endocrine therapy for advanced breast cancer (abc)...treatment guidelines for hr+, her2–advanced...

Endocrine Therapy

for Advanced Breast

Cancer (ABC)

Dr Yoon-Sim YAP

Division of Medical Oncology,

National Cancer Centre Singapore

2

Outline

• Guidelines and Evolving Clinical Treatment Landscape

for HR+ HER2- advanced breast cancer (ABC)

• Optimising endocrine therapy backbone

• Improving outcomes further with targeted therapy

• Sequencing of Treatments

– First Line setting vs Second-line setting & beyond

– Predictive Biomarkers

• Other Novel Therapeutic Strategies

• Conclusions

Treatment guidelines for HR+, HER2– advanced breast cancer

ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first

choice independent of metastatic site, unless rapid response is

needed. Limited visceral metastases are not a contraindication for

endocrine therapy

ABC2 Endocrine therapy is the preferred option for HR+ disease, even in

the presence of visceral disease, unless there is concern or proof

of endocrine resistance or rapidly progressive disease needing a

fast response

ASCO3 Endocrine therapy should be recommended as initial treatment for patients with HR+ metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy.

NCCN4 Endocrine therapy recommended unless there is visceral crisis, or

progression with no clinical benefit after 3 sequential endocrine therapy regimens.

3

1. Cardoso F et al. Ann Oncol 2012;23(Suppl 7):vii11-vii19 2. Cardoso F et al. Ann Oncol

2014;25(10):1871–1888 3. ASCO 2016. Available at https://www.asco.org/sites/new-

www.asco.org/files/content-files/practice-and-guidelines/documents/2016-adv-endocrine-breast-summary-

table.pdf 4. NCCN V3.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

4

Chemotherapy versus Endocrine Therapy

Wilcken et al, Cochrane System Database Review 2009

Chemotherapy has higher response rate.

5

Chemotherapy versus Endocrine Therapy

Wilcken et al, Cochrane System Database Review 2009

No significant differences in overall survival.

What are the Endocrine Therapy

Options?

What is the evidence for doing what

we do? (ie if people are practising

evidence-based medicine)

6

7

Breakthroughs in hormone receptor positive (HR+) breast cancer

1977Tamoxifen

1996Goserelin

1999Exemestane

2002Fulvestrant

2015Palbociclib + Letrozole

2016Palbociclib +Fulvestrant

1997Letrozole

FDA approvals of new treatments

2012Everolimus

+ Exemestane

Co

mb

inati

on

Th

era

py

19951980 2000 20162015

En

do

cri

ne

Th

era

py

2017Ribociclib(with AI)

2017

2017Abemaciclib(single agent

or with fulvestrant)

1995Anastrozole

1985MegestrolAcetate

8

ASCO Guidelines

Rugo et al, JCO 2016

Postmenopausal

Premenopausal

Courtesy of Ian Smith from ESMO 2014

Mechanism of Action of Tamoxifen

and Aromatase Inhibitors

Johnston, Nature Reviews Cancer 2003

First-line Comparative Tamoxifen Trials in

Advanced Breast Cancer 1981-96 (2004)

12

Tamoxifen versus

N=17

Progestogens 6Estrogens 1Androgens 1Anti-Estrogens 2Aminogluthetimide 3Formestane 1Fadrozole 2Fulvestrant 1

Tamoxifen always better or at least as good.

Schiavon and Smith, Haematol Oncol Clin North AM 2013

Rationale for OS + Tamoxifen in

Premenopausal MBC

Randomised study: n=161 (original target 348)

Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by

• objective response rate (48%, 34%, and 28% of patients who could be evaluated,respectively; P = .11 [x2 test]),

• median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P = .03), and

• overall survival (3.7 years, 2.5 years, and 2.9 years; P = .01).

• 5-year survival were 34.2% (95% confidence interval [CI] = 20.4%–48.0%), 14.9% (95% CI =3.9%–25.9%), and 18.4% (95% CI = 7.0%–29.8%), respectively.

