Dr Kamath on the Rationale for Investigating Early-Onset vs Average-Onset PDAC

Suneel Kamath, MD, assistant professor, medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, discusses the rationale for conducting an investigation into the tumor microbiome differences between early-onset and average-onset pancreatic ductal adenocarcinoma (PDAC), highlighting next steps with this research.

Findings from this investigation were presented at the 

. The study examined resected PDAC specimens classified by age at diagnosis, using metagenomic sequencing to identify bacterial and fungal microbiomes. The key findings indicated that early-onset PDAC had higher bacterial alpha diversity, and average-onset PDAC had higher fungal alpha diversity. Furthermore, there were significant differences in beta diversity and the relative abundance of top genera between early- and average-onset disease, highlighting distinct microbiome signatures.

The rationale behind the study was based on the observation that the incidence of several cancers, including pancreatic cancer, has substantially increased among younger people over the past few decades, Kamath begins. Although significant research has focused on this trend in cancers such as colorectal cancer, pancreatic cancer has received less attention, he says, adding that one goal of this study is to understand why more young people are developing pancreatic cancer now compared with in previous decades.

It is important to identify specific microbiome- and immune-based signatures of early-onset PDAC, Kamath continues. Investigators hope to use this information in 2 ways. First, these findings may be used to develop screening tests that can identify unique signatures of early-onset pancreatic cancer and distinguish patients with this disease from healthy individuals, enabling effective screening of younger populations, he reports. The microbiome is easily measured in plasma, stool, and other specimens, making it convenient to use for screening purposes, Kamath elucidates.

Second, investigators aim to develop more personalized treatments for patients with early-onset pancreatic cancer, who often present with advanced metastatic disease and poor outcomes, according to Kamath. By achieving early detection and creating tailored interventions, researchers hope to improve treatment outcomes for this disease, he concludes.

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Suneel Kamath, MD, discusses the rationale for conducting an investigation into the tumor microbiome differences between early- and average-onset PDAC.

Dr Kamath on the Tumor Microbiome of Early- and Average-Onset PDAC

Suneel Kamath, MD, assistant professor, medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, discusses tumor microbiome differences in early-onset vs average-onset pancreatic ductal adenocarcinoma (PDAC).

, investigators presented data from an investigation on the tumor microbiome differences between early-onset and average-onset disease. The study used resected pancreatic cancer specimens categorized by the age of diagnosis and performed shotgun metagenomic sequencing to identify bacterial and fungal microbiomes. The key findings revealed that early-onset PDAC exhibited higher bacterial alpha diversity, and average-onset PDAC showed higher fungal alpha diversity. Additionally, significant differences in beta diversity and the relative abundance of top genera were observed between early- and average-onset disease, indicating distinct microbiome signatures.

The findings indicated that higher bacterial diversity in early-onset PDAC correlated with better survival, highlighting the microbiome’s potential as a prognostic biomarker. However, the study faced limitations, including selection bias due to the need for surgically resected specimens and inherent challenges with shotgun sequencing. Despite these limitations, the study provides evidence supporting the role of the microbiome in PDAC, with potential implications for screening, predicting therapy responses, and prognostication.

Kamath says that investigators examined specimens from 44 patients, including 24 with early-onset PDAC and 20 with average-onset disease. Investigators compared specimens from the tumors with those from the adjacent normal tissues, Kamath reports, sharing that findings revealed that the early-onset group exhibited a higher degree of alpha diversity in their pancreatic cancer microbiomes compared with the microbiomes of both adjacent normal tissue and the average-onset group. This indicates that a higher degree of alpha diversity might reflect a more robust and varied microbiome, potentially indicating a broader and richer immune system profile typical of younger individuals, according to Kamath.

Additionally, researchers identified that certain bacterial species were more prevalent in early-onset pancreatic cancer, specifically enterobacter, neisseria, and escherichia genera, he explains. In contrast, Klebsiella and Bacillus genera were more commonly found in average-onset pancreatic cancer, Kamath concludes.

Suneel Kamath, MD, discusses tumor microbiome differences between early-onset and average-onset pancreatic adenocarcinoma.

Suneel Kamath, MD, assistant professor of Medicine, the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, discusses the prevalence of 

 fusions or rearrangements in cholangiocarcinoma.

 fusions and rearrangements are the most sensitive, and they present in approximately 10% to 15% of patients with intrahepatic cholangiocarcinoma, according to Kamath, who adds that rates of intrahepatic cholangiocarcinoma are higher than extrahepatic cholangiocarcinoma in the United States. Rates of 

 fusions and rearrangements are significantly lower in extrahepatic cholangiocarcinoma and gallbladder cancers, Kamath explains.

