The commercial prophylactic vaccines for human papillomavirus (HPV) are subunit vaccines composed of spontaneously assembled virus-like particles formed from 360 copies of the L1 major virion protein. The vaccines have exceeded expectations in immunogenicity, clinical trials efficacy, and effectiveness in national immunisation programmes. Booster doses are not required to generate these outcomes. In this Review, we discuss the immunological and virological considerations that can help with explaining the high potency of HPV vaccines. These considerations provide biological plausibility for HPV vaccines being the first subunit vaccines to confer high-level, long-term protection after a single priming dose, support projections of eliminating vaccine-targeted types in populations with achievable coverage rates in adolescents, and offer insights for developing future antimicrobial vaccines.

Bone marrow endothelial cells (ECs) form specialized vascular niches that support hematopoietic stem and progenitor cells (HSPC), yet the molecular regulators of this function remain incompletely defined. Here, we identify the Rho GTPase-activating protein Dlc1 as an essential regulator of developmental vasculogenesis, and adult bone marrow vascular niche integrity. Endothelial-specific deletion of Dlc1 caused embryonic lethality with severe vascular defects. In adult mice, inducible EC-specific Dlc1 deletion disrupted the bone marrow vascular architecture, associated with a significant reduction of multipotent hematopoietic progenitors and myeloid-lineage cells. Single-cell RNA sequencing revealed transcriptional reprogramming of Dlc1-deficient ECs, with the emergence of cell subsets displaying altered transcriptional profiles and disrupted expression of key niche signals, including Kitl, Cxcl12, and Pdgfb. Ligand-receptor interactome analysis demonstrated impaired EC-to-HSPC communication, and the hematopoietic cells exhibited transcriptional features of metabolic stress and reduced biosynthetic activity. These findings position Dlc1 as a central regulator of developmental vasculogenesis, adult vascular architecture in the bone marrow, and EC-derived hematopoietic cell support. This work uncovers a previously unrecognized role for Dlc1 in coupling vessel function to hematopoietic cell output, with implications for understanding bone marrow failure syndromes and targeting endothelial dysfunction in hematologic diseases.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, largely due to late diagnosis and limited response to currently available therapies. Identifying effective drug combinations that harness PDAC-specific vulnerabilities remains a major challenge for molecularly targeted therapy. Oncogenic mutations in the KRAS gene, which are found in over 90% of PDAC patients, play a critical role in PDAC. Although KRAS inhibitors may be found to be clinically useful for treating PDAC, it is likely that resistance will develop in most patients when given as single agent treatment. To overcome this anticipated limitation, effective drug combinations that include KRAS inhibitors will be necessary. We have determined in preclinical human and mouse lung cancer models that RAS facilitates the export of nuclear proteins into the cytoplasm via a mechanism independent of canonical RAS signaling (Tripathi et al., 2024, Nature Cancer). This observation suggests that new drug combinations that cooperate with the inhibition of the RAS nuclear export function might be suitable for targeted cancer therapy. Our preclinical PDAC studies suggest that the newly identified RAS-dependent nuclear export mechanism is also relevant to PDAC and may have implications for developing new drug combinations for PDAC treatment. In human PDAC models, we have found that the DLC1 tumor suppressor protein is a critical downstream target of KRAS-dependent nuclear protein export. Perinuclear binding of KRAS-GTP to RanGAP1 promotes the hydrolysis of RAN-GTP to RAN-GDP and the consequent release of nuclear protein cargo into the cytoplasm. In human PDAC models, export of the nuclear EZH2 methyltransferase into the cytoplasm leads to methylation of the cytoplasmic DLC1 protein, making it susceptible to ubiquitin-dependent proteasomal degradation. Conversely, KRAS inhibition prevents the nuclear export of EZH2, leading to an increase in DLC1 protein levels. Consistent with these findings, analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database