HIF Inhibition and Emerging Therapeutic Targets in Clear Cell Renal Cell Carcinoma
Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau (VHL) pathway, resulting in stabilization of hypoxia-inducible factors (HIFs) and activation of transcriptional programs involved in angiogenesis, metabolism, and tumour survival. This biology established HIF-2α as a rational therapeutic target and led to the development of belzutifan, the first HIF-2 inhibitor to demonstrate randomized clinical benefit in ccRCC. In this review, we summarize the biologic rationale for HIF inhibition in ccRCC, review the key data supporting belzutifan with a focus on the LITESPARK-005, LITESPARK-011, and LITESPARK-022 studies, discuss next-generation HIF-2 inhibitors, including casdatifan, and briefly highlight other emerging therapeutic targets in ccRCC.
Copyright (c) 2026 Canadian Oncology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Integrative Medicine and Cancer: 5 Ways to Incorporate Integrative Oncology into Routine Clinical Practice
Key Messages • Integrative oncology is patient-centred, evidence-informed field of comprehensive cancer care that utilizes mind-body practices, natural products and lifestyle modifications alongside conventional cancer treatment. • The Society of Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO) have produced four evidence-based clinical practice guidelines for integrative therapies in oncology care. • Practioners may consider non-pharmacologic evidence-based integrative therapies for a variety of cancer and treated related symptoms. • Encouraging patients to eat a high-quality diet and to be active before, during, and after cancer treatment is beneficial. • Establishing trust with patients who use dietary supplements is important in developing a therapeutic relationship.
Second-line Treatment Strategies in Biliary Tract Cancers
Biliary tract cancers (BTCs) are a highly heterogenous group of tumours arising from the bile ducts (cholangiocarcinoma [CCA]) and gallbladder. Of note, tumours of the ampulla of Vater typically fall under this definition but tend to be excluded from second-line treatment studies. Cholangiocarcinomas are further classified into intrahepatic (iCCA, including hilar) and extrahepatic (eCCA). Together, they account for approximately 15% of primary liver cancers and 3% of all gastrointestinal malignancies. However, iCCA and eCCA are separate entities that differ in incidence, clinical presentation, natural evolution, and molecular profile. Specifically, iCCA is less commonly associated with biliary obstructive symptoms and thus tends to be diagnosed incidentally and at a more advanced stage than eCCA. The diagnostic challenges partly stem from the localization of these tumours, deep in the hepatic and biliary systems, where it is often difficult to obtain a tissue biopsy or an adequate aspiration cytology. iCCA can be misclassified as carcinoma of unknown primary (CUP) as histologically it can be impossible to distinguish from metastatic adenocarcinoma of an extrahepatic primary tumour, and the primary tumour can be small and not well identified on imaging. The unique features of these tumours may in part explain their poor prognosis. Overall, the 5-year survival rate of CCA is estimated to be less than 25% for all stages combined, reflecting a very modest treatment effect. Chemoimmunotherapy combinations are now globally accepted as the standard first-line treatment, but uncertainties remain regarding second and later lines of treatment. This review will summarize the available treatments beyond the first line with a focus on the emerging field of molecular precision medicine.
Metastatic CRPC: Contemporary Therapeutic Options and Optimal Sequencing
Prostate cancer (PC) is the most common malignancy among men worldwide. In Canada, an estimated 27,900 new diagnoses were projected in 2024, accounting for approximately 22% of all new cancer cases, with nearly 5,000 related deaths, making PC the fifth leading cause of cancer mortality. Approximately 8% of patients present with metastatic disease at diagnosis. Moreover, rates of de novo metastatic PC have increased in recent years, likely reflecting both the widespread adoption of advanced imaging modalities and reduced systematic screening practices. Initial treatment for recurrent or de novo metastatic castration-sensitive prostate cancer (mCSPC) typically consists of androgen-deprivation therapy (ADT) combined with an androgen receptor pathway inhibitor (ARPI). In patients with high-volume disease, which is defined as ≥4 bone metastases (including ≥1 outside the vertebral column) or the presence of visceral metastases, triplet therapy with ADT, an ARPI, and docetaxel chemotherapy may be employed. In contrast, biochemical recurrence without radiographic metastases is generally managed with ADT alone, with treatment intensification using enzalutamide for patients with a prostate-specific antigen (PSA) doubling time between 3 and 9 months, as supported by the EMBARK trial.
