TKCC/Garvan Cancer Biology Seminars Seminal clinical ... · SERD: Fulvestrant. The University of Sydney Page 11 ER+ breast cancers are sensitive to endocrine therapy EBCTCG Overview,

The University of Sydney Page 1

TKCC/Garvan Cancer Biology Seminars

Seminal clinical trials in ER+ Breast Cancer

Elgene LimLab Head: Connie Johnson Breast Cancer Laboratory

Snr Medical Oncologist: TKCC


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

HER2Lum BLum ABasal

BRCA1 BRCA2


Breast cancer is a molecularly heterogeneous disease

TCGA, Nature 2012


ER dependent and independent signaling pathways

Cui et al, Trends Mol Med 2012


Cofactor Dynamics in ER regulated transcription

Shang et al, Cell 2000

ER Cofactors


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


ESR mutations in metastatic endocrine resistant breast cancer

Jesselsohn et al, Nature RV Clin Onc 2015

The University of Sydney Page 8Lim & Winer, Oncology 2012

Long natural history of ER+ Breast Cancer

ChemoTx Alternative

endocrine

strategy

Prevention:

Extended

Endocrine therapy

Treatment

at relapse

Earl

y B

CM

BC Progression on Tx

Early Late

De Novo

Late relapse

ChemoTx Alternative

endocrine

strategy

Endocrine therapy


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

outcome on

multivariate analyses


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


ER+ breast cancers are sensitive to endocrine therapy

EBCTCG Overview, Lancet 2011

Harvey et al. JCO 1999


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


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 5-91.08

(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



(Atlas trial: 5 vs 10yr Tam)

Davies et al, Lancet 2013

RFS BC Mortality



(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 +

The University of Sydney Page 16Cuzick 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


Benefits of adding OS to adjuvant endocrine therapy

(SOFT trial: Tam vs Tam + OS vs AI + OS)

Francis et al, NEJM 2015


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


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


All PatientsRS < 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


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 allowedMed FU 84m

Tam

Tam + ZA (4mg/6mth)

Anastrazole

Anas + ZA (4mg/6mth)

RSurgery± RT

Goserelin

PEP: DFS SEP: OS

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

Gnant et al. SABCS 2011

The University of Sydney Page 23De 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


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


Alternative growth signaling pathways in endocrine resistance

Johnston, JNCI 2015


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


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

TTP23.4

months

13.1

months


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


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%


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


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


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)

339/1261

(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%)

Ovarian2/332

(0.6%)

2/332

(0.6%)

4/132

(3%)≈ 40% Rare ≈ 20%

12/428

(2.8%)

90/132

(68%)

Endometrial73/246

(30%)

3/150

(2%)

20/76

(26%)≈ 50% Rare ≈ 8%

44/206

(21%)

9/96

(9%)

Unpublished data: SU2C Not included: PIK3CA amp


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


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 mHR = 0.46 (0.26 – 0.83)


Bolero 2 trial: PIII AI + Everolimus in MBC

Baselga et al, NEJM 2014

PFS

OS

EVE +

EXEEXE

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


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


Progression of the cell cycle is driven by CDKs

Asghar et al. Nat Rv Drug Disc 2015


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 +

FULFUL

mPFS

9.2

month

s

3.8

month

s

The University of Sydney Page 39| Presentation Title | Presenter Name | Date | Subject | Business Use Only39

PALOMA-3 trial: subgroup analyses

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


Paloma 1: PII AI + Palbociclib in MBC

Finn et al, Lancet Onc 2015

Patients with recurrence

<12 months since

adjuvant treatment were

excluded

PAL +

LETLET

mPFS20.2

months

10.2

months

The University of Sydney Page 41| Presentation Title | Presenter Name | Date | Subject | Business Use Only41

PALOMA-1: PFS subgroup analyses

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


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.

http://www.ncbi.nlm.nih.gov/pubmed/18332475

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TKCC/Garvan Cancer Biology Seminars Seminal clinical ... · SERD: Fulvestrant. The University of Sydney Page 11 ER+ breast cancers are sensitive to endocrine therapy EBCTCG Overview,