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Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.
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PURPOSE OF REVIEW: Claudins, components of tight cell junctions in epithelial and endothelial cells, have emerged as a therapeutic target in gastrointestinal (GI) malignancies, particularly claudin 18.2 (CLDN18.2). RECENT FINDINGS: Zolbetuximab, a chimeric anti-CLDN18.2 monoclonal antibody (mAb), is currently under FDA review and may emerge as the first claudin targeted therapy approved. Phase 3 trials show that zolbetuximab in combination with front-line fluoropyrimidine plus oxaliplatin improves survival in advanced CLDN18.2 positive (≥75% of tumor cells) gastric adenocarcinoma (GAC) patients. Many other therapies (mAbs; CART; bispecific; ADCs) are under investigation. SUMMARY: CLDN18.2 will be an important target in GAC. Early understanding of how to target CLDN18.2 based on the level of expression (high, moderate, low) will be the key to success in this area. Studying these as separate entities should be considered. Resistance patterns, loss of CLDN18.2 expression, role in the refractory setting, and if any role in localized disease are questions that remain. Other targets for claudin that target claudin six and four are under investigation. Their role in GI malignancies will soon be further clarified.
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Claudinas , Neoplasias Gastrointestinales , Humanos , Claudinas/antagonistas & inhibidores , Claudinas/metabolismo , Ensayos Clínicos Fase III como Asunto , Neoplasias Gastrointestinales/tratamiento farmacológico , Terapia Molecular DirigidaRESUMEN
BACKGROUND: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.
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Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.
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PURPOSE: GI medical oncology care presents unique medication challenges. Here, we captured our clinical pharmacy specialists' (CPSs) involvement in patients with GI cancers starting cycle 1 of a new treatment. METHODS: Our quality initiative was performed in three stages (preintervention, intervention, and postintervention). Preintervention: retrospective baseline data collection from May to December 2019. Intervention: one-time telephone encounters were conducted by a CPS between March 15 and June 11, 2021. The primary objective of the quality improvement initiative was to increase patient interaction with a CPS to 80%. Postintervention: data collection to review the impact of CPS telephone encounters. RESULTS: Preintervention: we reviewed the electronic health records of 262 patients. Sixty nine percent of patients reported at least one adverse event (AE; range 1-6 AEs) at the first physician follow-up after treatment start. Most reported AEs (78%) were considered modifiable within the scope of CPS practice. Postintervention: during the intervention, 92% of patients (n = 389) received a telehealth encounter with the CPS. At the encounter, 315 patients (81%) reported at least one AE. CPS provided recommendations and/or additional education for 88% of reported AEs. Medication lists required correction 75% of the time. The median time for CPS encounters (including documentation) was 40 minutes. CONCLUSION: During a 3-month period, this quality improvement initiative successfully provided an early CPS-based telehealth intervention to identify and make initial recommendations for management of AEs for patients on cycle 1 of systemic therapy for GI cancer.
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Oncología Médica , Farmacéuticos , Teléfono , Humanos , Masculino , Femenino , Oncología Médica/métodos , Persona de Mediana Edad , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/terapia , Estudios Retrospectivos , Anciano , Adulto , Estudios de Seguimiento , Mejoramiento de la CalidadRESUMEN
Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line advanced GACs. Unfortunately, outcomes remain poor for most patients. We anticipate finding a key to future discoveries in GACs in next-generation sequencing and more targeted approaches. Claudin 18.2 (CLDN18.2) has emerged as a therapeutic target in GACs. CLDN18.2 is reportedly expressed in 14-87% of GACs, and CLDN18.2 is available for monoclonal antibody (mAb) binding as it is expressed on the outer cell membrane. Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Anticuerpos Monoclonales/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Inmunoterapia , Claudinas/uso terapéuticoRESUMEN
Human epidermal growth factor receptor-2 (HER2) is a well-known cancer target. Many HER2-targeted agents are marketed and being investigated. Unfortunately, these therapies lack consistent responses and outcomes amongst different tumors. Questions remain as to why HER2 biology is different in different tumor types. Gastric adenocarcinomas (GACs) demonstrate both intra- and inter-tumor HER2 expression heterogeneity and show discordance amongst primary and metastatic disease sites. This creates barriers in determining HER2 agents' effectiveness and contributes to the failure of some HER2-targeted agents in the treatment of HER2-positive advanced GACs. Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients. There are exciting and newer therapies under investigation. Examining resistance patterns (both adaptive and acquired) along with establishing a better understanding of the intra- and inter-tumor heterogeneity is necessary to ensure successful progress. Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.
