Jeffrey N. Weitzel, M.D.

Germline Mutations

Hereditary Breast and

Ovarian Cancer Risk and

Management Issues

Cancer Screening &

Prevention Program

Kesselheim A and Mello M. N Engl J Med 2010;10.1056/NEJMp1004026

Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use

of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom)

June 2013 - U.S. Supreme

Court rules that as nature,

genes cannot be patented

BRCA1- and BRCA2-Associated Cancers: Lifetime Risk

Breast cancer 50%-85% (often early age at onset)

Second primary breast cancer 40%-60%

Ovarian cancer 15%-45%

Absolute risk likely to be higher than 10%

- Prostate cancer

Absolute risk 10% or lower

- Male breast cancer

- Fallopian tube cancer

- Pancreatic cancer

BRCA1 and BRCA2

On chromosomes 17 and 13, respectively

Autosomal dominant transmission

Proteins have a role in genomic stability

>2,000 different mutations, polymorphisms, and

variants distributed over both genes

Breast Cancer Information Core

Nonsense Missense Splice-site

BRCA1

5

BRCA: Selected Examples of Founder Mutations

Population BRCA1 Mutations BRCA2 Mutations

Ashkenazi

Jewish

185delAG 5382insC 6174delT

Icelandic 999del5

British 6-kb duplication of exon 13

4184del4

6503delTT

Dutch

(Netherlands)

2804delAA

Large deletions of exons 13 & 22

Chinese 1081delG

Russian 5382insC 4153delA

African A. 1832del5 5296del4

Hispanic 185delAG deletion exons 9-12 3492insT

Inherited Genomic Rearrangements of BRCA1 and BRCA2

35/300 (12%) sequence negative high risk families

Walsh et al, JAMA 295:1379-1388, 2006

Other:

CHEK2 n=14 (5%)

TP53 n=3 (1%)

k Comprehensive genetic testing includes full sequencing of BRCA1/BRCA2 and detection of large genomic rearrangements.

Influence of BRCA1 Genotype on

Histopathology in Breast Cancer (BC)

• Less likely to express estrogen receptor or Her2/neu

• Have a high nuclear grade

• Show less tubule formation

• Have a higher mitotic count

• Medullary histology more common (~ 6%)

• More BRCA1 mutations in “triple negative”

• DCIS is less associated with BRCA1 than BRCA2

• BRCA testing may be appropriate for triple negative BC or

early onset DCIS, especially if family history of BC and/or OC

Eisinger et al. Cancer Res 56:471, 1996; Claus et al, JAMA 293:964-969, 2005;

Breast Cancer Linkage Consortium. Lancet 349:1505, 1997; Kandel (ASCO), 2006

Contribution of known genes to explaining

familial aggregation of breast cancer

Other familial risk factors

(genes, environment)

BRCA1

BRCA2

TP53

PTEN

ATM

CHEK2,BRIP1,PALB2

8 WGA SNPs

CASP8

ASCO

Li-Fraumeni Syndrome

Bilateral Breast, 40

Leukemia, 33

Brain tumor, 32

Breast, 40 Osteosarcoma, 42

Breast, 35

Soft tissue sarcoma, 7

Leukemia, 6

Affected with cancer

TP53-mutation carrier 50

Cowden Syndrome Pedigree

Multinodular goiter,

dx 25

Follicular thyroid

cancer, dx 35

Trichilemmomas, dx 21

Breast cancer, dx 35

Macrocephaly

Papillomatous papules

Multinodular goiter, dx 22

Affected

Noncarrier

Eng C. J Med Genet. 2000;37:828-830

Risk for uterine,

but not ovarian

ca in CS

Emerging Breast Cancer Phenotype in

Women with TP53 Germline mutations

Cohort of TP53

Carriers

N ER+ Her2/neu+

LiFE Consortium 32 84% 63% Masciari et al.

BCRT 2012

UK 9 83% Wilson et al. J Med

Genet 2010

MDACC/Chi 30 70% 67% Melhem-Bertrandt et

al. Cancer 2012

Women < 40 BC,

unselected for FHx

- 52-66% 22-33% Collins et al. BCRT

2011; Gonalez-

Angulo et al. Cancer

2012

Genetic Predisposition Testing Is a Multi-Step Process

Identify at-risk

patients

Provide pretest

counseling

Obtain informed consent

Select and offer test

Disclose results

Provide post-test

counseling and

follow-up

Cancer Screening & Prevention Program

Estimating Cancer Risk

Family History

Empiric Data

Genetic Testing

Limited Paternal Family Structure

Br 47

Breast Cancer

57 y 65 y

85 y

60 y d. 55 y d. 36 y

MVA

87 y 88 y d. 73 y

62 y 55 y

Adequate Family Structure for both

Maternal and Paternal Lineage

57 y 65 y

85 y

55 y 60 y

87 y 88 y d. 73 y

55 y 58 y 62 y

Br 47

Breast Cancer

Weitzel et al. JAMA 297(2007) 2587-2595

Br-47

41

31 23 33

Ov-38 47

81

Br- 45

Br- Pm

43

30

Br-49

28 25

45

21 25 24 18 26 1 9 9 11

Pr- 50

71

Br- Pm

HEREDITARY BREAST AND OVARIAN CANCER

+ - - + ex9-12del

Clinical Management of BRCA

Mutation-Negative Patients

Negative BRCA1 and/or BRCA2 test result

Member of family w/ known BRCA1 or BRCA2 mutation?

