Avoiding lead-time bias by estimating stage-specific proportions of cancer and non-cancer deaths.

PURPOSE: Understanding how stage at cancer diagnosis influences cause of death, an endpoint that is not susceptible to lead-time bias, can inform population-level outcomes of cancer screening. METHODS: Using data from 17 US Surveillance, Epidemiology, and End Results registries for 1,154,515 persons aged 50-84 years at cancer diagnosis in 2006-2010, we evaluated proportional causes of death by cancer type and uniformly classified stage, following or extrapolating all patients until death through 2020. RESULTS: Most cancer patients diagnosed at stages I-II did not go on to die from their index cancer, whereas most patients diagnosed at stage IV did. For patients diagnosed with any cancer at stages I-II, an estimated 26% of deaths were due to the index cancer, 63% due to non-cancer causes, and 12% due to a subsequent primary (non-index) cancer. In contrast, for patients diagnosed with any stage IV cancer, 85% of deaths were attributed to the index cancer, with 13% non-cancer and 2% non-index-cancer deaths. Index cancer mortality from stages I-II cancer was proportionally lowest for thyroid, melanoma, uterus, prostate, and breast, and highest for pancreas, liver, esophagus, lung, and stomach. CONCLUSION: Across all cancer types, the percentage of patients who went on to die from their cancer was over three times greater when the cancer was diagnosed at stage IV than stages I-II. As mortality patterns are not influenced by lead-time bias, these data suggest that earlier detection is likely to improve outcomes across cancer types, including those currently unscreened.

Variation in patterns of second primary malignancies across U.S. race and ethnicity groups: a Surveillance, Epidemiology, and End Results (SEER) analysis.

PURPOSE: One in six incident cancers in the U.S. is a second primary cancer (SPC). Although primary cancers vary considerably by race and ethnicity, little is known about the population-based occurrence of SPC across these groups. METHODS: Using Surveillance, Epidemiology, and End Results (SEER) 12 data and relative to the general population, we calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPC among 2,457,756 Hispanics, non-Hispanic Asian American/Pacific Islanders (NHAAPI), non-Hispanic black (NHB), and non-Hispanic whites (NHW) cancer survivors aged 45 years or older when diagnosed with a first primary cancer (FPC) from 1992 to 2015. RESULTS: The risk of second primary bladder cancer after first primary prostate cancer was higher than expected in Hispanic (SIR = 1.18, 95% CI: 1.01-1.38) and NHAAPI (SIR = 1.41, 95% CI: 1.20-1.65) men than NHB and NHW men. Among women with a primary breast cancer, Hispanic, NHAAPI, and NHB women had a nearly 1.5-fold higher risk of a second primary breast cancer, while NHW women had a 6% lower risk. Among men with prostate cancer whose SPC was diagnosed 2 to <12 months, NHB men were at higher risk for colorectal cancer and Hispanic and NHW men for non-Hodgkin's lymphoma. In the same time frame for breast cancer survivors, Hispanic and NHAAPI women were significantly more likely than NHB and NHW women to be diagnosed with a second primary lung cancer. CONCLUSION: Future studies of SPC should investigate the role of shared etiologies, stage of diagnosis, treatment, and lifestyle factors after cancer survival across different racial and ethnic populations.

Potential for Cure by Stage across the Cancer Spectrum in the United States.

BACKGROUND: Cure fraction-the proportion of persons considered cured of cancer after long-term follow-up-reflects the total impact of cancer control strategies, including screening, without lead-time bias. Previous studies have not reported stage-stratified cure fraction across the spectrum of cancer types. METHODS: Using a mixture cure model, we estimated cure fraction across stages for 21 cancer types and additional subtypes. Cause-specific survival for 2.4 million incident cancers came from 17 US Surveillance, Epidemiology, and End Results registries for adults 40 to 84 years at diagnosis in 2006 to 2015, followed through 2020. RESULTS: Across cancer types, a substantial cure fraction was evident at early stages, followed by either a sharp drop from stages III to IV or a steady decline from stages I to IV. For example, estimated cure fractions for colorectal cancer at stages I, II, III, and IV were 62% (95% confidence interval: 59%-66%), 61% (58%-65%), 58% (57%-59%), and 7% (7%-7%), respectively. Corresponding estimates for gallbladder cancer were 50% (46%-54%), 24% (22%-27%), 22% (19%-25%), and 2% (2%-3%). Differences in 5-year cause-specific survival between early-stage and stage IV cancers were highly correlated with between-stage differences in cure fraction, indicating that survival gaps by stage are persistent and not due to lead-time bias. CONCLUSIONS: A considerable fraction of cancer is amenable to cure at early stages, but not after metastasis. IMPACT: These results emphasize the potential for early detection of numerous cancers, including those with no current screening modalities, to reduce cancer death.

Surgical resection as a predictor of cancer-specific survival by stage at diagnosis and cancer type, United States, 2006-2015.

BACKGROUND: When solid tumors are amenable to definitive resection, clinical outcomes are generally superior to when those tumors are inoperable. However, the population-level cancer survival benefit of eligibility for surgery by cancer stage has not yet been quantified. METHODS: Using Surveillance, Epidemiology and End Results data allowing us to identify patients who were deemed eligible for and received surgical resection, we examined the stage-specific association of surgical resection with 12-year cancer-specific survival. The 12-year endpoint was selected to maximize follow-up time and thereby minimize the influence of lead time bias. RESULTS: Across a variety of solid tumor types, earlier stage at diagnosis allowed for surgical intervention at a much higher rate than later-stage diagnosis. At every stage, surgical intervention was associated with a substantially higher rate of 12-year cancer-specific survival, with absolute differences of up to 51% for stage I, 51% for stage II, and 44% for stage III cancer, and stage-specific mortality relative risks of 3.6, 2.4, and 1.7, respectively. CONCLUSIONS: Diagnosis of solid cancers in early stages often enables surgical resection, which reduces the risk of death from cancer. Receipt of surgical resection is an informative endpoint that is strongly associated with long-term cancer-specific survival at every stage.

Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial.

We report the design of the NHS-Galleri trial (ISRCTN91431511), aiming to establish whether a multi-cancer early detection (MCED) test that screens asymptomatic individuals for cancer can reduce late-stage cancer incidence. This randomised controlled trial has invited approximately 1.5 million persons and enrolled over 140,000 from the general population of England (50-77 years; ≥3 years without cancer diagnosis or treatment; not undergoing investigation for suspected cancer). Blood is being collected at up to three annual visits. Following baseline blood collection, participants are randomised 1:1 to the intervention (blood tested by MCED test) or control (blood stored) arm. Only participants in the intervention arm with a cancer signal detected have results returned and are referred for urgent investigations and potential treatment. Remaining participants in both arms stay blinded and return for their next visit. Participants are encouraged to continue other NHS cancer screening programmes and seek help for new or unusual symptoms. The primary objective is to demonstrate a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention versus control arm 3-4 years after randomisation. NHS-Galleri will help determine the clinical utility of population screening with an MCED test.

Key risk factors for the relative and absolute 5-year risk of cancer to enhance cancer screening and prevention.

BACKGROUND: This study identifies populations who may benefit most from expanded cancer screening. METHODS: Two American Cancer Society prospective cohort studies, Cancer Prevention Study-II Nutrition Cohort and Cancer Prevention Study-3, were used to identify the risk factors associated with a > 2% absolute risk of any cancer within 5 years. In total, 429,991 participants with no prior personal history of cancer were followed for cancer for up to 5 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for association. By using these hazard ratios, individualized coherent absolute risk estimation was used to calculate absolute risks by age. RESULTS: Overall, 15,226 invasive cancers were diagnosed among participants within 5 years of enrollment. The multivariable-adjusted relative risk of any cancer was strongest for current smokers compared with never-smokers. In men, alcohol intake, family history of cancer, red meat consumption, and physical inactivity were also associated with risk (p < .05). In women, body mass index, type 2 diabetes, hysterectomy, parity, family history of cancer, hypertension, tubal ligation, and physical inactivity were associated (p < .05). The absolute 5-year risk exceeded 2% among nearly all participants older than 50 years and among some participants younger than 50 years, including current or former smokers (<30 years since quitting) and long-term nonsmokers with a body mass index >25 kg/m2 or a first-degree family history of cancer. The absolute 5-year risk was as high as 29% in men and 25% in women. CONCLUSIONS: Older age and smoking were the two most important risk factors associated with the relative and absolute 5-year risk of developing any cancer.

New genomic technologies for multi-cancer early detection: Rethinking the scope of cancer screening.

Cancers other than breast, colorectal, cervical, and lung do not have guideline-recommended screening. New multi-cancer early detection (MCED) tests-using a single blood sample-have been developed based on circulating cell-free DNA (cfDNA) or other analytes. In this commentary, we review the current evidence on these tests, provide several major considerations for new MCED tests, and outline how their evaluation will need to differ from that established for traditional single-cancer screening tests.

Racial/Ethnic Differences in Cancer Diagnosed after Metastasis: Absolute Burden and Deaths Potentially Avoidable through Earlier Detection.

BACKGROUND: Racial/ethnic disparities in cancer mortality are well described and are partly attributable to later stage of diagnosis. It is unclear to what extent reductions in the incidence of late-stage cancer could narrow these relative and absolute disparities. METHODS: We obtained stage- and cancer-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for persons ages 50 to 79 years between 2006 and 2015. For eight hypothetical cohorts of 100,000 persons defined by race/ethnicity and sex, we estimated cancer-related deaths if cancers diagnosed at stage IV were detected earlier, by assigning them outcomes of earlier stages. RESULTS: We observed a 3-fold difference in the absolute burden of stage IV cancer between the group with the highest rate (non-Hispanic Black males, 337 per 100,000) and the lowest rate (non-Hispanic Asian/Pacific Islander females, 117 per 100,000). Assuming all stage IV cancers were diagnosed at stage III, 32-80 fewer cancer-related deaths would be expected across subgroups, a relative reduction of 13%-14%. Assuming one third of metastatic cancers were diagnosed at each earlier stage (I, II, and III), 52-126 fewer cancer-related deaths would be expected across subgroups, a relative reduction of 21%-23%. CONCLUSIONS: Across population subgroups, non-Hispanic Black males have the highest burden of stage IV cancer and would have the most deaths averted from improved detection of cancer before metastasis. IMPACT: Detecting cancer before metastasis could meaningfully reduce deaths in all populations, but especially in non-Hispanic Black populations. See related commentary by Loomans-Kropp et al., p. 512.

Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA.

PURPOSE: We recently reported the development of a cell-free DNA (cfDNA) targeted methylation (TM)-based sequencing approach for a multi-cancer early detection (MCED) test that includes cancer signal origin prediction. Here, we evaluated the prognostic significance of cancer detection by the MCED test using longitudinal follow-up data. EXPERIMENTAL DESIGN: As part of a Circulating Cell-free Genome Atlas (CCGA) substudy, plasma cfDNA samples were sequenced using a TM approach, and machine learning classifiers predicted cancer status and cancer signal origin. Overall survival (OS) of cancer participants in the first 3 years of follow-up was evaluated in relation to cancer detection by the MCED test and clinical characteristics. RESULTS: Cancers not detected by the MCED test had significantly better OS (P < 0.0001) than cancers detected, even after accounting for other covariates, including clinical stage and method of clinical diagnosis (i.e., standard-of-care screening or clinical presentation with signs/symptoms). Additionally, cancers not detected by the MCED test had better OS than was expected when data were adjusted for age, stage, and cancer type from the Surveillance, Epidemiology, and End Results (SEER) program. In cancers with current screening options, the MCED test also differentiated more aggressive cancers from less aggressive cancers (P < 0.0001). CONCLUSIONS: Cancer detection by the MCED test was prognostic beyond clinical stage and method of diagnosis. Cancers not detected by the MCED test had better prognosis than cancers detected and SEER-based expected survival. Cancer detection and prognosis may be linked by the underlying biological factor of tumor fraction in cfDNA.

Anaplastic large cell lymphoma in human immunodeficiency virus-infected people and solid organ transplant recipients.

