Although cancer incidence and mortality rates for all cancers combined are considerably lower in younger adults than older adults, a disturbing pattern is beginning to emerge in the development of early-onset cancers, typically diagnosed in older patients, occurring in younger adults. The rising rates of obesity in the United States may be a key contributing factor in this trend—the prevalence of obesity is about 19% among children and adolescents between the ages of 2 and 19; 40% among adults between the ages of 20 and 39; 45% among adults between the ages of 40 and 59; and 43% among adults aged 60 and older1 and going up in all adult age groups. New research has found that by 2030, nearly one in two adults will have obesity.2
According to a recent study by the American Cancer Society and the National Cancer Institute, from 1995 to 2014, the incidence significantly increased for 6 of 12 obesity-related cancers—multiple myeloma, colorectal, uterine corpus, gallbladder, kidney, and pancreatic—in young adults between the ages of 25 and 49, with steeper increases seen in progressively younger ages and in successively younger generations.3
“We suspect that obesity might be one of the contributing factors for the increase in these cancers,” said Hyuna Sung, PhD, principal scientist and cancer epidemiologist in the Surveillance and Health Services Research Program at the American Cancer Society and lead author of this study. “Considering the latency period from the timing of exposure to cancer development, the impact of the obesity epidemic among youth may not have been fully manifested in the current cancer trends. The future burden of obesity-related cancers will likely increase in the population overall, as the younger birth cohorts at increased risk for cancer age enter the older age group.”
Weighing Risk Factors for Early-Onset Cancers
However, obesity alone does not fully explain the rise in early-onset cancers, especially colorectal cancer, in younger people. Other risk factors, such as smoking, diet, the microbiome, and lack of access to high-quality health care and screening, are also contributing to the development of early-onset cancers in this population.
In addition to colorectal cancer, which has seen an uptick of 2.2% a year from 2011 to 2016 in people younger than age 50,4 other cancers usually diagnosed in older individuals, including lung, pancreatic, breast, and multiple myeloma, are also now being found in younger adults. Although the incidences of these cancers in younger adults remain small, they are worth investigating in greater detail.
We asked five experts in these cancers to offer their perspective on the rise in early-onset cancers and their impact on young adults: Judy C. Boughey, MD, Professor of Surgery and a surgical oncologist at Mayo Clinic, Rochester, Minnesota; Benjamin A. Weinberg, MD, Assistant Professor of Medicine, Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center at Georgetown University; Geoffrey R. Oxnard, MD, a thoracic oncologist at Dana-Farber Cancer Institute [Editor’s Note: Since this interview was conducted, Dr. Oxnard has taken a position at Foundation Medicine as Vice President, Global Medical Lead, Liquid Franchise]; Caitlin Costello, MD, Associate Clinical Professor of Medicine at Moores Cancer Center at UC San Diego Health; and Brian M. Wolpin, MD, MPH, Director, Gastrointestinal Cancer Center and the Robert T. and Judith B. Hale Chair in Pancreatic Cancer at Dana-Farber Cancer Institute.
Why Younger Women Have More Advanced and Aggressive Breast Cancers
With the exception of skin cancer, breast cancer is the most common cancer found in women in the United States. In 2020, about 276,480 new cases of invasive breast cancer will be diagnosed in women, and more than 42,000 will die of the disease.5 Although less than 2% of breast cancers are detected in adolescents and young adults (AYAs), they are usually the more aggressive types of breast cancer, including HER2-positive and triple-negative, and more advanced when diagnosed, according to a study by Dr. Boughey and her colleagues.6
Among the AYAs studied, the very young (those between the ages of 15 and 29) had more advanced cancer at diagnosis and more cases of triple-negative or HER2-positive cancers than older patients (between the ages of 30 and 39). The study also found that these younger patients underwent higher rates of mastectomy and more aggressive chemotherapy than patients in their 40s.
“The study results reflect what we are seeing in practice. Women younger than age 30 are more likely to have aggressive breast cancers than women in their 70s; the tumors in the older women are usually smaller, indolent, estrogen receptor–positive tumors that respond well to lumpectomy and endocrine therapy,” said Dr. Boughey. However, why these cancers are developing in such young patients remains unclear.
Dr. Boughey continued: “I do not know why adolescents and young adults are more likely to develop more aggressive breast cancers. However, to answer that question, over the next 5 to 10 years, we are going to see significant advances in our understanding of tumor biology, patient and tumor genetics, and the tumor microenvironment within the breast, as well as the proteomics and epigenetics involved in the development of breast cancer.”
