Genomic spectrum of acquired driver alterations.

A) The circle graph represents for each case (n = 74) the proportion of driver mutations detected in primary and/or metastatic tumor samples. Outer numbers represent mutations of eBC, inner numbers represent mutations of mBC. B) Cumulative frequency of the difference (Δ) between number of mutations in metastatic vs. primary tumor samples (Δ vs. metastatic tumor; Δ > 0, number of driver mutations in the primary sample lower than in the metastatic sample. C) Non-linear relationship between the difference of driver mutations in metastasis/primary pair (Δ, x-axis), and DRFS hazard ratio of Schoenfeld residuals (y-axis). The analysis is adjusted for T/N status, Ki67, menopausal status and tumor grade. The solid line represents a penalized spline fit of the predicting variables, while the dashed lines show 95% confidence intervals. D) Functional analysis of Gene Ontology (GO) terms associated to cell cycle, DDR, epigenetic regulation, androgen receptor activity and WNT signaling pathway. The size of the dots is inversely proportional to the p values of estimated hazard ratio (x-axis) displayed in log10 scale. P values are reported in S5 Table.</p

Association between <i>MAP3K</i> alterations and clinical outcome.

Kaplan Meier curves displaying distant relapse-free survival (DRFS) (A) and overall survival (OS) (B) in patients with MAP3K gene alteration (red curves) as compared with patients with wild-type MAP3K status (blue curves). Forest plots indicating the hazard ratios for DRFS (C) and OS (D), and the corresponding confidence intervals, in MAP3K-altered and MAP3K-wild type patients. Multivariable Cox analysis is adjusted for tumor size, lymph node involvement, Ki67, menopausal status and tumor grade of the primary tumor.</p

Repertoire of genomic alterations in primary and metastatic HR+ HER2- breast cancer (BC).

A) Recurrent driver somatic mutations and copy number variations identified in matched primary and metastatic HR+ HER2- BC specimens (n = 74) subjected to targeted sequencing (n = 148). Cases are shown in columns, whereas genes are shown in rows. Mutation types are color-coded according to the legend. The total number of alterations detected in individual genes is displayed on the bar plot (right). For graphical purpose, only the top 25 genes are shown. B) The scatter plot reports the mutational frequencies in matched primary (n = 74) and metastatic (n = 74) tumor samples. Color indicates statistical significance (p-value adjusted by false discovery rate ≤ 0.1), the shape of the points reflects the difference between mutational frequency in metastatic vs. primary tumor samples (triangle = frequency difference ≥ 5%, circle = frequency difference ESR1, MAP3K1 and MAP3K13 and of the somatic mutations in matched primary and metastatic HR+ HER2- BC specimens (n  =  74). Mutations are color-coded according to the legend, and their overall occurrence is represented on the y-axis.</p

(Associations between gene alteration and ET, broad classes).

(TIF)</p

<i>ESR1</i> enrichment in metastatic HR+ HER2- BC samples.

A) ESR1 gene sCNV in three representative cases. Each row represents a case, and each box indicates the log-ratio levels for matched primary and metastatic tumor specimens. Red square shows the exact ESR1 region. The red background highlights the amplification of the ESR1 gene. FISH-based validation of each ESR1 amplification is also shown (right panel). B) Recurrent genomic alterations in metastatic tumor specimens, and their association with different types of endocrine therapy (ET). ET is classified according to specific clinically relevant groups. Statistically significant associations are shown as stars (adjusted p-value = 0.1).</p

Demographic and clinical characteristics of the study cohort.

Demographic and clinical characteristics of the study cohort.</p

(Supplementary methods).

(DOCX)</p

(Detailed Patient-Level Clinical and Treatment Data for the Study Cohort).

(XLSX)</p