The genomic landscape of metastatic histologic special types of invasive breast cancer

Abstract

Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs; n = 132 and n = 127, respectively), mixed mucinous (n = 5 metastatic and n = 14 primary), micropapillary (n = 12 metastatic and n = 8 primary), and metaplastic BCs (n = 6 metastatic and n = 5 primary), and compared metastatic histologic special types of BC to metastatic IDC-NSTs matched according to clinicopathologic characteristics and to primary special type BCs. The genomic profiles of metastatic and primary special types of BC were similar. Important differences, however, were noted: metastatic ILCs harbored a higher frequency of genetic alterations in TP53, ESR1, FAT1, RFWD2, and NF1 than primary ILCs, and in CDH1, PIK3CA, ERBB2, TBX3, NCOR1, and RFWD2 than metastatic IDC-NSTs. Metastatic ILCs displayed a higher mutational burden, and more frequently dominant APOBEC mutational signatures than primary ILCs and matched metastatic IDC-NSTs. ESR1 and NCOR mutations were frequently detected in metastatic mixed mucinous BCs, whereas PIK3CA and TP53 were the most frequently altered genes in metastatic micropapillary and metaplastic BCs, respectively. Taken together, primary and metastatic BCs histologic special types have remarkably similar repertoires of somatic genetic alterations. Metastatic ILCs more frequently harbor APOBEC mutational signatures than primary ILCs and metastatic IDC-NSTs.

Keywords: Breast cancer.

Fig. 1. Repertoire of genetic alterations in primary and metastatic invasive lobular carcinomas of the breast.

a Representative photomicrographs of a H&E-stained primary breast invasive lobular carcinoma (pILC; left) and a metastatic lobular carcinoma (mILC) involving ovarian stroma (right). Scale bars, 50 µm. b Boxplots depicting the non-synonymous tumor mutation burden of mILCs (n = 132), metastatic invasive ductal carcinomas of no special type matched by age, menopausal status, and estrogen receptor (ER)/HER2 status (mIDC-NSTs; n = 264), and pILCs (n = 127). Mann–Whitney U test, two-tailed. c Comparison of the cancer genes most frequently affected by non-synonymous somatic mutations, amplifications, or homozygous deletions in mILCs (n = 132), metastatic age-, menopausal status-, and ER/HER2 status-matched mIDC-NSTs (n = 264) and pILCs (n = 127). Cases are shown in columns and genes in rows. Mutation types are color-coded according to the legend. ER/HER2 status are shown on phenobars (top). *P < 0.05, **P < 0.01, ***P < 0.001; Fisher’s exact test, two-tailed. d Schematic representation of the protein domains of ERBB2 and the somatic mutations in metastatic mILCs (n = 132), mIDC-NSTs matched by clinicopathologic characteristics (n = 264) and pILCs (n = 127). Mutations are color-coded according to the legend, and their frequency is represented by the height of each lollipop (y-axis). e Mutual exclusivity analysis of ESR1 and ERBB2 hotspot, and oncogenic/likely oncogenic mutations in ER-positive mILCs (n = 113) and mIDC-NSTs (n = 226). Hom. homozygous, Indel insertion/deletion, LOH loss of heterozygosity, SNV single nucleotide variant.

Fig. 2. Repertoire of genetic alterations in primary and metastatic mixed mucinous breast cancers.

a Representative photomicrographs of a H&E-stained primary mixed mucinous breast cancer (pMUC; top), and a metastatic mixed mucinous breast cancer (mMUC) involving liver (bottom). Scale bars in a, 100 μm (top) and 50 μm (bottom). b Boxplots depicting the non-synonymous tumor mutation burden in mMUCs (n = 5), metastatic invasive ductal carcinoma of no special type matched by age, menopausal status, and estrogen receptor (ER)/HER2 status (mIDC-NST; n = 15), and pMUCs (n = 14). Mann–Whitney U test, two-tailed. c Comparison of the cancer genes most frequently affected by non-synonymous somatic mutations, amplifications, or homozygous deletions in mMUCs (n = 5), in age-, menopausal status-, and ER/HER2 receptor status-matched mIDC-NSTs (n = 15), and in pMUCs (n = 14). Cases are shown in columns and genes in rows. Mutation types are color-coded according to the legend. ER/HER2 status are shown on phenobars (top). *P < 0.05; Fisher’s exact test, two-tailed. Indel insertion/deletion, LOH loss of heterozygosity, SNV single nucleotide variant.

