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
The problem with TNBC…
1. Generally more aggressive 2. ONLY chemotherapy3. No other proven targets
In 2014…
1.Subtyping TNBC2.Platinums3.PARP-inhibitors4.Clinical Trials
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
Prevention
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
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
Triple Negative Subtyping
70-80% Basal-like20-30% Luminal/AR type
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
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
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
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
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
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
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)
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
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?
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
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
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.
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)