A Chinese multi-omics analysis of the largest triple-negative breast cancer (TNBC) database compiled to date has identified three new distinct TNBC metabolic-pathway-based subtypes (MPSs), which could be targeted therapeutically.
"This is the first study to identify the three distinct TNBC [subtypes] that could be therapeutically targeted," said study leader Zhi-Ming Shao, a professor and director of the Department of Breast Surgery at Fudan University Shanghai Cancer Center (FUSCC).
Reported in the November 11, 2020, online edition of Cell Metabolism, the study also showed that the functional significance of metabolic subtyping was supported by a consistent sensitivity of each MPS to inhibitors targeting the same metabolic pathway.
Comprising 12-17% of all breast cancers, TNBC expresses neither estrogen nor progesterone receptors and there is no amplification of the human epidermal growth factor receptor 2 (HER2), meaning there are also no specific therapeutic targets.
"Conventional chemotherapy is currently the only effective adjuvant therapy for TNBC," Shao told BioWorld Science.
Consequently, TNBC has a poor prognosis, a high rate of early relapse and limited therapeutic options, therefore representing a major unmet medical challenge.
"Although several studies have recently demonstrated that immunotherapy may have effects on TNBC, further therapeutic strategies are needed," said Shao.
Cancer cells are known to acquire metabolic alterations to sustain rapid proliferation, with such alterations affecting the fate of cancer cells and other cell types within the tumor microenvironment.
Metabolic reprogramming is thus considered a hallmark of cancer, providing opportunities for cancer diagnosis, prognosis and treatment.
However, it is increasingly apparent that there are heterogeneous metabolic requirements across tumor types and even among tumors in the same tissue, which has hindered previous trials of metabolism-targeting drugs.
This has prompted recent attempts to classify TNBCs into molecular subtypes with distinct mutational profiles, genomic alterations, and biological processes that might guide treatment decisions.
However, few studies have investigated the genomic basis of metabolic dysregulation and heterogeneity in TNBC, due to the small sample size and a lack of multi-omics data.
"Multi-omic analysis comprises a biological analytical approach involving data sets for multiple 'omes', including the genome, proteome, transcriptome, epigenome, metabolome, and the microbiome," explained Shao.
"By combining these data sets, scientists can analyze complex biological data to identify novel associations between biological entities and elaborate relevant markers of disease and physiology."
Hence the objectives of the new study led by Shao and his FUSCC colleagues, professors Xin Hu and Yi-Zhou Jiang, were to assess which metabolic pathways alter overall metabolic transcriptional profiles in TNBCs.
Using the multi-omics data of 465 TNBCs derived from the FUSCC cohort, the authors identified three metabolic TNBC subtypes on the basis of 86 different metabolic pathways.
The three MPSs were shown to have distinct metabolic gene expression, metabolite abundance, genomic drivers, and survival and sensitivity to various metabolic inhibitors.
The TNBC samples were classified into three MPSs with distinct metabolic features: MPS1, a lipogenic subtype with upregulated lipid metabolism; MPS2, a glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, a mixed subtype, with partial pathway dysregulation.
"In our database, the frequency of three subtypes was 26.4%, 36.9% and 36.7% for MPS1, MPS2 and MPS3, respectively," Shao said.
These three subtypes were then validated by metabolomic profiling of 72 samples and shown to have distinct prognoses, molecular subtype distributions, and genomic alterations.
Moreover, the MPS1 TNBCs were shown to be more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis.
Importantly, the inhibition of lactate dehydrogenase (LDH) combined with an anti-programmed cell death protein (anti-PD-1) monoclonal antibody was found to enhance tumor response to immunotherapy in MPS2 TNBCs.
Together, these findings demonstrate the metabolic heterogeneity of TNBCs and may enable the development of personalized therapies targeting unique tumor metabolic profiles.
In particular, they show that the preclinical efficacy of LDH inhibition in combination with anti-PD-1-targeted therapy justifies metabolic subtyping as a potential therapeutic strategy in MPS2 TNBC.
However, "extensive safety research needs to be performed before this combination therapy might be able to enter clinical trials," noted Shao.
Moreover, "for MPS1 patients, a fatty acid synthase (FAS/FASN) inhibitor might potentially be a therapeutic strategy," he suggested.
However, "therapeutic targets for MPS3 patients await further exploration, as do new targets for TNBC patients in general, which will be the focus of our ongoing research at FUSCC." (Gong, Y. et al. Cell Metab 2021, 33: 1).