Abstract Triple negative breast cancers are defined by the absence of oestrogen, progesterone and HER2 expression. Most triple negative cancers display distinct clinical and pathological ...characteristics with a high proportion of these tumours occurring at a younger age of onset and in African–American women. Triple negative tumours typically demonstrate high histological grade and are the most common breast cancer subtype in BRCA1 carriers. In addition, many of the features of triple negative cancers are similar to those identified in the basal-like molecular subtype which has recently been characterised by gene expression profiling. Although the two groups overlap, they are not synonymous. Triple negative breast cancers are of pivotal clinical importance given the lack of therapeutic options. The prognostic significance of triple negative tumours remains unclear since the group is heterogeneous and worst prognosis seems to be mostly confined to those that express basal cytokeratins or epidermal growth factor receptor (EGFR). This review focuses on outlining the pathological, molecular, and clinical features of triple negative breast cancers, discusses its prognostic value and summarises current therapeutic approaches and future directions of research.
Expression of programmed death ligand 1 (PD-L1) in solid tumours has been shown to predict whether patients are likely to respond to anti-PD-L1 therapies. To estimate the therapeutic potential of ...PD-L1 inhibition in breast cancer, we evaluated the prevalence and significance of PD-L1 protein expression in a large collection of breast tumours.
Correlations between CD274 (PD-L1) copy number, transcript and protein levels were evaluated in tumours from 418 patients recruited to the METABRIC genomic study. Immunohistochemistry was used to detect PD-L1 protein in breast tumours in tissue microarrays from 5763 patients recruited to the SEARCH population-based study (N = 4079) and the NEAT randomised, controlled trial (N = 1684).
PD-L1 protein data was available for 3916 of the possible 5763 tumours from the SEARCH and NEAT studies. PD-L1 expression by immune cells was observed in 6% (235/3916) of tumours and expression by tumour cells was observed in just 1.7% (66/3916). PD-L1 was most frequently expressed in basal-like tumours. This was observed both where tumours were subtyped by combined copy number and expression profiling 39% (17/44) of IntClust 10 i.e. basal-like tumours were PD-L1 immune cell positive; P < 0.001 and where a surrogate IHC-based classifier was used 19% (56/302) of basal-like tumours were PD-L1 immune cell positive; P < 0.001. Moreover, CD274 (PD-L1) amplification was observed in five tumours of which four were IntClust 10. Expression of PD-L1 by either tumour cells or infiltrating immune cells was positively correlated with infiltration by both cytotoxic and regulatory T cells (P < 0.001). There was a nominally significant association between PD-L1 and improved disease-specific survival (hazard ratio 0.53, 95% confidence interval 0.26–1.07; P = 0.08) in ER-negative disease.
Expression of PD-L1 is rare in breast cancer, markedly enriched in basal-like tumours and is correlated with infiltrating lymphocytes. PD-L1 inhibition may benefit the 19% of patients with basal-like tumours in which the protein is expressed.
NCT00003577.
T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a ...prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.
In ER-negative tumours triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive), presence of CD8+ T cells within the tumour was associated with a 28% 95% confidence interval (CI) 16% to 38% reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours hazard ratio (HR) = 0.54; 95% CI 0.37-0.79 versus CD8-negative tumours (HR = 0.87; 95% CI 0.55–1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (Pheterogeneity = 0.04) and approached significance in imputed data (Pheterogeneity = 0.1).
The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative supplementary Figure S1, available at Annals of Oncology online and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes.
NCT00003577.
Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 ...antibody–drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.
•Targeting HER2-low expression with novel antibody-drug conjugates has reshaped the treatment of metastatic breast cancer.•This advancement raised relevant questions pertaining to the definition, diagnosis and management of HER2-low breast cancer.•We gathered 32 international experts to build consensus regarding key controversial topics pertaining HER2-low breast cancer.•A modified Delphi voting methodology was deployed, leading to 20 consensus statements, each with at least 90% consensus among experts.•Ongoing studies may lead to further refinement in our understanding of HER2-low breast cancer.
Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is ...required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5'UTRs with potential to form G-quadruplexes and with 3'UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies.
Despite significant advances in early diagnosis and treatment, skin cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a new therapeutic modality that is emerging as an ...important resource against malignant tumors. This strategy is based on the action of photosensitizers, i.e. of molecules which may accumulate preferentially inside tumor cells where they exert a cytotoxic effect after excitation by light at appropriate wavelengths. Some forms of skin cancers and also some non-tumor pathologies are now treated with PDT. Several compounds with photosensitizing activity have been identified, and some of these molecules are commercially available. Many photoactive principles are natural compounds. Numerous reviews in the last decade have focused on photodynamic therapy, its effects and applications, but less attention has been paid to plant extracts or molecules of natural origin studied for their phototoxic activity to date.This review critically examines the potential role of various plant extracts and naturally occurring compounds in the treatment of skin cancer. Both in vitro and in vivo effects of these agents, together with their known related cellular and molecular mechanisms, are presented and discussed.
Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained ...widespread clinical acceptance.
We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini-chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation.
The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1-1.5; P=0.005), outperforming all other markers including Ki67.
Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice.
These multidisciplinary guidelines aim to provide clinically helpful, evidence-based recommendations on the surgical management of the axilla in patients who have received neo-adjuvant chemotherapy ...for early breast cancer.
Following a review of published evidence, a writing group representing all disciplines quorate within a breast cancer multidisciplinary meeting prepared the guidelines.
In patients presenting with clinically node negative axillae, sentinel node biopsy (SNB) may be performed prior to or on completion of neo-adjuvant chemotherapy (NACT). In patients presenting with clinically node positive axillae, SNB may be safely considered following completion of NACT. Four nodes should be removed with dual mapping. If evidence of complete pathological response of previous metastases is seen, axillary radiotherapy may be offered. If residual cancer (isolated tumour cells, micro- or macrometastes) is seen within the SNB, offer axillary node dissection.
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