American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting最新文献

Changes to sexual function after cancer treatment are extremely prevalent, affecting up to 90% of female patients with cancer and 40%-85% of male patients with cancer. Sexual health concerns include low libido, genitourinary syndrome of menopause, dyspareunia, erectile dysfunction (ED), hypogonadism, body image concerns, and impacts on intimate relationships. Given the significant impact of sexual dysfunction on quality of life, oncology professionals should integrate sexual health discussions into routine patient care, regardless of the patient's age, sex, or cancer type. Sexuality is best understood in a biopsychosocial framework and cancer treatments including chemotherapy, surgery, radiation, and endocrine therapy can affect all of these domains. Management of genitourinary syndrome of menopause includes nonhormonal and low-dose local hormonal options. Pelvic floor dysfunction and vaginal stenosis can be treated with pelvic floor physical therapy and use of vaginal dilator therapy. ED can be treated with phosphodiesterase type 5 inhibitors and if needed, interventions such as intracavernosal injection of vasoactive agents, urethral suppositories, vacuum erection devices, and surgical implants are available. Cancer treatments such as chemotherapy, radiation, and androgen-deprivation therapy can lead to hypogonadism in men, which can be treated with testosterone therapy, unless contraindicated. Psychosocial counseling, sex therapy, and couples counseling are options for impact to sexual response, body image, and relationship concerns. A comprehensive, patient-centered approach to sexual health can help improve outcomes and overall well-being for cancer survivors.

Until recently, the treatment of metastatic castration-resistant prostate cancer (mCRPC) relied exclusively on hormonal therapies and taxane chemotherapy. The advent of modern molecular profiling methods applied in the clinic, namely, next-generation sequencing and advanced positron emission tomography (PET) imaging, has allowed for the development of biomarker-driven therapeutics including anti-PD-L1 therapy for microsatellite instability-high or tumor mutation burden-high disease, poly(ADP-ribose) polymerase (PARP) inhibitors for patients with DNA damage repair mutations, and lutetium 177 vipivotide tetraxetan (¹⁷⁷Lu-PSMA-617) for patients with prostate-specific membrane antigen (PSMA) PET-avid disease. While these targeted therapies have improved outcomes, there is an opportunity to refine biomarkers to optimize patient selection, understand resistance, and develop novel combination strategies. In addition, studies in the laboratory and in patient-derived samples have shown that a subset of mCRPC tumors lose expression of common prostate cancer markers such as prostate-specific antigen and PSMA because of lineage plasticity and the development of non-androgen receptor (AR)-driven disease. Non-AR-driven prostate cancer has been associated with aggressive behavior and poor prognosis, including in some cases histologic transformation to a poorly differentiated neuroendocrine prostate cancer (NEPC). The clinical management of NEPC typically follows the treatment paradigm for small cell lung cancer and increasingly relies on genomic and phenotypic characterization of disease, including loss of tumor suppressors and expression of cell surface markers such as DLL3. Therefore, both genomic subtyping and phenotypic subtyping are important to consider and can guide the clinical management of patients with advanced prostate cancer.

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. Additionally, bsAbs targeting tumor growth factors or receptor tyrosine kinases offer solutions for overcoming drug resistance in solid tumors. Although bsAbs have shown remarkable success in hematologic malignancies, their expansion into solid tumors faces key challenges, including tumor heterogeneity, limited tumor penetration, and the risk of on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, and careful patient selection to maximize therapeutic benefit while mitigating adverse effects. The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in development. Combination strategies with chemotherapy, targeted agents, and immune CPIs could represent a promising strategy to further expand their potential. As research progresses, bsAbs are expected to play a role in reshaping the future of precision oncology, offering more effective and tailored treatment options.

Pancreatic adenocarcinoma remains one of the most aggressive and difficult-to-treat solid tumor malignancies, with a high mortality-to-incidence ratio. Globally, pancreatic cancer ranks 12th in terms of incidence but sixth for mortality signifying its aggressive behavior and limited treatment options. While the mortality rates for many other solid tumors have substantially improved over the past few decades, temporal trends in pancreatic cancer mortality rates are quite sobering. In the United States, from 2000 to 2020, the mortality rates from pancreatic cancer have increased, whereas at the same time, mortality rates from other cancers, such as lung, colorectal, or kidney, have fallen appreciably. Is this for lack of treatment innovation? How do we improve survival for patients with pancreatic cancer? In this chapter, we discuss the recent advances and future directions with targeted therapies and immunotherapies in the treatment of pancreatic cancer, and provide the reasons for both optimism and caution for the future of systemic treatment of pancreatic cancer.

