TKCC/Garvan Cancer Biology Seminars Seminal clinical trials in ER+ - PowerPoint PPT Presentation

TKCC/Garvan Cancer Biology Seminars Seminal clinical trials in ER+ Breast Cancer Elgene Lim Lab Head: Connie Johnson Breast Cancer Laboratory Snr Medical Oncologist: TKCC The University of Sydney Page 1

Breast cancer is a molecularly heterogeneous disease Basal Lum A Lum B HER2 BRCA1 BRCA2 Overall Survival Luminal A Luminal B HER2 amplified TNBC Pre-trastuzumab era Perou et al, Nature 2000; Sorlie et al, 2001; Sotiriou et al. PNAS 2003 The University of Sydney Page 2

Breast cancer is a molecularly heterogeneous disease TCGA, Nature 2012 The University of Sydney Page 3

ER dependent and independent signaling pathways Cui et al, Trends Mol Med 2012 The University of Sydney Page 4

Cofactor Dynamics in ER regulated transcription ER Cofactors Shang et al, Cell 2000 The University of Sydney Page 5

ESR mutations reported prior to 2013 Study Number of ER status Mutations Frequency of Samples Mutations Karnik PS, 5 prim. BRCA ER+ E352V(prim.) 5% of all mets Can Res 94 S432fs (met) 10% in TR 35 met. BRCA ER+ 454fs (met) mets Roody N, 118 prim. ER+ JNCI 1995 BRCA N69K (ER-) 1% of ER- 70 prim. BRCA ER- M396V (ER-) prim. Zhang QX, 30 met. BRCA N/A S47T 10% of mets. Can Res 97 K531E Y537N TCGA, 501 prim. Luminal 351 N27fs (ER+) 0.4% of prim. Nature 2012 BRCA HER2+ 57 P222S(ER+) 0.6% of Basal-like 93 luminal The University of Sydney Page 6

ESR mutations in metastatic endocrine resistant breast cancer Jesselsohn et al, Nature RV Clin Onc 2015 The University of Sydney Page 7

Long natural history of ER+ Breast Cancer Late relapse Early BC Alternative Prevention: ChemoTx Treatment endocrine Extended at relapse strategy Endocrine therapy Progression on Tx De Novo MBC Early Late Alternative ChemoTx Endocrine therapy endocrine strategy The University of Sydney Page 8 Lim & Winer , Oncology 2012

Dormant Metastasis in ER+ Breast Cancer Pooled analysis of BM micrometastases in 4703 pts with stage I- III breast cancer, of whom 1499 had hormonal therapy only BM micrometastases is a predictor of poor outcome on multivariate analyses Braun et al. NEJM 2005 The University of Sydney Page 9

Summary of Endocrine treatments for Breast Cancer Hypothalamus Pulsatile GnRH GnRH agonist Pituitary FSH/LH Oophorectomy Adrenals Ovaries Chemotherapy Aromatase Adipose Inhibitors SERM: Tamoxifen ER SERD: Fulvestrant Cell Proliferation Differentiation The University of Sydney Page 10

ER+ breast cancers are sensitive to endocrine therapy Harvey et al. JCO 1999 EBCTCG Overview, Lancet 2011 The University of Sydney Page 11

Adjuvant AI’s have lower recurrence rates cf Tamoxifen Meta-Analsysis 5 yrs Tam vs 5 yrs AI RFS BC Mortality The University of Sydney Page 12 EBCTCG Overview. Lancet 2015

Benefits of extended adjuvant endocrine therapy (Atlas trial: 5 vs 10yr Tam) Breast Cancer Mortality Overall Survival 10 yrs tam. vs 5: 10 yrs tam. vs 5: 10 yrs tam. vs 5: 10 yrs tam. vs 5: aTTom trial ATLAS trial* combined combined (n=6934 ER+) (n=10,543 ER+) (n=17,477 ER+) (n=17,477 ER+) 1.08 0.92 0.97 0.99 (0.89- yrs 5-9 (0.85-1.38 ) (0.77-1.09) (0.84-1.15) 1.10) 0.75 † 0.75 † 0.84 † (0.77- 0.75 § yrs 10+ (0.63-0.90) (0.63-0.90) (0.65-0.86) 0.93) 0.88 ‡ 0.83 ‡ 0.85 ‡ 0.91 ‡ All years (0.74-1.03) (0.73-0.94) (0.77-0.94) (0.84-0.97) § p=0.002 †p=0.0007 †p=0.007 †p=0.00004 ‡p=0.1 ‡p=0.004 ‡p=0.001 ‡p=0.008 Davies et al, Lancet 2013 The University of Sydney Page 13

Benefits of extended adjuvant endocrine therapy (Atlas trial: 5 vs 10yr Tam) RFS BC Mortality Davies et al, Lancet 2013 The University of Sydney Page 14

Benefits of extended adjuvant endocrine therapy (MA17 trial: Tam  AI) PLACEBO Tamoxifen for 4.5-6 yrs Postmenopausal 5 yrs rx planned N=5,187 LETROZOLE DFS OS OS in node + Goss et al, JNCI 2005 The University of Sydney Page 15

