Laura J. Van ‘t VeerHelen Diller Family Comprehensive Cancer Center

University of California, San Francisco

Biology of disease

Who is at risk for what type of breast cancer and how does type affect outcome

BOP breast course Nov 2010

Kaplan-Meier Survival Curves

Who gets what type of breast cancer?Which breast cancers return?

Breast Cancer - Survival

Disease Biology

• Genetic make-up of individual

• Biology of screen-detected cancers and of intervalcancers

• Biology informs need for systemic treatment

- who is at risk for what type of disease- does type affect outcome- how can type of detection inform management

Who is at risk for what type of disease

Opportunities for prevention

Opportunities for management

rs number Gene Chromo-some

MAF Per allele OR

P (trend test)

    rs1045485 CASP8 2q 0.13 0.88 1.1 x 10–7

    rs2981582 FGFR2 10q 0.38 1.23 2.0 x 10–76

    rs1219648 FGFR2 10q 0.39 1.32 1.1 x 10–10

    rs10941679 5p12 0.24 1.19 2.9 x 10–11

    rs3803662 TNRC9 16q 0.25 1.20 10–36

0.27 1.28 5 x 10–19

    rs13387042 2q34 0.50 1.20 1.3 x 10–13

    rs13281615 8q24 0.40 1.08 5 x 10–12

    rs889312 MAP3K1 5p 0.28 1.13 7 x 10–20

    rs3817198 LSP1 11p 0.30 1.07 3 x 10–9

Familial aggregation of breast cancer

5%(?) CHEK2 1100delC*

Multiple low-penetrance alleles (polygenic model)

25% BRCA1/2

4.7% SNPs

Breast cancer susceptibility loci

rs number Gene Chromo-some

MAF Per allele OR

P (trend test)

    rs1045485 CASP8 2q 0.13 0.88 1.1 x 10–7

    rs2981582 FGFR2 10q 0.38 1.23 2.0 x 10–76

    rs1219648 FGFR2 10q 0.39 1.32 1.1 x 10–10

    rs10941679 5p12 0.24 1.19 2.9 x 10–11

    rs3803662 TNRC9 16q 0.25 1.20 10–36

0.27 1.28 5 x 10–19

    rs13387042 2q35 0.50 1.20 1.3 x 10–13

    rs13281615 8q24 0.40 1.08 5 x 10–12

    rs889312 MAP3K1 5p 0.28 1.13 7 x 10–20

    rs3817198 LSP1 11p 0.30 1.07 3 x 10–9

Recent breast cancer susceptibility loci - SNPs

Easton et al; Cox et al; Stacey et al; Hunter et al

Association of 10 susceptibility loci with tumor subtypes

Broeks et al, BCAC, submitted

Triple negative

ER+PR+Her2-

ER+PR+Her2+

negative positive association(prevents) (increases)

N total = 1370

Breast cancer outcome: Example rs3803662 in TNRC9Second Breast Cancer Risk

Variant allele (homozygous carriers)

in BOSOM breast cancer series

Adjusted HR (95% CI)

2.7 (1.7-4.3)

rs3803662 in TNRC9: increase of contralateral breast cancer risk

Ongoing:

Validation in BCAC series (studies with follow-up data)

Same analyses for other breast cancer risk-related SNPs

Breast cancer outcome: MDM2 SNP309 *TP53 R72P

MDM2 SNP309 (G = variant allele)

GG

GT

TT

TP53 R72P ‘wildtype’

TP53 R72P ‘variant allele’

SNP-SNP interaction effect on survival:

MDM2 SNP309 and TP53 R72P variants combined: 7% worse survival (p<0.05)

also if adjusted for known prognostic factors

Schmidt et al Cancer Res 2007N total =3739

in BCAC breast cancer series

Schmidt et al. JCO 2007

Breast cancer outcome: CHEK2 1100delC

Contralateral breast cancer riskHR (95%CI) 2.1 (1.0-4.3)

Recurrence-free survivalHR (95%CI) 1.7 (1.2-2.4)

Breast cancer-specific survivalHR (95%CI) 1.4 (1.0-2.1)

CHEK2 1100del C carrier:

worse breast cancer outcome

Treatment interaction?

Interaction with SNPs?

Tumor characteristics?

Ongoing data collection and analyses in BOSOM and pooled BCAC series

in BOSOM breast cancer series

Biology informs need of systemic treatment

Opportunities to reduce over- and under-treatment

Effect on morbidity

Kaplan-Meier Survival Curves

Which breast cancers return?

Breast Cancer - Survival

Of 100 women with breast cancer (stage 1/2)

…………~25% will develop a recurrence

………..75% of all patients is treatedwith chemotherapy

So, overall 50% of patients receive toxic chemotherapy of which they do not benefit,

but may suffer the toxic side-effects

Can we do better?

Tumor samples of known clinical outcome

No distant metastasesgroup

Unbiased full genome gene expression

analysis

70 prognosis genes

Tu

mo

r s

amp

les

Distant metastasesgroup

Metasta

ses: wh

ite=

+

Prognosis reporter genes

b

Development of 70 gene

MammaPrint

Nature, 2002

Multi Gene Expression Profilesin Clinical Practice

Clinical Utility MammaPrint

Prospective study implementing MammaPrint, 2003-2006PIs Sabine Linn, Marc van de VijverSponsor: Dutch Health Insurance Council

Bueno et al, Lancet Oncol, 2007, Knauer et al, SABCS 2008 #1084

Discordant cases MammaPrint signature versus Guidelines The Netherlands and Adjuvant-on-line

~30 % discordant cases led in ~20% to adapted treatment advise

Bueno et al, Lancet Oncol, 2007, Knauer et al, SABCS 2008 #1084

Biology of screen detected cancers

Method of detection may inform management

US general population screening data from SEER 1973-2005

Age-adjusted incidence breast cancer by Stage at diagnosis

Distant

In SituRegional

Localized

-> Screening era

threshold set with 0% false negatives

70 Gene Prognosis SignatureSupervised analysis on n=78 tumors, >96% adjuvantly untreated

van´t Veer et al., Nature 415, p. 530-536, 2002

70 significant prognosis genes

Tum

or s

ampl

es

Nature, (2002)

threshold 2ultra-low

Biology of Screen-detected CancersAge 49-60

Screen detected cancers show increase in ultra-low risk cancers

P<0.001

Pre-screening n=143, sreen-detected n=73

12%

30%MammaPrint