(2024) 22:363
Cavazzani et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03574-x

BMC Medicine

RESEARCH

Open Access

Cancer incidence (2000–2020)
among individuals under 35: an emerging sex
disparity in oncology
Alessandro Cavazzani1,2,5, Claudia Angelini3, Dario Gregori4 and Luca Cardone1,2*Abstract
Background Aggressive malignancies, such as pancreatic cancer, are increasingly impacting young, female populations. Our investigation centered on whether the observed trends in cancer incidence were unique to pancreaticcancer or indicative of a broader trend across various cancer types. To delve deeper into this phenomenon, we
analyzed cancer incidence trends across different age and sex groups. Furthermore, we explored differences in cancer
incidence within specific young subgroups aged 18 to 26 and 27 to 34, to better understand the emerging incidence
trend among young individuals.
Methods This study collected cancer incidence data from one of the Surveillance, Epidemiology, and End Results
cancer registry databases (SEER22), with 10,183,928 total cases from 2000 to 2020. Data were analyzed through Joinpoint trend analysis approach to evaluate sex- and age-specific trends in cancer incidence. Exposure rates werereported as Average Annual Percentage Changes (AAPCs).
Results The analysis revealed significant age and sex-specific disparities, particularly among individuals aged
18–26 and 27–34. Pancreatic cancer incidence rates increased more in females aged 18–26 (AAPC, 9.37% [95% CI,
7.36–11.41%]; p < .0001) than in males (4.43% [95% CI, 2.36–6.53%]; p < .0001). Notably, among gender, age, and othermalignancies, young females had the highest AAPCs for pancreatic cancer. Additionally, the incidence of gastric cancer, myeloma, and colorectal malignancies also showed higher AAPCs in young females compared to males.
Conclusions Recognizing emerging risk populations for highly lethal malignancies is crucial for early detectionand effective disease management.
Keywords Pancreatic cancer, Gastrointestinal cancer, Incidence data, Young population, Age-sex differences, Risk
populations, Early-onset cancer*Correspondence:
Luca Cardone
luca.cardone@cnr.it; luca.cardone@ifo.it
1
Institute of Biochemistry and Cell Biology (IBBC), National ResearchCouncil (CNR), c/o Campus Internazionale “A.Buzzati-Traverso”, Via E.
Ramarini, 32, Monterotondo Scalo Rome (RM) 00015, Italy
2
Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena
National Cancer Institute, Via Elio Chianesi, 53, Rome 00144, Italy
3
Institute for Applied Computing, National Research Council (CNR),
Naples, Italy
4
Unit of Biostatistics, Epidemiology and Public Health, Universityof Padova, Padua, Italy

5
Present Address: Department of Biology, University of Rome Tor Vergata,00133 Rome, Italy© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Cavazzani et al. BMC Medicine(2024) 22:363

BackgroundThe existence of a significant sex gap in cancer incidence
is a recurring theme in descriptive epidemiology. It has
become increasingly apparent that disparities between
sexes significantly influence cancer occurrence, withmales recognized as having greater vulnerability to thedevelopment of cancer [1–5]. This notion has been challenged by recent studies revealing a higher incidence
trend of pancreatic cancer (PC) among females aged
15–34 years compared to males [6], indicating the emergence of a novel risk population for this aggressive cancer. This observation is concerning as pancreatic cancer
is currently the fourth leading cause of cancer-related
death worldwide [1], and it is anticipated to become oneof the deadliest cancers by 2030, primarily due to limited
therapeutic advancements [7].
Early disease detection in populations at risk of PC
may reduce the mortality rate. Pancreatic cancer primarily affects older adults, with approximately 90% ofcases diagnosed in patients older than 55 years [8, 9]. In
addition, males appear to have higher incidences thanfemales, with this disparity being most pronounced indeveloped nations [9]. Hence, the emerging trend ofincreasing pancreatic cancer incidence among young
female individuals was noteworthy since it underscores
an increasing trend of the early onset of a devastating
disease that has traditionally been considered to primarily affect the older adults. The observed trend of
higher pancreatic cancer (PC) incidence in females aged
15–34 years compared to males was unexpected, as it
deviates from common epidemiological trends typicallyseen in pancreatic cancer. As a possible explanation ofsuch cancer incidences, sex-based disproportional exposure to known or unknown risk factors has been suggested [6]. Possibly, differences in exposure trends by age
and sex to risk factors for pancreatic cancer, such as cigarette smoking, obesity, and diabetes, could have impacted
the population over the last decades. Recently, Yan et al.
analyzed the age-dependent association of risk factors
with pancreatic cancer by implementing prospective
cohorts with patients aged over 30 years, demonstratingthat established risk factors such as cigarette smoking,obesity, and diabetes were most strongly associated withearlier-onset pancreatic cancer in the population aged
60 years or younger [10].
A deeper understanding of this epidemiological trend
in cancer incidence among young populations is crucial
for the early detection or prevention of PC and otheraggressive cancers. This is particularly significant for theincreasing number of younger individuals who are diagnosed with cancer. Our primary objective was to determine whether the increase in cancer incidence among
young individuals, stratified by sex and age, was specificPage 2 of 10

