Clinical genetics of cancer family syndromes – Polish experience

Clinical genetics Clinical genetics of cancer family syndromes of cancer family syndromes

– Polish experience– Polish experience

J. LubińskiJ. Lubiński

INTERNATIONAL HEREDITARY CANCER CENTERINTERNATIONAL HEREDITARY CANCER CENTERPOMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLANDPOMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND

READ-GENE SAREAD-GENE SA

Sankt Petersburg 4.10.2014Sankt Petersburg 4.10.2014

Pomeranian Medical University:Cancer Genetics Outpatient Clinics Dept Genetics PathologyInternetional Hereditary Cancer Center (journal – Hereditary Cancer in Clinical Practice: IF 2.1)Oncology clinics:

Chemotherapy Surgery Gynecology Urology Others

Read-Gene Spin-off Company

Pomeranian Medical University:Cancer Genetics Outpatient Clinics Dept Genetics PathologyInternetional Hereditary Cancer Center (journal – Hereditary Cancer in Clinical Practice: IF 2.1)Oncology clinics:

Chemotherapy Surgery Gynecology Urology Others

Read-Gene Spin-off Company

Hereditary Cancer Center SzczecinHereditary Cancer Center SzczecinHereditary Cancer Center SzczecinHereditary Cancer Center Szczecin

Cybulski CezaryCybulski Cezary11, Byrski Tomasz, Byrski Tomasz11, Jakubowska Anna, Jakubowska Anna11, Gronwald Jacek, Gronwald Jacek11, Huzarski Tomasz, Huzarski Tomasz11, , Wokołorczyk DominikaWokołorczyk Dominika11, Masojć Bartłomiej, Masojć Bartłomiej11, Dębniak Tadeusz, Dębniak Tadeusz11, Górski Bohdan, Górski Bohdan11, Narod Steven , Narod Steven A.A.22, Marczyk Elżbieta, Marczyk Elżbieta33, Blecharz Paweł, Blecharz Paweł33, Ashuryk Oleg, Ashuryk Oleg11, Zuziak Dorota, Zuziak Dorota44, Wiśniowski Rafał, Wiśniowski Rafał44, , Godlewski DariuszGodlewski Dariusz55, Jaworska Katarzyna, Jaworska Katarzyna11*, Durda Katarzyna*, Durda Katarzyna11, Gupta Satish, Gupta Satish11*, Muszyńska *, Muszyńska MagdalenaMagdalena11, Sukiennicki Grzegorz, Sukiennicki Grzegorz11, Grodzki Tomasz, Grodzki Tomasz66, Waloszczyk Piotr, Waloszczyk Piotr66, Jaworowska Ewa, Jaworowska Ewa77, , Lubiński JakubLubiński Jakub77, Kładny Józef, Kładny Józef88, Wilk Grażyna, Wilk Grażyna99, Górecka Barbara, Górecka Barbara99, Sikorski Andrzej, Sikorski Andrzej1010, Gołąb , Gołąb AdamAdam1010, Tołoczko-Grabarek Aleksandra, Tołoczko-Grabarek Aleksandra11, Lubiński Jan, Lubiński Jan11::

11Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin; Pomeranian Medical University, Szczecin; 22Women’s College Research Institute, Toronto, Ontario, Canada; Women’s College Research Institute, Toronto, Ontario, Canada; 33Regional Oncology Center, Bielsko-Biała; Regional Oncology Center, Bielsko-Biała; 44Oncology Institute, Kraków; Oncology Institute, Kraków; 55Center for Epidemiology and Prevention, Poznań; Center for Epidemiology and Prevention, Poznań; 66Lung Diseases Hospital, Szczecin; Lung Diseases Hospital, Szczecin; 77Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Szczecin; Szczecin; 88Clinics of Surgey, Pomeranian Medical University, Szczecin; Clinics of Surgey, Pomeranian Medical University, Szczecin; 99Department of Radiology, Pomeranian Medical University, Szczecin; Department of Radiology, Pomeranian Medical University, Szczecin; 1010Clinics of Urology, Pomeranian Medical University, Szczecin; Clinics of Urology, Pomeranian Medical University, Szczecin; *Postgraduate School of Molecular Medicine, Warsaw Medical University.*Postgraduate School of Molecular Medicine, Warsaw Medical University.