The Management of Advanced Anal Squamous Cell Carcinoma
Cancers of the anal canal are rare malignancies defined anatomically from the anorectal junction to the perianal region. The most common histotype is anal squamous cell carcinoma (ASCC), which represents 1%–2% of all gastrointestinal cancers. Despite recent advances in the treatment of modifiable risk factors, the incidence of ASCC continues on a slow but unabated upward trajectory driven by predisposing factors including smoking, human papillomavirus (HPV) and human immunodeficiency virus (HIV) infections, and immunosuppression, amongst others. Metastatic ASCC (mASCC), either de novo stage IV disease or distant recurrence following definitive concurrent chemoradiation, is also increasing in frequency, representing 10%-30% of all diagnoses. While localized disease is curable with chemoradiation, using mitomycin-c and fluoropyrimidine-based sensitizing chemotherapy, advanced or metastatic disease is associated with significantly worse outcomes and a historical median overall survival (OS) below 20 months and 5-year OS between 19%–30%. The management of advanced or metastatic ASCC has undergone significant changes in the past decade, and herein we will highlight the current treatment paradigm and future directions in this field.
Treatment of dMMR Metastatic Colorectal Cancer in 2025
Deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), accounting for approximately 4–5% of cases, represents a distinct molecular subgroup with unique therapeutic implications. These malignancies are characterized by a high mutational burden and increased immune cell infiltration, making them particularly responsive to immune checkpoint inhibitors (ICI). Conversely, this subgroup tends to be less sensitive to traditional chemotherapy.
Copyright (c) 2025 Canadian Oncology Today https://creativecommons.org/licenses/by-nc-nd/4.0
First-line Treatment Selection for Advanced Unresectable Biliary Tract Cancer
Biliary tract cancer (BTC) comprises a group of heterogenous malignancies that arise from the bile ducts (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma) and the gallbladder (gallbladder cancer). Collectively, these malignancies carry a poor prognosis, which is attributed to the advanced stage at presentation. Historically, advanced BTC had a reputation of being less responsive to chemotherapy, a theory that was changed in the last decade, likely due to improved biliary drainage techniques that consequently improve liver function. Few advances have been made in the treatment of advanced and unresectable BTC in the past couple of years.
Original Research: Biomarker Testing in a Canadian Centre for Patients with Non‑small Cell Lung Cancer: Assessing Residual Risks
Biomarker testing is critical for guiding treatment decisions and clinical management in patients with non-small cell lung cancer (NSCLC). Although the clinical utility of comprehensive testing for point mutations and gene rearrangements is well established, access to next-generation sequencing (NGS)‑based assays in Ontario has historically been limited due to provincial funding constraints. We conducted a retrospective chart review of 215 patients diagnosed with lung adenocarcinoma over a five-year period (2016-2021) and report the observed biomarker testing practice. Testing primarily comprised polymerase chain reaction (PCR)-based detection of common epidermal growth factor receptor (EGFR) mutations and immunohistochemistry (IHC) for anaplastic lymphoma kinase (ALK) overexpression, with or without confirmatory fluorescence in situ hybridization (FISH), and programmed death-ligand 1 (PD-L1) IHC. IHC for ROS1 overexpression, as a surrogate for ROS1 fusion, was observed in the first quarter of 2020. Routine panel-based NGS testing was implemented in the first quarter of 2021. Noting the differences between PCR- and NGS-based EGFR assessment, risks of “false negative” were estimated based on Bayesian analyses. Given the limited scope of PCR tests in terms of variants detected, the post-test, residual risk of “false negative” EGFR was estimated to range ~1:90 in white, Caucasian patients, to ~1:9 in Asian patients. We observed consistent implementation of EGFR, ALK, and PD-L1 testing during the study period, which was in alignment with 2017 National Comprehensive Cancer Network (NCCN) guideline recommendations. However, the delayed adoption of ROS1 testing and NGS-based profiling, including assays for MET and RET alterations, reflects broader limitations in provincial funding policy and highlights the need for equitable access to comprehensive biomarker testing in Ontario.