Does OS add to Tam in premenopausal women? LHRH meta-analysis of 11,906 pts (16 trials). 1013 pts had LHRH agonist added to Tamoxifen. Recurrence Death After Recurrence No statistically significant reduction in HR for recurrence and death after recurrence with addition of LHRH agonist to Tamoxifen The University of Sydney Page 16 Cuzick et al , Lancet 2007

Benefits of adding OS to adjuvant endocrine therapy (SOFT trial: Tam vs Tam + OS vs AI + OS) Francis et al, NEJM 2015 The University of Sydney Page 17

Benefits of adding chemotx to endocrine therapy Combined analyses of IBCSG Trial VII and IBCSG 12-93 Post and perimenopausal women N = 893 Benefit of adding chemotherapy only in the low to intermediate ER levels Pagani et al, Breast Cancer Res Treat 2009 The University of Sydney Page 18

Multigene tests to predict prognosis and chemotx benefit: Oncotype RS 1) Quantifies The Likelihood Of (early) Recurrence In Women With ER+ Breast cancer 2) Predicts The Magnitude Of Chemotherapy benefit 3) Can be performed on FFPE Paik et al, NEJM 2004, J Clin Oncol 2006 The University of Sydney Page 19

Multigene tests to predict prognosis and chemotx benefit: Oncotype RS RS < 18 All Patients RS 18-30 RS > 30 Paik et al, NEJM 2004, J Clin Oncol 2006 The University of Sydney Page 20

ABCSG-12 Trial Tam N = 1803, Premenopausal, Tam + ZA (4mg/6mth) Stage 1 & II, ER+, Surgery R Goserelin 30% node pos, ± RT Only preop Anastrazole Chemo allowed Med FU 84m Anas + ZA (4mg/6mth) Δ =4.0% Δ =1.6% PEP: DFS SEP: OS Zoledronic acid improves DFS and OS compared to endocrine therapy alone The University of Sydney Page 21 Gnant et al . Lancet Onc 2011

ZA OS benefit primarily in >40 subgroup The anticancer potential of ZA may best be realized in a low estrogen environment The University of Sydney Page 22 Gnant et al . SABCS 2011

DFS in post-menopausal subsets in ZA trials The anticancer potential of ZA may best be realized in a low estrogen environment The University of Sydney Page 23 De Boer et al . SABCS 2011

Summary of Adjuvant anti-estrogen therapy options Postmenopausal Perimenopausal Premenopausal • 5 yrs AI or 5 yrs Tam • Tam 2-5yrs > 5 yrs • 5 yrs Tam AI (switch after • Tam 2-5yrs > 5 yrs • 10yrs Tam menopause) • OS + AI AI • OS + AI • AI beyond 5 yrs (No trial data) • AI only in confirmed post menopausal pts • Consider OS in high risk pts, if chemotx not given or in young pts whose periods have resumed after chemotx • Consider Extended therapy (>5yrs) in high risk pts The University of Sydney Page 24

Alternative growth signaling pathways in endocrine resistance Johnston, JNCI 2015 The University of Sydney Page 25

Mechanisms of endocrine resistance Fuqua et al, BCRT 2014 ESR enhancer hypermethylation ESR1 mutations Ellis et al, Nature 2014 Genomic Complexity Stone et al, Nat Comm 2015 The University of Sydney Page 26

FIRST trial: P2 Fulvestrant vs AI FAS ANA 23.4 13.1 TTP months months *Previous endocrine therapy for early disease completed >12 months before randomization permitted *In confirmatory FALCON study no prior endocrine therapy permitted Robertson JFR, BCRT 2012; 136: 503 – 511. The University of Sydney Page 27 27

SWOG 1222 trial: PIII Fulvestrant + AI in MBC PFS OS 1 st line study, 39% de novo (No prior endocrine therapy) • • >12 months from completion of adjuvant AI or prior adj Tam • Cross over permitted Mehta et al, NEJM 2012 The University of Sydney Page 28

Multiple abrations erlead to PI3K pathway activation PI3KCA activating mutation Uterus 30% Breast 25% Colon 15% Bladder 15%  Sites of mutation/deletion that result in aberrant activation Di Cosimo & Baselga. Clin Can Res 2009 The University of Sydney Page 29

PI3K pathway alterations in BC PI3K component Type of mutation Incidence P110 α (PIK3CA) Mutation 27% P110 α (PIK3CA) Amplification 8.7% P110 β (PIK3CB) Amplification 5% PDPK1 Amplification and overexpression 20% AKT1 Mutation (E17K) 3.7% AKT2 Amplification 3% PTEN Loss of heterozygosity 24.9% PTEN Mutation 6% PIK3CA mutations: More common in ER+ and HER2+ subtypes Series of 590 pts The University of Sydney Page 30 Liu et al. Nat RV Drug Dis 2009

Function of p110 isoforms major P110 α and P110 β : ubiquitous P 110 δ : immune system P110 α is the major isoform P110 β is the major mediating RTK/Ras mediated isoform mediating PTEN tumorigenesis deficient tumorigenesis (Samuels et al, Cancer Cell 2005, (Jia et al, Nature 2008, Berns et al, Cancer Cell 2007) Wee et al, PNAS 2008) Liu et al. Nat RV Drug Dis 2009 The University of Sydney Page 31