Cancer Treatment and Research

There is a growing global debate over barriers affecting the timely access to innovative anticancer therapies. Access to medicines is often traced back to the issue of costs: however, more commonly, the distance between valuable innovative treatments and the actual treatment of patients is far beyond the mere problem of financial barriers. A comprehensive approach to understand, assess to medicines should be pursued, to dissect the determinants and formulate solutions for all patients. In this chapter, we discuss drivers of access to innovation for patients with breast cancer, based on a case study of access to HER2-diagnositcs and therapeutics yielding a global landscape analysis, based on the efforts and expertise of the global collaborative group "ONCOLLEGE"...

The rapid implementation of precision medicine tools in diagnosing and treating breast cancer (BC) has widened the potential therapeutic options for patients. The applications of gene sequencing, including next-generation gene sequencing (NGS), have led to numerous questions on how to validate, implement, interpret, prioritize and operationalize precision medicine tools to deliver meaningful and impactful interventions. Limited benefit has been portended with earlier experiences of NGS-driven treatment, in BC...

Cancer and cardiovascular disease are the two major causes of morbidity and mortality in worldwide. Discovering new therapeutic agents for the management of breast cancer (BC) has increased the numbers of cancer survivors but with the risk of cardiovascular adverse events (CV-AEs). All drugs can potentially damage the cardiovascular system, with different types of clinical manifestations from ischemic myocardial disease to vasculitis, thrombosis or pericarditis. An early detection of CV-AEs guarantees an earlier treatment, which is associated with better outcomes...

Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as a mechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration...

Overexpression of human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor, has been described in about 15-20% of breast cancer (BC) and is associated with poor outcomes. Trastuzumab is the first anti-HER2 monoclonal antibody (mAB) that blocks receptor activity but it also activates immune response against cancer cells, thus, revolutionizing the prognosis of patients with HER2-positive BC. Over the years, new therapies have been developed, including other mAbs and tyrosine kinase inhibitors (TKIs) that required multimodal approaches with chemotherapy to optimize their anticancer activity...

Hormone receptor-positive (HR+) breast cancer (BC) accounts for approximately 70% of all breast invasive tumors. Endocrine therapy (ET) represents the standard treatment for HR + BC. Most patients, however, eventually develop resistance to ET, which limits their effectiveness and poses a major challenge for the management of HR + BC. Several mechanisms that contribute to ET resistance have been described. One of the most common mechanisms is the upregulation of alternative signaling pathways that can bypass estrogen dependency, such as activation of the PI3K/Akt/mTOR as well as mitogen-activated protein kinase (MAPK) and the insulin-like growth factor 1 receptor (IGF-1R) pathways...

The impact of nutritional patterns on the risk of breast cancer (BC) is well investigated in the oncology literature, including the type of diets and caloric intake. While obesity and elevated body mass index are well-reported critical risk factors of BC occurrence, there is an expanding area of oncology assessing the impact of caloric intake and nutritional patterns in patients with cancer. Caloric restriction and fast mimicking alimentary regimens have been consistently reported to improve survival outcomes based on preclinical models...

Radiotherapy is an integral part of the multidisciplinary management of breast cancer (BC). There have been multiple recent advances in the delivery of radiotherapy, reviewed with a critical discussion of the evidence from trials investigating adjuvant ultra-hypofractionation and partial breast irradiation for early-stage BC, and the locoregional management of lymph nodes in locally advanced BC. Multiple precision medicine-based approaches have been developed as prognostic and/or predictive for BC patients and identifying biomarkers of radioresistance could help identify patients that may benefit from dose-escalated radiotherapy or radiosensitizers...

Once reserved for locally advanced tumors which were deemed inoperable at presentation, preoperative systemic therapy (PST) is nowadays increasingly used to treat early breast cancer. PST allows for in vivo assessment of tumor response, for tailoring of adjuvant systemic therapy and for de-escalation of breast and the axillary surgery. Increased rates of pathological complete response together with more accurate response assessment and surgical planning have led to a significant reduction in surgical morbidity...

