Introduction

Decades of research have established that early life experiences heavily influence long-term developmental trajectories1,2. Adverse childhood experiences (ACEs) are traumatic events of childhood, such as physical, sexual, and emotional abuse, parental divorce/separation, domestic violence, or living with an adult experiencing mental illness, substance abuse/misuse, or incarceration and are among factors repeatedly correlated to a wide range of disorders and dysfunctions3. Repeated stress response activation before the age of 18 years has been shown to have severe long-lasting consequences on cardiovascular, immune, and metabolic function across the lifespan4,5. A growing body of epidemiologic evidence supports that, at the population level, individuals with an increased number of ACEs are at heightened risk for the development or exacerbation of conditions such as ischemic heart disease, mental and somatic disorders, liver disease, and chronic lung disease6,7,8. The financial burden of ACEs is felt across many sectors, including direct medical costs and lost productivity. Estimated costs related to ACEs totaled $581 billion in Europe and $748 billion in North America, in terms of 2017 USD dollar value9. More than 75% of these costs arose in individuals with two or more ACEs9. Harmful alcohol use, smoking, and cancer have been found to have the highest ACE-attributable costs in many countries10. These statistics demonstrate the potential global burden of ACEs on healthcare systems and the importance of proactively addressing their impact. A 1998 retrospective study of over 13,000 adults was the first to investigate the relationship between ACEs and health outcomes, during which the authors found a dose-response relationship between the number of ACEs and cancer risk1. Additionally, research into the protective effects of Positive Childhood Experiences (PCEs) on health outcomes in adulthood has recently gained traction. PCEs have been found to weaken the link between ACEs and self-reported health issues, mental health challenges, and physical activity later in life11.

While numerous publications have continued to investigate this relationship between ACEs and cancer, there have been mixed findings in the attempt to establish a strong correlation. The retrospective nature of these studies and the use of data corresponding to different regions or countries are some possible reasons for the discrepancy. This discrepancy in current literature highlights the need for continued research to explore the correlation between ACEs and cancer development. The first systematic review on this relationship was published by Holman et al in 2016, and the relationship between ACEs and any specific cancer type (i.e., hematologic, endocrine, gastrointestinal cancers, etc.) remains understudied. Additionally, limited research has explored how specific ACEs, such as emotional neglect, parental incarceration, or exposure to community violence may differentially influence cancer risk. Accordingly, the objectives of this literature review were to (1) investigate the consensus and gaps in the literature exploring the relationship between ACEs and cancer development and experiences, and (2) discuss implications for cancer prevention and screening in patients who have a history of ACEs.

This study argues that the integration of ACE prevention strategies, such as the promotion and development of PCEs, could mitigate morbidities and mortalities associated with related cancer development for vulnerable communities who have experienced early traumatic events. We also explore the capacity of PCEs, for example, stable neighborhood or peer support, which have been shown to be protective against certain negative health outcomes, to alleviate the impact of ACEs on well-being in adulthood12. These protective factors may reduce cancer risk by counteracting chronic stress responses, supporting healthier behavioral choices, and interrupting harmful biological cascades (i.e., inflammation, immune dysfunction, etc.) that contribute to carcinogenesis.

Methods

Search Strategy

To investigate the consensus and knowledge gaps related to the relationship between ACEs and cancer development, we performed a search of existing literature. The review incorporated peer-reviewed studies that were identified from two databases (PubMed and Embase) published between January 2010 and October 2022. Our search terms were utilized based on the thesaurus and keywords including “Adverse Childhood Experiences,” “Cancer,” “Cancer Risk,” and “Childhood Adversity.” Terms and keywords were combined to comprise search phrases, allowing for a more sensitive search. Search phrases included “Adverse Childhood Experiences and Cancer Risks”, and “Childhood Adversity and Cancer Risks.” Additionally, reference lists from selected papers were searched for possible matches and inclusion.