Current Issues in the Management of Sporadic Non-clear Cell Renal Cell Carcinoma (Non-ccRCC)
Renal cell carcinoma (RCC) is the 10th most common cancer type in Canada. Numerous developments in the management of RCC over the last decade have led to improved outcomes, though these have mostly focused on the ~80% of patients with clear cell renal cell carcinoma (ccRCC). The remaining 20% of cases are labelled non-clear cell renal cell carcinoma (non‑ccRCC) and represent a biologically and clinically heterogeneous group of diseases that are rare entities. Historically, non-ccRCC has been managed similarly to clear cell tumours. Localized non-ccRCC has better outcomes than ccRCC; however, survival of metastatic non-ccRCC is inferior to ccRCC (median overall survival [OS] of metastatic non-ccRCC reported as 39.2 months compared to 81.1 months for ccRCC). This has led to interest within the RCC scientific and patient communities to further improve outcomes for patients with non-ccRCC. This article describes the current management of patients with non-ccRCC and discusses future areas of interest in the field.
Antibody-Drug Conjugates in Breast Cancer: Current Landscape and Future Targets
Antibody-drug conjugates (ADCs) have transformed therapeutic options for patients with breast cancer, delivering targeted cytotoxic agents with enhanced efficacy, albeit with systemic toxicity. Since the approval of trastuzumab emtansine in 2012, the ADC landscape has rapidly expanded to include agents targeting HER2, TROP-2, and other novel targets. Currently, four ADCs are approved in breast cancer, showing clinical benefit across HER2-positive, HER2-low, hormone receptor (HR)-positive and triple-negative subtypes. Trastuzumab deruxtecan has demonstrated superior outcomes compared to earlier HER2-targeted ADCs and is the preferred treatment in multiple settings. Anti-TROP-2 ADCs, such as sacituzumab govitecan and datopotamab deruxtecan, have provided improvements in progression-free survival in both triple-negative and HR-positive/HER2-negative disease. Ongoing research is exploring additional targets, such as HER3, Nectin-4, B7-H4, and CD166, with several promising candidates showing efficacy in early phase trials. As ADCs move into earlier lines of therapy and combination regimens, understanding optimal sequencing, toxicity management, and cost considerations will be essential. This review summarizes the current ADC landscape in breast cancer and highlights future directions for this rapidly evolving therapeutic class.
Treatment of Neuroendocrine Tumours: Approach of GEP-NETS
Neuroendocrine tumours (NETs) represent a rare entity, with various anatomic primary tumour sites, three different grades, a functional or non-functional status, and differences in somatostatin receptor expression, making NETs a heterogeneous disease. The management of these tumours is challenging and varies from a simple watch-and-wait strategy to more complex multi-modality treatment combinations. The choice of treatments depends on the previously mentioned factors. NETs most frequently arise from the gastro-entero-pancreatic (GEP) tract. The article reviews the classification, diagnosis, and staging of well-differentiated GEP-NETs, and discusses different therapeutic options.
Perioperative Treatment Strategies for Lung Cancer in 2025: A Paradigm Shift
Perioperative management of resectable non-small cell lung cancer (NSCLC) has evolved significantly with the integration of immune checkpoint inhibitors and targeted therapies. This review synthesizes current evidence from key clinical trials, highlighting the improved survival outcomes achieved with neoadjuvant and perioperative chemoimmunotherapy in oncogene-wildtype NSCLC, as well as adjuvant tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)‑ and anaplastic lymphoma kinase (ALK)-altered tumours. While neoadjuvant immunotherapy has demonstrated high pathological response rates and long-term survival benefits, perioperative strategies may offer added value in selected subgroups. The ADAURA and ALINA trials have established adjuvant osimertinib and alectinib as new standards of care in oncogene-driven disease. Unresolved questions remain regarding optimal treatment sequencing, duration, and patient selection. Emerging tools such as circulating tumour DNA and artificial intelligence hold promise for refining risk stratification and guiding individualized treatment approaches.
