CDK4/6i-treated HR+/HER2- breast cancer tumors show higher ESR1 mutation prevalence and more altered genomic landscape.

As CDK4/6 inhibitor (CDK4/6i) approval changed treatment strategies for patients with hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer (BC), understanding how exposure to CDK4/6i affects the tumor genomic landscape is critical for precision oncology. Using real-world data (RWD) with tumor genomic profiling from 5910 patients with metastatic HR+/HER2- BC, we investigated the evolution of alteration prevalence in commonly mutated genes across patient journeys. We found that ESR1 is more often altered in tumors exposed to at least 1 year of adjuvant endocrine therapy, contrasting with TP53 alterations. We observed a similar trend after first-line treatments in the advanced setting, but strikingly exposure to aromatase inhibitors (AI) combined with CDK4/6i led to significantly higher ESR1 alteration prevalence compared to AI alone, independent of treatment duration. Further, CDK4/6i exposure was associated with higher occurrence of concomitant alterations in multiple oncogenic pathways. Differences based on CDK4/6i exposure were confirmed in samples collected after 2L and validated in samples from the acelERA BC clinical trial. In conclusion, our work uncovers opportunities for further treatment personalization and stresses the need for effective combination treatments to address the altered tumor genomic landscape following AI+CDK4/6i exposure. Further, we demonstrated the potential of RWD for refining patient treatment strategy and guiding clinical trial design.

Temporal Patterns and Adoption of Germline and Somatic BRCA Testing in Ovarian Cancer.

OBJECTIVE: To describe the testing rate, patient characteristics, temporal trends, timing, and results of germline and somatic BRCA testing in patients with ovarian cancer using real-world data. METHODS: We included a cross-sectional subset of adult patients diagnosed with ovarian cancer between January 1, 2011, and November 30, 2018, who received frontline treatment and were followed for at least 1 year in a real-world database. The primary outcome was receipt of BRCA testing, classified by biosample source as germline (blood or saliva) or somatic (tissue). Lines of therapy (frontline, second line, third line) were derived based on dates of surgery and chemotherapy. Descriptive statistics were analyzed. RESULTS: Among 2,557 patients, 72.2% (n=1,846) had at least one documented BRCA test. Among tested patients, 62.5% (n=1,154) had only germline testing, 10.6% (n=197) had only somatic testing, and 19.9% (n=368) had both. Most patients had testing before (9.7%, n=276) or during (48.6%, n=1,521) frontline therapy, with 17.6% (n=273) tested during second-line and 12.7% (n=129) tested during third-line therapy. Patients who received BRCA testing, compared with patients without testing, were younger (mean age 63 years vs 66 years, P <.001) and were more likely to be treated at an academic practice (10.4% vs 7.0%, P =.01), with differences by Eastern Cooperative Oncology Group performance score ( P <.001), stage of disease ( P <.001), histology ( P <.001), geography ( P <.001), and type of frontline therapy ( P <.001), but no differences based on race or ethnicity. The proportion of patients who received BRCA testing within 1 year of diagnosis increased from 24.6% of patients in 2011 to 75.6% of patients in 2018. CONCLUSION: In a large cohort of patients with ovarian cancer, significant practice disparities existed in testing for actionable BRCA mutations. Despite increased testing over time, many patients did not receive testing, suggesting missed opportunities to identify patients appropriate for targeted therapy and genetic counseling.

Disparities in Tumor Mutational Burden, Immunotherapy Use, and Outcomes Based on Genomic Ancestry in Non-Small-Cell Lung Cancer.

PURPOSE: In patients with advanced non-small-cell lung cancer (aNSCLC), tumor mutational burden (TMB) may vary by genomic ancestry; however, its impact on treatment outcomes is unclear. This retrospective, observational study describes treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and evaluates differences in TMB, cancer immunotherapy (CIT) access, and treatment outcomes across racial and ancestral groups. METHODS: Patients diagnosed with aNSCLC after January 1, 2011, were selected from a real-world deidentified clinicogenomics database and EHR-derived database; continuously enrolled patients were evaluated. Race and/or ethnicity was recorded using variables from the EHR database; genomic ancestry was classified by single-nucleotide polymorphisms on a next-generation sequencing panel. A threshold of 16 mutations per megabase was used to categorize TMB status. RESULTS: Of 59,559 patients in the EHR-derived database and 7,548 patients in the clinicogenomics database, 35,016 (58.8%) and 4,392 (58.2%) were continuously enrolled, respectively. CIT use was similar across EHR-reported race groups, ranging from 34.4% to 37.3% for non-Hispanic Asian and non-Hispanic Black patients, respectively. TMB levels varied significantly across ancestry groups (P < .001); patients of African ancestry had the highest median TMB (8.75 mutations per megabase; interquartile range, 4.35-14.79). In patients who had received CIT, high TMB was associated with improved overall survival compared with low TMB (20.89 v 11.83 months; hazard ratio, 0.60; 95% CI, 0.51 to 0.70) across genomic ancestral groups. CONCLUSION: These results suggest that equitable access to next-generation sequencing may improve aNSCLC outcome disparities in racially and ancestrally diverse populations.

