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
•
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
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
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
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
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
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
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
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
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)
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