Chemotherapy with cisplatin for BRCA1-positive breast cancer patients. T.Byrski, S.Narod, J.Lubiński Sopot, r.

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1 Chemotherapy with cisplatin for BRCA1-positive breast cancer patients T.Byrski, S.Narod, J.Lubiński Sopot, r. INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND BRCA1 / 2 testing Method: Cost: Time: Myriad sequencing USD few weeks IHCC founder mutations 50 Euro 2 3 days

2 Breast cancers with BRCA1 Treatment Neoadjuvant therapy Type of chemotherapy No of patients Complete Response Partial Response No Response BRCA1 44 AT Other types Total Non-BRCA1 41 AT Other types Total Byrski T et al.: Breast Cancer Res Treat 2007 PRECLINICAL STUDIES BRCA1 breast cancer cell lines - resistance to taxanes - sensitivity to cisplatin Kennedy RD et al. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst Nov 17;96(22):

3 BRCA1 dependent BC NEOADJUVANT STUDY Current Study Design BRCA1 Mutation Carriers Primary Breast Cancer Cisplatin 75mg/m2 q 3wks IV x 4 cycles S U R G E R Y AC N = Primary Endpoint: pcr (in breast and axilla, DCIS permitted)

4 PILOT STUDY Responses Complete Clinical Response Partial Clinical Response Stable Clinical Disease Progressive Clinical Disease Pathologic Complete Response N (%) (N=10) 9 (90) 1 (10) (90) Response to treatment RESULTS OF TREATMENT 50 pts 4 x CHTH (CISPL) + CHIR Completed: 26 Aug 2010

5 Kryteria włączenia do neo-chth (n=50) 23 (+) 13 pcr, 10 PR 27 (-) 21 pcr, 5 PR, 1 SD Response to treatment (n=50) Response No. % Clinical response Complete response Partial response No change 0 0 Progressive disease 0 0 Pathologic response Complete pathologic response Partial reseponse Stable disease 1 2 Residual disease in breast after CHTH None <2 cm cm 4 8 >5 cm 2 4

6 Response to treatment (n=50) Response No. % NODAL STATUS PRIOR CHTH N N N N NODAL STATUS AFTER CHTH N N N N Breast cancers with BRCA1 Treatment neoadjuvant therapy Cisplatin monotherapy pcr in 34/50 (68%)!!! PR in 15/50 (30%) SD in 1/50 (2%) 10/60 pts on treatment

7 Breast cancers with BRCA1 Treatment neoadjuvant therapy ATTENTION! Breast cancers with BRCA1 Treatment neoadjuvant therapy 50 pts 7 - second primary BC treated CHTH in the past 4 - treated CHTH before CISPL SURGERY + CHTH (CMF, AT, FAC, AC) 8 pts PR 3 pts - pcr

8 Breast cancers with BRCA1 Treatment neoadjuvant therapy 39 pts 31/39 = 79,5% pcr CISPLATIN first option of CHTH!

9 Retrospective analysis neoadjuvant treatment of 141 consecutive BRCA1 mutation carriers with diagnosis of breast cancer < 51 yrs (n=7000) Regimen Number treated Number of pcr % pcr CMF % AC % FAC % AT % Cisplatinum % C: cyclophosphamide M: methotrexate F: 5-flourouracil A: adriamycin T: docetaxel Byrski T et al.: J Clin Oncol Jan 20;28(3):375-9 and updated results CHEMOTHERAPY Neo-adjuvant treatment of breast cancer complete pathologic remission > 95% of five year survival! > 95% of five year survival!

10 Neo-CHTH w BRCA1 dependant breast cancers (literature) Among women who were treated with chemotherapy, the hazard ratio for death among BRCA1 carriers was 0.48 (95% CI, 0.19 to 1.21; p=0.12) Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 2 mutations. Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, Narod SA. N Engl J Med Jul 12;357(2): Projekt walidacji badania wieloośrodkowe randomizowane III fazy CISPLATYNA vs AC

11 PROJEKT WERSJI z dn r. Zastosowanie Cisplatyny w monoterapii w porównaniu do schematu AC w leczeniu przedoperacyjnym raka piersi u pacjentek z wykrytą mutacją w genie BRCA1 Główni badacze: prof. dr hab. Jan Lubiński, dr n.med. Tomasz Byrski STEERING COMITTEE: Przewodniczący: prof. dr hab. Maciej Krzakowski Prof. dr hab. Jacek Jassem Prof. dr hab. Cezary Szczylik Prof. dr hab. Tomasz Burzykowski Prof. Steven Narod CEL BADANIA Porównanie skuteczności leczenia przedoperacyjnego cisplatyną w monoterapii z programem AC ocenianej na podstawie częstości uzyskiwanych pcr

12 Ocena wykonalności badania wykonanie testu BRCA1 u około kolejnych nieselekcjonowanych pacjentek z rakiem piersi wykrycie około 400 chorych z konstytucyjną mutacją BRCA1 kwalifikacja chorych do CHTH przedoperacyjnej pcr u 70% po CISPL vs 30% po AC p<0.002 prof. T. Burzykowski BRCA1 dependent BC METASTATIC STUDY

13 Baseline clinical characteristics of the study population (N = 20) Jul Jan 2009 Sites of metastases LIVER - 10 LUNG - 9 BONE - 3 OTHER - 11 Line of CHTH of metastatic disease Response to treatment Response Number Evidence of progression Months since initiation of treatment,* mean Number deceased Complete Partial Stable disease Progressive

14 Response to treatment Overall RR 80% 9 pts CR (45%) 7 pts PR (35%) 1-year survival 93% Toxicity of treatment 1. nausea/vomiting 50% 2. neutropenia 35% 3. anemia 5% 1 pt neutropenia 4 grade GOOD DRUG TOLERANCE!

15 BRCA1 dependent cancers CANCERS OF OTHER SITES Opis przypadku (dowolna lokalizacja narządowa rak trzustki) 54-letnia pacjentka z rozpoznanym nieoperacyjnym rakiem trzustki (HP: Adenocarcinoma G3) w trakcie rozpoznania stwierdzone mnogie przerzuty do wątroby (największy śr. ok. 36 mm), potwierdzone BACC CA19.9 > IU/ml Otrzymała a 9 cykli CHTH (DDP 75mg/m 2 ev. 21d.) BADANIE KONTROLNE Zmiana w ogonie trzustki uległa a całkowitej remisji klinicznej (CR) w badaniu TK jamy brzusznej Zmiany metastatyczne w wątrobie uległy y częściowej ciowej regresji (PR), największa 36 mm 17mm CA19.9 ~ 550 IU/ml

16 CONCLUSIONS 1. Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancers 2. BRCA1 testing is a critical issue for choice of breast cancer treatment 3. Validating studies needed

17 Welcome for collaboration More information: phone: fax: