Somatic and germline genomic alterations in very young women with breast cancer

Adrienne G Waks; Dewey Kim; Esha Jain; Craig Snow; Gregory J Kirkner; Shoshana M Rosenberg; Coyin Oh; Philip D Poorvu; Kathryn J Ruddy; Rulla M Tamimi; Jeffrey Peppercorn; Lidia Schapira; Virginia F Borges; Steven E Come; Elena F Brachtel; Ellen Warner; Laura C Collins; Ann H Partridge; Nikhil Wagle

doi:10.1158/1078-0432.ccr-21-2572

Somatic and germline genomic alterations in very young women with breast cancer

Adrienne G Waks, Dewey Kim, Esha Jain, Craig Snow, Gregory J Kirkner, Shoshana M Rosenberg, Coyin Oh, Philip D Poorvu, Kathryn J Ruddy, Rulla M Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia F Borges, Steven E Come, Elena F Brachtel, Ellen Warner, Laura C Collins, Ann H Partridge, Nikhil Wagle^*

^*Corresponding author for this work

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

Abstract

PURPOSE: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared to older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.

EXPERIMENTAL DESIGN: We identified 100 patients {less than or equal to}35 years old at non-metastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole exome sequencing of tumor and germline samples was performed. Genomic alterations were compared to older women ({greater than or equal to}45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.

RESULTS: 93 tumors from 92 patients were successfully sequenced. Median age was 32.5 years. 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N=28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, while GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. 22 patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young breast cancer patients.

Original language	English
Pages (from-to)	2339-2348
Number of pages	10
Journal	Clinical Cancer Research
Volume	28
Issue number	11
Early online date	31 Jan 2022
DOIs	https://doi.org/10.1158/1078-0432.ccr-21-2572
Publication status	Published - 1 Jun 2022

Keywords

AGE
ALIGNMENT
DIAGNOSIS
LARGE COHORT
MOLECULAR PHENOTYPE
MUTATION
PATTERNS
PREGNANCY
SUSCEPTIBILITY

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Cite this

Waks, A. G., Kim, D., Jain, E., Snow, C., Kirkner, G. J., Rosenberg, S. M., Oh, C., Poorvu, P. D., Ruddy, K. J., Tamimi, R. M., Peppercorn, J., Schapira, L., Borges, V. F., Come, S. E., Brachtel, E. F., Warner, E., Collins, L. C., Partridge, A. H., & Wagle, N. (2022). Somatic and germline genomic alterations in very young women with breast cancer. Clinical Cancer Research, 28(11), 2339-2348. https://doi.org/10.1158/1078-0432.ccr-21-2572

@article{172cd685db954071a54d81ef19199904,

title = "Somatic and germline genomic alterations in very young women with breast cancer",

abstract = "PURPOSE: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared to older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.EXPERIMENTAL DESIGN: We identified 100 patients {less than or equal to}35 years old at non-metastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole exome sequencing of tumor and germline samples was performed. Genomic alterations were compared to older women ({greater than or equal to}45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.RESULTS: 93 tumors from 92 patients were successfully sequenced. Median age was 32.5 years. 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N=28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, while GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. 22 patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young breast cancer patients.",

keywords = "AGE, ALIGNMENT, DIAGNOSIS, LARGE COHORT, MOLECULAR PHENOTYPE, MUTATION, PATTERNS, PREGNANCY, SUSCEPTIBILITY",

author = "Waks, {Adrienne G} and Dewey Kim and Esha Jain and Craig Snow and Kirkner, {Gregory J} and Rosenberg, {Shoshana M} and Coyin Oh and Poorvu, {Philip D} and Ruddy, {Kathryn J} and Tamimi, {Rulla M} and Jeffrey Peppercorn and Lidia Schapira and Borges, {Virginia F} and Come, {Steven E} and Brachtel, {Elena F} and Ellen Warner and Collins, {Laura C} and Partridge, {Ann H} and Nikhil Wagle",