Patterns and Predictors of First-Line Taxane Use in Patients with Metastatic Triple-Negative Breast Cancer in US Clinical Practice.

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005-June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2,271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69-2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25-2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13-0.80)) or docetaxel (0.30 (0.10-0.89)) use. More recent index year (2011-2015 vs 2005-2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26-3.21)) or docetaxel (3.63 (2.11-6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.

Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma.

Immune checkpoint inhibitors (CPIs) have expanded treatment options for patients with solid tumors. Systemic corticosteroids (CSs) have an indispensable role in cancer care, but CS-related immunosuppression may counteract the CPI-driven antitumor immune response. This retrospective study investigated the association between baseline CS use (bCS; ≤14 days before, ≤30 days after CPI initiation) and clinical outcomes in patients with advanced non-small cell lung cancer (aNSCLC), melanoma (aMel), or urothelial carcinoma (aUC). We analyzed data from the Flatiron Health electronic health record-derived de-identified database for adults diagnosed with aNSCLC, aMel, or aUC between January 2011 and June 2017 who received ≥1 CPI monotherapy in any treatment line. Associations of bCS use with overall survival (OS) and time to next treatment (TTNT) were estimated using multivariable Cox proportional hazards models adjusting for demographic and clinical characteristics (i.e., ECOG performance status, site of metastases). In total, 2,213 patients were diagnosed with aNSCLC (n = 862), aMel (n = 742), or aUC (n = 609) and received ≥1 CPI administration. Most patients (67%-95%) received CSs, many during the baseline period (19%-30%). Patients with bCS use had shorter median OS than those with no bCS use for aNSCLC (6.6 vs 10.6 months; P= .00018), aMel (16.4 vs 21.5; P= .095), and aUC (4.1 vs 7.7; P= .0012). bCS use was associated with shorter OS (not significant for aMel) and TTNT in adjusted multivariable analyses, and clinical outcomes were not explained by prior CS use or other measured confounders. These findings suggest a potential association between bCS use and decreased CPI effectiveness, warranting further investigation.

Comparative effectiveness of first-line nab-paclitaxel versus paclitaxel monotherapy in triple-negative breast cancer.

Aim: This observational study evaluated the effectiveness of nab-paclitaxel versus paclitaxel monotherapy as first-line (1L) treatment for metastatic triple-negative breast cancer (mTNBC). Materials & methods: 200 patients from the US Flatiron Health electronic health record-derived database (mTNBC diagnosis, January 2011-October 2016) who received 1L nab-paclitaxel (n = 105) or paclitaxel (n = 95) monotherapy were included. Overall survival and time to next treatment were evaluated. Results: The adjusted overall survival hazard ratio was 0.98 (95% CI: 0.67-1.44), indicating a similar risk of death between groups. Adjusted time to next treatment hazard ratio was 0.89 (95% confidence interval: 0.62-1.29). Conclusion: Nab-paclitaxel and paclitaxel monotherapy showed similar efficacy, suggesting their interchangeability as 1L treatments for mTNBC.

Validation of diagnosis codes to identify side of colon in an electronic health record registry.