indicates DLC1 protein levels in PDAC are lower than would be expected from the relatively high DLC1 mRNA expression in these tumors. Remarkably, the low levels of DLC1 protein in PDAC are inversely correlated with the high levels of the FBXW5 E3 ubiquitin ligase. Our preclinical PDAC studies show that a three-drug combination, comprising a KRAS inhibitor plus AKT and SRC inhibitors, exhibits significantly greater antitumor activity than the KRAS inhibitor alone. The cooperative effect of the three-drug combination arises as the KRAS inhibitor increases DLC1 protein levels, while AKT and SRC kinase inhibitors block phosphorylations that attenuate DLC1 tumor suppressor activity. Mechanistically, this three-drug combination enhances antitumor effects in mutant KRAS PDAC by stabilizing and reactivating the DLC1 tumor suppressor protein. Citation Format: Brajendra K. Tripathi, Sophia M. Shahin, Elise Van Meter, Marian E. Durkin, Xiaolan Qian, Ross Lake, James H. Doroshow, Dunrui Wang, Douglas R. Lowy. Advancing new rational drug combinations to treat mutant KRAS-driven pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4473.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, largely due to late diagnosis and limited response to currently available therapies. Identifying effective drug combinations that harness PDAC-specific vulnerabilities remains a major challenge for molecularly targeted therapy. Oncogenic mutations in the KRAS gene, which are found in over 90% of PDAC patients, play a critical role in PDAC. Although KRAS inhibitors may be found to be clinically useful for treating PDAC, it is likely that resistance will develop in most patients when given as single agent treatment. To overcome this anticipated limitation, effective drug combinations that include KRAS inhibitors will be necessary. We have determined in preclinical human and mouse lung cancer models that RAS facilitates the export of nuclear proteins into the cytoplasm via a mechanism independent of canonical RAS signaling (Tripathi et al, 2024, Nature Cancer). This observation suggests that new drug combinations that cooperate with the inhibition of the RAS nuclear export function might be suitable for targeted cancer therapy. Our preclinical PDAC studies suggest that the newly identified RAS-dependent nuclear export mechanism is also relevant to PDAC and may have implications for developing new drug combinations for PDAC treatment. In human PDAC models, we have found that the DLC1 tumor suppressor protein is a critical downstream target of KRAS-dependent nuclear protein export. Perinuclear binding of KRAS-GTP to RanGAP1 promotes the hydrolysis of RAN-GTP to RAN-GDP and the consequent release of nuclear protein cargo into the cytoplasm. In human PDAC models, export of the nuclear EZH2 methyltransferase into the cytoplasm leads to methylation of the DLC1 protein, making it susceptible to ubiquitin-dependent proteasomal degradation. Conversely, KRAS inhibition prevents the nuclear export of EZH2 protein, leading to an increase in DLC1 protein levels. Consistent with these findings, analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database indicates DLC1 protein levels in PDAC are lower than would be expected from the relatively high DLC1 mRNA expression in these tumors. In the adjacent normal tissues, CPTAC indicates EZH2 protein levels are significantly lower and DLC1 protein levels are significantly higher than in the tumors. Remarkably, the low levels of DLC1 protein in PDAC are inversely correlated with the high levels of the FBXW5 E3 ubiquitin ligase. Our preclinical PDAC studies show that a three-drug combination, comprising a KRAS inhibitor plus AKT and SRC inhibitors, exhibits significantly greater antitumor activity than the KRAS inhibitor alone. The cooperative effect of the three-drug combination arises as the KRAS inhibitor increases DLC1 protein levels, while AKT and SRC kinase inhibitors block phosphorylations that attenuate DLC1 tumor suppressor activity. Mechanistically, this three-drug combination enhances antitumor effects in mutant KRAS PDAC by stabilizing and reactivating the DLC1 tumor suppressor protein. Citation Format: Brajendra K. Tripathi, Sophia M. Shahin, Elise Van Meter, Marian E. Durkin, Xiaolan Qian, Ross Lake, James H. Doroshow, Dunrui Wang, Douglas R. Lowy. Advancing new rational drug combinations to treat mutant KRAS-driven pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A010.