Study Selection

Studies were imported into Covidence, a review software, for screening. Studies were included for review if they met the following eligibility criteria: (1) explored the relationship between at least one type of ACE and cancer risk, or (2) explored the relationship between at least one type of ACE and the experience of cancer. Reviews and editorials were also included in our literature review. Studies were excluded if they were not original research, were not published in English, or did not include human subjects. Overall, 78 articles whose titles/abstracts were collectively screened by two reviewers (AH and BK) to ensure fit to the specified eligibility criteria. The following data were extracted: title, lead author, publication year, sample size, dataset, outcome(s), dose-response relationship between ACEs and cancer, other significant associations, and authors’ conclusions. All Behavioral Risk Factor Surveillance Systems listed in the “Dataset” column are managed by the CDC. Study characteristics and general information on articles selected for review are outlined in Table 1.

Table 1 Summary Table Representing the Characteristics of Selected Studies
Full size table

Results

Association between ACEs and cancer

Before exploring various pathways by which ACEs affect cancer development, we will recap recent studies establishing the relationship between ACEs and cancer. A recent systematic review and meta-analysis of 18 studies (n = 406,210) found that individuals with at least two ACEs were at an increased risk of cancer compared to those with none2. Physical abuse, sexual abuse, exposure to intimate partner violence, and familial financial difficulties are associated with an increased risk of cancer2.

Recent systematic reviews from Hu et al.2 and Holman et al.13 suggested relationships between abuse-specific ACEs and cancer risk. Hu et al. found sexual abuse to be the ACE most significantly associated with the risk of cancer among 8 pooled studies2. Similarly, Holman found among 4 pooled studies that physical and psychological abuse were most strongly associated with cancer risk in adulthood13.

Varying correlations between the severity/amount of ACE exposure and downstream cancer risk in adulthood have been identified. A dose-response relationship between ACEs and various types of cancer has been identified in studies based on data from the original ACE Study, the Cross-Sectional Primary Health Care Center from Central Eastern Tunisia, and the Danish Life Course cohort1,14,15,16. The dose-response relationship has also been observed in various reviews and meta-analyses2,17. On the other hand, the review by Holman et. al observed the dose-response relationship only in 1 of 5 studies that examined the ACE score and risk of cancer13. One study of rural health in the U.S. demonstrated an inverse relationship between ACE score and non-skin cancers in rural populations, i.e., as ACE score increased, the percentage of respondents reporting non-skin cancer diagnosis decreased. This may be due to self-reporting omissions that may increase with age, competing mortality risk from other ACE-related health effects, or due to under-diagnosis or exclusion of individuals not receiving regular medical care. It is also possible that limited access to preventive healthcare, particularly in rural or marginalized communities, contributed to underdiagnosis and may have skewed cancer reporting among those with high ACE scores.

Additionally, the survey used diverges slightly from the original ACE questionnaire18. However, a study based on the British National Child Development Study data did find that women in the cohort who had 2+ ACEs had a twofold increased risk of developing cancer before the age of 50 compared to those with no history of ACEs, even after adjusting for adult-age factors, such as education level and alcohol consumption, and early life confounders, such as breastfeeding and childhood pathologies19. Of note, another prospective cohort study found an association between ACEs and the development of lung cancer, including an increased risk of premature death14. Studies based on data from the Nord-Trøndelag Health Study (HUNT3), the China Health and Retirement Longitudinal Study, and pooled Behavioral Risk Factor Surveillance System Survey for 14 US States found the dose-response relationship between ACEs and disease burden held for certain diseases but not cancer20,21,22. Limited study power, recall bias, and the inherent complexity of ACE interactions make conclusions difficult to draw; this is an important area to prioritize for future interventional design and implementation. Although it is difficult to directly explain inconsistent associations across published studies, this is likely related to expected variation across study populations, differing tools used to measure ACEs, distinct associations across specific cancer types, and/or confounding environmental variables independently impacting cancer risk. Studies based on large scale data from prospective cohorts such as the British National Child Development Study would have adequate power and avoid potential recall bias by adjusting for confounding variables.

The relationship between ACEs and cancer has been found to vary across sexes. A study based on the British National Child Development Study data found a significant relationship between ACEs and cancer in women but not men19. Similarly, a study based on the 2012 Canadian Community Health Survey found that the dose-response relationship between ACEs and cancer was significant in women but not men23. One study demonstrated that multiple ACEs increase cancer risk in women, whereas only emotional abuse increases cancer risk in men24.