RLY-4008, an FGFR2 inhibitor selective for FGFR2, is under exploration in patients with cholangiocarcinoma harboring an 

Within the current treatment landscape for cholangiocarcinoma, 3 pan-FGFR inhibitors are available, Kamath continues. Although pan-FGFR inhibitors target 

, causing toxicities associated with the activity on those genes, Kamath concludes.

Suneel Kamath, MD, discusses the prevalence of FGFR2 fusions or rearrangements in cholangiocarcinoma.


Dr. Kamath on the Prevalence of FGFR2 Fusions/Rearrangements in Cholangiocarcinoma

Suneel Kamath, MD, assistant professor of Medicine, the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, discusses the importance of including underrepresented patient populations in clinical trials.

Including underrepresented groups in clinical trials helps those patients become voices for their communities at large by advocating for additional participation, Kamath says. Patients from underserved communities who do enroll in clinical trials benefit the most, and they can serve as examples of how clinical trials can provide necessary treatment, Kamath explains.

Clinical trials are a beneficial avenue for patients to voice their opinions, receive beneficial treatment, and help advocate for more inclusion, Kamath concludes.

Suneel Kamath, MD, discusses the importance of including underrepresented patient populations in clinical trials.


Dr. Kamath on the Inclusion of Underrepresented Groups in Clinical Trials

Despite a steady decline in incidence and mortality rates of many cancers among older individuals in the United States and other high-income countries, an alarming rise in young-onset gastrointestinal (GI) cancers has simultaneously occurred.

 The incidence of young-onset colorectal cancer has risen by 51% since 1994.

 As a result, approximately 11% of all new diagnoses of colorectal cancer occur in individuals younger than 50 years.

Increasing incidence rates of young-onset pancreatic cancer and gastric cancer also have been reported.

 An analysis of pancreatic cancer data from the Surveillance, Epidemiology, and End Results Program database from 2000 to 2018 showed that although the overall incidence rate has increased slightly, a significantly greater increase in incidence occurred in women younger than 55 years. Women aged 15 to 34 years were affected most, with an average relative annual increase of 7.68%.

 Our analysis of gastric cancer data from the National Cancer Database (NCDB) from 2004 to 2015 found the proportion of patients with young-onset gastric cancer increased from 23.9% from 2004 to 2006 to 26.2% from 2013 to 2015, a relative increase of 10%.

Young-onset malignancies are particularly devastating because they affect individuals in the prime of their lives and careers, often as they have responsibilities including raising young children and/or caring for aging parents. These patients often present at advanced stages because of delays in diagnosis, leading to a larger number of person-years of life lost compared with average-onset cancer diagnoses.

 Financial toxicity is also a major issue facing younger patients who are often at the start of their careers and may have more limited savings or have chosen insurance plans with reduced coverage compared with older patients.

Lack of awareness of the recent trends in young-onset GI cancers can lead patients and their physicians to think they are too young to have cancer despite having clear signs and symptoms. A survey of 1089 patients, survivors, and caregivers found that 62% of respondents waited 3 to 12 months after symptom onset to seek medical attention. Further, 75% of respondents said they saw at least 2 physicians and 20% saw 4 or more physicians about symptoms that eventually led to their diagnosis.

 We can do better in educating the public about the increasing rates of young-onset GI cancers so more patients will seek medical attention promptly. We as physicians also must be prepared to take alarm symptoms in younger individuals more seriously. 

Young-onset GI cancers appear to disproportionately affect racial and ethnic minority populations compared with White patients. For example, the previously mentioned study of gastric cancer data from the NCDB demonstrated that compared with late-onset gastric cancer, young-onset gastric cancer disproportionately affects Hispanic patients vs White patients (22.4% vs 7.2%, respectively; P < .0001) and Black patients vs White patients (16.7% vs 12.7%; P < .0001).

Another analysis of NCDB data on young-onset colorectal cancer from 2004 to 2015 found a disproportionate effect of young-onset disease on Black patients (15.1% vs 11.6%; P < .0001) and Hispanic patients (8.6% vs 5.0%; P < .0001) vs White patients. In terms of young-onset gastric cancer and colorectal cancer, Black patients experienced worse outcomes compared with White patients. 

Although socioeconomic disparities play a role, our analyses found the greatest disparities in young Black patients with colorectal cancer who had private insurance and lived in middle or high socioeconomic status communities. Only those who lived in the very highest socioeconomic status communities experienced similar outcomes compared with their White counterparts.

