treatment of metastatic negative breast · 2018. 1. 18. · raptor akt1 akt2 akt3 brca1 brca2 atm...
TRANSCRIPT
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Treatment of Metastatic
TRIPLE NEGATIVE BREASTCANCERSRebecca Dent, MD FRCP (Canada)Senior Consultant, Medical Oncology
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Overview of TNBC
Still best way to define in clinical practice!?
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Treatment options and survival vary greatly by breast cancer subtype
Metastatic breast cancer survival: SEER data1,2
TNBC15%
HER2+20%
ER/PR+65%
Chemotherapy+/-BevacizumabPARPi (BRCA)
TrastuzumabT-DM1PertuzumabLapatinibNeratinibChemotherapy
TamoxifenAromatase inhibitorsFulvestrantCDK4/6 inhibitorsmTOR inhibitors
100
80
60
40
20
00 10 20 30 40 50
Surv
ival
(%
)
Survival (months)
Log-rank p
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4
How Can TNBC be Stratified?
Perou C, SABCS 2016
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5
Clinically Targetable Pathways in TNBCN
um
be
r o
f s
am
ple
s w
ith
ab
err
ati
on
s
PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs0
10
20
30
40TSC1
PIK3CA
PTEN
PIK3R1
RICTORRAPTORAKT1AKT2
AKT3
BRCA1
BRCA2ATM
RB1
AURKA
CDNK2A
CCNE1
CCND3
CCND2
CCND1
CDK6CDK4
NF1CRAFBRAF
KRASEGFR
MET
IGF1RKITFGFR1
FGFR2
FGFR4
PI3K/mTOR/AKT inhibitors
Targeted RTK inhibitors
DNA-repair targeting
agents
Cell cycle/mitotic spindle inhibitors
RAF/MEK inhibitors
~90% of all patients had an aberration in at
least one of these pathways
IMMUNOTHERAPY
Balko JM et al. Cancer Discovery 2014.
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Epidemiology
Foulkes WD et al. NEJM 2010.
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HR of Progression & Death: TNBC vs non-TNBC
Dent R, CCR 2007 Liedtke C, JCO 2008
Median Time to Distant RecurrenceTNBC = 2.6 yrsOther = 5 yrsp < 0.0001
0.35
0.30
0.25
0.15
0.10
0.05
0
HR
0.20
0 1 2 3 4 5 6 7 8 9 10
Yrs After First Surgery
Other (290 of 1421)Triple negative (61 of 180)
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Chemosensitivity of TNBC:Post-NACT pCR & Survival
Liedtke C, JCO 2008
CTneoBC, Lancet 2014
1.0
0.9
0.8
0.7
0.6
0.5
0.41
Yrs After Surgery2 3 4 5 6 7
Pro
bab
ility
of
Bei
ng
Aliv
e
pCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC
98%94%
88%
68%
P = .24
P = .0001
von Minckwitz G, JCO 2012
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9Kassam F …Dent et al BCRT 2009
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What are the treatment options for metastatic TNBC in 1st line and beyond?
• Taxane (+/- Bevacizumab)• Nab-paclitaxel• Platinum single agent• Platinum combination (e.g. Gemcitabine/platinum)• Eribulin• Capecitabine (+/- Ixabepilone)• Vinorelbine (+/- Capecitabine)• Anthracycline (including liposomal)• Low dose Cyclophosphamide/MTX or CMF• Oral etoposide• Clinical trials
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If given in the adjuvant setting, a taxane can be re-
used as 1st line therapy, particularly if there has
been at least one year of disease-free survival
(LoE: 1 A) (92%).
HER-2 NEGATIVE MBC
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?
(01)
(00)
(43)
(44)
2.2%
0.0%
97.7%
Total # of votes:
1. YES:
2. NO:
3. ABSTAIN:
TRIPLE NEGATIVE ABC
New statement
For non-BRCA-associated triple negative ABC, there are no data supporting different or specific CT recommendations. Therefore, all CT recommendations for HER-2 negative disease also apply for triple negative ABC.(LoE: 1 A)
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Study 301: Eribulin vs Capecitabine in Previously Treated LABC or MBC
Eribulin Mesylate 1.4 mg/m2
D1,8 q21d(n = 554)
Capecitabine 1250 mg/m2 BDD1-14 q21d
(n = 548)
≤3 prior chemo(≤2 for advanced disease)
prior anthracycline & taxaneN = 1102
Stratified by geographical region, HER2 status
Kaufman PA et al, JCO 2015.
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Study 301: Eribulin vs Capecitabine
Twelves C et al, Breast Cancer (Auckl) 2016.
Overall 0.879 (0.770, 1.003) 15.9 14.5
HER2 status
Positive 0.965 (0.688, 1.355) 14.3 17.1
Negative 0.838 (0.715, 0.983) 15.9 13.5
ER status
Positive 0.897 (0.737, 1.093) 18.2 16.8
Negative 0.779 (0.635, 0.955) 14.4 10.5
Triple negative
Yes 0.702 (0.545, 0.906) 14.4 9.4
No 0.927 (0.795, 1.081) 17.5 16.6
Subgroup HR (95% CI) Eribulin CapecitabineMedian (months)
ITT population
0.2 0.5 1.0 2 5
n=755
n=449
n=284
Favours Eribulin Favours Capecitabine
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TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer
Tutt A et al. SABCS 2014.
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TNT: ORR of Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer
Tutt A et al. SABCS 2014.
0
10
20
30
40
50
60
70
80
90
Res
po
nse
at
Cyc
le 3
or
6 (
%)
All Pts(n = 376)
C→D D→CCrossover*
(All pts; n = 182)
BRCA1/2 Mutation(n = 43)
No BRCA1/2Mutation(n = 273)
31.4%35.6%
22.8%25.6%
P = .44
P = .73
68.0%
33.3%
P = .03
28.1%
36.6%P = .16
CarboplatinDocetaxelCrossover
*Excludes those with no first progression or not starting crossover treatment.
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TNT: Platinum Sensitivity Was Not Associated with Higher HRD Scores in mTNBC
Tutt A et al. SABCS 2014.
19/65(29.2%)
17/49(34.7%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at #3 or #6 (95% CI)
13/34(38.2%)
20/47(42.6%)
0 20 40 60 80 100
Carboplatin
Docetaxel
Percentage with OR at #3 or #6 (95% CI)
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Absolute difference (C-D)-4.4% (95% CI -26.0 to 17.2)
Exact P = 0.82
High HRD score(n = 81)
Low HRD score(n = 114)
Absolute difference (C-D)-5.4% (95% CI -22.7 to 11.9)
Exact P = 0.55
Interaction: randomised treatment & dichotomised HRD score: P = 0.91
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?
(02)
(02)
(39)
(43)
4.6%
4.6%
90.6%
Total # of votes:
1. YES:
2. NO:
3. ABSTAIN:
TRIPLE NEGATIVE ABC
New statement
In triple-negative ABC patients (regardless of BRCA status), previously treated with anthracyclines with or without taxanes in the (neo)adjuvant setting, carboplatin demonstrated comparable efficacy and a more favorable toxicity profile, compared to docetaxel, and is therefore an important treatment option.
(LoE: 1 A)
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?
(04)
(02)
(38)
(44)
9.0%
4.5%
86.3%
Total # of votes:
1. YES:
2. NO:
3. ABSTAIN:
In patients with BRCA-associated triple negative or endocrine-resistant MBC previously treated with an anthracycline with or without a taxane (in the adjuvant and/or metastatic setting), a platinum regimen is the preferred option, if not previously administered and no suitable clinical trial is available.
(LoE: 1 A)
All other treatment recommendations are similar to sporadic MBC.
BRCA-associated MBC
Modified statement
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Olaparib: Phase II Study in gBRCA mut Breast Cancer
Tutt A et al. Lancet 2010.
• Proof-of-concept phase II trial
• Olaparib 400 mg BD group:
– N = 27
– 67% BRCA1
– 50% TNBC
– Median 3 prior lines
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Olaparib versus physicians’ choice: the phase III OLYMPIAD study
Robson et al, New Engl J Med 2017
Olaparib
300 mg bd
Chemotherapy
TPC
163 (79.5) 71 (73.2)
7.0 4.2HR 0.58
95% CI 0.43 to 0.80; P=0.0009
Primary end point: centrally-evaluated PFS
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Clinical Practice?
• Not clear how it compares to platinum or if
efficacy similar in platinum resistant patients
• Not recommended in unselected TNBC
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TNBC ER positive
Mutation rate higher in TNBC compared to other subtypes
Luminal ALuminal BHER2BasalNormal
SynonymousNonsynonymous
10864
02
No
. mu
tati
on
s/M
b
Somatic mutations in breast cancer subtypes
Are All Cancers Equally Suitable for Immunotherapy?
Banerji S, et al. Nature. 2012;486(7403):405-409.
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Immune Checkpoint Inhibitors in mTNBC
Nanda et al, JCO 2016; Schmid et al, AACR 2017; Dirix et al, SABCS 2015
Pembrolizumab(n = 32)
Atezolizumab (n = 71)
Avelumab(n=58 /9)
Target PD-1 PD-L1 PD-L1
Tumour PD-L1 ≥1% (58%+) ≥5% All / ≥1%
ORR 18.5% 13% 8.6% / 44.4%
SD 25.9% 18% 22.4%
• Durable responses in heavily pre-treated pts
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Pembrolizumab Antitumor Activity in Previously Treated and Previously Untreated mTNBC
Cohort A (N = 170): Previously Treated,
Regardless of PD-L1 Expression
Cohort B (N = 52)1: Previously Untreated,
PD-L1 Positive
0
4
8
12
16
20
24
28
32
36
40
OR
R, %
0
4
8
12
16
20
24
28
32
36
40
OR
R, %
23.1%
Complete response
Partial response
Total PD-L1Positive
PD-L1Negative
Total(All PD-L1 Positive)
Stable disease≥24 wk
4.7%
9.5%7.6%
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Combination Immune-and Chemotherapy in
TNBCNab-Paclitaxel + anti-PD-L1 (atezolizumab)
Adams S, SABCS 2015; Tolaney, S SABCS 2016, ESMO 2017
2nd/≥3rd line Patients
1st line Patients
All1st line
(n=17)
2nd/3rd L
(n=18)
ORR 34.4% 41.2% 27.3%
CBR 40.6% 47.1% 36.4%
Eribulin + anti-PD-1 (pembrolizumab)
Independent
of PD-L1
status
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Basal immune activated
Basal immune suppressed
Mesenchymal
Luminal AR
TNBC: Gene expression subtypes (Baylor)
Heterogeneity of TNBC and Immunotherapy Strategies
Basal-like
Luminal
Inflamed
Uninflamed
Single agent immune therapy (eg, PD-1; PD-L1)
Combination immune therapy (eg, PD-1/PD-L1;
CTLA4)
Modify antigens?
Adapted from: Burstein MD, et al. Clin Cancer Res. 2015;21(7):1688-1698.
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Clinical Practice
• No evidence of immune check point inhibitors
outside of clinical trials (many ongoing!!!)
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Randomised, non-comparator, international, AZ Investigator Initiated TrialAnd Duke-Singapore/Duke-USA Collaborative Grant for Translational Studies
DORA Study Design: A Randomized Phase 2 Maintenance study of PARP Inhibition alone vs PARP Inhibition + Anti-PD-L1 therapy
Olaparib 300mg bid daily
1° Endpoint = PFS
Olaparib 300mg bid daily
Eligibility:
• Mets TNBC
• Response after 4 cycles of platinum chemo as 1st or 2nd line therapy
R
A
N
D
O
M
I
Z
E
D
Durvalumab 1500mg q 4 weeklyCT q8 weeks
R Dent, T Tan and K Blackwell
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Targeting the Androgen Receptor (AR) in TNBC
Bicalutamide Enzalutamide
RR (%) 0 7.7
CBR (%) 19 34.6
Enzalutamide
MDV3100-11. Cortes J et al, IMPAKT 2015.TBCRC011. Gulpa A et al, CCR 2013.
