GENETYKA W ONKOLOGII – ASPEKTY MEDYCZNE I EKONOMICZNE J. Lubiński INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY READGENE SA Warszawa r.

 If we want to solve problem / be successful  we need to: a) work hard and wise b) be lucky  If we want to solve problem / be successful  we need to: a) work hard and wise b) be lucky

 ~38 mln country with high level of genetic homogeneity Luck!!! Poland

Górski B. et al. AJHG, June 2000

POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200)  BRCA 1 ~65%  BRCA2~4%  BRCA 1 ~65%  BRCA2~4% Górski B. et al. Int. J. Can, 2004

POLISH PANEL OF BRCA1 MUTATIONS  5382 ins C  C 61 G  4153 del A  5382 ins C  C 61 G  4153 del A 90% of mutations Górski B. et al. Int. J. Can, 2004

BRCA1 FOUNDER MUTATIONS IN POLAND  GÓRSKI B. ET AL. - PATENT NO P MULTIPLEX PCR - 50€

A. BRCA1 PROPHYLACTICS RISK BR OV RISK BR OV  Oral contraceptives 30yrs  0.5  Breast feeding > 1 yrs  0.5  Later menarche per yr  0.9  Tubal ligation  0.5  Adnexectomy  0.2  0.05  Tamoxifen  0.5  Adnexectomy + tamoxifen  0.15  Mastectomy  0.01 RISK BR OV RISK BR OV  Oral contraceptives 30yrs  0.5  Breast feeding > 1 yrs  0.5  Later menarche per yr  0.9  Tubal ligation  0.5  Adnexectomy  0.2  0.05  Tamoxifen  0.5  Adnexectomy + tamoxifen  0.15  Mastectomy  0.01

DETECTION OF EARLY BREAST CANCERS IN BRCA1 MUTATION CARRIERS USGMAMMOGR.MRI ~20%~20%~90% USGMAMMOGR.MRI ~20%~20%~90% Narod S. et al Scientific background

 Prophylactic adnexectomy  Tamoxifen  Chemotherapy  Prophylactic adnexectomy  Tamoxifen  Chemotherapy DIFFERENCES IN TREATMENT OF BRCA1 BREAST CANCERS

MSH2 / MLH1 tests  In families matching the following criteria:  CRC + CRC  END  SB  UR. TR.  ≥1 of cancers DGN < 50 yrs  In families matching the following criteria:  CRC + CRC  END  SB  UR. TR.  ≥1 of cancers DGN < 50 yrs

FEATURES MODIFYING RISK OF COLORECTAL CANCER IN CARRIERS OF MSH2/MLH1 MUTATION BEGININGEVERY BEGININGEVERY  COLOSCOPY WITH POLYPECTOMY 25 YRS 2 YRS  INTRAVAGINAL USG 35 YRS 1 YRS   RISK FROM 80% TO 30%  DETECTION OF EARLY CANCERS BEGININGEVERY BEGININGEVERY  COLOSCOPY WITH POLYPECTOMY 25 YRS 2 YRS  INTRAVAGINAL USG 35 YRS 1 YRS   RISK FROM 80% TO 30%  DETECTION OF EARLY CANCERS

POPULATION SCREENINGS IN POLAND  4% (~200) of BRCA1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age  Thanks to geneticists - oncologists from 20 Polish centers!  4% (~200) of BRCA1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age  Thanks to geneticists - oncologists from 20 Polish centers!

WEST-POMERANIA REGION JANUARY 2001 – MAY 2002  1,258 mln questionaires out of 1,45 mln of inhabitants  the first worldwide large screening for hereditary cancers  1,258 mln questionaires out of 1,45 mln of inhabitants  the first worldwide large screening for hereditary cancers POPULATION SCREENINGS IN POLAND

BRCA 1  MUTATION DETECTION COST750 €  SURVEILLANCE COST1650 € (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN)  RISK REDUCTION  BREAST60%  10% (WITHOUT PROPHYLACTIC MASTECTOMY)  OVARY40%  5%  MUTATION DETECTION COST750 €  SURVEILLANCE COST1650 € (USG, MAMMOGRAPHY, FNAB, ADNEXECTOMY, TAMOXIFEN)  RISK REDUCTION  BREAST60%  10% (WITHOUT PROPHYLACTIC MASTECTOMY)  OVARY40%  5% POPULATION SCREENINGS IN POLAND

