Highlight
– In a statewide retrospective cohort of 48,406 adolescents and young adults (AYAs) with cancer, 9.5% experienced metastatic recurrence after an initial nonmetastatic diagnosis; 9.2% had metastatic disease at diagnosis.
– Five-year cumulative incidence (CMI) of metastatic recurrence was highest for sarcoma (24.5%) and colorectal cancer (21.8%), and exceeded 30% for most stage III cancers (except thyroid).
– Survival after metastatic recurrence was worse than for patients with metastatic disease at diagnosis across most tumor types, underscoring distinct biology and treatment challenges for relapsed disease.
Background: disease burden and unmet need in AYA cancer care
Adolescents and young adults (AYAs, commonly defined as ages 15–39) with cancer occupy a unique clinical space. They experience distinct incidence patterns, treatment exposures, psychosocial needs, and survivorship trajectories compared with children and older adults. Although improved treatments have reduced cancer-specific mortality for many tumor types, metastatic disease — whether present at diagnosis or arising after an initially localized presentation — remains the principal driver of late morbidity and mortality.
Large population registries traditionally provide robust data on incidence and stage at diagnosis but do not reliably capture recurrence. This gap leaves clinicians and policymakers with limited empiric data on how commonly AYA patients later develop metastases and how outcomes after recurrence compare to those presenting with de novo metastatic disease. Better quantification of metastatic recurrence can inform surveillance strategies, survivorship planning, and allocation of research resources to prevent and treat relapsed disease.
Study design and methods
The study by Brunson et al. (JAMA Oncology, 2025) addressed these gaps by constructing a retrospective population-based cohort of AYAs aged 15–39 years diagnosed with cancer in California from 2006 through 2018. Case ascertainment used the California Cancer Registry linked to statewide hospitalization, emergency department, and ambulatory surgery data from the California Department of Health Care Access and Information. Follow-up extended through December 31, 2020.
Key elements:
- Population: 48,406 AYAs with first primary cancer; median age 33 years; 67.4% female.
- Exposure categories: tumor types included melanoma, sarcoma, and breast, cervical, colorectal, testicular, and thyroid cancers — selected because they are common in AYA populations or have distinct clinical features in this age group.
- Primary outcome: metastatic recurrence identified using ICD-9-CM and ICD-10-CM diagnostic codes for metastatic disease occurring at least 6 months after primary cancer diagnosis, or metastatic disease recorded as an underlying cause of death.
- Analysis: cumulative incidence of metastatic recurrence (CMI) over time stratified by tumor type and stage at diagnosis; comparisons of survival after metastatic recurrence vs survival for those with metastatic disease at initial presentation.
Key findings
Overall burden and baseline stage
Of 48,406 AYAs, 9.2% presented with metastatic (stage IV) disease at diagnosis. Among the 43,935 patients who initially had nonmetastatic cancer, 9.5% subsequently developed metastatic recurrence during follow-up, indicating that the burden of metastatic disease in the AYA population derives roughly equally from de novo metastatic presentation and later recurrence.
Five-year cumulative incidence (CMI) of metastatic recurrence — by tumor type (among initially nonmetastatic cases)
- Sarcoma: 24.5% (95% CI, 22.6%–26.6%)
- Colorectal cancer: 21.8% (95% CI, 20.3%–23.4%)
- Cervical cancer: 16.3% (95% CI, 15.0%–17.6%)
- Breast cancer: 14.7% (95% CI, 14.0%–15.4%)
- Other tumor types (melanoma, testicular, thyroid) had lower absolute CMIs, but stage and histologic subgroups mattered.
Stage-specific risk
The CMI of metastatic recurrence increased monotonically with higher stage at diagnosis. Importantly, all stage III cancers (except thyroid) demonstrated 5-year CMIs exceeding 30%, highlighting that locally advanced disease confers a substantial near-term risk of metastatic progression in AYAs.
Temporal trends (2006–2018)
- Cervical cancer: 5-year CMI increased from 12.7% (95% CI, 10.8%–14.8%) for patients diagnosed in 2006–2009 to 20.4% (95% CI, 17.5%–23.6%) for those diagnosed in 2015–2018.
- Colorectal cancer: 5-year CMI decreased from 24.4% (95% CI, 21.3%–27.6%) in 2006–2009 to 19.2% (95% CI, 16.4%–22.2%) in 2015–2018.
Survival after metastatic recurrence vs de novo metastatic disease
Across almost all tumor types studied, patients who developed metastatic recurrence after an initial nonmetastatic diagnosis had worse survival than patients who presented with metastatic disease at diagnosis. Two exceptions were testicular and thyroid cancers, where survival after recurrence was comparable or better. The finding that post-recurrence survival is often poorer than de novo metastatic survival suggests differences in tumor biology (treatment-resistant clones), treatment exposure and cumulative toxicity, and potentially delays to re-initiation of effective systemic therapy.
