Breast cancer sensitivity to neoadjuvant therapy in BRCA1 and CHEK2 mutation carriers and non-carriers

Werner PfeiferN. N. Petrov Institute of Oncology

St. Petersburg / Russian Federation

Speech for the defence Szczecin / Poland

April 19th, 2016

POMERANIAN MEDICAL UNIVERSITY IN SZCZECIN DEPARTMENT OF

GENETICS AND PATHOMORPHOLOGY

Supervisor:Prof. Evgeny Imyanitov (St. Petersburg)

…to make a step forward towards improved personalized medicine…

Clinical approach

Neoadjuvant therapy

• Makes inoperable tumors operable and allows breast conserving surgery

• Assessment of tumor response to various anticancer agents

Neoadjuvant clinical series

• Different pattern of drug sensitivity require modified treatment schemes compared to standard treatments Imyanitov & Byrski 2013, Imyanitov & Moiseyenko 2011

• BRCA1 - associated BC appear to be resistant to the “gold standard” taxanes Kriege 2012, Hubert 2009, Byrski 2008, Wysocki 2008

• Anthracyclines are highly efficient in BRCA1-mutated BCByrski 2010, Liedtke 2008, Carey 2007, Chappuis 2002

• CHEK2 tumors may be resistant to anthracycline therapy Chrisanthar 2008

Key gene: BRCA1

Narod 2004

DNA repair

BRCA mutation (inactivation) may cause selective deficiency in DNA repair

► BRCA1/2-driven tumors respond to platinum compounds and PARP inhibitors in several type of cancers Imyanitov EN & Byrski T 2013

Recurrent mutations in Russia(founder mutations)

BRCA1 & CHEK2- related breast cancer incidences are high in Russia

Gene Mutation Exon Mutation Protein status DomainBRCA1 185delAG 2 frameshift truncated Ring finger

BRCA1 4153delA 11 frameshift truncatedexon 11–13

complex

BRCA1 5382insC 20 frameshift truncated BRCT

CHEK2 IVS2+1G>A 3 substitution, frameshift

truncated splice site of exon 2

CHEK2 del5395 9 + 10 deletion truncated Kinase

CHEK2 1100insC 10 frameshift truncated Kinase

Aims of the study

1) Identification of the BRCA1 or CHEK2 germline mutations among patients who received neoadjuvant therapy

2) Influence of different neoadjuvant treatment regimens in mutation carriers and non-carriers

► goal: to adapt therapeutic regimens for women with a hereditary background

All BC patients treated within years 2000-

2010:n = 7028

BC patients exposed to neoadjuvant

therapy: n = 1668

Patients aged 50 years or younger:

n = 788

Available paraffin blocks: n = 462

Successful genotyping and data analysis: n = 415

Endpoints: pathological complete response (pCR)

and overall response (OR)

Study design

Methods

Statistical analysis:Association between clinicopathological and biological parameters and efficacy of distinct treatment regimens by means of two-sided chi-square test. Fisher’s exact test was used if small patient groups were compared.

DNA extraction Fluorescence-based Real-Time PCR

Mutation diagnosisMelting point analysis

Results

Genotype frequencies

Gene Number of

patients with mutation

Frequency (current study)

Frequency in Slavic BC patients*

BRCA1 19/415 4.6 % 4-5 %

CHEK2 8/415 1.9 % 1-4 %

Total 27/415 6.5 % 7-10 %

Non-Carriers 388/415 93.5% -

• Gaj 2012, Kuligina 2010, Machackova 2008, Cybulski 2007, Sokolenko 2007, Chekmariova 2006, Gorski 2005, Kleibl 2005, Gorski 2004

Neoadjuvant drug regimens

Drug Therapy Petrov Institute (current study)

Mutation negative

BRCA1 mutation carrier

CHEK2 mutation carrier

Anthracycline-based

(FAC, FEC, AC, …)247 9 4

Taxane-based (TAC, TEC, AT, …) 112 7 3

Other (CMF, vinorelbine, capecitabine, …)

29 3 1

Total 388 19 8

Estrogen Receptor Status (ER) n = 241 P-ValueNr. of patients Nr of pCR [%]

0.023Positive 140 10 7.1

Negative 101 17 16.8

Progesterone Receptor Status n = 241Positive 123 7 5.7

0.007Negative 118 20 17.0

Triple Negative Status n = 240Yes 69 15 21.7

0.003No 171 12 7.0

BRCA1 mutation status vs non-carriers 0.024

Clinical characteristics in patients with pCR

Clinical characteristicsreceptor status

BRCA1 CHEK2 Non-carrier Total

patients [%] patients [%] patients [%] patients [%]

ER 15 8 218 241

Positive 2 13.3 6 75.0 132 60.6 140 58.1

Negative 13 86.7 2 25.0 86 39.4 101 41.9

PR 15 8 218 241

Positive 3 20.0 3 37.5 117 53.7 123 51.0

Negative 12 80.0 5 62.5 101 46.3 118 49.0Triple negative

15 8 217 240

No 3 20.0 7 87.5 161 74.2 171 71.3

Yes 12 80.0 1 12.5 56 25.8 69 28.8

pCR according to chemotherapy and mutation status

T-containing = Taxane-containing +/- anthracyclines A-based = Anthtracycline-based without taxanes

