The role of genetics in the development and treatment of

breast cancer?

Judith OffmanCancer Prevention Trials Unit

Wolfson Institute of Preventive MedicineBarts and The London School of Medicine and

Dentistry

DNA and mutations

Types of Mutations

Gene

Gene

Gene

GeneGene

Adopted from http://teampub.wordpress.com/2008/04/08/dna-chromosomes-and-genes-%E2%80%93-an-overview/

Genetic factors associated with breast cancer

High penetrance mutations

• Rare• Associated with

very high risk • Six genes

identified so far

Moderate penetrance mutations

• Uncommon• Moderate

increase in risk• Four genes

Low penetrance mutations

• Common• Small increase

in risk • Combination of

several result in breast cancer

• 13 genes so far

Genes associated with breast cancer

BRCA1 and BRCA2 cancer susceptibility genes

Mutations account for 3-10% of all breast

cancer cases

Breast cancer probability:• BRCA1: 57 – 65%• BRCA2: 45 - 49%

Ovarian cancer probability:• BRCA1: 39 - 40%• BRCA2: 11 - 18%

Mutation prevalence in the general population• BRCA1: 0.11 – 0.32 %• BRCA2: 0.12 – 0.69 %

Founder effect

Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute

Three mutations common in Ashkenazi Jewish women

• Mutations together yield a 2 – 3 % mutation carrier prevalence among US Ashkenazi Jews• High prevalence of BRCA1 mutations in Hispanics

Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute

What happens during tumour development?

Adopted from http://commons.wikimedia.org/wiki/File:Loss_of_heterozygosity.PNG

M, maternal; P, paternal

Tumours start with one mutated cell

Adopted from ‘Understanding Cancer Genomics’ by National Cancer Institute

Why are BRCA 1 and 2 important?

Why do mutations result in tumours?

Genes make protein

Adopted from illustrations by the ‘Human Genome Program’ of the U.S. Department of Energy

DNA damage and repair

10,000 events per cell/day

Mutations Cell death or tumour

development

DNA repair

BRCA1 and 2 functionRepair breaks in DNA

BRCA1

BRCA2

Cell nucleus

gH2AX foci in untreated S-phase cells

Mirzoeva and Petrini 2003

Karyotype

Human cells contain 23 pairs of chromosomes

Karyotype of BRCA- breast cancer

HCC1937 cells (BRCA1-) adopted from Grigorova M., et al.. Cytogenet Genome Res. 2004

Novel treatments and prevention

New cancer treatments for BRCA patients: PARP inhibitors

BRCA1/2: involved in repairing double

strand breaks

PARP1: protein involved in repairing single strand breaks

PARP Inhibitor in CellsBRCAPARP No effect

BRCAPARP No effectX

BRCAPARP No effectX

BRCAPARP Cell deathXX

Breast cancer cell: BRCA-/-

Non-cancer cell: BRCA+/-

In tumours

PARP inhibitorXXX

XXX

XX

XXXX

XXX

XXX

Clinical trials – monotherapy

Trials of PARP inhibitors mainly in BRCA1/2 patients

Olaparib in a BRCA1/2 mutation carrier enriched study population

Breast, ovarian and prostate

cancer

No obvious increase in adverse effects seen in mutation

carriers

Fewer adverse effects than conventional

chemotherapy

Antitumor activity was reported only

in mutation carriers

Tumour response to Olaparib in BRCA1/2 mutation carriers

19 BRCA mutation carriers evaluated for tumour response.

Fong et al. N Engl J Med 2009; 361:123-134

Combination with conventional chemotherapy for sporadic tumours

Large number of

chemotherapy agents work by damaging DNA

PARP inhibitors will

enhance toxicity of

these agents

> 100 proteins involved in

double strand break repair

Inactivated in sporadic cancers ?

“BRCAness” of triple-negative breast cancers

response to PARP inhibitors

like in BRCA mutation carriers

Combination Trials

Future Directions

Find ways to deal with emerging

resistance

Identify best combinations to

treat sporadic breast and ovarian cancers

PARP inhibitors used for breast cancer

prevention in BRCA1/2 patients