Novel approaches in molecular imaging and targeted therapeutics are transforming the management of renal cell carcinoma (RCC) and urothelial carcinoma (UC). This review focuses on three key areas of innovation: molecular imaging, hypoxia-inducible factor-2α (HIF-2α) inhibition, and antibody-drug conjugates (ADCs). In molecular imaging, prostate-specific membrane antigen positron emission tomography/computed tomography has shown promise in RCC, while novel tracers targeting carbonic anhydrase IX and nectin-4 are emerging for RCC and UC, respectively. These approaches may enable better characterization of disease and treatment response monitoring. HIF-2α inhibition represents a breakthrough in targeting the fundamental pathobiology of clear cell RCC, with belzutifan demonstrating significant clinical benefit in both von Hippel-Lindau disease and sporadic RCC. Next-generation HIF-2α inhibitors, including casdatifan, show promising early clinical results with distinct pharmacologic properties. ADCs have become a cornerstone of UC treatment, with enfortumab vedotin plus pembrolizumab now approved as first-line therapy. Multiple human epidermal growth factor receptor 2 (HER2)-directed ADCs have shown efficacy in HER2-expressing UC, including trastuzumab deruxtecan, which recently received tumor-agnostic approval. While ADC development in RCC faces unique challenges, novel approaches including immunostimulatory payloads and bispecific antibodies are being explored. The integration of these advances in molecular imaging and therapeutics offers opportunities for more personalized treatment approaches in RCC and UC.

Non-muscle-invasive bladder cancer (NMIBC) comprises 75% of newly diagnosed bladder cancer and poses significant clinical challenges because of high recurrence and progression rates. Despite the effectiveness of Bacillus Calmette-Guérin (BCG) therapy after transurethral resection of bladder tumor (TURBT), BCG fails nearly 40% of patients, requiring alternative treatments. Traditionally, radical cystectomy has been the standard for BCG-unresponsive disease, although it significantly affects quality of life. Recent advances have focused on bladder-preserving therapies that leverage immune checkpoint inhibitors, viral gene therapies, novel drug delivery systems, and targeted molecular agents. Emerging approaches such as TAR-200 and UGN-102 offer novel intravesical delivery systems that enhance therapeutic efficacy while minimizing systemic adverse effects. Viral therapies, including nadofaragene firadenovec and CG0070, deliver immune-activating and oncolytic agents directly to urothelial tumor cells. Additionally, immune checkpoint inhibitors such as pembrolizumab and durvalumab have demonstrated potential for systemic treatments in BCG-unresponsive NMIBC and may show even more promise in combinations. Ongoing trials are expected to provide crucial data on these therapies' efficacy, particularly in high-risk and intermediate-risk populations. For low-grade NMIBC, efforts are underway to de-escalate care through active surveillance and novel adjuvant therapies, reducing the need for repeated TURBT procedures. Together, these advancements highlight a promising shift toward personalized, bladder-preserving strategies that prioritize patient quality of life while addressing unmet needs in NMIBC management.

Cell-based therapies have become integral to the routine clinical management of hematologic malignancies. Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated efficacy in immunogenic solid tumors, such as melanoma. However, in the GI field, evidence supporting the clinical success of cell-based therapies is still awaited. CLDN18.2, a key tight junction molecule in stomach epithelium, has emerged as a promising target for gastric cancer (GC) treatment. Because of its lineage-specific expression, significant efforts have been made to develop chimeric antigen receptor T-cell (CAR-T) therapies targeting CLDN18.2. These therapies have shown encouraging tumor shrinkage in patients with heavily pretreated GC. However, durable responses remain uncommon. CAR-T exhaustion driven by immune-suppressive cells in the tumor microenvironment, along with the heterogeneous expression of target molecules, poses significant challenges. In addition, managing on-target, off-tumor toxicities remains a critical issue in therapies targeting tissue-associated antigens. Next-generation CARs are expected to address these resistance mechanisms. Furthermore, adoptive macrophage and natural killer cell therapies hold promise for not only their efficacy but also for the ease off-the-shelf production. Advanced neoantigen prediction and identification of optimal T-cell activation targets could facilitate the clinical application of TIL and T-cell receptor-T therapies in GI cancers. Cell-based therapies might have the potential to transform the treatment landscape for GI cancers.

