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SABCS 2014
Bülent Karabulut
Ege ÜTF Tıbbi Onkoloji BD
09.04.2015
Slide courtesy of Dr Markopoulos
>%50
TransCONFIRM: Genetic signature
•
Signature of 25 genes was identified that is inversely associated with PFS
on fulvestrant (False Discovery Rate <20%)
• Association between EGFR pathway activation and decreased PFS (P=0.01)
• PAM50 subtypes varied with the luminal subtype being the most common
(65%) and were generally concordant with the clinical subtype. However,
no significant trend between PAM50 subtype or ROR score and PFS or
overall survival was detected.
• High TFAP2C (AP-2γ) correlated with
decreased PFS
TransCONFIRM: Genetic signature
Conclusions:
• In this cohort of patients with early and de-novo
metastatic disease a gene signature was
identified in the primary tumors that is associated
with decreased response to fulvestrant treatment
in metastatic disease.
• This is an exploratory analysis and the signature
warrants further validation to determine it’s
predictive value and potential to assist in
treatment decision making for patients with HR+
metastatic disease.
S4-05: Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic
complete response (pCR) rates in triple-negative breast cancer (TNBC) after
neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev):
CALGB 40603/150709 (Alliance)
“The benefit of adding
Carbo was not limited to
basal-like patients.”
In basal-like, Bev lead
to increased pCR.
In contrast, Bev
lowered pCR rates in
non-basal-like
CALGB 40603/150709
• Expression of a variety of immune signatures (B
cell, T cell, IgG) was positively associated with
pCR, but not predictive of increased benefit
from either Cb or Bev
• High proliferation, high p53 mutation and low IE
(estrogen signaling) signatures were prognostic
for higher pCR rates and predictive of benefit
from Bev (interaction p=0.031, 0.0017, 0.0002,
respectively)
SABCS 2014, Oral: General Session 4 (S4-05)
William M. Sikov et al.
CALGB 40603/150709
•
•
•
•
Questions:
Predictive marker for carboplatin benefit?
BRCA status and carboplatin benefit?
Longer follow up and recurrence rates?
Second Validation of the Oncotype DX® Breast Cancer Assay for DCIS:
The Ontario Provincial
DCIS Cohort Analysis
Primary Analysis: Association of the DCIS
Score™ Result and Local Recurrence Risk
Endpoint1
HR (95% C.I.)*
P value*
Local recurrence in all patients
2.15 (1.43, 3.22)
<0.001
Local recurrence in ER+ DCIS
2.26 (1.41, 3.59)
<0.001
*Cox model HRs for a 50-point difference in the DCIS Score result
• The HR for local recurrence in E5194 was 2.31 (1.15, 4.49) 2
•
The primary analysis showed that the DCIS Score result was a strong predictor of LR in the
group of patients that had BCS alone and negative margins, confirming the results of E5194
•
The association of the DCIS Score result with LR in the ER+ group was similar to the
association in the overall population, indicating that ER status was not a driver of the score
13
1. Rakovitch et al. SABCS 2014.
2. Solin et al. J Natl Cancer Inst. 2013.
DCIS Score™ Result: 10-Year Risk of Any Local
Recurrence by Risk Group in the Ontario Provincial
DCIS Cohort
DCIS Score Groups
Continuous DCIS Score
•
The results confirmed the association of the DCIS Score result with LR and stratification of recurrence
risk based on underlying biology that is not apparent in the population as a whole
•
The proportion of patients within each risk group is also similar to what was observed in the E5194
study with the majority of patients (62%) having a low score
14
Rakovitch et al. SABCS 2014.
DCIS Score™ Result: 10-Year Invasive or DCIS Local
Recurrence by Risk Group in the Ontario Provincial
DCIS Cohort
DCIS Local Recurrence
Invasive Local Recurrence
•
As in the E5194 study, this study showed that the DCIS Score result stratifies patients for
risk of an invasive LR
•
Further, the DCIS Score result was able to stratify patients for risk of a DCIS LR
15
Rakovitch et al. SABCS 2014.
Multivariable Analysis: The DCIS Score™ Result
Is an Independent Predictor of Local
Recurrence
Characteristic
DCIS Score /
50
N
571
HR
(95% C.I.)