The Foundation for the National Institutes of Health Biomarkers Consortium is celebrating two decades of advancing biomarker science to enable earlier interventions, personalized medicine and improved outcomes in disease prevention, detection, diagnosis and treatment. The Foundation for the National Institutes of Health Biomarkers Consortium is celebrating two decades of advancing biomarker science to enable earlier interventions, personalized medicine and improved outcomes in disease prevention, detection, diagnosis and treatment.

Human papillomavirus (HPV) 16 and HPV 18 are the two most common HPV types leading to cervical cancer; however, HPV 35 accounts for about 2% of invasive cervical cancers worldwide and a higher percentage in women of African ancestry. Further investigation into potential cross-protection against HPV 35 by current vaccines is needed to determine whether the addition of HPV 35 antigens to the next generation of vaccines is warranted. In this study, we developed and qualified serology assays to measure antibodies against HPV 35, including enzyme-linked immunosorbent assays (ELISA) and pseudovirion (PsV)-based neutralization assays (PBNA). HPV 35 virus-like particles (VLP) and HPV 35 PsV both containing L1 (late-expressed major capsid protein) and L2 (late-expressed minor capsid protein) were successfully produced and qualified for use in these methodologies. ELISA qualification established a cutoff of 9.8 ELISA Units/mL (EU/mL) and excellent reproducibility, with an intraclass correlation coefficient (ICC) of 0.995. The PBNA qualification indicated a cutoff of 10 was suitable for assessing neutralization and that the assay was highly specific and exhibited good reproducibility with an ICC of 0.931. Qualified HPV 35 binding and neutralization assays will allow us to understand if current vaccines induce neutralizing antibody responses against HPV 35, as well as assess next-generation vaccines for HPV 35 immunogenicity, with the goal of improving protection against HPV 35 associated cancers in vulnerable populations.

BACKGROUND:Advances in cancer treatment and increased survivorship have altered the economic burden of cancer care. Updated patient-level estimates of cancer-attributable costs, based on clinical and socioeconomic factors, are required. METHODS:Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, we identified individuals aged ≥66 years who were diagnosed with cancer during 2008-2019 and matched controls without a cancer history based on demographic characteristics, comorbidity burden, and area-level socioeconomic status. Cancer-attributable costs were estimated for 2013-2019 according to cancer site, stage, age, sex, race, and calendar year. Phases of care were defined as initial (first 12 months after diagnosis), continuing, and end-of-life (EOL; final 12 months before death from cancer). Net annualized cancer-attributable costs were calculated as the difference between cases and matched controls and are reported in USD 2023. RESULTS:Net annualized cancer-attributable medical service costs were highest in the EOL phase ($121 746), followed by the initial ($45 063), and continuing ($7141) phases. Oral prescription drug costs increased over time across all phases, particularly in EOL (from $4823 in 2013 to $11 620 in 2019), whereas medical service and hospitalization costs remained relatively stable after adjustment for inflation. Acute leukemia and distant-stage cancers incurred the highest cost. Cancer-attributable costs were higher among Black individuals and individuals of other races than among White individuals. CONCLUSION(S):Cancer-attributable costs vary substantially according to the care phase, cancer type, stage at diagnosis, and race. Rising costs, particularly for EOL care and prescription drugs, highlight the importance of aligning treatment intensity with patient goals and providing critical inputs for simulation and cost-effectiveness analyses of cancer-control interventions.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis. Identifying useful drug combinations for PDAC treatment is an important challenge for molecularly targeted therapy. Oncogenic mutations in the KRAS gene, which are found in over 90% of PDAC patients, play a critical role in PDAC. Although KRAS inhibitors may be found useful in PDAC treatment, it is likely that resistance will develop in most patients given single agent treatment. To overcome this anticipated limitation, effective drug combinations that include KRAS inhibitors will be necessary. We have recently determined in lung cancer cells that RAS facilitates the export of nuclear proteins into the cytoplasm via a mechanism independent of canonical RAS signaling pathways (Tripathi et al, Nature Cancer, 2024). This suggests that new drug combinations that cooperate with the inhibition of the RAS nuclear export function might be suitable for cancer therapy. Our preclinical PDAC studies suggest the lung cancer mechanisms are relevant to PDAC, with implications for possible new drug combinations. In PDAC lines, we have found that the DLC1 tumor suppressor protein is a critical downstream target of KRAS-dependent nuclear protein export. Perinuclear binding of KRAS-GTP to RanGAP1 promotes the hydrolysis of RAN-GTP to RAN-GDP and the consequent release of nuclear protein cargo into the cytoplasm. Export of the nuclear EZH2 methyltransferase leads to methylation of the DLC1 protein, making it susceptible to proteasomal degradation. Conversely, KRAS inhibition prevents the nuclear export of EZH2, leading to an increase in DLC1 protein levels. Consistent with these findings, analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database indicates DLC1 protein levels in PDAC are lower than would be expected from the relatively high DLC1 mRNA expression in these tumors. In the adjacent normal tissues, CPTAC indicates EZH2 protein levels are significantly lower and DLC1 protein levels are significantly higher than in the tumors. Our preclinical studies indicate that a three-drug combination consisting of a KRAS inhibitor plus AKT and SRC inhibitors have significantly more antitumor activity than the KRAS inhibitor alone. It is likely that the cooperation of the three-drug combination is attributable to the KRAS inhibitor increasing DLC1 protein levels, while the inhibitors of AKT kinase and SRC kinase reverse and prevent the direct phosphorylation and attenuation of DLC1 tumor suppressor functions by these kinases, thereby reactivating the tumor suppressor activity of DLC1 protein, which enhances the antitumor activity against PDAC with mutant KRAS. In addition to this useful three-drug combination, we are currently testing other drug combinations that take advantage of the KRAS-mediated nuclear protein export function. Brajendra K. Tripathi, Sophia M. Shahin, Xiaolan Qian, Marian E. Durkin, Ross Lake, James H. Doroshow, Dunrui Wang, Douglas R. Lowy. Identification of new drug combinations that cooperatively target KRAS-dependent nuclear protein export to treat mutant KRAS-driven pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4387.