Management of Stage I–II Testicular Germ Cell Tumours: Current Treatment Paradigm and Future Perspectives
Testicular cancer is the most common solid tumour in males aged 15–44 years, with an estimated 1,300 new cases in Canada in 2024. Over 90% are germ cell tumours (GCTs) originating from spermatocyte precursors, with most arising in the testes. Risk factors include cryptorchidism, gonadal dysgenesis, genetic syndromes such as Klinefelter syndrome, family history, and possibly cannabis use. This review summarizes the evidence‑based diagnosis and management strategies of clinical stage I (CSI) and II (CSII) testicular GCTs used at the Princess Margaret Cancer Centre (PM), highlighting potential clinical pitfalls and future directions.
Small-Cell Lung Cancer: Integration of Radiation and Immunotherapy for All Stages
Small cell lung cancer is an aggressive cancer with a poor prognosis. New treatment paradigms have developed with the incorporation of new therapies in the last few years, aiming to improve patient survival. Some emerging therapies include the addition of immunotherapy to chemotherapy. This article provides a practical review of the current and upcoming treatment options for SCLC in both limited and extensive stages, focusing on integrating radiation and immunotherapy.
Advances in Adjuvant Therapy for High-Risk Breast Cancer: A Canadian Clinical Approach
Breast cancer remains the second leading cause of cancer-related death among women in Canada. In early-stage disease, the purpose of adjuvant therapies following surgical resection is to reduce the risk of recurrence. The advent of adjuvant endocrine therapy (ET) significantly reduced breast cancer recurrence and mortality; however, some patients have disease recurrence even 20 years after initial diagnosis. Therefore, several advancements have been made to optimize cure rates and improve outcomes. As a heterogeneous disease, breast cancer outcomes are impacted by clinical, histological, and genomic features, which guide prognosis and selection of adjuvant therapy. This review focuses on recent and emerging adjuvant therapies, specifically for high-risk patients across breast cancer subtypes: hormone receptor‑positive (HR‑positive), human epidermal growth factor receptor 2-positive (HER2-positive), and triple‑negative breast cancer (TNBC).
The Role of ctDNA in Breast Cancer: Prognosis and Clinical Utility
Breast cancer remains the most common cancer among women globally, with significant morbidity and mortality. Current treatment for breast cancer, both in the early stage and metastatic setting, is based on a tumour biopsy and immunohistochemical detection of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression. Though substantial research has been undertaken over the years to establish new prognostic and predictive biomarkers in breast cancer, most have not demonstrated significant clinical utility. Circulating tumour DNA (ctDNA) is increasingly used across various cancer types for precision medicine. In this article, we discuss the current roles of ctDNA in breast cancer prognosis and its clinical utility in treatment decision-making in early- and advanced-stage settings.
Clinical Considerations for the Management of Advanced PD-L1 ≥50% Non-small Cell Lung Cancer In 2025: Should All Patients Be Treated the Same?
