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1.  Genetic Variants That Presdispose to DNA Double-strand Breaks in Lymphocytes from a Subset of Patients With Familial Colorectal Carcinomas 
Gastroenterology  2015;149(7):1872-1883.e9.
BACKROUND & AIMS
DNA structural lesions are prevalent in sporadic colorectal cancer, so we proposed that gene variants that predispose to DNA double-strand breaks (DSBs) would be found in patients with familial colorectal carcinomas of an undefined genetic basis (UFCRC).
METHODS
We collected primary T cells from 25 patients with UFCRC and matched patients without colorectal cancer (controls) and assayed for DSBs. We performed exome sequence analyses of germline DNA from 20 patients with UFCRC and 5 undiagnosed patients with polyposis. The prevalence of identified variants in genes linked to DNA integrity was compared to that of individuals without a family history of cancer. The effects of representative variants found to be associated with UFCRC was confirmed in functional assays with HCT116 cells.
RESULTS
Primary T cells from most patients with UFCRC had increased levels of the DSB marker γH2AX following treatment with DNA damaging agents, compared to T cells from controls (P<.001). Exome sequence analysis identified a mean 1.4 rare variants/patient that were predicted to disrupt functions of genes relevant to DSBs. Controls (from public databases) had a much lower frequency of variants in the same genes (P<.001). Knockdown of representative variant genes in HCT116 CRC cells increased γH2AX. Detailed analysis of immortalized patient-derived B cells, which contained variants in the Werner syndrome, RecQ helicase-like gene (WRN, encoding T705I), and excision repair cross-complementation group 6 (ERCC6, encoding N180Y), revealed reduced levels of these proteins and increased DSBs, compared to B cells from controls. This phenotype was rescued by exogenous expression of WRN or ERCC6. Direct analysis of the recombinant variant proteins confirmed defective enzymatic activities.
CONCLUSIONS
These results provide evidence that defects in suppression of DSBs underlie some cases of UFCRC; these can be identified by assays of circulating lymphocytes. We specifically associated UFCRC with variants in WRN and ERCC6 that reduce capacity for repair of DNA DSBs. These observations could lead to a simple screening strategy for UFCRC, and provide insight into the pathogenic mechanisms of colorectal carcinogenesis.
doi:10.1053/j.gastro.2015.08.052
PMCID: PMC4663158  PMID: 26344056
colon cancer; hereditary cancer; genomic instability; tumorigenesis
2.  A Simple Method for Evaluating Within Sample Prognostic Balance Achieved by Published Comorbidity Summary Measures 
Health Services Research  2014;50(4):1179-1194.
Objective
To demonstrate how a researcher can investigate the appropriateness of a published comorbidity summary measure for use with a given sample.
Data Source
Surveillance, Epidemiology, and End Results linked to Medicare claims data.
Study Design
We examined Kaplan–Meier estimated survival curves for four diseases within strata of a comorbidity summary measure, the Charlson Comorbidity Index.
Data Collection
We identified individuals with early-stage kidney cancer diagnosed from 1995 to 2009. We recorded comorbidities present in the year before diagnosis.
Principal Findings
The use of many comorbidity summary measures is valid under appropriate conditions. One condition is that the relationships of the comorbidities with the outcome of interest in a researcher’s own population are comparable to the relationships in a published algorithm’s population. The original comorbidity weights from the Charlson Comorbidity Index seemed adequate for three of the diseases in our sample. We found evidence that the Charlson Comorbidity Index might underestimate the impact of one disease in our sample.
Conclusion
Examination of survival curves within strata defined by a comorbidity summary measure can be a useful tool for determining whether a published method appropriately accounts for comorbidities. A comorbidity score is only as good as those variables included.
doi:10.1111/1475-6773.12276
PMCID: PMC4545353  PMID: 25523400
Comorbidity scores; prognostic balance; SEER-Medicare; prognostic scores; diagnostics
3.  Evaluating Overall Survival and Competing Risks of Death in Patients With Localized Renal Cell Carcinoma Using a Comprehensive Nomogram 
Journal of Clinical Oncology  2009;28(2):311-317.