Fig. 3. Repertoire of genetic alterations in primary and metastatic micropapillary breast cancers.

a Representative photomicrographs of a H&E-stained primary micropapillary breast cancer (pMPC; left) and of a metastatic micropapillary BC (mMPC) involving bone (right). Scale bars, 50 µm. b Comparison of the cancer genes most frequently affected by non-synonymous somatic mutations, amplifications or homozygous deletions in mMPCs (n = 12), in age-, menopausal status-, and estrogen receptor (ER)/HER2 receptor status-matched metastatic invasive ductal carcinoma of no special type (mIDC-NST; n = 36), and pMPC (n = 8). Cases are shown in columns and genes in rows. Genetic alterations are color-coded according to the legend. ER/HER2 status are shown on phenobars (top). *P < 0.05, Fisher’s exact test; two-tailed. Indel insertion/deletion, LOH loss of heterozygosity, SNV single nucleotide variant.

Fig. 4. Repertoire of genetic alterations in primary and metastatic metaplastic breast cancers.

a Representative photomicrographs of a H&E-stained primary metaplastic breast cancer (pMETA) with predominant chondroid differentiation (top), and of a metastatic metaplastic breast cancer (mMETA) with predominant squamous differentiation involving lung (bottom). Scale bars, 100 μm. b Boxplots depicting the non-synonymous mutation burden of metastatic metaplastic BCs (mMETA; n = 6), metastatic invasive ductal carcinomas of no special type (mIDC-NSTs; n = 18) matched by age, menopausal status, and estrogen receptor (ER)/HER2 status, and primary metaplastic BCs (pMETA; n = 5). Mann–Whitney U test, two-tailed. c Comparison of the cancer genes most frequently affected by non-synonymous somatic mutations, amplifications, or homozygous deletions in mMETA (n = 6), age, menopausal status, and ER/HER2 receptor status-matched metastatic invasive ductal carcinomas of no special type (mIDC-NSTs; n = 18), and primary metaplastic BCs (pMETA; n = 5). Cases are shown in columns and genes in rows. Genetic alterations are color-coded according to the legend. ER/HER2 status and predominant histologic component are shown on phenobars (top). No significant different mutation frequencies were found using Fisher’s exact test. Indel insertion/deletion, LOH loss of heterozygosity, SNV single nucleotide variant.

Fig. 5. Mutational signatures in primary and metastatic histologic special types of breast cancer.

Proportion of dominant mutational signatures in a metastatic invasive lobular carcinomas (mILC; n = 103), metastatic invasive ductal carcinomas of no special type matched (mIDC-NSTs) by age, menopausal status, and estrogen receptor (ER)/HER2 status (n = 170) and in primary ILCs (pILCs; n = 72); b in metastatic mixed mucinous breast cancer (BC; mMUC; n = 4), metastatic IDC-NSTs matched by clinicopathologic characteristics (n = 11), and primary mixed mucinous BCs (pMUC; n = 2); c in metastatic micropapillary BCs (mMPCs; n = 10), metastatic IDC-NSTs matched by clinicopathologic characteristics (n = 30), and primary micropapillary BCs (pMPC; n = 4), and d in metaplastic BCs (mMETA; n = 4), metastatic IDC-NSTs matched by clinicopathologic characteristics (n = 17), and primary metaplastic BCs (pMETA; n = 3) with sufficient number of mutations for appropriate mutational signature inference.