BACKGROUND:Multidose human papillomavirus (HPV) vaccination is efficacious, yet the vaccine has been underused globally. Emerging data suggest that a single dose may provide protection. Whether a single dose of HPV vaccine would provide similar protection to two doses is uncertain. METHODS:In this trial, we assessed whether one dose of an HPV vaccine was noninferior to two doses. Girls 12 to 16 years of age were randomly assigned, in a 1:1:1:1 ratio, to receive one or two doses of a bivalent HPV vaccine or one or two doses of a nonavalent HPV vaccine. The primary end point was new HPV type 16 or 18 infection occurring from month 12 to month 60 and persisting for at least 6 months. The prespecified noninferiority margin was 1.25 infections per 100 participants. We also assessed vaccine effectiveness by comparing HPV16 or HPV18 infection among the trial participants with that among girls and women enrolled in a nonrandomized survey. RESULTS:A total of 20,330 participants were enrolled and underwent randomization, and 3005 unvaccinated participants were enrolled in the survey. The noninferiority analysis showed that one vaccine dose was noninferior to two doses in preventing HPV16 or HPV18 infection. The rate difference between one and two doses of the bivalent vaccine was -0.13 infections per 100 participants (95% confidence interval [CI], -0.45 to 0.15; P<0.001 for noninferiority), and the difference between one and two doses of the nonavalent vaccine was 0.21 infections per 100 participants (95% CI, -0.09 to 0.51; P<0.001 for noninferiority). The vaccine effectiveness was at least 97% in each of the four trial groups. No safety concerns were identified. CONCLUSIONS:One dose of either a bivalent or nonavalent HPV vaccine provided protection against HPV16 or HPV18 infection and was not inferior to two doses. (Funded by the National Cancer Institute and others; ESCUDDO ClinicalTrials.gov number, NCT03180034.).

BACKGROUND:Lung cancer mortality trends among Black and White populations and urban compared to rural populations are critical for assessing disparities in cancer outcomes. METHODS:This serial cross-sectional study used US national death certificate data from the National Center for Health Statistics and data from the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program. The study analyzed lung cancer incidence (2001-2021) and mortality (1990-2021) trends by race, sex, and urban-rural status. Age-adjusted incidence and mortality rates and average annual percent changes (AAPCs) were estimated. RESULTS:Since 1990, lung cancer death rates have declined faster for Black men, which has reduced the gap with White men, but White women have consistently had higher rates than Black women. Rural areas showed higher incidence and mortality rates compared to urban areas. During 2013-2021, incidence rates declined similarly among urban and rural Black men (AAPC, -3.4 and -4.3, respectively) and White men (AAPC, -3.6 and -2.7, respectively). However, mortality rates decreased faster for urban Black men than for rural Black men (AAPC, -5.4 vs. -4.5) and for urban White men than for rural White men (AAPC, -4.8 vs. -4.0). Incidence and mortality rates declined faster for urban Black and White women than for their rural counterparts. CONCLUSIONS:Although the disparity in lung cancer death rates between Black and White men has narrowed, significant disparities persist between urban and rural populations. The more rapid decline in mortality rates in urban areas suggests that recent treatment advancements may be less accessible to rural populations.

Federal initiatives, including the Childhood Cancer Data Initiative and the Childhood Cancer Survivorship, Treatment, Access, and Research Act, are advancing pediatric cancer data sharing and strengthening infrastructure required for clinical trials, biobanking, and biospecimen collection. These efforts aim to transform pediatric cancer research to ultimately improve treatment outcomes, quality of life, and survivorship.

