SABCS 2014 Bülent Karabulut Ege ÜTF Tıbbi Onkoloji BD 09.04.2015
Slide courtesy of Dr Markopoulos
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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 Endpoint 1 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) P value 0.02 Age 0.03 Characteristic N HR (95% C.I.) P value Tumor size 0.01 10mm 150 1.0 >10mm 140 2.07 (1.15, 3.83) 50 459 1.0 <50 110 1.75 (1.07, 2.76) Multifocality 0.003 Absent/unkn 457 1.0 Subtype 0.04 Cribriform 175 1.0 Solid 358 1.63 (0.97, 2.88) Present 114 1.97 (1.27, 3.02) 16 Rakovitch et al. SABCS 2014. DCIS Score result, tumor size, age, tumor subtype, and multifocality were all independent predictors of LR risk
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