Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing

D. Gareth Evans; Emma r. Woodward; George j. Burghel; Sophie Allen; Beth Torr; Monica Hamill; Grace Kavanaugh; Mike Hubank; Stephen Bremner; Christopher i. Jones; Helene Schlecht; Susan Astley; Sarah Bowers; Sarah Gibbons; Helen Ruane; Caroline Fosbury; Sacha j. Howell; Claire Forde; Fiona Lalloo; William g. Newman; Miriam j. Smith; Anthony Howell; Clare Turnbull; Ashu Gandhi

doi:10.1016/j.gimo.2023.100849

Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing

D. Gareth Evans, Emma r. Woodward, George j. Burghel, Sophie Allen, Beth Torr, Monica Hamill, Grace Kavanaugh, Mike Hubank, Stephen Bremner, Christopher i. Jones, Helene Schlecht, Susan Astley, Sarah Bowers, Sarah Gibbons, Helen Ruane, Caroline Fosbury, Sacha j. Howell, Claire Forde, Fiona Lalloo, William g. NewmanMiriam j. Smith, Anthony Howell, Clare Turnbull, Ashu Gandhi

Research output: Contribution to journal › Article › peer-review

Abstract

Purpose
To assess the contribution of germline pathogenic variants (PVs) in a population-based series of breast cancers and the best strategy to improve detection rates.

Methods
Three cohort studies were utilised, including a hospital-based series identified from new UK mainstream testing criteria (Group-1), offering testing to all women (Group-2-BRCA-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (Group-3-PROCAS). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and PALB2. The Manchester Score-(MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS≥15.

Results
Thirty-six PVs (BRCA1=9, BRCA2=18, PALB2=9) were identified amongst 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21/36 (58%) of PVs by testing 190 women; detection rate (DR=8.4%) specificity=83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7%-(24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS≥3 with specificity of 32.6%.

Conclusion
In order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing.

Original language	English
Article number	100849
Number of pages	8
Journal	Genetics in Medicine Open
Volume	2
Early online date	25 Nov 2023
DOIs	https://doi.org/10.1016/j.gimo.2023.100849
Publication status	Published - 1 Jan 2024

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Cite this

Evans, D. G., Woodward, E. R., Burghel, G. J., Allen, S., Torr, B., Hamill, M., Kavanaugh, G., Hubank, M., Bremner, S., Jones, C. I., Schlecht, H., Astley, S., Bowers, S., Gibbons, S., Ruane, H., Fosbury, C., Howell, S. J., Forde, C., Lalloo, F., ... Gandhi, A. (2024). Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing. Genetics in Medicine Open, 2, Article 100849. https://doi.org/10.1016/j.gimo.2023.100849

@article{2cd1985ac21a487284e44e454a6b1338,

title = "Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing",

abstract = "PurposeTo assess the contribution of germline pathogenic variants (PVs) in a population-based series of breast cancers and the best strategy to improve detection rates.MethodsThree cohort studies were utilised, including a hospital-based series identified from new UK mainstream testing criteria (Group-1), offering testing to all women (Group-2-BRCA-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (Group-3-PROCAS). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and PALB2. The Manchester Score-(MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS≥15.ResultsThirty-six PVs (BRCA1=9, BRCA2=18, PALB2=9) were identified amongst 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21/36 (58%) of PVs by testing 190 women; detection rate (DR=8.4%) specificity=83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7%-(24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS≥3 with specificity of 32.6%.ConclusionIn order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing.",

author = "Evans, {D. Gareth} and Woodward, {Emma r.} and Burghel, {George j.} and Sophie Allen and Beth Torr and Monica Hamill and Grace Kavanaugh and Mike Hubank and Stephen Bremner and Jones, {Christopher i.} and Helene Schlecht and Susan Astley and Sarah Bowers and Sarah Gibbons and Helen Ruane and Caroline Fosbury and Howell, {Sacha j.} and Claire Forde and Fiona Lalloo and Newman, {William g.} and Smith, {Miriam j.} and Anthony Howell and Clare Turnbull and Ashu Gandhi",