1.68
(1.08, 2.62)
Age
P value
0.02
0.03
≥50
<50
459
1.0
110
1.75
(1.07, 2.76)
Subtype
175
1.0
Solid
358
1.63
(0.97, 2.88)
N
HR
(95% C.I.)
Tumor size
≤10mm
150
1.0
>10mm
140
2.07
(1.15, 3.83)
0.003
Absent/unkn 457
Present
P value
0.01
Multifocality
0.04
Cribriform
Characteristic
114
1.0
1.97
(1.27, 3.02)
DCIS Score result, tumor size, age, tumor subtype, and multifocality were all independent
predictors of LR risk
16
Rakovitch et al. SABCS 2014.
Second Validation Study for the DCIS Score™
Result: Summary
•
The results of this analysis in a cohort from the province of Ontario
confirm the validity of the DCIS Score result to predict the 10-yr risk of LR
in patients with DCIS who underwent BCS alone
– The Ontario cohort was almost 2-fold larger and less selected
compared to the E5194 cohort in the first validation study
– The study confirmed that the continuous DCIS Score result and the
categorical risk groups are significantly associated with risk of:
• any (invasive and DCIS) LR
• invasive LR
• DCIS LR
– The multivariable analyses confirm that the DCIS Score result is a
strong, independent predictor of LR
17
Rakovitch et al. SABCS 2014.
Consistent Results in E5194 and the Ontario
Provincial Cohort
44 (13.5%)
LR Risk 25.9%
121 (21.2%)
LR Risk 27.8%
53 (16.2%)
LR Risk 26.7%
230 (70.3%)
LR Risk 10.7%
95 (16.6%)
LR Risk 33%
355 (62.2%)
LR Risk 12.7%
The DCIS Score™ result stratifies patients consistently as shown
in two separate validation studies
18
1. Solin et al. J Natl Cancer Inst. 2013.
2. Rakovitch et al. SABCS 2014.
Erken evrede Kemoterapi ve Hedefe Yönelik Tedaviler
PSN: HSK
SSN: GSK & toksisite & Yaşam Kalitesi n:2722
Med takip: 82.8 ay (7y)
2005 Mayıs-Aralık celecoxib 2x2 dizayn, Nisan 2005-2008 celecoxib kolu kapanmış: 2 kollu
Kasım 2005: adj Herceptin
Efficacy and safety of 5-FU in addition to EC->T
Efficacy and safety of an increase in dose-density of CT
NP
Grad 3 %45
Her-2 poz %22
HR neg %17
Adjuvan taksanlar
• Taksanların optimal kullanımı
Paklitaksel vs Docetaxel Fark yok
P veya D haftalık vs P veya D 3 haftada bir fark yok
SONUÇ
•
Tüm populasyonda 4AC arkasından ardışık olarak verildiğinde P3’e kıyasla a
P1 ve D3 HSK’ı anlamlı GSK’ı minimal düzeyde uzatıyorlar.
•
ÜN hastalıkta en etkili sıralama P1 ile:
10 y HSK %59 dan %69 a , GSK % 66dan 75’e uzuyor
•
HR poz, Her-2 neg grupta
>5 yılda D3 ve P1 ile P3 arası fark kalmıyor
Bu grupta uzatılmış endokrin tedavi önemli
Bu grupta siyah ırk ve obezite (BMI>30) tedaviden daha az fayda
alma ile ilişkili
Sonuçlar
• Ibandronate alan hastalarda tx e Cape eklenmesi
IHSK arttırmadı
• Ibandronat alan hastaların 5 y HSK 77% ve GSK %88
• Kemik olayları ( met hariç) sık: %25
• İyi px grup, bu nedenle kapesitabin eklenmesinin
etkisi ileri dönemde çıkabilir
• CALGB 49907 çalışması gibi yaşlı hastalarda uygun ise
kombine KT verilmeli
BEATRICE
% 59 ant-taksan almış
%63 NN
G3 toksisite/tx bırakma Bev
kolunda fazla
ÜN: neg ve düşük/merkez lab
Lancet Oncol 2013
56 ay medyan takip
5y GSK: 88 % iki kolda da
5 y IHSK: 77 % CT vs 80% CT+A.