The causes for the alarming trends in young-onset GI cancers remain unknown and are likely multifactorial. Certain risk factors such as obesity, sedentary lifestyle, diets high in red meat and processed foods, smoking, and alcohol consumption are associated with higher rates of many GI cancers, particularly colorectal and gastroesophageal cancers. However, these risk factors are not unique to the young-onset population, suggesting other unidentified factors must play a role. As we would expect, a higher proportion of young-onset GI cancers are associated with hereditary cancer syndromes, but surprisingly the majority are still sporadic and occur in the absence of a family history of cancer.

A series that included 759 patients with young-onset colorectal cancer (458 of whom underwent germline testing) found that only 17.5% of patients had a germline pathogenic or likely pathogenic variant.

 Other published series have found no clinically meaningful tumor genomic differences between young-onset and average-onset colorectal cancer.

 Data from Cleveland Clinic have shown that young-onset colorectal cancers are more likely to have mutations in FLT3 compared with average-onset colorectal cancers (12% vs 4%, respectively; P = .004). However, our sample size was small with 262 patients (51 had young-onset disease), and it is unclear whether this magnitude of difference is clinically meaningful.

There is a great deal of speculation about other potential causes for the recent trends in young-onset GI cancers. It is likely that some undiscovered environmental exposures are the culprit. Alterations in gut microbiome are a suspected factor. Obesity and Western diets can alter the gut microbiome, leading to an increase in carcinogenic, sulfur-metabolizing bacteria and a reduction in bacteria that produce short-chain fatty acids, which preserve immune homeostasis and protect against neoplasia.

 Chronic antibiotic use might also alter gut flora and increase the risk of GI tract cancers.

Certain bacterial species have been associated with increased risk for young-onset colorectal cancer, though the data are not consistent. Enterotoxigenic Bacteroides fragilis and the oral f lora pathogen Fusobacterium nucleatum have been associated with increased risk for colorectal cancer in many studies.

 A more recent tumor microbiome analysis of 278 patients (137 with young-onset and 141 with average-onset colorectal cancer) found that young-onset tumors had greater microbial α-diversity compared with average-onset tumors. Young-onset tumors also had a higher relative abundance of Akkermansia muciniphila, which was correlated with improved overall survival.17 Paradoxically, A muciniphila is considered a healthy gut microbe and it is possible this finding is a response to cancer development rather than the cause of it. Overall, there are many preliminary associations in the literature and more work is needed to fully understand how the microbiome affects carcinogenesis in the younger population. It is likely among many factors at play.

One reason that we know so little about the causes for the significant rise in young-onset GI cancers over the past 3 decades is that GI cancers are dramatically underfunded by the National Cancer Institute (NCI) and nonprofit organizations. A study that compared the amount of combined NCI and nonprofit organization funding for 12 of the most common cancers with their individual incidence and mortality rates found that GI cancers were consistently underfunded compared with their burden on society. These data are summarized in the figure. These funding disparities negatively affect the amount of research focused on a particular cancer type and lead to fewer clinical trials studying novel therapies for underfunded cancers.

There are many possible reasons for why GI cancers are underfunded. GI cancers generally have higher mortality rates compared with most cancers, which makes them more challenging from an advocacy, fundraising, and marketing perspective. It is harder to generate a hope-based message and to find success stories for advocacy campaigns when there are fewer survivors. These malignancies also involve internal organs that many may be unaware of or are uncomfortable discussing. We need more funding to raise awareness and to understand why more young individuals are developing GI cancers so we can stop this alarming trend.

Until then, improvements in our screening and early detection strategies are a good first step. The current screening guidelines from the US Preventive Services Task Force and the American Cancer Society both recommend starting colorectal cancer screening at age 45 years because the largest increase in young-onset colorectal cancer has occurred in the 45-year-to-49-year group. Although it is too early to assess the full effect of this update, a recent analysis of the Nurses’ Health Study II cohort has already shown that early initiation of colonoscopy screening before age 50 years is associated with a reduced risk of colorectal cancer.19 For many reasons, it would be challenging to justify endoscopic screening for individuals in their 20s and 30s, but it is possible that one of the many circulating tumor DNA screening assays in development could become a useful, noninvasive tool in the very young patient population. 

In summary, young-onset GI cancers are on the rise and disproportionately affect racial and ethnic minority populations. The reasons for this trend remain unknown but likely relate to environmental exposures rather than genomic differences in the cancer itself. More work is needed to increase funding and awareness for GI cancers so we can better understand and prevent young-onset cancers and find better ways to treat them.