Beyond biological sex, there are no published data available to specifically inform the potential impact of individual-defined gender minority identity on downstream cancer risk from ACEs. Collection of gender identity demographic data has only recently been recognized and endorsed in cancer patient populations, and this is a critical literature gap in need of prioritization. Given documented deficits in cancer screening and high rates of cancer-associated behaviors (such as smoking) in sexual and gender minority populations, it will be important to characterize ACE incidence and correlates in these individuals25.

Across countries, the relationship between ACEs and cancer has been consistent, while some ACEs may have more impact in some countries than others due to social differences. A comparative cross-sectional study between Japan and Finland found an association between ACEs and certain adult diseases across both countries, but certain ACEs were found to significantly increase the odds of cancer in adults in Finland but not in Japan, and vice versa. A comparative analysis of these two countries was selected due to similarities in social support as measured by the World Happiness Report, which used the metric of having someone to count on in times of trouble26. Social differences may make comparisons of ACEs and cancer risk across countries difficult. For instance, another cross-sectional study in Tunisia used the Arabic Adverse Childhood Experiences International Questionnaire (ACE-IQ) to investigate childhood social abuse and chronic conditions later in life. This data indicated a statistically significant positive correlation between childhood social abuse and chronic health conditions in adulthood, including cancer. Social abuse included exposure to peers, community, and collective violence (i.e., war)15. Additionally, it is possible that ACEs yield inconsistent impact on cancer risk across different countries due to differences in healthcare delivery systems, behavioral and cultural norms surrounding family-based trauma, and social/environmental health determinants. Further work focused on ACEs across specific geographic contexts promises to inform international ACE screening guidelines.

There is very limited information on the relationship between environmental exposures, ACEs, and cancer. A 2019 scoping review did not find any papers that examined the relationship between ACEs and environmental carcinogens27. Carcinogen exposures are a key risk factor for cancer, and ACEs may contribute to home and occupational exposures. Additionally, further research is necessary to determine if ACEs modify vulnerability to these carcinogens through biological mechanisms.

These studies demonstrate consistency in the relationship between ACEs and cancer risk across various geographic locations and cultures, while the relative importance of certain ACEs to cancer risk varies.

Biological mediators

The relationship between ACEs and cancer is likely shaped by a complex web of biological mechanisms, including immune dysregulation, chronic inflammation, and epigenetic changes. These processes may be triggered by prolonged stress exposure and altered HPA axis activity early in life, potentially resulting in long-term physiological disruptions. Although these biological mediators could explain relationships between ACEs and cancer, limited research has been conducted to mechanistically characterize these pathways. While the current evidence base remains limited, a small but growing number of studies suggest plausible biological pathways through which ACEs might influence cancer risk. In this section, we summarize emerging findings on epigenetic modification and inflammatory biomarkers linked to ACEs and cancer outcomes. There is little previous evidence suggesting that exposure to stressors during childhood can induce several known biological responses, which can provide explanations for cancer etiology19. Although childhood maltreatment has been associated with an elevated risk of psychological disorders via DNA methylation pathways, a consistent connection between ACEs and DNA methylation with somatic disorders has not been established28,29. Direct evidence of ACEs leading to DNA methylation can have clinical applications by employing prognostic biomarkers for the screening of cancer risk factors. However, these connections remain inconsistent, and further research is necessary to establish these epigenetic changes as prognostic tools. The mechanisms through which ACEs might contribute to disease development could be through direct biological changes, or due to behavioral tendencies that increase cancer risk, or a combination of the two. They can also impact the outcomes of patients with ACEs who have already been diagnosed with cancer.

The direct impact of ACEs on epigenetic changes related to cancer risk has not been explored directly, but one study of adolescent girls (n = 44) with multiple ACEs showed methylation changes in genes related to ACEs and cancer processes before and after a one-week intensive group program. This program was a residential experience that consisted of sessions on mindfulness training, artistic expression, and Eye Movement Desensitization and Reprocessing (EMDR) group therapy30. This finding could inform treatment programs for youth with ACEs that could mitigate cancer risk later in life.

Another study found that female mice who were exposed to maternal separation experienced accelerated melanoma growth compared to those who were not. These effects were mediated by increased expression of IL-6 and mTOR, as well as stimulation of eukaryotic elongation factor 2 expression and increase the number of circulating monocytes and DNA damage in peripheral blood leukocytes, which is associated with oxidative DNA damage31. Further investigation into epigenetic changes relating ACEs to cancer is necessary to better understand these mechanisms.