Cybulski CezaryCybulski Cezary11, Byrski Tomasz, Byrski Tomasz11, Jakubowska Anna, Jakubowska Anna11, Gronwald Jacek, Gronwald Jacek11, Huzarski Tomasz, Huzarski Tomasz11, , Wokołorczyk DominikaWokołorczyk Dominika11, Masojć Bartłomiej, Masojć Bartłomiej11, Dębniak Tadeusz, Dębniak Tadeusz11, Górski Bohdan, Górski Bohdan11, Narod Steven , Narod Steven A.A.22, Marczyk Elżbieta, Marczyk Elżbieta33, Blecharz Paweł, Blecharz Paweł33, Ashuryk Oleg, Ashuryk Oleg11, Zuziak Dorota, Zuziak Dorota44, Wiśniowski Rafał, Wiśniowski Rafał44, , Godlewski DariuszGodlewski Dariusz55, Jaworska Katarzyna, Jaworska Katarzyna11*, Durda Katarzyna*, Durda Katarzyna11, Gupta Satish, Gupta Satish11*, Muszyńska *, Muszyńska MagdalenaMagdalena11, Sukiennicki Grzegorz, Sukiennicki Grzegorz11, Grodzki Tomasz, Grodzki Tomasz66, Waloszczyk Piotr, Waloszczyk Piotr66, Jaworowska Ewa, Jaworowska Ewa77, , Lubiński JakubLubiński Jakub77, Kładny Józef, Kładny Józef88, Wilk Grażyna, Wilk Grażyna99, Górecka Barbara, Górecka Barbara99, Sikorski Andrzej, Sikorski Andrzej1010, Gołąb , Gołąb AdamAdam1010, Tołoczko-Grabarek Aleksandra, Tołoczko-Grabarek Aleksandra11, Lubiński Jan, Lubiński Jan11::

11Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin; Pomeranian Medical University, Szczecin; 22Women’s College Research Institute, Toronto, Ontario, Canada; Women’s College Research Institute, Toronto, Ontario, Canada; 33Regional Oncology Center, Bielsko-Biała; Regional Oncology Center, Bielsko-Biała; 44Oncology Institute, Kraków; Oncology Institute, Kraków; 55Center for Epidemiology and Prevention, Poznań; Center for Epidemiology and Prevention, Poznań; 66Lung Diseases Hospital, Szczecin; Lung Diseases Hospital, Szczecin; 77Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Szczecin; Szczecin; 88Clinics of Surgey, Pomeranian Medical University, Szczecin; Clinics of Surgey, Pomeranian Medical University, Szczecin; 99Department of Radiology, Pomeranian Medical University, Szczecin; Department of Radiology, Pomeranian Medical University, Szczecin; 1010Clinics of Urology, Pomeranian Medical University, Szczecin; Clinics of Urology, Pomeranian Medical University, Szczecin; *Postgraduate School of Molecular Medicine, Warsaw Medical University.*Postgraduate School of Molecular Medicine, Warsaw Medical University.

AcknowledgmentAcknowledgment

Family history of cancer Family history of cancer – strong indication – strong indication

of high genetic risk of malignanciesof high genetic risk of malignancies

Family history of cancer Family history of cancer – strong indication – strong indication

of high genetic risk of malignanciesof high genetic risk of malignancies

1.7 mln of inhabitants 1.28 mln (75%) of cancer family

histories collected via family doctors

1.7 mln of inhabitants 1.28 mln (75%) of cancer family

histories collected via family doctors

West Pomerania 2000-2001West Pomerania 2000-2001West Pomerania 2000-2001West Pomerania 2000-2001

BRCA1 testing – all of females with at least one breast / ovarian cancer among relatives

BRCA1 testing – all of females with at least one breast / ovarian cancer among relatives


Other DNA tests – MSH2 / MLH1; VHL; RB1; APC etc.

Limited to persons pre-selected depending on pedigrees and other clinical data

Other DNA tests – MSH2 / MLH1; VHL; RB1; APC etc.

Limited to persons pre-selected depending on pedigrees and other clinical data


1 CRCHNPCC ≥ 1 cancer from the spectrum (CRC, END, SB, urinary t.) ≥ 1 cancer dgn <50 yrs

Familial aggregation of the cancers of one-two sites i.e. colon, stomach, pancreas, breast – ovaries, etc.

Other strong cancer familial aggregations

1 CRCHNPCC ≥ 1 cancer from the spectrum (CRC, END, SB, urinary t.) ≥ 1 cancer dgn <50 yrs

Familial aggregation of the cancers of one-two sites i.e. colon, stomach, pancreas, breast – ovaries, etc.

Other strong cancer familial aggregations


IIf genetic events present f genetic events present they are expressed stronglythey are expressed strongly

IIf genetic events present f genetic events present they are expressed stronglythey are expressed strongly

Luck!!!Luck!!!Luck!!!Luck!!!PolandPolandPolandPoland

Górski B. et al. AJHG, June 2000Górski B. et al. AJHG, June 2000

BRCA 1 BRCA 1 ~65%~65% BRCA2BRCA2 ~4%~4%

BRCA 1 BRCA 1 ~65%~65% BRCA2BRCA2 ~4%~4%

POLISH PANEL POLISH PANEL OF BRCA1 MUTATIONSOF BRCA1 MUTATIONS

POLISH PANEL POLISH PANEL OF BRCA1 MUTATIONSOF BRCA1 MUTATIONS

Górski B. et al. Int. J. Can, 2004Górski B. et al. Int. J. Can, 2004

5382 ins C5382 ins C C 61 GC 61 G 4153 del A4153 del A

5382 ins C5382 ins C C 61 GC 61 G 4153 del A4153 del A

POLISH FAMILIES WITH STRONG AGGREGATION POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200)OF BREAST/OVARIAN CANCERS (n=200)

