Triple negative breast cancer - are we making progress -

Aleksandra Filipovic MD PhD

UMOS Belgrade , Serbia May 16th, 2015

Contents

Introduction / definition

Current treatments for triple-negative

breast cancers

Other targets for treatment of triple-

negative breast cancers

Conclusions

Basal-Like Carcinoma not a complete overlap with TNBC

Sub-type from gene expression profiling

Cytokeratines 5/6/17 or 14 + (CK8/18-) : 0,8%

Combined (CK 8/18+ ) : 10 %

Particular morphotype and immunophenotype:Central

necrosis (74%)

Pushing margins (60%)

Grade III / high mitotic index

RO-/ RP-/ HER2-/ p53 + / EGFR + (41%) or c-KIT+ (31%)

Challenges in treating TNBC

Absence of biomarkers

Aggressive natural history

Propensity for early visceral metastasis

Paradoxical response to chemotherapy

BRCA-1 pathway activity (DNA repair, cell

cycle check point responses) may be

impaired

•

7 different molecular subtypes

How might we target each subtype?

Basal-like 1 and 2: DNA damaging agents,

growth factor inhibition (i.e. EGFR)

Immunomodulatory: ? Immune regulators

Mesenchymal and mesenchymal / stem cell:

PI3K/mTOR pathway

LAR: Androgen blockade

Targets for TNBC

Proliferation →anthracyclines

p-53 →taxanes

Genetic instability →DNA-damaging agents

(platinum compounds, . . . )

Angiogenesis

EGF-R

c-Kit

Targeted therapies

something old something new

•Neoadjuvant

•Adjuvant

•Metastatic

Chemotherapy: Adverse events

Activity Toxicity

Fever Nausea Infusional reactions Oral complications Diarrhea Anemia Neuropathy Alopecia Rash, Extravasation Emotional

Cardiac

Secondary Malignancies

Fatigue

Neuropathy

Arthropathy

Current Treatments for TNBC

Traditional Adjuvant Chemotherapy :

Anthracycline + alkylating agent, followed by taxane

doxorubicin + cyclophosphamide followed by paclitaxel

CMF – a comeback in TNBC CMF reduces locoregional recurrence rate and prolongs DFS in LN-ve

TNBC, tumours > 2 cm

N = 687

56 months (range 14-156 months)

decreased recurrence compared to anthracycline- or taxane- (RR = 0.66,

95%; CI 0.45-0.96; P = 0.030)

CMF regimens for TNBC patients may be more effective than anthracycline-

or taxane-based regimens

TNBC ‘Paradox’: Chemotherapy

N > 1000

pCR rates: TNBC ~20 – 30%; non-TNBC ~5 – 15%; (P = .034)

3-yr DFS and OS lower in TNBC vs non-TNBC; (P<.0001)

Highest rates of pCR are seen in HER2 +ve and TNBC

Characteristics of Residual Disease Post NAC

Need for Post-NAC “Residual Disease Trials”

EA1131: A randomized phase III post-operative trial of platinum chemotherapy vs

observation in patients with residual TNBC post-neoadjuvant chemotherapy

Clinical Trials with Platinum

Neoadjuvant Carboplatin for TNBC

von Minckwitz, Lancet Oncol 2014; 15: 747–56; Sikov, SABCS 2013; Rugo SABCS 2013; Alba, BCRT, 2012 (136)

Summary of recent randomized trials

Study Design N

pCR

Control Platinum

GeparSixto nplDox/Pac/Bev

+/- wCb (AUC1.5) X 18 wks

315 42.7% 53.2%

ALLIANCE 40603

2x2 design

wPac +/- Cb (AUC 6) +/- bev

AC X 4

433 41% 54%

ISPY2 wPac+/-Cb/veliparib ACx4 71 26%(est) 52%(est)

Both GeparSixto and CALGB 40603 included Bev along with Cb and I spy included PARPi

Slide 28

Presented By Melinda Telli at 2014 ASCO Annual Meeting

Veliparib/Carboplatin GRADUATES

in the Triple Negative Signature

SIGNATURE

Estimated pCR Rate (95% probability interval)

Probability

Veliparib +

Carbo is

Superior to

Control

Predictive

Probability of

Success in

Phase 3 Veliparib/

Carbo

Concurrent

Control

All HER2- 33%

(22-43%)

22%

(10-35%) 92% 55%

HR+/HER2- 14%

(4-27%)

19% (6-35%)

28% 9%

HR-/HER2- 52% (35-69%)