There is limited available data as to whether inflammatory pathways can mediate the effects of ACEs on cancer risk. One study surveyed 408 adults with hepatobiliary-pancreatic cancer using the Traumatic Events Survey, and researchers uncovered a link between lower levels of IL-2 and having experienced an ACE, particularly that of a major upheaval between parents32. Another review of nine articles, including 2931 participants, found an association between certain ACEs and increased plasma levels of cytokines interleukin (IL-6), C-reactive protein (CRP), soluble tumor necrosis factor receptor type II (sTNF-RII), interleukin IL-1 receptor antagonist (IL-1ra), and subsequent increased risk of developing breast cancer33. These studies suggest that ACEs are associated with chronic inflammation and biological “weathering.” This is consistent with recognition of inflammatory stress as a mechanistic link between social and genomic determinants of cancer risk34.

Behavioral mediators

It has been hypothesized that ACEs mediate cancer risk through individual behavior. A qualitative review found that elevated ACE scores are associated with health behaviors that increase the risk of cancer, as well as cancer risks even after adjustment for these behaviors17. Two complementary mechanistic pathways could be implicated: (1) increased engagement in high-risk behaviors that increase cancer risk and (2) decreased participation in preventive health practices.

One hypothesized mechanism of the relationship between ACEs and cancer is through increased substance use associated with downstream cancer risk. One study found an association between ACEs and smoking, heavy drinking, and obesity. These behaviors were linked to adverse health consequences, including cancer, although ACEs were less consistently associated with cancer across states than other diseases20. Another study of Tunisian adults found an association between ACEs and cancer, with ACEs being associated with substance use15. This data suggests that substance use could act as a mediator between ACEs and adult cancer diagnoses.

ACEs have been associated with involvement in both the juvenile and adult justice systems. A study examining the relationship of ACEs with self-reported arrests and delinquent acts among non-incarcerated 16-year-olds found an association between ACEs and delinquent acts that was mitigated by PCEs. This association was not found between ACEs or PCEs and arrests35. Another study of youth involved with the juvenile justice system found that PCEs mitigated the association between ACEs and recidivism and reconviction36. Involvement with the juvenile justice system has been associated with poorer self-reported general health in adulthood than those who have never been incarcerated37. Given that incarceration is associated with the risk of chronic and infectious diseases, the influence of ACEs on high-risk behaviors leading to incarceration could mediate an increased risk of developing cancer as an adult. It is unclear the exact mechanisms by which incarceration may be associated with cancer risk, with very limited published data to draw conclusions from. Imprisoned individuals constitute an extremely vulnerable population, with limited access to quality healthcare and high rates of harmful environmental/social stress exposures. Our review confirms this to be a key evidence gap, with more research necessary to characterize associations between ACEs, direct or indirect exposure to incarceration, and adult cancer incidence. It would also be of interest to evaluate the potential protective impact of PCEs to identify opportunities to disassociate ACEs and incarceration from adult cancer risk.

It has also been hypothesized that ACEs could contribute to cancer through an association with decreased preventive health and screening practices. One possible explanation is that ACEs, like physical or sexual abuse, result in decreased screening behaviors due to avoidance of potentially triggering scenarios. One study used the 2011 Behavioral Risk Factor Surveillance System (n = 24,938) to investigate the relationship between ACEs and colorectal cancer screening. Physical abuse, divorced/separated parents, and living in households where adults were violent with each other were associated with lower odds of receiving screening38. Another study utilized the 2009 Tennessee Behavioral Risk Factor Surveillance System (n = 1527) to determine the relationship between ACEs and cervical cancer screening within the last three years. Physical and sexual abuse were associated with decreased odds of receiving screening39.