Neoadjuvant treatments (NAT) for breast cancer (BC) consist in the administration of chemotherapy-more rarely endocrine therapy-before surgery. Firstly, it was introduced 50 years ago to downsize locally advanced (inoperable) BCs. NAT are now widespread and so effective to be used also at the early stage of the disease. NAT are heterogeneous in terms of therapeutic patterns, class of used drugs, dosage, and duration. The poly-chemotherapy regimen and administration schedule are established by a multi-disciplinary team, according to the stage of disease, the tumor subtype and the age, the physical status, and the drug sensitivity of BC patients...

The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal...

Early detection of breast cancer (BC) comprises two approaches: screening of asymptomatic women in a specified target population at risk (usually a target age range for women at average risk), and early diagnosis for women with BC signs and symptoms. Screening for BC is a key health intervention for early detection. While population-based screening programs have been implemented for age-selected women, the pivotal clinical trials have not addressed the global utility nor the improvement of screening performance by utilizing more refined parameters for patient eligibility, such as individualized risk stratification...

Poor prognosis is a distinctive feature of triple-negative breast cancer (TNBC). Chemotherapy has long represented the main and unique treatment for patients with TNBC. Recently, immune checkpoint inhibitors (ICIs) were investigated in several clinical trials and were approved for clinical use in TNBC patients that express programmed cell death protein-1 (PD-1) in combination with chemotherapy in the first-line setting. ICIs are also being investigated in the neoadjuvant and adjuvant settings for TNBC. This chapter aims to discuss different ICIs used to treat all TNBC stages to date...

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subset associated with a worse prognosis and poor response to conventional chemotherapy. Despite recent advances in drug discovery, its management is still a challenge for clinicians, illuminating the unmet need to develop novel treatment approaches. Antibody-drug conjugates (ADC) are innovative oncology drugs that combine the specificity of monoclonal antibodies and the high efficacy of anticancer payloads, to deliver cytotoxic drugs selectively to cancer cells...

Tumor cells evolve through space and time, generating genetically and phenotypically diverse cancer cell populations that are continually subjected to the selection pressures of their microenvironment and cancer treatment.

The Ten-Eleven-Translocation (TET) family of genes, including TET1, TET2, and TET3, play critical roles in the oxidation of 5-methylcytosine marks in both DNA and RNA, thereby regulating the epigenome and epitranscriptome in cells. These genes are frequently mutated in both hematopoietic malignancies and in solid cancers. TET2, in particular, is one of the most frequently mutated genes in clonal hematopoiesis in the general population, which impacts both the transformation of hematopoietic malignancies and the immune responses in solid tumors...

Prostate cancer (PCa) is a heterogeneous disease exhibiting both genetic and epigenetic deregulations. Epigenetic alterations are defined as changes not based on DNA sequence, which include those of DNA methylation, histone modification, and chromatin remodeling. Androgen receptor (AR) is the main driver for PCa and androgen deprivation therapy (ADT) remains a backbone treatment for patients with PCa; however, ADT resistance almost inevitably occurs and advanced diseases develop termed castration-resistant PCa (CRPC), due to both genetic and epigenetic changes...

Dynamic regulation of the chromatin state by Polycomb Repressive Complex 2 (PRC2) provides an important mean for epigenetic gene control that can profoundly influence normal development and cell lineage specification. PRC2 and PRC2-induced methylation of histone H3 lysine 27 (H3K27) are critically involved in a wide range of DNA-templated processes, which at least include transcriptional repression and gene imprinting, organization of three-dimensional chromatin structure, DNA replication and DNA damage response and repair...

Histone proteins in eukaryotic cells are subjected to a wide variety of post-translational modifications, which are known to play an important role in the partitioning of the genome into distinctive compartments and domains. One of the major functions of histone modifications is to recruit reader proteins, which recognize the epigenetic marks and transduce the molecular signals in chromatin to downstream effects. Histone readers are defined protein domains with well-organized three-dimensional structures. In this Chapter, we will outline major histone readers, delineate their biochemical and structural features in histone recognition, and describe how dysregulation of histone readout leads to human cancer...

The switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex is a global regulator of gene expression known to maintain nucleosome-depleted regions at active enhancers and promoters. The mammalian SWI/SNF protein subunits are encoded by 29 genes and 11-15 subunits including an ATPase domain of either SMARCA4 (BRG1) or SMARCA2 (BRM) are assembled into a complex. Based on the distinct subunits, SWI/SNF are grouped into 3 major types (subfamilies): the canonical BRG1/BRM-associated factor (BAF/cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (GBAF/ncBAF)...