Despite advances in the treatment of non‑small cell lung cancer (NSCLC) due to the advent of immunotherapy in the form of immune checkpoint inhibitors (ICI), NSCLC remains the leading cause of cancer-related death in Canada. In addition, multiple first‑line options exist for patients with NSCLC without a sensitizing mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK), but no head‑to‑head comparisons of first-line treatment regimens have been made in randomized controlled trials. The programmed cell death ligand 1 (PD-L1) tumour proportion score (TPS)—which is derived from immunohistochemistry analysis—emerged as an important biomarker early in the advent of ICI in NSCLC. Approximately 30% of patients with NSCLC have PD-L1 expression in at least 50% of the tumour. This ≥50% threshold was established through retrospective biomarker analyses in pivotal trials, such as the KEYNOTE-001 and KEYNOTE-024 trials, in which patients with higher PD-L1 expression demonstrated superior response rates and overall survival (OS) benefits with immunotherapy compared to chemotherapy. The KEYNOTE-001 trial first identified ≥50% PD-L1 expression as an optimal cut-off for predicting response to pembrolizumab (anti-programmed cell death protein 1 [PD-1] antibody), showing an objective response rate (ORR) of ~45% in this group. Subsequently, the KEYNOTE-024 trial confirmed that patients with PD-L1 ≥50% had significantly improved progression-free survival (PFS) and OS with pembrolizumab than those treated with chemotherapy (hazard ratio [HR] for PFS: 0.50, 95% confidence interval [CI]: 0.37–0.68). Similar findings from the IMpower110 (atezolizumab) and EMPOWER-Lung 1 trials (cemiplimab) reinforced ≥50% PD-L1 TPS as a clinically meaningful biomarker. As a result, ≥50% PD-L1 TPS became an actionable biomarker in regulatory approvals and treatment guidelines, guiding immunotherapy decisions in advanced NSCLC.
Current Approaches and Future Directions for the Treatment of Solid Tumour Brain Metastases
Brain metastases (BrM) are most common among patients with metastatic lung cancer, breast cancer, and melanoma. Historically, management of BrM consisted of local treatments with surgical resection and/or radiation therapy, with either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Current guidelines recommend SRS as the initial therapy for patients who have up to four BrM, but several studies have demonstrated that upfront SRS may be considered for some patients who have more than four BrM given additional clinical benefits of improved memory function and quality of life compared to WBRT. Systemic therapies are increasingly understood to cross the blood-brain barrier (BBB) following disruption of its integrity upon BrM development. Disseminated tumour cells intravasate into the circulation and spread hematogenously with a “seed and soil” tropism for the brain that provides a suitable tumour microenvironment. Tumour cells extravasate and increase the permeability of the BBB by decreasing tight junction protein expression, decreasing astrocyte pedicles, reducing pericyte coverage, and increasing neoangiogenesis. The altered integrity of the BBB allows penetration of large drug molecules, such as antibody-drug conjugates (ADCs), which exert their therapeutic effects on BrM by binding to tumour cell-specific epitopes and releasing a cytotoxic payload, even in the absence of radiation. Other therapeutic mechanisms of action include molecular (passive or receptor-mediated transport), physical (radiation or focused ultrasound), direct delivery to the brain (intrathecal or intratumoral), and cell‑mediated (immune cell extravasation) (Figure 1).
The Role of Biomarkers in Upper Gastrointestinal Cancers
Upper gastrointestinal (GI) cancers include esophageal, esophagogastric junction, and stomach cancers, which together represent the second leading cause of cancer-related mortality worldwide in both sexes, with approximately 1,100,000 deaths in 2022. The disease is usually diagnosed at an advanced non-curable stage, and conventional chemotherapy treatment is associated with poor prognosis. Advances have been made in the development of new therapies, including immunotherapy and targeted therapies. Biomarker identification has expanded treatment options and guides treatment selection. This article reviews the molecular characterization of GI cancers, which has been the subject of increasing research, and biomarker-targeted agents, representing a continually evolving landscape in upper GI cancers.
First-line Treatment Selection for Advanced Hepatocellular Carcinoma
The treatment landscape of advanced/unresectable hepatocellular carcinoma (uHCC) has rapidly evolved since 2018. Over recent years, various systemic therapies and treatment approaches have been explored. Systemic therapy has primarily relied on tyrosine kinase inhibitors (TKIs); however, immune checkpoint inhibitors (ICIs) have more recently entered the realm of the treatment armamentarium.
