HER-2 Pozitif Metastatik Meme Kanserinde Optimal Tedavi Dr. Kadri Altundağ Hacettepe Üniversitesi Kanser Enstitüsü 28 Kasım 2013, Ankara

cErbB2 ve Meme Kanserindeki Rolü C-erbB2, EGFR Ailesinin bir üyesidir¹. Meme Kanserlerinin %20 sinde c-ErbB2 aşırı ekspresyonu görülür1 Mukohara T. Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer Cancer Sci 2011; 102: 1–8

HER family Proliferation and Survival Signaling Patways Ligand HER2 HER3, HER1, HER 4 Grb2 Shc SOS Grb2 PI3K Ras Akt PTEN Diagram of the ErbB (HER) signaling pathway. Ligand binding to HER1, HER3, or HER4 induces homodimerization (eg, HER3:HER3) or heterodimerization (eg, HER3:HER2) that leads to activation of the intracellular tyrosine kinase. Upon autophosphorylation and crossphosphorylation of the receptor complex, key downstream effectors are recruited. Two major signaling pathways are the MAPK proliferation pathway, and the Akt pathway that influences cell survival (apoptosis) and cell cycle progression Abbreviations: FasL = Fas ligand; FKHR = forkhead in rhabdomyosarcoma; Grb = growth factor receptor–bound protein; GSK = glycogen synthase kinase; MAPK = mitogen-activated protein kinase; MEK = MAPK kinase; mTOR = molecular target of rapamycin; PI3K = phosphatidylinositol 3-kinase; PTEN = phosphatase and tensin homolog deleted on chromosome 10; SOS = son-of-sevenless guanine nucleotide exchange factor. Raf mTOR FKHR GSK-3 Bad MEK 1/2 p27 MAPK Cyclin D1 FasL Proliferation Progression in cell cycle Survival Lin and Winer. Breast Cancer Res. 2004;6:204. Lin and Winer. Breast Cancer Res. 2004;6:204.

cErbB2 ve Meme Kanserindeki Rolü Trastuzumab, cErbB2’nin hücre dışında kalan bölümüne bağlanarak sinyal iletim yolaklarını inhibe eder¹ Mukohara T. Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer Cancer Sci 2011; 102: 1–8

cErbB2 ve Meme Kanserindeki Direnç Mekanizmaları: p95, MUC4, PTEN1 HER1 - HER1 HER1 - erbB2 HER1 - HER3 erbB2 - erbB2 p95 erbB2 - HER4 erbB2 - HER3 HER1 - HER4 PI3K Akt SOS RAS RAF MEK MAPK PTEN PTEN PI3K Akt SOS RAS Reference: O’Shaughnessy, ASCO 2008, Abs. 1015 RAF MAPK MEK Hücre çoğalması Hücre sağkalım Hücre hareketliliği ve invazivlik Transkripsiyon Mukohara T. Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer Cancer Sci 2011; 102: 1–8 5

Ortalama yanıt süresi: 9 ay³ Trastuzumab Direnci Primer direnç İkincil/edinilmiş direnç⁴ Başlangıçta yanıt veren metastatik hastalarda ortalama 9 ay içinde progresyon gelişir. Ortalama yanıt süresi: 9 ay³ ErbB2+ metastatik meme kanserli hastaların %30’dan azı tek ajan  trastuzumab tedavisine yanıt verir² ErbB2+ metastatik meme kanserli hastaların  %50’ye yakını ilk seçenek trastuzumab/taksan tedavisine cevap  vermiyor³ 2.Vogel et al. J. Clin. Oncol. 20 (2002) 719–726 ; 3-Slamon et al. N Engl J Med 2001;344:783–92; 4- Arribas et al. Cancer Res 2011;71:1515-1519

