Somatic and Germline Genomic Alterations in Very Young Women with Breast Cancer

Author:

Waks Adrienne G.12ORCID,Kim Dewey13,Jain Esha13ORCID,Snow Craig1,Kirkner Gregory J.1,Rosenberg Shoshana M.12,Oh Coyin2,Poorvu Philip D.12,Ruddy Kathryn J.4ORCID,Tamimi Rulla M.5ORCID,Peppercorn Jeffrey26,Schapira Lidia7ORCID,Borges Virginia F.8ORCID,Come Steven E.29,Brachtel Elena F.610ORCID,Warner Ellen11,Collins Laura C.29,Partridge Ann H.12,Wagle Nikhil123

Affiliation:

1. 1Dana-Farber Cancer Institute, Boston, Massachusetts.

2. 2Harvard Medical School, Boston, Massachusetts.

3. 3The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

4. 4Mayo Clinic, Rochester, Minnesota.

5. 5Weill Cornell Medicine, New York, New York.

6. 6Massachusetts General Hospital, Boston, Massachusetts.

7. 7Stanford Cancer Institute, Stanford University, Palo Alto, California.

8. 8University of Colorado Denver, Aurora, Colorado.

9. 9Beth Israel Deaconess Medical Center, Boston, Massachusetts.

10. 10Maastricht University Medical Center, Maastricht, the Netherlands.

11. 11Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Abstract

AbstractPurpose:Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with 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 ≤35 years old at nonmetastatic 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 with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype.Results:Ninety-three 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, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two 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 patients with breast cancer.See related commentary by Yehia and Eng, p. 2209

Funder

Susan G. Komen

Breast Cancer Research Foundation

Susan Smith Executive Council

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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