•
•
•
Str-TIL çok olan tmler genellikle HR neg tmler ( p<0.0001)
A kolunda (KT) LPBC vs non-LPBC: 10 y RSK 90.9 vs 64.3%
HR: 0.22 p:0.009
C kolunda (KT+T) LPBC vs non-LPBC 10 RSK 80.8 vs 79.6 %
HR:1.13 p:0.79
•
•
LPBC grupta ( str TIL >60%): 10 y RSK A kolu 90.9% vs B kolu 80%
HR: 2.43 p=0.22
Non-LPBC grubu: 10 RSK A kolu 64.4. vs C kolu 79.6 %
HR:0.49 p<0.0001
Sonuç
• Artan str-TIL % Her-2 pozitif erken evre meme
kanserinde KT den alınan fayda ile ilişkili
(XFinHer)
• Her-2 + Non-LPBC tek başına KT ye kıyasla
KT+T kolunda RSKları daha iyi
• Her-2 + LPBC de acaba T eklememeli mi?
Sonuçlar
• Tüm PAM 50 subtipleri T’dan fayda görüyor
• PIK3 CA mut ve T’ a direnç
8 gen T prediktif imza ve diğer imzaların arasında ilişki
Sonuç
• PAM 50 Intrinsik subtipleme ve PIK3CA
mut.ları trastuzumabdan fayda alacak grupları
belirleyemiyor
• Mikrometastatik hastalık biyolojisi metastatik
ve lokal ileri hastalık biyolojisinden farklı
olabilir.
Sonuç
• Post hoc analiz, eksplatuar subgrup analizler, 2004
sonrası hasta ile iletişim az/yok, 1990 ların adj
tedavileri ve bilgileri, Her-2 statüsü bilinmiyor…….
• Cerrahi sonrası std adj tedavilerini almış hastalarda
daha az yağ alımını içeren bir yaşam stili değişimi GSK
ı etkilemiyor.
• Exp. Analizlerde bu tür bir değişimden en fazla fayda
gören alt grup ÜN grup ve aktif çalışma sırasında…
Neo-adjuvan Tedavi
Untch M, et al
Hematolojik Yan Etkiler
Non-Hematolojik Yan Etkiler
Sonuç
• Pictilisib, Anastarazole ait anti-proliferatif
yanıtı anlamlı olarak arttırmıştır
– Özellikle Luminal B ve yüksek proliferatif
tümörlerde daha etkili görülmektedir
• Apoptotik yanıtı değiştirmemiştir
• PIK3CA veya PTEN mutasyonları etkinlik için
prediktif değildir
Rimawi TF, et al.
Sonuç
• Yeterli pCR hedefine ulaşılamadı
ANCAK
• Daha uzun endokrin tedavi ile pCR oranı
anlamlı derece artmış bulundu
– HR + alt-grupta bu oran 3 kat fazla idi
• Trastuzumab + Endokrin tedavinin süresi
uzatılınca pCR artışını gösteren ilk çalışma …
n:1200
Neo-Adjuvan Tedavi:
San Antonio 2014 ne getirdi?
• Triple negatif hastalıkta nab-PAC pratiğe
girmeli mi?
• Her-2 pozitif hastalıkta Trastuzumab +
Endokrin tedavi
• HR + hastalık & Bevacizumab: neoadjuvan
tedavide OS avantajı
MEME KANSERİNDE ADJUVAN
ENDOKRİN TEDAVİ
DR.YAVUZ ÖZIŞIK
HACETTEPE ÜNİVERSİTESİ ONKOLOJİ
ENSTİTÜSÜ
MEDİKAL ONKOLOJİ BİLİM DALI
Cumulative incidence of breast cancers over time
Cuzick et all Lancet Oncol 2014
Forest plot for subgroup analyses according to follow-up periods (0-10 years vs >10 years)
Cuzick et all Lancet Oncol 2014
St. Gallen 2015
Bülent Karabulut
Ege ÜTF Tıbbi Onkoloji BD
09.04.2015