26% (11-40%)

99% 90%

Rugo et. al. SABCS 2013

Impact of BRCA1/2 Mutation Status on Response to

Platinum-Based Chemotherapy in Triple-Negative

Breast Cancer in the TBCRC009 Trial

• The TBCRC009 phase II trial evaluated single-agent cisplatin or

carboplatin as first- or second-line therapy for metastatic TNBC

• 6 patients (7%) are long-term survivors who achieved durable

responses and remain off all therapy (22+ - 53+ months); all of

these patients are BRCA1/2 WT (5) or unknown (1), and

received platinum therapy as first-line treatment for MBC

All Patients

n=86

BRCA1/2

Positive

n=11

BRCA1/2 WT

n=65

Unknown

n=10

ORR 30.2% 54.6%* 26.2% 30%

Median PFS 88 days 96 days 86 days --

* P=.079 versus BRCA1/2 WT

Isakoff et al., SABCS 2012; abstract PD-09-03

Efficacy of Ixabepilone in Triple-negative Breast Cancer: Subgroup Analyses from Phase II Trials

Ixabepilone + Capecitabine Active inIxabepilone + Capecitabine Active in Triple-Negative Anthracycline-

andTriple-Negative Anthracycline-and Taxane-Resistant MBCTaxane-Resistant MBC

PARP1 inhibition

DNA-repair defect characteristics of BRCA1-related cancers confer

sensitivity to bi-functional alkylating agents, mitomycinC and platinum

drugs

Defective BCRA1 function could be more specifically targeted

– Rationale in triple-negative population:

evidence of deficient BRCA1

in vitro data showing activity of PARP1 inhibitors in BRCA1 null cells

Phase I/II studies ongoing

Other targets for treatment of triple- negative breast cancers

Treatment Directed Against Angiogenesis

Bevacizumab, sunitinib

Rationale in triple-negative population:

highly angiogenic phenotype

responses for heavily pretreated patients during early

phase II trials

Phase II/III studies ongoing

Bevacizumab

Activity, 2 first line trialsPaclitaxel +/- Bevacizumab

(Miller NEJM 2007)

Docetaxel +/- Bevacizumab (AVADO ASCO 2008)

Completed trials, analysis pending

RIBBON I first line

- Docetaxel +/- Bevacizumab

- Anthracycline-based +/- Bevacizumab

- Capecitabine +/- Bevacizumab

RIBBON II second line

- Capecitabine +/- Bevacizumab

Metastatic Breast Cancer Phase III Paclitaxel versus Paclitaxel + Bevacizumab (ECOG 2100)

Treatment targeting EGFR

Cetuximab, gefitinib, erlotinib

Rationale in triple-negative population:

overexpression of EGFR

no evidence of activity to date

Phase II studies ongoing

Other combinations

Gemcitabine + erlotinib Post A et T

ORR 25%

Paclitaxel + cetuximab

Skin relapse EGFR+

TCGA: Molecular Characteristics of TNBC -Provides Fuel for Future Therapeutics

P53 mut 84%

RB1 mut/loss 20%

PIK3CA mut 7%

MYC focal gain 40%

PTEN loss 35%

Global Hypomethylation

INPP4B loss 30%

Aneuploidy and genomic instability

Novel Trials: PI3K inhibition in TNBC

Novel Trials: Targeting the Androgen Receptor in TNBC

Immunotherapy - the breakthrough

KEYNOTE 012 : single agent pembrolizumab 10mg/kg

27 patients with measurable metastatic TNBC

overall response rate 18.5%,

one (3.7%) complete response

four (14.8%) partial responses.

seven patients (25.9%) stable disease

median duration of response ranging from 15 to 40 months

progression-free survival rate at 6 months 23.3% in heavily

pretreated patients

SWOG Proposed Study

R

TNBC Post NAC

PT1C or N+ N=400

Placebo x 1 year

MK3475 x 1 year Anti-PD1 antibody

Primary endpoint:

DFS

A randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes

(>pN1mic) after neoadjuvant chemotherapy

Cancer cell

Cancer cell

Durable response

So, Are We Making Progress in TNBC?

YES

Continued dissection of

complex biology

Incorporation of genetic

Factors in therapeutic choices

(ie, BRCA mutations/PARPi)

Plethora of ongoing clinical trials

(Clinicaltrials.gov ~ 120)

THANK YOU

Hvala mojim uciteljima i

kolegama na svom znanju

koje sam upila od Vas

Aleksandra