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BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is rare. Most cases are diagnosed in a localized setting. Metastatic SCCA is rare, and investigation has been limited in the past for these patients. We believe that hepatic-only metastatic disease could have a unique treatment landscape compared to diseases with diffuse metastatic involvement. Here, we describe cases at our institution. METHODS: We reviewed eight SCCA cases with hepatic-only metastatic disease (diagnosed February 2018-January 2022). The objectives were to determine the overall survival and disease-free survival with this approach. RESULTS: The median age was 62 years old (yo). Patients had an ECOG of 0-1. All patients received definitive chemoradiation to their primary anal tumor. A median of three months of neoadjuvant systemic therapy was provided. All patients had a response on their first scan after systemic therapy. Sixty-two percent received carboplatin + paclitaxel. A complete pathologic response was seen in 62% of patients. At their last follow-up, all patients were alive. Three patients had recurrent disease. The estimated 1-year disease-free survival probability was 56.2%. CONCLUSION: Our report shows the feasibility of a curative-intent approach for patients with hepatic-only metastatic SCCA following the neoadjuvant application of carboplatin + paclitaxel. This approach appears promising in these select patients and warrants further investigation.
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Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.
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Adenocarcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Gástricas , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patología , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/patologíaRESUMEN
INTRODUCTION: Esophageal cancers continue to confer a dismal prognosis. Targeted and immune therapies have skyrocketed in the world of cancer management. Unlike other solid tumors, esophageal squamous cell carcinoma (ESCC) has lacked effective targeted therapy. Promising outcomes with immune checkpoint inhibitors (ICIs) have recently changed ESCC management. AREAS COVERED: Nivolumab has been granted several approvals to treat ESCC patients. Nivolumab is recommended as adjuvant therapy for localized ESCC patients following trimodality therapy who have residual cancer in the surgical specimen (lymph node(s) and or the primary). CheckMate-648 led to dual ICI therapy approval with nivolumab plus ipilimumab or nivolumab plus platinum with fluoropyrimidine as first-line treatment for unresectable ESCC patients. ATTRACTION-3 resulted in nivolumab approval for second-line therapy of unresectable ESCC patients who have not been exposed to ICI. Here we provide a review of nivolumab and how this relates to ESCC management. EXPERT OPINION: Some ESCC patients will not experience a response to ICIs. Determining intrinsic and acquired resistance patterns are needed to further capitalize on ICI therapy for ESCC patients. PD-L1 expression has been explored as a potential biomarker. Data show, however, PD-L1 positive tumor patients benefit but this assessment is not always needed.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Nivolumab , Antígeno B7-H1 , IpilimumabRESUMEN
Gastric adenocarcinomas are a significant cause of cancer and cancer death, globally. The curative approach for those with diagnosed localized disease is with surgical resection and an adjunctive approach of perioperative chemotherapy, postoperative adjuvant therapy, or postoperative chemoradiation. Unfortunately, a universal standard approach is lacking for adjunctive therapy which in part has limited the progress achieved in this area. Metastatic disease is common in the Western world at diagnosis. Metastatic disease is treated palliatively with systemic therapy. Targeted therapy has stalled in approvals in gastric adenocarcinomas. Recently, we have seen the exploration of promising targets along with the addition of immune checkpoint inhibitors in select patients. Here, we review recent advances seen in gastric adenocarcinomas.
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INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.
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Adenocarcinoma , Anciano , Humanos , Anciano de 80 o más Años , Pronóstico , Estudios Retrospectivos , Adenocarcinoma/tratamiento farmacológico , Modelos de Riesgos ProporcionalesRESUMEN
The CROSS trial group deserves enormous credit for completing a well-powered randomized trial that has established the CROSS strategy as a standard of care for patients with potentially resectable esophageal cancer. However, the 10-year results are rather disappointing with only 38% of all patients treated with the CROSS strategy cured compared with approximately 25% who had surgery alone. Another standard, perioperative chemotherapy has produced similar disappointing results as the CROSS strategy. Although many of us are consumed by the question as to which option is better for our patients, we conclude that both strategies produce only marginal benefits. We should have better treatment options. The timing may be opportune to reflect on how to develop novel and rational strategies rather than propagate the historical empiric approaches.