Lapatinib Etki Mekanizması 1+1 2+2 1+2 EGFR (ErbB1) ve ErbB2 (HER2) reseptörlerinde: Kinazların hücre içi ATP bağlanma yerine bağlanarak reseptör fosforilasyonunu önler EGFR ve ErbB2'nin homodimer ve heterodimerleri yoluyla aşağı yönde iletişimlerini bloke eder Trastuzumaba dirençli ErbB2+ meme kanseri hücre serilerinde aktiftir Lapatinib Aşağı yönde iletişim kaskadı 5. Xia et al. Oncogene. 2002;21:6255-6263; 6. Konecny et al. Cancer Res. 2006;66:1630-1639 7

LAPATİNİB ENDİKASYON ÇALIŞMASI

GEYER Çalışması Tasarımı NDOMİ ZASYON Hedef N=528 ErbB2+ Metastatik , veya lokal ileri meme kanseri Daha önce antrasiklin, taksan ve trastuzumab* ile tedavi edilmiş Daha önce kapesitabin kullanmamış RECIST ile ölçülebilir hastalık LVEF ≥ kurum LLN (normalin alt limiti) Lapatinib 1250 mg po 1x1 sürekli + Kapesitabin 2000 mg/m2/gün po 1.-14. gün, 3 haftada bir Kapesitabin 2500 mg/m2/gün po 1-14. gün, 3 haftada bir *Trastuzumab metastatik hastalık için verilmişti. 7-Geyer (EGF100151) C et al. NEJM. 2006;355:2733-2743. 9 9

Lapatinib + Kapesitabin Progresyona Kadar Geçen Süre 4 ay arttırmıştır 100 Lapatinib + kap Kapesitabin 80 60 İlerleme olmayan hastalar (%) 40 20 10 20 30 40 50 60 70 Zaman (hafta) Lapatinib + Kapesitabin Kapesitabin Hasta sayısı 163 161 Progrese ya da ölen 49 72 Medyan TTP, ay 8.4 4.4 Risk oranı (%95 GA) 0.49 (0.34, 0.71) P değeri (log-sıra, 1-yönlü) <.001 7-Geyer C et al. NEJM. 2006;355:2733-2743.

Genel Sağkalım Sonuçları Tüm popülasyona bakıldığında Lapatinib + Kap kolundaki Genel Sağkalım 75 Hafta olarak bulundu ancak istatistiksel olarak anlamlı bir fark görülmedi 20 40 60 80 100 120 140 160 180 200 220 240 Cumulative Survival (%) Zaman (hafta) The mature, final analysis of overall survival in the overall patient population from 01 October 2008. At this final analysis, no statisically significant difference in overall survival was observed. Whilst the study was powered to demonstrate a significant overall survival benefit as a secondary endpoint, premature closure to randomisation and crossover from capecitabine monotherapy to lapatinib and capecitabine (following a review by the Independent Data Monitoring Committee after achieving the primary endpoint) may have reduced the likelihood of reaching a significant difference in overall survival. REFERENCE: Cameron D, et al. Oncologist 2010; 15:924–34 Olaylar Median OS P-değeri Lapatinib + kapesitabin (n=207) 168 (%81) 75.0 hafta 0.210 Kapesitabin (n=201) 172 (%86) 64.7 hafta HR: 0.87 (95% CI: 0.71, 1.08) 8-Cameron D, et al. Oncologist 2010; 15:924–34

