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What's Hot in Breast Cancer Treatment

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What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.

This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.

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What's Hot in Breast Cancer Treatment

  1. 1. What’s Hot in Breast Cancer Treatment 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. Breast Cancer is Not Just One Disease At least 4 major subtypes: Luminal A Luminal B HER2-positive Basal ER+ HER2- ER- PR- HER2-
  4. 4. What does all this complexity mean? •There is likely not going to be a single “cure for cancer” •Different cancers may have different strengths & weaknesses •Figuring this out won’t be easy! “half empty”
  5. 5. What does all this complexity mean? •There is likely not going to be a single “cure for cancer” •Different cancers may have different strengths & weaknesses •Figuring this out won’t be easy! “half empty” “half full” •The opportunity to individualize therapy—one size doesn’t fill all •We may be able take advantage of specific weaknesses and knock out specific strengths •It should be possible!
  6. 6. What’s Hot for ER+ Breast Cancer? 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. PALOMA-3 Study Design • Larger trial in women whose cancer previously showed resistance to endocrine therapy (Phase III) • Placebo controlled Placebo + Fulvestrant Palbociclib + Fulvestrant• Metastatic breast cancer • ER+/HER2- • Tumor has shown resistance to endocrine therapy
  12. 12. 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. PALOMA-3: Results in Younger Women
  15. 15. 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….
  17. 17. The HER2 Timeline 1981 neu described as a transforming oncogene in rat brain tumor carcinogenesis model 1985 a) neu is homologous to the v-erb B viral oncogene b) “EGFR-like” gene amplified in a human breast cancer cell line – named “HER2” 1986 HER2 found to have tyrosine kinase activity similar to EGFR 1987 HER2 amplification correlated with poor OS in human breast cancer 1989 Discovery of HER3 1993 Discovery of HER4 1998 FDA approval of trastuzumab 2007 FDA approval of lapatinib 2012 FDA approval of pertuzumab 2013 FDA approval of trastuzumab emtansine (T-DM1)
  18. 18. Pertuzumab (Perjeta) • Dual targeting of the HER2 receptor – prevents growth stimulation of cancer cell – promotes cancer cell destruction Herceptin Pertuzumab HER2 receptor
  19. 19. CLEOPATRA: Phase III Trial of Docetaxel + Trastuzumab vs Docetaxel + Trastuzumab + Pertuzumab 1:1HER2-positive Advanced Breast Cancer Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab N=808
  20. 20. Results from CLEOPATRA • Women receiving chemotherapy with both herceptin and pertuzumab had – Longer period of disease control – Longer survival • Overall very well tolerated • Quickly “THP” has become a new standard of care for advanced HER2+ breast cancer
  21. 21. Can we Offer Pertuzumab Before Cancer is Advanced? • “NeoSPHERE” study added pertuzumab to chemotherapy and herceptin before breast surgery • Patients receiving the 3 drugs had a doubling in “pathologic complete response” – complete eradication of cancer from breast and nodes at time of surgery • FDA approved “THP” in 9/2013 in preoperative setting
  22. 22. TDM1 (Kadcyla) • Antibody-drug-conjugate • A “smartbomb” • A “Trojan horse”
  23. 23. T-DM1 selectively delivers DM1 to HER2-positive tumor cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell T-DM1 binds to the HER2 protein on cancer cells HER2
  24. 24. EMILIA Study Design HER2+ Advanced breast cancer Prior treatment with chemotherapy and herceptin T-DM1 Capecitabine (Xeloda) + Lapatinib (Tyberk, oral HER2)
  25. 25. Results of EMILIA • Patients receiving TDM1 had better cancer control and lived longer than those receiving the other arm • TDM1 contributed SIGNIFICANTLY fewer side effects than the chemotherapy containing arm. • FDA approved for treatment of advanced breast cancer in February 2013
  26. 26. Will there be a role for TDM1 earlier in therapy? ATEMPT Trial Stage I HER2+ 500 patients Trastuzumab-DM1 q3weeks X17 Paclitaxel + Trastuzumab x12 Trastuzumab q3weeks x13 N=375 N=125 R 3 1 PI: Sara Tolaney, MD, MPH
  28. 28. PARP Inhibitors: Mechanism • If BRCA1/2 is not working, the cell depends on PARP for all DNA repair • PARP inhibitors prevent DNA repair in cancer cells – May increase cancer cell death – May help chemo and radiation work better • PARP and BRCA1/2 function to repair daily DNA damage • Too much DNA damage-> cell death Ellisen, Cancer Cell 2011; Tutt et al, Lancet 2010
  29. 29. Phase II trial of the PARP inhibitor olaparib in BRCA- deficient advanced breast cancer Study design: - To assess efficacy/tolerability of olaparib in BRCA 1/2 mutation carriers - Phase II single arm sequential cohort multicenter trial Confirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer (stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease (med prior regimens = 3) Olaparib 400 mg po bid 28-day cycles; 27 patients Cohort 1 (enrolled first) Olaparib 100 mg po bid 28-day cycles; 27 patients Cohort 2 Tutt et al, ASCO 2009
