Background: Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and Methods: By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). Results: We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [−], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR−, CD8−, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC-based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion: We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNA) play a vital role in tumor growth and progression. Here, we identified a lncRNA LINC00926 negatively correlated with PGK1 and predicting good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression by enhancing the ubiquitination of PGK1 mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate BC growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.

The notion of personalized medicine demands proper prognostic biomarkers to guide the optimal therapy for an invasive breast cancer patient. However, various risk prediction models based on conventional clinicopathological factors and emergent molecular assays have been frequently limited by either a low strength of prognosis or restricted applicability to specific types of patients. Therefore, there is a critical need to develop a strong and general prognosticator.

Deep and durable responses with zanubrutinib plus obinutuzumab in patients with R/R FL.

Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress‐responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1‐mediated down‐regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.

Purpose: The Chinese bridging study PUFFIN (NCT02896855) aimed to assess consistency of efficacy with CLEOPATRA (NCT00567190), investigating pertuzumab with trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer. Methods: Patients were randomized 1:1, stratified by visceral/non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (in patients with measurable baseline disease), overall survival, and safety. The consistency threshold for PFS (hazard ratio [HR] < 0.81) (maintaining ≥ 50% of the risk reduction determined in CLEOPATRA [HR 0.62]) determined the target sample size (n = 240). Results: Two hundred forty-three patients were randomized. Median PFS was 14.5 months in the pertuzumab arm (95% confidence interval [CI] 12.5, 18.6) and 12.4 months in the placebo arm (95% CI 10.4, 12.7) in the intention-to-treat population (HR: 0.69 [95% CI 0.49, 0.99]). Objective responses were recorded in 83/105 (79.0%) and 67/97 (69.1%) patients, respectively. Grade ≥ 3 adverse events (70.5% and 69.2%, respectively) and serious adverse events (19.7% and 19.2%, respectively) were similar across both arms. No heart failure cases or symptomatic left ventricular ejection fraction declines were reported. Conclusions: PUFFIN met its primary objective. Overall, efficacy data were consistent with CLEOPATRA. Safety was consistent with the known pertuzumab safety profile. PUFFIN adds to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit–risk profile of pertuzumab in Chinese patients Trial registration: ClinicalTrials.gov, NCT02896855, registered 7 September 2016