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Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia NeoadyuvanteRESUMEN
INTRODUCTION: Esophageal cancer (EC) represents a complicated heterogenous group of malignancies. ECs are divided broadly into two types, histologically: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Historically, EC study designs have used bucket type groupings (all subtypes and/or all gastroesophageal cancers) reducing contribution to developing precision oncology. AREAS COVERED: Surgery remains the curative modality for resectable disease with reasonable patient physiology. Trimodality is recommended for localized ESCC. An exception is cervical EC. For EAC, preoperative chemoradiation or perioperative chemotherapy is utilized. For those who undergo trimodality, nivolumab is recommended as an adjuvant therapy for those with a non-pathological complete response (pCR). Additionally, immunotherapy and other targets have been added to advanced EC treatment. EXPERT OPINION: Organ sparing approaches for localized tumors are starting to be investigated in many solid tumors and have been standard approaches for decades in certain tumors (i.e. certain head and neck tumors and anal SCCs). pCR differs between esophageal histologies with trimodality indicating potential of discriminating localized approaches. To determine if a watch and wait approach is feasible, prospectively correlating clinical complete response to pCR is needed, determining the best active surveillance strategy, and the best use of tools like liquid biopsies.
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Adenocarcinoma , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Adenocarcinoma/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Medicina de Precisión , Nivolumab/uso terapéutico , Terapia CombinadaRESUMEN
INTRODUCTION: Gastroesophageal cancers (GEC) are frequently found at the advanced stage. GEC treatment advancements have been limited and prognosis, therefore, remains poor. Through numerous clinical trials, the addition of immune checkpoint inhibitors, including nivolumab, to conventional therapy has demonstrated a survival benefit. AREAS COVERED: Here, we focus on the function of nivolumab in patients with advanced GECs. We discuss the most recent trials that led to nivolumab's incorporation into therapy and pathways forward. EXPERT OPINION: Nivolumab in combination with chemotherapy appears well tolerated, with only a small number of patients reporting severe toxicity; therefore, it may be possible to add additional biological agents to improve outcomes. A number of 'nivolumab plus other agents' is currently being investigated, and we anticipate continued advancement in GEC management in the coming years.
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Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Nivolumab/uso terapéutico , Inmunoterapia , Anticuerpos Monoclonales/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológicoRESUMEN
Immune checkpoint inhibitors have revolutionized cancer management. Some patients with gastrointestinal (GI) tract malignancy have experienced remarkable results. Here, in our review, we discuss predictive/prognostic GI tumor biomarkers that appear to correlate with benefits with this strategy. Remarkable progress has been made in certain subsets of patients including the potential for solid tumor patients to avoid local therapies such as radiation and/or surgery (organ preservation), which come with acute and chronic risks that have historically been the only curable strategies for these GI tumors. These results provide new and exciting strategies for solid tumor management. Unfortunately, immune checkpoint inhibitors can correlate with biomarkers, but benefits occur in a small subset of patients with GI malignancies. Most frequently, immune checkpoint inhibitors fail to induce response in GI malignancies due to the "cold" tumor microenvironment that protects cancer. Translational strategies are needed to develop effective combination strategies and novel biomarkers to overcome the intrinsic resistance.
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Background: Colorectal cancer in young adults is on the rise. This rise combined with delayed childbearing increases the likelihood of colorectal cancer diagnosed during pregnancy or in the postpartum period. Methods: Electronic health records were used to identify individuals with colorectal cancer in pregnancy or the postpartum period from 1 August 2007 to 1 August 2019. Results: Forty-two cases were identified. Median age at diagnosis was 33 years. Most (93%) were diagnosed in an advanced stage (III or IV) and had left-sided colorectal cancer tumors (81%). Molecular analysis was completed in 18 (43%) women with microsatellite status available in 40 (95%). The findings were similar to historical controls. Sixty percent were diagnosed in the postpartum period. Common presenting symptoms were rectal bleeding and abdominal pain. Conclusion: Currently there is no consensus recommendation regarding how to manage colorectal cancer during pregnancy. Given the overlapping symptoms with pregnancy, patients often present with advanced disease. We encourage all health care professionals caring for pregnant women to fully evaluate women with persistent gastrointestinal symptoms to rule out colorectal cancer.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
Anal squamous cell carcinoma (SCAC) is a human papillomavirus (HPV) driven malignancy. Given inadequate HPV-vaccination rates, SCAC will continue to be a public health concern. SCAC is commonly diagnosed in the local or locoregional setting in which definitive chemoradiation provides the opportunity for cure and has high control rates. A minority of patients will develop recurrence or present with metastatic SCAC. Given the rarity of this disease, research has lagged compared to many other solid tumors. Historically, treatment has been based on extrapolating management approaches from more common squamous cell carcinoma malignancies and/or small case series or case reports. Fortunately, dedicated prospective clinical trial investigation in the advanced setting has emerged in recent years. Here, we review the current strategies for treatment along with remaining challenges and viable next steps for the management of metastatic SCAC.