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Deciphering the normal-like molecular subtype of breast cancer

Veerla, Srinivas LU orcid ; Kimbung, Siker LU ; Vallon-Christersson, Johan LU orcid ; Ebbesson, Anna LU and Hedenfalk, Ingrid LU orcid (2023) AACR Special Conference in Cancer Research: Advances in Breast Cancer Research
Abstract
The normal-like molecular subtype of breast cancer has not been well characterized and is currently not included in the clinically approved PAM50 molecular subtype classification. Tumors classified as normallike display high expression of basal epithelial genes and low expression of luminal epithelial genes, but also high expression of genes expressed by non-epithelial cell types including adipocytes [1]. The normal-like subtype has been suggested to represent tumors with low invasive tumor cell content, hence challenging its legitimacy as an intrinsic subtype. To clarify this issue we aimed to characterize the features of early breast cancers classified as normal-like using RNA sequencing and immunohistochemistry (IHC). Using a... (More)
The normal-like molecular subtype of breast cancer has not been well characterized and is currently not included in the clinically approved PAM50 molecular subtype classification. Tumors classified as normallike display high expression of basal epithelial genes and low expression of luminal epithelial genes, but also high expression of genes expressed by non-epithelial cell types including adipocytes [1]. The normal-like subtype has been suggested to represent tumors with low invasive tumor cell content, hence challenging its legitimacy as an intrinsic subtype. To clarify this issue we aimed to characterize the features of early breast cancers classified as normal-like using RNA sequencing and immunohistochemistry (IHC). Using a consecutive series of 14,000 early breast cancers from the population-based multi-center observational Sweden Cancerome Analysis Network – Breast (SCAN-B)
and a recently published RNAseq-based single-sample molecular subtype predictor [2] the subtype distribution was: 39% luminal A, 25% luminal B, 12% HER2-enriched, 9% basal and 15% normal-like. The median tumor size did not differ significantly between the subtypes, while tumor cellularity assessed
on H&E slides was lower among normal-like breast cancers (median 20%) compared to the other subtypes (median range 40-70%). Using a version of the classifier that excludes the normal-like subtype, i.e. akin to clinical PAM50 subtyping, 67.5% of the tumors classified as normal-like were reclassified
as luminal A, with the remaining cases re-classified as either basal (17.5%) or HER2-enriched (14.9%). The distribution of hallmark features among normal-like tumors was 75% ER+, 67% PR+, 20% Ki67 high and 10% HER2 positive by IHC/CISH. IHC further revealed loss of E-cadherin in 30% of normal-like breast cancers, in line with 30% lobular histology. Significantly differentially expressed genes between lobular and non-lobular normal-like breast cancers included CDH1, PGC, CPB1, SERPINA6, TRH, MSLN, MMP1 and AKR1B15. The lobular normal-like breast cancers were enriched for the ER+/HER2- /node negative clinical subgroup (58%). Mutation calling using the SCAN-B MutationExplorer application [3] revealed enrichment of PIK3CA (46% vs. 18%), CDH1 (37% vs. 18%), TP53 (7% vs 0%) and ESR1 (6% vs. 0%) mutations in normal-like lobular vs. luminal lobular breast cancers. Finally, overall survival within the normal-like group was significantly different from all other subtypes and was intermediate
between the luminal A and B groups (p<0.05 for pairwise comparisons). To conclude, the normal-like subgroup is enriched for lobular breast cancers and displays downregulation of genes involved in cell adhesion and hormone regulation. Normal-like breast cancers are primarily classified as luminal A tumors
with current clinical subtype classification algorithms, but the inferior survival and distinct features of these tumors do not preclude that this may be a true intrinsic subtype, thus warranting further investigation of the normal-like subtype. (Less)
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AACR Special Conference in Cancer Research: Advances in Breast Cancer Research
conference location
San Diego, CA, United States
conference dates
2023-10-19 - 2023-10-22
language
English
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yes
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6807347f-9f10-427d-b300-0bf46a086ec9
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2024-02-12 13:20:01
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2024-02-14 14:35:29
@misc{6807347f-9f10-427d-b300-0bf46a086ec9,
  abstract     = {{The normal-like molecular subtype of breast cancer has not been well characterized and is currently not included in the clinically approved PAM50 molecular subtype classification. Tumors classified as normallike display high expression of basal epithelial genes and low expression of luminal epithelial genes, but also high expression of genes expressed by non-epithelial cell types including adipocytes [1]. The normal-like subtype has been suggested to represent tumors with low invasive tumor cell content, hence challenging its legitimacy as an intrinsic subtype. To clarify this issue we aimed to characterize the features of early breast cancers classified as normal-like using RNA sequencing and immunohistochemistry (IHC). Using a consecutive series of 14,000 early breast cancers from the population-based multi-center observational Sweden Cancerome Analysis Network – Breast (SCAN-B)<br/>and a recently published RNAseq-based single-sample molecular subtype predictor [2] the subtype distribution was: 39% luminal A, 25% luminal B, 12% HER2-enriched, 9% basal and 15% normal-like. The median tumor size did not differ significantly between the subtypes, while tumor cellularity assessed<br/>on H&amp;E slides was lower among normal-like breast cancers (median 20%) compared to the other subtypes (median range 40-70%). Using a version of the classifier that excludes the normal-like subtype, i.e. akin to clinical PAM50 subtyping, 67.5% of the tumors classified as normal-like were reclassified<br/>as luminal A, with the remaining cases re-classified as either basal (17.5%) or HER2-enriched (14.9%). The distribution of hallmark features among normal-like tumors was 75% ER+, 67% PR+, 20% Ki67 high and 10% HER2 positive by IHC/CISH. IHC further revealed loss of E-cadherin in 30% of normal-like breast cancers, in line with 30% lobular histology. Significantly differentially expressed genes between lobular and non-lobular normal-like breast cancers included CDH1, PGC, CPB1, SERPINA6, TRH, MSLN, MMP1 and AKR1B15. The lobular normal-like breast cancers were enriched for the ER+/HER2- /node negative clinical subgroup (58%). Mutation calling using the SCAN-B MutationExplorer application [3] revealed enrichment of PIK3CA (46% vs. 18%), CDH1 (37% vs. 18%), TP53 (7% vs 0%) and ESR1 (6% vs. 0%) mutations in normal-like lobular vs. luminal lobular breast cancers. Finally, overall survival within the normal-like group was significantly different from all other subtypes and was intermediate<br/>between the luminal A and B groups (p&lt;0.05 for pairwise comparisons). To conclude, the normal-like subgroup is enriched for lobular breast cancers and displays downregulation of genes involved in cell adhesion and hormone regulation. Normal-like breast cancers are primarily classified as luminal A tumors<br/>with current clinical subtype classification algorithms, but the inferior survival and distinct features of these tumors do not preclude that this may be a true intrinsic subtype, thus warranting further investigation of the normal-like subtype.}},
  author       = {{Veerla, Srinivas and Kimbung, Siker and Vallon-Christersson, Johan and Ebbesson, Anna and Hedenfalk, Ingrid}},
  language     = {{eng}},
  title        = {{Deciphering the normal-like molecular subtype of breast cancer}},
  year         = {{2023}},
}