Downloaded 10 times
More Related Content
Similar to Metastatic bc research
Metastatic bc research
- 1. Metastatic Breast Cancerand Emerging Research Kathryn J. Ruddy, MD MPH Assistant Professor of Oncology Mayo Clinic
- 2. Overview • What ismetastatic disease? • Breast cancer subtypes – Treatment of Her2+ disease – Treatment of ER+ disease – Treatment of ER-/Her2- disease • Exciting new research directions
- 3. Metastatic breast cancer •Stage IV disease – Has spread from the breast and axillary lymph nodes to other organs • Accounts for 5-10% of all breast cancer at the time of diagnosis • Stage IV breast cancer is usually incurable, but can often be controlled for years utilizing sequential drug therapy
- 4. Treatment for metastaticdisease • Treated primarily with systemic therapy, but sometimes with palliative radiation also; surgery is rarely utilized • After the disease develops resistance to one drug, a patient is switched to a new drug • Aims of therapy are to: – Prolong time to progression – Prolong survival – Palliate • Reduce tumor burden • Minimize treatment toxicity • Disease subtype is critical to treatment decision-making
- 5. • There arethree main subtypes of breast cancer • Oncologists use breast cancer subtype to guide treatment decisions • Clinical trials often focus on specific subtypes Breast cancer subtypes
- 6. Subtypes TALK to yourdoctor if you are not sure what type of breast cancer you have Slide courtesy of Nancy Lin
- 7. Hormone receptor positive Triple-negative HER2-Positive *Note, theseare just examples. Each patient is different and treatment is tailored accordingly. Slide courtesy of Nancy Lin Treatment
- 8. HER2+ disease: a paradigmfor advances in targeted therapy
- 9. HER2+ disease: majoradvances • HER2 is an important target; anti-HER2 drugs can be effective with chemo, with endocrine therapy, or alone • Meaningful progress has been made with novel therapies that are well tolerated • Resistance is a major challenge but new technologies are allowing this to be overcome 1998 Trastuzumab Approved 2002 First Preoperative Trials Reported Paving The Way For Use in Early Stage Disease 2005 Three Large Adjuvant Trials Reported 2005 Lapatinib Approved 2007- 2008 Initial Trials of T-DM1, Neratinib 2010 Preoperative Trials of Dual Blockade Pertuzumab Approved 2012 2013 T-DM1 Approved Slide courtesy of Ian Krop
- 10. Trastuzumab in HER2+ metastaticbreast cancer Graphic adapted from image at http://www.gene.com/gene/research/focusareas/oncology/herpathwayexpertise.jsp Protein Receptor HER2 Gene Normal Cell HER2+ Cell Slamon et al, NEJM 2001 Can combine with many different chemotherapies (e.g., paclitaxel, docetaxel, vinorelbine, capecitabine) and targeted agents (e.g., lapatinib)
- 11. Lapatinib • Oral dualtyrosine kinase inhibitor of HER2 and EGFR • FDA approved in combination with capecitabine for trastuzumab- resistant disease • May have CNS penetration • Well tolerated; common toxicities include rash and diarrhea Geyer et al, NEJM 2006
- 12. Pertuzumab with trastuzumab HER2receptor Trastuzumab Pertuzumab Dimerisation domain of HER2 • Inhibitor of HER dimerization: binds HER2 and prevents formation of homo- or heterodimers • Suppresses activation of several intracellular signaling cascades driving cancer cell growth • Synergistic with trastuzumab • Approved for first-line treatment of metastatic Her2+ breast cancer in combination with trastuzumab and taxane chemotherapy Slide courtesy of Ian Krop
- 13. CLEOPATRA: phase 3study of pertuzumab in untreated metastatic disease 1:1HER2-positive MBC Docetaxel + trastuzumab + placebo Docetaxel + trastuzumab + pertuzumab N=808 Pertuzumab prolongs time until progression by six months (from 12.5 to 18.5 months) Baselga et al, SABCS 2011 and NEJM, 2011
