Molecular features of breast cancer metastatic to gynecologic sites.

Background: Breast Cancer (BC) is the leading cause of cancer-related deaths among women worldwide. Both molecularly and histologically, BC is a heterogenous disease. Further investigation into the molecular and immunologic mechanisms underlying patterns of BC metastasis are warranted to identify potential therapeutic targets. Methods: 6722 breast cancer specimens (5923 primary; 664 skin metastases; 135 reproductive tract metastases) were analyzed by Next Generation Sequencing (WES: NextSeq, 592 genes and NovaSeq and WTS: NovaSeq). PAM50 algorithm used to calculate molecular intrinsic subtypes. Gene signature calculated for an 18-gene IFNg signature predictive of immune checkpoint gene response. Statistical significance was determined using Chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q < 0.05). Results: A total of 6722 BC specimens (5923 primary; 664 skin mets; 135 reproductive tract mets) were identified. The median age of BC patients with skin mets (back: 71y; axilla: 69y; abdomen: 65y) was older than those with reproductive tract mets (ovary: 51y; endometrium: 55y; cervix: 58y). Skin mets were also less likely to be histologically luminal A (Back: n = 4, 22.2%; Axilla: n = 7, 33.3%; abdomen: n = 3, 11.1%; chest: n = 25, 19.5%; head: n = 7, 31.8% breast: n = 41, 16.9%) than ovarian (n = 35, 51.5%), endometrial (n = 7, 46.7%) or cervical mets (n = 6, 54.6%). However, reproductive tract mets were more likely to be lobular than ductal (ovary (n = 21, 21.2% vs n = 5, 5.05%), endometrium (n = 5, 23.8% vs n = 0, 0%) or cervix (n = 1, 6.67% vs n = 0, 0%)) and were predominantly hormone receptor (HR)+/HER2-: ovary (n = 83, 89.3%), endometrium (n = 12, 63.2%) and cervix (n = 9, 75%). None were HR-/HER2+. TP53 mutations were higher in primary BC (59%) and mets to skin of breast (55.1%) and cervix (54.2%) than ovarian mets (19.1%) (q < 0.0001). PIK3CA-mt were more common in BC mets to endometrium (57.1%) and ovary (58.2%) than primary BC (30.9%) or BC mets to skin (back) (32.1%) (q < 0.01). CDH1-mt were higher in ovarian mets (49.5%) compared to primary BC (8.9%), skin of breast (14.5%) or cervical mets (21.5%) (q < 0.0001). Immunologically, mets to ovary and endometrium had lower CD80, CD86 and IFNG expression (2.01-6.15-fc) but higher LAG3 expression (2.23-4.53-fc) (q < 0.05) than primary BC. This was accompanied by lower signatures associated with CD8+ T, monocytes, dendritic cells (1.25-12.9-fold, q < 0.05) and lower IFN scores (4.35-7.14-fc, q < 0.05). Conclusions: Breast cancers metastatic to gynecologic sites demonstrate unique histologic, mutational, and immunologic characteristics that may render them uniquely susceptible to immunotherapy. These features distinguish them from both primary breast cancer and breast cancer metastases to other anatomic locations, such as skin. More research is needed to better understand how these findings can improve clinical outcomes.