Increased expression of lnc-FANCI-2, a newly discovered long noncoding RNA, is associated with cervical lesion progression from cervical intraepithelial neoplasia stage 1 (CIN1, low grade), CIN2–3 (high grade), to cervical cancer. Viral oncoprotein E7 of high-risk human papillomaviruses (HR-HPVs) and host transcription factor YY1 are two major factors promoting lnc-FANCI-2 expression. Using CRISPR-Cas9 technology, we knocked out the expression of lnc-FANCI-2 in the HPV16-positive cervical cancer cell line, CaSki cells. The selected knockout (KO) single-cell clones displayed altered cell morphology and proliferation with changes of cellular soluble receptors, but normal HPV16 E6 and E7 expression. Relative to the parental cells, lnc-FANCI-2 KO cells exhibited significantly increased RAS signaling and epithelial-mesenchymal transition, but decreased response to IFN signaling, along with increased p-Akt and p-Erk1/2 (two RAS signaling effectors), IGFBP3, MCAM, VIM, and CCND2 (cyclin D2) and decreased expression of RAC3. lnc-FANCI-2 in CaSki interacts with cellular proteins H13, HNRH1, K1H1, MAP4K4, and RNPS1. MAP4K4 knockdown led to enhance the expression of p-Erk1/2 and p-Akt. High lnc-FANCI-2 and low MCAM levels in cervical cancer tissues were found to be associated with patients’ survival. A key function of lnc-FANCI-2 intrinsically regulates RAS signaling to impact cervical lesion progression and cervical cancer prognosis.

Background: New approaches to control HPV infections and prevent progression to cervical precancer are needed. We investigate the probability of viral clearance and progression to cervical precancer in women infected with HPV16/18 without evidence of precancer at study enrollment to inform research efforts targeted at reducing cervical cancer. Methods: We included 530 women aged 18-25 who tested HPV16/18 DNA-positive and did not have cytological evidence of high-grade-squamous-intraepithelial-lesion (HSIL) at enrollment in CVT. At each visit, clinicians collected cervical cells for cytology and HPV-DNA testing. Those with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. We estimated the probability of HPV clearance (loss of detection) and progression to intraepithelial neoplasia grades 2 or 3 or worse (CIN2+, CIN3+) based on histological findings by expert pathologists over 4-years of follow-up. Results: At enrollment, there were 550 prevalently detected HPV16 and/or HPV18 infections among 530 women without cytologic HSIL. Corresponding probabilities of HPV16 and HPV18 clearance were 68.5 % (95 %CI 63.6 %-73.0 %) and 85.0 % (78.6 %-90.1 %) by 24-months and 82.1 % (78.0 %-85.7 %) and 90.2 % (84.7 %-94.2 %) by 48-months after initial detection. Risk of clearance of prevalently detected HPV16 and HPV18 infections decreased with increasing age by 12-, 24-, 36-, and 48-months after initial detection (p(trend)-values >= 0.31). Among the same 530 women, by 24-months and 48-months of follow-up, the corresponding probabilities of progression to CIN2+ were 5.5 % (3.8 %-7.7 %) and 13.0 % (10.4 %-16.1 %), and to CIN3+ were 2.6 % (1.5 %-4.3 %) 7.5 % (5.5 %-10.0 %). Probability of progression was 2-5 times higher in women with HPV16 infections than with HPV18. Risk of progression to CIN2+ and CIN3+ increased with increasing age during the follow-up period (p(trend)-values >= 0.11). Conclusions: Among young adult women without evidence of HSIL by cytology, clearance of prevalently detected HPV16/18 infection is a common event, and progression to precancer occurs infrequently but in a sizeable proportion of those with prevalent infection.

HPV vaccines exhibit high type-specific and antibody-mediated protection against anogenital infection, even after a single dose. Complete and long-term “sterilizing” immunity against incident infection appears to be established in most HPV vaccinees, suggesting that not only are persistent levels of virus-inhibiting antibodies routinely generated but that they are also exceptionally potent at preventing infection. The process of HPV infection is unusually protracted at several steps, including slow internalization after the virions bind to the cell surface. This observation prompted us to comprehensively evaluate the ability of neutralizing antibodies to prevent infection subsequent to HPV pseudovirion attachment to cells. Using sera and memory B cell-derived monoclonal antibodies from Gardasil-vaccinated women, we observed almost complete post-attachment neutralization of HPV16 pseudovirion infection of HaCaT cells three hours after attachment, even when vaccinees’ sera were diluted 250-fold, with a gradual loss of activity up to 18 h. Unexpectedly, three distinct mechanisms of post-attachment neutralization were discovered, capsid shedding from the cell surface, capsid retention on the cell surface, and rapid capsid degradation after internalization.

