 41 (49) 59 (73) Median PFS, months (95% CI) 20.2 (13.8, 27.5) 10.2 (5.7, 12.6) Hazard Ratio (95% CI) 0.488 (0.319, 0.748) p-value 0.0004 90 80 70 60 50 40 30 20 10 0 Progressionfreesurvivalprobability(%) 0 4 8 12 16 20 24 28 32 36 40 Time (months) 84 67 60 47 36 28 21 13 8 5 1 81 48 36 28 19 14 6 3 3 1 PAL + LET LET Number of patients at risk 100
  18. 18. PALOMA-3 Study Design • Larger trial in women whose cancer previously showed resistance to endocrine therapy (Phase III) Placebo + Fulvestrant Palbociclib + Fulvestrant• Metastatic breast cancer • ER+/HER2- • Tumor has shown resistance to endocrine therapy
  19. 19. 0 2 4 6 8 10 12 Time (Month) 0 10 20 30 40 50 60 70 80 90 100 ProgressionFreeSurvivalProbability(%) 347 279 132 59 16 6PAL+FUL 174 109 42 16 6 1FUL Number of patients at risk PALOMA 3: Palbociclib delays cancer progression when added to fulvestrant CI=confidence interval; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival. Placebo + Fulvestrant n=174 Palbociclib + Fulvestran t n=347 # Events (%) 93 (53.4) 102 (29.4) Median PFS 3.8 (3.5, 5.5) 9.2 (7.5, NE) Hazard Ratio 0.422 (0.318, 0.560) <0.000001 Similar benefit seen in all subgroups examined
  20. 20. HOW CAN WE OVERCOME RESISTANCE TO ENDOCRINE THERAPY?
  21. 21. Dual Targeting An endocrine sensitive cell depends on the estrogen receptor nucleus Cancer cell Estrogen receptor
  22. 22. Dual Targeting In setting of endocrine resistance, other pathways are activated nucleus Cancer cell Estrogen receptor Growth factor receptor PI3K mTOR
  23. 23. Dual Targeting In setting of endocrine resistance, other pathways are activated nucleus Cancer cell Estrogen receptor Growth factor receptor PI3K mTOR
  24. 24. Dual Targeting In setting of endocrine resistance, dual targeting may be important nucleus Cancer cell Estrogen receptor Growth factor receptor mTOR PI3K
  25. 25. BOLERO-2 Study Design • Trial of mTOR inhibitor added to exemestane (AI) in endocrine resistant ER+ advanced breast cancer Placebo + Exemestane Everolimus + Exemestane• Metastatic breast cancer • ER+/HER2- • Tumor has shown resistance to endocrine therapy
  26. 26. Everolimus delays cancer progression 4 month improvement in PFS over AI alone Baselga et al, NEJM 2012
  27. 27. Hormonal therapy Hormonal therapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Herceptin + perjeta + chemotherapy TDM1 Lapatinib + Capecitabine Herceptin + chemotherapy Herceptin + chemotherapy Hormone receptor positive Triple-negative HER2-Positive *Note, these are just examples. Each patient is different and treatment is tailored accordingly. How Do We Treat Metastatic Breast Cancer?
  28. 28. USING THE IMMUNE SYSTEM TO FIGHT CANCER
  29. 29. Immune system targets • Bacteria • Viruses
  30. 30. Immune system targets • Bacteria • Viruses • Transplanted organs
  31. 31. Immune system targets • Bacteria • Viruses • Transplanted organs • Cancer cells
  32. 32. Our immune system has an on/off switch
  33. 33. T-cells are designed to recognize and kill tumor cells
  34. 34. PD-1 acts as an “off-switch” for T-Cells
  35. 35. PD-1/PD-L1 inactivates T-Cells
  36. 36. Antibodies to PD-1 or PD-L1 prevent tumor cells from inactivating T-cells
  37. 37. Antibodies to PD-1 shrinks cancers in the majority of patients with metastatic melanoma
  38. 38. Why such durable responses in very advanced cancers? • Immune system targets many parts of the cancer (antigens) – Harder for cancer to escape recognition • Advanced cancers’ frequent mutations make them more “foreign” to immune system
  39. 39. IMMUNOTHERAPY IN BREAST CANCER
  40. 40. Immune therapy in triple negative cancers • Highest rate of PD-L1 expression • Highest rate of mutations • High level of immune cells in the tumor (TILS)
  41. 41. This presentation is the intellectual property of the presenter, Rita Nanda. Contact rnanda@medicine.bsd.uchicago.edu for permission to reprint and/or distribute. December 9-13, 2014 Change From Baseline in Target Lesions Over Time (Central Review) -100 -80 -60 -40 -20 0 20 40 60 80 100 0 8 16 24 32 40 48 56 ChangeFromBaseline,% Time, weeks Analysis cut-off date: November 10, 2014. On treatment Discontinued treatment
  42. 42. What do these trials tell us? • Provides proof that immunotherapy can work in breast cancer • Important to note that: – Only patients with PD-L1 positive TNBC were included – Only a minority of these patients benefited
  43. 43. Immunotherapy in ER+ breast cancer – Low PD-L1 expression – Fewer mutations – Likely will need something to increase recognition by immune system
  44. 44. Other immunotherapy targets in development Activating Inhibiting Mellman et al. Nature, 2011 Ipilimumab Pembrolizumab Nivolumab
  45. 45. Conclusion • Patients with ER+ breast cancer have many treatment options – Hormonal therapies (tamoxifen, AI’s, fulvestrant) – Palbociclib + hormonal therapy – Everolimus + hormonal therapy – Chemotherapy • A better understanding of mechanisms of resistance to therapy is leading to new treatments • Clinical trials allow access to new therapies and help us make progress
  46. 46. 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!
  47. 47. What are clinical trial phases? Clinical trials are conducted in a series of steps (phases) - each phase is designed to answer a separate research question. • Phase I: Testing a new treatment in a small group 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. FDA
  48. 48. 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
  49. 49. Clinical Trials: 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.

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