Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer

Abstract

Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment.

Exome-capture RNA sequencing of decade-old breast cancers and matched decalcified bone metastases

“…Subtle Her2 and LumB profile shifts were also the most common when observing continuous PAM50 probability scores, even in samples that remained concordant in their discrete PAM50 assignments. A recent targeted expression study analyzed PAM50 assignments in 123 matched breast cancer metastases, and the authors found similar frequencies of LumB and Her2 acquisitions in ER-positive metastatic tumors (30). Given this transcriptional evolution to more LumB and Her2 profiles, a thoughtful reevaluation of therapy selection in the advanced and perhaps the adjuvant setting may be necessary -especially considering HER2-targeted therapies are generally reserved for patients with HER2-positive primary disease.…”

“…Consistent with the observed LumB enrichments, our data suggest breast cancer cells may develop a more proliferative phenotype following bone colonization, and the strong enrichment of E2F signature in metastatic disease again highlights the CDK/Rb/E2F pathway as a prime target. Interestingly, another study that utilized a targeted gene expression platform found proliferative gene signatures in ER-positive metastases may be more accurate at predicting overall survival than signatures in the primary tumor (30). A survival analysis for this work was impractical given the small set of patient-matched pairs, but future meta-analyses are warranted to determine if gene expression signatures in metastases are better predictors of overall survival in the advanced setting, especially given the significant transcriptomic shifts observed in this study.…”

Integrated RNA and DNA sequencing reveals early drivers of metastatic breast cancer

“…Previous reports have described HER2 amplification as a known mechanism of resistance to endocrine therapy (39). Furthermore, preliminary evidence has shown that ER + tumors that metastasize often have features of HER2 enrichment in them (40). This molecular diversity of ER + tumors (16,41) may explain the differential response of many patients' metastases to AI therapy.…”

Breast Cancer: Multiple Subtypes within a Tumor?

“…In this particular study, molecular changes in Her2 and intrinsic subtype switching to Her2-enriched subtypes can be associated with brain metastasis, indicating that the brain micro-environment may favor the progression of Her2 driven malignancies. In a separate study, PAM50 subtype classification of 123 paired primary and metastatic breast tumors revealed that subtype switching does indeed occur predominantly in cases where the primary tumors were classified as luminal A, luminal B or Her2-enriched [40], albeit these subtype switches could be driven by other mechanisms such as clonal evolution rather than plasticity. Notwithstanding that, evidence for a hierarchical model in breast cancer metastases has been reported [41].…”