Additionally, the 2014 Kansas Behavioral Risk Factor Surveillance System (n = 11,794) was used to determine the relationship between ACEs and PSA screening, clinical breast exams, pap tests, and colorectal cancer screening. Individual ACEs were associated with a lower likelihood of receiving these screenings. Certain ACEs were associated with greater odds of receiving colorectal cancer screening in women and lower odds in men. Physical abuse had the strongest correlation with screening40. Moreover, differences in behavior in men and women may result in different screening behaviors that affect lifelong cancer risk. A sample of 9783 men and 12,132 women from the 2012 Canadian Community Health Survey found that women, but not men, who experienced childhood maltreatment were more likely to be diagnosed with cancer in adulthood than those who did not. These effects remained consistent in a dose-response relationship for individuals experiencing 2–3 types of abuse when age and socio-demographic factors were controlled. Limited healthcare utilization and cancer screening as a response to child mistreatment was proposed as a possible mechanism for increased risk among women, although the reasons for the disparity between men and women with respect to screening behaviors were not explored23.

The specific relationship between certain ACEs and cancer screening behavior may vary, but cancer may be detected later in patients who have had one or more ACEs due to a negative association with certain screening behaviors. This may be due to avoidance of screening and gender differences as discussed above, among other factors, including decreased financial stability and/ or decreased access to care.

Socioeconomic status and ACEs

Socioeconomic status (SES) is a significant determinant of both the frequency and impact of ACEs. Individuals from lower SES backgrounds are disproportionately exposed to ACEs, including household dysfunction, abuse, and neglect, possibly due to factors such as housing instability, community violence, and caregiver stress41. At the same time, exposure to ACEs can contribute to poorer socioeconomic outcomes in adulthood, including lower educational attainment, reduced income potential, and employment instability41. This bidirectional relationship creates a cycle of compounded vulnerability, wherein SES disadvantage both increases the likelihood of early adversity and exacerbates its biological and behavioral consequences over the life course. Notably, even when SES status is controlled for, ACEs are still associated with a higher risk of chronic diseases, including cancer, suggesting that this relationship is multifactorial21. SES may also influence how ACEs affect long-term cancer risk by modifying stress physiology, health behaviors, and access to preventive care42.

ACE-related experiences in cancer care

In adults who have already been diagnosed with cancer, ACEs could impact the experience of their disease and treatment in terms of health-related quality of life and healthcare anxiety.

Regardless of current cancer diagnosis, ACEs may impact health-related quality of life. ACEs were associated with a worse health-related quality of life in breast cancer survivors43. One community-based assessment in Tampa, Florida, found that each additional reported ACE contributed to an additional 20% odds of reporting at least 14 days of unhealthy days in a given month44. ACEs can affect health-related quality of life by influencing interaction with the healthcare system. Women who experienced ACEs undergo bilateral oophorectomy at higher rates than those without, and they may elect to undergo bilateral oophorectomy before age 45 despite an average risk of ovarian cancer45. This decision may impact health-related quality of life due to secondary effects such as stress or complications from surgery.

Another behavioral aspect that could contribute to poor health outcomes is health anxiety. A study of emerging adults with chronic medical conditions (n = 121) found that ACEs may increase healthcare anxiety by contributing to negative illness appraisals46. These effects could contribute to worse outcomes by decreasing access to care. Currently, work is being done to explore the association between ACEs and cancer-related PTSD for head and neck cancer patients (n = 85)47.

Discussion

The established correlation between ACEs and cancer provides a unique opportunity to provide targeted intervention for high-risk individuals. In the following section, we provide recommendations for interventional opportunities based on ACE-related cancer risk.

Characterization of mechanistic relationships between ACEs and cancer will be necessary to effectively identify and support at-risk individuals. Several recent studies have investigated how behavioral interventions can impact the experiences of people with ACEs. A 2021 study discovered that tailoring non-pharmacological interventions, such as breathing exercises, physical activity, and gratitude exercises, to individual patients is possible through consideration of genetic susceptibilities to comorbidities, ACEs, heightened vulnerability to viral infections like seasonal influenza or COVID-19, as well as immediate stress-inducing and traumatic situations. These findings could be tailored to leverage holistic interventions in high-risk individuals48. Additionally, a study of adolescents and young adults with cancer found that a program called “Promoting Resilience in Stress Management” improved benefit-finding for those who had experienced one or more traumatic events49. Future research could analyze whether similar programs are effective in adult populations. Another study of breast cancer patient biographies found that psychological therapies combining somatic techniques and talking therapy potentially counteract the epigenetic effects of ACEs on the development of breast cancer50. This evidence suggests that psychological interventions could be effective in mitigating biological damage caused by ACE exposure.