Human immunodeficiency virus (HIV)-infected people and solid organ transplant recipients have elevated risk of anaplastic large cell lymphoma (ALCL). Little is known regarding ALCL risk factors in immunosuppressed populations. We used data from US cancer registries linked to HIV registries (1996-2016) and to the national transplant registry (1992-2017). ALCL risk in HIV-infected people and transplant recipients relative to the general population was calculated as a standardized incidence ratio (SIR). ALCL risk factors were evaluated using Poisson regression. We identified 121 incident ALCL cases in the HIV (n = 86) and transplant (n = 35) populations. We reviewed pathology reports for 45 cases and most (86·7%) were confirmed as ALCL. Epstein-Barr virus tested positive in 1/8 (12·5%) cases. Compared to the general population, ALCL risk was strongly elevated among HIV-infected people [SIR 5·43; 95% confidence interval (CI) 4·27-6·81] and transplant recipients (5·96; 4·03-8·49). Among HIV-infected people, ALCL incidence was strongly related to CD4 count [adjusted incidence rate ratio (aIRR) 0·15 for ≥500 vs. <200 cells/µl; P trend < 0·001]. Among transplant recipients, risk was highest within the first year (aIRR 6·82) and 10+ years post-transplant (5·99). In conclusion, ALCL risk is strongly increased in these immunosuppressed populations but may be unrelated to EBV infection based on limited reports.

Modeled Reductions in Late-stage Cancer with a Multi-Cancer Early Detection Test.

BACKGROUND: Cancer is the second leading cause of death globally, with many cases detected at a late stage when prognosis is poor. New technologies enabling multi-cancer early detection (MCED) may make "universal cancer screening" possible. We extend single-cancer models to understand the potential public health effects of adding a MCED test to usual care. METHODS: We obtained data on stage-specific incidence and survival of all invasive cancers diagnosed in persons aged 50-79 between 2006 and 2015 from the US Surveillance, Epidemiology, and End Results (SEER) program, and combined this with published performance of a MCED test in a state transition model (interception model) to predict diagnostic yield, stage shift, and potential mortality reductions. We model long-term (incident) performance, accou.

Projected Reductions in Absolute Cancer-Related Deaths from Diagnosing Cancers Before Metastasis, 2006-2015.

BACKGROUND: New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer-related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages. METHODS: We obtained stage-specific incidence and survival data from the Surveillance, Epidemiology, and End Results Program for 17 cancer types for all persons diagnosed ages 50 to 79 years in 18 geographic regions between 2006 and 2015. For a hypothetical cohort of 100,000 persons, we estimated cancer-related deaths under assumptions that cancers diagnosed at stage IV were diagnosed at earlier stages. RESULTS: Stage IV cancers represented 18% of all estimated diagnoses but 48% of all estimated cancer-related deaths within 5 years. Assuming all stage IV cancers were diagnosed at stage III, 51 fewer cancer-related deaths would be expected per 100,000, a reduction of 15% of all cancer-related deaths. Assuming one third of metastatic cancers were diagnosed at stage III, one third diagnosed at stage II, and one third diagnosed at stage I, 81 fewer cancer-related deaths would be expected per 100,000, a reduction of 24% of all cancer-related deaths, corresponding to a reduction in all-cause mortality comparable in magnitude to eliminating deaths due to cerebrovascular disease. CONCLUSIONS: Detection of multiple cancer types earlier than stage IV could reduce at least 15% of cancer-related deaths within 5 years, affecting not only cancer-specific but all-cause mortality. IMPACT: Detecting cancer before stage IV, including modest shifts to stage III, could offer substantial population benefit.

Magnitude of reduction in risk of second contralateral breast cancer with bilateral mastectomy in patients with breast cancer: Data from California, 1998 through 2015.

