triple negative breast cancer -neoadjuvant and...
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Triple negative breast cancer
-neoadjuvant and adjuvant systemic therapy
Sung-Bae Kim, MD, PhD
Department of Oncology
Asan Medical Center
University of Ulsan College of Medicine
Seoul, Korea
DISCLOSURE SLIDE
Nothing to declare
Outline
• Preferred chemotherapy regimen
• Platinum
• Capecitabine in non-pCR
• Practical issues
-impact of delaying adjuvant CT in TNBC
-small tumor
-TIL
Triple negative breast cancer
• TNBC = ER (0), PgR (0) and HER2 (IHC 0-1+ or FISH -)
• TNBC comprises approximately 15-20% of incident breast cancers
• Generally exhibit poor clinical outcomes
• BRCA mutations in nearly 20% of TNBC patients (vs 5% in non-
TNBC)
– 16% BRCA1
– 4% BRCA2
• No targeted treatment available for non-BRCA mutated TNBC
• Main treatment remains chemotherapy
Clinical Characteristics of TNBC
• Relapse pattern[1]
• Short disease-free interval
• Increase in visceral mets
• Differs from luminal:
• CNS mets in 46% of cases
1 2 3 4 5 6 7 8 9 10
0.35
0.30
0.25
0.15
0.10
0.05
0
0.20
An
nu
al
Hazard
Rate
0
Yrs After First Surgery
Other (290 of 1421)
Triple negative (61 of 180)
1. Lin NU, et al. Cancer. 2008;113:2638-2645. 2. Liedtke C, et al. J Clin Oncol.
2008;26:1275-1281. 3. Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.
Rate of
Recurrence[2] n Bone, %Soft
Tissue, %Viscera, %
TNBC 79 13 13 74
ER+ 123 39 7 54
HER2+ 78 7 12 81
Distant Recurrence Following Surgery[3]
TNBCs are heterogenous
• IDC NOS, high-grade
• ILC high-grade, pleomorphic
• Metaplastic, high-grade Poor Prognosis
• Myoepithelial carcinoma
• High-grade (oat-cell) neuroendocrine
• Apocrine
• Medullary
• Adenoid-cystic
• Metaplastic, low-grade Good Prognosis
-low grade adenosquamous
• Firbromatosis -like
BEATRICE TRIAL• ~2600 early TNBC received adjuvant CT
• median FU 56Mo: 7% died
Cameron et al. Lancet Oncol 2013 Molinero et al. SABCS 2015
Adjuvant Chemotherapy Options for HER2-Negative Breast Cancer Warranting Chemotherapy Treatment
JAMA Oncol. 2016;2(11):1399-1400
Triple-negative BC
• Adjuvant therapy
• Neo-adjuvant therapy
Role of Anthracycline: Joint Analysis of the ABC (Anthracyclines in early Breast Cancer) Trials
Blum JL Clin Oncol 34, 2016 abstr# 1000
Joint Analysis of the ABC (Anthracyclines in early Breast Cancer) Trials
Blum JL Clin Oncol 34, 2016 abstract # 1000
CALGB 9344: AC4 Paclitaxel
Hayes D et al. N Engl J Med 2007;357:1496-1506
It’s All Relative:
Taxanes are
Effective in
Double
Negative
NSABP B-30: AC4→T4 vs TAC4 vs AT4
Swain SM et al. N Engl J Med 2010;362:2053-2065
8Y OS
AC→T 83%
AT4 79%
TAC4 79%
8Y DFS
AC→T 74 %
AT4 69%
TAC4 69%
Standard adjuvant regimen:
A/EC x 4 q 21→weekly paclitaxel x 12
Sparano et al. JCO 2015
New standard adjuvant regimen?
EC x 4 q 2wks→Paclitaxel x 4 q 2wks
Del Mastro et al. Lancet 2015
TNBC patients
Gold standard adjuvant regimen:
EC q2wks x4→weekly paclitaxel x 12
Budd et al. JCO2015
pCR as prognostic factor
Neoadjuvant Cisplatin (CDDP) in TNBC
• N = 28, stage II/III triple negative
• Cisplatin 75 mg/m2 q3w x 4 cycles
Silver DP et al. J Clin Oncol 28 (7): 1145-53, 2010
Pathologic CR 6 (22%)
Clinical CR 4 (14%)
Clinical PR 10 (36%)
Stable Disease 5 (17%)
Not bad for a single agent
•15% expected for AC
•22% AC-T (B27)
• N = 30, stage II/III triple negative
• ECisFpaclitaxel
• 43% in-breast pCR rate
Torrisi et al, Cancer Chemother Pharmacol, 2007
GeparSixto
CALGB 40603 – randomised phase II trial
Clinical
stage II-III
TN
Primary EP – pCR in breast (trial did not mandate surgery of axilla)
*Gcsf primary prophylaxis for ddAC cycles Sikov et al, SABCS 2013
pCR (carboplatin)
pCR breast pCR breast/axilla
OR 1.76 (p=0.0018) OR 1.71 (p=0.0029)
Sikov et al, SABCS 2013
The Role of Platinum in TNBC
N pCR in Carbo arm
pCR in Control arm
P-value
CALGB 40603
443 54% 41% P=0.003
GeparSixto 315 59% 38% P<0.05
I-SPY 2 116 52% 26% 90%probability
Pusztai L. SABCS 2013
Disease Free SurvivalGeparSixto (Med FU 35Mo) vs CALGB 40603 (Med FU 39Mo)
Differences GeparSixto Trial CALGB 40603 Trial
pCR• Without carbo• With carbo