  30. 30. Objective tumor response rate (RECIST) Overall Response Rate, n (%) Complete Response, n (%) Partial Response, n (%) 11 (41)* 1 (4) 10 (37) Olaparib 400 mg bid (n=27)ITT cohort Adverse Events: Fatigue grade 1 or 2, 56% grade 3, 15% Nausea grade 1 or 2, 26%, grade 3 11% ASCO 2009; #suppl. CRA501 • Median of 3 prior lines of chemotherapy. Substantial activity with biologic monotherapy in a heavily pretreated BRCA1/2 population!
  31. 31. Single Agent PARP Inhibition: Ongoing Trials evaluating Chemotherapy vs PARPi in Patients with BRCA Mutations gBRCA1/BRCA2 Carriers Advanced anthracycline+taxane resistant breast cancer PARP inhibitor Physician Choice chemotherapy R Olaparib – OLYMPIAD – NCT02000622 Niraparib – BRAVO – NCT01905592 BMN673 – EMBRACA – NCT01945775
  32. 32. Immunotherapy in Cancer • First generation (anti-CTLA4) – Ipilumumab: approved for melanoma • Second generation (anti-PD1 or PDL1) – Nivolumab: approved for melanoma, lung cancer – Pembrolizumab: approved for melanoma What about breast cancer?
  33. 33. Early PD1/PDL1 Experience in Breast Cancer • Immune cells often found infiltrating triple negative breast cancer – potentially indicates candidacy for immune therapy! • Two Phase 1 trials completed in patients with advanced triple negative breast cancer – More response seen than expected with chemotherapy – Will tolerated • Phase 2 and 3 trials opening now • Many questions need to be figured out: – Is immunotherapy for everyone or can we find tumor markers that predict who will get more benefit? – Do we need to test tumor for PDL1 – Will immunotherapy have benefit in other types of breast cancer, ie HR+, HER2+?
  35. 35. THE PRECISION MEDICINE INITIATIVE “Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type — that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?” - President Obama, January 30, 2015
  36. 36. Obtain tumor biopsy material Extract DNA/RNA from tumor to profile for somatic alterations The Path to Precision Cancer Medicine MacConaill and Garraway, JCO, 2010
  37. 37. Designed to obtain genomic information on all patients who come to DFCI / BWH / BCH for cancer-related care Goals: • Collect genomic information on all patients who have cancer, are presumed to have cancer, or are at risk for developing cancer • Return clinically relevant results to providers • Store results in searchable database • Enable linkage of specimen results to clinical database PROFILE: Towards Precision Cancer Medicine Since August 2011, >30,000 patients have consented (75%) and >8,000 tests have been performed
  38. 38. 0 20 40 60 80 100 120 140 160 180 PIK3CA TP53 AKT1 JAK3 M ET PTEN KRAS HRAS BRAFCDKN2ACTNNB1 EGFR ERBB2 GNASM AP2K1 M LH1 RB1 RET Mutations Identified in > 500 Breast Tumor Specimens at DFCI Using OncoMap Samples with mutation: 268 (48%) PI3 kinase / AKT / MTOR inhibitors RAF / MEK inhibitors AKT / MTOR inhibitors EGFR inhibitors EGFR / Her2 inhibitors Slide courtesy of Nikhil Wagle MD
  39. 39. Potential Genomic Targets in Breast Cancer Selected genes with Mutations, Amplifications/Deletions, Rearrangements in Breast Cancer ERBB2 PIK3CA PTEN AKT1 AKT2 AKT3 PIK3R1 INPP4B MTOR TSC1 TSC2 KRAS NRAS BRAF MAP2K1 MAP3K1 NF1 FGFR1 FGFR2 FGFR3 CDKN2A CDKN1B CCND1 CCNE1 CDK4 RB1 BRCA1 BRCA2 ATM EGFR TP53 MDM2 MYC KIT NTRK3 NOTCH1 Anti-Her2 Therapies PI3k / AKT / MTOR Inhibitors RAF / MEK / ERK Inhibitors FGFR Inhibitors CDK Inhibitors PARP Inhibitors Platinums Nutlins Anti-p53 Strategies Anti-MYC Strategies Others EGFR Inhibitors
  40. 40. Clinical Breast Cancer Cancer Genomics • To date, genomic studies in breast cancer have highlighted the landscape of genomic alterations in breast cancer overall • Now, we have developed clinically-focused studies to help us understand: – The genetics of specific types of breast cancer – Why breast cancers behave in different ways – How breast cancers develop resistance to therapies – Why some breast cancers are exquisitely sensitive to some therapies
  41. 41. 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)
  42. 42. 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!
  43. 43. 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 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. FDA approval
  44. 44. 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
  45. 45. 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.
  46. 46. How to learn about trials? Or ask your provider…
  47. 47. Conclusions • Incredibly exciting work going on in breast cancer research – New targets – Advances for all subtypes – Moving away from chemotherapy – Learning a tremendous amount from each biopsy • Future progress depends on.....Making every woman count!