NO YES

Emphasize empirically increased risk of breast and/or ovarian cancer

Provide individualized risk-management plan

Encourage adherence to population screening

guidelines

Emphasize risk of sporadic cancer

Clinical Management of BRCA Mutation-Positive Patient

Cancer Screening & Prevention Program

Positive BRCA1 or BRCA2

test result

Possible testing for

other adult relatives

Increased

surveillance

Prophylactic

surgery

Lifestyle

changes

Chemo-

prevention

Dense Breast Tissue

Mammo

Size

Time

?

MRI and Breast Cancer Detection in BRCA Carriers - Sensitivity

N with mutations

Invasive cancers % by MRI % by

mammogram

Warner

(2004) 236 16 81% 31%

Kriege

(2004) 358 20 80% 33%

MARIBS (2005) 120 12 92% 23%

TOTAL 714 48 83% 30%

Breast MRI may be considered the

standard of care for high risk patients

Cumulative incidence of early-stage (stages 0 to I)

breast cancer in magnetic resonance imaging (MRI)

Warner E et al. JCO 2011;29:1664-1669

Is risk reduction mastectomy (RRM) effective?

Skin-Sparing Mastectomy With Immediate Reconstruction

Comparison of 214 high risk

women who underwent RRM

(1960-1993) to sister

controls:

3 cases BC observed vs.

37.4 expected = 92% Risk

Reduction Hartmann L. et al, NEJM, 340:77, 1999;

JNCI 93:1633, 2001

Study of 483 BRCA carriers:

>90% risk reduction Rebbeck, T.R., et al. JCO 22:1055, 2004

New Primary Cancer Risk and Modifiers Among 491 BRCA Carriers

10-year contralateral breast cancer risk

43.4% for BRCA1; 34.6% for BRCA2

Age 50 at diagnosis: HR 0.63; 95% CI 0.36-1.10

Tamoxifen use: HR 0.59; 95% CI 0.35-1.01

Oophorectomy: HR 0.44; 95% CI 0.21-0.91

10-year ovarian cancer risk after breast cancer:

12.7% for BRCA1, 6.8% for BRCA2 (p=0.03)

Ovarian cancer was the cause of death in 25% of the Stage I breast cancer patients

Metcalfe et al. J Clin Oncol 2004, 22:2328-2335. Gyn Onc 2005; 96:222-226

Options for breast cancer patients

with BRCA mutations

• Surgical options for the breast – therapeutic mastectomy versus breast conservation

therapy on affected breast

– risk reduction mastectomy on contralateral breast

• Hormonal risk reduction options – BSO

– tamoxifen

• Screening – mammography

– MRI

Genetic Cancer

Risk Assessment

Prevention Treatment

Oncologic

Consultation

Decisions, decisions…

Prophylactic

Oophorectomy

CA125 Screening

Chemoprevention

Options for BRCA1, BRCA2 Carrier

CASH study. N Engl J Med 316:650, 1987.

Rosenberg L et al. Am J Epidemiol

139:654, 1994. Ursin G et al. Cancer Res

57:3678, 1997. Narod et al, NEJM

339:424, 1998Narod SA, et al. Oral

contraceptives and the risk of breast

cancer in BRCA1 and BRCA2 carriers. J

Natl Cancer Inst 2002;94:1773-9.

Oophorectomy Reduces

Ovarian Cancer, Breast Cancer,

and all cause mortality

Greatest breast cancer risk

reduction among BRCA1

mutation carriers without a prior

dx of breast cancer who had

their oophorectomy < age 50

HR: 0.15 (95% CI 0.04-0.63)

Genetic status is on the cusp of

helping to determine composition

of breast and ovarian cancer

treatment regimens

PARP inhibition and tumor-selective synthetic

lethality

DSB, double-strand break; HR, homologous recombination

SSB, single-strand break

PARP

DNA damage (SSBs)

DNA replication

(accumulation of DNA DSBs)

Normal cell

with functional HR pathway HR-deficient tumor cell

(e.g. BRCA 1/2-/-)

Cell survival Cell death

HR-mediated

DNA repair

Impaired HR-

mediated

DNA repair

Tumor-selective cytotoxicity

PARP inhibition

Farmer H et al. Nature 2005;434:917–921

Bryant HE et al. Nature 2005;434:913–917

McCabe N et al. Cancer Res 2006;66:8109–8115

PARP inhibitors in cancer therapy

Agent Company Single / Combination

therapy

Route of

administr

ation

Disease Clinical status

AG014699 Pfizer (New

York, NY)