note = "Funding Information: This research was supported by Susan G. Komen (A.H. Partridge), the Breast Cancer Research Foundation (A.H. Partridge), and the Susan Smith Executive Council (N. Wagle). The authors wish to acknowledge the patients who participated in this study. Funding Information: A.G. Waks reports other support from Genentech/Roche and MacroGenics outside the submitted work. J. Peppercorn reports personal fees and other support from GlaxoSmithKline outside the submitted work. N. Wagle reports personal fees from Eli Lilly and Co., Relay Therapeutics, and Flare Therapeutics and grants from Puma Biotechnologies outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

month = jun,

day = "1",

doi = "10.1158/1078-0432.ccr-21-2572",

language = "English",

volume = "28",

pages = "2339--2348",

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publisher = "American Association for Cancer Research Inc.",

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Waks, AG, Kim, D, Jain, E, Snow, C, Kirkner, GJ, Rosenberg, SM, Oh, C, Poorvu, PD, Ruddy, KJ, Tamimi, RM, Peppercorn, J, Schapira, L, Borges, VF, Come, SE, Brachtel, EF, Warner, E, Collins, LC, Partridge, AH & Wagle, N 2022, 'Somatic and germline genomic alterations in very young women with breast cancer', Clinical Cancer Research, vol. 28, no. 11, pp. 2339-2348. https://doi.org/10.1158/1078-0432.ccr-21-2572

TY - JOUR

T1 - Somatic and germline genomic alterations in very young women with breast cancer

AU - Waks, Adrienne G

AU - Kim, Dewey

AU - Jain, Esha

AU - Snow, Craig

AU - Kirkner, Gregory J

AU - Rosenberg, Shoshana M

AU - Oh, Coyin

AU - Poorvu, Philip D

AU - Ruddy, Kathryn J

AU - Tamimi, Rulla M

AU - Peppercorn, Jeffrey

AU - Schapira, Lidia

AU - Borges, Virginia F

AU - Come, Steven E

AU - Brachtel, Elena F

AU - Warner, Ellen

AU - Collins, Laura C

AU - Partridge, Ann H

AU - Wagle, Nikhil

N1 - Funding Information: This research was supported by Susan G. Komen (A.H. Partridge), the Breast Cancer Research Foundation (A.H. Partridge), and the Susan Smith Executive Council (N. Wagle). The authors wish to acknowledge the patients who participated in this study. Funding Information: A.G. Waks reports other support from Genentech/Roche and MacroGenics outside the submitted work. J. Peppercorn reports personal fees and other support from GlaxoSmithKline outside the submitted work. N. Wagle reports personal fees from Eli Lilly and Co., Relay Therapeutics, and Flare Therapeutics and grants from Puma Biotechnologies outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: © 2022 The Authors.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - PURPOSE: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared to older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.EXPERIMENTAL DESIGN: We identified 100 patients {less than or equal to}35 years old at non-metastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole exome sequencing of tumor and germline samples was performed. Genomic alterations were compared to older women ({greater than or equal to}45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.RESULTS: 93 tumors from 92 patients were successfully sequenced. Median age was 32.5 years. 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N=28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, while GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. 22 patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young breast cancer patients.

AB - PURPOSE: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared to older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients.EXPERIMENTAL DESIGN: We identified 100 patients {less than or equal to}35 years old at non-metastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole exome sequencing of tumor and germline samples was performed. Genomic alterations were compared to older women ({greater than or equal to}45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.RESULTS: 93 tumors from 92 patients were successfully sequenced. Median age was 32.5 years. 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N=28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, while GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. 22 patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. Conclusions: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young breast cancer patients.

KW - AGE

KW - ALIGNMENT

KW - DIAGNOSIS

KW - LARGE COHORT

KW - MOLECULAR PHENOTYPE

KW - MUTATION

KW - PATTERNS

KW - PREGNANCY

KW - SUSCEPTIBILITY

U2 - 10.1158/1078-0432.ccr-21-2572

DO - 10.1158/1078-0432.ccr-21-2572

M3 - Article

C2 - 35101884

SN - 1078-0432

VL - 28

SP - 2339

EP - 2348

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 11

ER -