Kevin R. Fox, MD Rena Rowan Breast Center Abramson Cancer Center University of Pennsylvania Perelman School of MedicineR

Kevin R. Fox, MD Rena Rowan Breast Center Abramson Cancer Center University of Pennsylvania Perelman School of MedicineR

Treatment of early stage, HER2 positive breast cancer Treatment of early stage, ER positive breast cancer in young women Acupuncture

Estrogen receptor: most have it Progesterone receptor: goes with the estrogen receptor, but not in every case HER2: only 20% have it

HRG (NRG1) Ligand binding domain Transmembrane Tyrosine kinase domain HER1/ EGFR HER2 HER3 HER4 Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21; Roskoski. Biochem Biophys Res Commun. 2004;319:1; Rowinsky. Annu Rev Med. 2004;55:433.

EGF HER1 (Open) HER1 (Closed) EGF * Dimerization HER2 (Open) *One of numerous ligands involved Phosphorylation Activation of Downstream Signaling Roskoski. Biochem Biophys Res Commun. 2004;319:1; Herbst. Int J Radiat Oncol Biol Phys. 2004;59(suppl):21. For Background Information Only. Do Not Duplicate or Distribute US.DOC.08.05.007 6

LPA, Amphiregulin(3,4) (4) Cytokines Ligands NRG1 NRG2 TGF EGF Epiregulin -cellulin HB-EGF NRG3 NRG4 thro (1) (1) (1,4) (1) (1,4) (4) (4) mbin, (1) Input ET, layeretc Receptor dimers Src CblPLC PI(3)K Shc Crk Jak Ras-GDP Shp2GAP Grb2 Nck VavGrb7 Ras-GDPSos Rac Signal-processing layer PKCBad Akt RAF PAK S6K MER JNKK MAPK JNK Abl Multiple pathway interactions (eg, ER) Sp1 Myc Jun Fos Elk Adapted from Yarden and Sliwkowski. Nat Rev Mol Cell Biol. 2001;2:127. Egr1 Stat Adaptors and enzymes Cascades Transcription factors Output Apoptosis Migration Growth Adhesion Differentiation layer For Background Information Only. 7

OVEREXPRESSION: marked increase in number of HER2 receptors on the cell surface AMPLIFICATION: increase in number of HER2 gene copies in the nucleus HER2-normal (HER2 ) breast epithelium cell (~20,000 receptors) HER2-positive (HER2+) breast cancer cell (up to 1-2 million receptors) p185 HER2 Protein HER2 Gene HER2 mrna HER2 Gene Pegram and Slamon. Semin Oncol. 2000;27(suppl 9):13. HER2 mrna p185 HER2 Protein For Background Information Only. Do Not Duplicate or Distribute 8 US.DOC.08.05.007

P P P P P P P P Excessive cell proliferation, survival, and angiogenesis Potentiation of chemotherapy Inhibition of tumor cell proliferation Facilitation of immune function Adapted 9 from Noonberg and Benz. Drugs. 2000;59:753. For Background Information Only. Do Not Duplicate or Distribute US.DOC.08.05.007

Patients node+ or high-risk node, HER2 IHC 3+/FISH (qw 12) (q3w 4) (qw 52) Time (mo) 0 3 (qw 52) 6 9 * 18-21 A 60 mg/m 2 + C 600 mg/m 2 Paclitaxel 80 mg/m 2 qw Trastuzumab 4 mg/kg first week; Trastuzumab 2 mg/kg qw. Perez et al. Proc Am Soc Clin Oncol. 2003;22:19. Abstract 75.

Time to First Distant Recurrence 100 90 AC TH AC->T+H AC T AC->T 90% 90% 90% % 80 70 60 50 N Events N Events AC TH 1672 96 AC T AC->T 1679 1679194 194 AC->T+H 1672 96 HR=0.47, 2P=8x10-10 81% 81% 74% 74% HR=0.47, 2P=8x10-10 0 1 2 3 4 5 Years From Randomization B31/N9831

HER2 HER3 Ligand binds Conformational change from closed to open state Exposes the dimerization domain and allows the formation of dimers Triggers intracellular signaling pathways through transphosphorylation

HER2 HER3 Pertuzumab P P P P P PDK1 GSK3 P13K NF B mtor BAD Cyclin D1 p27 AKT survival cell cycle angiogenesis control proliferation apoptosis

