Subtypes of Breast Cancer Show Preferential Site of Relapse

Abstract

We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The ''intrinsic'' gene list describing the subtypes was used to classify 344 primary breast tumors of lymph node-negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment. Modulated genes and pathways were identified in the various groups using Significance Analysis of Microarrays and Global Testing. Bone relapse patients were most abundant in the luminal subtypes but were found less than expected in the basal subtype. The reverse was true for lung and brain relapse patients with the remark that absence of lung relapse was luminal A specific. Finally, a pleura relapse, although rare, was found almost exclusively in both luminal subtypes. Many differentially expressed genes were identified, of which several were in common in a subtype and the site to which the subtype preferentially relapsed. WNT signaling was up-regulated in the basal subtype and in brain-specific relapse, and downmodulated in the luminal B subtype and in bone-specific relapse. Focal adhesion was found up-regulated in the luminal A subtype but down-regulated in lung relapse. The five major molecular subtypes in breast cancer are evidently different with regard to their ability to metastasize to distant organ(s), and share biological features and pathways with their preferred distant metastatic site. [Cancer Res 2008;68(9):3108-14]

Incidence proportions and prognosis of breast cancer patients with bone metastases at initial diagnosis

“…In addition, our study demonstrated that different tumor subtypes showed a different tendency to bone metastases. The incidence proportion of bone metastases was highest among patients with the HR‐positive HER2‐negative and HR‐positive HER2‐positive subtypes, which are in accordance with other publications describing the patterns of metastatic breast cancer 11, 12, 36. The multivariable logistic regression indicated that patients with the HR‐positive HER2‐negative subtype had significantly greater odds of having bone metastases at diagnosis than patients with other subtypes, whether among the entire cohort or within the subset with metastatic disease.…”

“…Previous findings have confirmed that patients with an HR‐positive status are more likely to have bone metastases than those with HR‐negative status. The absence of WNT/β‐catenin signaling and the involvement of transforming growth factor β and fibroblast growth factor signaling have been found to promote HR‐positive breast cancer metastases to bone 12, 37…”

“…There is growing evidence indicating that patterns of metastases vary between different hormone receptor (HR) and human epithelial growth factor receptor 2 (HER2) statuses of breast tumors 11, 12, 13, 14, 15, 16, 17, 18. Patients with HR‐positive breast cancer are at increased risk for the development of bone metastases, whereas bone metastases are less frequent in cases of triple‐negative tumors 15, 16, 17, 18, 19, 20, 21.…”

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…19,116 The pattern of metastatic spread of tumors with a basal-like phenotype seems to be different from that of non-basal-like cancers: they are reported to less frequently disseminate to axillary nodes and bones 42,117 and to favor a hematogenous spread, 42,[117][118][119] with a peculiar proclivity to develop metastatic deposits in the brain and lungs. 120 It should be noted that patients with triple-negative and basal-like cancers tend to develop adverse events and die due to disease within the first 5-8 years after diagnosis. After the 8-year mark, the hazard rate for patients with grade 2 or ERpositive cancers is actually higher than that of patients with basal-like cancers.…”

Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines

“…ER-negative breast cancers included the ERBB2+, basal-like and normal-like subtypes. The intrinsic subtypes of breast cancer have clinical relevance [5][6][7], as have gene expression signatures that had been defined based on clinical outcome of breast cancer patients [8][9][10][11]. Importantly, the success of gene expression profiling in breast cancer classification implies a relatively restricted set of recurrent expression patterns among breast cancer subtypes.…”