Breast cancer metastasis to gynaecological organs: a clinico‐pathological and molecular profiling study

Abstract

Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico‐pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy‐number profiling, and targeted sequencing of 386 cancer‐related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0–20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0–18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A‐like phenotype were over‐represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co‐expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A‐like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression.

GATA3 suppresses human fibroblasts-induced metastasis of clear cell renal cell carcinoma via an anti-IL6/STAT3 mechanism

“…Initial studies suggested that GATA3 is relatively sensitive and specific for tumors of breast or urothelial origin, and the downregulation of GATA3 has also been found to be associated with a poor prognosis of breast cancer. The significance of this transcription factor, especially for the inhibition of cancer cell metastasis, has been discussed in recent reports [22,23]. However, how does GATA3 participate in ccRCC development and metastasis is still unknown.…”

Clinicopathologic significance of nuclear HER4 and phospho-YAP(S127) in human breast cancers and matching brain metastases

“…This study involved immunohistochemistry (IHC) analysis of: (1) a clinically annotated, consecutive series of primary breast tumours with >20 years follow up, herein referred to as the ‘general breast cancer cohort’ (described previously) 46 – 52 ; and (2) patient-matched pairs of primary and brain-metastatic breast tumours, herein referred to as the ‘brain-metastatic breast cancer cohort’ (br.MBC) ( Table 1 ). Both were sourced from the same diagnostic pathology centres in Queensland, Australia, and represent a similar patient population.…”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…Thus, there is a clear clonal ancestry during progression, and the early molecular drivers of behaviour and phenotype (e.g., mutations in TP53, PIK3CA, CDH1, GATA3, amplification of MYC, CCND1, ERRB2/HER2) remain prevalent drivers in metastatic deposits [71][72][73][74][76][77][78][79][80]. Despite this, significant intra-patient heterogeneity develops during progression, even in the absence of systemic therapy; this occurs to a greater extent in progression to distant metastases relative to local lymph nodes and is exacerbated by the selective pressures applied during adjuvant therapy [73,77,[81][82][83][84]. Changes in tumour phenotype or in the intrinsic molecular subtype during progression occurs in around 30% of patients (most often involving the down regulation of PR, but may also involve ER and less frequently a change in HER2 status) and may occur in a non-random manner at specific metastatic sites (e.g., lung, liver and bone metastases) [85][86][87][88].…”

“…Changes in tumour phenotype or in the intrinsic molecular subtype during progression occurs in around 30% of patients (most often involving the down regulation of PR, but may also involve ER and less frequently a change in HER2 status) and may occur in a non-random manner at specific metastatic sites (e.g., lung, liver and bone metastases) [85][86][87][88]. To further complicate matters, the phenotype of different metastases within a patient can be heterogenous [83,86,[89][90][91][92].…”

“…The genomic analysis of matched primary and metastatic samples has revealed fascinating insight regarding the evolution of metastatic disease [73,75,[82][83][84]86,90,[98][99][100]. Such efforts reveal, for example, that driver mutations that are enriched in metastasis are indeed rarely found in the matched primary tumour, indicating they arose either in a small subclone not sampled when the primary tumour was sequenced, or they occurred during the metastatic process after cells had disseminated from the breast (i.e., treatment induced mutations) [39,73,79,80,82,101].…”