Genel Sağkalım Sonuçları GEYER çalışmasında 35 hastaya cross over yapılmasaydı LAPATİNİB tedavi kolunda 75 haftalık anlamlı OS datasına ulaşılabilirdi Analiz Ortalama Sağkalım (hafta) Hazard ratio (95% CI) P-değeri Lapatinib + kapesitabin (n=198) Kapesitabin (n=165) Cross over yapılan hastalar, çalışma dışında bırakıldığında 75.0 56.4 0.78 (0.62-0.97) 0.023 Excluding crossover patients Patients who crossed over were removed from this analysis, so comparison was between subjects randomised to lapatinib + capecitabine (n=198) vs those randomised to capecitabine alone who did not crossover (n=165). The method may bias outcomes in favour of lapatinib + capecitabine, as it removed the longer surviving patients from the capecitabine arm. While it excluded any benefit these subjects may have received from lapatinib + capecitabine therapy, it discounted the benefit these subjects may have received from capecitabine alone prior to crossover. Censoring crossover patients This is an analysis where any patient who crossed over was censored at the date of crossover. This means that overall survival for crossover patients was measured from the date of randomisation to the date of crossover. For all other subjects, overall survival was measured from date of randomisation to death or last contact. This analysis reflects the benefits these patients received from capecitabine alone; however, it ignores the fact that patients could have died soon after crossover. In addition, it does not account for the time crossover patients spent on lapatinib + capecitabine. Considering crossover as a time-dependent covariate This method accounts for time on capecitabine alone as well as time on lapatinib + capecitabine. Unlike the previous methods, it does not exclude the effect of capecitabine on the survival of patients who crossed over to lapatinib + capecitabine . The method does not provide estimates of median OS and therefore the treatment effect can be represented only by hazard ratios. Median overall survival gains were calculated using a Weilbull survival model for the purposes of the lapatinib EOL submission as being 3.3 months and 2.7 months for lapatinib + capecitabine, with and without adjustment for baseline characteristics, respectively. REFERENCE: Cameron et al. Oncologist 2010; 15: 924-34. 8. Cameron et al. Oncologist 2010; 15: 924-34.

Yapılan Alt Grup Analizinde, Metastatik 2 Yapılan Alt Grup Analizinde, Metastatik 2. Sıra Lapatinib Kullanan Hastalarda TTP 11.3 Ay Olarak Bulunmuştur 15 10 5 Lapatinib + kapesitabin Tek başına kapesitabin RO:0.37 (0.18-0.77) p=0.006 11,3 ay TTP (ay) RO:0.59 (0.43-0.82) p=0.001 5,8 ay 4,5 ay 4,2 ay n=29 n=37 n=169 n=164 1 veya 2 sıra trastuzumab tedavi 3 veya daha fazla sıra trastuzumab tedavi 9- Crown L, et al. Eur J Cancer Suppl 2009;7:5082

Lapatinib Erken Sıra Kullanımı Genel Sağkalım Avantajı Sağlar Lapatinib + kapesitabin 100 90 80 70 60 50 40 30 20 10 HR (95%CI): 0.51 (0.30, 0.86) p=0.009 Kapesitabin 87.3 HR (95%CI): 0.95 (0.76, 1.21) p=0.698 71.4 66.6 Genel sağkalım (hafta) 55.1 Overall survival was also analysed by stratification of patients according to prior therapy (i.e., 1 or 2 or 3 or more prior regimens, including neo adjuvant and adjuvant). Prior regimens may or may not have included immediate exposure to trastuzumab (the majority of patients [98%] in the study had prior exposure to trastuzumab at some point). For example, a patient in the 1 or 2 prior regimen analysis could have had an anthracycline in the adjuvant setting and single agent taxane in the 1L metastatic setting. These exploratory analysis in a limited number of patients suggested that the earlier introduction of lapatinib and capecitabine is associated with a 49% reduction in risk of death. The outcome in the population receiving 3 or more prior regimens is not statistically significant and is consistent with the overall population, reflecting the fact that patients in study 151 were heavily pre-treated. GUIDANCE: Key Messages These exploratory analysis in a limited number of patients suggested that the earlier introduction of lapatinib and capecitabine is associated with a 49% reduction in risk of death. The outcome in the population receiving 3 or more prior regimens is consistent with the overall population, reflecting the fact that patients in study 151 were heavily pre-treated. These subgroup analyses were not pre-planned and are thus exploratory; these data may only be considered as hypothesis generating. User Notes Must be shown with slide 22 & 23 REFERENCES: Crown L, et al. Eur J Cancer Suppl 2009;7:Abstract 5082 Öncesinde <3 sıra tedavi n=31 n=37 Öncesinde ≥3 sıra tedavi n=176 n=164 9- Crown L, et al. Eur J Cancer Suppl 2009;7:5082