Purpose
Many patients with localized node-negative renal cell carcinoma (RCC) are elderly with competing comorbidities. Their overall survival benefit after surgical treatment is unknown. We reviewed cases in the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the impact of kidney cancer versus competing causes of death in patients with localized RCC and develop a comprehensive nomogram to quantitate survival differences.
Methods
We identified individuals with localized, surgically treated clear-cell, papillary, or chromophobe RCC in SEER (1988 through 2003). We used Fine and Gray competing risks proportional hazards regressions to predict 5-year probabilities of three competing mortality outcomes: kidney cancer death, other cancer death, and noncancer death.
Results
We identified 30,801 cases of localized RCC (median age, 62 years; median tumor size, 4.5 cm). Five-year probabilities of kidney cancer death, other cancer death, and noncancer death were 4%, 7%, and 11%, respectively. Age was strongly predictive of mortality and most predictive of nonkidney cancer deaths (P < .001). Increasing tumor size was related to death from RCC and inversely related to noncancer deaths (P < .001). Racial differences in outcomes were most pronounced for nonkidney cancer deaths (P < .001). Men were more likely to die than women from all causes (P < .002). This nomogram integrates commonly available factors into a useful tool for comparing competing risks of death.
Conclusion
Management of localized RCC must consider competing causes of mortality, particularly in elderly populations. Effective decision making requires treatment trade-off calculations. We present a tool to quantitate competing causes of mortality in patients with localized RCC.
doi:10.1200/JCO.2009.22.4816
PMCID: PMC2815719  PMID: 19933918
4.  Survival Impact of Increasing Time to Treatment Initiation for Patients With Head and Neck Cancer in the United States 
Journal of Clinical Oncology  2015;34(2):169-178.
Purpose
To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC).
Methods
Using the National Cancer Data Base (NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds.
Results
A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio [HR], 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days.
Conclusion
TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.
doi:10.1200/JCO.2015.61.5906
PMCID: PMC4858932  PMID: 26628469
5.  Endogenous sex hormones and breast density in young women 
Background
Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women.
Methods
We conducted cross-sectional study among 180 women aged 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone-binding globulin (SHBG) with %DBV, ADBV, and ANDBV.
Results
Testosterone was significantly positively associated with %DBV and ADBV. The multivariable geometric mean of %DBV and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6cm3 to 82.3cm3, respectively (Ptrend ≤ 0.03). There was no association of %DBV or ADBV with estrogens, progesterone, non-SHBG bound testosterone or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase.
Conclusions
These findings suggest a modest positive association between testosterone and breast density in young women.
Impact
Hormonal influences at critical periods may contribute to morphological differences in the breast associated with breast cancer risk later in life.
doi:10.1158/1055-9965.EPI-14-0939
PMCID: PMC4323882  PMID: 25371447
estradiol; non-SHBG bound estradiol; progesterone; testosterone; non-SHBG bound testosterone; SHBG; breast density; absolute dense breast volume; non-dense breast volume; young women
6.  Why summary comorbidity measures such as the Charlson Comorbidity Index and Elixhauser score work 
Medical care  2013;10.1097/MLR.0b013e318297429c.
Background
Comorbidity adjustment is an important component of health services research and clinical prognosis. When adjusting for comorbidities in statistical models, researchers can include comorbidities individually or through the use of summary measures such as the Charlson Comorbidity Index or Elixhauser score. We examined the conditions under which individual versus summary measures are most appropriate.
Methods
We provide an analytic proof of the utility of comorbidity summary measures when used in place of individual comorbidities. We compared the use of the Charlson and Elixhauser scores versus individual comorbidities in prognostic models using a SEER-Medicare data example. We examined the ability of summary comorbidity measures to adjust for confounding using simulations.
Results
We devised a mathematical proof that found that the comorbidity summary measures are appropriate prognostic or adjustment mechanisms in survival analyses. Once one knows the comorbidity score, no other information about the comorbidity variables used to create the score is generally needed. Our data example and simulations largely confirmed this finding.