BACKGROUND: The use of real-world data to generate evidence requires careful assessment and validation of critical variables before drawing clinical conclusions. Prospective clinical trial data suggest that anatomic origin of colon cancer impacts prognosis and treatment effectiveness. As an initial step in validating this observation in routine clinical settings, we explored the feasibility and accuracy of obtaining information on tumor sidedness from electronic health records (EHR) billing codes. METHODS: Nine thousand four hundred three patients with metastatic colorectal cancer (mCRC) were selected from the Flatiron Health database, which is derived from de-identified EHR data. This study included a random sample of 200 mCRC patients. Tumor site data derived from International Classification of Diseases (ICD) codes were compared with data abstracted from unstructured documents in the EHR (e.g. surgical and pathology notes). Concordance was determined via observed agreement and Cohen's kappa coefficient (κ). Accuracy of ICD codes for each tumor site (left, right, transverse) was determined by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and corresponding 95% confidence intervals, using abstracted data as the gold standard. RESULTS: Study patients had similar characteristics and side of colon distribution compared with the full mCRC dataset. The observed agreement between the ICD codes and abstracted data for tumor site for all sampled patients was 0.58 (κ = 0.41). When restricting to the 62% of patients with a side-specific ICD code, the observed agreement was 0.84 (κ = 0.79). The specificity (92-98%) of structured data for tumor location was high, with lower sensitivity (49-63%), PPV (64-92%) and NPV (72-97%). Demographic and clinical characteristics were similar between patients with specific and non-specific side of colon ICD codes. CONCLUSIONS: ICD codes are a highly reliable indicator of tumor location when the specific location code is entered in the EHR. However, non-specific side of colon ICD codes are present for a sizable minority of patients, and structured data alone may not be adequate to support testing of some research hypotheses. Careful assessment of key variables is required before determining the need for clinical abstraction to supplement structured data in generating real-world evidence from EHRs.

Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer.

Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program.

BACKGROUND: Onartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program. METHODS: Adverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) "gastrointestinal (GI) perforation", "embolic and thrombotic events, venous (VTE)", and "embolic and thrombotic events, arterial (ATE)", and the Adverse Event Group Term (AEGT) "edema." The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis. RESULTS: A total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1-2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4-65.7% for all grades and from 1.2-14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0-5.6% (grade ≥3, 0-5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0-6.2%) and grade ≥3 (0-6.2%). CONCLUSIONS: The frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.

PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors.

PURPOSE: Clonal loss of PTEN expression occurs frequently in endometrial carcinoma and endometrial hyperplasia. Limited data from immunohistochemical studies suggest that PTEN-null appearing endometrial glands are detectable in women without pathologic abnormalities, but the relationship of PTEN expression to endometrial cancer risk factors has not been extensively explored. We evaluated relationships between endometrial cancer risk factors and loss of PTEN expression in a set of benign endometrial samples prospectively collected from women undergoing hysterectomy and in endometrial cancer tissues from a population-based case-control study. METHODS: We used a validated PTEN immunohistochemical assay to assess expression in epidemiological studies designed to assess benign endometrium [Benign Reproductive Tissue Evaluation Study (n = 73); Einstein Endometrium Study (n = 19)], and endometrial cancer [Polish Endometrial Cancer Study (n = 148)] tissues. Associations between endometrial cancer risk factors (collected via study-specific risk factor questionnaires) and PTEN expression in endometrial tissues were determined using Fisher's exact tests. RESULTS: PTEN loss was detected in 19% of benign endometrial tissues versus 55% in endometrial cancers. NSAID use was statistically significantly associated with PTEN loss in the benign endometrium (p = 0.02). CONCLUSION: Our data demonstrate that PTEN loss is detectable in endometrial tissues that are benign and malignant, with substantially more frequent loss in endometrial cancer compared with benign endometrium. However, alterations in expression were unrelated to most risk factors in this analysis, except for the association with NSAID use, which may represent a chance finding or reverse causality among patients with endometriosis who may have PTEN pathway abnormalities in eutopic endometrium. Further evaluation of factors associated with PTEN loss and long-term follow-up of women with PTEN-null endometrial glands may be useful in understanding early events in endometrial carcinogenesis.

Discovery and validation of methylation markers for endometrial cancer.