YAŞAM KALİTESİ

FACT-B total skorlaması GEYER Çalışmasının Yaşam Kalitesi Analizinde, Lapatinib + Kapesitabin Kombinasyonunun Q-TWIST’i anlamlı Derecede Arttırdığı Görülmüştür Başlangıç 6 Hafta 12 Hafta 18 Hafta 24 Hafta 8 7 6 5 4 3 2 –1 –2 1 Kapesitabin (n=166) Lapatinib + kapesitabin (n=163) FACT-B total skorlaması Daha kötü Daha iyi The addition of lapatinib to capecitabine significantly increases time to progression, without any evidence of a deleterious effect on patients' QoL; changes from baseline were not considered to be clinically meaningful and between-treatment differences were not statistically significant. FACT-B=Functional Assessment of Cancer Therapy-Breast REFERENCE: Zhou X, et al. Breast Cancer Res Treat 2009;117:577–589. 10-Zhou X, et al. Breast Cancer Res Treat 2009;117:577–589. 11- Sherill et al. British Journal of Cancer (2008) 99, 711 – 715

ARDIŞIK KULLANIM

Ardışık Kullanım Preklinik Kanıt Lapatinib, ErbB2+ hücrelerini sonraki trastuzumab tedavisine duyarlılaştırabilir (in vitro bulgular) Trastuzumab tedavisi sırasında ErbB2 reseptörleri inaktive olup hücre içine göç edebilir Lapatinib tedavisi sırasında inaktif ErbB2 reseptörlerinin yeniden hücre yüzeyindeki biriktiği gösterilmiştir Lapatinib may sensitise ErbB2+ cells to subsequent trastuzumab (in vitro findings) In an in vitro preclinical study of breast cancer cells, lapatinib has been shown to enhance trastuzumab-dependent cytotoxicity1 While this finding will require validation in clinical studies, it may provide a rationale for proposing efficacy of trastuzumab as a follow-on treatment after first-line trastuzumab and second-line lapatinib Reference Scaltriti M et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytoxicity. Oncogene 2009; 28: 803-814. Bu sayede trastuzumab tedavisine duyarlılık artar 12-Scaltriti M et al. Oncogene 2009; 28: 803-814.

Lapatinib, ErbB2+ Hücrelerini Sonraki Trastuzumab Tedavisine Duyarlılığını Arttırır Hücredışı alan K K K K K K Lapatinib İnaktif ErbB2 reseptörleri hücre yüzeyinde birikmesini sağlar Lapatinib Hücreiçi alan NK cell Trastuzumab etki mekanizmalarından biri olan Antikor Bağımlı Hücresel Sitotoksisiteyi (ADCC) indükler ve tedaviye duyarlılığı artırır Trastuzumab inaktif ErbB hücrelere bağlanır Lapatinib may sensitise ErbB2+ cells to subsequent trastuzumab (in vitro findings) In an in vitro preclinical study of breast cancer cells, lapatinib has been shown to enhance trastuzumab-dependent cytotoxicity (antibody-dependent cell cytotoxicity; ADCC)1 While this finding will require validation in clinical studies, it may provide a rationale for proposing efficacy of trastuzumab as a follow-on treatment after first-line trastuzumab and second-line lapatinib Reference Scaltriti M et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytoxicity. Oncogene 2009; 28: 803-814. K ErbB2 12-Scaltriti M et al. Oncogene 2009; 28: 803-814.