Conclusions
Summary comorbidity measures, such as the Charlson Comorbidity Index and Elixhauser scores, are commonly used for clinical prognosis and comorbidity adjustment. We have provided a theoretical justification that validates the use of such scores under many conditions. Our simulations generally confirm the utility of the summary comorbidity measures as substitutes for use of the individual comorbidity variables in health services research. One caveat is that a summary measure may only be as good as the variables used to create it.
doi:10.1097/MLR.0b013e318297429c
PMCID: PMC3818341  PMID: 23703645
7.  Development of a Communication Protocol for Telephone Disclosure of Genetic Test Results for Cancer Predisposition 
JMIR Research Protocols  2014;3(4):e49.
Background
Dissemination of genetic testing for disease susceptibility, one application of “personalized medicine”, holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of “cancer genes” and genes for other diseases (eg, cardiovascular and Alzheimer’s disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
Objective
The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes.
Methods
Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders’ feedback were utilized to evaluate the efficacy and inform refinements to this protocol.
Results
Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training.
Conclusions
Analyses of stakeholders’ experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.
doi:10.2196/resprot.3337
PMCID: PMC4259920  PMID: 25355401
genetic testing; test result disclosure; communication; telemedicine; cancer risk assessment; self-regulation theory of health behavior
8.  Correlation Between Financial Relationships With Commercial Interests and Research Prominence at an Oncology Meeting 
Journal of Clinical Oncology  2013;31(21):2678-2684.
Purpose
Little is known about the effects of financial relationships between biomedical researchers and industry (financial conflicts of interest [FCOIs]) on research prominence. We examined the prevalence of FCOIs in oncology and associations between FCOIs and research prominence among abstracts presented at American Society of Clinical Oncology (ASCO) annual meetings.
Methods
We analyzed 20,718 abstracts presented at ASCO meetings in 2006 and 2008 to 2011. Measures included the following: financial relationships, peer review score (PRS), and meeting placement prominence (descending order of prominence: plenary session, clinical science symposium, oral presentation, poster discussion, general posters, and publish only).
Results
Of 20,718 abstracts, 36% reported at least one author with an FCOI. The proportion of abstracts with any FCOI increased from 33% in 2006 to 38% in 2011 (P < .001). Abstracts with FCOIs had significantly higher meeting prominence compared with publish only and general poster abstracts. The odds ratios compared with general posters were 7.3 for plenary session, 2.2 for clinical science symposium, 1.9 for oral presentation, and 1.7 for poster discussion (P < .001). Abstracts with FCOIs had significantly better PRSs compared with those without FCOIs. For all abstracts, PRS was 2.76 (95% CI, 2.75 to 2.77) with FCOIs compared with 3.01 (95% CI, 3.001 to 3.02) without FCOIs (P < .001). Omitting publish-only abstracts, PRS was 2.62 (95% CI, 2.61 to 2.63) with FCOIs compared with 2.73 without FCOIs (95% CI, 2.71 to 2.73).
Conclusion
Abstracts with FCOIs had more prominent meeting placement and better PRSs. FCOIs were reported more frequently by year, suggesting an increasing influence of industry on cancer research, greater disclosure, or both.
doi:10.1200/JCO.2012.46.6375
PMCID: PMC3709055  PMID: 23775973
9.  Competing Risks of Death in Patients with Localized Renal Cell Carcinoma: A Comorbidity Based Model 
The Journal of urology  2012;188(6):2077-2083.
Purpose
Multiple risks compete with cancer as the primary cause of death. These factors must be considered against the benefits of treatment. We constructed a competing causes of death model to help contextualize treatment tradeoff analyses in patients with localized RCC.
Patients and Methods
6,655 individuals ≥66 years old with localized RCC were identified in the linked SEER Medicare dataset (1995–2005). We used Fine and Gray’s competing risks proportional hazards regressions to predict probabilities of competing mortality outcomes. Prognostic markers included race, gender, tumor size, age, and the CCI Score.
Results
After a median follow-up of 43 months, age and comorbidity score strongly correlated to patient mortality and were most predictive of non-kidney cancer deaths as measured by concordance statistics. We demonstrate that patients with localized node negative kidney cancer have low 3 (4.7%), 5 (7.5%) and 10 (11.9%) year probabilities of cancer specific death, but significantly higher overall risk of death from competing causes within 3 (10.9%), 5 (20.1%) and 10 (44.4%) years of diagnosis of RCC, depending on their comorbidity scores.