- 14. Adverse event, n(%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea 184 (46.3) 272 (66.8) Alopecia 240 (60.5) 248 (60.9) Neutropenia 197 (49.6) 215 (52.8) Nausea 165 (41.6) 172 (42.3) Fatigue 146 (36.8) 153 (37.6) Rash 96 (24.2) 137 (33.7) Decreased appetite 105 (26.4) 119 (29.2) Mucosal inflammation 79 (19.9) 113 (27.8) Asthenia 120 (30.2) 106 (26.0) Peripheral edema 119 (30.0) 94 (23.1) Constipation 99 (24.9) 61 (15.0) Febrile neutropenia* 30 (7.6) 56 (13.8) Dry skin 17 (4.3) 43 (10.6) Toxicities Baselga et al, SABCS 2011 and NEJM, 2011 *Febrile neutropenia rate 12% vs 26% in Asia, 10% or less in all other regions --No difference in cardiac toxicity rate (2% v 1%)
- 15. Trastuzumab Emtansine (T-DM1) •T-DM1 is an antibody drug-conjugate • Trastuzumab linked to a potent chemotherapy (DM1) • Average of 3.5 DM1 per antibody Slide courtesy of Ian Krop
- 16. T-DM1 selectively deliversDM1 to HER2+ 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 Slide courtesy of Ian Krop
- 17. EMILIA: randomized trialcomparing T-DM1 to capecitabine and lapatinib in previously treated patients 1:1 HER2+ MBC (N=980) •Prior taxane and trastuzumab PD T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w + Lapatinib 1250 mg/day orally qd PD Blackwell et al, ASCO 2012 T-DM1 prolongs time until progression by three months (from 6.4 to 9.6 months)
- 18. Th3RESA: randomized trialcomparing T-DM1 to physician’s choice Study treatment continues until disease progression or unmanageable toxicity HER2 positive Metastatic breast cancer Prior trastuzumab, lapatinib and chemotherapy T-DM1 q3w Treatment of physician’s choice N = 795 2:1 randomization 2 1 Wildiers et al, ECC-ESMO 2013 T-DM1 prolongs time until progression by three months (from 3.3 to 6.2 months)
- 19. T-DM1 is well-tolerated •Common side effects: – Decreased platelet count – Elevated liver tests • Does not cause typical chemotherapy side effects • No hair loss • Significant nausea or diarrhea are not common • Does not cause immune suppression or significant neuropathy
- 20. Novel HER2-directed agentsin clinical development Class Example(s) HER2-targeted TKI Neratinib, afatinib, ARRY-380 HER2-targeted liposome MM-302 Trifunctional antibody Ertumaxomab HER2 vaccine AE37
- 21. ER+ disease: improvingon already very effective treatments
- 22. Endocrine therapy for metastaticdisease • Premenopausal – Tamoxifen – Ovarian suppression/ablation – Ovarian suppression + aromatase inhibition – Megace • Postmenopausal – Tamoxifen – Aromatase Inhibitor +/- everolimus – Fulvestrant – Megace
- 23. Polyak and Filho,Cancer Cell, 2012 Targeting the PI3Kinase pathway
- 24. Everolimus is anMTOR inhibitor
- 25. New drug approval:everolimus Approved by the FDA in 2012 for patients with metastatic, hormone-receptor positive, HER2-negative breast cancer *Median time from study entry until worsening of cancer Slide courtesy of Nancy Lin
- 26. What’s next foreverolimus? • Multiple studies underway – In HER2+ cancers – In triple negative cancers – Studying this drug in combination with other therapies
- 27. Testing the additionof an HSP90 inhibitor to hormonal therapy Slide courtesy of Nancy Lin
- 28. Testing the additionof an HSP90 inhibitor to hormonal therapy Ganetespib induces regression in tumors progressing on fulvestrant Days of treatment Tumorvolume (mm3 ) Slide courtesy of Nancy Lin
- 29. Other agents ofinterest in ER+ disease • Endoxifen • CDK 4/6 inhibitors • PI3Kinase inhibitors • Anti-IGF-1R Ab • SRC/Abl tyrosine kinase inhibitors • Combination therapy with targeted agents that may overcome endocrine resistance
- 30. Triple negative breastcancer: still searching for a target
- 31. Triple negative recurrenceshappen early Dent et al, Clin Cancer Res 2007 Rates of distant recurrence following surgery in triple-negative vs other breast ca