Lokal ilerlemiş ya da metastatik meme kanseri Post-Hoc Analiz Sonuçlarına göre En Yüksek Genel Sağkalım Verisine Lapatinib Sonrası Tedaviye Trastuzumab ile Devam Eden Hastalarda Ulaşılmıştır1-5 GEYER çalışması Lokal ilerlemiş ya da metastatik meme kanseri (n=408) Lapatinib+ Kapesitabin (n=207) Kapesitabin (n=201) ErbB2 tedavisi almış (n=80) ErbB2 tedavisi almamış (n=70) (n=57) (n=102) 109,1 68,1 96 56 Post-hoc analiz Sağkalım (Ortalama hafta) %38 %34 %50 %28 Evidence base: EGF100151 trial The EGF100151 trial was a phase III randomised multicentre study designed to compare the efficacy and tolerability of:1,2 Lapatinib + capecitabine Capecitabine alone Patients had advanced or metastatic breast cancer previously treated with regimens containing an anthracycline, a taxane and trastuzumab in the metastatic setting Primary endpoint was time to progression Following a review by the Independent Data Monitoring Committee, the trial was halted early due to achievement of the primary endpoint (TTP), and women in the capecitabine monotherapy arm were offered lapatinib + capecitabine Subsequently, a post-hoc, retrospective analysis was conducted to determine outcomes in patients who received further anti-ErbB2 therapy3*† Data collected on case report forms were used to document whether patients received anti-ErbB2 therapy or not *Note there is currently no therapy licensed for use after progression on lapatinib + capecitabine †Of patients that received follow-on anti-ErbB2 therapy, the majority received a trastuzumab-containing regimen References Geyer CE et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733-2743. Cameron D et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; 112: 533-543. GSK. Data on file, DOF0110/007/1. 2010. 7- Geyer CE et al. N Engl J Med 2006; 355: 2733-2743. 13- Crown, Annals of Oncology 21 (supplement 8): viii96-viii121,2010

The first demonstration that continuing HER2 inhibition after 1st line MBC trastuzumab treatment is a valid option Geyer et al. Von Minckwitz et al.

ErbB2+Metastatik Meme Kanserinde Endikasyon Çalışmaları ve Sonuçları

ErbB2 + Metastatik Meme Kanserinde Endikasyon Çalışmaları ve Sonuçları Lapatinib⁷ Trastuzumab¹⁹ Hedef hasta sayısı Alınan hasta sayısı 324 324 (2 yıl) 482 156 (3,5 yıl) Hasta özellikleri Daha önce 3 sıra trastuzumab, antrasiklin ve taksan tedavisi almış ileri seviye hastalardır. Hastalar metastatik dönemde 1 veya 2 sıra trastuzumab tedavisi almışlardır. Son trastuzumab dozundan sonraki 6 hafta içerisinde çalışmaya dahil olmuşlar ve uzun süre tedavisiz kalmamışlardır. Kombinasyon kolu kapesitabin dozu 2000 mg/m2 2500 mg/m2 Beyin met. verisi %6 (K) %2 (L+K); p=0,045 %8,3 (K) %13,8 (T+K); p=N/A 1. sonlanım noktası TTP 4,4 ay (K) 8,4 ay (L+); p<0,001 5,6 ay (K) 8,2 ay (L+K); p=0,0338 Yayınlanma tarihi 2006 (NEJM) 2009 (JCO) Evidence from retrospective and observation studies suggests that anti-HER2 therapy continues to be beneficial following disease progression. REFERENCES: Herceptin Summary of Product Characteristics Mannocci et al. Tumori 2010; 96: 385-91. Montemurro et al. J Clin Oncol 2005;23:2866-8. Pusztai & Esteva. Cancer Invest 2006;24:187-91. von Minckwitz et al. J Clin Oncol 2009; 27: 1999-2006. 7-Geyer (EGF100151) C et al. NEJM. 2006;355:2733-2743. 19--Von Minckwitz et al. J Clin Oncol 2009; 27: 1999-2006.

