, ,

Intestinal Bacteria: Biomarkers and Targets for Colorectal Cancer

By Parker Lynch

According to a study published in Cancer Biology & Medicine, the role of intestinal bacteria in the development of colorectal cancer (CRC) has been receiving a lot of attention in recent years. Various bacteria such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, Enterococcus faecalis, and Salmonella sp., have been known to cause DNA damage. Additionally, these bacteria also help tumor cells evade the body’s immune response, creating a pro-inflammatory environment. The DNA damage and other hindrances upon one’s immune system and bodily function have been associated with the development and progression of CRC.

These bacteria can be useful biomarkers for CRC. Additionally, progress is being made in developing effective antibacterial therapies, which could prove useful in the treatment of CRC.

Parker Lynch is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

/by
, ,

How Quickly Should a CRC Patient Start Their Treatment? Does It Matter?

By Parker Lynch

In a recent study conducted in Canada, 5,026 patients with colorectal cancer (CRC, all younger than 50) were evaluated between 2007 and 2018. This study evaluated the time between a patient’s first presentation with CRC and their treatment initiation. The overall objective of this study was to determine if a longer time from presentation to treatment start would result in worse survival rates for CRC patients, particularly those under 50.

Relation Between Treatment Start and Disease Outcome

The median age of the participants was 44 years, with about an equal number of males and females:

  • 25.2% overall had metastatic disease
  • 31.2% had rectal cancer

The lower-urgency subset consisted of 2,548 patients. Patients with metastatic CRC had shorter median (IQR) overall intervals (83 days) compared with those with less advanced disease. Five-year overall survival was 69.8%. Overall intervals longer than 18 weeks were not associated with significantly worse overall survival (OS) or cancer specific survival (CSS) compared with those waiting 12 to 18 weeks. Additional analysis by the researcher where patients were stratified by stage of disease  did not show significantly worse OS or CSS with increasing overall interval lengths.

One would expect the findings to support that a later treatment start would result in worse outcomes for the patient. In other words, starting treatment as soon as possible would yield the best prognosis for patients. However, this study found something quite different: time from presentation to treatment was not associated with advanced disease or poor survival. This finding insinuates that a patient has a little bit of “leeway” in terms of the time it takes for them to begin their actual treatment, without having to worry that this delay will correspond to decreased survival.

Another Study With a Different Perspective

In another study, the administrative time of adjuvant chemotherapy following a curative surgical procedure for stage 3 CRC was evaluated. Specifically, researchers wanted to determine if there was a so-called “sweet spot” for when a patient should begin chemotherapy to maximize their chances of survival. 

In this study, 159 patients with stage III CRC, who had undergone a curative resection, were enrolled. Patients were categorized into 3 groups representing different timings to initiate chemotherapy treatments:

  • less than 2 weeks (group 1)
  • 3 to 4 weeks (group 2)
  • more than 5 weeks (group 3)

The OS and relapse-free survival rate (RFS) were analyzed to evaluate the effectiveness of adjuvant chemotherapy. The 5-year OS was:

  • 73.7% in group 1
  • 67.0% in group 2
  • 55.2% in group 3

The 5-year RFS was:

  • 48.8% in group 1
  • 64.7% in group 2
  • 57.1% in group 3

When specifically considering CRC patients who have undergone resection procedures, it was loosely determined that chemotherapy should be administered 6-8 weeks after one undergoes an operation. However, the administration prior to the 6-week mark didn’t result in a statistical difference in outcomes.

This, however, should not encourage patients to “wait out” their cancer; rather, that time should still be spent on interactions with providers to come up with a treatment plan. CRC, on average, takes around two years before it metastasizes to other organs such as the lungs, liver, lymph nodes, peritoneum, etc. Though this sounds like a lot of time, it is always best to be aware of one’s condition as soon as possible. 

The Dangers of Misdiagnosis 

When CRC is discovered at an advanced stage, it can be one of the deadliest and most difficult cancers to tackle. This is why misdiagnosis is such a prominent fear and active issue within the CRC community, particularly among younger CRC patients, who often struggle with getting the right diagnosis in the first place. 

When a younger person experiences CRC symptoms, it is often easy for them to be excused as hemorrhoids, irritable bowel syndrome, inflammatory bowel disease, or other gastrointestinal conditions. When properly diagnosed after the initial misdiagnosis, patients would have typically already progressed to a more intense and worrisome stage of CRC, therefore making their treatment plans and overall survival rates more complicated. 

Every CRC patient is different–they may vary in age, sex, predisposing health, stages of CRC, etc. Therefore, it is impossible for researchers to determine the perfect time in which every single patient should start treatment while keeping their survival rates in mind. However, the dangers of waiting too long are known. Though beginning chemotherapy treatments early (less than six weeks after resection procedures) don’t typically have a significant impact on one’s survival rate, significant delays in initiating treatment may result in negative outcomes. 

Parker Lynch is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

/by
, ,

Could Blood-based Testing Improve CRC Screening Barriers?

By Parker Lynch

Despite the current methods that exist for people to receive preventative screenings, colorectal cancer (CRC) screening rates remain below the 80% national goal. Since the utilization of the current testing methods are subpar among average-risk adults in America, researchers are testing the reliability of a blood-based test, which remains a preferable screening method for a variety of preventive tests in the general population. The hope is that a preferred screening method would improve screening rates for CRC among average-risk adults. 

Testing the Reliability and Validity of a Blood-Based Test

The ECLIPSE clinical trial evaluated the performance of a cell-free DNA blood-based CRC screening test. Individuals who were average-risk (those with no identifiable risk factors or abnormal predispositions to being diagnosed with CRC), 45 years of age or older, and presenting for colonoscopy screening were recruited from 265 U.S. clinical sites between October 2019 and September 2022. This population was diverse, which makes the findings generalizable:

  • 54% female
  • 7% Asian
  • 12% Black/African-American 
  • 79% white
  • 12% Hispanic/Latino 

Prior to their colonoscopy, participants provided whole blood samples. In doing so, researchers were able to compare the validity of the blood-based tests when compared to the actual results that were obtained from the colonoscopy procedures. 

