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

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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 2

Breast cancer is a molecularly heterogeneous disease

Perou et al, Nature 2000; Sorlie et al, 2001; Sotiriou et al. PNAS 2003

Overall Survival

Pre-trastuzumab era

Luminal A Luminal B HER2 amplified TNBC

HER2 Lum B Lum A Basal

BRCA1 BRCA2

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Breast cancer is a molecularly heterogeneous disease

TCGA, Nature 2012

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ER dependent and independent signaling pathways

Cui et al, Trends Mol Med 2012

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Cofactor Dynamics in ER regulated transcription

Shang et al, Cell 2000

ER Cofactors

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ESR mutations reported prior to 2013

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

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ESR mutations in metastatic endocrine resistant breast cancer

Jesselsohn et al, Nature RV Clin Onc 2015

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Lim & Winer , Oncology 2012

Long natural history of ER+ Breast Cancer

ChemoTx Alternative endocrine strategy Prevention: Extended Endocrine therapy

Treatment at relapse Early BC MBC Progression on Tx

Early Late De Novo

Late relapse ChemoTx Alternative endocrine strategy Endocrine therapy

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Dormant Metastasis in ER+ Breast Cancer

Braun et al. NEJM 2005 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

• utcome on

multivariate analyses

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Summary of Endocrine treatments for Breast Cancer

Adrenals Pituitary Ovaries FSH/LH Hypothalamus Pulsatile GnRH Adipose ER Cell Proliferation Differentiation GnRH agonist Oophorectomy Chemotherapy Aromatase Inhibitors SERM: Tamoxifen SERD: Fulvestrant

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ER+ breast cancers are sensitive to endocrine therapy

EBCTCG Overview, Lancet 2011 Harvey et al. JCO 1999

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Adjuvant AI’s have lower recurrence rates cf Tamoxifen

EBCTCG Overview. Lancet 2015

Meta-Analsysis 5 yrs Tam vs 5 yrs AI

RFS BC Mortality

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Benefits of extended adjuvant endocrine therapy (Atlas trial: 5 vs 10yr Tam)

Breast Cancer Mortality Overall Survival 10 yrs tam. vs 5: aTTom trial (n=6934 ER+) 10 yrs tam. vs 5: ATLAS trial* (n=10,543 ER+) 10 yrs tam. vs 5: combined (n=17,477 ER+) 10 yrs tam. vs 5: combined (n=17,477 ER+) yrs 5-9 1.08 (0.85-1.38 ) 0.92 (0.77-1.09) 0.97 (0.84-1.15) 0.99 (0.89- 1.10) yrs 10+ 0.75† (0.63-0.90) 0.75§ (0.63-0.90) 0.75† (0.65-0.86) 0.84† (0.77- 0.93) All years 0.88‡ (0.74-1.03) 0.83‡ (0.73-0.94) 0.85‡ (0.77-0.94) 0.91‡ (0.84-0.97) †p=0.007 ‡p=0.1 †p=0.0007 ‡p=0.008 †p=0.00004 ‡p=0.001 §p=0.002 ‡p=0.004

Davies et al, Lancet 2013

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Benefits of extended adjuvant endocrine therapy (Atlas trial: 5 vs 10yr Tam)

Davies et al, Lancet 2013

RFS BC Mortality

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Benefits of extended adjuvant endocrine therapy (MA17 trial: Tam  AI)

Goss et al, JNCI 2005

DFS OS Tamoxifen for 4.5-6 yrs Postmenopausal

N=5,187 PLACEBO LETROZOLE

5 yrs rx planned OS in node +

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Cuzick et al, Lancet 2007 Recurrence Death After Recurrence

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.

No statistically significant reduction in HR for recurrence and death after recurrence with addition of LHRH agonist to Tamoxifen

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Benefits of adding OS to adjuvant endocrine therapy (SOFT trial: Tam vs Tam + OS vs AI + OS)

Francis et al, NEJM 2015

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Benefits of adding chemotx to endocrine therapy

Pagani et al, Breast Cancer Res Treat 2009

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

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Multigene tests to predict prognosis and chemotx benefit: Oncotype RS

Paik et al, NEJM 2004, J Clin Oncol 2006 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

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All Patients RS < 18 RS 18-30 RS > 30 Paik et al, NEJM 2004, J Clin Oncol 2006

Multigene tests to predict prognosis and chemotx benefit: Oncotype RS

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ABCSG-12 Trial

Zoledronic acid improves DFS and OS compared to endocrine therapy alone

Δ=4.0% Δ=1.6%

N = 1803, Premenopausal, Stage 1 & II, ER+, 30% node pos, Only preop Chemo allowed Med FU 84m