The prognosis of endometrial cancer is strongly associated with stage at diagnosis, suggesting that early detection may reduce mortality. Women who are diagnosed with endometrial carcinoma often have a lengthy history of vaginal bleeding, which offers an opportunity for early diagnosis and curative treatment. We performed DNA methylation profiling on population-based endometrial cancers to identify early detection biomarkers and replicated top candidates in two independent studies. We compared DNA methylation values of 1,500 probes representing 807 genes in 148 population-based endometrial carcinoma samples and 23 benign endometrial tissues. Markers were replicated in another set of 69 carcinomas and 40 benign tissues profiled on the same platform. Further replication was conducted in The Cancer Genome Atlas and in prospectively collected endometrial brushings from women with and without endometrial carcinomas. We identified 114 CpG sites showing methylation differences with p values of ≤ 10(-7) between endometrial carcinoma and normal endometrium. Eight genes (ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) were selected for further replication. Age-adjusted odds ratios for endometrial cancer ranged from 3.44 (95%-CI: 1.33-8.91) for ASCL2 to 18.61 (95%-CI: 5.50-62.97) for HTR1B. An area under the curve (AUC) of 0.93 was achieved for discriminating carcinoma from benign endometrium. Replication in The Cancer Genome Atlas and in endometrial brushings from an independent study confirmed the candidate markers. This study demonstrates that methylation markers may be used to evaluate women with abnormal vaginal bleeding to distinguish women with endometrial carcinoma from the majority of women without malignancy.

Health disparities around the world: perspectives from the 2012 Principles and Practice of Cancer Prevention and Control course at the National Cancer Institute.

INTRODUCTION: The National Cancer Institute Principles and Practice of Cancer Prevention and Control course is a 4-week course encompassing a variety of cancer prevention and control topics that is open to attendees from medical, academic, government, and related institutions around the world. Themes related to the challenges health disparities present to cancer prevention efforts and potential solutions to these issues emerged from facilitated group discussions among the 2012 course participants. MATERIALS AND METHODS: Small-group discussion sessions with participants (n = 85 from 33 different countries) and facilitators (n = 9) were held once per week throughout the 4-week course. Facilitators prepared open-ended questions related to course topics. Participants provided responses reflecting their opinions of topics on the basis of experiences in their countries. A thematic analysis was conducted to explore themes emerging from the discussion groups. RESULTS: The varied influences of health disparities on cancer prevention efforts among > 30 countries represented prominent themes across discussion groups. Participants discussed the interplay of individual characteristics, including knowledge and culture, interpersonal relationships such as family structure and gender roles, community and organizational factors such as unequal access to health care and access to treatment, and national-level factors including policy and government structure. CONCLUSION: The ideas and solutions presented here are from a geographically and professionally diverse group of individuals. The collective discussion highlighted the pervasiveness of health disparities across all areas represented by course participants and suggested that disparities are the largest impediment to achieving cancer prevention goals.

Risk factors for anal HPV infection and anal precancer in HIV-infected men who have sex with men.

BACKGROUND: Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM. METHODS: Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer. RESULTS: Low CD4 count (<350 cells/mm(3)) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28-10.40 and OR, 4.24; 95% CI, 1.16-15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43-5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection. CONCLUSIONS: We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.

Chromosomal gains measured in cytology samples from women with abnormal cervical cancer screening results.

OBJECTIVE: Chromosomal gains at 3q26, 5p15 and 20q13 have been described in cervical precancer and cancer. We evaluated a novel fluorescence in situ hybridization (FISH) assay that detects gains at these three loci simultaneously as a possible biomarker for detecting cervical precancer. METHODS: Chromosomal copy numbers at 3q26, 5p15, 20q13 and the centromere of chromosome7 (cen7) in liquid-based cytology specimens from 168 women enrolled in the Biopsy Study were determined by FISH. The number of cells with ≥ 3 or ≥ 4 signals for a genomic locus was enumerated and diagnostic test performance measures were calculated using receiver operating characteristic (ROC) analyses. Sensitivity and specificity values were determined for the detection of CIN2+ and/or HSIL. RESULTS: The median number of cells with ≥ 3 signals increased with the severity of cervical lesion for each genomic locus (p-trend<0.02 for each locus). ROC analysis for the number of cells with ≥ 3 signals resulted in area under the curve values of 0.70 (95% CI: 0.54-0.86), 0.67 (0.52-0.83), 0.67 (0.51-0.83) and 0.78 (0.64-0.92) for 3q26, 5p15, 20q13 and cen7, respectively, for the detection of CIN2+ and/or HSIL. Positivity for gains at multiple loci resulted in only slightly better test performance measures than those for the individual probes for four distinct combinations of probes. CONCLUSIONS: Chromosomal gains at 3q26, 5p15, 20q13 and cen7 are associated with severity of cervical lesions. Further studies are required to quantify risk stratification of FISH assays for cervical cancer screening.