Increasing Survival Odds
In the study, which analyzed demographics, tumor characteristics, and treatment variables among AYAs retrieved from the National Cancer Database, Dr. Boughey and her colleagues found that 48.2% of the patients between the ages of 15 and 29 presented with stage 2 breast cancer at diagnosis, and 17.3% had stage 3 disease. For patients between the ages of 30 and 39, 43.8% were diagnosed with stage 2 disease, and 13.6% were diagnosed with stage 3 cancer. For the control patients, those between the ages of 40 and 49, the rates were 29.9% and 7.7%, respectively.
“Over the next 5 to 10 years, we are going to see significant advances in our understanding of tumor biology, patient and tumor genetics, and the tumor microenvironment within the breast.”— Judy C. Boughey, MD
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Age was also a factor in treatment decisions, with the youngest group of patients opting more often for mastectomy, 75.4%, compared with 68.5% for those between the ages of 30 and 39. AYAs were also more likely to undergo chemotherapy if they had invasive disease, compared with patients between the ages of 40 and 49.
“I think younger patients want to do anything that will give them the best advantage in cancer survival. Older patients may view their risks and benefits differently,” explained Dr. Boughey. “A 30-year-old who may live to be 100 has 70 years to have a recurrence in the breast and is facing 40-plus years of annual mammograms, so I think these patients tend to opt for more aggressive therapy in terms of mastectomy than older patients.”
Is the Microbiome a Clue to the Steep Increase in Colorectal Cancer in Young Adults?
Although alarms about the increase in colorectal cancer among people younger than age 50 have been sounding for years, the shocking death of actor Chadwick Boseman from the cancer at age 43 has renewed concern about a disease that has seen declines in both incidence and mortality among people older than 65 by 3.3% annually and 3% annually, respectively. Among individuals younger than age 50, the incidence rate has risen by about 2% annually, and death rates have increased by 1.3% annually.4
Colorectal cancer is the second most common cause of cancer death in the United States. In 2020, approximately 147,950 people will be diagnosed with colorectal cancer, and 53,200 will die of the disease, including 17,930 cases and 3,640 deaths in individuals younger than age 50.4
A study presented at the 2020 Gastrointestinal Cancers Symposium comparing colorectal cancer in patients aged 45 and younger and aged 65 and older offered a tantalizingclue about what may be driving the increases in young-onset colorectal cancer, especially in the distal colon and rectum (left-sided colorectal cancer).7 According to the study results, certain bacteria may disrupt colonic luminal integrity and promote inflammation in the colon, leading to oncogenic mutations in colonic epithelial cells.
In the study, Fusobacterium nucleatum, an oral bacterium that promotes colorectal cancer by suppressing an immune response within the tumor microenvironment by activating the Wnt/beta-catenin signaling pathway and causing chemoresistance due to autophagy, was found in a greater number of colorectal cancer tumors in patients diagnosed before the age of 45. Another type of bacteria, Moraxella osloensis, was found at a nearly fourfold higher rate in patients older than 75 than in those younger than 45. This finding illustrates how differences in the bacteria in the body’s microbiome could influence the development of colorectal cancer.7
“Many people want to blame the increase in early-onset colorectal cancer on the epidemics in obesity, diabetes, and metabolic syndrome, but we have patients in their 30s and 40s with none of these conditions who are often diagnosed with left-sided, late-stage colorectal cancer,” said Dr. Weinberg. “We know a lot of young adults tend to develop more left-sided colon cancers—those found in the descending colon, sigmoid colon, and rectum—and older patients tend to develop more right-sided colon cancers near the liver. We know there are genetic differences and clinical differences between left- and right-sided colon cancers, but when we performed genetic studies on these tumors in younger vs older patients, with the exception of hereditary diseases such as Lynch syndrome, we did not find dramatic genetic differences between the two patient groups.”
Dr. Weinberg continued: “So, if it’s not genetics, something else must be involved in the development of this cancer in younger adults. We are doing additional research to investigate the potential role of the microbiome in early-onset colorectal cancer.”
“We are doing additional research to investigate the potential role of the microbiome in early-onset colorectal cancer.”— Benjamin A. Weinberg, MD
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New Insights Into Lung Cancers in Younger Patients, Especially Women
Although lung cancer in younger adults is relatively rare, approximately 10% of lung cancers are diagnosed in people younger than age 55, with the rates dramatically dropping with every preceding decade, going down to 1.4% in people younger than age 35.8,9 The cancer is decidedly different in these patients compared with older adults. For instance, young adults (aged 40 and younger) have a higher frequency of tumors with targetable genomic alterations. And, survival is worse, except for in patients older than age 70, regardless of whether a targetable genotype is present, according to a study by Dr. Oxnard and his colleagues.
