Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets

Zambelli, Alberto; Sgarra, Riccardo; Sanctis, Rita De; Agostinetto, Elisa; Santoro, Armando; Manfioletti, Guidalberto

doi:10.1080/14728222.2022.2084380

Cited by 5 publications

(5 citation statements)

References 131 publications

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“…In clinical trials the response to ICIs is very heterogeneous and discovering new predictive biomarkers is un unmet need. However, to date, none of the translational research efforts have identified clinically useful biomarkers that can accurately predict the response to immunotherapy [75].…”

Section: Other Predictive Biomarkersmentioning

confidence: 99%

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

Jacobs

Agostinetto

Miggiano

et al. 2023

Cancers

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Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials.

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Section: Other Predictive Biomarkersmentioning

confidence: 99%

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

Jacobs

Agostinetto

Miggiano

et al. 2023

Cancers

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“…TNBC is the most aggressive and difficult to treat subtype of breast cancer. The overall biologic heterogeneity that characterizes TNBC can greatly complicate the identification of effective therapies with lasting efficacy, making TNBC difficult to treat with current therapies [ 112 ]. High metastatic potential and poor prognosis remains an important clinical feature of this breast cancer subtype.…”

Section: Diagnostic and Therapeutic Possibilities Linked To Tumor Met...mentioning

confidence: 99%

Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer

Munkácsy

Santarpia

Győrffy

2023

IJMS

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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with clinical features of high metastatic potential, susceptibility to relapse, and poor prognosis. TNBC lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It is characterized by genomic and transcriptional heterogeneity and a tumor microenvironment (TME) with the presence of high levels of stromal tumor-infiltrating lymphocytes (TILs), immunogenicity, and an important immunosuppressive landscape. Recent evidence suggests that metabolic changes in the TME play a key role in molding tumor development by impacting the stromal and immune cell fractions, TME composition, and activation. Hence, a complex inter-talk between metabolic and TME signaling in TNBC exists, highlighting the possibility of uncovering and investigating novel therapeutic targets. A better understanding of the interaction between the TME and tumor cells, and the underlying molecular mechanisms of cell–cell communication signaling, may uncover additional targets for better therapeutic strategies in TNBC treatment. In this review, we aim to discuss the mechanisms in tumor metabolic reprogramming, linking these changes to potential targetable molecular mechanisms to generate new, physical science-inspired clinical translational insights for the cure of TNBC.

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“…TNBC is an aggressive BC subtype with limited treatment options [ 5 ]. Neoadjuvant polychemotherapy regimens remain the standard of care for early-stage TNBC larger than 2 cm or with positive nodes [ 6 ].…”

Section: Triple-negative Breast Cancermentioning

confidence: 99%

“…In this trial, 910 patients with HER2-negative disease and residual tumor after NAC with anthracyclines and taxanes were randomly assigned to either observation or six to eight cycles of adjuvant capecitabine. Both the endpoints of disease-free survival (DSF) and overall survival (OS) were significantly better in the experimental group, especially in the TNBC subgroup (N = 286, hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.39–0.87 for DFS and HR 0.52, 95% CI 0.30–0.90 for OS) [ 5 ]. Post-neoadjuvant capecitabine now represents the standard of care for patients with TNBC and residual disease after completing NAC [ 6 , 10 , 11 ].…”

Section: Triple-negative Breast Cancermentioning

confidence: 99%

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

Agostinetto

Jacobs

Debien

et al. 2022

Cancers

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Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be “salvaged” through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies.

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Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets

Cited by 5 publications

References 131 publications

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer

Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

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