POLISH FAMILIES WITH STRONG AGGREGATION POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200)OF BREAST/OVARIAN CANCERS (n=200)

Górski B. et al. Int. J. Can, 2004Górski B. et al. Int. J. Can, 2004

90% of mutations90% of mutations

GÓRSKI B. ET AL. GÓRSKI B. ET AL. - - PATENT NO P335917PATENT NO P335917

- MULTIPLEX PCR - 50€- MULTIPLEX PCR - 50€

GÓRSKI B. ET AL. GÓRSKI B. ET AL. - - PATENT NO P335917PATENT NO P335917

- MULTIPLEX PCR - 50€- MULTIPLEX PCR - 50€

BRCA1 FOUNDER MUTATIONS BRCA1 FOUNDER MUTATIONS IN POLANDIN POLAND

BRCA1 FOUNDER MUTATIONS BRCA1 FOUNDER MUTATIONS IN POLANDIN POLAND

4% (~200) of BRCA1 4% (~200) of BRCA1 carriers among 5000 carriers among 5000 relatives of women with relatives of women with breast cancer dgn < 50 breast cancer dgn < 50 yrs or ovarian cancer dgn yrs or ovarian cancer dgn at any ageat any age

Thanks to geneticists Thanks to geneticists - oncologists from 20 - oncologists from 20 Polish centers!Polish centers!

4% (~200) of BRCA1 4% (~200) of BRCA1 carriers among 5000 carriers among 5000 relatives of women with relatives of women with breast cancer dgn < 50 breast cancer dgn < 50 yrs or ovarian cancer dgn yrs or ovarian cancer dgn at any ageat any age

Thanks to geneticists Thanks to geneticists - oncologists from 20 - oncologists from 20 Polish centers!Polish centers!

POPULATION SCREENINGS POPULATION SCREENINGS IN POLANDIN POLAND

POPULATION SCREENINGS POPULATION SCREENINGS IN POLANDIN POLAND

THE LARGEST REGISTRY THE LARGEST REGISTRY IN THE WORLDIN THE WORLD

THE LARGEST REGISTRY THE LARGEST REGISTRY IN THE WORLDIN THE WORLD

BRCA1 – REGISTRY BRCA1 – REGISTRY – SZCZECIN – POLAND– SZCZECIN – POLAND

BRCA1 – REGISTRY BRCA1 – REGISTRY – SZCZECIN – POLAND– SZCZECIN – POLAND

>> 5000 CARRIERS5000 CARRIERS>> 5000 CARRIERS5000 CARRIERS

CHEK2 mutations CHEK2 mutations - Poland - epidemiology- Poland - epidemiology

CHEK2 mutations CHEK2 mutations - Poland - epidemiology- Poland - epidemiology

a)a) Protein truncating mutationsProtein truncating mutations 1100 delC1100 delC IS2 + 1 G IS2 + 1 G A A 1,5%1,5% del5000del5000

b)b) Missense mutationMissense mutation I157TI157T 5%5%

a)a) Protein truncating mutationsProtein truncating mutations 1100 delC1100 delC IS2 + 1 G IS2 + 1 G A A 1,5%1,5% del5000del5000

b)b) Missense mutationMissense mutation I157TI157T 5%5%

a)a) PTM + family historyPTM + family historyC. Cybulski et al. 2011 JCOC. Cybulski et al. 2011 JCO

b)b) PTM + I157TPTM + I157TC. Cybulski et al. 2009 JMGC. Cybulski et al. 2009 JMG

c)c) PTM + CYP1 B1 PTM + CYP1 B1 T. Huzarski et al. 2012 in prep.T. Huzarski et al. 2012 in prep.

d)d) I157T + BRCA2 5972 C/T I157T + BRCA2 5972 C/T P. Serrano-FernP. Serrano-Fernáández Br Can Res Treat 2009ndez Br Can Res Treat 2009

a)a) PTM + family historyPTM + family historyC. Cybulski et al. 2011 JCOC. Cybulski et al. 2011 JCO

b)b) PTM + I157TPTM + I157TC. Cybulski et al. 2009 JMGC. Cybulski et al. 2009 JMG

c)c) PTM + CYP1 B1 PTM + CYP1 B1 T. Huzarski et al. 2012 in prep.T. Huzarski et al. 2012 in prep.

d)d) I157T + BRCA2 5972 C/T I157T + BRCA2 5972 C/T P. Serrano-FernP. Serrano-Fernáández Br Can Res Treat 2009ndez Br Can Res Treat 2009

CHEK2 mutations CHEK2 mutations - high risk of breast cancer OR > 5- high risk of breast cancer OR > 5

CHEK2 mutations CHEK2 mutations - high risk of breast cancer OR > 5- high risk of breast cancer OR > 5

Sequencing in diagnostics of high genetic risk of breast cancer

Cybulski C., Scott R. Lubiński J., 2014Cybulski C., Scott R. Lubiński J., 2014

144 women with breast cancer from 144 women with breast cancer from families with ≥ 3 BC casesfamilies with ≥ 3 BC cases 11 BRCA1/2 founder mutations (−)11 BRCA1/2 founder mutations (−) 4 CHEK2 founder mutations (−)4 CHEK2 founder mutations (−)