Interpretation and clinical implications
This study quantifies a substantial, and previously underappreciated, burden of metastatic recurrence among AYAs. Clinicians and survivorship programs should recognize that a sizable minority of AYA survivors — particularly those with sarcoma, colorectal cancer, and stage III disease — are at appreciable risk of metastatic relapse within five years. The fact that survival after recurrence is often worse than for de novo metastatic disease should prompt attention to:
- Risk-stratified survivorship care: surveillance intensity and duration should be tailored to tumor type and stage at diagnosis, balancing early detection of treatable recurrence against harms of overtesting.
- Rapid access to multidisciplinary re-staging and systemic therapy: administrative or access delays at relapse may adversely affect outcomes; streamlined pathways for re-evaluation and referral to specialized centers or clinical trials are essential.
- Trial enrollment and translational research: recurrent disease in AYAs appears to have distinct clinical behavior; dedicated trials and correlative science to define mechanisms of resistance are priorities.
- Psychosocial and supportive care: the prognostic shock of metastatic recurrence in young people demands robust psychosocial, fertility, employment, and palliative support integrated into oncology services.
Plausible explanations for observed trends
The increase in cervical cancer metastatic recurrence CMI over time may reflect multiple, nonmutually exclusive factors: changes in screening uptake, vaccination coverage, shifts in stage distribution at presentation, disparities in access to high-quality treatment, or temporal changes in tumor biology. The observed decrease in colorectal recurrence risk may be due to earlier detection, improved multimodality therapy, or broader adoption of effective systemic regimens in more recent years. Causal attribution cannot be made from these observational data and will require focused investigation.
Methodological strengths and limitations
Strengths
- Large, population-based cohort covering a diverse, contemporary AYA population in California.
- Linkage of registry and statewide administrative data allowed detection of metastatic disease events outside of initial registry capture.
- Use of cumulative incidence metrics that account for competing risks (death) provided clinically meaningful absolute risk estimates.
Limitations
- Metastatic recurrence was identified using administrative ICD-9/ICD-10 codes and an algorithm requiring events ≥6 months post-diagnosis or metastatic cause of death. Administrative coding can misclassify disease status (both false positives and negatives) and lacks granularity on recurrence site and burden.
- Potential under-ascertainment of recurrences managed entirely in outpatient settings without coded hospital encounters.
- The cohort is limited to California; generalizability to other regions with different healthcare systems or population demographics may be limited.
- Limited information on systemic therapies, molecular tumor characteristics (e.g., MSI, HER2, hormone receptor status), surgical details, and participation in clinical trials — all of which influence recurrence risk and survival.
- Follow-up extended through 2020; more recent therapeutic advances (e.g., expanding immunotherapy indications) could alter recurrence patterns and outcomes after 2020.
Research and policy implications
This study underscores important priorities:
- Improving population-level ascertainment of recurrence: cancer registries and health systems should explore standardized, validated methods to capture recurrence and progression, potentially leveraging electronic health records, claims data, and structured clinician reporting.
- Prospective cohorts and trials focused on AYA recurrent disease to identify biological drivers of relapse and resistance and to test therapeutic strategies optimized for younger patients.
- Targeted public health measures to address rising cervical recurrence — evaluating screening, vaccination uptake, and equity of care in younger populations.
- Development of evidence-based survivorship guidelines that incorporate recurrence risk by tumor type and stage and provide clear pathways for surveillance, psychosocial support, and expedited access to re-treatment.
Conclusion
Brunson and colleagues provide critical population-level evidence that metastatic recurrence is a major contributor to the overall metastatic disease burden among AYAs, with nearly one in ten patients experiencing relapse after an initially nonmetastatic diagnosis. Recurrence risks are high for sarcoma and colorectal cancer and for stage III disease across multiple histologies. Worse survival after recurrence compared with de novo metastatic presentation for most tumor types highlights the urgent need for better prevention, early detection, and treatment strategies tailored to relapsed disease in AYAs. Improving recurrence surveillance in registries and conducting translational research into the biology of AYA relapse are priorities to reduce the personal and public-health impact of these findings.
Funding and trial registration
Refer to the original publication for funding and trial registration information: Brunson A, Wun T, Abrahão R, et al. Metastatic Recurrence Among Adolescents and Young Adults With Cancer. JAMA Oncol. 2025 Nov 26. doi:10.1001/jamaoncol.2025.4971. PMID: 41296369.
Selected reference
Brunson A, Wun T, Abrahão R, Quesenberry CP, Chubak J, Ruddy KJ, Chao CR, Hahn EE, Sauder CAM, Nichols HB, Kushi LH, Keegan THM. Metastatic Recurrence Among Adolescents and Young Adults With Cancer. JAMA Oncol. 2025 Nov 26. doi: 10.1001/jamaoncol.2025.4971. Epub ahead of print. PMID: 41296369.