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492

Gaddam S, Abboud Y, Oh J, et al. Incidence of pancreatic cancer by age and sex in the US, 2000-2018. JAMA. 2021;326(20):2075-2077. doi:10.1001/jama.2021.18859

Sinicrope FA. Increasing incidence of early-onset colorectal cancer. N Engl J Med. 2022;386(16):1547-1558. doi:10.1056/NEJMra2200869

Torrejon NV, Deshpande S, Wei W, Tullio K, Kamath SD. Proportion of early-onset gastric and esophagus cancers has changed over time with disproportionate impact on Black and Hispanic patients. 

l Pract. 2022;18(5):e759-e769. doi:10.1200/ OP.21.00692

Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1695-1698. doi:10.1158/10559965.EPI-09-0186

Kamath SD, Torrejon N, Wei W, et al. Racial disparities negatively impact outcomes in early-onset colorectal cancer independent of socioeconomic status. Cancer Med. 2021;10(21):7542-7550. doi:10.1002/cam4.4276

Rydbeck D, Asplund D, Bock D, et al. Younger age at onset of colorectal cancer is associated with increased patient’s delay. Eur J Cancer. 2021;154:269-276. doi:10.1016/j.ejca.2021.06.020

Newcomer KL, Porter LD. A delayed path to diagnosis: findings from young-onset colorectal cancer patients and survivors. J Clin Oncol. 2021;39(suppl 3):5. doi:10.1200/JCO.2021.39.3_suppl.5

Cercek A, Chatila WK, Yaeger R, et al. A comprehensive comparison of early-onset and average-onset colorectal cancers. J Natl Cancer Inst. 2021;113(12):1683-1692. doi:10.1093/jnci/djab124

Lieu CH, Golemis EA, Serebriiskii IG, et al. Comprehensive genomic landscapes in early and later onset colorectal cancer. Clin Cancer Res. 2019;25(19):5852-5858. doi:10.1158/1078-0432.CCR-19-0899 

Torrejon NV, Deshpande S, Wei W, et al. Comparison of comprehensive genomic profiles between young-onset and average-onset colorectal cancer. J Clin Oncol. 2022;40(suppl 4):167. doi:10.1200/ JCO.2022.40.4_suppl.167 

Flemer B, Lynch DB, Brown JMR, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66(4):633-643. doi:10.1136/gutjnl-2015-309595 

Garrett WS. The gut microbiota and colon cancer. Science. 2019;364(6446):1133-1135. doi:10.1126/science.aaw2367 

O’Keefe SJD. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 2016;13(12):691-706. doi:10.1038/nrgastro.2016.165 

Kilkkinen A, Rissanen H, Klaukka T, et al. Antibiotic use predicts an increased risk of cancer. Int J Cancer. 2008;123(9):2152-2155. doi:10.1002/ijc.23622 

Zhang J, Haines C, Watson AJM, et al. Oral antibiotic use and risk of colorectal cancer in the United Kingdom, 1989-2012: a matched case-control study. Gut. 2019;68(11):1971-1978. doi:10.1136/ gutjnl-2019-318593 

Barot SV, Sangwan N, Nair KG, et al. Tumor microbiome variation in young versus average onset colorectal cancer. J Clin Oncol. 2022;40(suppl 4):144. doi:10.1200/JCO.2022.40.4_suppl.144 

Kamath SD. Disparities in government and nonprofit organization funding may hinder clinical trial development for underfunded cancers. J Clin Oncol. 2021;39(suppl 15):1573. doi:10.1200/ JCO.2021.39.15_suppl.1573 

Ma W, Wang M, Wang K, et al. Age at initiation of lower gastrointestinal endoscopy and colorectal cancer risk among US women. JAMA Oncol. Published online May 5, 2022. doi:10.1001/jamaoncol.2022.0883

Articles

Despite a steady decline in incidence and mortality rates of many cancers among older individuals in the United States and other high-income countries, an alarming rise in young-onset gastrointestinal cancers has simultaneously occurred.

Suneel Kamath, MD

Articles

Dr Kamath on the Rationale for Investigating Early-Onset vs Average-Onset PDAC

Dr Kamath on the Tumor Microbiome of Early- and Average-Onset PDAC

Dr. Kamath on the Prevalence of FGFR2 Fusions/Rearrangements in Cholangiocarcinoma

Dr. Kamath on the Inclusion of Underrepresented Groups in Clinical Trials

Efforts Are Needed to Address the Enigmatic Rise of Young-Onset Gastrointestinal Cancers