144 women with breast cancer from 144 women with breast cancer from families with ≥ 3 BC casesfamilies with ≥ 3 BC cases 11 BRCA1/2 founder mutations (−)11 BRCA1/2 founder mutations (−) 4 CHEK2 founder mutations (−)4 CHEK2 founder mutations (−)

„„Exom sequencing”Exom sequencing”„„Exom sequencing”Exom sequencing”

Cybulski C. 2014Cybulski C. 2014

12 BRCA2 mutations 12 BRCA2 mutations 17/14417/144 11,8%11,8% 5 BRCA1 mutations5 BRCA1 mutations

3 PALB23 PALB2 2 ATM2 ATM 1 BARD11 BARD1 9/1449/144 6,3%6,3% 1 CHEK21 CHEK2 1 XRCC21 XRCC2

+ candidate genes + candidate genes 5/1445/144 3,5%3,5%single mutationssingle mutations

12 BRCA2 mutations 12 BRCA2 mutations 17/14417/144 11,8%11,8% 5 BRCA1 mutations5 BRCA1 mutations

3 PALB23 PALB2 2 ATM2 ATM 1 BARD11 BARD1 9/1449/144 6,3%6,3% 1 CHEK21 CHEK2 1 XRCC21 XRCC2

+ candidate genes + candidate genes 5/1445/144 3,5%3,5%single mutationssingle mutations

ResultsResultsResultsResults

Mutations detected usingMutations detected using„Exom sequencing”„Exom sequencing”

Mutations detected usingMutations detected using„Exom sequencing”„Exom sequencing”

Gen Exon 1 HGVS Protein 1

ATM 49 p.Glu2366*

ATM 40 p.Glu1991*

ATM 8 p.Glu564*

BRIP1 19 p.Ser895_IIe896delins*

CHEK2 8 p.Leu301fs

PALB2 12 p.Tyr1108*

PALB2 4 p.Arg170fs

PALB2 3 p.Gln60fs

XRCC2 2 p.Phe32fs

Costs of sequencingCosts of sequencing BRCA1/2 BRCA1/2 ~500 €~500 € Gene panel Gene panel ~1500 €~1500 €

It is It is important important to develop a to develop ann algorithm algorithm for for selection of families with breast cancers for selection of families with breast cancers for diagnostic sequencingdiagnostic sequencing

Costs of sequencingCosts of sequencing BRCA1/2 BRCA1/2 ~500 €~500 € Gene panel Gene panel ~1500 €~1500 €

It is It is important important to develop a to develop ann algorithm algorithm for for selection of families with breast cancers for selection of families with breast cancers for diagnostic sequencingdiagnostic sequencing

Conclusions Conclusions Conclusions Conclusions

BRCA1BRCA1/2/2 mutation frequency mutation frequency in in triple negative breast cancerstriple negative breast cancers

BRCA1BRCA1/2/2 mutation frequency mutation frequency in in triple negative breast cancerstriple negative breast cancers

Scott R. 2014Scott R. 2014

BRCA1/2 mutations – breast cancersBRCA1/2 mutations – breast cancersBRCA1/2 mutations – breast cancersBRCA1/2 mutations – breast cancers

No — triple negative

Test <51 r.ż. 51–60 r.ż. > 60 r.ż.

Standard - 3 mutations 8/469 (1,7%) 10/1115 (0,9%) 5/1093 (0,5%)

Triple negative

Test <51 r.ż. 51–60 r.ż. > 60 r.ż.

Standard - 3 mutations 35/90 (38,9%) 22/170 (12,9%) 7/1242 (4,7%)

Extended - 8 mutations 3/90 (3,3%) 0/170 (0%) 0/1242 (0%)

„NGS” 8/90 (8.8%) 9/170 (5,3%) 6/1242 (4%)

Scott R. 2014Scott R. 2014

11/55 = 20%11/55 = 20%

Assuming an acceptable costAssuming an acceptable cost of of 10 000 zł 10 000 zł of of detection of one detection of one BRCA1BRCA1/2 mutation /2 mutation carriercarrier, , sequencingsequencing costs of costs of 2 000 zł is economically 2 000 zł is economically justifiedjustified for for patients with breast cancers: triple patients with breast cancers: triple negative and negative and early onsetearly onset ((<51 years of age<51 years of age))

Assuming an acceptable costAssuming an acceptable cost of of 10 000 zł 10 000 zł of of detection of one detection of one BRCA1BRCA1/2 mutation /2 mutation carriercarrier, , sequencingsequencing costs of costs of 2 000 zł is economically 2 000 zł is economically justifiedjustified for for patients with breast cancers: triple patients with breast cancers: triple negative and negative and early onsetearly onset ((<51 years of age<51 years of age))

ConclusionsConclusionsConclusionsConclusions

TTo estimateo estimate the influence of the influence of the the oral contraceptive oral contraceptive use by BRCA1 carriers on risk of breast cancer with use by BRCA1 carriers on risk of breast cancer with respect:respect:

