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PurposeWe investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities.MethodsNon-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC).ResultsThis study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

BACKGROUND: Half of countries in Africa lack access to radiation (RT), which is essential for standard treatment of locally advanced cervical cancers. We evaluated outcomes for patients treated with neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in settings where no RT is available. METHODS: We performed a retrospective descriptive study of all patients with FIGO stage IB2-IIA2 and some exceptional stage IIB cases who received NACT and surgery at Kigali University Teaching Hospital in Rwanda. Patients were treated with NACT consisting of carboplatin and paclitaxel once every 3 weeks for 3-4 cycles before radical hysterectomy. We calculated recurrence rates and overall survival (OS) rate was determined by Kaplan-Meier estimates. RESULTS: Between May 2016 and October 2018, 57 patients underwent NACT and 43 (75.4%) were candidates for radical hysterectomy after clinical response assessment. Among the 43 patients who received NACT and surgery, the median age was 56 years, 14% were HIV positive, and FIGO stage distribution was: IB2 (32.6%), IIA1 (7.0%), IIA2 (51.2%) and IIB (9.3%). Thirty-nine (96%) patients received 3 cycles and 4 (4%) received 4 cycles of NACT. Thirty-eight (88.4%) patients underwent radical hysterectomy as planned and 5 (11.6%) had surgery aborted due to grossly metastatic disease. Two patients were lost to follow up after surgery and excluded from survival analysis. For the remaining 41 patients with median follow-up time of 34.4 months, 32 (78%) were alive with no evidence of recurrence, and 8 (20%) were alive with recurrence. One patient died of an unrelated cancer. The 3-year OS rate for the 41 patients who underwent NACT and surgery was 80.8% with a recurrence rate of 20%. CONCLUSIONS: Neoadjuvant chemotherapy with radical hysterectomy is a feasible treatment option for locally advanced cervical cancer in settings with limited access to RT. With an increase in gynecologic oncologists skilled at radical surgery, this approach may be a more widely available alternative treatment option in countries without radiation facilities.

BACKGROUND: Despite the increased risk of cervical cancer (CC) among women living with HIV (WLHIV), CC screening and treatment (CCST) rates remain low in Africa. The integration of CCST services into established HIV programs in Africa can improve CC prevention and control. However, the paucity of evidence on effective implementation strategies (IS) has limited the success of integration in many countries. In this study, we seek to identify effective IS to enhance the integration of CCST services into existing HIV programs in Nigeria. METHODS: Our proposed study has formative and experimental activities across the four phases of the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework. Through an implementation mapping conducted with stakeholders in the exploration phase, we identified a core package of IS (Core) and an enhanced package of IS (Core+) mostly selected from the Expert Recommendations for Implementing Change. In the preparation phase, we refined and tailored the Core and Core+ IS with the implementation resource teams for local appropriateness. In the implementation phase, we will conduct a cluster-randomized hybrid type III trial to assess the comparative effectiveness of Core versus Core+. HIV comprehensive treatment sites (k = 12) will be matched by region and randomized to Core or Core+ in the ratio of 1:1 stratified by region. In the sustainment phase, we will assess the sustainment of CCST at each site. The study outcomes will be assessed using RE-AIM: reach (screening rate), adoption (uptake of IS by study sites), IS fidelity (degree to which the IS occurred according to protocol), clinical intervention fidelity (delivery of CC screening, onsite treatment, and referral according to protocol), clinical effectiveness (posttreatment screen negative), and sustainment (continued integrated CCST service delivery). Additionally, we will descriptively explore potential mechanisms, including organizational readiness, implementation climate, CCST self-efficacy, and implementation intentions. DISCUSSION: The assessment of IS to increase CCST rates is consistent with the global plan of eliminating CC as a public health threat by 2030. Our study will identify a set of evidence-based IS for low-income settings to integrate evidence-based CCST interventions into routine HIV care in order to improve the health and life expectancy of WLHIV. TRIAL REGISTRATION: Prospectively registered on November 7, 2023, at ClinicalTrials.gov no. NCT06128304. https://classic. CLINICALTRIALS: gov/ct2/show/study/NCT06128304.

UNLABELLED: Rapid proliferation is a hallmark of cancer associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent advances in deep learning to facilitate multidrug prediction and mechanistic interpretation. Initial studies in tumor cells identify 41 molecular assemblies that integrate alterations in hundreds of genes for accurate drug response prediction. These cover roles in transcription, repair, cell-cycle checkpoints, and growth signaling, of which 30 are shown by loss-of-function genetic screens to regulate drug sensitivity or replication restart. The model translates to cisplatin-treated cervical cancer patients, highlighting an RTK-JAK-STAT assembly governing resistance. This study defines a compendium of mechanisms by which mutations affect therapeutic responses, with implications for precision medicine. SIGNIFICANCE: Zhao and colleagues use recent advances in machine learning to study the effects of tumor mutations on the response to common therapeutics that cause RS. The resulting predictive models integrate numerous genetic alterations distributed across a constellation of molecular assemblies, facilitating a quantitative and interpretable assessment of drug response. This article is featured in Selected Articles from This Issue, p. 384.

