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 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.

Figure 1.

Significant SNVs, short indels, and signature analysis. Comutation plot showing recurrent somatic alterations in significantly mutated genes across the cohort (N = 93) as analyzed by MutSig2CV. TP53, GATA3, ARID1A, MAP3K1, PIK3CA, and SLC22A2 are significantly mutated. The P values were computed using the Fisher method and truncated product method. FDR (q values) were generated using the Benjamini–Hochberg method to correct for multiple hypotheses. Genes that have a −log10 q-value ≥1 (red line) are considered significant. Bar graph (top) depicts the TMB (mutations/megabase) of each patient's tumor samples, followed by clinical annotations depicting histology, disease recurrence, and breast cancer subtype (key to the right of panel). Bottom panel annotations show cancer-specific pathogenic germline variants, and somatic mutational signatures of homologous recombination (HR) deficiency, APOBEC activity, and microsatellite instability (MSI).

Figure 2.

Comparison of single nucleotide and short indel prevalence between Young Women's Breast Cancer Study cohort (≤35 years old) and TCGA patients ≥45 years old. A, All intrinsic subtypes; B, Luminal A; C, Luminal B; D, Basal-like. HER2-enriched subtype is not shown as there were only 4 Young Women's Breast Cancer Study cohort samples in this subtype. Analysis excluded patients with pure lobular tumor histology. Forty genes identified from the 2016 METABRIC study (35), in addition to one gene found to be significant by MutSig, were included for analysis. Only differences in the frequencies of alteration of each gene between the two cohorts, as opposed to the absolute frequency of alterations within each cohort, are depicted by the bars. Statistically significant differences (FDR < 5%) are highlighted in red.