Tam Tam + ZA (4mg/6mth) Anastrazole Anas + ZA (4mg/6mth)

R

Surgery ± RT Goserelin PEP: DFS SEP: OS Gnant et al. Lancet Onc 2011

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ZA OS benefit primarily in >40 subgroup

The anticancer potential of ZA may best be realized in a low estrogen environment

Gnant et al. SABCS 2011

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De Boer 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

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Summary of Adjuvant anti-estrogen therapy options

Postmenopausal

• 5 yrs AI or 5 yrs Tam
• Tam 2-5yrs > 5 yrs

AI

• AI beyond 5 yrs

(No trial data)

Perimenopausal

• Tam 2-5yrs > 5 yrs

AI (switch after menopause)

• OS + AI

Premenopausal

• 5 yrs Tam
• 10yrs Tam
• OS + AI
• 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

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Alternative growth signaling pathways in endocrine resistance

Johnston, JNCI 2015

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Mechanisms of endocrine resistance

ESR1 mutations Genomic Complexity Fuqua et al, BCRT 2014 Ellis et al, Nature 2014 ESR enhancer hypermethylation Stone et al, Nat Comm 2015

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FIRST trial: P2 Fulvestrant vs AI

Robertson JFR, BCRT 2012; 136: 503–511.

*Previous endocrine therapy for early disease completed >12 months before randomization permitted *In confirmatory FALCON study no prior endocrine therapy permitted

FAS ANA TTP 23.4 months 13.1 months

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SWOG 1222 trial: PIII Fulvestrant + AI in MBC

Mehta et al, NEJM 2012

• 1st line study, 39% de novo (No prior endocrine therapy)
• >12 months from completion of adjuvant AI or prior adj Tam
• Cross over permitted

PFS OS

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Multiple abrations erlead to PI3K pathway activation

Di Cosimo & Baselga. Clin Can Res 2009

 Sites of mutation/deletion that result in aberrant activation PI3KCA activating mutation Uterus 30% Breast 25% Colon 15% Bladder 15%

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PI3K component Type of mutation Incidence P110α (PIK3CA) Mutation 27% P110α (PIK3CA) Amplification 8.7% P110β (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%

PI3K pathway alterations in BC

Liu et al. Nat RV Drug Dis 2009

PIK3CA mutations: More common in ER+ and HER2+ subtypes Series of 590 pts

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Function of p110 isoforms

Liu et al. Nat RV Drug Dis 2009 major

P110β is the major isoform mediating PTEN deficient tumorigenesis (Jia et al, Nature 2008, Wee et al, PNAS 2008) P110α is the major isoform mediating RTK/Ras mediated tumorigenesis (Samuels et al, Cancer Cell 2005, Berns et al, Cancer Cell 2007)

P110α and P110β: ubiquitous P 110δ: immune system

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PI3K pw alteration and BC subtype

PIK3CA mut AKT1 mut PTEN mut PTEN protein loss PDK1 amp INPP4B del RAS/RAF mut P53 mut Breast (total) 339/126 1 (26.9%) 27/1008 (2.6%) 6/209 (2.3%) 25/110 (22.7%) 27/129 (20.9%) ≈ 20% 2/406 (0.5%) 46/121 (38%) Breast HR+ 101/305 (33.1%) 6/232 (2.6%) 4/131 (3.4%) 10/69 (14.5%) 16/79 (23.2%) Rare 18/73 (24.6%) Breast HER2+ 24/98 (24.5%) 0/75 0/33 2/18 (11%) 5/19 (26.3%) Rare 14/23 (60.9%) Breast TNBC 21/262 (8%) 0/111 0/41 11/21 (52%) 2/15 (13.3%) ≈ 60% 12/22 (63.6%) Ovarian 2/332 (0.6%) 2/332 (0.6%) 4/132 (3%) ≈ 40% Rare ≈ 20% 12/428 (2.8%) 90/132 (68%) Endometrial 73/246 (30%) 3/150 (2%) 20/76 (26%) ≈ 50% Rare ≈ 8% 44/206 (21%) 9/96 (9%)

Unpublished data: SU2C Not included: PIK3CA amp

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TamRAD trial: PII Tamoxifen + Everolimus in MBC

Bachelot et al, J Clin Oncol 2012 n = 111 Prior exposure to AI No cross over Median FU 22 mths

– Primary End Point: Clinical Benefit rate @ 6 mths

– Tam = 42.1% (29.1-55.9) – Tam + RAD001 = 61.1% (46.9-74.1)