In addition to behavioral or psychological intervention, recent research efforts have focused on understanding how PCEs may help to counter the risks of ACEs11,51. Early access to safe, stable, and nurturing relationships and environments, positive attachments with caregivers, teachers, and peers, opportunities for emotional growth, school engagement, and connection to culture and community have been identified as positive experiences that bolster childhood resilience and promote overall health and well-being52,53. Such experiences aid in the vital development of a sense of belonging and connectedness, which often serve as a helpful buffer to the negative effects of ACEs, including reductions in associated cancer54.

One of the ways that PCEs have been hypothesized to improve health outcomes is through the development of resilience. In a study of childhood and young adult cancer patients (N = 52), patients with ACEs had lower resilience scores on either the “Child and Youth Resilience Measure” or “Adult Resilience Measure” than those without55. Diminished resilience is one way in which ACEs could influence attitudes about future adverse events, including health events like cancer diagnosis. A study examining the experience of breast cancer patients reported that some patients may believe that stress factors in their disease development, either by directly causingthe disease or by weakening their body’s defenses. As an example, one patient’s surveyed observations emphasized this issue, saying “…I think it’s a whole picture … your life experiences are your life experiences, and they add up, and what happens is what happens, and I think your health issues have something to do with that”56. Reduced resilience and stress surrounding ACEs could impact patients’ understanding of cancer as a progression of their adverse experiences.

Harnessing the potential of PCEs, the Family Resilience Initiative (FRI) at LeBonheur Children’s Hospital in Memphis, Tennessee, uses outreach coordinators to provide eligible families with early childhood educational programming that focuses on building resiliency, establishing mentoring relationships, and sharpening developmental skills. Furthermore, the FRI clinic relies on the results of these interventions to evaluate child development, health outcomes, and healthcare utilization for future endeavors57.

PCEs are suggested to ameliorate poor outcomes associated with ACEs, potentially mitigating the associated impacts on health and well-being in adulthood for children at the highest risk11,51.

There is also recent literature surrounding Post Traumatic Growth (PTG), which is defined as “positive psychological changes experienced as a result of the struggle with trauma or highly challenging situations.”56 While the negative consequences of traumatic experiences are often emphasized, PTGs have been shown to co-exist with these negative effects58. Further research is necessary to define relationships between ACEs, PCEs, and PTG, as well as the health-related consequences of these pathways.

While expanding resilience and post-traumatic growth can potentially reduce the negative impacts of ACEs, the addition of external social support may provide complementary benefits to cancer patients with ACEs. PCEs should be crafted to establish support for children, such as that of a teacher or other trusted adult, which has been associated with higher psychosocial function in adults59. Researchers investigating the relationship between ACEs and adult disease in Hispanics and Latinos (n = 5117) found that the association between ACEs and cancer was unchanged when social support was considered. However, the absence of a social support effect in the study may be due to limitations in the data, which was only sourced from Hispanic and Latino individuals60. This could also be due to the timing of adequate social support provision. It may be that social support has a more beneficial effect when provided as a positive childhood experience than to an adult who has experienced ACEs.

Although resilience and patient support are important to provide to those with ACEs, screening is the first step towards meaningful health intervention. If specific types of ACEs are to be considered in assessing cancer risk, considerations on how to screen for ACEs effectively and compassionately need to be made. The original ACE questionnaire (ACE-q) is a 10-item inventory. With some questions being compound, some have called for a more streamlined ACE screening tool. As an alternative to the later developed 11-item CDC Behavioral Risk Factor Surveillance System, Wade et al developed a 2-item ACE screening tool that did not have significant predictive disadvantages over the longer questionnaire61. This should significantly reduce the time and burden of screening for ACEs, making it more realistic for healthcare providers to provide this screening in the clinic. It has been suggested that while there are potential benefits to ACE screening, there has not been any investigation to identify benefits significantly greater than existing screening practices for alcohol and drug use disorder, interpersonal violence, and others62. In children, the Pediatric ACEs and Related Life Events Screener (PEARLS) tool, a 17-item inventory, has been proposed for use in pediatric primary care settings. Caregivers completing the PEARLS tool were found to report more ACEs and related life events when responding to a version of the screener that collected an aggregate count of events than when responding to a screener that collected itemized responses to individual events63. There may be an opportunity to consolidate ACE screening into existing screening practices, should a benefit be demonstrated. This would provide the opportunity to identify the patients with the highest ACE-related risk and target them for appropriate interventions. Additionally, there is a lack of longitudinal studies exploring the effects of ACEs on long-term biological changes and thus increased cancer risk. This would allow a better understanding of specific biomarkers that could be used in cancer screening of high-risk individuals with elevated ACE scores.