BACKGROUND: Increasingly, patients with breast cancer undergo bilateral mastectomy (BLM). To the authors' knowledge, the magnitude of benefit is unknown. METHODS: The authors used data from the Surveillance, Epidemiology, and End Results (SEER) program regarding all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 through 2015 and treated with BLM versus breast-conserving therapy including surgery and radiotherapy (BCT) or unilateral mastectomy (ULM). The authors measured relative risks of second contralateral breast cancer (CBC) and breast cancer death using Fine and Gray multivariable regression modeling adjusted for the competing risk of death and death from another cause, respectively, and potential confounding factors. Absolute excess risk of CBC was measured as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk. RESULTS: Among 245,418 patients with a median follow-up of 6.7 years, 7784 patients (3.2%) developed CBC. Relative risks were lower after BLM (hazard ratio [HR], 0.10; 95% CI, 0.07-0.14) and higher after ULM (HR, 1.07; 95% CI, 1.02-1.13) versus BCT. Absolute excess risks were higher after BCT and ULM (5.0 and 13.6 more cases, respectively) compared with BLM (28.6 fewer cases). BLM reduced risk more among older women (38.0 fewer cases for women aged ≥50 years vs 17.9 fewer cases among women aged <50 years) but provided similar risk reduction across categories of tumor grade and tumor hormone receptor status. Compared with BCT, the risk of breast cancer death was equivalent after BLM (HR, 1.03; 95% CI, 0.96-1.11) and higher after ULM (HR, 1.21; 95% CI, 1.17-1.25). CONCLUSIONS: BLM may reduce second breast cancer risk by 34 to 43 cases per 10,000 person-years compared with other surgical procedures, but is not associated with a lower risk of death. Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM.

Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.

OBJECTIVES: Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California. METHODS: Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival. RESULTS: The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites. CONCLUSIONS: Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.

Risk of Kaposi sarcoma after solid organ transplantation in the United States.

Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population-based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987-2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two-sided. We identified 163 KS cases during follow-up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non-US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross-sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non-KS skin cancer may also be at high KS risk.

Risk of oral tongue cancer among immunocompromised transplant recipients and human immunodeficiency virus-infected individuals in the United States.

BACKGROUND: Oral tongue cancer incidence has increased among whites in the United States; however, the cause remains unknown. If an infectious agent is implicated, then elevated risk would be expected among immunosuppressed individuals. METHODS: By using population-based registry linkage information from the US Transplant Cancer Match and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) Cancer Match studies, the authors examined the risk of oral tongue squamous cell carcinoma (SCC) among immunocompromised transplantation recipients and HIV-infected individuals. In addition, the risks of oropharyngeal SCC (strongly related to human papillomavirus infection; modestly affected by immunosuppression), other tobacco/alcohol-related oral cavity SCCs (not thought to be infection/immunosuppression-related), and non-Hodgkin lymphoma of oral cavity/pharynx (strongly related to Epstein-Barr virus; profoundly affected by immunosuppression) were evaluated. RESULTS: Compared with the general population, the risk of non-Hodgkin lymphoma was strongly increased (standardized incidence ratio [SIR] > 8.0). The risk of all SCCs was modestly and similarly elevated among transplantation recipients (SIR range, 2.2-2.7; Pheterogeneity = .2); whereas, among HIV-infected individuals, the risk of oral tongue SCC was higher compared with the risk of other SCCs (SIR, 3.0 vs 1.7 [for oropharyngeal SCCs] and 2.3 [for other oral cavity SCCs]; Pheterogeneity < .001). The risk of SCCs was significantly higher among men, older individuals, and whites; and risk increased with the time since transplantation/AIDS onset. The risk of oral tongue SCC was significantly higher among HIV-infected men who have sex with men compared with the average risk in HIV-infected individuals (adjusted incidence rate ratio = 2.0). CONCLUSIONS: Similar modest increases in the risk of oral tongue and other oral cavity SCCs do not suggest that an infectious agent or exposure profoundly affected by immunosuppression underlies the increase in oral tongue cancer. Cancer 2018;124:2515-22. © 2018 American Cancer Society.

Pediatric neuro-oncology survival disparities in California.

The objective of this study was to investigate racial/ethnic differences in survival for pediatric high-grade glioma (HGG) and medulloblastoma in the state of California. We obtained data from the California Cancer Registry on 552 high-grade glioma patients (110 brainstem, 442 non-brainstem) and 648 medulloblastoma patients ages 0-19 years from 1988 to 2012. Using multivariate Cox proportional hazards regression, we examined the impact of individual and neighborhood characteristics on survival. Socioeconomic quintile and insurance status differed significantly by race for both diagnoses. Hispanic children with non-brainstem HGG had worse survival than non-Hispanic white children: hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.24-2.11, but the difference was mitigated some by accounting for socioeconomic status (HR 1.48, CI 1.10-1.99). Racial/ethnic differences in survival exist for children with high-grade glioma, particularly Hispanic children with non-brainstem high-grade glioma, and are likely related to sociologic factors.