Dr. Oxnard’s study found that gene mutations in EGFR, ALK, ERBB2, and ROS1 were associated with a diagnosis of non–small cell lung cancer at a younger age. The study also showed that these patients had poorer survival compared with other age groups, suggesting a more aggressive disease biology.10
In addition, a recent study by the American Cancer Society and the National Cancer Institute investigating lung cancer incidence across 40 countries found that women between the ages of 30 and 49 are being diagnosed with lung cancer at higher rates than men of the same age, even though the rates of smoking were similar in both genders.11 What is driving these increased incidences of lung cancer in younger adults?
One possibility may be greater awareness of the cancer in this age group. “There may be an actual increase in incidence of young-onset lung cancer, but the other possibility is there is an increased awareness and appreciation of this phenomenon, and I’m not sure which is true,” said Dr. Oxnard. “About 10 or 20 years ago, the dominant narrative about lung cancer was that it was caused by smoking, and I wonder whether young individuals diagnosed with lung cancer were blended into that dominant narrative. What has happened since then is that we’ve discovered the incredible variety of lung cancer biology and the various clinical factors that impact lung cancer biology. So, it is also possible that we are now able to see young-onset lung cancer in a new light.”
Genomic Differences in Early-Onset Lung Cancer
What is indisputable, said Dr. Oxnard, is these lung carcinomas are genetically different from those found in older adults and are more aggressive. However, it is not clear whether the cancer has more aggressive biology in younger patients or is found at more advanced stages, when a cure is more difficult.
“It doesn’t cross the mind of young patients that they could have lung cancer, and early symptoms can often be dismissed as a respiratory infection, so the cancer is often diagnosed at a later stage. Also, younger people tend to have poor or no health insurance compared with older patients and may have a more difficult time accessing medical advances.”
A genetic predisposition to the cancer may also be playing a much larger role in the development of lung cancer in younger vs older adults than previously thought. “As environmental lung cancer decreases in prevalence, we need to better understand the genes that may predispose young people to develop this cancer because inherited lung cancer risk might be growing,” continued Dr. Oxnard. “The persistent problem with young-onset lung cancer is not going away and requires us to revisit the epidemiology of why lung cancer happens in folks who do not fit the dominate narrative for the disease. With modern genomic technology, we now have an opportunity to figure out the inherited genetics of young-onset lung cancer and also to identify other causes of the cancer in younger adults.”
What Influences Outcomes in Young-Onset Multiple Myeloma?
Although a rare hematologic malignancy, multiple myeloma is the second most commonly diagnosed blood cancer, after non-Hodgkin lymphoma, in the United States. Despite treatment advances over the past 2 decades, which have extended survival for patients with multiple myeloma, the cancer remains incurable. This year, about 32,270 new cases of multiple myeloma will be diagnosed, and nearly 13,000 people will die of the disease.12 Although the cancer is largely a disease found in people aged 70 and older—about 37% of patients are younger than age 65 and approximately 2% are younger than age 40—the overall incidence of the cancer appears to be increasing among all age groups, especially in young adults between the ages of 40 and 49 and in young adult women.13
Some studies have suggested that multiple myeloma in young adult patients is also associated with high-risk features and worse outcomes, possibly because the cancer is usually found at a more advanced stage in these patients. However, other studies have shown that younger patients have as good a prognosis or better than older patients.
A small retrospective study conducted by Dr. Costello found that patients aged 40 and younger exhibited several high-risk features, including extramedullary plasmacytomas. These younger patients had a median overall survival of 60.7 months compared with 78.6 months for patients aged 41 and older,
despite all patients receiving at least one treatment with a novel agent, 15 patients receiving high-dose therapy, and 4 patients receiving an allogeneic stem cell transplant after at least one prior autologous stem cell transplant.13
How Myeloma Affects Younger vs Older Patients
“There are differences in the retrospective data published on myeloma in younger adults,” said Dr. Costello. “When we looked at our data, we found that our patients were presenting with much more advanced disease in terms of the extent of bone disease, renal failure, and rarer findings in multiple myeloma, including extramedullary plasmacytomas and primary plasma cell leukemia, and there was a trend toward worse outcome. Ours was a small study of only about 20 patients, so I hesitate to make broad generalizations of our findings when there are larger prospective cohort studies showing better survival for younger patients.”