Copyright (c) 2024 Canadian Oncology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Prostate-specific Membrane Antigen (PSMA): A Diagnostic and Therapeutic Target in Advanced Prostate Cancer
Prostate cancer is among the most prevalent malignant conditions globally, and both incidence and mortality are expected to increase markedly over the next two decades. Recently, the diagnostic and treatment landscape for managing this disease underwent remarkable advances that led to the incorporation of innovative approaches, such as prostate-specific membrane antigen (PSMA) theranostics. PSMA, which is also known as folate hydroxylase or glutamate carboxypeptidase, is a transmembrane protein 100- to 1000-fold overexpressed by prostate cancer cells compared to healthy cells found in the benign prostate gland, salivary glands, proximal renal tubules, small intestine mucosa, and hepatocytes, amongst others. Since its discovery over 30 years ago (see Figure 1 for this and other milestones), PSMA has caught the attention of the scientific community as a potential therapeutic target, and for the past two decades many efforts have been undertaken to identify and develop PSMA ligands and antibodies that could be exploited as prostate cancer therapeutics. This review aims to provide an overview of available PSMA ligands, their mechanisms of action, diagnostic and therapeutic applications, and future perspectives of PSMA-targeted therapeutic approaches within the field of radioligand therapy (RLT).
Breast cancer remains the most common type of cancer among Canadian women, with 28,900 new cases in 2022 alone. Improved detection through screening mammography and advances in multi-modality therapy account for the decline in breast cancer mortality seen in Canada since the 1980s. As 5-year survival rates reach 89%, the number of breast cancer survivors is rising. The concept of cancer survivorship has existed for decades, as has the appreciation that it is a complex domain of cancer care that begins at the time of diagnosis. Even within the group of patients with breast cancer, survivorship experiences and care needs are diverse, reflecting variability in tumour clinicopathologic characteristics, treatment plans, and prognosis. Evidence-based tools and guidelines suggest the assessment and management of cancer survivor’s physical, psychological, social, financial, and employment well-being. There is a need to clinically monitor for breast cancer recurrence and the development of secondary malignancies through screening. Survivorship also warrants attention to health promotion, including weight management, nutrition, physical activity, preventive health, and cessation of alcohol and cigarettes. The provision of survivorship care is the responsibility of all healthcare professionals, which requires close coordination between primary care and specialized cancer centres. In this article, we focus on the physical and psychosocial long-term and late effects faced by survivors of early-stage breast cancer. Many adjuvant therapies for breast cancer are associated with toxicities that negatively impact quality of life (QoL) and adherence. Nonadherence is important to address because it compromises breast cancer outcomes.
Tailored Approaches and Patient-centered Care: The Current Landscape of Neoadjuvant Therapy in Rectal Cancer
Colorectal cancer (CRC) is the third most diagnosed cancer in Canada and worldwide. Although mortality rates have declined, it remains the second most lethal malignancy worldwide. For patients with locally advanced rectal cancer (LARC), several new concepts have been introduced in recent years for treatment sequencing and de-escalation. The use of pelvic magnetic resonance imaging (MRI) for initial staging and neoadjuvant therapy response assessment has become a key part of the workup for LARC, utilizing the expertise of specialist radiologists. High-volume rectal cancer centers have adopted total neoadjuvant therapy (TNT) as a preferred approach for many patients with LARC. There is rising interest in shortening the duration of chemotherapy or radiation, or even omitting radiation altogether for select patients, to reduce the burden of long-term toxicities. For patients who achieve clinical complete or near-complete responses (cCR or nCR) to neoadjuvant therapies, nonoperative management (NOM) has emerged as an option to avoid the complications of a total mesorectal excision (TME). This paradigm shift has resulted in numerous treatment options for many patients with rectal cancer, enabling a more individualized, multidisciplinary approach to care. Clinicians must understand how to interpret the evidence around these new concepts to successfully implement them into clinical practice. This review summarizes the recent evidence for neoadjuvant therapy approaches in rectal cancer to provide a context for this paradigm shift to a tailored therapeutic strategy.
