Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer

Elena Castro; Chee Goh; David Olmos; Ed Saunders; Daniel Leongamornlert; Malgorzata Tymrakiewicz; Nadiya Mahmud; Tokhir Dadaev; Koveela Govindasami; Michelle Guy; Emma Sawyer; Rosemary Wilkinson; Audrey Ardern-Jones; Steve Ellis; Debra Frost; Susan Peock; D Gareth Evans; Marc Tischkowitz; Trevor Cole; Rosemarie Davidson; Diana Eccles; Carole Brewer; Fiona Douglas; Mary E Porteous; Alan Donaldson; Huw Dorkins; Louise Izatt; Jackie Cook; Shirley Hodgson; M John Kennedy; Lucy E Side; Jacqueline Eason; Alex Murray; Antonis C Antoniou; Douglas F Easton; Zsofia Kote-Jarai; Rosalind Eeles

doi:10.1200/JCO.2012.43.1882

Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer

Elena Castro, Chee Goh, David Olmos, Ed Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Nadiya Mahmud, Tokhir Dadaev, Koveela Govindasami, Michelle Guy, Emma Sawyer, Rosemary Wilkinson, Audrey Ardern-Jones, Steve Ellis, Debra Frost, Susan Peock, D Gareth Evans, Marc Tischkowitz, Trevor Cole, Rosemarie DavidsonDiana Eccles, Carole Brewer, Fiona Douglas, Mary E Porteous, Alan Donaldson, Huw Dorkins, Louise Izatt, Jackie Cook, Shirley Hodgson, M John Kennedy, Lucy E Side, Jacqueline Eason, Alex Murray, Antonis C Antoniou, Douglas F Easton, Zsofia Kote-Jarai, Rosalind Eeles

Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.

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

628 Citations (Scopus)

Abstract

PURPOSE: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.

PATIENTS AND METHODS: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).

RESULTS: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.

CONCLUSION: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

Original language	English
Pages (from-to)	1748-57
Number of pages	10
Journal	Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume	31
Issue number	14
DOIs	https://doi.org/10.1200/JCO.2012.43.1882
Publication status	Published - 10 May 2013

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Hormonal/therapeutic use
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Brachytherapy
Follow-Up Studies
Genetic Predisposition to Disease
Germ-Line Mutation
Heterozygote
Humans
Kaplan-Meier Estimate
Lymph Nodes/pathology
Lymphatic Metastasis
Male
Middle Aged
Neoplasm Grading
Neoplasm Staging
Nomograms
Palliative Care/methods
Phenotype
Predictive Value of Tests
Prognosis
Proportional Hazards Models
Prostatectomy
Prostatic Neoplasms/genetics
Radiotherapy, Adjuvant
Retrospective Studies
Risk Assessment
Risk Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1200/JCO.2012.43.1882

Cite this

Castro, E., Goh, C., Olmos, D., Saunders, E., Leongamornlert, D., Tymrakiewicz, M., Mahmud, N., Dadaev, T., Govindasami, K., Guy, M., Sawyer, E., Wilkinson, R., Ardern-Jones, A., Ellis, S., Frost, D., Peock, S., Evans, D. G., Tischkowitz, M., Cole, T., ... Eeles, R. (2013). Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 31(14), 1748-57. https://doi.org/10.1200/JCO.2012.43.1882

@article{b4448c5a1563460cb77fbd92100be845,

title = "Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer",

abstract = "PURPOSE: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.PATIENTS AND METHODS: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).RESULTS: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.CONCLUSION: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal/therapeutic use, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Brachytherapy, Follow-Up Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Humans, Kaplan-Meier Estimate, Lymph Nodes/pathology, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Nomograms, Palliative Care/methods, Phenotype, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Prostatectomy, Prostatic Neoplasms/genetics, Radiotherapy, Adjuvant, Retrospective Studies, Risk Assessment, Risk Factors",