Chemotherapy - stratified Mutation - stratified

P = 0.024

ns

ns ns

ns

T-containing A-based Other drugs Non-carriers BRCA1 mut carriers

CHEK2 mut carriers

13(16/122)

13(33/260) 9

(3/33)

12(46/388)

32(6/19)

0(0/8)

ns

OR according to chemotherapy and mutation status

T-containing = Taxane-containing +/- anthracyclines A-based = Anthtracycline-based without taxanes

Chemotherapy - stratified Mutation - stratified

P = 0.001

ns P = 0.001 ns ns

P = 0.02

T-containing A-based Other drugs Non-carriers BRCA1 mut carriers

CHEK2 mut carriers

88(107/122

)

87(226/260

)

55(18/33)

86(333/388

) 77(14/19)

50(4/8)

Efficacy of distinct treatment regimens in BRCA1 carriers / pCR

Taxanes +/- anthracyclines Anthracyclines without taxanes

Other drugs

0(0/7)

56(5/9)

33.3(1/3)

P = 0.002

Author Year Gene No. of patients

cancer Therapy %pCR %OR

Byrski 2009 BRCA1 10 BC Cisplatin 90 100

Byrski 2010 BRCA1 23282512 T:102

BC ACFACATCisplatin

2221883

Byrski 2012 BRCA1 20 MBC Cisplatin 45 80

Byrski 2014 BRCA1 107(82 TNBC)

BC Cisplatin 676361566161

Age 20-40yPrior CTER neg statusER pos statusTNTotal

Pfeifer 2014 Non-CarrierBRCA1BRCA1CHEK2

3881998T: 415

BC *1 *2*1 *2*2*1 *2

1232560

86748950

Comparison of pCR and OR with other studies conducted in Szczecin

*1 +/- Anthracyclines and taxanes – containing regimens and other drug types; *2 Anthracycline-based regimens only

Efficacy of distinct treatment regimens in CHEK2 carriers / OR

Taxanes +/- anthracyclines Anthracyclines without taxanes

Other drugs

67(2/3)

25(1/4)

1 PR(1/1)

ns

Conclusions • BRCA1 mutation carriers achieve pathological complete

response more frequently than non-carriers

• The benefit of BRCA1-mutation is limited to women treated with anthracycline-based therapy without taxanes

• Taxane - containing therapy is associated with a poor outcome in BRCA1 mutation carriers

• The efficacy of anthracyclines without taxanes is poor in CHEK2 mutation carriers, however there is partial response with the use of taxanes

• The findings need to be validated in independent studies

Grants and Promotions

Dr. Margarete-Fischer-Bosch Institute for Clinical Pharmacology (IKP) and Robert-Bosch-Hospital, Stuttgart / Germany

N. N. Petrov Institute of Oncology in St. Petersburg / Russian Federation

Pommeranian Medical School in Szczecin / Poland

Marie Curie Initial Training Networks (ITN)

Werner Pfeifer, N. N. Petrov Institute of Oncology, St. Petersburg, Russian Federation

St. Petersburg (Host Institute): Anna SokolenkoAlexandr BessonovSwetlana AbyschewaEkatherina KuliginaOlga PotapovaEvgeny SuspitsinGrigory YanusNatalia MitiushkinaAglaya IyevlevaEkatherina IrklienkoAlexandr TogoEvgeny Imyanitov

Stuttgart: Secondment Werner SchrothReiner HoppeJana IhringMatthias SchwabAgapi TheodoridouHiltrud Brauch

Acknowledgements:

Stettin:Jacek Gronwald

BRCA1/CHEK2-treatment and responseBRCA1

Complete response FACFECCMF

321

Partial response FACFECCMFVinorelbine+ACFEC+TACTACFAC+docetaxelAT+CMF

31211311

CHEK2Partial response FEC + RT

Goserelin11

Partial response after SD(additional treatment)

FEC + docetaxel 2

Stable disease FACTAC

31

6

Recommendations for therapy

• Physicians should consider the same neoadjuvant and adjuvant chemotherapy for routine use.

• All chemotherapy ought to be given before surgery rather than split into preoperative and postoperative treatment (Kaufmann et al. 2012).

• Polychemotherapy is more effective than single therapy (Cleator et al. 2002).

• Response-guided approach• (von Minckwitz et al. 2013)

BC risk• Breast cancer (BC) is the most common disease among

women.

• The individual risks vary from 0.06% in the age of 20 - 30 years up to 3.8% in the age over 70.

• The individual BC development risk, provided the life length is over 70 years, is 12.3%

Founder effect

• Small groups of people remain isolated for substantial period of time – descendants of a single person?► increase in inbreeding – rare mutations become more and more common…!!! (Ferla 2007)

• In genetically homogeneous populations with strong founder effect (like Ashkenazi Jews) it is much easier to perform the molecular diagnostics of hereditary breast cancer. (Lynch 2008, Ferla 2007)

• Russian hereditary BC demonstrates a surprisingly strong founder effect - multimillion nation spread from Baltic Sea to Pacific Ocean. (Iyevleva 2010; Imyanitov 2008, Sokolenko 2007)