13

Klijn et al, JNCI 2000

Use of 2nd line AIs v megesterol acetate

AIs: RR, TTP and overall survival only slightly better than megestrol acetate

Smith NEJM 2003

Progestins

• Mechanism of action unclear.

• May inhibit aromatase activity or increase estrogen turnover, since estrogen levels fall during therapy.

• May also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor.

• Activity appears to be maintained in patients who are refractory to SAIs.

• Side-effects: weight gain, fluid retention, thromboembolic complications, PV bleeding.

Willemse, EJC 1990; Abrams, JCO 1999

What is the optimal 1st-line endocrine therapy?

16

TrialAI

(response rate, %)

Tamoxifen (response

rate, %)

AI (PFS, mths)

Tamoxifen(PFS, mths)

Hazard Ratio

Nabholtz et al, 2000 (n=353)Anastrozole vs tamoxifen

21 17 11.1 5.6 0.81

Bonneterre et al, 2001 (n=668)Anastrozole vs tamoxifen

33 33 8.2 8.3 0.99

Mouridsen et al, 2001 (n=907)Letrozole vs tamoxifen

30 20 9.4 6.0 0.72

Paridaens et al, 2008 (n=371)Exemestane vs tamoxifen

46 31 9.9 5.8 0.84

Range 8–12 6–8

PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC

Johnston, SABCS 2016

Meta-analysis: compared to tamoxifen, there was a statistically significant

survival benefit (11 percent relative hazard reduction, 95% CI 1 to 19 percent)

for first-line third generation SAIs, but not for aminoglutethimide or second

generation SAIs. Mauri et al, JNCI 2006

AI + Ovarian Suppression in Premenopausal

• Is it better than tamoxifen + ovarian suppression??

• No randomised trials with tamoxifen and OS for comparison in metastatic setting.

17

What are the endocrine options after AI?

• How good is tamoxifen after an AI?

– TAMRAD (Tamoxifen vs Tamoxifen + Everolimus after AI) (Bachelotet al, JCO 2012) Tamoxifen arm (26% received 1 line of palliative chemo): 6mth clinical benefit rate 42%; TTP 4.5 mths; response rate 13%

• How good is exemestane (monotx) after an AI?

– EFECT (Chia, JCO 2008): median TTP 3.7mths; response rate 6.7%

– SOFEA (Johnston, Lancet Oncol 2013): median PFS 3.4mths; response rate 2.8%

– BOLERO-2 (Baselga, NEJM 2012): median PFS 2.8mths, response rate 0.4%.

• How good are progestins after an AI?

– No prospective data

• How good is fulvestrant after an AI?

– See following ….

18

No

dimerisation

NO

TRANSCRIPTION

(no tumour cell

division)

AF1 + AF2

INACTIVE

Fulvestrant

AF1

ER+F F F

ACCELERATED RECEPTOR DEGRADATION

Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.

Mode of Action of Estradiol, Tamoxifen

and Fulvestrant

Tamoxifen

AF1

ER+

PARTIALLY

INACTIVATED

TRANSCRIPTION

(reduced rate of

tumour cell

division)

T T

T

AF1

AF1

ACTIVE

AF2

INACTIVE

AF1

ERE

E

E+ AF1 +

AF2

ACTIVEReceptor

dimerisation

FULLY

ACTIVATED

TRANSCRIPTION

(tumour cell

division)

AF2

AF1

Estradiol

20

Fulvestrant: Preclinical Activity

Osborne et al, JNCI 1995 Osborne et al, Cancer

Chemo and Pharm 1994

21

Clinical Trials on Fulvestrant (250mg LD)

Howell, JCO 2004

Howell, JCO 2002 Osborne, JCO 2002

Only just as good as

tamoxifen or anastrozoleTreatment-naive

Pretreated Pretreated

22

Clinical Trials on Fulvestrant (250mg LD)

Only just as good as exemestane

even after relapse/progresson on

non-steroidal AI

Caveat: 250mg dose was

suboptimal

Johnston, Lancet Oncol 2013

Chia, JCO 2008

CONFIRM phase III Trial:

Fulvestrant 250mg vs 500mg

Di Leo et al, JNCI 2014

Median OS 26.4mths vs 22.3mths

24

Clinical Trials on Fulvestrant (500mg HD)

Ellis et al, JCO 2015

Caveat: OS not preplanned analysis; not all patients participated in OS followup.