Single IV Advanced BC

and OC

Phase 1 in solid

tumors, phase 2 in

BC and OC

AZD2281

(Olaparib)

AstraZeneca/Ku

DOS (London,

UK)

Single, combinations with

carbo/paclitaxel or

paclitaxel alone

Oral Advanced BC

and OC

Phase 2, 3

ongoing

ABT-888

(Veliparib)

Abbott

Laboratories

(North Chicago,

IL)

Combination with carbo,

temozolomide, or

cisplatin/vinorelbine

Oral Advanced BC Phase 1, 2, 3

ongoing

BSI-201

(Iniparib)

Sanofi-Aventis

(Bridgewater,

NJ)

Gemcitabine/carboplatin IV Triple-negative

BC

Phase 2, 3

ongoing

GPI 21016 MGI Pharma

(Bloomington,

MN)

Combination with

temozolomide

Oral Solid tumors Phase 1 planned

Phase II trial of the oral PARP

inhibitor olaparib in BRCA-deficient

advanced breast cancer: Best %

change from baseline in target BC

lesions by prior chemotherapy

–100

–80

–60

–40

–20

0

20

40

60

80

100

Previous anthracycline, taxane and capecitabine

Increasing tumor shrinkage

Best %

change from

baseline

*Prior platinum Tx

* *

* *

*

*

Tutt et al. Lancet 2010

Olaparib 400 mg bid cohort

ORR, n (%) 11 (42)

CR, n (%) 1 (4)

PR, n (%) 10 (39)

Protocol NCI #8264: ABT-888 +/- Carbo

Adv/Mets BRCA- Breast Cancer

ABT-888 400 mg

BID >2 cycles

ABT-888 150 mg BID

+ Carbo AUC=5

Safety Lead-In

21 patients

Endpoints: BRCA1 vs. BRCA2 •RECIST Criteria •PFS ABT-888 single agent; post-progression for combination •Safety & Tolerability, Pharmacokinetics •Correlative studies will include biomarkers of PARP and carboplatin effect, as well as prospective analyses of mechanism(s) of resistance •in vivo selection for BRCA “reversion” mutants that restore the reading frame and functional domains such as HRR may be one mechanism of drug resistance

Post-progression

How Much Breast and Ovarian Cancer Is Hereditary? It depends on what tests you use to answer the question

Sporadic

Family clusters

Hereditary

Ovarian Cancer Breast Cancer

5%–7% 10-23%

15% -20%

Proportions ovarian, fallopian tube, or peritoneal cancer

patients with respective germ-line loss-of-function mutations

Walsh T et al. PNAS 2011;108:18032-18037

Domchek SM, et al. Multiplex

genetic testing for cancer

susceptibility: out on the high

wire without a net? J. Clin.

Oncol. 2013;31(10):1267-

1270.

Weitzel et al. Genetics, Genomics, and Cancer Risk Assessment: State of the Art and

Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 2011;61:327–359

clinical utility

accepted

clinical utility

unclear

directed by

HCP high

penetrance

intermediate

penetrance

directed by

individual DTC

testing

low penetrance

variants

Clinical Utility and professional

mediation of genetic testing

American Society of Clinical Oncology Policy Statement Update: Genetic

and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 2010.

Key advances and evidence for advice:

• There are advances in protocols for screening (MRI), risk reduction

(RRSO, RRM), and targeted treatment

Warner et al, 2004; Kriege et al, 2004; Rebbeck et al, 2002, Kauff et al, 2002;

Weitzel et al, 2007

• GCRA influences surgical decisions in a risk-appropriate way and

should be considered for women with newly diagnosed early stage

breast cancer and suspicion of BRCA gene mutation

• Timing of GCRA in the sequence of events in cancer diagnosis

and treatment is dependent on both patient and provider

variables and limitations

Weitzel et al, 2003; Schwartz et al, 2004, 2005.

Cancer Screening & Prevention Program

Breast and Ovarian Cancer Screening and Prevention

Key advances and evidence for advice:

• BRCA testing for early onset DCIS, and for single cases of BC

<50 years if limited family structure; <60 if “triple negative”

Claus et al, 2005; Kandel et al, 2006; Weitzel et al, 2007

• Large rearrangements account for a significant proportion of

high risk families without sequence detected BRCA mutations

Walsh et al, 2006; Weitzel et al, 2007; MGL 2012

• Documented efficacy of interventions for BRCA mutation

carriers drives medical necessity and liability issues, making

GCRA a standard of care

• GCRA along with risk reduction interventions are cost-effective

tools for increasing quality-adjusted life

Cancer Screening & Prevention Program

Breast and Ovarian Cancer Screening and Prevention