Breast cancer: pathogenesis and treatments

Abstract

Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.

Fig. 1

Comprehensive overview of breast cancer pathogenesis and treatment. Breast cancer is one of the most prevalent tumors in women, and its occurrence is associated with a multitude of factors, such as genetic mutations, late menopause, and obesity. The progression of breast cancer is shaped by numerous factors, encompassing both tumor cell characteristics and elements within the tumor microenvironment, whether cellular or non-cellular. In recent years, there have been significant advancements in diagnostic technologies for breast cancer. Alongside traditional imaging techniques and pathological diagnosis methods, liquid biopsy, and multiple immunofluorescence assays, digital pathology approaches are gradually being incorporated into clinical practice. Treatment options for breast cancer are diverse, and recent clinical studies emphasize the importance of individualized and precision treatments. Long-term follow-up management of breast cancer patients is also crucial, as it may impact both the therapeutic outcomes and enhancing patients’ quality of life. BUS B-scan ultrasonography, CT computed tomography, MRI magnetic resonance imaging, IF immunofluorescence, ctDNA circulating tumor DNA, CSC cancer stem cell, SASP senescence-associated secretory phenotype, TCA cycle tricarboxylic acid cycle. The figure was created with Biorender.com

Fig. 2

Risk factors for breast cancer. Hormonal factors such as long-term exposure to estrogen, nulliparity and no breastfeeding, late menopause, or early menarche increase the risk of breast cancer. Genetic predisposition is a serious health hazard. High penetrant mutations and genetic polymorphisms are the two parts. Patients with genetic mutations such as BRCA1/2 or patients whose first-degree relative has history of breast cancer are more susceptible to this malignancy. Low penetrant mutations, including GSTM1 and NQO2, are included in genetic polymorphisms of breast cancer susceptibility. Unhealthy lifestyle may also lead to breast cancer. Overdose exposure to radiation and/or heavy alcohol consumption, smoking, having diet high in fat or sugar, obesity, physical inactivity are the leading causes. HR hazard ratio, CI confidence interval. The figure was created with Biorender.com

Fig. 3

General timeline for redefining breast cancer molecular subtypes. The subtypes of breast cancer can be divided into two groups, namely unsupervised-clustering-based molecular subtypes and therapeutic-purpose-relative subtypes. a Perou et al. firstly proposed the concept of molecular typing of breast cancer in 2000 by using DNA microarrays representing >8000 genes. b Parker et al. constructed PAM50 subtypes in 2009, which was a simplified version of the “intrinsic” subtypes. c In 2012, Christina et al. offered an integration of the genome and transcriptome from representative patients, which provided a novel molecular stratification of the breast cancer population. d Bernard et al. identified ten subtypes of breast cancer from the landscape of mutations, driver copy number aberrations. e Unsupervised proteogenomics identified four molecular subtypes underscore the potential of proteomics for clinical investigation in 2020. f In 2021, another update called single-cell method of intrinsic subtype stratified the complex cellular ecosystems into nine clusters. g IHC-based subtype was the first therapeutic-purpose-relative subtype raised in 2011. h An alternative subtype was constructed in 2022 according to various regimens redefined and supported the usage of response-based subtypes to guide future treatment prioritization. i Reclassifications of the specific subtypes include Vanderbilt TNBC subtypes in 2011, Vanderbilt redefining TNBC subtypes in 2015, FUSCC TNBC subtypes in 2019 and FUSCC HR+/HER2− subtypes in 2023. IHC immunohistochemistry, TNBC triple-negative breast cancer, FUSCC Fudan University Shanghai Cancer Center, HR hormone receptor, HER2 human epidermal growth factor receptor-2. The figure was created with Biorender.com

Fig. 4

Diverse factors regulating the progression of breast cancer. Many factors contribute to the progression of breast cancer, resulting in local recurrence (i), metastasis (j), and treatment resistance (k) of breast cancer. These factors include tumor stemness (a), cellular senescence (b), novel types of programmed cell death (c), intra-tumoral microbiota (d), circadian rhythm (e), metabolic reprogramming (f), immune reprogramming (g), as well as tumor dormancy (h). CSC cancer stem cell, SASP senescence-associated secretory phenotype. The figure was created with Biorender.com

Fig. 5

Surgical treatment for breast cancer. Traditional treatments for breast cancer include breast conservative surgeries and mastectomy, while axillary surgeries include axillary lymph node dissection and sentinel lymph node dissection. Currently, there have been some novel approaches for breast cancer treatment. Thermal ablation/cryoablation is a potential non-surgical technique for tumor destruction that can possibly replace surgical excision in some situations. Moreover, there has also been an emerging concept of using neoadjuvant therapy (NAT) to eradicate tumors and completely avoid surgery, which requires core biopsy or magnetic resonance imaging (MRI) to confirm no residual tumor. Sentinel lymph node biopsy allows safe axillary lymph node dissection exemption for certain patients. pCR pathological complete response. The figure was created with Biorender.com

Fig. 6

Systematic treatment for breast cancer. In HR+/HER2− breast cancer, aromatase inhibitors (AIs) are a traditional regimen for estrogen synthesis inhibition. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) started the new era of endocrine therapy for HR+/HER2− breast cancer. Cyclin-dependent kinases (CDK) 4/6 inhibitors are another novel treatment strategy for HR+/HER2− breast cancer. Furthermore, the inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway also showed promising clinical efficacy. In HER2+ breast cancer, dual HER2−targeted therapy with trastuzumab and pertuzumab is established as the standard treatment. Following the failure of conventional anti-HER2 therapies, the introduction of tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) continues to extend patients’ clinical prognosis through distinct mechanisms of action. For triple-negative breast cancer (TNBC), chemotherapy has long been a classic and effective treatment approach. In recent years, advances in translational medicine have expanded treatment options with the introduction of Poly (ADP-ribose) polymerase inhibitors (PARPi) and anti-Trophoblast cell surface antigen 2 (Trop2) ADCs. Notably, in the era of immunotherapy, immune checkpoint inhibitors (ICIs) have shown promising results in both advanced cases and in early-stage neoadjuvant settings. HR hormone receptor, HER2 human epidermal growth factor receptor-2, ER estrogen receptor, ERC ER coactivator, Rb retinoblastoma-associated protein, PAMi PI3K/AKT/mTOR pathway inhibitors, RTK receptor tyrosine kinase, PD-1 programmed cell death 1, PD-L1 programmed cell death 1 ligand 1. The figure was created with Biorender.com