ErbB2 + Metastatik Meme Kanserinde Endikasyon Çalışmaları ve Sonuçları Hedef hasta sayısı Alınan hasta sayısı Geyer çalışmasında hedeflenen hasta sayısı belirtilen süre içerisinde tamamlanmıştır. GBG çalışması 3,5 yılda hedeflediği hasta sayısına ulaşamadığı için Bağımsız İzleme Komitesi hasta alımını erken sonlandırmıştır Hasta özellikleri Geyer çalışmasındaki hastalar ortalama 3 sıra tedavi aldıkları için geç basamaklarda Lapatinib kullanmışlardır. Çalışmaya katılmadan önce tedavisiz kaldıkları süre daha uzundur. Buna rağmen çalışma sonuçları pozitif bulunmuştur. Kombinasyon kolu kapesitabin dozu Geyer çalışmasındaki kullanılan kap dozu düşük olmasına rağmen kombinasyon kolu etkilidir Beyin met. verisi GBG Çalılşmasında karşılaşılan beyin metastazlı hasta sayısı kombinasyon kolunda fazla olmasına rağmen istatistiksel analiz yapılmamıştır Evidence from retrospective and observation studies suggests that anti-HER2 therapy continues to be beneficial following disease progression. REFERENCES: Herceptin Summary of Product Characteristics Mannocci et al. Tumori 2010; 96: 385-91. Montemurro et al. J Clin Oncol 2005;23:2866-8. Pusztai & Esteva. Cancer Invest 2006;24:187-91. von Minckwitz et al. J Clin Oncol 2009; 27: 1999-2006. . 7-Geyer (EGF100151) C et al. NEJM. 2006;355:2733-2743 19- Von Minckwitz et al. J Clin Oncol 2009; 27: 1999-200 20- Cameron . Breast Cancer Rest Treatment 2008

Beyin/CNS Metastazları

Lapatinib+ Kap kombinasyonu Beyin Metastazlı hastalarda Trastuzumab’a göre anlamlı sağkalım farkı yaratmıştır 50 40 30 20 10 OS (ay) (p 0,04) 23,6 19,1 12 Ardışık Kullanım TYKERB+kap. Herceptin+KT N:150 Ardışık Kullanım – Trastuzumab ve Lapatinib ardarda kullanılmıştır 21- Kaplan et al. Oncology 2012;83:141–150

LANDSCAPE Çalışmasının Sonuçlarına Göre Lapatinib, Beyin Metastazlı Hastalarda Tüm Beyin Radyoterapisine (WBR) Kadar Geçen Süreyi 8,3 Ay Uzatmıştır SSS-Objektif Yanıt Oranı*: %67 80 70 60 50 40 30 20 10 Hasta oranları (%) %67 (%95 CI, 51-81) Time to progression in patients with untreated CNS disease is usually short. The median survival of patients with untreated brain metastases is approximately 1 month. Addition of steroids increases survival to 2 months and whole brain radiotherapy further improves survival to 3 to 6 months. Although we do not have survival data for a lapatinib plus capecitabine regimen in patients with CNS disease who were not previously treated with whole brain radiotherapy, time to progression in the Landscape trial was considered clinically significant.    The inclusion criteria and hence the patient characteristics in the Landscape trial differed from EGF100151. EGF100151 allowed stage III/T4 as well as stage IV patients not limited to CNS metastases (which -if present needed to be stable). Therefore, inter-study comparison of efficacy results (time to progression) cannot be made.   Patients who received combination therapy with lapatinib and capecitabine had a 67% CNS-objective response, as defined in this trial. The primary endpoint reflects not only tumour response in the CNS but also absence of symptomatic progression in the brain and absence of progression elsewhere in the body, demonstrating the activity of lapatinib in combination with capecitabine, in both CNS and ex-CNS disease. In addition, the patient would benefit from a suggested increase in time to WBR by avoiding some of the cognitive side effects associated to whole brain radiotherapy. GUIDANCE: Key Messages A separate module for brain metastases is under development. These studies only represent a select number of studies that have used lapatinib plus capecitabine as per the label. REFERENCE: Bachelot et al. ASCO 2011 Presentation. Tedavi görmemiş beyin metastazlı hastalardaki ortalama sağkalım yaklaşık 1 aydır ve radyoterapi ile tedavi sağkalımı 3 ila 6 ay arasında uzatır. *Landscape çalışmasında beyin metastazı olan ErbB2 + meme kanserli 43 hastada Lapatinib+kapesitabin’in etkinliği değerlendirilmiştir. 22- Bachelot et al. ASCO 2011 Presentation