Primary Endpoint:

CBR fulvestrant HD

vs anastrozole

72.5% v 67.0%

(odds ratio, 1.30;

95% CI, 0.72 to

2.38; P .386).

Robertson et al, JCO 2009

▪ ER +ve , HER2 negative

▪ Locally advanced (not suitable for

surgery) or metastatic disease

▪ Up to 1 line of chemotherapy

▪ At least 1 lesion that can be assessed

FALCON: Phase III 1st line study of

Fulvestrant 500 vs AI in Endocrine

Therapy Naïve MBC / LABC

• Primary endpoint: PFS

• Secondary endpoint: OS

– Other secondary endpoints include ORR, CBR, duration of response, duration of clinical

benefit, time to deterioration of HRQoL, Safety

Fulvestrant 500mg i.m.

Anastrozole1mg OD

N=450

Note no prior endocrine therapy allowed

Ellis et al, LBA14 ESMO 2016

FALCON: Fulvestrant 500 vs anastrozole in

1st-line endocrine therapy naïve ER+ MBC

HR 0.797

(95% CI 0.637, 0.999)

p=0.0486

Median PFS

Fulvestrant: 16.6 months

Anastrozole: 13.8 months

Number of

patients at risk:

Fulvestrant

Anastrozole

230

232

187

194

171

162

150

139

124

120

110

102

96

84

81

60

63

45

44

31

24

22

11

10

2

0

0

0

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d p

rog

res

sio

n f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 3 6 9 12 15 18 21 24 27 30 3633 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

PFS without visceral disease

HR 0.59

(95% CI 0.42, 0.84)

Median PFS


Anastrozole: 13.8 monthsPro

po

rtio

n o

f p

ati

en

ts a

live

an

d p

rog

res

sio

n-f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2

0 5 10 15 20 25 30 35 40

Fulvestrant (n=95) Anastrozole (n=113)

PFS with visceral disease

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d

pro

gre

ssio

n-f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0 5 10 15 20 25 30 35 40

0.2

HR 0.99

(95% CI 0.74, 1.33)

Median PFS


Anastrozole: 15.9 months

Fulvestrant (n=135)

Anastrozole (n=119)

Primary endpoint: PFS

Ellis et al, LBA14 ESMO 2016; Robertson et al, Lancet 2016

What is the optimal 1st-line endocrine therapy?

27

Trial DateAI

(months)Tamoxifen(months)

AI + fulvestrant 250mg (months)

Fulvestrant500mg

(months)

Hazard Ratio

Nabholtz et alAnastrozole vs tamoxifen

2000 11.1 5.6 - 0.81

Bonneterre et al Anastrozole vs tamoxifen

2001 8.2 8.3 - 0.99

Mouridsen et al Letrozole vs tamoxifen

2001 9.4 6.0 - 0.72

Chernozemsky et alExemestane vs tamoxifen

2007 12.0 8.3 - -

Paridaens et alExemestane vs tamoxifen

2008 9.9 5.8 - 0.84

Mehta et alAnastrozole vs anastrozole + fulvestrant 250mg

2012 13.5 - 15.0 0.80

Bergh et alAnastrozole vs anastrozole + fulvestrant 250mg

2012 10.2 - 10.8 0.99

Ellis et alAnastrozole vs Fulvestrant500mg

2016 13.8 16.6 0.797

Range 8–13 6–8 10–15 16-17

PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC

Is Fulvestrant the gold standard for 1st-line treatment now?

• PFS benefit “modest”

• PFS benefit restricted to patients without visceral mets.

• Only applies to endocrine naïve patients?

• Activity of other endocrine therapies post-fulvestrant unclear.

• Await overall survival data …. …….

• Other more effective alternative options available now.