The use of digital health technologies (DHTs) and artificial intelligence (AI)-based patient risk triage to mitigate negative consequences of ACEs on adult health holds promise. A scoping review of literature from 2017–2022 found that incorporating these tools can potentially improve management of mental health consequences of ACEs64. Our team has implemented a set of data standards, terminologies, knowledge bases, and knowledge graphs65,66,67, as well as AI frameworks68,69,70, to inform future development of clinically focused technologies.

From our group’s prior experience, we would argue that DHTs could be further leveraged to address modifiable risk factors for cancer and proactively promote PCE-based intervention inat-risk populations with prior ACE exposure. Recent studies show that game-based digital therapeutic devices (such as the FDA-approved EndeavorRx platform) support positive outcomes when used to treat mental health conditions among children aged 8-12 years old without the need for pharmacological intervention71 The impact of such conveniently available, patient-friendly, and inexpensive digital tools confirm the potential of digital health interventions to promote memory training and neurofeedback to reduce the negative downstream health consequences of ACEs71,72 Complementary applications providing real-time positive reinforcement to sharpen perseverance and self-efficacy skills may likewise promote protective PCEs.

Ultimately, effective refinement, personalization, and implementation of digital health technologies could fortify communication between patients, providers, and researchers. This could equitably expand access to mental health and social support, cancer screening resources, cancer risk behavior modification, and environmental risk abatement. In addition, chronic stress and immune dysregulation associated with ACEs may increase biological sensitivity to carcinogens by altering DNA repair capacity, weakening detoxification pathways, and promoting and sustaining inflammatory states.

Our group’s planned work will focus on validation of an analytic framework to identify mechanistic pathways linking ACEs to specific cancers and treatment outcomes to guide candidate intervention strategies73.

Prospective cohort studies remain sparse16,19,21. Prospective data collection avoids recall bias and confounding patient/treatment factors, which complicate retrospective analysis. Few series have corrected for confounding variables, such as environmental and behavioral risks, which could obscure associations between ACEs and cancer15,17,23. Additionally, generalizing cancer risk across studies is inherently difficult due to the wide variety of malignancy types and distinct biological mechanisms underlying each. This heterogeneity complicates efforts to draw overarching conclusions. Furthermore, many of the included studies are from diverse global regions that use different instruments to assess ACEs, making cross-country comparisons challenging unless standardized measures are employed. Finally, although our search was comprehensive, it is possible that some relevant sources were not included in this review. Rigorous studies measuring the potential protective effects on PCEs also remain sparse, exemplified by the lack of an available formal PCE exposure scoring system until 201953.

Available literature suggests plausible relationships between ACEs and downstream cancer risk during adulthood. Potential mechanisms include biological, environmental, social, behavioral, and healthcare delivery/access factors. Complex pathways would be expected to play varying roles across individual patients, complicating screening, high-risk case identification, and intervention.

Intervention strategies in this vulnerable population are urgently needed2,13,26. Exact relationships between specific ACEs and cancer risk require improved categorization1,14,18,20,21,22. In particular, certain ACEs may impact biological sexes and specific sexual-gender minorities differently, requiring novel personalization19,24. Sex-based differences in hormonal regulation, immune response, and stress reactivity may contribute to these observed disparities and should be considered for exploration in future mechanistic studies.

At present, there remains no prospective data to support specific interventions for potential ACE-related cancer screening deficits, psychosocial hardship, and/or elevated cancer incidence rates in adulthood. Promising avenues may include face-to-face support strategies as well as mobile digital health technologies. Of note, educational strategies focused on raising awareness of ACEs and PCEs among oncology providers, patients, and communities alike should be prioritized. PCEs could be leveraged to build resilience and may nurture the ability to share feelings and/or maintain adaptive behaviors in real-world social situations. This could be reinforced by mobile health technologies designed to engage patients toward self-directed improvement of their own cancer screening and prevention outcomes.