Geyer Çalışmasının Post-Hoc Analizine Göre Lapatinib, CNS Metastazlarının Gelişmesini Engeller 10 9 8 7 6 5 4 3 2 1 p=0.045 %6.0 Brain metastases as site of first progression, % %2.0 The central nervous system (CNS) and brain are ‘sanctuary sites’ for the metastatic spread of breast cancer during disease progression. The trastuzumab antibody molecule is large in size, making it difficult to cross the blood–brain barrier. In contrast, lapatinib is a small molecule, which has the potential to cross the blood–brain barrier and may, therefore, be able to effectively treat breast cancer metastases in the brain. An additional exploratory analysis revealed that the incidence of CNS/brain metastases as the first site of relapse was lower in those treated with lapatinib plus capecitabine than among patients taking capecitabine alone. In patients treated with lapatinib plus capecitabine: 4 of 198 (2%) had CNS metastases as first sign of relapse. In patients treated with capecitabine alone: 13 of 201 (6%) had CNS metastases as first sign of relapse. GUIDANCE: Key Messages This subgroup analysis was not pre-planned and is thus exploratory. These data may only be considered as hypothesis generating. REFERENCE: Cameron D, et al. Breast Cancer Res Treat 2008;112:533–43. n=127 n=102 Lapatinib + kapesitabin Kapesitabin 20- Cameron D, et al. Breast Cancer Res Treat 2008;112:533–43.

VAKA # 1 53 yaşında kadın, postmenopozal Nisan 2010- Sağ MRM IDC, grade III, ER (-), PR (-), IHC: c-erb B2 (3+) T3 N3 (37/46) M0

VAKA # 1 Adjuvan Kemoterapi Seçenekleri? TAC x 6 + 9 hafta trastuzumab TAC x 6 + trastuzumab x 52 hafta AC x 4 + paklitaksel x 12 veya docetaxel x 4 + trastuzumab x 52 hafta AC x 4 +paklitaksel x 12 veya docetaxel x 4 + trastuzumab x 9 hafta CEF X 3 +Docetaxel x 3 + trastuzumab x 52 hafta Docetaxel x3 + 9 hafta trastuzumab + CEF X3 Docetaxel + karboplatin + trastuzumab

Perez et al. ASCO 2005

VAKA # 1 Adjuvan Kemoterapi: AC x 4 + Docetaxel x 4 + trastuzumab x 1 yıl Adjuvant radyoterapi almış.

VAKA # 1 Ocak 2012 BT de Multipl Akciğer metastazları

1 Yıllık Sağkalım Oranları HER-2 negatif: % 75 HER-2 pozitif + trastuzumab yok: % 80 HER-2 pozitif + trastuzumab var: % 86 Dawood et al. J Clin Oncol 2009

VAKA # 1 Tedavi seçenekleri? Docetaxel + Trastuzumab Docetaxel + Karboplatin + Trastuzumab Paklitaksel haftalık + Trastuzumab Paklitaksel 3 haftada bir + Trastuzumab Paklitaksel + Karboplatin + Trastuzumab Kapesitabin + Lapatinib Vinorelbin + Trastuzumab Kapesitabin + Trastuzumab Gemsitabin + Trastuzumab

VAKA # 1 14 kez haftalık paclitaxel-karboplatin-trastuzumab ile tam cevap Takiben trastuzumab tek başına alıyor Eylül 2012– Beyinde multipl metastazlar Eksternal radyoterapi

VAKA # 1 Tedavi seçenekleri? Kapesitabin + Lapatinib Lapatinib + Trastuzumab Docetaxel + Trastuzumab Docetaxel + Karboplatin + Trastuzumab Vinorelbin + Trastuzumab Kapesitabin + Trastuzumab Gemsitabin + Trastuzumab Gemistabin + Cisplatin İlaçsız takip

VAKA # 1 Ekim 2012 Lapatinip + Kapesitabin başlandı Ocak 2013 Beyin MRI: metastazların sayı ve boyutunda belirgin regresyon- Tedaviye devam Eylül 2013 Beyin MRI: Stabil metastatik lezyonlar

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