Antibody-drug Conjugates in The Management of Advanced Urothelial Carcinoma
For decades, the cornerstone for treatment of advanced urothelial carcinoma (aUC) has consisted of platinum-based chemotherapy regimens, such as GC (gemcitabine plus cisplatin/carboplatin) or MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin). Thereafter, immune checkpoint inhibitors (ICI) were incorporated into the standard of care, initially as monotherapy in subsequent-line settings and more recently as maintenance treatment with chemotherapy in the first-line setting. Recently, the development of antibody-drug conjugates (ADCs) has dramatically shifted the treatment landscape for aUC. ADCs are engineered to function as a biologic “honing missile”, with the aim of delivering its cytotoxic payload to the target cancer cell while remaining stable in circulation and minimizing off-target toxicity. Enfortumab vedotin was the first to demonstrate efficacy in urothelial carcinoma (UC), initially as monotherapy and later in combination with ICI, surpassing the decades-old standard of first-line chemotherapy. The aim of this review is to discuss the evolving field of ADCs in aUC, highlighting the main targets, clinical data, toxicities, and future opportunities. ADCs are engineered to function as a biologic “honing missile”, with the aim of delivering its cytotoxic payload to the target cancer cell while remaining stable in circulation and minimizing off-target toxicity. Enfortumab vedotin was the first to demonstrate efficacy in urothelial carcinoma (UC), initially as monotherapy and later in combination with ICI, surpassing the decades-old standard of first-line chemotherapy. The aim of this review is to discuss the evolving field of ADCs in aUC, highlighting the main targets, clinical data, toxicities, and future opportunities.
Current and Emerging Treatment Options for HER2‑Positive Gastroesophageal Cancer
Gastroesophageal cancer (GEC) is the fifth most common cancer and the second most common cause of cancer-related mortality, with 1.3 million annual deaths worldwide. The global incidence is increasing, particularly among younger patients. GEC can be classified into subtypes based on anatomic location, histology, molecular characteristics, or tumour biology and genomics. In approximately 20% of all GECs overexpression of HER2 is identified. The landscape of treatment options in this patient population is evolving rapidly. This review summarizes the progress of HER2-directed therapies for advanced disease and highlights future directions in targeting the disease. The epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinase receptors, EGFR/HER1, HER2/neu, HER3, and HER4, all have an extracellular ligand-binding domain, lipophilic transmembrane domain, and an intracellular domain with tyrosine kinase activity, binding to these receptors results in activation of downstream RAS/MAPK and PI3K/AKT pathways. In turn, this induces cell proliferation, differentiation, migration, and survival. The phase III Trastuzumab for Gastric Cancer (ToGA) trial reported the incidence of HER2-positive gastric cancer to be 22%. Therefore, targeting HER2 and its downstream signaling pathways holds important potential as a therapeutic strategy. Figure 1 illustrates potential targeting mechanisms that will be discussed in this review.
Current Uses and Pitfalls of Liquid Biopsy in NSCLC
Liquid biopsy has emerged as an important tool in the diagnosis and management of lung and other cancers. Various analytes and analytical methods have been studied, including genomic testing by next-generation sequencing (NGS) and non-NGS approaches, including those examining methylation or DNA fragment size. Liquid biopsy, especially from plasma or blood, has several advantages over percutaneous or endoscopic tissue biopsy. It is less invasive, can be used serially for monitoring, and better reflects tumoural heterogeneity across metastatic sites, as opposed to a single area of the biopsied tumour. Herein, we highlight the current uses of liquid biopsy using circulating tumour DNA (ctDNA) analysis in routine clinical practice and potential pitfalls.
From Intractable to Treatable: Milestones and Horizons in the Management of HER2+ Breast Cancer
The human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family that initiates various signalling pathways that control cell proliferation and tumourigenesis. Historically, approximately 15% of breast cancers have been characterized by overexpression or amplification of HER2, known as “HER2+” breast cancers. This subtype has been associated with an adverse prognosis, along with a high risk of recurrence and worse survival outcomes. However, with the discovery and subsequent development of HER2‑targeted therapies, the clinical course of HER2+ breast cancers has fundamentally changed. Optimizing therapeutic strategies using existing and emerging HER2-targeted therapies to build upon these advances remains a major priority for clinical development and treatment delivery. In 1998, the American Food and Drug Administration (FDA) and Health Canada approved trastuzumab, the first HER2-targeted therapy. Trastuzumab, a monoclonal antibody that binds to the HER2 receptor, has demonstrated clinical activity and improved outcomes in patients with metastatic HER2+ breast cancer when combined with chemotherapy. Following soon after, the first trial of adjuvant trastuzumab (HERA) demonstrated improvements in outcomes when combined with chemotherapy for early HER2+ breast cancer. More than 25 years after its first approval, trastuzumab retains a central role in the treatment of both early and advanced HER2+ breast cancer and has provided a backbone for both new therapeutic combinations (eg. with small molecule inhibitors of HER2) and new classes of therapeutic agents (antibody drug conjugates [ADC]). These successors of trastuzumab are currently redefining the HER2+ treatment landscape in both advanced and early breast cancer.
