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Breast Cancer Treatments: Updates and New Challenges.

ABSTRACT: Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatment. Along with chemotherapy and radiotherapy, these therapies can have severe adverse effects and patients can develop resistance to these agents. Moreover, TNBC do not have standardized treatments. Hence, a deeper understanding of the development of new treatments that are more specific and effective in treating each BC subgroup is key. New approaches have recently emerged such as immunotherapy, conjugated antibodies, and targeting other metabolic pathways. This review summarizes current BC treatments and explores the new treatment strategies from a personalized therapy perspective and the resulting challenges.

SUBMITTER: Burguin A

PROVIDER: S-EPMC8399130 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Breast Cancer Treatments: Updates and New Challenges.

Burguin Anna A Diorio Caroline C Durocher Francine F

Journal of personalized medicine 20210819 8

Breast cancer (BC) is the most frequent cancer diagnosed in women worldwide. This heterogeneous disease can be classified into four molecular subtypes (luminal A, luminal B, HER2 and triple-negative breast cancer (TNBC)) according to the expression of the estrogen receptor (ER) and the progesterone receptor (PR), and the overexpression of the human epidermal growth factor receptor 2 (HER2). Current BC treatments target these receptors (endocrine and anti-HER2 therapies) as a personalized treatme ...[more]

PMID: 34442452

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Project description:Systemic therapy has been viewed as the mainstay for de novo metastatic breast cancer (dnMBC). However, as dnMBC is highly heterogeneous both biologically and clinically, and with ever-improving systemic strategies, it has been implied that the local therapy of the primary tumor (PT) may be beneficial for certain patients with dnMBC. However, the results from retrospective studies have been questioned due to their selection bias and retrospective nature. To the best of our knowledge, there are two published randomized clinical trials addressing this issue with conflicting conclusions: i) TATA study from India indicated no overall survival (OS) superiority with early local radiotherapy (LRT); and ii) MF07-01 indicated a 5-year OS rate improvement of 17% with upfront LRT. The updated results of a randomized phase III ECOG-ACRIN E2108 trial released in the 2020 American Society of Clinical Oncology (ASCO) meeting reported a negative survival effect of early LRT treatment in patients with dnMBC responding to initial systemic treatment, despite LRT significantly reducing the locoregional failure. Thus, a number of issues, such as the exact value of LRT, the optimal means of LRT (surgery and/or RT to the PT), the ideal timing of LRT and the population most likely to benefit from LRT, warrant further investigation. Herein, the related studies focusing on these aspects were comprehensively reviewed and a decision algorithm was proposed to select suitable patients with dnMBC for reasonable LRT. Generally, upfront systemic therapy is recommended. For good respondents and a subgroup of favorable profiles (young age, good general condition, low tumor burden, hormone receptor-positive and so on), radical LRT including PT surgery followed by RT and the resection of distant metastases is recommended. LRT should also be administered if the PT is still symptomatic. LRT may benefit patients with dnMBC due to the following reasons: Control of the PT decreases tumor burden, eliminates the source of dissemination, enhances the sensitivity to therapy and exerts positive immunomodulation. Therefore, the treatment paradigm for dnMBC may change from 'palliative LRT' into 'curative LRT' in a highly selected entity with careful evaluation.

Project description:Triple-negative breast cancer (TNBC) is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification. TNBC includes a collection of multiple distinct disease entities based upon genomic, transcriptomic and phenotypic characterization. Despite improved clinical outcomes with the development of novel therapeutics, TNBC still yields the worst prognosis among all clinical subtypes of breast cancer. We will systematically review evidence of the genomic evolution of TNBC, as well as potential mechanisms of disease progression and treatment resistance, defined in part by advances in next-generation DNA sequencing technology (including single cell sequencing), providing a new perspective on treatment strategies, and promise to reveal new potential therapeutic targets. Moreover, we review novel therapies aimed at homologous recombination deficiency, PI3 kinase/AKT/PTEN pathway activation, androgen receptor blockade, immune checkpoint inhibition, as well as antibody-drug conjugates engaging novel cell surface targets, including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC. Despite major advances in treatment for TNBC, including FDA approval of 2 PARP inhibitors for metastatic TNBC, the crossing of the superiority boundary in a phase 3, placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer, the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC, and the FDA approval of the first antibody drug conjugate for TNBC, significant challenges remain. For example, despite the dawn of immunotherapy in metastatic TNBC, durable responses are limited to a small subset of patients, definitive biomarkers for patient selection are lacking, and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 checkpoint antibody high risk early-stage TNBC in the neoadjuvant setting. Also, despite early positive randomized phase 2 studies of AKT inhibition in metastatic TNBC, a recent phase 3 registration trial failed to validate earlier phase 2 data. Finally, we note that level one evidence for clinical efficacy of androgen receptor blockade in TNBC is still lacking. To meet these and other challenges, we will catalogue the ongoing exponential increase in interest in basic, translational, and clinical research to develop new treatment paradigms for TNBC.

Dataset Information

Breast Cancer Treatments: Updates and New Challenges.

Publications

Breast Cancer Treatments: Updates and New Challenges.

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