BRCA1 mutation carriers with breast/ovarian cancers N=50  Treatment costs~5 500 €  Social security costs~8 800 €  GP per capita lost~ € ~ € ~ €  Average annual cost~ €  Treatment costs~5 500 €  Social security costs~8 800 €  GP per capita lost~ € ~ € ~ €  Average annual cost~ € Marska N, US 2004 COMPELLING ECONOMICS OF PREVENTION

 Family history  DNA tests BRCA1 BRCA1 BRCA2 BRCA2 CHEK2 – homozygotes – htr + FH – BRCA2 (5972 C/T) CHEK2 – homozygotes – htr + FH – BRCA2 (5972 C/T) ATM ATM  Family history  DNA tests BRCA1 BRCA1 BRCA2 BRCA2 CHEK2 – homozygotes – htr + FH – BRCA2 (5972 C/T) CHEK2 – homozygotes – htr + FH – BRCA2 (5972 C/T) ATM ATM High penetrance/risk – breast ca

NATIONAL PROGRAMME URGENTLY NEEDED!!!

2.Complete remission of BRCA1 – dependant breast cancers using Cis-platinum Milestone discoveries International Hereditary Cancer Center 2008/9

 44 patients  15 (+) – 10/15 pCR – 67%  29 (−) – 24/29 pCR – 83%  44 patients  15 (+) – 10/15 pCR – 67%  29 (−) – 24/29 pCR – 83% BRCA1-dependendnt breast cancer Preoperative treatment

Retrospective analysis neoadjuvant treatment of 141 consecutive BRCA1 mutation carriers with diagnosis of breast cancer < 51 yrs (n=7000) Retrospective analysis neoadjuvant treatment of 141 consecutive BRCA1 mutation carriers with diagnosis of breast cancer < 51 yrs (n=7000)

 Neo-adjuvant treatment of breast cancer – complete pathologic remission  > 95% of five year survival !  Neo-adjuvant treatment of breast cancer – complete pathologic remission  > 95% of five year survival ! CHEMOTHERAPYCHEMOTHERAPY

 METASTATIC STUDY BRCA1 – dependent BC

Response to treatment ResponseNumber Evidence of progression Months since initiation of treatment,* mean Number deceased Complete Partial Stable disease Progressive From date of first treatment untill July 31, 2011 if alive, or untill date of death, if dead Byrski T et al.

CONCLUSIONSCONCLUSIONS 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 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

Milestone discoveries  Cancer chemoprevention using selenium International Hereditary Cancer Center 2011

 Stężenia Se w diecie / organizmie?  Osobnicze różnice w genotypach?  Stężenia Se w diecie / organizmie?  Osobnicze różnice w genotypach? Przyczyny dotychczasowych niepowodzeń

Asocjacja pomiędzy poziomem Se we krwi a ryzykiem raków piersi zależnie od genotypów a) Kolejne raki piersi b) Raki piersi u nosicielek mutacji BRCA1

Asocjacja pomiędzy poziomem Se we krwi a ryzykiem raków piersi zależnie od genotypów

Asocjacja pomiędzy poziomem Se we krwi a ryzykiem raków płuca i krtani niezależnie od genotypów

 I vs IV ćwiartka p< OR 13.2 CI  Se μg/l 0/15 !!! p μg/l 0/15 !!! p< OR  I vs IV ćwiartka p< OR 13.2 CI  Se μg/l 0/15 !!! p μg/l 0/15 !!! p< OR Rak płuca

Ryzyko raka płuca a stężenie selenu we krwi PolskaUSA Ryzyko stężenie Se [μg/l]

Wniosek – podsumowanie  Poziom selenu markerem grup ryzyka raków tytoniozależnych np. kwalifikacja do TK płuc?  optymalizacja poziomu selenu – kilkakrotne obniżenie ryzyka raków tytoniozależnych?  Poziom selenu markerem grup ryzyka raków tytoniozależnych np. kwalifikacja do TK płuc?  optymalizacja poziomu selenu – kilkakrotne obniżenie ryzyka raków tytoniozależnych?

Wniosek – podsumowanie  Genetyka w onkologii – wielki innowacyjny potencjał do wdrożenia zwłaszcza w POLSCE

ECONOMICAL CRISIS APPLIED RESEARCH COMMERCIALISATION – SPIN OFFS READ GENE SA

Main task: global leadership in cancer chemoprevention

Welcome for collaboration…