AR-Driven Biology in TNBC using Gene Expression Profiling Assay
Parker et al, ASCO 2015
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Is AR PREDICT picking out good prognosis
TNBC?Progression-Free Survival
ITT Population 100
80
60
40
20
0
Pro
gre
ssio
n-F
ree
Su
rviv
al
(%)
0 8 16 24 3341 49 6164 80 85Weeks
Subpopulation 0–1 Prior Regimens100
80
60
40
20
0
Pro
gre
ssio
n-F
ree
Su
rviv
al (%
)
0 8 16 24 33 41 49 6164 80 85Weeks
ITT Population100
80
60
40
20
0
Ove
rall
Su
rviv
al (%
)
Weeks0 8 16 24 33 41 49 6164 10285
Subpopulation 0–1 Prior Regimens100
80
60
40
20
0
Ove
rall
Su
rviv
al (%
)
Weeks0 8 16 24 33 41 49 6164 10285
Dx+ (n = 26)mPFS 32.3 weeks(95% CI: 14.7, 60.3)
Dx− (n = 36)mPFS 8.3 weeks(95% CI: 7.1, 16.1)
Dx+ (n = 56) mPFS 16.1 weeks(95% CI: 10.4, 27.4)
Dx− (n = 62)mPFS 8.1 weeks(95% CI: 7.4, 12.6)
Dx+ (n = 56)
mOS 21.3 months(95% CI: 12.9, 21.3)
Dx+ (n = 28) mOS NYR(95% CI: 14.0, NYR)
Dx− (n = 62)
mOS 7.5 months(95% CI: 4.8, 11.2)
Dx− (n = 37)
mOS 10.1 months(95% CI: 6.6, NYR)
Overall Survival
Dx+ Dx–
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Clinical Practice?
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LOTUS: AKT Inhibition in mTNBC
Stratified by
• (Neo)adjuvant chemo (yes vs no)
• Chemo-free interval (≤12 vs >12 mo vs no prior)
• Tumour PTEN status (H-score 0 vs 1-150 vs >150, by Targos IHC)
• LABC/MBC• No prior systemic therapy for
ABC/MBC• Archival or newly obtained tumor
tissue for central PTEN assessment• Chemo-free interval ≥6 mo
N = 124
R1:1
Paclitaxel 80 mg/m2 D1, 8, & 15 + Ipatasertib 400 mg OD D1-21 q28d
Paclitaxel 80 mg/m2 D1, 8, & 15 + placebo D1-21 q28d
Treatment until PD, intolerable toxicity, or withdrawal of consent
Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017
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LOTUS: AKT Inhibition in MBC
Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017
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LOTUS: AKT Inhibition in MBC
PFS
(%
)
PIK3CA/AKT1/PTEN Altered* Ipat + Pac(n = 26)
Pbo + Pac(n = 16)
PFS events, n (%) 12 (46) 13 (81)
mPFS, mos (IQR) 9.0 (3.7-NE) 4.9 (1.9-6.3)
Unstratified HR (90% CI) 0.44 (0.22-0.87)
100
80
60
40
20
0
Ipatasertib + Paclitaxel (n = 26)Placebo + Paclitaxel (n = 16)
0 2 4 6 8 10 12 14 16 18Mos
Dent R ASCO 2017; Kim SB et al, Lancet Oncol 2017
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Cell Surface Markers: Targets for Antibody-Drug Conjugates
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Glembatumab (gpNMB) vedotin (CDX-011):
Antibody Drug Conjugates
ParameterHigh gpNMB
Expression
Triple Negative &
High gpNMB
Expression
CDX-011
n=25
IC
n=8
CDX-011
n=12
IC
N=4
Response 32% 13% 33% 0%
Disease Control Rate 64% 38% 75% 25%
Median PFS (months) 2.7 1.5 3.0 1.5
p=0.14 p=0.008
Median OS (months) 10.0 5.7 10.0 5.5
p=0.18 p=0.003
CR011 Ab MMAE
GPNMB
Cell membrane
CDX-011 binds to GPNMB
on cancer cells
vc Linker
CDX-011 is internalized
and the linker is cleaved
by endosomal enzymes
Cleavage
Free MMAE inhibits
tubulin polymerization,
leading to cell death
Tubulin inhibition
Binding
Rose AA, et al. CCR 2010
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METRIC: Ongoing Phase III Trial
Pts with mTNBCoverexpressing gpNMB
(≥ 25% tumour cells by IHC)N = 300 Capecitabine
1250 mg/m2 BDD1-14 q21d
Glembatumumab vedotin1.88 mg/kg IV
D1 q21d
Treat until unacceptable toxicity or PD
Tumour assessments (6w intervals x 6 mo; 9w intervals thereafter) until documented PD
Survival follow-up (12w intervals)
RA
ND
OM
ISE
2:1
• Study at approx 100-150 sites in US, Canada and Australia
• Primary endpoint: PFS
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Sacituzumab Govitecan (IMMU-132)
• Humanised IgG Antibody against Trop-2
• Conjugated with a pH-sensitive linker to SN-38
• Heavily pretreated TNBC
• Median number of prior therapies = 4 (1-11)
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Sacituzumab Govitecan: FDA Breakthrough Designation
Bardia A et al. JCO 2017.
