São Paulo

29/03/2019

Current Practice: Early TNBC Carlos H Barrios MD

POTENTIAL CONFLICTS OF INTEREST 2019

• Clinical Research: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp Dohme (MSD), Novartis, Pfizer, PharmaMar, Roche/Genentech.

• Academic Research Projects: CPO, PUCRS, LACOG, GBECAM, INCA-Brazil.

• Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai.

• No financial conflicts to declare.

Carlos H. Barrios, MD barrios@tummi.org

Conflict of Interest Statement

This presentation reflects my personal opinion, and not that of my employer or the sponsor of this activity. Its main objective is to stimulate independent scientific discussion and does not intend to promote a specific product or indication. The information presented may be different from the local/regional label of some of the medications. Please refer to your local label for further clarification.

Carlos H. Barrios, MD barrios@tummi.org

What Is TNBC?

• “Triple negative” - ER negative, PgR negative, HER2 negative

• TNBC accounts for 10% to 17% of all breast carcinomas

• Heterogeneous group of diseases, in general, with significantly more aggressive behavior than other molecular subtypes

• Majority are Grade 3 tumors

• Histologically, most frequently high-grade invasive ductal carcinomas of no special type

Boyle P. Ann Oncol. 2012;23(suppl 6):vi7-vi12.

Anders CK, et al. Clin Breast Cancer. 2009;9(suppl 2):S73-S81.

Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844

Luminal Epithelial Cells

Low molecular wt CK 7, 8, 18 and 19

Mucin, BCL2, Hormone Receptors

Basal Cells (Myoepithelial cells)

High molecular wt CK 5, 6, 14 and 17

SMA, Calponina, p63, P-caderin

Perou C, et al. Nature 460:747-752, 2000

Triple Negative

Basal

~75% of TNBC have

Basal gene expression

Pal & Mortimer. Maturitas 2009; Gluz et al. Ann Oncol 2009;

Ander & Carey. Oncology 2008. Young et al. BMC Cancer 2009

Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018

Triple-Negative vs. Basal-Like: Definitions

• ER- / PR- / HER2- • ~15% of all breast carcinomas • Poorly differentiated • Express CK 5/6, 17, EGFR (+)

• BRCA1-2 mutated tumors

•~5% of Breast Cancer

• 50% BRCA-1 carriers are basal-like

• Basal but not triple negative

• Definition by gene expression

• Includes some if not most of BRCA1 mutated tumors

• 15-40% are ER+, PR+ or HER2+

• Triple negative but not basal

• Definition by IHC

• Includes other histologies (medullar, adenoid cystic)

• 10-30% can also include “claudin-low,” a subtype notable for high expression of stem cell markers

• 90% of TNBC do not have BRCA mutations

BRCA 1-2

Prat A, et al. The Oncologist 2013

TNBC: Classifications

Basallike (BL)

TNBC

Mesenchymallike (ML)

TNBC Immune-associated

(IM) TNBC

Luminal/apocrine (LA) TNBC

HER2-enriched (HER2e)

TNBC

Immune signature

BL2

Cell cycle DNA damage

Basallike cytokeratine

Growth signaling (EGF, IGF)

Low proliferation

AR pathway

IM

Claudin- Low

BL1

M

Normal BL

LA/LB

HER2e

LAR

PI3K mutations

EMT signature: cell motility

growth factor signaling (TFG6, Notch,

Wnt/β-catenin, Hedgehog)

Angiogenesis

MSL

Lehmann’s classification

PAM50/claudin-low classification

Le Du F. Oncotarget. 2015;6:12890-12908.

This work is licensed under a Creative Commons Attribution 3.0 Unported License.

Evolution of Treatment Strategies for EBC

ADJUVANT THERAPY

Adapted from: Bonadonna, NEJM, 2006; EBCTCG, Lancet, 2011; Bonilla, JNCI, 2010; Martin, ASCO 2010; Slamon, NEJM 2011; Tolaney, NEJM 2015.

1 3 5 7 9 11 13 15 y

% D

ise

ase

Fre

e S

urv

iva

l

100%

50%

0%

26%

Surgery

32%

CMF

35%

Antra

62%

TAC

67%

DD

75%

Trastuz

93%

APT

A significant proportion of patients are cured by Surgery. We have not been able to single them out!

Patient selection (HER2 or clinical characteristics) has lead to dramatic improvements in outcomes

Adjuvant Approach to EBC

Patient Selection Issues in Early TNBC

• TNM classification

• Histology

• Gene expression profiles

• Platinum in the treatment of Early TNBC

• BRCA 1/2 mutated vs. non mutated

• Basal vs. Non-Basal

• Tumor Infiltrating Lymphocytes

• Neo-Adjuvant response (pCR) vs. non-response (non-pCR)

• Residual disease after neo-adjuvant therapy

Prat A, et al. The Oncologist 2013

How should we define the disease?