to pancreatic cancer or if it extended to other malignancies. Secondly, we aimed to investigate sex differences incancer incidence within young subgroups to better delineate the emerging risk population among the young. To
achieve this, we conducted an analysis of the SEER22
database, which reports cancer cases from 2000 to 2020.

Methods
Cancer incidence trend analysis

The Surveillance, Epidemiology, and End Results (SEER)
Program is a National Cancer Institute (NCI) instrumentused for cancer surveillance. It collects cancer data fromseveral locations and sources throughout the USA, covering almost 50% of the US population. For the aims ofthis study, SEER*Stat version 8.4.2 was used to calculatedelay-adjusted cancer incidence rates per year. In particular, we considered pancreatic cancer, stomach cancer, lung and bronchus cancers, brain and other nervous
system cancers, myeloma, colon and rectum cancers,
melanoma, cervical cancer, ovarian cancer, breast cancer (female cases only), prostate cancer, and testicularcancer from the SEER22 database, spanning from 2000
to 2020. The patients were stratified into multiple agesex non-overlapping groups. Then, Joinpoint Commandversion 4.9.0.0 (Statistical Methodology and Applications
Branch, Surveillance Research Program, National Cancer
Institute) was implemented in R to run all trend analyses.
Briefly, the simplest Joinpoint models were fit throughMonte Carlo permutation tests on incidence rate data,
and then Average Annual Percentage Changes (AAPCs)
were estimated along with 95% confidence intervals; thesignificance of AAPC values was tested with 2-sided
t-tests, and pairwise comparisons were carried out toevaluate the significance of sex as an interaction factor
against it not being significant.
AAPCs measured in these analyses are summary estimates of the trend over a pre-specified fixed interval.
They allow us to use a single number to describe theaverage APCs over a period of multiple years. They arecomputed as a weighted average of the APCs from the
Joinpoint model, with the weights equal to the length of
the APC interval. More info on the AAPC method canbe found here: https://​surve​illan​ce.​cancer.​gov/​help/​joinp​
oint/​setti​ng- ​param​eters/​method-​and- ​param​eters- ​tab/​
apc-​aapct​au-​confi​dence-​inter​vals/​avera​ge-​annual-​perce​
nt-​change-​AAPC.
Statistical analysis

P-values computed for AAPCs and for sex interactions were corrected for multiplicity using the Benjamini-Hochberg (BH) methodology. In all cases, theresults were considered statistically significant when

Cavazzani et al. BMC Medicine(2024) 22:363

the adjusted p-values resulting from BH correction
were < 0.05.