28

ESR1 Mutations

Toy et al, Nature Genetics 2013

New generation SERDs (Selective

Estrogen Receptor Degraders - oral)

• Limitations of fulvestrant

– Poor bioavailability

– Requires oil-based IM formulation; limitations with increasing dose intensity

– Variable ER down-regulation

29

Van Kruchten et al, 2015

SERD Company Current status

GDC-0810 Genentech Phase I/II

GDC-0927 Genentech Phase I

RAD1901 Radius Phase I

AZD9496 Astra Zeneca Phase I

LSZ-102 Novartis Phase I

SAR439859 Sanofi Phase I

H3b-6545 (SERCA) H3 BioMedicine Phase I

FDA

Breakthrough

Drug

Designation

2017

Definitions of Endocrine Resistance in ER+ MBC

PRIMARY ENDOCRINE RESISTANCE

Relapse while on the first 2 years of

adjuvant ET, or PD within first 6 months

of 1st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE

Relapse while on adjuvant ET but after the first 2 years,

or relapse within 12 months of completing adjuvant ET,

or PD ≥ 6 months after initiating ET for MBC, while on ET

Courtesy of Johnston, SABCS 2016; Cardoso, Annals Onc 2014

What can we add to endocrine therapy to

overcome endocrine resistance?

31

• First-line setting

– CDK4/6 Inhibitor

(Trials using Temsirolimus, Bevacizumab, EGFR Inhibitors negative

or mixed results.)

• Second-line and beyond

– CDK4/6 Inhibitor vs mTOR Inhibitor

– ? PI3K inhibitor

Cyclin Dependent Kinase(CDK) 4/6 Inhibitors

32

Lange and Yee, Endocrine Related Cancer 2011

Ma, ASCO 2016

CDK4/6 Inhibitors

O’Leary et al, Nat Rev Clin Onc 2016

PALOMA-2 & MONALEESA-2: Design of Phase III

Studies


• Secondary endpoints:

– Response, OS, safety, biomarkers, PROs

PALOMA-2

R

A

N

D

O

M

I

S

E

Palbociclib (125 mg QD, 3/1

schedule) + letrozole

(2.5 mg QD)

Placebo + letrozole

(2.5 mg QD)

Postmenopausal ER+

HER2– advanced

breast cancer with no

prior treatment for

advanced disease.

AI-resistant patients

excluded

N=666

(2:1)

Stratified by the presence/absence of

liver and/or lung metastases

Ribociclib (600 mg QD,

3/1 schedule) +letrozole

(2.5 mg QD)

Placebo+ letrozole

(2.5 mg QD)



– OS (key), ORR, CBR, safety

Postmenopausal

women with

HR+/HER2–

advanced breast

cancer with

no prior therapy for

advanced disease

N=668

MONALEESA-2

R

A

N

D

O

M

I

S

E

(1:1)

Courtesy of Johnston, SABCS 2016

PALOMA-2

Finn R, et al. NEJM. 2016;375(20):1925–1936

mPFS (months)Palbociclib–letrozole: 24.8Placebo–letrozole: 14.5

MONALEESA-2

Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748

mPFS (months)ribociclib–letrozole: NRplacebo–letrozole: 14.7

PALOMA-2 & MONALEESA-2: PFS

mPFS (months)Ribociclib–letrozole: NRPlacebo–letrozole: 14.7

PALOMA-2 & MONALEESA-2: Secondary

endpoints

PALOMA-2Measurable disease

MONALEESA-2Measurable disease

55.3

84.3

44.4

70.8

0

10

20

30

40

50

60

70

80

90

100

Objective response rate Clinical benefit rate

Palbociclib + letrozole

Placebo + letrozole

53

80.1

37

71.8

0

10

20

30

40

50

60

70

80

90

100

Objective response rate Clinical benefit rate

Ribociclib + letrozole

Placebo + letrozole

OR (95% CI): 1.55 (1.05–2.28)p=0.03

OR (95% CI): 2.23 (1.39–3.56)p<0.001

p=0.00028

p=0.02

Rat

e (%

)

Finn R, et al. NEJM. 2016;375(20):1925–1936

Finn R, et al. Abstract 507, ASCO 2016

Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748

Hortobagyi G, et al. LBA01, ESMO 2016

Rat

e (%

)

PALOMA-2 MONALEESA-2

Finn R, et al. NEJM. 2016;375(20):1925–1936 Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748

PALOMA-2 & MONALEESA-2: Toxicity

Other potential AEs: Transaminitis, prolonged QT

MONARCH-1: Abemaciclib (Inhibitor of

CDK4>CDK6)

38

Dickler et al, ASCO 2016; CCR 2017

• Phase 2 single-agent trial in metastatic HR+HER2- mBC.