Conclusions
Informed treatment decisions regarding patients with solid tumors must integrate not only cancer-related variables, but also factors that predict for non-cancer death. Here we establish a comorbidity based predictive model, which may assist in patient counseling by allowing quantification and comparison of competing risks of death in patients 66 and older with localized RCC who choose to proceed with surgery.
doi:10.1016/j.juro.2012.07.100
PMCID: PMC4659779  PMID: 23083850
renal cell carcinoma; nomogram; survival; competing risks; comorbidities
10.  Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer 
Oncotarget  2015;6(37):39614-39633.
Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation.
PMCID: PMC4741850  PMID: 26485759
familial prostate cancer; whole exome sequencing; DNA damage response; genetic susceptibility to prostate cancer; case-only study
11.  Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients 
Purpose
Circulating tumor cells (CTC) represent a new outcome-associated biomarker independently from known prognostic factors in metastatic breast cancer (MBC). The objective here was to develop and validate nomograms that combined baseline CTC counts and the other prognostic factors to assess the outcome of individual patients starting first-line treatment for MBC.
Experimental Design
We used a training set of 236 MBC patients starting a first-line treatment from the MD Anderson Cancer Center to establish nomograms that calculated the predicted probability of survival at different time points: 1, 2, and 5 years for overall survival (OS) and 6 months and 1 and 2 years for progression-free survival (PFS). The covariates computed in the model were: age, disease subtype, visceral metastases, performance status, and CTC counts by CellSearch. Nomograms were independently validated with 210 MBC patients from the Institut Curie who underwent first-line chemotherapy. The discriminatory ability and accuracy of the models were assessed using Harrell’s c-statistic and calibration plots at different time points in both training and validation datasets.
Results
Median follow-up was of 23 and 29 months in the MD Anderson and Institut Curie cohorts, respectively. Nomograms demonstrated good C-statistics: 0.74 for OS and 0.65 for PFS and discriminated OS prediction at 1, 2, and 5 years, and PFS prediction at 6 months and 1 and 2 years.
Conclusions
Nomograms, which relied on CTC counts as a continuous covariate, easily facilitated the use of a web-based tool for estimating survival, supporting treatment-decisions and clinical trial stratification in first-line MBC.
doi:10.1158/1078-0432.CCR-12-3137
PMCID: PMC3662240  PMID: 23340302
circulating tumor cells; first-line; metastatic breast cancer; nomogram; survival
13.  Skin Involvement and Breast Cancer: Are T4B Lesions of All Sizes Created Equal? 
Background
Nonmetastatic non-inflammatory invasive breast cancers having skin involvement (SI) are classified as T4b, regardless of size. This study evaluated disease specific survival (DSS) to determine whether size should be considered for these lesions, rather than grouping them all into Stage III.
Study Design
Surveillance Epidemiology and End Results data linked to Medicare claims were reviewed. SI and nonSI tumors were reclassified using AJCC 7th Edition groupings using tumor size and nodal involvement alone without considering SI (neostage). DSS was adjusted for demographics, histology and treatment using competing risk methods with propensity score-based weighting and bootstrap standard errors.
Results
Among 924 SI patients diagnosed between 1992 and 2005, tumors were 0.1–2.0, 2.1–5.0, and >5.0 cm in 11.6%, 51.1%, and 37.3% of cases, respectively. There were no nodal metastases in 22.3%, 1–3 positive nodes in 31.7%, 4–9 positive in 28.6% and ≥10 positive in 17.4% of cases. For SI patients, adjusted 5-year DSS was 95.8% [95%CI: 95.6–96.0] for neostage I, declining progressively to 36.4% [95%CI: 33.8–39.2] for neostage IIIC patients. Adjusted 5-year DSS for SI and nonSI tumors (n=66,185) was similar for neostage I, IIA, and IIB, and markedly lower for IIIA and IIIC. Adjusted DSS for SI IIIA was similar to nonSI IIIC.
Conclusions
Noninflammatory SI breast cancers have widely varied DSS that differs by tumor size and nodal involvement, and therefore should not all be stage III. SI should be subordinate to T and N groupings to classify SI with nonSI lesions having similar prognoses.
doi:10.1016/j.jamcollsurg.2014.04.003
PMCID: PMC4143438  PMID: 25026875
14.  A pilot study of psychosocial functioning and vascular endothelial growth factor in head and neck cancer patients 
Head & neck  2013;36(8):1113-1119.