Data have matured to support incorporation of integrative oncology modalities into comprehensive cancer care. Clinical practice guidelines have recently been published by ASCO for diet and exercise (2022) and use of cannabinoids and cannabis (2024) and jointly by ASCO and the Society for Integrative Oncology (SIO) for application of integrative approaches in the management of pain (2022), anxiety and depression (2023), and fatigue (2024) among adults with cancer. Following the ASCO-SIO guidelines, clinicians should recommend mindfulness-based interventions (MBIs) to patients with symptoms of anxiety or depression and MBIs and exercise for management of fatigue during or after completion of cancer treatment. We will review the basis of these recommendations and evidence to support use of other mind-body approaches, exercise, nutrition, acupuncture/acupressure, and natural products in the specific contexts of GI cancers. For example, optimizing physical activity and diet is associated with improved survival after a colorectal cancer (CRC) diagnosis, in addition to conferring symptom management benefits. We will also highlight gaps in research, including that most studies enrolling patients with GI malignancies have focused on CRC. A limitation of nonpharmacologic evidence-based guidelines is that they list broad categories (eg, yoga or acupuncture) and lack implementation details. How to safely and equitably incorporate integrative approaches into conventional cancer care will be addressed. This ASCO Educational Book article aims to be both evidence-informed and practical, with attention to unique considerations for people with GI cancers.

The growing sophistication of tumor molecular profiling has helped to slowly transition oncologic care toward a more personalized approach in different tumor types, including in bladder cancer. The National Comprehensive Cancer Network recommends that all patients with stage IVA and stage IVB urothelial carcinoma have molecular analysis that integrates at least FGFR3 testing to help facilitate the selection of future therapeutic options. Sequencing of tumor-derived tissue is the mainstay to obtain this genomic testing, but as in other cancers, there has been extensive research into the integration of liquid biopsies in longitudinal management. Liquid biopsies broadly refer to the isolation of both cellular and noncellular tumor components including proteins and nucleic acids such as mRNA and circulating free DNA within a liquid sample. Although protein-based testing and testing of circulating tumor cells are options, the bulk of promising research in bladder cancer is investigating the role of plasma-based circulating tumor DNA (ctDNA). Currently, a universal consensus on optimal preanalytic and analytic approaches has not been fully defined, and the exact role that liquid biopsies should have in screening, diagnosis, prognostication, treatment selection, and monitoring is not yet known. Still, it can be expected that ctDNA testing will be a part of appropriate management of muscle-invasive bladder cancer and metastatic bladder cancer in the near future. In this review, the goal is to provide a practical overview of the current and future role of ctDNA in bladder cancer including ongoing trials.

Antibody-drug conjugates (ADCs) represent an emerging class of therapeutics across solid tumor oncology and are already positioned as a cornerstone therapy for patients with urothelial carcinoma (UC). In recent years, there has been a paradigm shift in the therapeutic landscape as frontline treatment of UC formerly relied on the use of platinum-based agents and has now evolved to include combination strategies with ADCs. These dramatic changes are due in part to our improved understanding of the molecular features of bladder tumors and the identification of tumor-associated antigens specific to UC, which may serve as druggable targets. Despite notable advances and the clinical success of ADCs in other malignancies, their full potential in UC remains largely unmet. Early clinical success of enfortumab vedotin and sacituzumab govitecan demonstrated antitumor activity; however, there are multiple challenges with these ADCs, including on-target, off-tumor toxicity and difficulty in maintaining sustained responses. Newer-generation ADC constructs, either alone or as part of combination approaches, are currently under investigation. This review examines the historical development, current landscape, and emerging trends in ADC therapy for UC, highlighting both the progress made and obstacles that continue to hinder optimal therapeutic outcomes.