- age of beginning- age of beginning-- durationduration

TTo estimateo estimate the influence of the influence of the the oral contraceptive oral contraceptive use by BRCA1 carriers on risk of breast cancer with use by BRCA1 carriers on risk of breast cancer with respect:respect:

- age of beginning- age of beginning-- durationduration

PurposePurpose

72 participating centers (13 countries)72 participating centers (13 countries) CASE-CONTROL STUDY: BRCA1 carriers - 2492 CASE-CONTROL STUDY: BRCA1 carriers - 2492

women affected with breast cancer vs. 2492 matched women affected with breast cancer vs. 2492 matched healthy controlshealthy controls

Data were collected from the questonnairesData were collected from the questonnaires

Varibles between cases and controls were compared using Student’s t-test Varibles between cases and controls were compared using Student’s t-test and chi-square test; conditional logistic regression was used to estimate and chi-square test; conditional logistic regression was used to estimate OR and 95% CIOR and 95% CI

72 participating centers (13 countries)72 participating centers (13 countries) CASE-CONTROL STUDY: BRCA1 carriers - 2492 CASE-CONTROL STUDY: BRCA1 carriers - 2492

women affected with breast cancer vs. 2492 matched women affected with breast cancer vs. 2492 matched healthy controlshealthy controls

Data were collected from the questonnairesData were collected from the questonnaires

Varibles between cases and controls were compared using Student’s t-test Varibles between cases and controls were compared using Student’s t-test and chi-square test; conditional logistic regression was used to estimate and chi-square test; conditional logistic regression was used to estimate OR and 95% CIOR and 95% CI

Patients and MethodsPatients and Methods

Relationship between oral contraceptive use and breast cancer risk among BRCA1 mutation carriers

Relationship between oral contraceptive use and breast cancer risk among BRCA1 mutation carriers

Variable Controls (n) Cases (n) OR (95 % CI)a P

Oral contraceptive use

Never 1,084 1,048 1,00

Ever 1,408 1,474 1,18 (1,03–1,36) 0,02

Trend per year 1,01 (1,00–1,03) 0,05

Duration of use (years)

Never 1,084 1,018 1,00

0–<5 629 630 1,14 (0,97–1,35) 0,11

5–<10 431 455 1,19 (0,99–1,43) 0,07

10–<15 225 258 1,27 (1,02–1,60) 0,04

15–<30 123 131 1,23 (0,92–1,65) 0,16

Trend 0,02

Age at first use (years)

Never 1,084 1,018 1,00

<20 526 619 1,45 (1,20–1,75) 0,0001

20–<25 235 534 1,19 (0,99–1,42) 0,06

25–<30 205 191 1,06 (0,84–1,33) 0,62

30–>60 142 130 0,98 (0,76–1,27) 0,88

Trendb 0,0003

Age of diagnosis, ever/never use

<40 years 1,302 1,302 1,40 (1,14–1,70) 0,001

40–50 years 980 980 0,95 (0,76–1,20) 0,68

>50 years 210 210 1,08 (0,66–1,77) 0,75

Relationship between duration of oral contraceptive use prior to age 20 and breast cancer risk among BRCA1 mutation carriers

Relationship between duration of oral contraceptive use prior to age 20 and breast cancer risk among BRCA1 mutation carriers

Relationship between oral contraceptive use and risk of breast cancer diagnosed prior to age 40 among BRCA1 mutation carriers

Relationship between oral contraceptive use and risk of breast cancer diagnosed prior to age 40 among BRCA1 mutation carriers

Effect of oral contraceptive is harmful for early-onset Effect of oral contraceptive is harmful for early-onset breast cancer if use is initiated prior to age 25breast cancer if use is initiated prior to age 25

Women with BRCA1 mutation should be advised to Women with BRCA1 mutation should be advised to avoid oral contraceptive use before age of 25avoid oral contraceptive use before age of 25

Effect of oral contraceptive is harmful for early-onset Effect of oral contraceptive is harmful for early-onset breast cancer if use is initiated prior to age 25breast cancer if use is initiated prior to age 25

Women with BRCA1 mutation should be advised to Women with BRCA1 mutation should be advised to avoid oral contraceptive use before age of 25avoid oral contraceptive use before age of 25

ConclusionConclusion

TTo estimate the reduction in risk of ovarian, fallopian tube, oro estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1peritoneal cancer in BRCA1/2 carriers/2 carriers after oophorectomy; after oophorectomy;

TTo estimate the impact of prophylactic oophorectomy on all-o estimate the impact of prophylactic oophorectomy on all-cause mortality; cause mortality;

TToo estimate 5-year survival associated with clinically detected estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancersovarian, occult, and peritoneal cancers diagnosed in the diagnosed in the cohort.cohort.

TTo estimate the reduction in risk of ovarian, fallopian tube, oro estimate the reduction in risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1peritoneal cancer in BRCA1/2 carriers/2 carriers after oophorectomy; after oophorectomy;

TTo estimate the impact of prophylactic oophorectomy on all-o estimate the impact of prophylactic oophorectomy on all-cause mortality; cause mortality;

TToo estimate 5-year survival associated with clinically detected estimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancersovarian, occult, and peritoneal cancers diagnosed in the diagnosed in the cohort.cohort.