Background
Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis.
Methods
Forty-two newly diagnosed patients completed assessments of psychosocial functioning (i.e. depressive symptoms, perceived stress, anxiety, social support) prior to surgery. Tumor samples were obtained for VEGF analysis and HPV-typing.
Results
Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (OR=4.55, 95% CI = 1.72, 12.0, p < 0.01). When examined by HPV-status, the association between psychosocial functioning and VEGF remained significant among HPV-negative patients (OR=5.50, 95% CI = 1.68, 17.3, p < 0.01), but not among HPV-positive patients.
Conclusions
These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs.
doi:10.1002/hed.23421
PMCID: PMC4099415  PMID: 23804308
depressive symptoms; perceived stress; anxiety; social support; human papillomavirus
16.  Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints 
Cell Cycle  2014;13(14):2172-2191.
Inhibitors of the DNA damage checkpoint kinase, Chk1, are highly effective as chemo- and radio-sensitizers in preclinical studies but are not well-tolerated by patients. We exploited the promiscuous nature of kinase inhibitors to screen 9 clinically relevant kinase inhibitors for their ability to sensitize pancreatic cancer cells to a sub-lethal concentration of gemcitabine. Bosutinib, dovitinib, and BEZ-235 were identified as sensitizers that abrogated the DNA damage checkpoint. We further characterized bosutinib, an FDA-approved Src/Abl inhibitor approved for chronic myelogenous leukemia. Unbeknownst to us, we used an isomer (Bos-I) that was unknowingly synthesized and sold to the research community as “authentic” bosutinib. In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1, with Bos-I showing greater potency. Imaging data showed that Bos-I forced cells to override gemcitabine-induced DNA damage checkpoint arrest and destabilized stalled replication forks. These inhibitors enhanced sensitivity to the DNA damaging agents’ gemcitabine, cisplatin, and doxorubicin in pancreatic cancer cell lines. The in vivo efficacy of Bos-I was validated using cells derived directly from a pancreatic cancer patient’s tumor. Notably, the xenograft studies showed that the combination of gemcitabine and Bos-I was significantly more effective in suppressing tumor growth than either agent alone. Finally, we show that the gatekeeper residue in Wee1 dictates its sensitivity to the 2 compounds. Our strategy to screen clinically relevant kinase inhibitors for off-target effects on cell cycle checkpoints is a promising approach to re-purpose drugs as chemosensitizers.
doi:10.4161/cc.29214
PMCID: PMC4111673  PMID: 24955955
Checkpoint override; DNA damage; Kinase inhibitors; Mitosis; drug repurposing
17.  Adolescent endogenous sex hormones and breast density in early adulthood 
Introduction
During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer.
Methods
Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25–29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV.
Results
Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all Ptrend ≤0.03) but not when measured in postmenarche samples (all Ptrend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all Ptrend ≥0.16).
Conclusions
Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown.
Clinical trials registration
ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999
doi:10.1186/s13058-015-0581-4
PMCID: PMC4468804  PMID: 26041651
18.  The Impact of Dose-Escalated Radiotherapy Plus Androgen Deprivation for Prostate Cancer Using 2 Linked Nomograms 
Cancer  2012;119(5):1080-1088.
BACKGROUND
Randomized trials have demonstrated that escalated-dose external-beam radiotherapy (EDRT) is better than standard-dose radiotherapy (SDRT) for patients with prostate cancer and that adding androgen-deprivation therapy (ADT) to SDRT is better than SDRT alone; however, no trials have compared EDRT versus SDRT plus ADT or EDRT versus EDRT plus ADT. The authors designed a model to estimate the results of various doses of radiotherapy (RT) combined with various durations of ADT.