PURPOSE: To achieve the WHO cervical cancer elimination targets, countries globally must achieve 70% cervical cancer screening (CCS) coverage. We evaluated CCS uptake and predictors of screening positive at two public HIV care programs in western Kenya. METHODS: From October 2007 to February 2019, data from the Family AIDS Care and Education Services (FACES) and Academic Model Providing Access to Healthcare (AMPATH) programs in western Kenya were analyzed. The study population included women age 18-65 years enrolled in HIV care. Screening uptake was calculated annually and overall, determining the proportion of eligible women screened. Multivariate logistic regression assessed predictors of positive screening outcomes. RESULTS: There were 57,298 women living with HIV (WLWHIV) eligible for CCS across both programs during the study period. The mean age was 31.4 years (IQR, 25.9-37.8), and 39% were on antiretroviral therapy (ART) at the first CCS-eligible visit. Of all eligible women, 29.4% (95% CI, 29.1 to 29.8) underwent CCS during the study period, 27.0% (95% CI, 26.5 to 27.4) in the AMPATH program, and 35.6% (95% CI, 34.9 to 36.4) in the FACES program. Annual screening uptake varied greatly in both programs, with coverage as low as 1% of eligible WLWHIV during specific years. Age at first screening, CD4 count within 90 days of screening, current use of ART, and program (AMPATH v FACES) were each statistically significant predictors of positive screening. CONCLUSION: CCS uptake at two large HIV care programs in Kenya fell short of the WHOs 70% screening target. Screening rates varied significantly on the basis of the availability of funding specific to CCS, reflecting the limitations of vertical funding programs.

The high incidence of epithelial malignancies in HIV-1 infected individuals is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), mostly HPV16. The molecular mechanisms underlying the HIV-1-associated increase in epithelial malignancies are not fully understood. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells has long been anticipated. Here, we delineated the effects of HIV-1 reverse transcriptase on the in vitro and in vivo properties of HPV16-infected cervical cancer cells. A human cervical carcinoma cell line infected with HPV16 (Ca Ski) was made to express HIV-1 reverse transcriptase (RT) by lentiviral transduction. The levels of the mRNA of the E6 isoforms and of the factors characteristic to the epithelial/mesenchymal transition were assessed by real-time RT-PCR. The parameters of glycolysis and mitochondrial respiration were determined using Seahorse technology. RT expressing Ca Ski subclones were assessed for the capacity to form tumors in nude mice. RT expression increased the expression of the E6*I isoform, modulated the expression of E-CADHERIN and VIMENTIN, indicating the presence of a hybrid epithelial/mesenchymal phenotype, enhanced glycolysis, and inhibited mitochondrial respiration. In addition, the expression of RT induced phenotypic alterations impacting cell motility, clonogenic activity, and the capacity of Ca Ski cells to form tumors in nude mice. These findings suggest that HIV-RT, a multifunctional protein, affects HPV16-induced oncogenesis, which is achieved through modulation of the expression of the E6 oncoprotein. These results highlight a complex interplay between HIV antigens and HPV oncoproteins potentiating the malignant transformation of epithelial cells.

BackgroundRecently-updated global guidelines for cervical cancer screening incorporated new technologies-most significantly, the inclusion of HPV DNA detection as a primary screening test-but leave many implementation decisions at countries' discretion. We sought to develop recommendations for Malawi as a test case since it has the second-highest cervical cancer burden globally and high HIV prevalence. We incorporated updated epidemiologic data, the full range of ablation methods recommended, and a more nuanced representation of how HIV status intersects with cervical cancer risk and exposure to screening to model outcomes of different approaches to screening.MethodsUsing a Markov model, we estimate the relative health outcomes and costs of different approaches to cervical cancer screening among Malawian women. The model was parameterized using published data, and focused on comparing "triage" approaches-i.e., lesion treatment (cryotherapy or thermocoagulation) at differing frequencies and varying by HIV status. Health outcomes were quality-adjusted life years (QALYs) and deaths averted. The model was built using TreeAge Pro software.ResultsThermocoagulation was more cost-effective than cryotherapy at all screening frequencies. Screening women once per decade would avert substantially more deaths than screening only once per lifetime, at relatively little additional cost. Moreover, at this frequency, it would be advisable to ensure that all women who screen positive receive treatment (rather than investing in further increases in screening frequency): for a similar gain in QALYs, it would cost more than four times as much to implement once-per-5 years screening with only 50% of women treated versus once-per-decade screening with 100% of women treated. Stratified screening schedules by HIV status was found to be an optimal approach.ConclusionsThese results add new evidence about cost-effective approaches to cervical cancer screening in low-income countries. At relatively infrequent screening intervals, if resources are limited, it would be more cost-effective to invest in scaling up thermocoagulation for treatment before increasing the recommended screening frequency. In Malawi or countries in a similar stage of the HIV epidemic, a stratified approach that prioritizes more frequent screening for women living with HIV may be more cost-effective than population-wide recommendations that are HIV status neutral.