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. 

With an observed increase of distant-stage colorectal cancer (CRC) among young patients in recent years, researchers have been searching for the reasons behind rising numbers and ways to counteract them. Carcinoids, a subtype of slow-growing cancer, have been found to contribute to the steadily rising incidence rate of early-onset colorectal cancer, which is diagnosed before the age of 50. This has created a need to assess the shifts toward distant-stage adenocarcinoma and its impact on public health.

Why Are We Seeing This Increase?

A study recently published in Cancer Epidemiology, Biomarkers & Prevention sought to understand how the proportions of distant-stage disease changed over time. Several studies have identified a significant increase (49%) in the average annual percent change for distant stage colorectal cancer in the 20-34 years age group. However, many of these studies do not report histological subtypes of CRC. 

With carcinoids increasing in younger patients, it is important to look at adenocarcinoma (most common cancer of the colon and rectum) staging independently from carcinoids (neuroendocrine tumors). Therefore, these researchers focused specifically on adenocarcinomas. Yearly adenocarcinoma incidence rates from the 2000-2016 Surveillance Epidemiology And End Results (SEER) data were stratified by stage, age, subsite, and race for 103,975 patients. Changes in the three-year annual incidence rate were calculated with the percent contribution of each cancer stage. Lastly, the subgroup with the highest proportion of distant-stage disease was determined.

The greatest percent increases were seen in distant-stage cancer when comparing data from 2000-2002 with 2014-2016. Here are a few significant findings of the study:

  • Colon-only distant adenocarcinoma increased most in 30-39-year-olds (49%)
  • Rectal-only distant-stage adenocarcinoma increased most in 20-29-year-olds (133%)
  • Based on race:
    • Distant stage proportions increased most for both colon- and rectal-only subsites in 20-29-year-old non-Hispanic Blacks (14% and 46%, respectively) 
    • The second most-impacted group was 20-29-year-old Hispanics with a 13% increase in the proportion of those affected by rectal-only, distant stage adenocarcinoma.

From these findings, we can conclude that the greatest burden of disease was on younger patients, highest in the non-Hispanic Black and Hispanic subgroups (despite relatively low absolute case counts). The researchers also uncovered that there is a decrease in early-stage disease in these early-onset groups. As we now know, younger patients are presented with higher risks, but the absolute incidence rates in the youngest subgroups remain relatively low.

These findings are important because they set a new precedent for patients under 50 who may not be aware that preventive screening for those at average risk of CRC starts at 45 years. Studies moving forward should also note that not all adenocarcinomas are categorized as early-onset CRC. Although this study is limited in its observational nature, it raises important questions in analyzing staging results, promoting screening opportunities, and keeping the general public aware of their risks. This study also presents potential solutions, including optimizing earlier screening and the risk-stratification of younger patients by family history and symptoms.

 

Juhi Patel is  Colon Cancer Prevention Intern.

The Colon Cancer Foundation (CCF) spoke with Dr. Rami James Aoun, 11th winner of the Dr. Thomas K. Weber Colorectal Cancer Research Scholar Award, for his work looking at biomarkers of radiation response in rectal cancer patients. He is a surgical resident at The Ohio State Wexner Medical Center. Instituted in 2011 by CCF and the Society of Surgical Oncology to recognize translational research focused on the molecular biology of colorectal cancer, the award was renamed in 2020 to honor CCF’s founder, the late Dr. Thomas K. Weber.

Born in West Palm Beach, Florida, Dr. Aoun was raised in Beirut, Lebanon, where he was a student at the American University of Beirut. After completing his undergraduate years and medical school, Dr. Aoun joined Columbia University in New York where he received a Master of Public Health degree in Healthcare Management and Policy. As part of his ongoing residency at The Ohio State Wexner Medical Center, he is completing a research fellowship with Dr. Matthew Kalady, a colorectal surgeon at The James Cancer Center.

Dr. Rami James Aoun

Q: What motivated you to work in the oncology research space, and colorectal cancer in particular?

Dr. Aoun: I am motivated to work in oncology research because I have seen some of my own family members suffer from cancer. However, what specifically interests me in colon cancer research are the patients that I encounter here at The James Cancer Center and my mentors. Their guidance when I was a junior resident was extremely important to set the direction for me as a future colorectal surgeon. That’s how I met Dr. Kalady, and now I am a part of his lab conducting research on colorectal cancer, with the goal of improving patient care outcomes.

Q: Can you summarize the significance of your findings for which you have received this award? Can you also share the prior work or observations that laid the foundation for this project?

Dr. Aoun: We observed a difference in how patients with rectal cancer reacted to neoadjuvant radiation therapy. Some of the patients who were exposed to neoadjuvant therapy had a complete response—the cancer disappeared. However, there were patients who had almost no response to the therapy. The response can be determined and graded by examining the tumor under a microscope. Patients who had a better response end up living longer without cancer.

We sought to identify the reason certain cancers responded to neoadjuvant radiation and certain cancers did not. To do that, we tried to understand these cancers at the genetic level by studying how a rectal cancer expressed particular genes, as measured by mRNA. By comparing the gene expression in both, patients who responded to radiation therapy and those who did not, we were able to obtain a gene signature that helps us identify patterns of gene expression that are different between responders and non-responders.

While this is just a starting point, it can help us develop a more predictive model to use clinically. Once we validate this model, we could be able to distinguish between a responder and non-responder to radiation based on the gene expression that we obtained from their biopsies even before any treatment is administered. This would allow us to provide individualized patient-specific therapy and avoid any unnecessary treatments and procedures.

We also think that certain genes in this signature can be further studied to see if they might be able to be blocked or changed to improve the response to treatment.

Q: What was the size of your current cohort and what is the ‘n’ that you are looking for to be able to validate your study results?

Dr. Aoun: Our ‘n’, or sample size, was 33 patients for this study. In genetic studies like this, it is difficult to design a statistical power needed to validate, but we hope to test this in about 100 different patients.

Q: Did you see any commonality in the gene signatures between rectal cancer and colon cancer?

Dr. Aoun: The gene signature we investigated was related to radiation resistance in rectal cancer, whereas colon cancer is not usually treated with radiation therapy. So, we did not study this for colon cancer. However, some of the pathways we identified are known to be relevant to colon cancer. In terms of the common pathways, what we know is the WNT pathway specifically is involved in the development and progression of colon cancer and rectal cancer. In the gene signature that we identified, six of the genes are involved in the WNT pathway. So, the question is whether the WNT pathway is also involved in radiation resistance in rectal cancer.

Q: Rectal cancer has been steadily increasing in the younger population. Do we know why that may be happening?

Dr. Aoun: An increasing number of younger patients are being afflicted with colorectal cancer and we don’t fully know why. There are lots of different theories about diet, lifestyle, and the microbiome (i.e. the bacterial content in the colon and rectum). This is a hot area of research and many groups are trying to figure out this question.