METHODS
From 1989 to 2007, 3215 men consecutively received definitive EDRT with or without ADT. In total, 2012 patients had complete records available for creating the nomogram. The duration of ADT varied for patients who received no RT (n = 1562), ≤6 months of RT (n = 145), from >6 months to <24 months of RT (n = 140), and ≥24 months of RT (n = 165) with a median follow-up of 65.7 months, 66.2 months, 60.1 months, and 63 months, respectively. The model included the following covariates: palpation T-category, biopsy Gleason score, the percentage of tumor cells with a Gleason pattern of 4 or 5, the percentage of tumor tissue, initial pretreatment prostate-specific antigen (PSA) level, ADT duration, and RT dose. Two nomograms, for outcomes with and without ADT, were created from a single competing-risks model. Biochemical failure was defined as a rise in serum PSA of 2 ng/mL over the post-treatment PSA nadir.
RESULTS
According to the results from analyzing representative intermediate-risk to high-risk patient parameters, the gains from increasing the RT dose from 70 Gray (Gy) to 80 Gy were far less than the gains from adding ≥3 months of ADT.
CONCLUSIONS
The nomograms provided unique patient-specific estimates of the effects of various doses and durations of RT and ADT. The results indicated that adding ADT to treatment for intermediate-risk and high-risk prostate cancer is far more beneficial than a modest RT dose escalation.
doi:10.1002/cncr.27857
PMCID: PMC4347814  PMID: 23096533
nomogram; prostate cancer; radiation treatment; androgen-deprivation therapy
19.  Small Renal Masses Progressing to Metastases under Active Surveillance: A Systematic Review and Pooled Analysis 
Cancer  2011;118(4):997-1006.
Purpose
We conducted a systematic review and pooled analysis of small renal masses under active surveillance to identify progression risk and characteristics associated with metastases.
Materials and Methods
A MEDLINE search was performed to identify all clinical series reporting surveillance of localized renal masses. For studies reporting individual level data, clinical and radiographic characteristics of tumors without progression were compared to those progressing to metastases.
Results
18 series (880 patients, 936 masses) met screening criteria from which 18 patients progressing to metastasis were identified (mean 40.2 months). Six studies (259 patients, 284 masses) provided individual level data for pooled analysis. With a mean follow up of 33.5±22.6 months, mean initial tumor diameter was 2.3±1.3 cm and mean linear growth rate was 0.31±0.38 cm/year. 65 masses (23%) exhibited zero net growth under surveillance; of which none progressed to metastasis. Pooled analysis revealed increased age (75.1±9.1 vs. 66.6±12.3 years, p=0.03), initial tumor diameter (4.1±2.1 vs. 2.3±1.3 cm, p<0.0001), initial estimated tumor volume (66.3±100.0 vs. 15.1±60.3 cm3, p<0.0001), linear growth rate (0.8±0.65 vs. 0.3±0.4 cm/yr, p=0.0001), and volumetric growth rate (27.1±24.9 vs. 6.2±27.5 cm3/yr, p<0.0001) in the progression cohort.
Conclusions
A substantial proportion of small renal masses remain radiographically static following an initial period of active surveillance. Progression to metastases occurs in a small percentage of patients and is generally a late event. These results indicate that in patients with competing health risks, radiographic surveillance may be an acceptable initial approach with delayed intervention reserved for those exhibiting significant linear or volumetric growth.
doi:10.1002/cncr.26369
PMCID: PMC4329724  PMID: 21766302
20.  Patterns of nodal staging during breast conservation surgery in the medicare patient: will the ACOSOG Z0011 trial change the pattern of care? 
ACOSOG Z0011 spares axillary dissection (AD) in breast conservation surgery (BCS) patients with T1/T2 tumors and 1–2 positive nodes. Current patterns of care and the impact of Z0011 on AD versus additional surgery rates for Medicare patients undergoing BCS are unknown. SEER data linked to Medicare claims for 1999–2005 were reviewed for women with invasive non-metastatic breast cancer who underwent nodal staging on the same day as BCS. There were 3,280 women with T1/T2 tumors and positive nodes who underwent same-day nodal staging; 2,532 (77.2 %) of these women had 1–2 positive nodes. Assuming 25.7 % have extracapsular extension, 651 women would require AD. However, 1,881 women, or 57.4 % of those with T1/T2 tumors and positive nodes, would be spared AD. Meanwhile, among the 748 women having ≥3 positive nodes, 579 underwent same-day AD, but under Z0011, would now wait for permanent section. A total of 160 of these women underwent re-excision or completion mastectomy at a later date anyway, when delayed AD could be performed. The remaining 419 women with ≥3 positive nodes would require an additional surgery date for the sole purpose of completion AD. The Z0011 paradigm would consequently necessitate an additional surgery date for 1,070 (651 + 419) women, or 32.6 % of those with T1/T2 tumors and positive nodes. The Z0011 paradigm appears to increase the number of Medicare patients undergoing BCS who require an additional surgery date but decrease the number requiring AD to a greater extent. Future changes in the use of AD or axillary irradiation may yet modify that impact substantially.