Circulating adipokine levels and endometrial cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.

BACKGROUND: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. METHODS: We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw, and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). ORs and 95% confidence intervals (CIs) for the associations of adiponectin, leptin, and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. RESULTS: Adiponectin levels were inversely associated with risk of endometrial cancer [ORT3vsT1 = 0.48; 95% CI, 0.29-0.80); Ptrend < 0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); Ptrend < 0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.25 (0.08-0.75); Ptrend = 0.01 and 4.72 (1.15-19.38); Ptrend = 0.02, respectively]. Nonsignificant positive associations were observed for visfatin. CONCLUSION: Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT. IMPACT: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association.

HPV-based Tests for Cervical Cancer Screening and Management of Cervical Disease.

Current cervical cancer screening programs are changing due to the development of tests that detect the presence of human papillomavirus (HPV), the cause of cervical cancer. These tests are more sensitive than cytology-based methods for detecting cervical precancer and a negative test offers long-term assurance that cervical cancer will not develop and therefore longer screening intervals can be achieved. In screening programs, HPV-based tests have been approved to triage women with equivocal cytology results and as a primary testing method in conjunction with cytology. HPV-based tests also have a role in determining risk of recurrence after treatment for cervical precancer as well as in surveillance for vaccine-related changes in HPV genotype prevalence.

The role of co-factors in the progression from human papillomavirus infection to cervical cancer.

OBJECTIVE: Co-factors for cervical cancer, including oral contraceptive (OC) use, smoking and multiparity have been identified; however, the stage at which they act in cervical carcinogenesis is not clear. We compared established risk factors among women with CIN2 and CIN3 to evaluate the heterogeneity of these factors in precancer and also assessed their role during cervical carcinogenesis. METHODS: The current analysis included 2783 women with various stages of cervical disease who were enrolled in the Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED) and the Biopsy Study. Associations of co-factors within cervical precancer and at different stages of cervical carcinogenesis were estimated using logistic regression. RESULTS: Long-term OC use (10+years vs. never: OR=2.42, 95% CI: [1.13-5.15]), multiparity (3+ births vs. nulliparous: OR=1.54 [1.04-2.28]), smoking (ever vs. never: OR=1.95 [1.48-2.58]), and no Pap test in the previous five years (2.05 [1.32-3.17]) were positively associated with CIN3 compared to CIN2. We observed that long-term OC use, parity and smoking were associated with an increased risk of CIN3 compared to

Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts.

While organized screening programs in industrialized countries have significantly reduced cervical cancer incidence, cytology-based screening has several limitations. Equivocal or mildly abnormal Pap tests require costly retesting or diagnostic work-up by colposcopy and biopsy. In low-resource countries, it has been difficult to establish and sustain cytology-based programs. Advances in understanding human papillomavirus biology and the natural history of human papillomavirus-related precancers and cancers have led to the discovery of a range of novel biomarkers in the past decade. In this article, we will discuss the potential role of new biomarkers for primary screening, triage and diagnosis in high-resource countries and their promise for prevention efforts in resource constrained settings.

Identification of FAKTS as a novel 14-3-3-associated nuclear protein.

Through bioinformatics and experimental approaches, we have assigned the first biochemical property to a predicted protein product in the human genome as a new 14-3-3 binding protein. 14-3-3 client proteins represent a diverse group of regulatory molecules that often function as signaling integrators in response to various environmental cues and include proteins such as Bad and Foxo. Using 14-3-3 as a probe in a yeast two-hybrid screen, we identified a novel 14-3-3 binding protein with unknown function, initially designated as clone 546. Confocal microscopy revealed that clone 546 localized to the nucleus of mammalian cells. Additional studies show that the gene encoding clone 546 is expressed in many human tissues, including the thymus, as well as a number of cancer cell lines. The interaction of clone 546 with 14-3-3 was confirmed in mammalian cells. Interestingly, this interaction was markedly enhanced by the expression of activated Akt/PKB, suggesting a phosphorylation dependent event. Mutational analysis was carried out to identify Ser479 as the predominant residue that mediates the clone 546/14-3-3 association. Phosphorylation of Ser479 by AKT/PKB further supports a critical role for Akt/PKB in regulation of the clone 546/14-3-3 interaction. On the basis of these findings, we named this undefined protein FAKTS: Fourteen-three-three associated AKT Substrate.