Disclosures: Cercek reports advisory board roles with Array BioPharma and Bayer and research funding from Rgenix, Seattle Genetics and Tesaro/GlaxoSmithKline. Please see the study for all other authors’ relevant financial disclosures. Eng and Hochster report no relevant financial disclosures.
August 18, 2021
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Early-onset colorectal cancer may not be biologically different from average-onset disease

Disclosures: Cercek reports advisory board roles with Array BioPharma and Bayer and research funding from Rgenix, Seattle Genetics and Tesaro/GlaxoSmithKline. Please see the study for all other authors’ relevant financial disclosures. Eng and Hochster report no relevant financial disclosures.
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Early-onset colorectal cancer did not appear genomically distinct from average-onset disease, according to results of a retrospective, single-institution analysis published in Journal of the National Cancer Institute.

The findings indicate more aggressive treatment for early-onset colorectal cancer is neither necessary nor effective, researchers noted.

Andrea Cercek, MD, medical oncologist, section head of colorectal cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center

“This suggests that, biologically, the tumors are the same,” Andrea Cercek, MD, medical oncologist, section head of colorectal cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center, told Healio. “What we still do not know, and what research should focus on, is why there are changes in the intestinal lining that are leading to the development of colorectal cancer so much earlier in life.”

Cercek and colleagues pursued the work because of the increase in colorectal cancer cases among individuals aged younger than 50 years during the past quarter century.

“It is a worldwide phenomenon, and the reasons behind this rise are unknown,” Cercek said. “In order to determine why this is happening — and, more importantly, how we can identify individuals at risk and improve outcomes in these patients — we need to know if this is the same disease that we see in older ‘average-onset’ individuals occurring decades earlier than it used to, or if it is a completely new disease.”

The analysis included 1,446 patients aged younger than 50 years with a pathologic diagnosis of colorectal cancer from January 2014 to June 2019 at Memorial Sloan Kettering Cancer Center. Researchers assessed clinical characteristics across three groups in order to elucidate the differences in age at diagnosis: Two groups included those with early-onset disease, diagnosed at age 35 years or younger (n = 151; median age, 31 years; range, 14-35; 51% women; 74.8% white) or between the ages of 36 and 49 years (n = 608; median age, 44 years; range, 36-49; 57.1% men; 78.1% white). The third group included those with average-onset colorectal cancer, diagnosed at age 50 years or older (n = 687; median age, 61 years ; range, 50-93; 53.9% men; 81.7% white).

Cercek and colleagues excluded patients with mismatch repair-deficient tumors, colorectal cancer-related hereditary syndromes and inflammatory bowel disease from all but the germline analysis.

Results showed significantly higher percentages of patients with early-onset disease had left-sided tumors (aged 35 years, 80.8%; 36-49 years, 83.7%; 50 years, 63.9%), rectal bleeding (41.1% and 41% vs. 25.9%) and abdominal pain (37.1% and 34% vs. 26.8%).

However, researchers observed no differences in histopathologic tumor characteristics among microsatellite-stable tumors. Although researchers initially observed differences in TP53 and receptor tyrosine kinase signaling pathway alterations by age, multivariable analysis showed no statistically significant differences at the gene or pathway level.

When comparing clinical outcomes of the three groups in response to therapy and survival — focusing on patients with microsatellite-stable tumors who had metastatic disease — Cercek and colleagues found the cohorts had similar use and type of first-line chemotherapy, site of first metastases and metastastectomy frequency, so these factors did not confound survival data.

Radiographic response to first-line chemotherapy and median OS did not differ statistically among the three cohorts.

Researchers identified pathogenic variants in 23.3% of patients aged 35 years and younger vs. 14.1% of patients with average-onset disease (P = .01)

“These findings have several important clinical implications,” Cercek told Healio. “Often, young patients receive more aggressive chemotherapy due to concerns of more aggressive disease; however, we demonstrated that responses to chemotherapy are similar to those of average-onset patients and, therefore, more aggressive therapy just adds toxicity and does not change outcomes. This has been supported by other studies, as well, including the recent analysis of the IDEA data in early-stage disease.”

Future research should target the why, what and how questions that result from these findings, Cercek said.

“If we accept that the disease is not ‘new’ but rather the same disease occurring decades earlier, research should focus on elucidating why this is happening, what potential environmental changes are causing these cancers to form and how we can identify individuals at risk,” she said.

The results also reaffirm “the importance of germline testing in young adults,” along with the need for a referral for genetic counseling for evaluation, with physicians from all specialties diligently reviewing the family history of their young patients, Cathy Eng, MD, FACP, FASCO, co-leader of the gastrointestinal cancer research program, David H. Johnson chair in surgical and medical oncology, and director of the young adult cancers initiative at Vanderbilt-Ingram Cancer Center, and Howard S. Hochster, MD, FACP, distinguished professor of medicine, associate director for clinical research and director of GI oncology at Rutgers Cancer Institute of New Jersey, and director of oncology research at RWJBarnabas Health, wrote in an editorial that accompanied the study.

“It is our duty as medical providers to discuss real-world topics that are often underrecognized and may be difficult to discuss, such as family planning, fertility, sexual dysfunction, psychosocial issues, job security, mental health, overall quality of life and longevity,” Eng and Hochster wrote. “For many of us who have been assisting in the care of these young adults, we serve as their voices in the medical community.”

References:

Cercek A, et al. J Natl Cancer Inst. 2021;doi:10.1093/jnci/djab124.
Eng C and Hochster H. J Natl Cancer Inst. 2021;doi:10.1093/jnci/djab127
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For more information:

Andrea Cercek, MD, can be reached at Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: cerceka@mskcc.org.