Cancer treatment and research最新文献

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. Radiotherapy after breast reconstruction is an area of current controversy in the field, and we evaluated the decision-making considerations in this situation. The oligometastatic state is an emerging field for many cancer sites based on recent trials investigating ablative radiotherapy for oligometastatic BC. This chapter is an overview of radiotherapy for BC, with a focus on recent advances in early-stage, locally advanced, and oligometastatic disease.

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. This chapter gives a comprehensive overview of the last advancements including new approaches and future combinations, which seem to be very promising in overcoming resistance to the traditional anti-HER2 treatments. A modern therapeutic algorithm should include treatment options based on tumour patterns and a patient-centred approach. A proper patient's selection is crucial to derive maximal benefits from a treatment strategy and emerging biomarkers should be integrated along with the HER2 status, which is currently the only validated biomarker in the context of HER2-positive disease. These biomarkers might include molecular features with reported prognostic/predictive significance, such as phosphatidylinositol 3' -kinase (PI3K) or mitogen-activated protein kinase (MAPK) pathways, programmed cell death protein ligand 1 (PD-L1), and tumour-infiltrating lymphocytes (TILs), which all affect prognosis and response to treatments.

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. Another common mechanism of endocrine resistance is the acquisition of activating mutations of ESR1, which encodes for the estrogen receptor, that lead to structural changes of the receptor, prevent the binding to anti-estrogen drugs and result in constitutive activation of the receptor, even in the absence of estrogens. Epigenetic changes, such as DNA methylation and histone modifications, can also contribute to ET resistance by altering the expression of genes that are involved in estrogen signaling. Understanding the mechanisms of resistance to ET is crucial for the development of new therapies that can overcome resistance and improve outcomes for patients with HR + BC.

The use of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of patients with germline BRCA mutations (gBRCAm) and breast cancer, both in the early and advanced settings, is a success of genomically-directed treatment. These agents have been shown to be associated with longer progression-free survival when compared to standard chemotherapy, with an acceptable toxicity profile. A recent randomized trial demonstrated improved survival with the use of olaparib for 2 years compared to placebo in patients with early-stage high risk gBRCAm associated breast cancer. Ongoing research efforts are focused on identifying patients beyond those with BRCA1/2 or PALB2 mutations who may benefit from PARP inhibitors, exploring the overlapping mechanisms of resistance between platinum and PARP inhibitors and developing agents with less toxicity that will allow combinational strategies.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) represent the first medicines based on the targeting of the DNA damage response (DDR). PARPi have become standard of care for first-line maintenance treatment in ovarian cancer and have also been approved in other cancer indications including breast, pancreatic and prostate. Despite their efficacy, resistance to PARPi has been reported clinically and represents a growing patient population with unmet clinical need. Here, we describe the various mechanisms of PARPi resistance that have been identified in pre-clinical models and in the clinic.

Cancers with wild-type BRCA, homologous recombination proficiency, or de novo or acquired resistance to PARP inhibition represent a growing population of patients who may benefit from combinatorial PARP inhibitor strategies. We review targeted inhibitors of angiogenesis, epigenetic regulators, and PI3K, MAPK, and other cellular signaling pathways as inducers of homologous recombination deficiency, providing support for the use of PARP inhibitors in contexts not previously considered susceptible to PARP inhibition.

A subset of patients with pancreatic adenocarcinomas (PDAC) harbor mutations that are exploitable in the context of DNA-damage response and repair (DDR) inhibitory strategies. Between 8-18% of PDACs harbor specific mutations in the DDR pathway such as BRCA1/2 mutations, and a higher prevalence exists in high-risk populations (e.g., Ashkenazi Jews). Herein, we will review the current trials and data on the treatment of PDAC patients who harbor such mutations and who appear sensitive to platinum and/or poly ADP ribose polymerase inhibitor (PARPi) based therapies due to a concept known as synthetic lethality. Although this current best-in-class precision treatment shows clinical promise, the specter of resistance limits the extent of therapeutic responses. We therefore also evaluate promising pre-clinical and clinical approaches in the pipeline that may either work with existing therapies to break resistance or work separately with combination therapies against this subset of PDACs.

Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly improved treatment outcomes of homologous recombination (HR) repair-deficient cancers. While the activity of these agents is largely linked to multiple mechanisms underlying the synthetic lethality of PARP inhibition and HR deficiency, emerging data suggest that their efficacy is also tied to their effects on the immune microenvironment and dependent upon cytotoxic T-cell activation. Effects observed in preclinical models are currently being validated in on-treatment biopsy samples procured from patients enrolled in clinical trials. Although this work has stimulated the development of combinations of PARP inhibitors with immunomodulatory agents, results to date have not demonstrated the superiority of combined PARP inhibition and immune checkpoint blockade compared with PARP inhibition alone. These results have stimulated a more comprehensive assessment of the immunosuppressive components of the tumor microenvironment that must be addressed so that the efficacy of PARP inhibitor agents can be maximized.

The delivery of culturally congruent, person-centered, family-focused quality care requires an exploration of the values, beliefs, and preferences of those we serve [13]. Nuanced advance care planning conversations lay the foundation for shared decision making and promotes the delivery of goal-concordant care. This chapter will provide clinicians with guidance and resources to aid this process with a focus on contextualized communication with those with serious illness.

Members of The Church of Jesus Christ of Latter-day Saints accept modern medical science and believe in receiving medical treatment along with seeking divine guidance and inspiration. At the same time, situations of life and death can throw people into stressful places they have never been before, bringing challenges even to people of deep faith. Medical professionals can better support Latter-day Saints if they understand how their beliefs answer questions about life and death, including, "Where did I come from? Why am I here on earth? Where am I going after death?" This chapter examines the origin, beliefs, and practices of the Church to give medical professionals a foundational understanding of what is important to members at the end of life. It includes sections on beliefs and practices, including those relevant to medical treatment, end-of-life decisions, death and burial.