author = "Elena Castro and Chee Goh and David Olmos and Ed Saunders and Daniel Leongamornlert and Malgorzata Tymrakiewicz and Nadiya Mahmud and Tokhir Dadaev and Koveela Govindasami and Michelle Guy and Emma Sawyer and Rosemary Wilkinson and Audrey Ardern-Jones and Steve Ellis and Debra Frost and Susan Peock and Evans, {D Gareth} and Marc Tischkowitz and Trevor Cole and Rosemarie Davidson and Diana Eccles and Carole Brewer and Fiona Douglas and Porteous, {Mary E} and Alan Donaldson and Huw Dorkins and Louise Izatt and Jackie Cook and Shirley Hodgson and Kennedy, {M John} and Side, {Lucy E} and Jacqueline Eason and Alex Murray and Antoniou, {Antonis C} and Easton, {Douglas F} and Zsofia Kote-Jarai and Rosalind Eeles",

year = "2013",

month = may,

day = "10",

doi = "10.1200/JCO.2012.43.1882",

language = "English",

volume = "31",

pages = "1748--57",

journal = "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "14",

}

Castro, E, Goh, C, Olmos, D, Saunders, E, Leongamornlert, D, Tymrakiewicz, M, Mahmud, N, Dadaev, T, Govindasami, K, Guy, M, Sawyer, E, Wilkinson, R, Ardern-Jones, A, Ellis, S, Frost, D, Peock, S, Evans, DG, Tischkowitz, M, Cole, T, Davidson, R, Eccles, D, Brewer, C, Douglas, F, Porteous, ME, Donaldson, A, Dorkins, H, Izatt, L, Cook, J, Hodgson, S, Kennedy, MJ, Side, LE, Eason, J, Murray, A, Antoniou, AC, Easton, DF, Kote-Jarai, Z & Eeles, R 2013, 'Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 31, no. 14, pp. 1748-57. https://doi.org/10.1200/JCO.2012.43.1882

Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. / Castro, Elena; Goh, Chee; Olmos, David et al.
In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 31, No. 14, 10.05.2013, p. 1748-57.

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

TY - JOUR

T1 - Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer

AU - Castro, Elena

AU - Goh, Chee

AU - Olmos, David

AU - Saunders, Ed

AU - Leongamornlert, Daniel

AU - Tymrakiewicz, Malgorzata

AU - Mahmud, Nadiya

AU - Dadaev, Tokhir

AU - Govindasami, Koveela

AU - Guy, Michelle

AU - Sawyer, Emma

AU - Wilkinson, Rosemary

AU - Ardern-Jones, Audrey

AU - Ellis, Steve

AU - Frost, Debra

AU - Peock, Susan

AU - Evans, D Gareth

AU - Tischkowitz, Marc

AU - Cole, Trevor

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Brewer, Carole

AU - Douglas, Fiona

AU - Porteous, Mary E

AU - Donaldson, Alan

AU - Dorkins, Huw

AU - Izatt, Louise

AU - Cook, Jackie

AU - Hodgson, Shirley

AU - Kennedy, M John

AU - Side, Lucy E

AU - Eason, Jacqueline

AU - Murray, Alex

AU - Antoniou, Antonis C

AU - Easton, Douglas F

AU - Kote-Jarai, Zsofia

AU - Eeles, Rosalind

PY - 2013/5/10

Y1 - 2013/5/10

N2 - PURPOSE: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.PATIENTS AND METHODS: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).RESULTS: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.CONCLUSION: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

AB - PURPOSE: To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.PATIENTS AND METHODS: This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).RESULTS: PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.CONCLUSION: Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents, Hormonal/therapeutic use

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Brachytherapy

KW - Follow-Up Studies

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Heterozygote

KW - Humans

KW - Kaplan-Meier Estimate

KW - Lymph Nodes/pathology

KW - Lymphatic Metastasis

KW - Male

KW - Middle Aged

KW - Neoplasm Grading

KW - Neoplasm Staging

KW - Nomograms

KW - Palliative Care/methods

KW - Phenotype

KW - Predictive Value of Tests

KW - Prognosis

KW - Proportional Hazards Models

KW - Prostatectomy

KW - Prostatic Neoplasms/genetics

KW - Radiotherapy, Adjuvant

KW - Retrospective Studies

KW - Risk Assessment

KW - Risk Factors

U2 - 10.1200/JCO.2012.43.1882

DO - 10.1200/JCO.2012.43.1882

M3 - Article

C2 - 23569316

SN - 0732-183X

VL - 31

SP - 1748

EP - 1757

JO - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology

IS - 14

ER -

Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 May 10;31(14):1748-57. doi: 10.1200/JCO.2012.43.1882

Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer

Abstract

Keywords

UN SDGs

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