Review

22 pages, 648 KiB

Open AccessReview

Targeted Therapies and Developing Precision Medicine in Gastric Cancer

by Rille Pihlak, Caroline Fong and Naureen Starling

Cancers 2023, 15(12), 3248; https://doi.org/10.3390/cancers15123248 - 19 Jun 2023

Cited by 4 | Viewed by 1575

Gastric cancer is an aggressive disease with survival remaining poor in the advanced setting. More than a decade after the first targeted treatment was approved, still only HER2, MSI and PDL-1 status have reached everyday practice in terms of guiding treatment options for [...] Read more.

Gastric cancer is an aggressive disease with survival remaining poor in the advanced setting. More than a decade after the first targeted treatment was approved, still only HER2, MSI and PDL-1 status have reached everyday practice in terms of guiding treatment options for these patients. However, various new targets and novel treatments have recently been investigated and have shown promise in improving survival outcomes. In this review, we will summarise previous and currently ongoing studies on predictive biomarkers, possible new targeted treatments, potential reasons for conflicting trial results and hope for the future of precision medicine in gastric cancer. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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16 pages, 1902 KiB

Open AccessReview

Perspectives on the Management of Oligometastatic Disease in Esophago-Gastric Cancer

by Thorsten Oliver Goetze and Salah-Eddin Al-Batran

Cancers 2022, 14(21), 5200; https://doi.org/10.3390/cancers14215200 - 23 Oct 2022

Cited by 4 | Viewed by 2163

Abstract

Gastric adenocarcinoma and esophageal cancer are the fifth and seventh most common cancer types worldwide. At the time of initial diagnosis, up to 50% of esophagogastric cancers present with distant metastatic lesions and are candidates for chemotherapy. Curative surgery in this stage is [...] Read more.

Gastric adenocarcinoma and esophageal cancer are the fifth and seventh most common cancer types worldwide. At the time of initial diagnosis, up to 50% of esophagogastric cancers present with distant metastatic lesions and are candidates for chemotherapy. Curative surgery in this stage is still an experimental approach. Only a small number of these metastatic patients show an oligometastatic disease with no uniform definition of what oligometastatic means in gastric cancer. Nevertheless, the question remains unanswered as to whether these patients are still candidates for curative concepts. Some studies have attempted to answer this question but have not been adequately designed to address the role of a curative-intended multimodal therapy in this setting. The current FLOT-5 is designed to potentially provide a definitive answer to the question of whether curatively intended surgery plays a role or is a disadvantage in this setting. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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20 pages, 333 KiB

Open AccessReview

The Role of ctDNA in Gastric Cancer

by Justin Mencel, Susanna Slater, Elizabeth Cartwright and Naureen Starling

Cancers 2022, 14(20), 5105; https://doi.org/10.3390/cancers14205105 - 18 Oct 2022

Cited by 12 | Viewed by 2331

Abstract

Circulating tumour DNA (ctDNA) has potential applications in gastric cancer (GC) with respect to screening, the detection of minimal residual disease (MRD) following curative surgery, and in the advanced disease setting for treatment decision making and therapeutic monitoring. It can provide a less [...] Read more.

Circulating tumour DNA (ctDNA) has potential applications in gastric cancer (GC) with respect to screening, the detection of minimal residual disease (MRD) following curative surgery, and in the advanced disease setting for treatment decision making and therapeutic monitoring. It can provide a less invasive and convenient method to capture the tumoural genomic landscape compared to tissue-based next-generation DNA sequencing (NGS). In addition, ctDNA can potentially overcome the challenges of tumour heterogeneity seen with tissue-based NGS. Although the evidence for ctDNA in GC is evolving, its potential utility is far reaching and may shape the management of this disease in the future. This article will review the current and future applications of ctDNA in GC. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

20 pages, 350 KiB

Open AccessReview

HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

by Caroline Fong and Ian Chau

Cancers 2022, 14(15), 3824; https://doi.org/10.3390/cancers14153824 - 06 Aug 2022

Cited by 7 | Viewed by 2639

Abstract

Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of HER2 gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine [...] Read more.

Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of HER2 gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. Although limited progress was made in the decade following ToGA, there is now an abundance of novel therapeutic approaches undergoing investigation in parallel. Additionally, new data from randomised trials have indicated efficacy of the antibody-drug conjugate trastuzumab deruxtecan in chemorefractory patients and increased responses with the addition of first-line immune checkpoint blockade to trastuzumab and chemotherapy. This review will outline the data supporting HER2 targeting in gastric cancers, discuss mechanisms of response and resistance to HER2-directed therapies and summarise the emerging therapies under clinical evaluation that may evolve the way we manage this subset of gastric cancers in the future. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

10 pages, 257 KiB

Open AccessReview

Considerations and Challenges in the Management of the Older Patients with Gastric Cancer

by Sotiris Loizides and Demetris Papamichael

Cancers 2022, 14(6), 1587; https://doi.org/10.3390/cancers14061587 - 21 Mar 2022

Cited by 7 | Viewed by 1868

Abstract

Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients [...] Read more.

Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients in randomised clinical trials is poor, presumably due to concerns about increased toxicity, co-existing comorbidities and impaired performance status. Therapeutic strategies for this patient group are therefore mostly based on retrospective subgroup analysis of randomised clinical trials. Review of currently available evidence suggests that older gastric cancer patients who are fit for trial inclusion may benefit from surgical intervention and peri-operative systemic chemotherapy strategies. For patients with metastatic disease, management has been revolutionized by the use of anti-HER2 directed therapies as well as immune checkpoint inhibitors with or without chemotherapy. Early data suggest that fit older patients may also benefit from these therapeutic interventions. However, once again there may be limitations in extrapolating these data to everyday clinical practice with older patients being less likely to have a good performance status and an intact immune system. Therefore, determining the functional age and not just the chronological age of a patient prior to initiating therapy becomes very important. The functional decline including reduced organ function that may occur in older patients makes the integration of some form of geriatric assessment in routine clinical practice very relevant. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

12 pages, 523 KiB

Open AccessReview

Chemorefractory Gastric Cancer: The Evolving Terrain of Third-Line Therapy and Beyond

by Maria Alsina, Josep Tabernero and Marc Diez

Cancers 2022, 14(6), 1408; https://doi.org/10.3390/cancers14061408 - 10 Mar 2022

Cited by 3 | Viewed by 2577

Abstract

Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to [...] Read more.

Gastric and gastro-oesophageal junction cancer (GC) represent a global healthcare problem being the fifth most common tumour type and the fourth cause of cancer mortality. Extremely poor median survival of approximately 10 months is normally reported within advanced GC patients, mainly secondary to two factors, i.e., the fragility of these patients and the aggressiveness of this disease. In this context, the correct treatment of GC patients requires not only a multidisciplinary team with special attention to palliative and nutritional care but also a close follow-up with regular monitoring of disease symptoms and tumour evaluation. Sequential treatment lines with few toxic adverse events have emerged as the best therapeutic approach, and a third line of therapy could further improve survival and quality of life of GC patients. Chemotherapy, immunotherapy, and targeted agents -when indicated- constitute the treatment armamentarium of these patients. In this review, we discuss treatment options in the refractory setting as well as novel approaches to overcome the poor prognosis of GC. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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15 pages, 589 KiB

Open AccessEditor’s ChoiceReview

The New Era of Immunotherapy in Gastric Cancer

by Shogo Takei, Akihito Kawazoe and Kohei Shitara

Cancers 2022, 14(4), 1054; https://doi.org/10.3390/cancers14041054 - 18 Feb 2022

Cited by 64 | Viewed by 10081

Abstract

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at [...] Read more.

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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18 pages, 326 KiB

Open AccessReview

Optimising Multimodality Treatment of Resectable Oesophago-Gastric Adenocarcinoma

by Ali Abdulnabi Suwaidan, Anderley Gordon, Elizabeth Cartwright and David Cunningham

Cancers 2022, 14(3), 586; https://doi.org/10.3390/cancers14030586 - 24 Jan 2022

Cited by 3 | Viewed by 2901

Abstract

Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there [...] Read more.

Oesophago–gastric adenocarcinoma remains a leading cause of cancer-related morbidity and mortality worldwide. Although there has been an enormous progress in the multimodality management of resectable oesophago–gastric adenocarcinoma, most patients still develop a recurrent disease that eventually becomes resistant to systemic therapy. Currently, there is no global consensus on the optimal multimodality approach and there are variations in accepted standards of care, ranging from preoperative chemoradiation to perioperative chemotherapy and, more recently, adjuvant immune checkpoint inhibitors. Ongoing clinical trials are aimed to directly compare multimodal treatment options as well as the additional benefit of targeted therapies and immunotherapies. Furthermore, our understanding of the molecular and genetic features of oesophago–gastric cancer has improved significantly over the last decade and these data may help inform the best approach for the individual patient, utilising biomarker selection and precision medicine. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

27 pages, 206789 KiB

Open AccessReview

Advances in the Aetiology & Endoscopic Detection and Management of Early Gastric Cancer

by Darina Kohoutova, Matthew Banks and Jan Bures

Cancers 2021, 13(24), 6242; https://doi.org/10.3390/cancers13246242 - 13 Dec 2021

Cited by 5 | Viewed by 8701

Abstract

The mortality rates of gastric carcinoma remain high, despite the progress in research and development in disease mechanisms and treatment. Therefore, recognition of gastric precancerous lesions and early neoplasia is crucial. Two subtypes of sporadic gastric cancer have been recognized: cardia subtype and [...] Read more.

The mortality rates of gastric carcinoma remain high, despite the progress in research and development in disease mechanisms and treatment. Therefore, recognition of gastric precancerous lesions and early neoplasia is crucial. Two subtypes of sporadic gastric cancer have been recognized: cardia subtype and non-cardia (distal) subtype, the latter being more frequent and largely associated with infection of Helicobacter pylori, a class I carcinogen. Helicobacter pylori initiates the widely accepted Correa cascade, describing a stepwise progression through precursor lesions from chronic inflammation to gastric atrophy, gastric intestinal metaplasia and neoplasia. Our knowledge on He-licobacter pylori is still limited, and multiple questions in the context of its contribution to the pathogenesis of gastric neoplasia are yet to be answered. Awareness and recognition of gastric atrophy and intestinal metaplasia on high-definition white-light endoscopy, image-enhanced endoscopy and magnification endoscopy, in combination with histology from the biopsies taken accurately according to the protocol, are crucial to guiding the management. Standard indications for endoscopic resections (endoscopic mucosal resection and endoscopic submucosal dissection) of gastric dysplasia and intestinal type of gastric carcinoma have been recommended by multiple societies. Endoscopic evaluation and surveillance should be offered to individuals with an inherited predisposition to gastric carcinoma. Full article

(This article belongs to the Special Issue Contemporary Perspectives and Emerging Trends in the Management of Gastric Cancer)

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