Hereditary Breast Cancer Genes and Outcome in Young-Onset Breast Cancer (POSH Study)Diana M Eccles

Genetics in Clinical Cancer Care: From Family Reunions to the Frontline of Developmental Therapeutics

Chicago 17th-19th April 2020

Disclosures (none current)• Advisory board – Astra Zeneca

• Lecture fee – Pierre Fabre

• Norwegian Research Council – Advisory Board

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• What else should we know to help clinicians and patients make well informed choices

• Effect of each breast CSG on response to conventional therapies compared to non-carriers

• Influence of specific breast CSGs on cancer phenotype

• Personalised treatment decisions

– Surgery timing and type

– Adjuvant treatment

– Experimental treatment

Inherited breast cancer susceptibility genes increase risk of cancer

Prospective study of Outcomes for Sporadic versus Hereditary breast cancer (POSH)• Setting: UK NHS oncology clinics 2000-2008

• Eligibility: Invasive breast cancer diagnosed ≤ 40 years

• Blood DNA samples stored at recruitment

• Oncological management decided by MDT per national guidelines

• Comprehensive diagnosis and treatment data from hospital records, tumour blocks, long term follow up

Study recruited 23% of UK population diagnosed with BC ≤40 years

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Conclusions: increased frequency of ER-negative tumors and earlyrelapse in young patients but an equally poor longer-term outlookfor young patients who have ER-positive tumors with HER2-negativeor -positive disease.

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Kaplan-Meier survival

a) All patients DRFS 5YR 76.6%

b) ER+ v ER-ve 8YR –68.1% v 68.2%

c) All patients OS 8YR 67.6%

d) ER+ v ER- 67.7 v 67.5%

Time varying hazard ratio

7Copson et al JNCI 2013

Non-genetic factors that impact BC risk• Hormonal

– OCP, HRT, age at menarche

• ER+ve BC Risk• Socio-economic status

• Obesity (postmenopausal) and physical activity

• Alcohol

• Radiation

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Obesity adversely affects outcomesCopson et al Annals of Oncology 2014

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EthnicityCopson et al British Journal of Cancer (2014) 110, 230–241

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Primary outcome analysis

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• Clinical genetic services test results were collected if available from NHS genetics laboratories

• Research DNA sample available for n=2857 patients

• All available tested on a customised breast cancer gene panel included BRCA1, BRCA2, TP53, PALB2and others

• BOADICEA >10% also with MLPA

Genetic testing

• 2733 patients were included

–8/2733 (0.3%) patients were known gene carriers pre cancer

–337/2733 (~12.3%) had pathogenic BRCA1(201) or BRCA2 (136) mutations

• Clinical genetic testing results were available for 388/2733 (14.2%) 182 (46.9%) had pathogenic mutations

Results – genetic testing

Significant differences in tumour characteristics BRCA1, BRCA2, BRCA-• Higher grade tumours BRCA1 > BRCA2 > BRCA- (p<0.001)

• Fewer HER2+ tumours in BRCA1 (6.8%) and BRCA2(11.2%) compared to BRCA– (29.5%) [BRCA+ vs BRCA-(p<0.001)

• More ER-ve in BRCA1 (75.5%) compared to 30.9% in BRCA-ve

• More ER+ve in BRCA2 (84.6%) compared to 69.1% in BRCA-ve

Primary outcome (all) BRCA+ v BRCA-

Overall Survival

UVA HR 0.99 (0.80 to 1.23)p=0.938

MVA HR 0.96 (0.77 to 1.21)p=0.742

Median follow up time (years) = 8.2 (0.4-15.6)Lost to follow up 91 = (3.3%)

Overall Survival

MVA HR 0.96 (0.76 to 1.22), p=0.764

All cases - BRCA1 versus non-carriers

No differenceBRCA1 vs BRCA-BRCA2 vs BRCA-

Triple negative breast cancer in POSH cohort

n=558 (20%)

BRCA1 = 123/558 (22%)

BRCA2 = 13/558 (2%)

TNBC - overall survival

Hazard rates for death over time

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Excluding 31 patients who had bilateral mastectomies in first year after diagnosis

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Hazard ratio changes over time

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New primary cancer incidence - all• 151 contralateral breast tumours

• 37/201 (18·4%) in BRCA1 • 17/137 (12·4%) in BRCA2 carriers • 97/2395 (4·1%) in non-carriers

• 3 ovarian cancer, 1 PPC

• All in BRCA1 carriers

• Potentially preventable with BRRM and BRRSO

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Excluding all patients with second primary BRCA-attributable cancers

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• Medium term, there is no significant difference in survival between BRCA gene carriers and non-carriers amongst symptomatic young breast cancer patients.

• Deaths from primary breast cancer are higher than the incidence of new primary cancers in the first 10 years

• Breast surveillance (MRI) or BRRM and timely BRRSO should improve overall longer term survival for BRCA carriers who survive their initial cancer

Is there a difference?

Some other genes

TP53 – high risk rare

CHEK2 – moderate risk

p53 – the guardian of the genome (David Lane, Nature July 1992)

Somatic mutations frequent in TNBC and HER2+ BC

Germline pathogenic variants in TP53 gene

• First described as cause of Li Frameni Syndrome (Malkin, Science 1990)

• Variable frequency found on panel testing BC patients

• Association with HER2+ breast cancer (Wilson et al J Med Genet 2010)

• Densely sclerotic tumours (Packwood et al JPCR 2019)26

POSH cohort findings• ≤ 40 with invasive breast cancer tested and validated

• Pathogenic TP53 variants amongst all cases 15/2304 (0.6%)

• Pathogenic TP53 variants amongst TNBC = 1/588 (0.2%)

• Pathogenic TP53 variants amongst HER2+ = 14/664 (2%)

• Pathogenic TP53 variants reported no FH = 9/14 (64%)

• No difference in survival but very small numbers

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Phenotype in patients with germline CHEK2 pathogenic variant

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Presenting tumours were significantly more likely to have axillary nodes involved (p=0.0098) and to be grade 2hormone receptor positive (p=0.029)

CHEK2+ve n=53/2344 (2.3%)

Symptomatic early onset CHEK2+ve breast cancer associated with an adverse prognosis

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Greville-Heygate et al JCO Precision Oncology in press

POSH team DataSue GertyLorraine DurcanStatsTom MaishmanLouise StantonDoug Altman BioinformaticsWill TapperStephanie Greville-HeygateClinical teamEllen CopsonBryony EcclesRamsey Cutress

Patients, principle investigators and staff in 127 UK NHS hospitals

Pathology: TMAs, IHC: Louise Jones, Linda Haywood and others at Queen Mary University London

Sequencing: Doug Easton, Alison Dunning and team, Cambridge University

Thanks to:-

POSH Steering GroupDiana EcclesPeter SimmondsDoug AltmanLouise JonesPaul Pharoah

Sunil LakhaniAndy HanbyGareth EvansRos Eeles

Hisham HammedAlastair ThompsonFiona GilbertShirley Hodgson