PurposePurpose

5,7835,783 BRCA1/2 carriers BRCA1/2 carriers An average follow-up period An average follow-up period -- 5.6 years 5.6 years

Hazard ratios (HRs) for cancer incidence and all-Hazard ratios (HRs) for cancer incidence and all-cause mortality associatedcause mortality associated with oophorectomy were with oophorectomy were evaluatedevaluated

5,7835,783 BRCA1/2 carriers BRCA1/2 carriers An average follow-up period An average follow-up period -- 5.6 years 5.6 years

Hazard ratios (HRs) for cancer incidence and all-Hazard ratios (HRs) for cancer incidence and all-cause mortality associatedcause mortality associated with oophorectomy were with oophorectomy were evaluatedevaluated

Patients and MethodsPatients and Methods

91.6%91.6%

54.4%54.4%

38.4%38.4%

Preventive oophorectomy was associated with an 80% Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopianreduction in the risk of ovarian, fallopian tube, or peritoneal tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.all-cause mortality.

Preventive oophorectomy was associated with an 80% Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopianreduction in the risk of ovarian, fallopian tube, or peritoneal tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.all-cause mortality.

ConclusionConclusion

Studies on micro- and Studies on micro- and macro- elements – summarizationmacro- elements – summarization

Selection of individuals with a few times Selection of individuals with a few times of increased chance of cancer detection of increased chance of cancer detection – CT of the lung, coloscopy, PSA and – CT of the lung, coloscopy, PSA and prostate biopsiesprostate biopsies

Selection of individuals with a few times Selection of individuals with a few times of increased chance of cancer detection of increased chance of cancer detection – CT of the lung, coloscopy, PSA and – CT of the lung, coloscopy, PSA and prostate biopsiesprostate biopsies

Lubiński J. 2014Lubiński J. 2014

Retrospective studiesRetrospective studiesRetrospective studiesRetrospective studies

Micro- macro- elements levels Micro- macro- elements levels as cancer risk factoras cancer risk factor

Micro- macro- elements levels Micro- macro- elements levels as cancer risk factoras cancer risk factor

Lubiński J. 2014Lubiński J. 2014

Prospective observational Prospective observational studiesstudies

Prospective observational Prospective observational studiesstudies

Mortality – all causesMortality – all causesn=13887 adults, 18 yrs follow-up, USA n=13887 adults, 18 yrs follow-up, USA

M. Rayman, Lancet 2012M. Rayman, Lancet 2012

Serum selenium concentration (µg/l)

60 70Poland

140USA

Ris

k o

f dea

th (

95

% C

I)

Se; independantly on genotypesSe; independantly on genotypesSe; independantly on genotypesSe; independantly on genotypesBRCA(−) BRCA(+) Quartiles Quartiles

Se Cancers n=45

Control n=221 Se Cancers

n=45 Control

n=90 48.2–69.4 11 54 49.9–67.0 12 22 69.5–75.9 8 58 67.1–72.9 14 20 75.9–84.1 10 55 73.1–80.1 9 25

84.4–128.1 16 50 80.2–131.1 11 23 16 & 50 vs 8 & 58

p=0,11; OR=2.3; CI=0.9–5.8 14 & 20 vs 9 & 25

p=0,3; OR=1.94; CI=0.7–5.4

BRCA(−) BRCA(+) Ranges Ranges

Se Cancers Control Se Cancers n=45

Control n=90

<70 11 57 <70 23 31 70–85 18 116 70–85 17 44

85–100 7 35 85–100 3 10 >100 9 9 >100 2 3

9 & 9 vs 36 & 212 p=0,0004; OR=5.89; CI=2.19–15.84

23 & 31 vs 17 & 44 p=0,14;OR=1.9; CI=0.8–4.2

Fe/Zn; „S” nAAFe/Zn; „S” nAAFe/Zn; „S” nAAFe/Zn; „S” nAA

BRCA(−) BRCA(+) Quartiles Quartiles

Fe/Zn Cancers n=32

Controls (n=173) Fe/Zn Cancers

n=35 Controls

n=68 <0.88 10 41 <0.78 13 12

0.88–1.10 8 43 0.80–1.13 5 21 1.10–1.30 0 51 1.13–1.46 4 22

>1.30 51 38 1.51–4.22 13 13 14 & 38 vs 0 & 51

p=0.0002; OR=38.8; CI=2.24–671 26 & 25 vs 9 & 43

p=0,0007; OR=4.97; CI=2.01–12.28

BRCA(−) BRCA(+) Ranges Ranges

Fe/Zn Cancers Controls Fe/Zn Cancers Controls >1.10–1.40 0 65 0.80–1.50 9 43

≤1.10–>1.40 32 108 <0.8 & >1.5 26 25 p<0,0001; OR=39.24; CI=2.36–652 p=0,0007; OR=4.97; CI=2.01–12.28

Cancer risk can be decreased Cancer risk can be decreased by supplementation?by supplementation?