- 32. There are manychemotherapies that are active against metastatic disease • Mitotic inhibitors – vinorelbine – paclitaxel – docetaxel • Antifolates – methotrexate • Topoisomerase inhibitors – doxorubicin
- 33. Platinums • Sledge (JCO1988) reported 47% response rate in first line metastatic disease • Abandoned for many years because of concerns about toxicity—largely replaced by taxanes • Recent interest in patients with triple negative breast cancer – DNA crosslinking mechanism of action • New data from a series of neoadjuvant studies supports activity in TNBC Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009; Sikov SABCS 2013
- 34. New chemotherapy: eribulin Approvedby the FDA in 2011 Halichondria okadai•Metastatic breast cancer •At least 2 prior chemotherapies
- 35. PARP inhibitors • PARP1is a protein that is important for repairing single-strand DNA breaks • PARP inhibitors prevent DNA repair, leading to cell death • Fast-dividing tumors and tumors containing BRCA mutations, which also impair DNA repair, may be most sensitive to PARP inhibitors • Ongoing trials are investigating the efficacy of PARP inhibitors in breast cancer, particularly triple negative breast cancer and BRCA-associated breast cancer
- 36. Inhibit binding toreceptor (AR) T AR T Cell nucleus AR Cell cytoplasm Inhibit nuclear translocation of AR Inhibit AR-mediated DNA binding Targeting the androgen receptor in triple negative breast cancer
- 37. Other agents ofinterest in triple negative disease • PI3Kinase inhibitors • SRC/Abl tyrosine kinase inhibitors • HSP90 inhibitors • More to come…
- 38. What does allthis 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” Slide courtesy of Erica Mayer
- 39. What does allthis 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 full” •The opportunity to individualize therapy—one size doesn’t fit all •We may be able take advantage of specific weaknesses of cancers and knock out specific strengths •But should be possible! Slide courtesy of Erica Mayer
- 40. 1. How manysubtypes of breast cancer are there, and by understanding this, can we find new targets and new treatments? Can we better “tailor” treatments? 2. What causes resistance to hormonal therapy? To chemotherapy? Can it be prevented or overcome? 3. What lifestyle factors (e.g., exercise?) might be important for patients with metastatic disease? 4. How can we minimize toxicities of treatment? Outstanding research questions
- 41. Summary • Not allbreast cancers are alike • We have many clues to guide therapy • But we need clinical trials and continued basic and translational research to make new breakthroughs that make a difference for patients
- 42.
Editor's Notes
- #5 In considering the goals of chemotherapeutic treatment for patients with metastatic breast cancer, it is important to recognize that a cure, while being the optimal outcome, is rare and cannot be considered a goal of currently available treatments. However, first-line treatment regimens which can produce statistically significant increases in disease-free survival are a major focus of current oncologic practice. Palliation is the most achievable goal of treatment, and a prolonged time to progression serves as a surrogate as does measurable reductions in tumor burden. Unfortunately, this benefit can be compromised by treatment toxicities. Hence, the clinician must strive to decrease the toxicity of treatment while striving to maintain an aggressive chemotherapy regimen.
- #6 Top panel: ductal cancer, lower panel, lobular cancer
- #15 No difference in cardiac tox rate
- #16 by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents
- #19 No crossover allowed for control arm to T-DM1 after PD (OS)
- #32 cohort of 1,601 women dx’d between 1987-1997 at Women’s College Hosp in Toronto, median f/u 8.1 yr.
- #35 Mention erica’s trial