2017-esmo-preceptorship-breast-endocrine-therapy-advanced-yoon-sim-yap.pdf

Endocrine Therapy for Advanced Breast Cancer (ABC) Dr Yoon-Sim YAP Division of Medical Oncology, National Cancer Centre Singapore

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

2

Treatment guidelines for HR+, HER2– advanced breast cancer ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first

ABC2

ASCO3

choice independent of metastatic site, unless rapid response is needed. Limited visceral metastases are not a contraindication for endocrine therapy 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 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. 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/newwww.asco.org/files/content-files/practice-and-guidelines/documents/2016-adv-endocrine-breast-summarytable.pdf 4. NCCN V3.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

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Chemotherapy versus Endocrine Therapy Chemotherapy has higher response rate.

Wilcken et al, Cochrane System Database Review 2009 4

Chemotherapy versus Endocrine Therapy No significant differences in overall survival.

Wilcken et al, Cochrane System Database Review 2009 5

What are the Endocrine Therapy Options? What is the evidence for doing what we do? (ie if people are practising evidence-based medicine)

6

Breakthroughs in hormone receptor positive (HR+) breast cancer FDA approvals of new treatments Combination Therapy

2012 Everolimus + Exemestane 2015 Palbociclib + Letrozole

1980

1995

Endocrine Therapy

1977 Tamoxifen

7

2017 Ribociclib (with AI)

1985 Megestrol Acetate

2000

1996 Goserelin

1999 Exemestane

1995 Anastrozole 1997 Letrozole

2002 Fulvestrant

2015

2016 Palbociclib + Fulvestrant

2017 Abemaciclib (single agent or with fulvestrant)

2016

2017

ASCO Guidelines

Premenopausal

Postmenopausal

Rugo et al, JCO 2016 8

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)

Tamoxifen versus

Progestogens Estrogens Androgens Anti-Estrogens Aminogluthetimide Formestane Fadrozole Fulvestrant

N=17 6 1 1 2 3 1 2 1

Tamoxifen always better or at least as good. Schiavon and Smith, Haematol Oncol Clin North AM 2013 12

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. Klijn et al, JNCI 2000 13

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? PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC Trial Nabholtz et al, 2000 (n=353) Anastrozole vs tamoxifen Bonneterre et al, 2001 (n=668) Anastrozole vs tamoxifen Mouridsen et al, 2001 (n=907) Letrozole vs tamoxifen Paridaens et al, 2008 (n=371) Exemestane vs tamoxifen Range

AI (response rate, %)

Tamoxifen (response rate, %)

AI (PFS, mths)

Tamoxifen (PFS, mths)

Hazard Ratio

21

17

11.1

5.6

0.81

33

33

8.2

8.3

0.99

30

20

9.4

6.0

0.72

46

31

9.9

5.8

0.84

8–12

6–8

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 Johnston, SABCS 2016 16

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) (Bachelot et 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

Mode of Action of Estradiol, Tamoxifen and Fulvestrant AF2

Estradiol E

+ ER

AF1 + AF2 ACTIVE

E E

AF1

Receptor dimerisation

AF1

Tamoxifen T

+ ER

AF1 ACTIVE AF2 INACTIVE

T T

AF1 AF1

Fulvestrant F

+ ER AF1

F

No dimerisation

F

AF1 + AF2 INACTIVE

FULLY ACTIVATED TRANSCRIPTION (tumour cell division) PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumour cell division) NO TRANSCRIPTION (no tumour cell division)

ACCELERATED RECEPTOR DEGRADATION

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

Fulvestrant: Preclinical Activity

Osborne et al, JNCI 1995

20

Osborne et al, Cancer Chemo and Pharm 1994

Clinical Trials on Fulvestrant (250mg LD)

Pretreated

Osborne, JCO 2002

Howell, JCO 2002

Treatment-naive

Howell, JCO 2004 21

Pretreated

Only just as good as tamoxifen or anastrozole

Clinical Trials on Fulvestrant (250mg LD)

Chia, JCO 2008

Only just as good as exemestane even after relapse/progresson on non-steroidal AI Caveat: 250mg dose was suboptimal Johnston, Lancet Oncol 2013 22

CONFIRM phase III Trial: Fulvestrant 250mg vs 500mg

Median OS 26.4mths vs 22.3mths

Di Leo et al, JNCI 2014

Clinical Trials on Fulvestrant (500mg HD) 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

Caveat: OS not preplanned analysis; not all patients participated in OS followup. Ellis et al, JCO 2015 24

FALCON: Phase III 1st line study of Fulvestrant 500 vs AI in Endocrine Therapy Naïve MBC / LABC N=450 ▪ 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

Fulvestrant 500mg i.m. Anastrozole 1mg OD

Note no prior endocrine therapy allowed • •

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 Ellis et al, LBA14 ESMO 2016

