Tag Archive for: immunotherapy

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Genetic Disparity May Contribute to Worse CRC Outcomes Among African-Americans

Health disparities are present in a multitude of different health issues and drive inequity among populations. These populations can be defined by factors like race, income, gender, or even geographic location. Improving access to colorectal cancer screening involves addressing these populations. Researchers can utilize data to identify geographic disparities, but understanding racial disparities becomes more complicated due to sociodemographic and cultural considerations. Yet, scientists at the Memorial Sloan Kettering Cancer Center (MSKCC) may have discovered reasons for these disparities on a microscopic level.

MSKCC researchers analyzed DNA sequencing data of over 4,000 patients at the hospital over the course of 8 years and compared it to ancestry information. They found that patients with African ancestry had shorter median survival post-diagnosis, had less accurately predicted outcomes, and were less likely to have the genetic mutations needed to be considered for immunotherapy. Overall survival  for the African ancestry group was only 45.7 months post-diagnosis compared to 67.1 months for the European ancestry group.

Mutations in the adenomatous polyposis (APC) gene, which is a known tumor suppressor, are associated with better CRC outcomes. However, this mutation appeared to make no difference in survival for Black patients while improving survival rates among European, East Asian, and South Asian CRC patients.

Disparity in Treatment Response

When it came to treatment, the African ancestry group had less genetic markers for effective immunotherapy treatment as defined by the FDA. While the European ancestry group had a 20.4% qualification rate, the African ancestry group had only 13.5%. Even compared to those who did not qualify for immunotherapy treatments based on FDA guidelines, those with African ancestry still experienced less actionable genetic alterations than the European group (5.6% and 11.2% respectively). Researchers propose that this may be due to fewer BRAF V600E mutations in the African ancestry group. Patients who carry this mutation typically respond well to certain targeted treatments.

A limitation of this study is its exclusion of environmental and lifestyle factors that are important in CRC outcomes.

Addressing health disparities in screening and treatment benefits researchers and community efforts by identifying how and where to implement interventions. This study suggests that these large-scale issues may have solutions hidden within the population of interest itself.

 

Kaylinn Escobar is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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Neoadjuvant Immunotherapy Effective for Mismatch Repair–Deficient Colorectal Cancer

Mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) colorectal cancer (CRC) is an advanced form of CRC that is highly responsive to treatment with immunotherapy, especially PD-1 inhibitors. Preliminary research results demonstrate that PD-1 inhibitors are significantly effective cancer treatments, with high response rates and sustained progression-free survival. 

A new study investigated the treatment impact of neoadjuvant PD-1 inhibitors on the long-term survival of dMMR CRC patients. The study found that PD-1 inhibitor treatment before surgery was significantly effective among patients with dMMR/MSI-H CRC.

Seventy-three patients with dMMR/MSI-H CRC who had previously been treated with PD-1 inhibitors were included in a retrospective review. The most common locations of primary tumors were in the rectum (24.7%) and ascending colon (24.7%). 79.5% of patients were treated with PD-1 inhibitor alone. The study found:

  • Nearly all patients involved in the study benefited from neoadjuvant PD-1 inhibitors, with 25% experiencing complete response.
  • 84.9% of patients experienced an objective response, with 61.6% achieving a partial response. 
  • The two-year tumor-specific overall survival and disease-free survival rates for patients who underwent surgery after PD-1 blockade were both 100%.

These findings are promising for patients with nonmetastatic dMMR/MSI-H CRC, including those with locally advanced disease. Dustin A. Deming, MD, University of Wisconsin Carbone Cancer Center, stated in an NCCN newsletter, “The treatment of mismatch repair deficient locally-advanced colorectal cancer is a highly active area of research. This retrospective analysis highlights the potential for significant treatment responses with limited toxicities for these patients treated with immune checkpoint inhibitors. It will be exciting to see how these results, and other completed and ongoing studies, will be utilized to incorporate anti-PD1 treatments into the standard-of-care for locally-advanced colorectal cancers.”

To read more about types of immunotherapy drugs and their impact on cancer care, visit Understanding Cancer Immunotherapy Research. 

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

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PD-1 Inhibition Effective in Treating Mismatch Repair-Deficient, Locally Advanced Rectal Cancer

Locally advanced rectal cancer may involve multistep neoadjuvant therapy to shrink the tumor before the main treatment, which is often surgery. Although this approach results in a complete pathological response in up to 25% of patients, it involves the risk of complications and toxic effects, including bowel, urinary, and sexual dysfunction; infertility; and altered quality of life in a significant number of patients. A new study, published in the New England Journal of Medicine, has found that patients with mismatch repair-deficient, locally advanced rectal cancer can be effectively treated with neoadjuvant programmed death-1 (PD-1) blockade.  

Approximately 5-10% of rectal adenocarcinomas are attributed to mismatch-repair deficiency, and this subset of tumors respond poorly to standard chemotherapy treatments. Immune checkpoint blockade could be an effective treatment option for this subset of patients. PD-1 elicits an immune checkpoint response of T-cells, allowing tumor cells to bypass the immune system defense, as well as resist the effects of chemotherapy. To test this hypothesis, researchers at Memorial Sloan Kettering Cancer Center and Yale University School of Medicine conducted a phase 2 investigation to analyze the overall response and frequency of sustained clinical complete response to neoadjuvant treatment with a PD-1 inhibitor, dostarlimab. 

PD-1 Blockade Eliminated Rectal Tumors

Of the sixteen patients enrolled in the study, twelve were enrolled for more than six months and completed nine cycles of dostarlimab. The resulting clinical complete response was measured by a combination of rectal MRI, visual endoscopic inspection, and digital rectal examination in twelve patients who had at least six months of follow-up. Endoscopic biopsies were performed at baseline and during visual inspection of tumor response at six weeks, three months, and 6 months, and then every four months thereafter. Serial FDG-PET scans to evaluate tumor eradication presented similar results to that seen with pathological examination and genomic analysis of the evolution of tumor eradication. 

The elimination of tumors after six months of therapy with PD-1 blockade allowed Dr. Cercek and her team to be able to omit both chemoradiotherapy and surgery and to move forward with observation alone. Single-agent dostarlimab was significantly influential in treating mismatch repair-deficient, locally advanced rectal cancer. It provided a clinical complete response in all 12 patients who completed treatment to date. 

Surgery and radiation can permanently impact fertility, sexual health, and bowel and bladder function. With the rise in incidence of rectal cancer among young patients of child-bearing age, anti-PD-1 antibodies can be a good alternative to chemoradiotherapy and surgery and may specifically benefit this cohort of patients. Dostarlimab promotes a refined approach toward treatment that can significantly improve the quality of life of patients, especially younger patients who may not yet have started a family. These findings also encourage the potential for using PD-1 inhibitors in the treatment of other mismatch repair-deficient tumors, such as localized pancreatic, gastric, and prostate cancers.

 

Sahar Alam is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation. 

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