debu tripathy, md professor of medicine university of southern california
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Challenges in Breast Cancer Management : Navigating the Heterogeneity of Triple-Negative Breast Cancer without getting lost in the details. Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center. - PowerPoint PPT PresentationTRANSCRIPT
Debu Tripathy, MDProfessor of MedicineUniversity of Southern CaliforniaNorris Comprehensive Cancer Center
Challenges in Breast Cancer Management:
Navigating the Heterogeneity of Triple-Negative Breast
Cancerwithout getting lost in the details
Triple Negative is typically A-E“Basal” also may include F-H
High grade
ER- PR - HER-
p53Mut
HighKi-67 CK14 p63
Basal-like Breast Cancer
• Unique subtype seen in gene array analyses accounting for 10-15% of all breast cancer; 85% of BRCA-/- breast cancer
• ER-, PgR-, and HER2- • High grade• Scant DCIS component• Other characteristics
o Mutations in p53 tumor suppressor geneo EGFR + (approximately 50%)o C-kit +o CK 5/6, 14, 17 + (basal cytokeratins)o High Ki-67
• High degree of genomic instability
Basal subtype1. 10-15% of tumors2. ER/PR/HER2-negative3. very proliferative4. EGFR, c-kit, c-myc +5. includes BRCA1 mutations
HER2+ subtype1. 15-20% of tumors2. prognostic/predictive2. proliferation3. two types (ER -/+)
Luminal A and B (ER+)1. continuum 2. prognostic/predictive3. ER-GATA3-HNF3a-XBP14. proliferation (mutant p53)5. cyclin D1 and BCL2 +
Ki-67, STK6, Survivin, Cyclin B1 and MYBL2
Gene Expression Profiling Reveals Distinct Clusters
Sorlie T et al. PNAS 2003
BRCA1-Tumors Are Basal-like
Sorlie T, PNAS, 2003
p <0.0001
p <0.001
Sorlie T et al. PNAS 2003
What Should We Actually Be Doing for TNBC in 2014 ??
All Patients• Genetic counseling/testing for age <60 or positive family
history• Use standard evidence-based chemotherapyEarly Stage
• Increase estimation of recurrence risk and benefit from chemo
• No role (yet) for adding or extending therapy for higher risk or residual disease after NAC
Advanced Stage• Consider platinums earlier on (beware they may
exclude from clinical trials)• Clinical trials (PARP, PI3K, Stem cell inhibitors)
TNBC isHeterogeneous
Prat A, et al, Molec Oncol 2010
Prat A, et al, The Oncologist, 2013
Heterogeneity of Triple Negative Breast Cancer
Otto Metzger-Filho O et al., 2012
TN Cancers and Chromosomal Anomalies
Stephens PJ et al. Nature 2009
Cisplatin PaclitaxelDoxorubicin
BRCA1-Deficient Cells May Be Hypersensitive to Cisplatin
Tassone et al BJC 2003
TNBC Responses to Platinum Agents
Baselga J et al. ESMO 2010; O’Shaughnessy J et al. SABCS 2007; Carey L, et al ASCO 2008; Isakoff J, et al. ASCO 2011; Byrski T et al. JCO 2010; Gronwald, J, et al. ASCO 2009; Silver DP, et al. JCO 2010, Alba E, et al. BCRT 2012
Neo Adjuvant Population N pCR Rate RefCMF
BRCA 1 Mutation (retrospective)
14 7%
ByrskiAC 23 22%FAC 28 21%AT 25 8%Cisplatin 12 83%Cisplatin BRCA1 Mut 25 72% GronwaldCisplatin TNBC 28 21% SilverEC D
TNBC Basal46 35%
AlbaEC DP 48 30%
Stage IV Population ORR RefControl arm BALI-1 (CDDP) TNBC 10% BaselgaControl arm Phase III iniparib (Gem/carbo) TNBC 30% O’Shaughnessy