BACKGROUND:In 2022, WHO recommended single-dose human papillomavirus (HPV) vaccination as an alternative schedule to multidose regimens. To provide evidence to support approval of a single-dose indication for the AS04-adjuvanted bivalent HPV vaccine (Cervarix, GlaxoSmithKline), we investigated whether the immune response to a single dose of the bivalent vaccine in girls aged 9-14 years was non-inferior to the immune response to three doses of the quadrivalent HPV vaccine (Gardasil-4, Merck) in women aged 18-25 years, a dose and population combination with demonstrated efficacy. METHODS:This non-randomised, open-label, immunobridging trial enrolled girls aged 9-14 years and women aged 18-25 years in Guanacaste Province, Costa Rica. Healthy girls aged 9-14 years received one dose of bivalent HPV vaccine, whereas healthy women aged 18-25 years received three doses of quadrivalent HPV vaccine at 0, 2, and 6 months. The primary endpoint was geometric mean concentrations (GMCs) of HPV-specific serum antibodies measured by a validated virus-like-particle-based ELISA assay at 36 months. The per-protocol cohort included participants who received the correct number of doses within the predefined vaccination windows, had blood collected at the 36-month study visit for the final analysis, were seronegative at baseline for the specified HPV type, and did not receive additional HPV vaccine doses outside the study. Non-inferiority was declared when the lower bound of the 96% CI for the GMC ratio was greater than or equal to 0·67 for HPV-16 and HPV-18. Seropositivity was a secondary objective. Safety was analysed in the total vaccinated population. This trial is registered with ClinicalTrials.gov, NCT03728881, and is complete. FINDINGS:Between April 1 and Aug 16, 2019, 620 girls and 620 women were enrolled and received their first HPV vaccination. After exclusions, 539 girls and 366 women were HPV-16 seronegative at enrolment and were included in the HPV-16 per-protocol cohort; 523 girls and 373 women were HPV-18 seronegative at enrolment and were included in the HPV-18 per-protocol cohort. At 36 months, the HPV-16 GMC was 21·4 international units (IU)/mL (95% CI 19·7-23·3) in girls in the single-dose bivalent vaccine group and 42·9 IU/mL (95% CI 38·9-47·3) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 0·50 (96% CI 0·44-0·57); the HPV-18 GMC was 8·0 IU/mL (95% CI 7·4-8·8) in girls in the single-dose bivalent vaccine group and 7·2 IU/mL (95% CI 6·4-8·1) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 1·11 (96% CI 0·95-1·29). At 36 months, 538 (99·8%, 95% CI 99·1-100) of 539 girls in the single-dose bivalent vaccine group were seropositive for HPV-16 compared with 366 (100%, 99·2-100) of 366 women in the three-dose quadrivalent vaccine group (p=1·00). The proportion of participants who were seropositive for HPV-18 was higher in the single-dose bivalent vaccine group (517 [98·9%, 95% CI 97·6-99·5] of 523 girls) than in the three-dose quadrivalent vaccine group (358 [96·0%, 93·6-97·6] of 373 women; p=0·0065). Two serious adverse events were reported in 620 girls and 13 serious adverse events were reported in 620 women; all serious adverse events were deemed to be unrelated to HPV vaccination. INTERPRETATION:Non-inferior antibody responses for the single-dose bivalent HPV vaccine were seen for HPV-18 but not HPV-16, which would be insufficient evidence to motivate regulatory change, even though seropositivity approached 100% in the follow-up phase and the observed antibody concentrations were similar to protective levels seen in previous trials. Trials that directly evaluate protection afforded by single-dose HPV vaccination against persistent HPV infection will definitively address the level of protection afforded by single-dose HPV vaccination. FUNDING:National Cancer Institute, Cancer Research UK, and the Gates Foundation. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.

