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What's New in Treatment of ER+ Breast Cancer?

Learn about the latest research and treatment for ER+ breast cancer. Erica Mayer, MD, MPH, medical oncologist with the Susan F. Smith Center for Women's Cancers, discusses new clinical trials and treatment options for this subset of breast cancer patient.

This presentation was originally given on Oct. 17, 2015, at the Metastatic Breast Cancer Forum, hosted by the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.

Learn more: http://www.susanfsmith.org

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What's New in Treatment of ER+ Breast Cancer?

  1. 1. What’s New in Treatment of ER+ Breast Cancer? Erica L. Mayer MD MPH Dana-Farber Cancer Institute
  2. 2. Invasive Breast Cancer Subsets Defined by IHC All Breast Cancers Triple negative 15% Burstein, Goldhirsch. St Gallen 2007. ER+ 65%-75% HER2+ 15%-20% 2
  3. 3. Therapy for Advanced ER+ Breast Cancer • Strong preference to begin treatment using endocrine (hormone) therapy, unless cancer is causing significant symptoms/problems • At least 4+ choices (“lines”) of therapy; generally can be very effective at controlling the cancer with minimal side effects • New approaches are needed to improve efficacy of endocrine therapy and delay onset of resistance
  5. 5. 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
  6. 6. What’s Hot for ER+ Breast Cancer? CDK 4/6 inhibition • CDK 4/6 Inhibition: – puts the brakes on cell growth – pushes cancer cells towards cell death
  7. 7. 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
  8. 8. 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
  9. 9. PALOMA-1 Trial: Results • Women taking the 2 medications had substantially better disease control that those taking the 1 medication • The combination arm was well tolerated
  10. 10. 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
  11. 11. PALOMA-3 Results • Combination arm again did substantially better than fulvestrant and placebo • Toxicity profile very similar to PALOMA-1 • Validates activity of palbociclib seen in PALOMA-1 • No new toxicity signals with the drug • Await results of PALOMA-2: similar to PALOMA-1 but a larger trial
  13. 13. PALLAS: Phase III Randomized Trial of Adjuvant Endocrine Therapy +/- Palbociclib Patient Population •N = 4600 •HR+ and HER2- • Stage II or III Arm A Palbociclib (2 yrs) + Endocrine Treatment (5+ yrs) Arm B Endocrine treatment (5+ yrs) R A N D O M I Z E 1:1 Survival/Disease Follow-up Arm A: palbociclib at a dose of 125 mg once daily, Day 1-21 in a 28-day cycle for total duration of 2 years, in addition to standard adjuvant endocrine therapy Arm B: standard adjuvant endocrine therapy (AI, tamoxifen) Opening 11/2015….
  15. 15. Dual Targeting An endocrine sensitive cell depends on the estrogen receptor nucleus Cancer cell Estrogen receptor
  16. 16. Dual Targeting In setting of endocrine resistance, other pathways are activated nucleus Cancer cell Estrogen receptor Growth factor receptor mTOR PI3K
  17. 17. Dual Targeting In setting of endocrine resistance, dual targeting may be important nucleus Cancer cell Estrogen receptor Growth factor receptor mTOR PI3K
  18. 18. 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
  19. 19. BOLERO-2 Results • Combination arm had better cancer control than exemestane and placebo • Toxicity profile: mouthsores, fatigue diarrhea, can be controlled with dose reduction • Enhancement of activity in setting of resistance validates laboratory model • Results of BOLERO-2 led to FDA approval of everolimus for breast cancer in July 2012 • Currently under study in the adjuvant setting
  20. 20. What About Targeting PI3K? • Laboratory work suggests PI3K inhibitor + endocrine therapy is synergistic • Almost 40-45% of ER+ breast cancer has a PIK3CA mutation – does this predict a cancer will be sensitive? • Trials of 1st generation PI3K inhibitors did not show enough signal to move forward. • 2nd generation agents are more selective (“alpha specific”) and may show greater activity 21 MCF-7 (E545K) 1. Miller et al. JCO 2010 2. Baselga et al. NEJM 2012; Bachelot et al. JCO 2012 3. Raynaud et al., MCT 2009
  21. 21. Alpha Specific PI3K Inhibitors are Now in Phase III Trials! SANDPIPER trial Normal Assignment of treatment by presence of mutation: an example of “precision medicine”
  22. 22. How Can We Do Better? Participate in Trials! • “One reason I chose to participate in a clinical trial was to help women with triple-negative breast cancer. It is thanks to women who have enrolled in clinical trials that we have the treatments that give us hope.” – Natalia (LBBC, Guide to Understanding TNBC)
  23. 23. 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!
  24. 24. 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 approval
  25. 25. 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
  26. 26. 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.
  27. 27. How to learn about trials? Or ask your provider…
  28. 28. Current Trials at DFCI for Advanced ER+ Breast Cancer (as of 10/15/15) Protocol # Short Title 15-060 Palbociclib + Bazedoxifene 15-058 Abemaciclib in Patients with Brain Metastases secondary to HR+ Breast Cancer 14-569 Ph I SRN-927 in Postmenopausal ER+ MBC 14-565 Ph III Rand. DB LEE011 or Placebo in comb. w/TAM + Goserlin or NSAI + Goserlin for Premenopausal BC (MONALEESA-7) 14-518 Fulvestrant +/- Abemaciclib 14-098 LEE011/Fulvestrant/BYL719/ BKM120 for BC 14-070 LY2835219 + Endocrine for HR+ MBC 13-157 BYL719+Letrozole in HR+ BC 11-477 Faslodex +/- Ganetespib for HR+ MBC 11-010 GDC0032 + Endocrine 11-208 Cabozantinib + Fulvestrant for MBC
  29. 29. Conclusions • Incredibly exciting work going on in breast cancer research for ER+ breast cancer – New targets – Moving away from chemotherapy – Learning a tremendous amount from each biopsy • Future progress depends on.....Making every woman count!