TBCRC 001 (Cetuximab/Carbo) TNBC 17% CareyTBCRC 009 (Carboplatin or Cisplatin) TNBC 30% Isakoff
Efficacy of Ixabepilone/Capecitabine in TN Metastatic Breast Cancer Resistant to
Anthracyclines and Taxanes
Rugo et al. SABCS 2007, Abstract 6069
Receptor Subgroup
All Patients ER/PR/HER2 Negative
Non-Triple-Negative HER2+ ER+
I + Cn=375
Cn=377
I + Cn=91
Cn=96
I + C n=284
Cn=281
I + Cn=59
Cn=53
I + Cn=173
Cn=178
ORR 35% 14% 27% 9% 37% 16% 31% 8% 40% 19%
Median PFS 5.8 mo 4.2 mo 4.1 mo 2.1 mo 7.1 mo 5.0 mo 5.3 mo 4.1 mo 7.6 mo 5.7 mo
HR 0.75 0.68 0.74 0.69 0.81
Eribulin vs. Capecitabine OS HR by Subsets
Kaufman P, et al. SABCS 2012, Abstr S6-6
E2100: Paclitaxel ± Bevacizumab as First-line Therapy in MBC (HER2-)
HR = 0.60 (0.51-0.70)Log Rank Test p<0.001
Pac.+ Bev. 11.8 monthsPaclitaxel 5.9 months
Miller K et al. N Engl J Med. 2007
Prog
ress
ion-
free
Sur
viva
l (%
)
Month
80
6
20
12
40
100
60
00 18 24 30 36 42 48 54
Paclitaxel
Paclitaxel plus bevacizumab
Subgroups: PFS HR
ER-/PR-ER+/PR-ER+/PR+Overall
Randomized Trials of Bevacizumab in TNBCStage IV Trial Regimen DFS HR (95% CI)ECOG 2100 Weekly paclitaxel + bevacizumab 0.53 (0.41-0.70)AVADO Docetaxel + bevacizumab 0.68 (NR~1.00)RIBBON-1 Chemotherapy + bevacizumab 0.72 (0.49-1.06
OS HR (95% CI)Meta-analysis 3 first-line studies chemo + bevacizumab
0.96 (0.79-1.16)
TNBC subsetRIBBON II
chemo + bevacizumab
HR (95% CI)PFS 0.494(0.33–0.74)OS 0.624(0.39–1.007)
O’Shaughnessy J et al, ASCO 2011;Brufsky A, et al. BCRT 2012
EGFR is Expressed in 30-50% of TNBCRandomized Trials Testing Cetuximab in TNBC
Carey L, et al JCO 2012; O’Shaughnessy J et al. SABCS 2007; Baselga J et al. JCO 2013
TBCRC 001N=102
USONN=138
BALI-1N=173
Endpoint Cetux Cetux + Carbo
Irino +Carbo
Irino/ Carbo + Cetux
Cisplatin Cisplatin + Cetux
ORR (%) 6 17 30 49 11 20
CBR (%) 9 31 NR NR
PFS (mo) 1.4 2.1 5.1 4.7 1.5 3.7
OS (mo) 12.3 15.5
Replication Lesions• Base excision repair
PARP1
Mechanisms of DNA Repair
Single Strand Breaks• Nucleotide excision
repair• Base excision repair
PARP1
Double Strand Breaks• Non-homologous end-joining• Homologous recombination
BRCA1/BRCA2• Fanconi anemia pathway• Endonuclease-mediated repair
DNA DAMAGE
Cell Death
Environmental factors(UV, radiation, chemicals)
Normal physiology(DNA replication, ROS)
MAJOR DNA REPAIRPATHWAYS
Chemotherapy(alkylating agents, antimetabolites)
Radiotherapy
Helleday et al. Nature Reviews. 2008
x
DNA Adducts/Base Damage • Alkyltransferases• Nucleotide excision repair• Base excision repair
PARP1x
• Mostly low grade toxicities• Grade III/IV toxicities (400 mg
cohort)– Fatigue 15%– Nausea 19%– Vomiting 11%
• 30% dose interruptions or reductions
Tutt A et al. Lancet 2010
400 mg bidN=27
100 mg bidN=27
ORR 11 (41%) 6 (22%)
CR 1 (4%) 0 (0)
PR 10 (37%) 6 (22%)
PFS (mo)
5.7 (4.6 – 7.4)
3.8 (1.9-5.5)
A Phase II trial of the Oral PARPInhibitor Olaparib in BRCA Deficient
Advanced Breast Cancer
BRCA 1BRCA 2
Phase II Veliparib (ABT-888) + Temozolamide in TNBC
-80-70-60-50-40-30-20-100
102030405060708090100
* * * * *
* = BRCA carriers
% c
hang
e
p-value = 0.0042
Noncarriers: PFS = 1.8 Mo
BRCA carriers: Median PFS = 5.5 Mo
Isakoff S, et al, ASCO 2011
Response rate = 7% - ONLY in BRCA1/2+ (RR 38%)
• Phase I dose escalation. Mixed tumor types.