Dr. Costello proposed: “In trying to understand differences in outcomes, it may be that younger patients are generally healthier than older patients and may have fewer comorbidities and can tolerate more aggressive treatment, allowing for improved outcomes.
There are several large prospective observation studies underway, including Connect MM—The Multiple Myeloma Disease Registry (ClinicalTrials.gov identifier NCT01081028) and the INSIGHT MM Study (NCT02761187), which include many thousands of patients. “We will be able to pull data from subgroups of patients in these studies and, hopefully, answer many of the questions about how myeloma affects younger vs older patients and whether there are any biologic differences in the cancer in different ages,” said Dr. Costello. “One thing is clear: The average age of diagnosis in myeloma is declining. We just don’t know the reason.”
“One thing is clear: The average age of diagnosis in myeloma is declining. We just don’t know the reason.”— Caitlin Costello, MD
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Assessing Risk Factors for Early-Onset Pancreatic Cancer
Pancreatic cancer is the third-leading cause of cancer-related death in the United States, surpassing breast cancer, and, for all stages combined, the 5-year survival rate is a dismal 9%. Although treatment options, including surgery, radiation therapy, and chemotherapy, can extend survival, the majority of patients present with advanced-stage disease, when a cure is generally not possible.
Although a diagnosis of pancreatic cancer in individuals aged 45 and younger is rare—less than 3%—the total burden of the disease on young adults compared with older adults can be significantly greater because of the number of years of potential life lost. Studies have shown that a number of risk factors might be responsible for the development of early-onset or very early–onset—defined as patients younger than age 60 and 45, respectively—pancreatic cancer. Among the top risk factors is obesity, which, according to a study by the American Cancer Society and the National Cancer Institute, accounted for an increase (on average) of 4.3% in people between the ages of 25 and 29.3 Smoking, diabetes, heavy alcohol use, family history, and BRCA1/2 gene mutations may all
contribute to the development of pancreatic cancer, although there have not been large studies to determine the specific risk factors for the cancer in younger adults.
Linking Obesity to Pancreatic Cancer
“It is difficult to say for certain that obesity directly causes pancreatic cancer, but obesity and type 2 diabetes, which are on the rise in the United States, are clearly associated with an increased risk for pancreatic cancer,” said Dr. Wolpin. “We are also starting to gain a better understanding of the genetic basis of pancreatic cancer.”
At Dana-Farber, Dr. Wolpin noted that about 10% of patients who come to the clinic will have an inherited pathogenic genetic mutation, which is a higher percentage than previously realized. “These patients, on average, present with pancreatic cancer at an earlier age than people who do not have germline-associated tumors,” he said. “However, the age differential is not nearly as profound as what we see for these mutations in other cancer types, such as breast and ovarian.”
Although the percentage of younger adults diagnosed with pancreatic cancer is still modest, it is worth noting, according to Dr. Wolpin. “The incidence of pancreatic cancer is rising across all ages, including younger individuals, and, therefore, having knowledge about this disease in younger adults is important. We don’t have the depth of data on this patient population in pancreatic cancer that we do in early-onset colorectal and lung cancers, but this is an area for substantial additional research.”
DISCLOSURE: Dr. Sung reported no conflicts of interest. Dr. Boughey has received institutional research funding from Eli Lilly. Dr. Weinberg has received honoraria from OncLive, Rafael Pharmaceuticals, and Tempus; has served as a consultant or advisor to Bayer; has participated in a speakers bureau for Bayer, HalioDx, Lilly, Sirtex, and Taiho Pharmaceutical; has received institutional research funding from AbbVie, Ipsen, Isofol Medical, and Novartis; has provided expert testimony on behalf of AstraZeneca; and has been reimbursed for travel, accommodations, or other expenses by Boehringer Ingelheim and Caris Life Sciences. Dr. Oxnard is an employee of Foundation Medicine and has equity in Roche Pharmaceuticals. Dr. Costello has received research support from Celgene, Janssen, Poseida Therapeutics, and Takeda and has received honoraria for consultancy from Celgene, Takeda, Oncopeptides, and Karyopharm. Dr. Wolpin has received honoraria from Celgene and G1 Therapeutics; has served as a consultant or advisor to BioLineRx, Celgene, G1 Therapeutics, Genentech, and GRAIL; and has received research funding from Celgene and Eli Lilly.
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