36.9%53.2%
41%54%
EFS• Without carbo• With carbo• HR
76.1%85.8%
0.56 (0.33-0.96)
71.6%76.5%
0.84 (0.58-1.22)
Pts prognostic factors cT1 26%cN0 60%
cT1 11%cN0 42%
Control CT• Anthra• Taxane• Beva
Concurrent360 x 18 wks
1140 x 18 wksAll pts
Sequential240 x 12 wks960 x 12 wksOne arm
Carbo dose/schedule AUC 2 or 1.5 weekly AUC 6 q 3 wks
Higher G 3-4 toxicity• Neutropenia• Thombocytopenia• Anemia• GI toxicity
X
X
X
X
X
X
X
XCourtesy of Giuseppe Curigliano
When to consider for platinum in daily practice?•Need for rapid loco-regional control
-increased resectability
•Highest risk of relapse-stage III, very young patient
• Benefit to BRCA mutation carriers still under consideration
•Careful patient selection due to added risks of short term and long term toxicity
DeMichele et al. SABCS 2015
Basal-like prognosis is particularly dependent upon responsiveness
pCR do well,regardless of subtype
Non-pCR do not do well,especially if triple negative
Liedtke, C. et al. J Clin Oncol; 26:1275-1281 2008
Capecitabine in non-pCR HER2-
Toi et al. NEJM 2017
Capecitabine
Outline
• Preferred chemotherapy regimen
• Platinum
• Capecitabine in non-pCR
• Practical issues
-impact of delaying adjuvant CT in TNBC
-small tumor
-TIL
Impact of delaying adjuvant CT in TNBC
Gagliato et al. JCO 2014
Farolfi et al. EJC 2015
Chavez-MacGregor et al. JAMA Oncol 2016
Breast cancer subtypeHormone receptor–positive 1
ERBB2+ 1.04 (0.95-1.15) TNBC 0.72 (0.63-0.81) Unknown 1.02 (0.88-1.19)
2016 SABCS
Prognostic value of TIL. DFS for all patients (A) and in ER+/HER2 (B) ER−/HER2− (C) HER2+ (d).
M. V. Dieci et al. Ann Oncol 2015;annonc.mdv239
Prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer.
Sylvia Adams et al. JCO 2014;32:2959-2966
©2014 by American Society of Clinical Oncology
Ongoing clinical trials – immune checkpoints (IO)Phase NCT ID & number Defined condition
of breast Cancer subtype
setting stage Experimental Drugs Control Primary endpoint
IO monotherapy
III SWOG1418(NCT02954874)
Residual TNBC(ypT> 1cm or ypN+)
Adjuvant after NAC Pembrolizumab for 1 year Observation as per guideline
Invasive DFS (IDFS)
III NCT02926196 High risk TNBC Adjuvant or post-NAC Avelumab for 1 year Observation as per guideline
- Overall DFS - DFS in PD-L1(+) patients
IO-based combination
II I-SPY 2(NCT01042379)
* Neoadjuvant, personalized adaptive trial with novel agents
Locally advanced breast cancer including TNBC and HR+HER2- BC
Neoadjuvant II, III - Pembrolizumab+paclitaxel- Followed by doxorubicin + cyclophosphosphamide
Standard NAC pCR: 62.4% vs 22.3%
IB KEYNOTE-173(NCT02622074)
Locally advanced TNBC
Neoadjuvant II, III (Arm A) : Pembrolizumab Pembrolizumab +nabPaclitaxel(Arm B) : Arm A+ Carboplatin Followed by ddAC
NA pCR (Arm A vs B): 60% vs 90%
III KEYNOTE-522(NCT03036488)
TNBC Neo/adjuvant - Neoadjuvant : Pembrolizumab + wPaclitaxel + Carboplatin (4C)Pembrolizumab + AC (4C)- Adjuvant : Pembrolizumab (9C)
placebo rather than pembrolizumab
pCR, EFS
I/II NCT02489448 TNBC Neoadjuvant I-III - Durvalumab + nab-paclitaxel for 12 weeks- Followed by ddAC
NA pCR
II Triple-Negative First-Line Study (NCT02530489)
TNBC (Neo)adjuvant - Neo : Atezolizumab + nab paclitaxel (4C) - Adj : Atezolizumab alone (4C)
NA pCR
III NeoTRIPaPDL1(NCT02620280)
Locally advanced TNBC
Neoadjuvant Atezolizumab + nab-paclitaxel + carboplatin Nab-paclitaxel+ carboplatin
EFS
Ib NCT02826434 TNBC Adjuvant II/III - Peptide vaccine PVX-410 (6 infusion) + Durvalumab (2C)- After standard adjuvant chemotherapy
NA DLT rate of PVX-410 in combination with durvalumab
Neo/Adjuvant ongoing trials in BRCA+
Conclusion
• Current standard treatment for early TNBC remains the chemotherapeutic approaches
- Anthracycline+ alkylator+ taxane-based chemotherapy
backbone for all patients.
- Sequential strategy, dose-dense preferred
• Consider platinum drugs if patient has known BRCA1/BRCA2 germline mutation.
• Consider neoadjuvant approach to tailor use of adjuvant therapy with capecitabine on the basis of residual disease burden at surgical excision.
• Exceptions made for: extremely small cancers, ineligible patients.