Lorraine Hartles West Midlands Regional Genetics Laboratory

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Presentation transcript:

Lorraine Hartles West Midlands Regional Genetics Laboratory Implementation of the extended panel analysis for improved cancer diagnosis (EXPAND) study Lorraine Hartles West Midlands Regional Genetics Laboratory

Hereditary breast and ovarian cancer More than 58,000 new cases of breast and ovarian cancer in the UK per year 5-10% are caused by hereditary factors 20% of these caused by BRCA1 and BRCA2 mutations Current testing strategy Sequencing and MLPA analysis of BRCA1 and BRCA2 PALB2 sequencing for most breast cancer referrals

Current detection rates (2015-2017)

International breast and ovarian cancer genetic testing There is a global effort to identify the elements causing this missing heritability in breast and ovarian cancer Country Gene panel size (excluding BRCA1/BRCA2) Cohort size Detection rate (excluding BRCA1/BRCA2) USA (2017) 17 300 8% China (2018) 38 937 6.8% Italy (2017) 92 255 6.6% Germany (2018) 8 5589 6.1%

Aims of EXPAND Increase the diagnostic yield for patients with hereditary breast/ovarian cancer Increase understanding of the genetic contribution to these cancers Expand the understanding of the phenotypic spectrum associated with known cancer predisposition genes Support the development of clinical management decisions for patients with variants in moderate risk genes

Genes on the EXPAND panel Gene panel is based upon recommendations following the UK CGG workshop in May 2017 BRCA1 MLH1 ATM PTEN RAD51D BRCA2 MSH2 CHEK2 STK11 BRIP1 PALB2 MSH6 TP53 RAD51C NBN * * NBN is for research only and results in these genes should not influence clinical management Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group. Taylor, A., Brady, A., Frayling, I., et al. J Med Genet 2018;55:372–377.

Genes on the EXPAND panel Ovarian cancer risk Breast cancer risk ATM OR 1.69 (1.19-2.4) OR 2.78 (2.22-3.62) c.7271T>G OR 11.0 (1.42-85.7) BRIP1 OR 2.62 (1.72-3.98) No association found CHEK2 OR 2.26 (1.89-2.72) c.1100delC OR 2.31 (1.88-2.85) MLH1 20% by age 70 19% by age 70 MSH2 24% by age 70 11% by age 70 MSH6 1% by age 70 OR 1.93 (1.16-3.27) Gene Ovarian cancer risk Breast cancer risk NBN OR 1.85 (1.05-3.24) OR 3.0 PTEN No association found OR 5.83 (2.43-10.4) RAD51C 9% by age 80 RAD51D 12% by age 80 OR 3.07 (1.21-7.88) STK11 13% by age 60 32% by age 60 TP53 OR 5.00(1.07-46.9)

EXPAND pathways – retrospective patient cohort Identified 1200 patients No BRCA1/BRCA2/PALB2 pathogenic variants Re-analysis of data from previous TSCP testing 55% uptake rate with 414 patients reported to date Aim to re-analyse ~700 patients in total

EXPAND pathways – prospective patient cohort Clinical Genetics referrals only Opt-in test ~50% uptake rate with 113 patients reported Aim to screen ~300 patients in total

EXPAND pathways – reporting strategy All likely pathogenic and pathogenic variants are reported Variants of uncertain significance are not routinely reported unless In standard of care genes Further studies of benefit 2 MDT meetings 10 patients discussed Considered whole family history Considered further tests to offer

Variant detection rate Data for all patients, excluding standard of care genes (BRCA1, BRCA2 and PALB2)

Variant detection rate by gene

Retrospective vs Prospective detection rate Patient Cohort Pathogenic Variants (LP/P) Diagnostic Yield (excl. SoC) (incl. SoC) Retrospective (n=414) 24 6% n/a Prospective (n=113) 22 5% 19%

CHEK2: a moderate risk gene Pathogenic CHEK2 variants detected in 3.6% patients across both cohorts 62% all reportable variants c.1100delC frameshift variant detected in 14/527 patients across both cohorts (2.7%) 1 patient found to be homozygous for CHEK2 c.1100delC Management of these patients can be a challenge, wider family may benefit from testing

Incidental findings? c.955G>A, p.(Arg319*) in RAD51C Personal and family history of breast cancer No reported ovarian cancer c.1263delT, p(Ser422Valfs*15) in CHEK2 Ovarian cancer family No reported breast cancer

Conclusions An additional 6% of patients have a diagnosis of hereditary breast and/or ovarian cancer Overall improved hereditary breast/ovarian cancer diagnostic rate ~19% Project is supporting the development of protocols for managing moderate risk in these patients Learning outcomes will help to embed this panel into routine clinical service

Thanks to… Beth Young Yvonne Wallis Kai Ren Ong Rachel Hart Jonathon Hoffman Camilla Huber Oliver Ridgway Sarah Burns