year = "2024",

month = jan,

day = "1",

doi = "10.1016/j.gimo.2023.100849",

language = "English",

volume = "2",

journal = "Genetics in Medicine Open",

issn = "2949-7744",

publisher = "Elsevier BV",

}

Evans, DG, Woodward, ER, Burghel, GJ, Allen, S, Torr, B, Hamill, M, Kavanaugh, G, Hubank, M, Bremner, S, Jones, CI, Schlecht, H, Astley, S, Bowers, S, Gibbons, S, Ruane, H, Fosbury, C, Howell, SJ, Forde, C, Lalloo, F, Newman, WG , Smith, MJ , Howell, A, Turnbull, C & Gandhi, A 2024, 'Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing', Genetics in Medicine Open, vol. 2, 100849. https://doi.org/10.1016/j.gimo.2023.100849

Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing. / Evans, D. Gareth; Woodward, Emma r.; Burghel, George j. et al.
In: Genetics in Medicine Open, Vol. 2, 100849, 01.01.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom

T2 - Evidence to support extended testing and definition of groups who may not require testing

AU - Evans, D. Gareth

AU - Woodward, Emma r.

AU - Burghel, George j.

AU - Allen, Sophie

AU - Torr, Beth

AU - Hamill, Monica

AU - Kavanaugh, Grace

AU - Hubank, Mike

AU - Bremner, Stephen

AU - Jones, Christopher i.

AU - Schlecht, Helene

AU - Astley, Susan

AU - Bowers, Sarah

AU - Gibbons, Sarah

AU - Ruane, Helen

AU - Fosbury, Caroline

AU - Howell, Sacha j.

AU - Forde, Claire

AU - Lalloo, Fiona

AU - Newman, William g.

AU - Smith, Miriam j.

AU - Howell, Anthony

AU - Turnbull, Clare

AU - Gandhi, Ashu

PY - 2024/1/1

Y1 - 2024/1/1

N2 - PurposeTo assess the contribution of germline pathogenic variants (PVs) in a population-based series of breast cancers and the best strategy to improve detection rates.MethodsThree cohort studies were utilised, including a hospital-based series identified from new UK mainstream testing criteria (Group-1), offering testing to all women (Group-2-BRCA-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (Group-3-PROCAS). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and PALB2. The Manchester Score-(MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS≥15.ResultsThirty-six PVs (BRCA1=9, BRCA2=18, PALB2=9) were identified amongst 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21/36 (58%) of PVs by testing 190 women; detection rate (DR=8.4%) specificity=83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7%-(24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS≥3 with specificity of 32.6%.ConclusionIn order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing.

AB - PurposeTo assess the contribution of germline pathogenic variants (PVs) in a population-based series of breast cancers and the best strategy to improve detection rates.MethodsThree cohort studies were utilised, including a hospital-based series identified from new UK mainstream testing criteria (Group-1), offering testing to all women (Group-2-BRCA-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (Group-3-PROCAS). DNA samples from women with breast cancer were sequenced for PVs in BRCA1, BRCA2, and PALB2. The Manchester Score-(MS) was used at different points thresholds. Current mainstream criteria include women diagnosed <40 years and all triple negative <60 years or an MS≥15.ResultsThirty-six PVs (BRCA1=9, BRCA2=18, PALB2=9) were identified amongst 1061 women with breast cancer (3.4%). Mainstreaming criteria identified 21/36 (58%) of PVs by testing 190 women; detection rate (DR=8.4%) specificity=83.5%. A better detection rate was found using an MS threshold of 12-points with 66.7%-(24/36) sensitivity and 85.7% specificity in 171 women. No PVs were identified in 158 women with grade-1 invasive cancers. The best strategy to detect all PVs was an MS≥3 with specificity of 32.6%.ConclusionIn order to detect higher PV rates on a population basis the best strategy is to reduce the MS threshold for genetic testing.

U2 - 10.1016/j.gimo.2023.100849

DO - 10.1016/j.gimo.2023.100849

M3 - Article

SN - 2949-7744

VL - 2

JO - Genetics in Medicine Open

JF - Genetics in Medicine Open

M1 - 100849

ER -

Population-based germline testing of BRCA1, BRCA2, and PALB2 in breast cancer patients in the United Kingdom: Evidence to support extended testing and definition of groups who may not require testing

Abstract

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