– Secondary End Points

TTP OS

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Benefit of Everolimus primarily in 2°endocrine resistance

Bachelot et al, J Clin Oncol 2012

Primary hormone resistance (n = 54) (Relapse during adjuvant AI or < 6m after starting AI for MBC) Tam: 3.8 m vs Tam + RAD: 5.4 m HR = 0.70 (0.40 – 1.21) Secondary hormone resistance (n = 56) (Relapse ≥ 6m on adjuvant AI or prior AI response and subsequent progression) Tam: 4.6 m vs Tam + RAD: 14.8 m HR = 0.46 (0.26 – 0.83)

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Bolero 2 trial: PIII AI + Everolimus in MBC

Baselga et al, NEJM 2014

PFS OS EVE + EXE EXE mPFS

7.8 month s 3.2 month s Patients refractory to prior NSAI therapy:

• Recurrence during or

within 12 months after end of adjuvant treatment; OR

• Progression during or

within 1 month after end of treatment for advanced disease

Piccart et al, Ann Onc 2014

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Impact on Treatment by Genetic Status The Most Frequently Altered Single Genes and Pathways

Positive treatment effect in favor of everolimus across the various genetic marker subgroups

Pathway composition

• PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt:

47.6%, total alteration: 55.5%)

• Cell Cycle: CCND1, CDK4, CDK6,

CDKN2A, CDKN2B, (CCND1 Alt: 31.3%, total alteration: 35.7%)

• p53: TP53, MDM2, MDM4 (TP53 Alt:

23.3%, total alteration: 36.1%)

• FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt:

18.1%, total alteration: 21.1%)

log10 (hazard)

• 0.6
• 0.4
• 0.2

0.0

WT : PI3K Alt : PI3K WT : PIK3CA Alt : PIK3CA WT : Cell Cycle Alt : Cell Cycle WT : CCND1 Alt : CCND1 WT : p53 Alt : p53 WT : TP53 Alt : TP53 WT : FGFR1/2 Alt: FGFR1/2 WT : FGFR1 Alt : FGFR1

EVE+EXE better

Genetically altered (Alt) Wild Type (WT)

Hortobagyi et al. ASCO 2011

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Progression of the cell cycle is driven by CDKs

Asghar et al. Nat Rv Drug Disc 2015

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Paloma 3 trial: PIII Fulvestrant + Palbociclib in MBC

Turner et al, NEJM 2015

Patients refractory to prior NSAI therapy:

• Recurrence during or

within 12 months after end of adjuvant treatment; OR

• Progression during or

within 1 month after end of treatment for advanced disease

PAL + FUL FUL mPFS 9.2 month s 3.8 month s

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PALOMA-3 trial: subgroup analyses

Turner NC, NEJM 2015; 373:209-19.

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Paloma 1: PII AI + Palbociclib in MBC

Finn et al, Lancet Onc 2015 Patients with recurrence <12 months since adjuvant treatment were excluded

PAL + LET LET mPFS 20.2 months 10.2 months

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PALOMA-1: PFS subgroup analyses

Finn RS, Lancet Oncol 2015; 16: 25–35.

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1. Comprehensive Molecular Portraits of Human Breast tumours. TCGA. Nature 2012. 2. The natural history of luminal breast cancer. Lim and Winer. Oncology 2012. 3. ESR1 mutations -a mechanism for acquired endocrine resistance in breast cancer. Jesselsohn et al. Nat RV Clin Oncol 2015. 4. Adjuvant Endocrine Therapy for Women With Hormone Receptor+ Breast Cancer: ASCO Clinical Practice Guideline. Bernstein et al. JCO 2014. 5. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. EBCTCG. Lancet 2015. 6. Prognostic Value of Ki67 Expression After Short- Term Presurgical Endocrine Therapy for Primary Breast Cancer. Dowsett et al. JNCI 2007. 7. Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor + Breast Cancer. Goss et al. JNCI 2005. 8. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor + breast cancer: ATLAS, a randomised trial. Davies et al. Lancet 2013. 9. Adjuvant Ovarian Suppression in Premenopausal Breast Cancer. Francis et al. NEJM 2015. 10. A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast

• Cancer. Paik et al. NEJM 2004.

11. Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. Mehta et al. NEJM 2012. 12. Everolimus in Postmenopausal Hormone-Receptor + Advanced Breast Cancer. Baselga et al. NEJM 2012. 13. Palbociclib in Hormone-Receptor + Advanced Breast Cancer. Turner et al. NEJM 2015.