• No. of prior systemic regimens (any setting); 5 (2-11).

• 1-2 chemotherapy regimens in metastatic setting.

MONARCH-3

39

Goetz et al, JCO 2017

MONARCH-3

40


CDK 4/6 inhibitors for ER+ MBC

• New “Gold Standard” in 1st-line treatment

• Adjuvant trials have also commenced.

Unanswered Questions

• Does every patient need CDK4/6 inhibitor upfront?

Potential Predictors of CDK4/6 Inhibitor Activity

In sensitive cell lines:

• ↑ Cyclin D1 (CCND1)

• ↑ Retinoblastoma (Rb)

• ↓ p16

Finn RS, et al. Br Ca Research 2009 Finn RS, et al. Lancet Oncol 2015

ER+HER2- Unselected

ER+HER2- Plus

Amplification of CCND1

and/or Loss of p16

PALOMA-1

Predictive Biomarkers?

PALOMA-2: No subgroup of ER+ patients was found that

did not benefit from the addition of palbociclib to letrozole.

43

Finn RS, et al. ESMO 2016. Abstract LBA15 [oral].

Predictive Biomarkers?Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), HER2-

negative (HER2–) advanced breast cancer (ABC): efficacy by baseline tumor markers

44

Andre et al, AACR 2017

Subgroup Analyses

45

Hortobagyi et al, NEJM 2016Finn et al, NEJM 2016

PALOMA-2

MONALEESA-2

MONARCH-3

46


Patients with bone-only disease Patients without bone-only disease

Not all patients reach the next line of

ABC therapy

• After failure of first-line therapy, a proportion of patients cannot undergo second line therapy due to rapid disease progression

• In general, response to further lines of therapy is worse

• About one third of patients stop their treatment with each new line of therapy

• These results are concordant with large retrospective cohort studies

47

1. Dufresne A et al. Breast Cancer Res Treat 2008;107:275–279 2. Tacca O et al. Cancer Invest 2009;27:81–85

3. Bernardo G et al. Cancer Res 2010;70(Suppl 24):446s,P6-11-03 4. Planchat E et al. Breast 2011;20:574–578

5. Jackisch C et al. BMC Cancer 2014;14:924 6. Jackisch et al. P4-13-28, SABCS 2016

Study 2nd line 3rd line 4th line 5th line

Dufresne et al. 20081 100% 56% 25% 11%

Tacca et al. 20092 100% 68% 43% 23%

Bernardo et al. 20103 100% 82% 36% 11%

Planchat et al. 20114 100% 76% 56% 37%

Current study; Jackisch etal. 20145,6 100% 70% 46% 27%

Courtesy of Harbeck, ESMO Asia 2016

Considerations in choosing 1st-line therapy in ER+ MBC

Tumour Biology

• ER & PR levels

• Luminal Subtype / Proliferation

Clinical Features

• Prior Endocrine Rx / DFI / Pace of Disease

• Visceral vs non-visceral mets / Symptoms / Tumor Burden

Patient Factors

• Age / Co-morbidities / Geographical Logistics

• Patient Preference / Availability of Rx / Quality of Life

Partly adapted from Johnston, SABCS 2016


• New “Gold Standard” in 1st-line treatment




• Will there be improvement in Overall Survival?

PALOMA-1 OS data (not powered)

50

Finn et al, ASCO 2017

MONALEESA-2 Update

(OS data still immature)

51

Hortobagyi et al, ASCO 2017


• New “Gold Standard” in 1st-line treatment.




• Will there be improvement in Overall Survival?