S U R G E R Y S U R G E R Y 6 cycles Approach 2 R Arm 1 Approach 2: TC Trastuzumab IV q3w 52 w Central confirmation of HER2 status Randomization within 7 weeks of surgery von Minckwitz, et al. Poster. SABC. 2011. M2.P.BC.Early.Ow.72 3-4 cycles 3-4 cycles Approach 1 R Arm 1 Approach 1: A Anthracycline-based chemotherapy A T N D Trastuzumab IV q3w 52 w Central O M confirmation Pertuzumab IV q3w 52 w I of HER2 3-4 cycles 3-4 cycles Z A status T A T I Trastuzumab IV q3w 52 w Patients will be recruited O from 700 centers and 44 N Arm 2 Placebo IV q3w 52 w countries. First patient recruited in Radiotherapy and/or endocrine therapy may be started at the end of adjuvant therapy November 2011 N=3806 A N D O M I Z A T I O N Arm 2 Start treatment within 1 week Pertuzumab IV q3w 52 w 6 cycles Non anthracycline based chemotherapy TC Trastuzumab IV q3w 52 w Placebo IV q3w 52 w A Anthracycline-based TTaxane-based TC Docetaxel + carboplatin *Genentech/Roche Sponsored Study F O L L O W - U P 10 Y E A R S

Presented By Arlene Chan at 2015 ASCO Annual Meeting

Presented By Arlene Chan at 2015 ASCO Annual Meeting

Presented By Arlene Chan at 2015 ASCO Annual Meeting

Presented By Arlene Chan at 2015 ASCO Annual Meeting

What are we doing here? Cost Inconvenience Lives saved? Two camps: Give it all you can Do no harm

Almost all patients with estrogen-receptor positive breast cancer, whether they also receive chemotherapy or not, are advised to consider anti-estrogen therapy ( hormone therapy, endocrine therapy ) to reduce their risk of recurrence Tamoxifen was the standard of care in younger (premenopausal) women Aromatase inhibitors became the standard of care in older (postmenopausal) women in 2001

Pan H et al. N Engl J Med 2017;377:1836-1846.

San Antonio Breast Cancer Symposium, December 5-9, 2017 Dawn L. Hershman, Joseph M. Unger, Heather Greenlee, Jillian Capodice, Danika L. Lew, Amy Darke, Alice Kengla, Marianne K. Melnik, Carla W. Jorgensen, William H. Kreisle, Lori M. Minasian, Michael J. Fisch, N. Lynn Henry, Katherine D. Crew This presentation is the intellectual property of the presenter. Contact her at dlh23@columbia.edu for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 5-9, 2017 PRIMARY ENDPOINT True Acupuncture True Acupuncture No Acupuncture 2 2x week x 6 weeks 1x week x 6 weeks 12 weeks AI > 3/10 Worst Pain N=226 1 Sham Acupuncture 2x week x 6 weeks Sham Acupuncture 1x week x 6 weeks No Acupuncture 12 weeks 1 Wait List Control 6 weeks Wait List Control 6 weeks Wait List Control 12 weeks Assessment Week 0 6 12 24 This presentation is the intellectual property of the presenter. Contact her at dlh23@columbia.edu for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 5-9, 2017 Stage 1-3 hormone sensitive breast cancer Third-generation AI for at least 30 days prior to registration Score of >3 (range, 0-10) on the worst pain item of the BPI Symptoms started or increased since starting AI No opioids or corticosteroid and no alternative/physical therapy for the treatment of joint pain within 28 days prior to registration No prior acupuncture treatment for joint symptoms at any time, but allowed for other reasons >12 months prior This presentation is the intellectual property of the presenter. Contact her at dlh23@columbia.edu for permission to reprint and/or distribute.

Percent 2-pint change Percent with 2-point chan San Antonio Breast Cancer Symposium, December 5-9, 2017 WORST PAIN True v. Sham True v. Waitlist Fitted Difference* 0.92 (0.20-1.65) 0.96 (0.24-1.67) P-value.01.01 70 60 50 40 30 20 10 0 P<0.009 P<0.004 Sham v. Waitlist 0.05 (-0.81-0.90).92 * Corrected for baseline score and study site This presentation is the intellectual property of the presenter. Contact her at dlh23@columbia.edu for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium, December 5-9, 2017 This presentation is the intellectual property of the presenter. Contact her at dlh23@columbia.edu for permission to reprint and/or distribute.

Be mindful of risk, discomfort, and benefit Question the value of these interventions for yourselves Acknowledge the good news, that most patients do quite well Acupuncture has a bright future