FALCON: Fulvestrant 500 vs anastrozole in 1st-line endocrine therapy naïve ER+ MBC 1.0

Fulvestrant (n=230)

0.8

Anastrozole (n=232)

0.7 0.6 0.5

PFS without visceral disease

1.0

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

0.9 0.8 0.7 0.6

HR 0.59 (95% CI 0.42, 0.84)

0.5 0.4 0.3

Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months

0.2 0.1 0.0

HR 0.797 0.4 (95% CI 0.637, 0.999) 0.3 p=0.0486 0.2

Median PFS 0.1 Fulvestrant: 16.6 months Anastrozole: 13.8 months

0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Number of Time (months) patients at risk: Fulvestrant 230 187 171 150 124 110 96 81 63 44 24 11 2 0 Anastrozole 232 194 162 139 120 102 84 60 45 31 22 10 0 0

0

5

10

15

20

25

30

35

40

Time (months) 1.0

Proportion of patients alive and progression-free

Proportion of patients alive and progression free

0.9

Proportion of patients alive and progression-free

Primary endpoint: PFS

PFS with visceral disease

0.9 0.8

Fulvestrant (n=135) Anastrozole (n=119)

0.7 0.6

HR 0.99 (95% CI 0.74, 1.33)

0.5 0.4 0.3

Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months

0.2 0.1 0.0

0

5

10

15

20

25

Time (months)

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

30

35

40

What is the optimal 1st-line endocrine therapy? PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC Trial

Date

AI (months)

Tamoxifen (months)

AI + fulvestrant 250mg (months)

Nabholtz et al Anastrozole vs tamoxifen

2000

11.1

5.6

-

Fulvestrant 500mg (months)

0.81

Is Fulvestrant2001 the gold8.2standard8.3for 1st-line treatment now? Mouridsen•et alPFS benefit “modest” 2001 9.4 6.0 Letrozole vs tamoxifen Chernozemsky et al • PFS benefit restricted without -visceral mets. 2007 12.0 to patients 8.3 Exemestane vs tamoxifen to endocrine naïve patients?Paridaens•et al Only applies 2008 9.9 5.8 Exemestane vs tamoxifen Activity of other endocrine therapies post-fulvestrant unclear. Mehta et al• Anastrozole vs anastrozole 2012 13.5 15.0 + fulvestrant 250mg • Await overall survival data …. ……. Bergh et al Anastrozole anastrozole 2012 10.2alternative • vs Other more effective options 10.8 available now. + fulvestrant 250mg Bonneterre et al Anastrozole vs tamoxifen

Ellis et al Anastrozole vs Fulvestrant 500mg Range

27

2016

13.8

8–13

16.6

6–8

10–15

Hazard Ratio

16-17

0.99

0.72 0.84 0.80 0.99 0.797

ESR1 Mutations

Toy et al, Nature Genetics 2013 28

New generation SERDs (Selective Estrogen Receptor Degraders - oral) • Limitations of fulvestrant – Poor bioavailability – Requires oil-based IM formulation; limitations with increasing dose intensity Van Kruchten et al, 2015 – Variable ER down-regulation SERD GDC-0810 GDC-0927 RAD1901 AZD9496 LSZ-102 SAR439859 H3b-6545 (SERCA)

Company Genentech Genentech Radius Astra Zeneca Novartis Sanofi H3 BioMedicine

Current status Phase I/II Phase I Phase I Phase I Phase I Phase I Phase I

FDA Breakthrough Drug Designation 2017

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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? • 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

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Cyclin Dependent Kinase(CDK) 4/6 Inhibitors

Lange and Yee, Endocrine Related Cancer 2011 Ma, ASCO 2016 32

CDK4/6 Inhibitors

O’Leary et al, Nat Rev Clin Onc 2016

PALOMA-2 & MONALEESA-2: Design of Phase III Studies PALOMA-2 Postmenopausal ER+ HER2– advanced breast cancer with no prior treatment for advanced disease. AI-resistant patients excluded N=666

R A N D O M I S E

(2:1)

MONALEESA-2 Palbociclib (125 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Placebo + letrozole (2.5 mg QD)

Postmenopausal women with HR+/HER2– advanced breast cancer with no prior therapy for advanced disease N=668

R A N D O M I S E

(1:1)

Ribociclib (600 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Placebo + letrozole (2.5 mg QD)

Stratified by the presence/absence of liver and/or lung metastases

• •

Primary endpoint: PFS Secondary endpoints: – Response, OS, safety, biomarkers, PROs

• •

Primary endpoint: PFS Secondary endpoints: – OS (key), ORR, CBR, safety

Courtesy of Johnston, SABCS 2016

PALOMA-2 & MONALEESA-2: PFS PALOMA-2

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

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

MONALEESA-2

mPFS (months) mPFS (months) ribociclib–letrozole: NR Ribociclib–letrozole: NR placebo–letrozole: 14.7 Placebo–letrozole: 14.7