• 7/35 partial responses– 6/13 BRCA1/2+
Phase I Veliparib + oral Cyclophosphamide
*
Veliparib (ABT-888) + Chemotherapy Combinations
Kummar, et al, Clin Cancer Res 2012
HRD Score Distribution – A New Measure of “BRCAness”
Neoadjuvant gemcitabine, carboplatin and iniparib
HRD score
Non-responders
BRCA1/2 intact responders
BRCA1/2 mutant responders
HRD score ≥ 10 in 16/19 BRCA1/2 mutants
No difference in mean HRD scores in BRCA1/2 mutant vs. intact responders
Telli ML, et al. SABCS 2012
The PI3K/Akt/mTOR pathway and Breast Cancer
Ras
4EBP1
Raf
Erk
Rsk
PI3K
TORC1
S6K
Rheb
S6
PIP3
Tuberin
PTEN
TORC2MEKAkt PDK1
HER2/HER3Agent Target
BYL719 PI3Kα
INK-1117 PI3Kα
GDC-0032 PI3Kα,δ,ϒ
XL-147 Pan-PI3K
BKM120 Pan-PI3K
GDC-0941 Pan-PI3K
PKI-587 Pan-PI3K
XL-765 PI3K / mTOR
BEZ-235 PI3K / mTOR
PF-4691502 PI3K / mTOR
Everolimus mTOR (mTORC1)
AZD8055 mTOR (mTORC1/2)
INK 128 mTOR (mTORC1/2)
MK-2206 AKT1,2,3
GDC-0068 AKT
Phase I Trial of mTOR Inhibitor BKM120
Bendell JC, et al. JCO 2012
TNBC
TBCRC 011: Bicalutamide in AR+ TNBC
Consented for AR testing
(n=452)
Screened for AR expression
(n=424)
AR(+)(n=51)
On study (n=28)
Eligible on study (n=26)
Ineligible for testing(n=28)
AR(-)(n=373)
Ineligible for therapy(n=8)
Eligible for therapy; trial closed to accrual
(n=15)Ineligible post therapy
(n=2)
Bicalutamide 50 mg daily• No Responses• Clinical Benefit
Rate = 5/26 evaluable (19%) (95% CI 7-39%)
Gucalp A, et al. Clin Cancer Res 2013
12%
Also in testing: enzalutamide, abiraterone
Tigatuzumab (Anti-DR5) for TNBCDeath Receptor DR5on 2LMP TNBC Cells
In Phase II trial with nab-paclitaxelfor advanced TNBC
Buchsbaum DJ , et al. Clin Cancer Res 2003
Triple-Negative Breast Cancers: Potential Therapeutic Targets
Cell Cycle
Transcriptional Control
MAP Kinase Pathway Akt Pathway
IGF-1R EGFR
Tyrosine Kinase
C-KIT tyrosine kinase
Cell DeathModified from:
Cleator S et al. Lancet Oncol 2006
DNA Repair pathways
Anti-Angiogenesis
Cetuximab
Dasatinib Sunitinib
PARP inhibitors; Trabectedin
Bevacizumab
Wnt, NOTCH inhibitors
Src inhibitors
PI3K, Akt, MEK inhibitors
HDAC, DNMT inhibitors
Multiple potential targets?• Basal-like 1 and 2 – DNA damage response genes, growth factor
paths (EGFR)• Immunomodulatory - ? Immune approaches• Mesenchymal and mesenchymal / stem cell – PI3K/mTOR pathway• LAR – androgen receptor signaling
Targeting Heterogeneity of TNBC
Lehmann BD, et al, JCI 2011
Prat et al, Molec Oncol 2010
Triple Negative Breast Cancer is Heterogeneous and Includes a “HER2-like” Subset
Reverse Phase Protein Array Reveals HER2 signaling in TNBC (I-SPY1)
Wulfkuhleet JD al, Clin Cancer Res 2012
HER2 Somatic Mutations in 25 Patients
• 8 publications, total of 1499 patients (estimated incidence of 1.7%)• 20% of mutations at AA 309 or 310• 80% of mutations from 755-781
Bose R, et al. Nature Discovery, 2013
Bose R, et al. Nature Discovery, 2013
Bose R, et al. Nature Discovery, 2013
HER2 Mutations Differentially Activate HER2 Signaling
Bose R, et al. Nature Discovery, 2013
Colony formation of HER2 Mutants inhibited by HER1/2 Kinase Inhibitor Neratinib
Bose R, et al.
CancerDiscovery
2013
Multi-center Phase IITrial withNeratinib Initiated
TNBC: Where are We Going?
• Risk-based stratification for additional chemotherapy or radiotherapy
• Testing of post (neo) adjuvant of platinum agents and PARP inhibitors
• Sequencing and target-drive therapy (eg. PI3K inhibitors, JAK2 inhibitors)
• Use of gene profiling to identify and treat variantso Androgen blockade for AR expressorso HER2 TKIs for HER2 mutationso Stem cell pathways inhibitor for Notch/Wnt
upregulation