Clinical trialsClinical trials

Cancer risk can be decreased Cancer risk can be decreased by supplementation?by supplementation?

Clinical trialsClinical trials

n=1312; n=1312; mean age 63 yrs (18–80)mean age 63 yrs (18–80) randomised study; randomised study; Se 200 μg/day or placebo; Se 200 μg/day or placebo; observation length 6–8 yrs; observation length 6–8 yrs; initial level of Se concentration initial level of Se concentration

114 μg/l plasma 114 μg/l plasma

n=1312; n=1312; mean age 63 yrs (18–80)mean age 63 yrs (18–80) randomised study; randomised study; Se 200 μg/day or placebo; Se 200 μg/day or placebo; observation length 6–8 yrs; observation length 6–8 yrs; initial level of Se concentration initial level of Se concentration

114 μg/l plasma 114 μg/l plasma

American studyAmerican study— NPC (Nutritional Prevention of Cancer) — NPC (Nutritional Prevention of Cancer)

AAmermericicaan study n study — NPC— NPC

Independantly on tumor site Mortality

Se Placebo Risk p

40 66 0,59 0,008 Morbidity

Se Placebo Risk p

105 137 0,75 0,03

Independantly on tumor site Mortality

Se Placebo Risk p

40 66 0,59 0,008 Morbidity

Se Placebo Risk p

105 137 0,75 0,03

Total morbidity depending on initial concentration of Se

Se level Se Placebo Risk p

≤ 105,2 μg/l 27 54 0,51 0,005

105,3–121,6 μg/l 34 46 0,70 0,11

> 121,6 μg/l 44 37 1,20 0,43

Total morbidity depending on initial concentration of Se

Se level Se Placebo Risk p

≤ 105,2 μg/l 27 54 0,51 0,005

105,3–121,6 μg/l 34 46 0,70 0,11

> 121,6 μg/l 44 37 1,20 0,43


Morbidity on cancer

Site Se Placebo Risk p

Prostate 22 42 0,48 0,005

Lung 25 35 0,74 0,26

Colon 9 19 0,46 0,057

Breast 11 6 1,89 0,21

Morbidity on cancer

Site Se Placebo Risk p

Prostate 22 42 0,48 0,005

Lung 25 35 0,74 0,26

Colon 9 19 0,46 0,057

Breast 11 6 1,89 0,21


Meta-analysis of Randomized Controlled Trials of Selenium Supplements in Cancer

PreventionLee et al. Nutrition & Cancer, 2011; 63:1185-959 RCTs were included; 8 involved high-risk populations

Main analysisSe supplementation alone was found to have an overall preventive effect on cancer incidence

RR = 0.76; 95% CI = 0.58 to 0.99; n = 9

Subgroup analysesThe preventive effect was observed in

populations with low baseline serum Se (<125.6 g/L) RR = 0.64; 95% CI = 0.53 to 0.78; n = 7

populations at high risk for cancer RR = 0.68; 95% CI = 0.58 to 0.80; n = 8.

RaymanRayman M. Szczecin 30.08.2012 M. Szczecin 30.08.2012

Prevention of hereditary breast cancer by Prevention of hereditary breast cancer by personalized optimization of body Se, Zn, Fe personalized optimization of body Se, Zn, Fe levels using diet supplementslevels using diet supplements

N=12000 females HBC, HBON=12000 females HBC, HBO N=2000 females BRCA1 carriersN=2000 females BRCA1 carriers 7000 supplementation with measurement of 7000 supplementation with measurement of

microelements levels microelements levels 7000 controls7000 controls 5 years follow up (2014-2019)5 years follow up (2014-2019)

Prevention of hereditary breast cancer by Prevention of hereditary breast cancer by personalized optimization of body Se, Zn, Fe personalized optimization of body Se, Zn, Fe levels using diet supplementslevels using diet supplements

N=12000 females HBC, HBON=12000 females HBC, HBO N=2000 females BRCA1 carriersN=2000 females BRCA1 carriers 7000 supplementation with measurement of 7000 supplementation with measurement of

microelements levels microelements levels 7000 controls7000 controls 5 years follow up (2014-2019)5 years follow up (2014-2019)

Clinical trialClinical trial

Cisplatinum Cisplatinum in preoperative treatmentin preoperative treatment

T. Byrski, T. Huzarski, R. Dent, E. Marczyk, J. Gronwald, J. Jakubowicz, T. Byrski, T. Huzarski, R. Dent, E. Marczyk, J. Gronwald, J. Jakubowicz, C. Cybulski, R. Wiśniowski, D. Godlewski, J. Lubiński, S. NarodC. Cybulski, R. Wiśniowski, D. Godlewski, J. Lubiński, S. Narod

T. Byrski, T. Huzarski, R. Dent, E. Marczyk, J. Gronwald, J. Jakubowicz, T. Byrski, T. Huzarski, R. Dent, E. Marczyk, J. Gronwald, J. Jakubowicz, C. Cybulski, R. Wiśniowski, D. Godlewski, J. Lubiński, S. NarodC. Cybulski, R. Wiśniowski, D. Godlewski, J. Lubiński, S. Narod