Results
PC incidence in females aged 18 to 34 years (henceforthdefined as the young group) had a higher Average Annual
Percentage Change (AAPC) increase in incidence (AAPC,
6.22% [95% CI, 5.2–7.24%]; p < 0.0001) than young males(AAPC, 4.04% [95% CI, 2.84–5.26%]; p < 0.0001) with
non-parallel trends (p = 0.017) (Fig. 1A and Table 1).
The AAPC for PC in females aged 18 to 34 years washigher than that in females aged 35 to 54 years (hereafterreferred to as the “Adult group”) (AAPC, 1.53% [95% CI,
1.24–1.82%]; p < 0.0001). Additionally, adult females had
a higher AAPC compared to adult males (AAPC, 0.67%[95% CI, 0.4–0.95%]; p = 0.0001), with non-parallel trends(p = 0.0058). Overall, the AAPC of PC among young individuals was significantly higher than that among adults.
Furthermore, the AAPC of PC incidence in the 55 + years
age group was lower compared to young groups in both
females (AAPC, 0.64% [95% CI, 0.54–0.75%]; p < 0.0001)
and males (AAPC, 0.74% [95% CI, 0.58–0.9%]; p < 0.0001)(Fig. 1A and Table 1).
We then examined the time-trend incidence statistics
for various types of cancer. Among the analyzed tumor
types, young females showed a more significant percentage increase in the incidence of stomach cancer (AAPC,
2.37% [95% CI, 0.47–4.31%]; p = 0.019) compared tomales (AAPC, -0.17% [95% CI, -1.05–0.72%]; p = 0.704),with non-parallel trends (p = 0.024). Similarly, in myeloma, young females exhibited a higher AAPC (AAPC,
2.82% [95% CI, 1.06–4.60%]; p < 0.0045) than males(AAPC, -0.16% [95% CI, -1.52–1.22%]; p < 0.814), alsowith non-parallel trends (p = 0.0073). Colorectal cancer
also demonstrated a moderate relative increase in incidence rates among young females (AAPC, 3.95% [95%CI, 1.85–6.09%]; p = 0.0003) compared to males (AAPC,
3.22% [95% CI, 2.84–3.59%]; p < 0.0001), with non-parallel trends (p = 0.0058). In contrast, AAPC studies on lungand bronchus cancers, brain and nervous system cancers,
and melanoma did not reveal a similar sex-specific trendof incidence growth in the young population (Fig. 1A and
Table 1). Of note, in the 35–54 age group, females also

Page 3 of 10

showed higher AAPC than males for pancreatic andstomach cancer, myeloma, and melanoma.
To investigate whether the heightened incidence wasspecific to certain tumor types or indicative of a shift
in cancer incidence rates based on sex, we also examined the trend in the incidence of sex-specific cancers
over the same period. Young females did not show asubstantial percentage increase in the incidence rate ofcervical cancer (AAPC, -1.0% [95% CI, -1.69 − -0.3%];
p = 0.0068), ovarian cancer (AAPC, 0.71% [95% CI,
0.28–1.13%]; p = 0.0036), or breast cancer (AAPC,
1.16% [95% CI, 0.98–1.13%]; p < 0.0001) (Fig. 1A and
Additional file1: Tables S1). Additionally, the analysisof sex-specific tumors in young males revealed a mild
yet significant increase in AAPC for testicular cancer(AAPC, 1.0% [95% CI, 0.48–1.53%]; p = 0.0003) (Fig. 1A
and Additional file1: Tables S1). Overall, AAPC forpancreatic cancer, gastrointestinal (GI) cancers, andmyeloma in young females ranked the highest among
the investigated sex and age groups, as well as in comparison to other malignancies (Fig. 1B). These data areparticularly relevant, given that these tumors are among
the most lethal types.
To further investigate sex differences in cancer incidence among young subgroups, individuals aged lessthan 34 years were divided into two age subgroups:
18–26 years and 27–34 years. Remarkably, females aged
18 to 26 years exhibited the highest relative increase inincidence rates of pancreatic cancer (AAPC, 9.37% [95%CI, 7.36–11.41%]; p < 0.0001) compared to males (AAPC,
4.43% [95% CI, 2.36–6.53%]; p = 0.0005), with non-parallel trends (p = 0.041). Females aged 27 to 34 years showeda trend of increasing incidence similar to males (AAPC,
4.46% [95% CI, 3.62–5.31%]; p < 0.0001), with parallel
trends (Fig. 2 and Table 2). Therefore, the change of theincidence of pancreatic cancer over time among females
was highest in the 18 to 26 age subgroup. Additionally, a
substantial increase in AAPC was observed in the 27 to
34 age subgroup, albeit not differing by sex.
In the 18–26 age subgroup, females also exhibited
higher AAPC for colorectal cancer incidence rates(AAPC, 6.18% [95% CI, 2.91–9.55%]; p = 0.0004) compared to males (AAPC, 5.15% [95% CI, 4.23–6.07%];p < 0.0001), with non-parallel trends (p = 0.0056) (Table 2).

(See figure on next page.)
Fig. 1 Time trend of incidence for twelve cancer types, including pancreatic cancer, by sex and age. A Sex- and age-specific age-adjusted
incidence rates per 100,000 population for 12 cancer types in the USA, as extracted from SEER22 data. Sex and age are grouped into six categories:
18–34-year-old (yo) males, 18–34yo females, 35–54yo males, 35–54yo females, 55 + yo males, and 55 + yo females. B Sex- and age-specific AAPC
values of 2000–2020 cancer incidence trends for 12 cancer types in the USA. Sex and age are grouped into six categories: 18–34yo males, 18–34yo
females, 35–54yo males, 35–54yo females, 55 + yo males, and 55 + yo females. Bars represent 95% CI. Statistical significance of AAPC values is labeled(ns: p ≥ 0.05; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001)

Cavazzani et al. BMC Medicine(2024) 22:363

Fig. 1 (See legend on previous page.)

Page 4 of 10

Cavazzani et al. BMC Medicine(2024) 22:363

Page 5 of 10

Table 1 Sex- and age-specific trends of 2000–2020 cancer incidence for seven cancer types in the US, as extracted from SEER22 dataand calculated using Joinpoint

Sex and age are grouped into six categories: 18–34yo males, 18–34yo females, 35–54yo males, 35–54yo females, 55+yo males, and 55+yo females. AAPC (95% CI)= Average Annual Percent Change (95% confidence interval). p-value (Average Annual Percentage Change) = p-value yielded by testing the significance of thedifference of the AAPC from 0. pADJ (Average Annual Percentage Change) = p-value yielded by correcting for multiplicity p-values from the p-value (Average Annual
Percentage Change) column, using the BH procedure. Values corrected account for both sexspecific and non-sex-specific cancer types (N = 57). Model = modeling of
the difference between males and females cancer incidence trends. “NP” indicates the difference is statistically different, thus the trends are “Not-Parallel”; “P” indicatesthe difference is not statistically different, thus the trends are “Parallel”. p-value (sex interaction) = p-value yielded by testing the significance of the difference between
males and females trends. pADJ (Ssex Iinteraction) = p-value yielded by correcting for multiplicity p-values from the p-value (sex interaction) column, using the BH
procedure. Values corrected account for non-sex-specific cancer types (N = 21)

Cavazzani et al. BMC Medicine(2024) 22:363

Page 6 of 10

Fig. 2 Time trend of incidence for pancreatic cancer by sex in young subgroups. Sex- and age-specific age-adjusted incidence rates per 100,000
population for pancreatic cancer in the USA, as extracted from SEER22 data. Sex and age are grouped into six categories: 18–34yo males, 18–34yo
females, 18–26yo males, 18–26yo females, 27–34yo males, and 27–34yo females. Males = red line; females = blue line

On the other hand, the AAPC of incidence for stomach
cancer and myeloma showed the highest rate increase
among females within the 27–34 age subgroup. For stomach cancer, the AAPC was 2.65% (95% CI, 0.06–5.32%)(p = 0.084) for females and -0.28% (95% CI, -1.23% to0.68%) for males (p = 0.66), with non-parallel trends(p = 0.075). The differences were statistically significant
when tested individually, yet they did not remain significant after correction for multiplicity (Table 2). Regarding myeloma, the AAPC was 2.8% (95% CI, 1.03–4.61%)(p = 0.0076) for females and -0.35% (95% CI, -1.83–1.15%)
for males (p = 0.727), with non-parallel trends (p = 0.015)(Table 2).
Notably, the increase in PC incidence among females
18 to 26 subgroups, nearly a 10% annual percentagechange, was the highest among all demographic groups
and tumor types investigated in this study.

Discussion
The data confirmed the emergence of an unexpected sex
gap in oncology, particularly among individuals younger
than 35 years old. There are possible explanations forthe above phenomenon: it is possible that changes inyouth lifestyle over the past two decades have resulted
in increased exposure to risk factors for pancreatic cancer and other gastrointestinal malignancies, previously
relevant to the lifestyles of adults and seniors. There is a
widespread belief that the young population is increasingly exposed to risk factors for cancer, yet a databasedriven, systematic investigation is lacking. For instance,
chronic pancreatitis or gastric inflammation are significant risk factors for digestive tract cancers [11, 12].
Alongside, longstanding diabetes, obesity, cigarettesmoking, and heavy drinking are consolidated modifiable risk factors for both PC and GI cancers [13–15].

Therefore, addressing the prevalence of these risk factors in at-risk populations becomes crucial. Establishinga registry that documents chronic inflammations, suchas pancreatitis, along with other identified risk factors,
annotated with age, sex, and demographic information,
could greatly contribute to our pathological understanding of PC and GI cancers in young individuals at risk.
Previous studies have shown sex-dependent differencesin pancreatic cancer risk factors exposure [16–18]. Other
studies have suggested an enrichment of risk factors forpancreatic cancer among younger cases [19–21], which
partly supports the differential etiology of pancreaticcancer by age at diagnosis. Obesity is a significant risk
factor for pancreatic cancer. A more pronounced correlation between higher body mass index (BMI) and therisk of pancreatic cancer in men, possibly because ofvariations in fat distribution and hormonal factors has
been found [22]. Furthermore, Genkinger and colleagues
reported that being obese throughout early adulthood
carries a greater risk compared to gaining weight later inlife, highlighting the significance of the length of time aperson is obese in relation to cancer development [23].
Diabetes, namely type 2 diabetes, has been recognized
as a risk factor for pancreatic cancer [24]. Meta-analysis
studies showed that diabetes had a more pronounced
correlation risk for pancreatic cancer with both genders[25]. Although several studies have addressed age- andsex-dependent differences in exposure to risk factors forpancreatic cancer, these studies focused mainly on population aged > 30/40 years, and there is a lack of researchthat systematically investigates the pattern of young individuals’ exposure to risk factors for pancreatic or gastrointestinal cancers.
We present data on time trend incidence among different types of cancer by sex and age. Caution is necessaryCavazzani et al. BMC Medicine(2024) 22:363

Page 7 of 10

Table 2 Sex- and age-specific trends of 2000–2020 cancer incidence for seven cancer types in the US, as extracted from SEER22 dataand calculated using Joinpoint

Sex and age are grouped into four categories: 18–26yo males, 18–26yo females, 27–34yo males, and 27–34yo females. AAPC (95% CI) = Average Annual Percent
Change (95% Cconfidence Iinterval). p-value (Average Annual Percentage Change) = p-value yielded by testing the significance of the difference of the AAPC from 0.
pADJ (Average Annual Percentage Change) = p-value yielded by correcting for multiplicity p-values from the p-value (Average Annual Percentage Change) column,
using the BH procedure. Values corrected account for all cancer types (N = 28). Model = modeling of the difference between male and female cancer incidence trends.
“NP” indicates the difference is statistically different, thus the trends are “Not-Parallel”; “P” indicates the difference is not statistically different, thus the trends are“Parallel”. p-value (sex interaction) = p-value obtained by testing the significance of the difference between male and female trends. pADJ (sex interaction) = p-value
yielded by correcting for multiplicity p-values from the p-value (sex interaction) column, using the BH procedure. Values corrected account for all cancer types (N =14). “NP*” indicates the difference is statistically different when tested alone, but not after correction for multiplicity

when comparing incidence time trends among different
tumor types due to the distinct epidemiological pathways
and preventive measures affecting certain tumors, particularly when compared to pancreatic cancer. Indeed,in addition to the changing exposure to risk factors, thealtered trend in cancer incidence over the years can also
be related to other factors that are peculiar to each tumor
type, such as participation in early-detection screening programs, changes in diagnostic methods, or tumor
prevention campaigns. In certain cases, particularlycolorectal, cervical, and breast cancer, participation inearly-detection cancer screening programs, preventive
vaccination campaigns, and a higher awareness about
the role of active prevention in cancer have changed andreduced the age of cancer diagnosis. This is the case of
the anti-HPV vaccination campaign against cervical cancer that has greatly reduced cervical cancer incidence
among young women and has specifically influenced thetrend of age-dependent cancer incidence. Consequently,
while cancer incidence may be rising among females

Cavazzani et al. BMC Medicine(2024) 22:363

overall, the trends for certain tumors, such as cervicalcancer, are uniquely influenced by the success of ongoing
screening programs for early disease detection or prevention and do not necessarily reflect trends of exposure torisk factors. It is also important to recall that participation in cancer prevention or early detection programsmight only partially explain the observed trends in cancer-type incidence within age-specific groups. This isbecause the recommended initiating screening ages areoften different among cancer types and age groups. For
example, in 2016, the United States Preventive Services
Task Force (USPSTF) recommended screening for colorectal cancer starting at age 50 years and continuing until
age 75 years. The USPSTF changed its guidelines in 2021
to recommend initiating screening at 45 years due to anincreasing incidence of young-onset colorectal cancer.
Therefore, screening programs might have influenced theprevalence of diagnoses for colorectal cancer by increasing the number of individuals diagnosed before the ageof 54 and decreasing the risk for those over 54. However,
the extent to which these screening programs influence
the diagnosis of individuals aged 18 to 35 is unknown andprobably restricted to certain tumor types [26]. Similarly,
the HPV vaccine is recommended for routine vaccination
at age 11 or 12 years. It is also recommended for everyone through age 26 years if not adequately vaccinatedwhen younger. However, HPV vaccination is not recommended for individuals older than 26 years. Thus, preventive vaccination might have a peculiar age-dependent
impact and should be considered. Furthermore, due tothe lack of nationwide screening initiatives and established guidelines for early detection of pancreatic cancer,
gastric cancer, and myeloma, the influence of screening programs on the incidence of these diseases among
the overall population is probably limited. Conversely,heightened knowledge regarding the symptoms, genetic
susceptibility, and family history associated with cancer
could have increased both physician and population consciousness regarding targeted diagnostic methodologies.
This, in turn, could have facilitated the early detectionof the disease and impacted the variability observed inearly-disease diagnosis trends.
Data presented here prompts the question of whether asex disparity in cancer-associated risk among young individuals, particularly concerning exposures to risk factors
for various malignancies including PC, may exist. Most
studies examining the association between cancer risks,
exposure to risk factors, and age typically focus on individuals aged 30 and above. Therefore, conducting additional ad hoc surveys is imperative to explore whether adiscernible asymmetry in cancer-associated risk between
sexes exists among the younger population, especially in
relation to risk behaviors prevalent among adolescents.

Page 8 of 10

While lifestyle choices and exposure to risk factors
contribute to some sex disparities in cancer incidence,others are likely influenced by hormonal fluctuations,
genetic, epigenetic, and immune-related factors, including differences in sex chromosomes [4, 27–30]. As forhormonal influences, a protective role of estrogens has
been described, while testosterone and other androgens
promote cellular proliferation and inhibit apoptosis, leading to increased cancer risk. Genetic differences between
men and women can also play a significant role in the sex
disparities observed in pancreatic cancer incidence [30].
Several genetic polymorphisms and mutations are associated with pancreatic cancer risk, and these can differ
based on sex. Similarly, BRCA2 mutations are associatedwith a higher risk of pancreatic cancer, and the prevalenceof these mutations can differ between men and women[30]. Furthermore, differences in immune response, particularly in terms of inflammation and immune surveillance, further explain the disparity in pancreatic cancer
incidence between men and women. Sex differences in
immune response to cancer can also be related to sex
hormones or sex chromosome-associated genes impacting immune cells such as myeloid cells and T cells toshape the tumor microenvironment of both innate andadaptive immunity. For example, sex hormones can differentially regulate macrophage polarization with estrogen controlling the tumor-suppressive (M1) state, while
androgens induce pro-inflammatory, tumor-promoting(M2) polarization of macrophages, a key event associatedwith pancreatic cancer progression [29, 30].
How can the insights provided here contribute to theprevention of pancreatic and GI cancers at earlier stages
and reduce the mortality rate? Firstly, it is suggested that
future targeted media campaigns should raise awarenessabout the correlation between behavioral risks and disease
incidence among individuals aged 18 to 34 years. Secondly,
these findings can serve as a foundation for the development of precise screening programs aimed at the early
detection of pancreatic and GI cancers in emerging risk
populations. Such programs can be tailored to specific sex
and age subgroups, particularly those with heightened susceptibility to cancer or increased exposure to risk factors.

Conclusions
Recognizing these emerging risk groups for early-onset
malignancies is crucial for early detection and reducing
the overall lethality of cancer. The data presented here
also hint at the initiation of debates concerning gender medicine, preventive medicine, and health program
management—all crucial competencies for addressing
the future impact of the rising incidence of early-onset
malignancies, which unfortunately still bear the highest
lethality rate.

Cavazzani et al. BMC Medicine(2024) 22:363

Abbreviations
PC	Pancreatic cancer
GI	Gastrointestinal
AAPC	Average Annual Percentage Change
CI	Confidence interval
SEER	Surveillance, Epidemiology, and End Results
NCI	National Cancer Institute
BH	Benjamini-Hochberg

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03574-x.
Additional file 1. Table S1. Age-specific trends of 2000-2020 cancer
incidence for five sex-specific cancer types in the US, as extracted fromSEER22 data and calculated using Joinpoint. Sex and age are grouped into
six categories: 18-34yo males, 18-34yo females, 35-54yo males, 35-54yo
females, 55+yo males, and 55+yo females. AAPC [95% CI] = Average
Annual Percent Change [95% Confidence Interval]. p-value (Average
Annual Percentage Change) = p-value yielded by testing the significanceof the difference of the AAPC from 0. pADJ (Average Annual Percentage
Change) = p-value yielded by correcting for multiplicity p-values fromthe p-value (Average Annual Percentage Change) column, using the BH
procedure. Values corrected account for both sex-specific and non-sexspecific cancer types (N = 57).
Acknowledgements
We would like to thank the members of the Cardone Lab for their insightful
discussions.
Authors’ contributions
A.C. and L.C. conceptualized the study and were responsible for data curation and analysis. A.C. developed and implemented the formal analysis
methodology. Both A.C. and L.C. drafted the original manuscript and wrote
the first draft of the paper. Additionally, L.C. played a key role in securing
the necessary funding for the research project and provided guidance andoversight throughout its execution to ensure smooth progress. L.C. edited thefinal version of the manuscript. C.A. and D.G. contributed to data analysis andmethodology, as well as to editing the first draft of the paper. All authors readand approved the final manuscript.
Funding
A. Cavazzani was supported by a fellowship from the IRCCS Regina Elena
National Cancer Institute. L. Cardone’s research laboratory is supported by
Associazione “Nastro Viola” Italy, for Pancreatic Cancer research.
Availability of data and materials
The data underlying this article were generated by using publically available
data retrieved from the Surveillance, Epidemiology, and End Results (SEER)
database, which is a National Cancer Institute (NCI) instrument used for cancer
surveillance activities. Data extracted from publically available databases
and according to the provided licensing have been extracted and analyzed
as described in Methods. Further details regarding the statistical analysis
and study protocols for all pertinent variable analyses can be obtained bycontacting the authors, A. Cavazzani (cavazzani.alessandro@gmail.com) and L.
Cardone (luca.cardone@cnr.it).

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.

Page 9 of 10

Received: 9 March 2024 Accepted: 20 August 2024

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