Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy

David J. VanderWeele, Richard Finney, Kotoe Katayama, Marc Gillard, Gladell Paner, Seiya Imoto, Rui Yamaguchi, David Wheeler, Justin Lack, Maggie Cam, Andrea Pontier, Yen Thi Minh Nguyen, Kazuhiro Maejima, Aya Sasaki-Oku, Kaoru Nakano, Hiroko Tanaka, Donald Vander Griend, Michiaki Kubo, Mark J. Ratain, Satoru MiyanoHidewaki Nakagawa

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. Objective: To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer. Design, setting, and participants: Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. Outcome measurements and statistical analysis: Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. Results and limitations: Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. Conclusions: Treatment-naïve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. Patient summary: Untreated patients’ tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.

Original languageEnglish
Pages (from-to)416-424
Number of pages9
JournalEuropean Urology Focus
Volume5
Issue number3
DOIs
Publication statusPublished - 05-2019

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Prostatic Neoplasms
Biomarkers
Therapeutics
Exome
Survival
Castration
Prostatectomy
Secondary Prevention
Point Mutation
Neoplasms
Nucleotides
Lymph Nodes
Neoplasm Metastasis
Recurrence
Mutation
DNA
Population
Genes

All Science Journal Classification (ASJC) codes

  • Urology

Cite this

VanderWeele, D. J., Finney, R., Katayama, K., Gillard, M., Paner, G., Imoto, S., ... Nakagawa, H. (2019). Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy. European Urology Focus, 5(3), 416-424. https://doi.org/10.1016/j.euf.2018.01.006
VanderWeele, David J. ; Finney, Richard ; Katayama, Kotoe ; Gillard, Marc ; Paner, Gladell ; Imoto, Seiya ; Yamaguchi, Rui ; Wheeler, David ; Lack, Justin ; Cam, Maggie ; Pontier, Andrea ; Nguyen, Yen Thi Minh ; Maejima, Kazuhiro ; Sasaki-Oku, Aya ; Nakano, Kaoru ; Tanaka, Hiroko ; Vander Griend, Donald ; Kubo, Michiaki ; Ratain, Mark J. ; Miyano, Satoru ; Nakagawa, Hidewaki. / Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy. In: European Urology Focus. 2019 ; Vol. 5, No. 3. pp. 416-424.
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title = "Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy",
abstract = "Background: Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. Objective: To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-na{\"i}ve prostate cancer. Design, setting, and participants: Ten patients with treatment-na{\"i}ve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. Outcome measurements and statistical analysis: Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. Results and limitations: Exome sequencing and copy number estimates demonstrate branched evolution with >75{\%} of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25{\%} of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. Conclusions: Treatment-na{\"i}ve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. Patient summary: Untreated patients’ tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.",
author = "VanderWeele, {David J.} and Richard Finney and Kotoe Katayama and Marc Gillard and Gladell Paner and Seiya Imoto and Rui Yamaguchi and David Wheeler and Justin Lack and Maggie Cam and Andrea Pontier and Nguyen, {Yen Thi Minh} and Kazuhiro Maejima and Aya Sasaki-Oku and Kaoru Nakano and Hiroko Tanaka and {Vander Griend}, Donald and Michiaki Kubo and Ratain, {Mark J.} and Satoru Miyano and Hidewaki Nakagawa",
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VanderWeele, DJ, Finney, R, Katayama, K, Gillard, M, Paner, G, Imoto, S, Yamaguchi, R, Wheeler, D, Lack, J, Cam, M, Pontier, A, Nguyen, YTM, Maejima, K, Sasaki-Oku, A, Nakano, K, Tanaka, H, Vander Griend, D, Kubo, M, Ratain, MJ, Miyano, S & Nakagawa, H 2019, 'Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy', European Urology Focus, vol. 5, no. 3, pp. 416-424. https://doi.org/10.1016/j.euf.2018.01.006

Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy. / VanderWeele, David J.; Finney, Richard; Katayama, Kotoe; Gillard, Marc; Paner, Gladell; Imoto, Seiya; Yamaguchi, Rui; Wheeler, David; Lack, Justin; Cam, Maggie; Pontier, Andrea; Nguyen, Yen Thi Minh; Maejima, Kazuhiro; Sasaki-Oku, Aya; Nakano, Kaoru; Tanaka, Hiroko; Vander Griend, Donald; Kubo, Michiaki; Ratain, Mark J.; Miyano, Satoru; Nakagawa, Hidewaki.

In: European Urology Focus, Vol. 5, No. 3, 05.2019, p. 416-424.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy

AU - VanderWeele, David J.

AU - Finney, Richard

AU - Katayama, Kotoe

AU - Gillard, Marc

AU - Paner, Gladell

AU - Imoto, Seiya

AU - Yamaguchi, Rui

AU - Wheeler, David

AU - Lack, Justin

AU - Cam, Maggie

AU - Pontier, Andrea

AU - Nguyen, Yen Thi Minh

AU - Maejima, Kazuhiro

AU - Sasaki-Oku, Aya

AU - Nakano, Kaoru

AU - Tanaka, Hiroko

AU - Vander Griend, Donald

AU - Kubo, Michiaki

AU - Ratain, Mark J.

AU - Miyano, Satoru

AU - Nakagawa, Hidewaki

PY - 2019/5

Y1 - 2019/5

N2 - Background: Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. Objective: To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer. Design, setting, and participants: Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. Outcome measurements and statistical analysis: Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. Results and limitations: Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. Conclusions: Treatment-naïve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. Patient summary: Untreated patients’ tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.

AB - Background: Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. Objective: To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer. Design, setting, and participants: Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. Outcome measurements and statistical analysis: Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. Results and limitations: Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. Conclusions: Treatment-naïve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. Patient summary: Untreated patients’ tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.

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DO - 10.1016/j.euf.2018.01.006

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VL - 5

SP - 416

EP - 424

JO - European Urology Focus

JF - European Urology Focus

SN - 2405-4569

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