AuthorsAuthorsAuthorsAuthors

M. Siołek, M. Szwiec, H. Symonowicz, D. Surdyka, O. Ashuryk, M. Siołek, M. Szwiec, H. Symonowicz, D. Surdyka, O. Ashuryk, A. Jakubowska, B. Górski, T. Dębniak, D. Zuziak, D. SawkaA. Jakubowska, B. Górski, T. Dębniak, D. Zuziak, D. Sawka

M. Siołek, M. Szwiec, H. Symonowicz, D. Surdyka, O. Ashuryk, M. Siołek, M. Szwiec, H. Symonowicz, D. Surdyka, O. Ashuryk, A. Jakubowska, B. Górski, T. Dębniak, D. Zuziak, D. SawkaA. Jakubowska, B. Górski, T. Dębniak, D. Zuziak, D. Sawka

AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments

Thanks toThanks to Estēe Lauder Estēe Lauder Thanks toThanks to Estēe Lauder Estēe Lauder

107 BRCA1 carriers with breast cancers 107 BRCA1 carriers with breast cancers in clinical stage I-III treated with cisplatinum in clinical stage I-III treated with cisplatinum (4 cycles every 3 weeks 75 mg/m(4 cycles every 3 weeks 75 mg/m22) ) December 2006 – June 2014December 2006 – June 2014

107 BRCA1 carriers with breast cancers 107 BRCA1 carriers with breast cancers in clinical stage I-III treated with cisplatinum in clinical stage I-III treated with cisplatinum (4 cycles every 3 weeks 75 mg/m(4 cycles every 3 weeks 75 mg/m22) ) December 2006 – June 2014December 2006 – June 2014

PatientsPatientsPatientsPatients

Response for treatmentResponse for treatmentResponse for treatmentResponse for treatment

N3 N3 22 N2N2 77 T4T4 44 T3+NT3+N 1010

N3 N3 22 N2N2 77 T4T4 44 T3+NT3+N 1010

Cisplatinum subgroup of advanced cancersCisplatinum subgroup of advanced cancersCisplatinum subgroup of advanced cancersCisplatinum subgroup of advanced cancers

N3 N3 1/21/2 N2N2 3/73/7 T4T4 2/42/4 T3+NT3+N 5/105/10

N3 N3 1/21/2 N2N2 3/73/7 T4T4 2/42/4 T3+NT3+N 5/105/10

Pathological complete response – resultsPathological complete response – resultsPathological complete response – resultsPathological complete response – results

4 314 breast cancer patients 4 314 breast cancer patients 113 BRCA1 carriers113 BRCA1 carriers 29 standard preoperative treatment 29 standard preoperative treatment

(AT, TAC, FAC, FEC, AC)(AT, TAC, FAC, FEC, AC)

4 314 breast cancer patients 4 314 breast cancer patients 113 BRCA1 carriers113 BRCA1 carriers 29 standard preoperative treatment 29 standard preoperative treatment

(AT, TAC, FAC, FEC, AC)(AT, TAC, FAC, FEC, AC)

Cisplatinum Cisplatinum in preoperative treatment – control groupin preoperative treatment – control group

Cisplatinum Cisplatinum in preoperative treatment – control groupin preoperative treatment – control group

Results Results Results Results

Effects Groups

Cisplatinum Controls

Pathological complete remission 48% (11/23) 10% (3/29)

Partial remission 52% (12/23) 69% (20/29)

No response 0% (0/23) 21% (6/29)

Cisplatinum + adnexectomy, n=48Cisplatinum + adnexectomy, n=48Deaths 1 (2%)Deaths 1 (2%)

Controls n=70Controls n=70standard treatmentstandard treatment

Death 9 (12,9%)Death 9 (12,9%)

Cisplatinum + adnexectomy, n=48Cisplatinum + adnexectomy, n=48Deaths 1 (2%)Deaths 1 (2%)

Controls n=70Controls n=70standard treatmentstandard treatment

Death 9 (12,9%)Death 9 (12,9%)

BRCA1 BRCA1 – dependant breast cancers – dependant breast cancers Treatment 2006-2014 Treatment 2006-2014 (4,5 yrs „follow up”) (4,5 yrs „follow up”)

Cisplatinum is extremaly effective Cisplatinum is extremaly effective in preoperative treatment of breast cancers in preoperative treatment of breast cancers in BRCA1 mutation carriers A1 in BRCA1 mutation carriers A1

Cisplatinum is extremaly effective Cisplatinum is extremaly effective in preoperative treatment of breast cancers in preoperative treatment of breast cancers in BRCA1 mutation carriers A1 in BRCA1 mutation carriers A1

ConclusionConclusionConclusionConclusion

Welcome for collaboration Welcome for collaboration

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Other arrangements: Other arrangements: [email protected]


http://www.read-gene.com/

mailto:[email protected]

http://www.read-gene.com/

mailto:[email protected]

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Clinical genetics of cancer family syndromes – Polish experience