BACKGROUND:Progress against cancer mortality has been driven by primary prevention, early detection, and cancer treatment. We estimated the number of cancer deaths that were avoided due to stage-specific improvements in cancer survival among patients diagnosed in 2010-2019 followed through 2020. METHODS:We used cancer incidence data from 17 Surveillance, Epidemiology, and End Results (SEER) cancer registries during 2004-2019. We estimated the number of cancer deaths prevented due to cancer- and stage-specific survival improvements (based on SEER summary stage) as the observed minus expected number of cancer deaths through 2020. We calculated the expected number of cancer deaths from estimated cumulative incidence models setting the calendar year effect to 2009. RESULTS:During 2010-2019, there were 3 310 270 incident cancers and 966 733 cancer deaths through 2020 in SEER-17. Improvements in stage-specific cancer survival resulted in a 4.7% (95% CI = -5.3% to -4.2%) decline in cancer deaths in females (22,874 fewer deaths) and a 4.4% (95% CI = -4.9% to -3.9%) decline in males (23 198 fewer deaths) in SEER-17 regions, corresponding to approximately 173 900 fewer cancer deaths in the full US population. The largest absolute declines were for lung and liver cancers, whereas the largest relative declines were observed for melanoma and leukemia. Cancer deaths prevented were not statistically significant for colorectal or prostate cancers. All statistical tests were 2-sided. CONCLUSIONS:Stage-specific survival gains, reflecting treatment advances and improved access to cancer treatment from 2010 to 2019, resulted in an estimated 173 900 fewer cancer deaths among US cancer patients diagnosed during this time period.

11051 Background: Cancer screening can decrease cancer incidence, mortality, and treatment costs. However, the annual cost of screening to the U.S. healthcare system is unknown. Methods: We used data from national healthcare surveys and standard costing sources to model the healthcare system cost of breast, cervical, colorectal, lung, and prostate cancer screening in the U.S. in 2021. Models projected the number of individuals in the U.S. eligible for each screening test based on current guidelines/recommendations; the number of eligible individuals screened by insurance status; and the costs associated with screening (in 2021 US dollars). Multiple sensitivity analyses were performed to examine the effects of changing model population parameters and costs on projected outcomes. Results: Total 2021 cancer screening costs to the U.S. healthcare system were estimated to be $57 billion; approximately 88% of the costs were attributable to private insurance, 9% to Medicare, and 3% to Medicaid, other government programs, and uninsured individuals. Most screened individuals had private insurance except for lung cancer screening, where a majority of individuals screened had Medicare coverage. Individuals with private insurance accounted for the majority of costs for each screening modality. Screening for colorectal cancer represented approximately two-thirds of the total cost; screening colonoscopy was approximately 60% of the total cost of cancer screening. Breast and cervical cancer screening represented the second and third largest screening costs, 15.4% and 14.7% (respectively) of total screening costs. Facility costs (amounts paid to facilities where testing occurred) were generally larger components of the total estimated costs of screening than were physician costs. Cost estimates were robust to a range of variations in eligible populations and screening costs. Conclusions: The $57 billion estimated annual cost for cancer screening in the U.S. in 2021 is similar to the estimated annual cost of cancer treatment in the U.S. in the first 12 months following diagnosis. Screening may have been suboptimal in 2021, with higher screening rates and costs in subsequent years. Identification of cancer screening costs and their drivers is critical to help inform policy and develop programmatic priorities. The model can be used to estimate the increased costs of enhanced access to recommended cancer screening services among underscreened populations, which would provide population-wide benefits.

Canonical RAS signaling, including PI3K/AKT- and RAF/MEK-dependent activities, results mainly from RAS•GTP interaction with its effectors at the plasma membrane. Here, we identified a fundamental, oncogenic, noncanonical RAS•GTP activity that increases XPO1-dependent export of nuclear protein cargo into the cytoplasm and is independent of PI3K/AKT and RAF/MEK signaling. This RAS-dependent step acts downstream from XPO1 binding to nuclear protein cargo and is mediated by a perinuclear protein complex between RAS•GTP and RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP, which promotes release of nuclear protein cargo into the cytoplasm. The export of nuclear EZH2, which promotes cytoplasmic degradation of the DLC1 tumor suppressor protein, is a biologically important component of this pro-oncogenic activity. Conversely, preventing nuclear protein export contributes to the antitumor activity of KRAS inhibition, which can be further augmented by reactivating the tumor suppressor activity of DLC1 or potentially combining RAS inhibitors with other cancer treatments.