Survivorship Issues in Testicular Cancer
Testicular cancer (TC) is the most prevalent tumor in young men aged 15–40 years, with an annual incidence of 3–11 new cases per 100,000 males in Western countries. In 2020, the International Agency for Research on Cancer reported 74,458 newly diagnosed cases of TC globally. The etiology of TC is complex and includes both genetic and environmental factors. The prognosis of TC is excellent with a >90% cure rate and a >95% 5-year survival rate with appropriate treatment. Treatments for TC include active surveillance, chemotherapy, radiotherapy, and retroperitoneal lymph node dissection, depending on the clinical stage and tumor subtype. It is crucial that patients receive information on the diagnosis, therapeutic management options, consequences of treatments, and surveillance protocols, which allows the patient to play an active role in the decision-making process. Fear of recurrence often affects TC survivors. Therefore, it is essential to fully involve the patient in the choice of the treatment to ensure an optimal compliance, especially when selecting the active surveillance strategy. In the modern era, in light of the excellent outcomes achieved in TC management, one of the high priorities is to deliver curative treatments while minimizing long-term toxicity. This focus can have a positive impact on quality of life and life expectancy of TC survivors.
An Evolving Paradigm in Borderline Resectable and Locally Advanced Pancreatic Cancer: Current Strategies and Opportunities for the Future
Pancreatic ductal adenocarcinoma (PDAC), a cancer of the gastrointestinal tract, has been increasing in incidence, with an estimated doubling worldwide over the past two decades. Despite increases in awareness and innovations in genomics and drug discovery, 5-year survival remains low, at only 10%. This is in part owing to the majority of patients being diagnosed at the advanced stage of the disease, in addition to chemotherapy recalcitrant disease. Surgical resection is necessary for a potential cure, however, this is only possible for the 10% of patients who present with resectable disease and potentially for those with borderline resectable disease. Locally advanced pancreatic cancer accounts for approximately 30% of those with PDAC and most of those patients are often precluded from curative intent surgery due to major vascular invasion and local infiltration into peri-pancreatic soft tissue. In cases of locally advanced disease, induction chemotherapy is often used, identifying the subgroup of patients more suited for local treatments and those who may later develop metastases. The treatment regimens used for patients with locally advanced PDAC are often extrapolated from trials involving patients with metastatic disease. In some cases, responses to neoadjuvant therapy have allowed for surgical resection, albeit these aggressive resections were associated with significant morbidity. There is growing interest in identifying the optimal neoadjuvant treatment for patients with borderline resectable pancreatic cancer (BRPC) and locally advanced PDAC (LAPC) in an effort to improve outcomes. Here we review therapeutic strategies for borderline resectable and locally advanced PDAC, with a focus on novel systemic therapy regimens, chemoradiation, and different radiation modalities.
A Review of EGFR-Mutant Non‑Small Cell Lung Cancer (NSCLC) in 2024
Twenty years ago, our understanding of non-small cell lung cancer (NSCLC) treatment was revolutionized by the demonstration of a strong relationship between activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and the response to tyrosine kinase inhibitors such as gefitinib. These experiments, among many others, have paved the way for two decades of exponential therapeutic growth that we have witnessed. EGFR-mutant lung cancers account for as much as 23% of NSCLC cases diagnosed in Canada, with significant variations based on geography and ethnicity including a higher prevalence in regions where the Asian population is more important. Therefore, the latest data discussed in this article have the potential to improve outcomes for a large number of patients.