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

PALOMA-2 & MONALEESA-2: Secondary endpoints MONALEESA-2 Measurable disease

PALOMA-2 Measurable disease 90 80

Rate (%)

70

Palbociclib + letrozole Placebo + letrozole OR (95% CI): 1.55 (1.05–2.28) p=0.03

60 50 40

OR (95% CI): 2.23 (1.39–3.56) p<0.001

100 90

Ribociclib + letrozole Placebo + letrozole

p=0.02

80

84.3 70.8

55.3

70

Rate (%)

100

80.1 p=0.00028

71.8

60 50

53

40

44.4

30

30

20

20

10

10

0

37

0 Objective response rate

Clinical benefit rate

Finn R, et al. NEJM. 2016;375(20):1925–1936 Finn R, et al. Abstract 507, ASCO 2016

Objective response rate

Clinical benefit rate

Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748 Hortobagyi G, et al. LBA01, ESMO 2016

PALOMA-2 & MONALEESA-2: Toxicity PALOMA-2

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

MONALEESA-2

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

Other potential AEs: Transaminitis, prolonged QT

MONARCH-1: Abemaciclib (Inhibitor of CDK4>CDK6) • 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.

Dickler et al, ASCO 2016; CCR 2017 38

MONARCH-3

Goetz et al, JCO 2017 39

MONARCH-3

Goetz et al, JCO 2017 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 PALOMA-1

In sensitive cell lines: • ↑ Cyclin D1 (CCND1) • ↑ Retinoblastoma (Rb) • ↓ p16

ER+HER2- Unselected

ER+HER2- Plus Amplification of CCND1 and/or Loss of p16

Finn RS, et al. Br Ca Research 2009

Finn RS, et al. Lancet Oncol 2015

Predictive Biomarkers? PALOMA-2: No subgroup of ER+ patients was found that did not benefit from the addition of palbociclib to letrozole.

Finn RS, et al. ESMO 2016. Abstract LBA15 [oral]. 43

Predictive Biomarkers? Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), HER2negative (HER2–) advanced breast cancer (ABC): efficacy by baseline tumor markers

Andre et al, AACR 2017 44

Subgroup Analyses PALOMA-2 MONALEESA-2

Hortobagyi et al, NEJM 2016 45

Finn et al, NEJM 2016

MONARCH-3 Patients with bone-only disease

Patients without bone-only disease

Goetz et al, JCO 2017 46

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 Study Dufresne et al. 20081 Tacca et al. 20092 Bernardo et al. 20103 Planchat et al. 20114 Current study; Jackisch et al. 20145,6

2nd line 3rd line 4th line 5th line 100% 56% 25% 11% 100% 68% 43% 23% 100% 82% 36% 11% 100% 76% 56% 37% 100%

70%

46%

27%

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

Courtesy of Harbeck, ESMO Asia 2016 47

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

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? • Will there be improvement in Overall Survival?

PALOMA-1 OS data (not powered)

Finn et al, ASCO 2017 50

MONALEESA-2 Update (OS data still immature)

Hortobagyi et al, ASCO 2017 51

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? • 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 BOLERO-2 Postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole

• •

R A N D (2:1) O M I S E

PALOMA-3

Everolimus 10 mg daily + exemestane 25 mg daily (n=485) Placebo + exemestane 25 mg daily (n=239)

Primary endpoint: PFS Secondary endpoints: – OS, ORR, Safety, QoL, CBR

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

• •

R A N D (2:1) O M I S E

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)

Primary endpoint: PFS Secondary endpoints: – OS, OR, CBR, Safety, QoL

BOLERO-2 & PALOMA-3: PFS BOLERO-2

Baselga J, et al. N Engl J Med 2012;366:520-9

PALOMA-3

Turner N, et al. N Engl J Med 2015;373:209-19

MONARCH-2

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. Sledge et al, ASCO 2017; JCO 2017 55

BOLERO-2: Overall Survival Results

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?

Piccart et al, Ann Onc 2014 56

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 mTOR inhibition. • Somatic FGFR mutations associated with poor prognosis. • High chromosomal instability associated with less everolimus benefit and worst outcome. Hortobagyi et al, JCO 2015 57

PI3K/AKT/mTOR Pathway

Rodon et al, Nature Reviews Clin Onc 2013 58

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 Immunotherapy, Bone-modifying agents

• HDAC Inhibitors? • Immunotherapy? • Etc etc

Novel SERD Epigenetic Modulators?

RTK Inhibitor

• Still a role for chemotherapy …

Endocrine Resistance Inhibitors of MDM2?BCL2?

CDK Inhibitor

Inhibitors of PI3K/MEK pathway

Inhibitors of NOTCH?WNT?

Ma et al, Nature Rev Ca 2015

Pink Ribbon Walk, October 2016

Thank you for your attention! 61