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Molecular Determinants of Post-Mastectomy Breast Cancer Recurrence

ABSTRACT: Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM and 25 controls) identified significantly more NF1 mutations and mitogen activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p<0.0001 and p=0.0070, respectively). Three patients had matched primary vs LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) versus controls (14%,p= 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE119937 | GEO | 2018/09/14

REPOSITORIES: GEO

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Project description:Gene expression in histologically normal epithelium from breast cancer patients and cancer-free prophylactic mastectomy patients share a similar profile Introduction: We hypothesized that gene expression in histologically normal epithelium (NlEpi) would differ in breast cancer patients (HN) compared to usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomies from high-risk women (PM), would resemble HN gene expression. Methods: We analyzed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 cases, we used Affymetrix HU133A microarrays to compare gene expression in 18 RM vs 18 age-matched HN (9 ER+, 9 ER-) and 6 PM. Data were validated with qPCR in 31 independent NlEpi samples (8 RM, 17 HN, 6 PM). Results: 98 probesets (86 genes) were differentially expressed between RM and HN samples. Perfoming supervised hierarchical analysis with these 98 probesets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM vs HN, and lower (58%), but more heterogeneous, in RM vs PM. The 86 genes were implicated in many processes including transcription and the MAPK pathway. Conclusion: Gene expression differs between NlEpi of cancer cases and controls. The cancer cases' profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. We determined that 98 probesets significantly differed between reduction mammoplasty and histologically normal epithelium from breast cancer patients. We also found that the histologically normal epithelium from prophylactic mastectomy patients' gene expression was more similar to histologically normal epithelium from breast cancer patients' than to reduction mammoplasty patients' gene expression. These results demonstrate that gene expression differs between NlEpi of cancer cases and controls. The cancer casesâ?? profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. 42 total laser capture microdissected histologically normal breast tissue samples were analyzed with Affymetrix HU133A microarrays. 36 samples were age-matched between reduction mammoplasty (n=18) and histologically normal epithelial samples from breast cancer patients (n=18; 9ER+, 9ER-). 6 histologically normal epithelial samples from prophylactic mastectomy patients were then compared to data generated from the original 36 sample comparison. Sample numbers correspond to individual patient samples.

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Molecular Determinants of Post-Mastectomy Breast Cancer Recurrence

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