ORR 30%
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Case AH
• 38F previously well, nulliparous, no family
history
• Sep 2011
– 3.5cm, Grade 3, 2 LN +, TNBC
– BRCA negative
– Treated with AC-weekly paclitaxel completed Jan
2012
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AH cont…
• 2 years after completion of adjuvant
chemotherapy, presents with…
– Cough, SOBOE, nausea and headaches
– CT CAP – multiple pulmonary nodules consistent with
metastases, left supraclavicular LN and mediastinal
LN
– CT brain – multiple CNS metastases
• Biopsy of supraclavicular LN = TNBC
• Treated with Whole brain radiation treatment
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CNS & Lung metastases
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Question 1:
What systemic therapy would you offer this patient? (note: recent CNS mets post WBRT, ineligible for trial – received adjuvant AC-T 2 years ago)
1. Taxane single agent
2. Eribulin
3. Capecitabine +/- Navelbine
4. Platinum alone
5. Platinum combo (ie. Carbo/Gem)
6. Other
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AH cont…
Patient treated with 3 cycles of carbo/gem with
resolution of cough and SOB and first restaging
scan shows response
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46
After 3 cycles Carbo/Gem
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47
After 6 cycles, significant
myelosuppression, pt requesting
break…
• Chemo break
• Continue carbo/gem until max response or
toxicity
• Continue carboplatin only
• Switch to maintenance oral cyclo/MTX
• Switch to maintenance oral capecitabine
• Switch to other chemo
• Palliative care
-
Usually each regimen (except anthracyclines) should be given until
progression of disease or unacceptable toxicity. What is considered
unacceptable should be defined together with the patient.
(LoE: 1 B) (72%)
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AH cont…
• Unfortunately after 6 cycles, by the time patient
had restaging scans - new onset cough and
mild hemoptysis (i.e. patient didn’t get
opportunity to make decision)
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50
AH cont…
• What will you offer her?
1. Eribulin
2. Capecitabine +/- Vinorelbine
3. Taxane
4. Liposomal doxorubicin
5. CMF (oral or IV)
6. Palliative Care
7. Other
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AH cont…
• After cycle 1 clinical improvement with resolution
of hemoptysis and cough
• After cycle 3, new onset fever, worsening cough
and hemoptysis
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AH cont…
• Patient worked up for pembrolizumab trial,
biopsy sent for central review, ER 30% +, thus
ineligible for trial
• And Asx Progression of
Brain Metastases
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AH cont…
• Asymptomatic brain metastases – minimal
burden of disease, opted not to treat
• What would you offer her now?
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In Practice: Management of Metastatic TNBC
• No standard chemotherapy• mOS remains 12mo – get pall care early!• PARP inhibitors show very promising results await
approval for germline BRCA• Immunotherapy
– Await results of ongoing trials– Single agent vs combination therapy– Need for predictive signature
• PIK3CA/mTOR/AKT pathway is intriguing• Await Phase III data on ADCs• Refer tor trials early!!
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