79.6%

89.5%

Log-rank p-value: 0.007 100

90

80

70

60

50

1 0 3 4 5 6 7 2 8 9 10

84.9%

Log-rank p-value: 0.286

88.0%

100

90

80

70

60

50

1 0 3 4 5 6 7 2 8 9 10

OS

Pro

bab

ilit

y

Basal (EGFR and/or CK5/6 positive)

Time (Years)

Subgroup Analysis of OS (ITT)

OS

Pro

bab

ilit

y

Non-basal (EGFR and CK5/6 negative)

Time (Years)

Cape. 329

307

286

263

256

249

238

200

139

63 21

Obs. 318

301

284

268

259

242

223

179

123

64 25

Number of patients at risk

Cape. 119 110 107 104 98 98 86 67 31 8 3

Obs. 110 106 91 82 80 76 73 53 22 9 3

Number of patients at risk

p-value interaction test: 0.0052

Group Events

Capecitabine 13

Observation 27

Group Events

Capecitabine 58

Observation 46 HR: 1.23

(95% CI: 0.84, 1.82) HR: 0.42

(95% CI: 0.21, 0.81)

Evolution of Treatment Strategies for EBC

ADJUVANT THERAPY

NEO-ADJUVANT THERAPY

TNBC: Responsiveness to Neoadjuvant Conventional Chemotherapy

• TNBC is responsive to conventional NAC with good outcome similar to other subtypes

• < pCR = poorer outcome

Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

1 Yrs After Surgery

2 3 4 5 6 7

Pro

bab

ilit

y o

f B

ein

g A

live

pCR/non-TNBC pCR/TNBC RD/non-TNBC RD/TNBC

98%

94% P = .24

88%

68%

P = .0001

Cortazar P, et al. Lancet.2014;384(9938):164-172.

pCR and long-term outcome in TNBC:

The CTNeoBC pooled analysis

Symmans WF, et al. J Clin Oncol. 2017;35(10):1049-1060

Recurrence in TNBC correlates with volume of

residual disease

RCB-0 (pCR) 35%

RCB-1 16%

RCB-2 33%

RCB-3 17%

Evolution of Treatment Strategies for EBC

NEO-ADJUVANT THERAPY

POST NEO-ADJUVANT

THERAPY

CREATE-X: DFS and OS Full Analysis Set

Masuda N, et al. N Engl J Med 2017;376:2147-59. DOI: 10.1056/NEJMoa1612645

Medium Follow up of 3.6 years

Outcome Capecitabine

(n = 440) Observation

(n = 445) HR

(95% CI) P Value

5-yr DFS 74.1% 67.6% 0.70 (0.53-0.92) 0.01

5-yr OS 89.2% 83.6% 0.59 (0.39-0.90) 0.01

CREATE-X: DFS and OS in TNBC

Masuda N, et al. N Engl J Med 2017;376:2147-59. DOI: 10.1056/NEJMoa1612645

Medium Follow up of 3.6 years

Outcome Capecitabine

(n = 440) Observation

(n = 445) HR

(95% CI)

5-yr DFS 69.8% 56.1% 0.58 (0.39-0.87)

5-yr OS 78.8% 70.3% 0.52 (0.30-0.90)

Evolution of Treatment Strategies for EBC

ADJUVANT THERAPY

NEO-ADJUVANT THERAPY

NEO-ADJUVANT THERAPY

POST NEO-ADJUVANT

THERAPY

Unlikely to evolve unless in very well characterized patient subgroups.

It is becoming almost UNETHICAL to treat intermediate and high risk HER2 + and TNBC patients with surgery and adjuvant therapy. Almost mandatory for high risk patients Will need EFS endpoint to change clinical practice Most powerful strategy to select patients and explore new treatments

Personal Treatment Algorithm

“Low Risk” TNBC (TNM and histology based definition)

cT <1cm - clin N0

SURGERY

Discussion on ADJUVANT THERAPY

RT, CT

Not yet ready to apply the CIBOMA Trial findings of discriminating basal vs. non-basal patients to

recommend Capecitabine to these patients

Personal Treatment Algorithm

“Intermediate/high Risk” TNBC (TNM and histology based definition)

cT >1cm - clin N0

Neo-Adjuvant Therapy

Capecitabine for 6 months

cT any - clin N+

pCR non-pCR

Clinical Trials addressing patient selection issues

and EFS endpoints should also be considered in the

discussion with each patient

SURGERY

TAKE HOME MESSAGES

• We should never forget where we are coming from…

• The cure of EBC with adjuvant therapy has been achieved (since the early 70’) based on the concept of treating patients with estimations of risk and offering treatment to a large number of patients that we know do not need any treatment.

• Therapy individualization remains an important and worth-pursuing goal but is an imperfect exercise.

• Still today, most treatment decisions in this area are based in our ability of practicing the “art of medicine” and defining the balance of the potential benefits and harms for each individual patient.

Subgroup Analysis of DFS (ITT)

Hazard Ratio No. of events HR (95% CI)

Subgroup Overall Menopausal Status Premenopausal Postmenopausal Phenotype Basal Non-basal Chemotherapy Neoadjuvant Adjuvant Type of CT Taxanes No taxanes N0 vs. N+ N0 N+ Region Spain Latin America

Subgroup n=876 (100%) 276 (32) 600 (68) 628 (72) 248 (28) 164 (19) 705 (80) 285 (33) 591 (67) 444 (51) 420 (49) 532 (61) 344 (39)

Capecit. 105 24 81 84 21 29 74 33 72 34 70 60 45

Observ.

120 35 85 86 34 24 96 36 84 52 67 75 45

0.819 (0.630-1.065) 0.686 (0.408-1.153) 0.867 (0.639-1.176) 0.942 (0.697-1.272) 0.530 (0.307-0.913) 1.006 (0.586-1.727) 0.747 (0.552-1.012) 0.884 (0.551-1.418) 0.798 (0.583-1.093) 0.685 (0.445-1.057) 0.878 (0.628-1.228) 0.750 (0.534-1.053) 0.934 (0.618-1.413)

0.4 0.6 0.8 1 1.2 1.6 2 <-Capecitabine Observation->