1. 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

2. 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

3. Current detection rates (2015-2017)

4. 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%

5. 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

6. 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.

7. Genes on the EXPAND panel
Ovarian cancer risk
Breast cancer risk
ATM
OR 1.69 ( )
OR 2.78 ( )
c.7271T>G OR 11.0 ( )
BRIP1
OR 2.62 ( )
No association found
CHEK2
OR 2.26 ( )
c.1100delC OR 2.31 ( )
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 ( )
Gene
Ovarian cancer risk
Breast cancer risk
NBN
OR 1.85 ( )
OR 3.0
PTEN
No association found
OR 5.83 ( )
RAD51C
9% by age 80
RAD51D
12% by age 80
OR 3.07 ( )
STK11
13% by age 60
32% by age 60
TP53
OR 5.00( )

8. 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

9. 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

10. 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

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

12. Variant detection rate by gene

13. 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%

14. 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

15. 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

16. 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

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