Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection

By B. Lehmann, B. Jovanovic, Xi Chen, M. V. Estrada, Kimberly N. Johnson, Y. Shyr, H. Moses, M. Sanders, J. Pietenpol. PLoS ONE, 2016

1,247 citations recorded by the source corpus.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; [33, 51], [9, 28], [17, 41], respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/b8522c733d6d013f6f487182c2b483777e3ade8e

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In Cancer Research

1. K. Polyak
2. Balázs Győrffy

In Oncology

1. A. Garrido-Castro
2. K. Polyak
3. Yongheng Chen
4. S. Leonov
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6. Lin Chen
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8. Yun R Li

Citations in the corpus

• Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment (2019, positive): “In a follow-up study, by performing histologic assessment and laser microdissection prior to RNA isolation and geneexpression analysis, Lehmann and colleagues confirmed that the presence of stromal cells in tumor specimens—such as infiltrating lymphocytes and tumor-associated mesenchymal cells—influ”
• Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge (2019, background): “Interestingly, Ashgar and colleagues showed that LAR tumors are relatively quiescent, which could partially explain their chemoresistance [202].”
• Survival analysis across the entire transcriptome identifies biomarkers with the highest prognostic power in breast cancer (2021, background): “Basal tumors are heterogenous and can be further subdivided into four molecular subtypes based on their transcriptomic fingerprint including the basal-like 1, basal-like 2, the mesenchymal, and the luminal androgen receptor subtypes [30].”
• Recent advances in therapeutic strategies for triple-negative breast cancer (2022, background): “This was a great contribution of Balko and colleagues, who identified the molecular profile of residual TNBC after NAC [14].”