The trial found that the blood test was:

  • 90% sensitive to detecting Stage I – III CRC
  • 100% sensitive to detecting Stage IV CRC
  • 90% specific

In another study, researchers retrospectively analyzed blood samples of 425 individuals who were to undergo a colonoscopy. The blood samples were tested for specific genetic and epigenetic changes and these were then correlated with the individual’s colonoscopy results. 

Here’s a fun video that explains what genetic and epigenetic changes are.

The test was found to be:

  • 82% sensitive for CRC
  • 90% specific

Overall, the researchers concluded that this test provides clinically meaningful performance and has utility for CRC screening.  A limitation of the specificity/sensitivity study was the utilization of an older version of the assay. However, should the results of up-to-date versions of the assay remain statistically significant, blood-based screening could be a very effective and preferable CRC screening method. 

Both these studies demonstrate the effectiveness of blood-based tests, which will hopefully improve the rate at which people get their preventative testing for CRC.

 

Parker Lynch is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

 

Photo credit: Photo by Testalize.me on Unsplash  

/by
, ,

Inflammatory Biomarkers Can Predict Colorectal Cancer Recurrence and Mortality 

Interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-a) are inflammatory biomarkers that are capable of activating Janus kinase signaling pathways, nuclear factor signaling pathways, and C-reactive protein (CRP) transcription. CRP tests are commonly used in cancer care to predict prognosis, as activation of the Janus kinase and nuclear factor signaling pathways can  aid in tumor expansion and metastasis. Additionally, high-sensitivity CRP tests (hsCRP) are able to identify small amounts of CRP in blood samples.

One recent study assessed the association between these inflammatory biomarkers (IL-6, TNF-a, and hsCRP) with CRC recurrence and mortality in 1,494 stage III colorectal cancer (CRC) patients. This was the largest study assessing the relationship between these inflammatory biomarkers and CRC survival as of yet. 

While the study recruited a diverse sample of individuals, the final sample was overwhelmingly White (82.3%) and non-Hispanic (94.5%). Future studies should prioritize racial diversity to more accurately assess this association, as racial disparities exist in CRC diagnoses and outcomes. 

Researchers collected plasma samples from participants 3-8 weeks following their surgery but prior to chemotherapy. These plasma samples were then analyzed for IL-6, TNF-a, and hsCRP. The primary study outcome was disease-free survival and secondary outcomes were recurrence-free survival and overall survival. Participants who had higher concentrations of IL-6, TNF-a, and hsCRP were more likely to have CRC recurrence. High levels of these biomarkers were also found to be associated with an increased risk of mortality.

This study reveals that there is a significant association between inflammation following stage III diagnosis and poor CRC outcomes. Clinicians can utilize this information to better monitor their patients and improve CRC outcomes with evidence-based treatment solutions.

Emma Edwards is a Colorectal Cancer Prevention Intern with the Colon Cancer Foundation.

/by
, , ,

Can Circulating Tumor DNA Predict Who Will Benefit from Colorectal Cancer Chemotherapy?

Over 30% of patients with stage II or stage III colorectal cancer (CRC) and 60-70% of patients who undergo oligometastatic resection experience cancer recurrence. Stage II or III CRC is usually treated with surgery followed by adjuvant chemotherapy (ACT). However, patients with clinical and pathological risk factors only see a 10-15% decrease in cancer recurrence with standard ACT. 

Now, a new study proposes using circulating tumor DNA (ctDNA) as a predictive biomarker to guide chemotherapy treatment decisions in CRC patients. 

ctDNA is a minimally invasive biomarker that can help oncologists measure disease status and progression during cancer therapy, including the detection of molecular residual disease (MRD). In this study, researchers evaluated whether ctDNA following surgery could predict disease recurrence in early-stage CRC. 

The study enrolled 1,563 patients with:

  • Stage II or III CRC 
  • Surgically resectable stage IV CRC 
  • Recurrent CRC were prospectively enrolled in the study 

Blood samples were collected before and at predetermined time intervals after surgery (up to 18 months), and imaging was performed every six months until 18 months after surgery. MRD, defined as ctDNA positivity after surgery or therapy, is strongly associated with poor prognosis in patients with surgically resectable CRC. Of the 1,039 patients included in the ctDNA analysis, 18.0% were ctDNA positive four weeks after surgery.

Researchers discovered that patients with high-risk stage II, stage III, and stage IV CRC, who were ctDNA-positive four weeks after surgery, benefited from ACT. ctDNA was identified as the most significant risk factor for CRC recurrence in these patients, and ctDNA positivity is an important predictor of ACT benefit. 

Regardless of the pathological stage of CRC, patients with a higher risk of recurrence based on ctDNA status may benefit from ACT, while those with negative ctDNA status may be able to avoid unnecessary ACT. These findings can guide clinicians in making evidence-based treatment decisions for CRC patients.

 

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

/by
, , , ,

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.

/by
, , ,

Studies at ASCO Point to Biomarker-Directed Treatment for Colorectal Cancer

CCCF Research

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, several research studies were presented that shared a targeted approach to colorectal cancer (CRC) treatment that can ensure efficacy and reduction of side effects. The infographic below highlights those studies and their key findings.

Left column:
Right column:
/by
, ,

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. 

/by
, , ,

In Conversation With Dr. Rami James Aoun: Biomarkers for Radiation Response in Rectal Cancer

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.

 

/by