TNBC: What’s new… Déjà vu All Over Again? · What’s new in 2016? 1. Prevention of TNBC 2....
Transcript of TNBC: What’s new… Déjà vu All Over Again? · What’s new in 2016? 1. Prevention of TNBC 2....
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TNBC: What’s new…Déjà vu All Over Again?
Lucy R. Langer, MD MSHSCompass Oncology - SABCS 2016 Review
February 21, 2017
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The problem with TNBC…
1. Generally more aggressive 2. ONLY chemotherapy3. No other proven targets
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In 2014…
1.Subtyping TNBC2.Platinums3.PARP-inhibitors4.Clinical Trials
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & a brief word on the PD-1 inhibitors
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Prevention
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Prevention
HER-2 Strategies
• DCIS trastuzumab trials• Lapatinib in mouse, now
being evaluated in women• VADIS trial: HER2 peptide
vaccineDHEA: omega-3 fatty acids
statins
PolyphenonE(active agent in green tea)
retinoids
Metformin
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & a brief word on the PD-1 inhibitors
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Triple Negative Subtyping
70-80% Basal-like20-30% Luminal/AR type
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & a brief word on the PD-1 inhibitors
6. Neoadjuvant and post-neoadjuvant
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Luminal/AR type TNBC
Enriched in hormonal pathways, like the Androgen Receptor
HER2-enriched, even though HER2 ‘negative’
Bicalutamide, a prostate drug, no benefit
Enzalutamide, some benefit predicted by Predict-AR
Lapatinib shows possible benefit
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & a brief word on the PD-1 inhibitors
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Basal-Like TNBC
Most BRCA1 breast cancers are Basal-Like
Basal-Like breast cancers have DNA repair defects like BRCA1
Carboplatin shows some promise in BRCA+ cancers
Parp inhibitor Olaparib shows effect in BRCA+ cancer
HRD test not predictive of BRCA-ness
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & a brief word on the PD-1 inhibitors
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What about PD-1?
10-15% of TNBC falls into the ‘immunomodu-latory’ subtype
Enriched immune processes, TILs
Higher expression of PDL-1
Atezolizumab(Tecentriq) + nab-paclitaxel
PembrolizumabAwaiting RCTs
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Conclusions… TNBC subtyping tools are
nearly ready
TNBC is chemo-sensitive, biomarkers such as Basal/non, TILs, and HRD signature are emerging
Many promising new drugs exist and are being tested (AR blockers, lapatinib, immune modulators, etc)
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What’s new in 2016?
1. Prevention of TNBC2. More on TNBC
subtyping3. AR, a potential new
target4. “BRCA”-ness5. Tumor infiltrating
lymphocytes & A brief word on the PD-1 inhibitors
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Neoadjuvant therapy in TNBC• GeparSixto: Phase II chemo/bev +/- carbo
- 36.9% vs 53.2% pCR, slight incr DFS• CALGB 40603: Phase II chemo+/-bev+/- carbo
- 41% vs. 64% pCR, no DFS or OS benefit at 5 years• What increase in pCR is needed to translate into DFS or OS?
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Post-neoadjuvant treatment trialsJapan: CREATE-X trial
- Capecitabine vs. obs/endocrine- Benefit appears limited to TNBC, requires HIGH chemo doses
• PAM50 Analysis basal-like has worse prognosis in non-pCR group
ECOG-ACRIN EA1131- Phase III, platinum vs. obs in Basal TNBC
SWOG 1418- Phase III pembrolizumab for TNBC post-neo or adjuvant
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CREATE-X: Study Design
Preplanned interim analysis of a randomized, open-label phase III study[1]
Primary endpoint: DFS
Secondary endpoints: OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness
Pts 20-74 yrs of age with stage I-IIIB HER2- BC and
residual disease (non-pCR, N+) after neoadjuvant
chemotherapy* and surgery;ECOG PS 0 or 1;
no previous oral fluoropyrimidines(N = 910)†
Capecitabine2500 mg/m²/day PO Days 1-14
Q3W for 8 cycles‡
Hormonal therapy if ER/PgR+(n = 455)†
Hormonal therapy if ER/PgR+No further therapy if ER/PgR-
(n = 455)†
Slide credit: clinicaloptions.com
Stratified by ER status, age, neoadjuvantchemotherapy, use of 5-FU, institution, node status
*Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide.†25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria.‡IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles.[2]
1. Toi M, et al. SABCS 2015. Abstract S1-07.2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.
Wk 24
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CREATE-X: 5-Yr EfficacyCapecitabine achieved significantly higher 5-yr DFS and OS in HER2-
BC pts with residual disease
Slide credit: clinicaloptions.com
Characteristic, %
Capecitabine
(n = 440)
No Capecitabin
e(n = 445)
HR (95% CI) P Value
5-yr DFS 74.1 67.7 0.70 (0.53-0.93) .00524
5-yr OS 89.2 83.9 0.60 (0.40-0.92) < .01
Toi M, et al. SABCS 2015. Abstract S1-07.
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CREATE-X: DFS by Subgroup
Slide credit: clinicaloptions.comToi M, et al. SABCS 2015. Abstract S1-07.
Subgroup HR(95% CI)
Total (N = 885) 0.70 (0.53-0.93)
Age < 50 yrs (n = 531) ≥ 50 yrs (n = 354)
0.72 (0.50-1.03)0.68 (0.45-1.04)
Hormone receptor status Positive (n = 561) Negative (n = 296)
0.84 (0.57-1.23)0.58 (0.39-0.87)
Node stage ypN0 (n = 345) ypN1 (n = 339) ypN2 or 3 (n = 199)
0.88 (0.48-1.62)0.54 (0.36-0.83)0.82 (0.52-1.29)
Path grade by NAC 0-1b (n = 482) 2-3 (n = 385)
0.63 (0.45-0.88)0.84 (0.52-1.34)
Subgroup HR(95% CI)
Total (N = 885) 0.70 (0.53-0.93)
Taxane-containing NAC Yes (n = 849) No (n = 36)
0.70 (0.53-0.93)0.87 (0.12-6.24)
5-FU–containing NAC Yes (n = 529) No (n = 356)
0.74 (0.52-1.04)0.65 (0.42-1.02)
Nationality Japanese (n = 599) Korean (n = 286)
0.74 (0.53-1.02)0.63 (0.37-1.05)