New Treatment Directions for

Triple Negative Breast Cancer

(TNBC)

Naoto T. Ueno, MD, PhD, FACP

Professor of Medicine

Executive Director, Morgan Welch IBC Research

Program and Clinic

Chief, Section of Translational Breast Cancer Research

Department of Breast Medical Oncology

TNBC and basal-like breast cancer

Basal but not TNBC

15-40% are ER+,

PR+, or HER2+

TNBC

but not basal

10-30%

Can also include

“claudin-low”, a

subtype notable for

high expression of

stem cell markers

IHC Array TNBC

&

Basal-like

High grade ER- PR - HER-

p53Mut Hig Ki-67 CK14 p63

Prat A, et al, The Oncologist, 2013

Clonal and mutational evolution

spectrum of primary TNBC

Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashivili G, Ding, J, Tes K, Haffari G, Bashashati A, et al. Nature 2012. PMID 22495314

Lehmann BD et al. J Clin Invest 2011. PMID: 21633166

Training set Validation set 1. Basal-like subtype 1 (BL1)

2 Basal-like subtype 2 (BL2)

Increased expression of cell cycle

and DNA damage response genes

3. Immunomodulatory (IM)

Enriched for gene ontologies in

immune cell processes

4. Mesenchymal (M)

5. Mesenchymal stem-like (MSL)

Enriched for gene expression of

epithelial-mesenchymal transition

and growth factor pathways

6. Luminal androgen receptor

(LAR) Characterized by androgen

receptor signaling

7. Unknown (unstable)

TNBC gene signatures

Basal (n = 75)

BL1

BL2

M

IM

MSL

LAR

US

21%

8%

20% 23%

10%

17% 1%

Non-basal (n = 17)

LAR

MSL

M59%

35%

6%

Basal

BL1 16

BL2 6

M 15

IM 17

MSL 7

LAR 1

US 13

non Basal

LAR 10

MSL 6

M 1

Relationship between PAM 50 subtypes and

the Vanderbilt 7 subtypes

Masuda H, Baggerly K , Symmans F, Ueno NT. Clin Cancer Research, 2013. PMID: 23948975

0.0

20.0

40.0

60.0

80.0

100.0

BL1

BL2 M IM

MSL

LAR

UN

S

RCB-III

RCB-II

RCB-I

pCR

Dis

trib

utio

n (

%)

Pro

po

rtio

n o

f p

atie

nts

su

rviv

ing

Days

pCR

RCB-I

RCB-II

RCB-III

P<.0001

Relationship between RCB index and the

7 subtypes

130 TNBC gene expression microarrays

obtained between March 2000 and March

2010 at MD Anderson Masuda H, Baggerly K , Symmans F ,Ueno NT. Clin Cancer Research, 2013. PMID: 23948975

Basal-like

Mesenchymal-like

Luminal/Apocrine-like

HER2-enriched

Immune-associated

Le Du F, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam, Gonzalez-

Angulo M, Ueno NT. Oncotarget, 2015.

TNBC subtype Functions enriched according to ingenuity

pathway analysis

Basal-like subtype 1 (BL1) Characterized by increased expression of cell cycle and DNA damage response genes

Basal-like subtype 2 (BL2) Enriched for EGF pathway

Immunomodulatory (IM) Enriched for gene ontologies in immune cell processes. Do they exist?

Mesenchymal (M) Enriched for gene expression of epithelial-mesenchymal transition and growth factor pathways such as Wnt, ERK, IGFR, ALK, PIK3CA mutation

Mesenchymal stem-like (MSL)

Luminal androgen receptor (LAR)

Characterized by androgen receptor signaling

Unknown/undefined (UNS)

Basal-like

Le Du F, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam, Gonzalez-Angulo M, Ueno NT. Oncotarget, 2015.

Cytokines

Recruitment of tumor-associated macrophages,

MSC, adipose tissue

5111156

TNBC targeting model

Hypothesis: Suppression of the EGFR pathway in breast cancer induces

improved clinical outcome

IBC-TNBC: IIT Amgen/Celgene Flagship 2 Moonshots IIS

Epidermal growth factor receptor tyrosine kinase inhibitor reverses mesenchymal to epithelial phenotype and inhibits metastasis in inflammatory breast cancer. Zhang D, LaFortune TA, Krishnamurthy S, Esteva FJ, Cristofanilli M, Liu P, Lucci A, Singh B, Hung MC, Hortobagyi GN, Ueno NT. Clin Cancer Res. 2009;15(21):6639-48.

Sensitivity of breast cancer cells to erlotinib depends on CDK 2 activity. Yamasaki F, Zhang D, Bartholomeusz C, Sudo T, Hortobagyi GN, Kurisu K, Ueno NT. Mol Cancer Ther. 2007;6(8):2168-77.

Role of epidermal growth factor receptor in breast cancer. Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Breast Cancer Res Treat. 2012;136(2):331-45.

Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, Valero V, Lehmann BD, Pietenpol JA, Hortobagyi GN, Symmans WF, Ueno NT. Clin Cancer Res. 2013;19(19):5533-40.

Silencing kinase-interacting stathmin gene enhances erlotinib sensitivity by inhibiting Ser¹⁰ p27 phosphorylation in epidermal growth factor receptor-expressing breast cancer. Zhang D, Tari AM, Akar U, Arun BK, LaFortune TA, Nieves-Alicea R, Hortobagyi GN, Ueno NT. Mol Cancer Ther. 2010;9(11):3090-9.

Summary of clinical data

• Unique gene pathway signatures that

determine the prognosis

• No clear gene mutation drivers

• Few targets have been clinically proven

• pCR is an important clinical readout for

long-term outcomes

Accelerate the implementation of

personalized cancer medicine

• Need to define clinically relevant TNBC-like category

• Need to validate targets as druggable

• Need to validate target measurement methodology

and predictability

• Need to define the dynamic molecular changes

before, during, and after treatment

• Clinically pragmatic, molecular discovery-driven,

and “in-between” approaches

Challenges with T/FAC

preoperative chemotherapy

• Addition of active agents in preoperative

chemotherapy increases toxicity

• Patients often opt out of additional

chemotherapy after T/FAC

• Diagnostic imaging response at 12 weeks

(~50-80% accuracy for pathologic complete

response [pCR]/RCB-I)

• Genomic predictor of T/FAC developed at

MD Anderson

(~80% accuracy and positive association with

survival) Hatzis et al. JAMA, 2011

Patients with localized TNBC who will receive neoadjuvant chemotherapy

No predictive results given

Predictive results reported

Biopsy with molecular profiling

RA

ND

OM

IZE

Primary objective: Δ % pCR/RCB-I

Primary objective: Δ recurrence-free

survival

Chemo-sensitive Chemo-insensitive 4 cycles of anthracycline-based therapy, then assess reduction in tumor size with imaging

<10% decrease >80% decrease

Responder: taxane therapysurgery; assess pCR/RCB-I

Nonresponder: **BIOPSY** recommend experimental therapy in clinical trial selected on

the basis of molecular profiling surgery; assess pCR/RCB-I

>10% decrease <80% decrease

Chemo-insensitive (prediction & interim imaging)

Vimentin +

(mesenchymal)

AR+ Other

(enriched for basal-like)

mTORi +

chemo

Improved rate of

pCR/RCB-I?

ARi +

chemo

PDL-1i +

chemo

*comparison with control

“predictor unknown”

group

BRCA1/2 +

PARPi+

chemo

• Single-arm phase II trials

• pCR improvement: 5%20%

• n = 37

• Two-stage design; close if pCR/RCB-

I not seen in >1 of 14 patients

EGFRi +

chemo

Treatment strategy for newly diagnosed

primary TNBC

AC Paclitaxel Chemo-sensitive

Trial Agent

PDL-1i MPDL3280A

EGFRi panitumumab

ARi enzalutamide

mTORi everolimus

PARPi TBD

FAKi defactinib

AC x 4 cycles

Weekly paclitaxel, 12 cycles

Decision

Targeted therapy

Data from translational work

informs/generates the next line

of targeted therapy trials for

resistant disease

Pretreatment

biopsy

Biopsy

residual

disease

Biopsy

residual

disease

Biopsy

residual

disease

Tissue to determine

mechanisms of disease

resistance

Molecular diagnostics

to guide treatment

decision-making

Conclusion

• Need for strong basic/preclinical

justification for target development

• Need for a comprehensive drug

combination that targets both cancer

and cancer microenvironment

• Need for feedback mechanism from

clinical trials to identify novel targets in

TNBC

Acknowledgment

Pathology

Fraser Symmans

Mike Gilcrease

Aysegul Sahin

Surgical Oncology

Beth Mittendorf

Alastair Thompson

Kelly Hunt

Dalliah Black

Diagnostic Imaging

Rosalind Candelaria

Beatriz Adrada

Mia Rauch

Wei Yang

Radiation Oncology

Mike Stauder

Women’s Cancer Moonshot Leadership

Gordon Mills

Anil Sood

Mien-Chie Hung

Debu Tripathy

Breast Medical

Oncology

Stacy Moulder

Naoto T. Ueno

Jennifer Litton

Banu Arun

Vicente Valero

Bora Lim

Rashmi Murthy

Biostatistics

Ken Hess

Joe Ensor

Basic Science

Helen Piwnica-Worms

Sendurai Mani

Pete Davies

Cliff Stephan

Research Staff

Betsy Williams

Thorunn Helgason

Alyson Clayborn

Akshara Raghavendra

Administrative Staff

Jason Books

Walker Averitt

Investigational Cancer Therapeutics

Funda Meric-

Bernstam