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Tumor Discovery Fact & challenges of immunotherapy in TNBC

pathways (regulated by actin), extracellular matrix- Moreover, the IMpassion130 trial has shown a
receptor interaction pathways, and differentiation pathways significant, modest improvement in progression-free
[87]
(Wnt pathway, anaplastic lymphoma kinase pathway, and survival (PFS) but a marked difference in OS . The
transforming growth factor [TGF]-β signaling). The M subgroup of patients with PDL1 > 1% (185/451 patients)
subtype has sarcoma-like or squamous epithelial cell-like benefited from atezolizumab; a trend toward a higher
tissue characteristics and is prone to developing resistance ORR was observed in patients with PD-L1-positive versus
[69]
to chemotherapy drugs . Patients with the M subtype PD-L1-negative ICs in the overall population . With the
[79]
may be treated with mTOR inhibitors or drugs that target various outcomes from clinical trials, the focus of further
[15]
epithelial-mesenchymal transition . Compared with the research is on identifying more prognostic biomarkers
M subtype, the MSL subtype shows a lower expression to demonstrate the benefit for each patient receiving
of cell proliferation-related genes but a higher expression immunotherapy (Table 3).
of stem cell-related genes, HOX genes, and mesenchymal
stem cell-specific markers. Presumably, patients with the 4. Conclusion
MSL subtype can be treated with PI3K inhibitors, Src TNBC, compared with other BC subtypes, has a poor
[80]
antagonists, and angiogenesis inhibitors . Compared with prognosis and is still a complicated cancer for immunotherapy
other TNBC subtypes, the LAR subtype has a significantly to be developed thus far. However, to improve the prognosis,
different gene expression profile . This subtype does not immunotherapy techniques must be used. Research efforts
[81]
express ERs, but has highly activated hormone-related should focus on using the ICB we have in relation to the
signaling pathways (e.g., steroid synthesis, porphyrin molecular biology of TNBC to discover mono antibody
metabolism, and androgen/estrogen metabolism). Notably, therapies and other more effective drug combinations. For
androgen receptors (ARs) are highly expressed in breast this highly diverse subtype of BC, personalized medicine
cancers of the LAR subtype, with messenger ribonucleic appears to be of great importance. When deciding on a
acid (mRNA) levels nine times higher than in other treatment plan, tumor molecular profiling should be carried
TNBC subtypes. Immunohistochemistry has also shown out at the time of diagnosis, after each tumor recurrence
that several metabolic markers of AR and its associated or progression, and as needed. The functions of a cluster
activators (24-dehydrocholesterol reductase [DHCR , of biomarkers may be crucial to predicting an individual’s
24]
activated leukocyte cell adhesion molecule [ALCAM], fatty response to future TNBC immunotherapy.
acid synthase [FASN], FK506-binding protein 5 [FKBP ,
5]
apolipoprotein D [APOD], prolactin-induced protein Acknowledgments
[PIP], sterile alpha motif pointed domain-containing ETS Not applicable.
transcription factor [SPDEF], and claudin-8 [CLDN ) are
8]
highly expressed in the LAR subtype. Therefore, anti-AR Funding
therapy is recommended for breast cancer patients with This work was supported by the National Natural Science
the LAR subtype. Foundation of China (82173554); Natural Science
Besides, biomarkers that predict the clinical benefit Foundation of Jiangsu Province (BK20201444); Qing Lan
of immunotherapy in TNBC are also required. PD-L1 Project for Excellent Young Key Teachers of Colleges and
expression on immune cells and mismatch-repair Universities of Jiangsu Province (2020); and Project List of
deficiency are the only two validated biomarkers that Nantong University Student Innovation Training Program
are currently available [82,83] . The majority of patients with in 2022 (202210304049Z, 2022155).
mTNBC are PD-L1-negative by the presently authorized Conflict of interest
SP142 test , despite the fact that mismatch repair failure is
[83]
uncommon in breast cancer but more frequent in the early- The authors declare that they have no competing interests.
stage illness . The variability of PD-L1 expression over
[73]
[84]
time and at metastatic sites , the discrepancy between Author contributions
PD-L1 assays, particularly when staining immune cells, the Conceptualization: Xuehai Wang, Fengxu Wang, Weiyi Xia
observation that some PD-L1-negative patients respond to Funding acquisition: Xinyuan Zhao
ICIs , and the recent trials in early disease setting that Investigation: Hongxiang Zhang
[85]
show little to no correlation of PD-L1 expression with Supervision: Siyuan Deng, Xinyuan Zhao
benefit specific to ICIs, such as the KEYNOTE522 and Writing – original draft: Xuehai Wang
NeoTRIPaPDL1 trials, are additional factors that limit the Writing – review & editing: Xuehai Wang, Fengxu Wang,
utility of PD-L1 [85,86] . Weiyi Xia, Siyuan Deng, Xinyuan Zhao

Volume 1 Issue 2 (2022) 7 https://doi.org/10.36922/td.v1i2.196