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Metastatic Breast Cancer and Emerging Research PowerPoint Presentation

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Description : Check out this medical presentation on Breast Cancer (Metastatic), which is titled "Metastatic Breast Cancer and Emerging Research", to know about metastatic disease, breast cancer subtypes (Treatment of Her2+ disease, Treatment of ER+ disease, Treatment of ER-/Her2- disease), and exciting new research directions.

Tags : Breast Cancer, Metastatic, Cancer, Metastatic Breast Cancer, Emerging Research, metastatic disease, breast cancer subtypes, Treatment of Her2+ disease, Treatment of ER+ disease, Treatment of ER-/Her2- disease

Published on : May 13, 2021 | Views : 2132 | Downloads : 3

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Slide 1-

Metastatic Breast Cancer and Emerging Research Kathryn J. Ruddy, MD MPH Assistant Professor of Oncology Mayo Clinic
Slide 2-

Overview What is metastatic disease? Breast cancer subtypes Treatment of Her2+ disease Treatment of ER+ disease Treatment of ER-/Her2- disease Exciting new research directions
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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
Slide 4-

Treatment for metastatic disease 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
Slide 5-

There are three main subtypes of breast cancer Oncologists use breast cancer subtype to guide treatment decisions Clinical trials often focus on specific subtypes Breast cancer subtypes
Slide 6-

Subtypes TALK to your doctor if you are not sure what type of breast cancer you have Slide courtesy of Nancy Lin
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Hormone receptor positive Triple-negative HER2-Positive *Note, these are just examples. Each patient is different and treatment is tailored accordingly. Slide courtesy of Nancy Lin Treatment
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HER2+ disease: a paradigm for advances in targeted therapy
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HER2+ disease: major advances 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
Slide 10-

Trastuzumab in HER2+ metastatic breast cancer Graphic adapted from image at http://www.gene.com/gene/research/focusareas/oncology/herpathwayexpertise.jsp Slamon et al, NEJM 2001 Can combine with many different chemotherapies (e.g., paclitaxel, docetaxel, vinorelbine, capecitabine) and targeted agents (e.g., lapatinib)
Slide 11-

Lapatinib Oral dual tyrosine 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
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Pertuzumab with trastuzumab HER2 receptor 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
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CLEOPATRA: phase 3 study of pertuzumab in untreated metastatic disease 1:1 HER2-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
Slide 14-

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%)
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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
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T-DM1 selectively delivers DM1 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
Slide 17-

EMILIA: randomized trial comparing 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)
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Th3RESA: randomized trial comparing 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 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)
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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
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Novel HER2-directed agents in clinical development
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ER+ disease: improving on already very effective treatments
Slide 22-

Endocrine therapy for metastatic disease Premenopausal Tamoxifen Ovarian suppression/ablation Ovarian suppression + aromatase inhibition Megace Postmenopausal Tamoxifen Aromatase Inhibitor +/- everolimus Fulvestrant Megace
Slide 23-

Polyak and Filho, Cancer Cell, 2012 Targeting the PI3Kinase pathway
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Everolimus is an MTOR inhibitor
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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
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What’s next for everolimus? Multiple studies underway In HER2+ cancers In triple negative cancers Studying this drug in combination with other therapies
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Testing the addition of an HSP90 inhibitor to hormonal therapy Slide courtesy of Nancy Lin
Slide 28-

Testing the addition of an HSP90 inhibitor to hormonal therapy Ganetespib induces regression in tumors progressing on fulvestrant Days of treatment Tumor volume (mm3) Slide courtesy of Nancy Lin
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Other agents of interest 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
Slide 30-

Triple negative breast cancer: still searching for a target
Slide 31-

Triple negative recurrences happen early Dent et al, Clin Cancer Res 2007 Rates of distant recurrence following surgery in triple-negative vs other breast ca
Slide 32-

There are many chemotherapies that are active against metastatic disease Mitotic inhibitors vinorelbine paclitaxel docetaxel Antifolates methotrexate Topoisomerase inhibitors doxorubicin
Slide 33-

Platinums Sledge (JCO 1988) 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
Slide 34-

New chemotherapy: eribulin Approved by the FDA in 2011 Halichondria okadai Metastatic breast cancer At least 2 prior chemotherapies
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PARP inhibitors PARP1 is 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
Slide 36-

Inhibit binding to receptor (AR) T T Tumor Death Cell nucleus Cell cytoplasm Inhibit nuclear translocation of AR Inhibit AR-mediated DNA binding Targeting the androgen receptor in triple negative breast cancer
Slide 37-

Other agents of interest in triple negative disease PI3Kinase inhibitors SRC/Abl tyrosine kinase inhibitors HSP90 inhibitors More to come…
Slide 38-

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” Slide courtesy of Erica Mayer
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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 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
Slide 40-

How many subtypes of breast cancer are there, and by understanding this, can we find new targets and new treatments? Can we better “tailor” treatments? What causes resistance to hormonal therapy? To chemotherapy? Can it be prevented or overcome? What lifestyle factors (e.g., exercise?) might be important for patients with metastatic disease? How can we minimize toxicities of treatment? Outstanding research questions
Slide 41-

Summary Not all breast 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
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Thank you!