doi:10.1007/s10549-014-2834-9
PMCID: PMC4161134  PMID: 24442687
Clinical trials; ACOSOG Z0011; Lymph node metastases; Sentinel lymphadenectomy; Sentinel node biopsy; Axillary lymphadenectomy; Axillary lymph node dissection; Patterns of care; Surveillance, epidemiology and end results; Medicare; Medicare claims
21.  A tutorial on principal stratification-based sensitivity analysis: Application to smoking cessation studies 
Background
One problem with assessing effects of smoking cessation interventions on withdrawal symptoms is that symptoms are affected by whether participants abstain from smoking during trials. Those who enter a randomized trial but do not change smoking behavior might not experience withdrawal related symptoms.
Purpose
We present a tutorial of how one can use a principal stratification sensitivity analysis to account for abstinence in the estimation of smoking cessation intervention effects. The paper is intended to introduce researchers to principal stratification and describe how they might implement the methods.
Methods
We provide a hypothetical example that demonstrates why estimating effects within observed abstention groups is problematic. We demonstrate how estimation of effects within groups defined by potential abstention that an individual would have in either arm of a study can provide meaningful inferences. We describe a sensitivity analysis method to estimate such effects, and use it to investigate effects of a combined behavioral and nicotine replacement therapy intervention on withdrawal symptoms in a female prisoner population.
Results
Overall, the intervention was found to reduce withdrawal symptoms but the effect was not statistically significant in the group that was observed to abstain. More importantly, the intervention was found to be highly effective in the group that would abstain regardless of intervention assignment. The effectiveness of the intervention in other potential abstinence strata depends on the sensitivity analysis assumptions.
Limitations
We make assumptions to narrow the range of our sensitivity parameter estimates. While appropriate in this situation, such assumptions might not be plausible in all situations.
Conclusions
A principal stratification sensitivity analysis provides a meaningful method of accounting for abstinence effects in the evaluation of smoking cessation interventions on withdrawal symptoms. Smoking researchers have previously recommended analyses in subgroups defined by observed abstention status in the evaluation of smoking cessation interventions. We believe that principal stratification analyses should replace such analyses as the preferred means of accounting for post-randomization abstinence effects in the evaluation of smoking cessation programs.
doi:10.1177/1740774510367811
PMCID: PMC2874094  PMID: 20423924
22.  Opposing Effects of Inhibitors of Aurora-A and EGFR in Autosomal-Dominant Polycystic Kidney Disease 
Frontiers in Oncology  2015;5:228.
Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal-dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia-localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinib-­restrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities.
doi:10.3389/fonc.2015.00228
PMCID: PMC4607875  PMID: 26528438
PKD1; Aurora-A kinase; mouse models; renal cyst; EGFR; SRC
23.  Inhibiting Heat Shock Protein 90 (HSP90) Limits the Formation of Liver Cysts Induced by Conditional Deletion of Pkd1 in Mice 
PLoS ONE  2014;9(12):e114403.
Polycystic liver disease (PLD) occurs in 75–90% of patients affected by autosomal dominant polycystic kidney disease (ADPKD), which affects 1∶400–1,000 adults and arises from inherited mutations in the PKD1 or PKD2 genes. PLD can lead to bile duct obstructions, infected or bleeding cysts, and hepatomegaly, which can diminish quality of life. At present, no effective, approved therapy exists for ADPKD or PLD. We recently showed that inhibition of the molecular chaperone heat shock protein 90 (HSP90) with a small molecule inhibitor, STA-2842, induced the degradation of multiple HSP90-dependent client proteins that contribute to ADPKD pathogenesis and slowed the progression of renal cystogenesis in mice with conditional deletion of Pkd1. Here, we analyzed the effects of STA-2842 on liver size and cystic burden in Pkd-/- mice with established PLD. Using magnetic resonance imaging over time, we demonstrate that ten weeks of STA-2842 treatment significantly reduced both liver mass and cystic index suggesting selective elimination of cystic tissue. Pre-treatment cystic epithelia contain abundant HSP90; the degree of reduction in cysts was accompanied by inhibition of proliferation-associated signaling proteins EGFR and others, and induced cleavage of caspase 8 and PARP1, and correlated with degree of HSP90 inhibition and with inactivation of ERK1/2. Our results suggest that HSP90 inhibition is worth further evaluation as a therapeutic approach for patients with PLD.
doi:10.1371/journal.pone.0114403
PMCID: PMC4256400  PMID: 25474361
24.  Menstrual and reproductive characteristics and breast density in young women 
Cancer causes & control : CCC  2013;24(11):1973-1983.
Purpose
Breast density is strongly related to breast cancer risk, but determinants of breast density in young women remain largely unknown.
Methods
Associations of reproductive and menstrual characteristics with breast density measured by magnetic resonance imaging were evaluated in a cross-sectional study of 176 healthy women, 25–29 years old, using linear mixed effects models.
Results
Parity was significantly inversely associated with breast density. In multivariable adjusted models that included non-reproductive variables, mean percent dense breast volume (%DBV) decreased from 20.5 % in nulliparous women to 16.0 % in parous women, while mean absolute dense breast volume (ADBV) decreased from 85.3 to 62.5 cm3. Breast density also was significantly inversely associated with the age women started using hormonal contraceptives, whereas it was significantly positively associated with duration of hormonal contraceptive use. In adjusted models, mean %DBV decreased from 21.7 % in women who started using hormones at 12–17 years of age to 14.7 % in those who started using hormones at 22–28 years of age, while mean ADBV decreased from 86.2 to 53.7 cm3. The age at which women started using hormonal contraceptives and duration of hormone use were inversely correlated, and mean %DBV increased from 15.8 % in women who used hormones for not more than 2.0 years to 22.0 % in women who used hormones for more than 8 years, while mean ADBV increased from 61.9 to 90.4 cm3 over this interval.
Conclusions
Breast density in young women is inversely associated with parity and the age women started using hormonal contraceptives but positively associated with duration of hormone use.
doi:10.1007/s10552-013-0273-2
PMCID: PMC3960004  PMID: 23933948
Breast density; Parity; Breast feeding; Hormonal contraceptives; Menarche; Menstrual cycle
25.  Implementation and outcomes of telephone disclosure of clinical BRCA1/2 test results⋆ 
Patient education and counseling  2013;93(3):413-419.
Objectives:
With an increasing demand for genetic services, effective and efficient delivery models for genetic testing are needed.
Methods:
In this prospective single-arm communication study, participants received clinical BRCA1/2 results by telephone with a genetic counselor and completed surveys at baseline, after telephone disclosure (TD) and after in-person clinical follow-up.
Results:
Sixty percent of women agreed to participate; 73% of decliners preferred in-person communication. Anxiety decreased from baseline to post-TD (p = 0.03) and satisfaction increased (p < 0.01). Knowledge did not change significantly from baseline to post-TD, but was higher post-clinical follow-up (p = 0.04). Cancer patients had greater declines in state anxiety and African-American participants reported less increase in satisfaction. 28% of participants did not return for in-person clinical follow-up, particularly those with less formal education, and higher post-disclosure anxiety and depression (p < 0.01).
Conclusions:
Telephone disclosure of BRCA1/2 test results may not be associated with negative cognitive and affective responses among willing patients, although some subgroups may experience less favorable responses. Some patients do not return for in-person clinical follow-up and longitudinal outcomes are unknown.
Practice implications:
Further evaluation of longitudinal outcomes of telephone disclosure and differences among subgroups can inform how to best incorporate telephone communication into delivery of genetic services.
doi:10.1016/j.pec.2013.08.009
PMCID: PMC4199583  PMID: 24075727
Genetic testing; Cancer susceptibility; Cancer risk assessment; Communication

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