• What is the optimal treatment after CDK4/6 Inhibition?

• What is the optimal sequence of treatment?

Second-Line and Beyond

BOLERO-2 & PALOMA-3: Design of Phase III studies

(2:1)

Palbociclib (125 mg

QD; 3 weeks on, 1

week off) +

fulvestrant (500 mg

IM Q4W)

(n=347)

Placebo

(3 weeks on, 1 week

off) + fulvestrant

(500 mg IM Q4W)

(n=174)

HR+, HER2- ABC

Pre/peri or postmenopausal

Progressed on prior ET on

or within 12 months of

adjuvant therapy and/or on

therapy for advanced breast

cancer

1 or more prior

chemotherapy regimen for

advanced cancer



– OS, ORR, Safety, QoL, CBR

(2:1)

Everolimus 10 mg daily +

exemestane 25 mg daily(n=485)

Placebo + exemestane 25 mg daily

(n=239)

Postmenopausal

women with estrogen

receptor positive

locally advanced or

metastatic breast

cancer who are

refractory to letrozole

or anastrozole



– OS, OR, CBR, Safety, QoL

BOLERO-2 PALOMA-3

R

A

N

D

O

M

I

S

E

R

A

N

D

O

M

I

S

E

BOLERO-2 & PALOMA-3: PFS

Turner N, et al. N Engl J Med 2015;373:209-19Baselga J, et al. N Engl J Med 2012;366:520-9

BOLERO-2 PALOMA-3

MONARCH-2

55

Sledge et al, ASCO 2017; JCO 2017

Patients were required to have disease that progressed while receiving neoadjuvant or adjuvant ET, # 12 months after adjuvant ET, or while receiving ET for ABC. Patients must not have received more than one ET or any prior chemotherapy for ABC.

BOLERO-2: Overall Survival Results

56

Piccart et al, Ann Onc 2014

Why?Not statistically powered to detect 4.4mth OS benefit.Imbalance in poststudy salvage chemo use?Higher rate of discontinuation of EVE due to AE: 26% vs 5%Paradoxical activation of AKT via negative feedback loop?Need predictive biomarkers?

BOLERO-2 Correlative Genomic Analysis

• Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components.

• However, mTOR somatic mutations may be associated with greater benefit from mTORinhibition.

• Somatic FGFR mutations associated with poor prognosis.

• High chromosomal instability associated with less everolimusbenefit and worst outcome.

57

Hortobagyi et al, JCO 2015

PI3K/AKT/mTOR Pathway

58

Rodon et al, Nature Reviews Clin Onc 2013

PI3K Inhibitors – still promising?

• Efficacy limited in unselected patients.

• Significant toxicities with Pan-PI3K Inhibitors.– FERGI (n=168): fulvestrant + pictilisib vs fulvestrant + placebo:

negative

– BELLE2 (n=1147): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; benefit mainly with PIK3CA mutated (cDNA)

– BELLE3 (n=432)(post-mTOR inhibitor): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; ; benefit mainly with PIK3CA mutated (tumour or cDNA)

• Alpha-specific PI3K Inhibitors– Better tolerated?

– Ongoing phase 3 trials• Taselisib + fulvestrant vs placebo + fulvestrant (SANDPIPER)

• Alpelisib + fulvestrant vs placebo + fulvestrant (SOLAR)

– Potential activity after progression on CDK4/6 Inhibitors?

59

Other Novel Therapeutics

• HDAC Inhibitors?

• Immunotherapy?

• Etc etc

• Still a role for

chemotherapy …

Ma et al, Nature Rev Ca 2015

Inhibitors of PI3K/MEK

pathway

Immunotherapy,

Bone-modifying agents

RTK Inhibitor

Novel SERD

Epigenetic Modulators?

Endocrine

Resistance

Inhibitors of MDM2?BCL2?

Inhibitors of NOTCH?WNT?CDK Inhibitor

61

Thank you for your attention!

Pink Ribbon Walk, October 2016

endocrine therapy for advanced breast cancer (abc)...treatment guidelines for hr+, her2–advanced...

Documents