Overcoming Resistance in Gastrointestinal Cancers

Aparna Raj Parikh, MD

Assistant Professor of Medicine

Harvard Medical School Assistant in Medicine,

Hematology and Oncology

Attending Oncologist

Tucker Gosnell Center for Gastrointestinal Cancers

Henri and Belinda Termeer Center for Targeted Therapies

Massachusetts General Hospital

Boston, MA

Biomarkers predict acquired resistance (AR) to immune checkpoint inhibitors (ICIs) in patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) advanced gastrointestinal (GI) cancers.

ICIs are approved for dMMR/MSI-H GI cancer treatment; however, approximately half of patients with dMMR/MSI-H GI cancer exhibit primary resistance to ICIs.¹ GI tumors that are dMMR/MSI-H contain abundant somatic mutations and consequently express many neoantigens inducing immune infiltrates at the tumor site, which indicates that dMMR/ MSI-H GI cancers should respond to ICIs.2,3 Indeed, ICI efficacy in advanced or metastatic dMMR/MSI-H GI cancer has been well established in several clinical and postmarket trials, with objective response rates of 33% to 57%.^4-7

The 2 main reasons why patients do not respond to ICIs are misdiagnosis of dMMR/ MSI-H status and intrinsic resistance to ICI therapy.^8-10 Thus, correct dMMR/MSI-H status determination and uncovering the predictors of resistance are critical for screening patients who are expected to respond to ICI treatment. Although the molecular mechanisms of resistance to ICIs have been the subject of extensive research, the underlying mechanism remains largely unknown.^6,7,11,12 Thus, identifying effective biomarkers predicting resistance to ICI therapy is an urgent unmet medical need.

“We are still learning to understand the predictors of primary resistance in GI cancers. There is the inherent lack of immunogenicity of some GI tumors, but beyond that, there can be primary resistance,” Aparna Raj Parikh, MD, an assistant professor in medicine at Harvard Medical School and assistant in medicine in hematology and oncology at Massachusetts General Hospital in Boston, said during an interview with Targeted Therapies in Oncology. “We have worked extensively in the AR resistance space using both tissue and model to understand resistance.” Parikh is also an attending oncologist at the Tucker Gosnell Center for Gastrointestinal Cancers and the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital.

Patterns of Disease Relapse

Understanding the patterns of disease relapse among patients with GI tumors is essential to determine characteristics and prognosis of AR to ICIs and delineate predictors of ICI resistance. Patterns of disease relapse were investigated in a retrospective cohort study of patients with luminal (89.0%), hepatobiliary (7.5%), and pancreatic (2.4%) GI cancers.13 Overall, 46% of patients developed AR to ICI treatment; however, the AR rate varied for different GI cancers.13 Patients developed AR at a rate of 49% in esophageal cancer, 51% in gastric or esophagogastric junction cancer, 27% in intestinal cancer, and 57% hepatobiliary or pancreatic cancers.13 Oligoprogression was the most common pattern of disease relapse (71%) rather than polymetastatic progression (22%).¹³ Overall lymph nodes were the most susceptible site for AR (58%); however, the patterns of disease progression varied for different GI cancers.¹³

The most common sites of disease progression were the peritoneum in the lower GI cancers, the lymph nodes in esophageal or gastric cancer, and the liver in hepatobiliary or pancreatic cancers.¹³ Together these data suggest that tumor-specific factors are predictive of ICI response, which is supported by preclinical studies demonstrating that tumor cell signaling pathways modulate immune cell infiltration.¹⁴

According to Parikh, the prognosis of resistance to ICIs in GI cancers is due to an inherent lack of immunogenicity of some GI tumors. The characteristics of primary resistance are immune activation, lack of or inability to present neoantigens, dendritic cells not maturing, chemokine imbalance that prevents trafficking of immune cells, and upregulation of certain immune checkpoints, Parikh noted.

Furthermore, VEGF overexpression, which is important in many GI cancers, may inhibit T-cell trafficking and immune infiltration. “It is certainly complex and interplay of tumor… and the immune system,” Parikh said.

Liquid Biopsies

Tissue biopsy has been the most established clinical practice to detect AR in GI cancers. However, liquid biopsies are becoming increasingly important, according to Parikh. “Liquid biopsies are becoming more mainstream not only for molecular profiling, but to track resistance,” Parikh said.

Liquid biopsies are important in the development of new strategies to overcome AR and can help determine whether resistant subclones decay and patients are likely to respond to initial targeted therapies, Parikh continued. Liquid biopsies enable detection of genetic mutations that predict resistance to ICIs.

Several mutations that are independent predictors of primary resistance to ICIs and poor progression-free survival have been identified. These include AKT1 and CDH1 mutations, which predicted primary resistance to ICIs in 52% of patients with dMMR/MSI-H GI cancer, with a positive predictive value of 92%.¹

Higher number of mutated genes in the PI3K/AKT/mTOR pathway predicted lower density of tumor-infiltrating immune cells and primary resistance to ICIs in 86% of patients with dMMR/MSI-H gastric adenocarcinomas.¹⁵

A comparative efficacy study demonstrated MSI-H predicted favorable ICI treatment outcomes and appeared superior to dMMR in predicting ICI outcomes.¹⁶ Together these data demonstrate the ability of mutational data to predict ICI resistance.

Microenvironment and Microbiota

Other important factors include the tumor microenvironment and microbiota.

“There are data [showing that] the immune microenvironment may be laden with suppressive cells. It is certainly complex and interplay of tumor [and] the microenvironment,” Parikh said.

For example, immunosuppressive tumor microenvironments with a significantly decreased M1/M2 ratio of tumor-associated macrophages were observed in dMMR/MSI-H GI tumors with AKT1 mutations. Thus, the tumor microenvironment and microbiota association with acquired ICI resistance warrant further exploration.¹⁷

Patients with dMMR/MSI-H GI cancers with peritoneal metastases and ascites represent a subgroup with highly unfavorable outcomes to current ICI therapies.¹⁸

Two multicohort studies demonstrated peritoneal metastases with ascites is a predictor of poor prognosis and resistance to ICIs in patients with dMMR/MSI-H metastatic colorectal cancer and gastric cancer.^16,19

To achieve improved outcomes for these patients, strategies to target the immune- suppressive niche in malignant effusions should be investigated, including next- generation ICIs or intraperitoneal approaches.

Identification of biomarkers predicting treatment response to ICI therapies is critical. “In GI cancers, we are making tremendous strides to unearth biomarkers that portent sensitivities to targeted therapies.

The most exciting in cancers such as pancreatic and colon has been new approaches to target ARS,” Parikh said.

The somatic mutations in AKT1, CDH1, and the PI3K/AKT/mTOR pathway and high microsatellite instability predict primary resistance to ICIs,^1,15 which can help guide clinical decision-making that patients with these mutations should not be recommended for ICI therapy.

Mutation biomarkers can be easily translated into a simple clinical assay via detection of decisive common genes and should be recommended for standard clinical practice in dMMR/MSI GI cancer. However, there remains a critical gap in clinical practice of how to best treat patients with dMMR/MSI GI cancers that are resistant to ICI therapies.

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