Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Τετάρτη 31 Μαΐου 2017
Type II Diabetes, Obesity, and Breast Cancer Risk: The Multiethnic Cohort
Background: Obesity has been more consistently associated with breast cancer than type II diabetes. This analysis examined the combination of the two factors in the Multiethnic Cohort (MEC).
Methods: Women ages 45–75 years entered the MEC in 1993–1996 by completing a questionnaire. Type II diabetes status was self-reported at baseline, two follow-up questionnaires, and confirmed by administrative data. Cancers were identified from tumor registries and deaths through vital records until 2010. Cox regression was applied to estimate HRs and 95% confidence intervals (CI) for BMI and type II diabetes status alone and in combination.
Results: Among 103,721 (25,146 white, 20,255 African American, 7,681 Native Hawaiian, 28,012 Japanese American, 22,627 Latina) women with 14,558 type II diabetes cases, 6,692 women developed breast cancer during 14.8 ± 4.1 years of follow-up. Type II diabetes was significantly associated with breast cancer risk (HR, 1.15; 95% CI, 1.07–1.23), but including body mass index (BMI) lowered the HR to 1.08 (95% CI, 1.00–1.16). Ethnic-specific BMI-adjusted models showed elevated risks for type II diabetes in Latinas only (HR, 1.30; 95% CI, 1.11–1.52). In contrast, obesity predicted statistically significant 21%–46% higher risks, after type II diabetes adjustment, in all ethnic groups except Latinas (HR, 1.17; 95% CI, 0.99–1.38).
Conclusions: As reported previously, inclusion of BMI weakened the association of type II diabetes with breast cancer. Type II diabetes status, but not BMI, was primarily associated with higher breast cancer risk in Latinas.
Impact: The role of obesity and type II diabetes in breast cancer etiology may differ by ethnicity suggesting metabolic differences related to obesity. Cancer Epidemiol Biomarkers Prev; 26(6); 854–61. ©2017 AACR.
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Aspirin Use Reduces the Risk of Aggressive Prostate Cancer and Disease Recurrence in African-American Men
Background: Men of African descent experience a disproportionately high prostate cancer mortality. Intratumoral inflammation was found to be associated with aggressive prostate cancer. We and others have shown that prostate tumors in African-American (AA) patients harbor a distinct immune and inflammation signature when compared with European-American (EA) patients. These observations suggest that inflammation could be a driver of aggressive disease in men of African descent, leading to the hypothesis that an anti-inflammatory drug like aspirin could prevent disease progression.
Methods: We examined the relationship between aspirin use and prostate cancer in the NCI-Maryland Prostate Cancer Case-Control Study consisting of 823 men with incident prostate cancer (422 AA and 401 EA) and 1,034 population-based men without the disease diagnosis (486 AA and 548 EA).
Results: We observed a significant inverse association between regular aspirin use and prostate cancer among AA men. Stratification of AA patients by disease stage showed that daily and long-term (>3 years) aspirin use significantly decreased the risk of advanced disease [adjusted ORs for T3/T4 disease: 0.35, 95% confidence interval (CI), 0.17–0.73; and 0.22, 95% CI, 0.08–0.60, respectively], but not early-stage disease (T1/T2). Regular aspirin use also reduced disease recurrence in AA men.
Conclusions: Regular aspirin use is associated with a decreased risk of advanced stage prostate cancer and increased disease-free survival in AA men.
Impact: Regular aspirin use before and after a prostate cancer diagnosis may prevent the development of aggressive disease in AA men who are at risk of a lethal malignancy. Cancer Epidemiol Biomarkers Prev; 26(6); 845–53. ©2017 AACR.
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Serum C-peptide, Total and High Molecular Weight Adiponectin, and Pancreatic Cancer: Do Associations Differ by Smoking?
Background: Studies examining associations between circulating concentrations of C-peptide and total adiponectin, two biomarkers related to obesity and insulin secretion and sensitivity and pancreatic ductal adenocarcinoma (PDA) risk have shown inconsistent results and included limited numbers of smokers.
Methods: We examined associations of these biomarkers and high molecular weight (HMW) adiponectin with PDA, overall, and by smoking status. We conducted a pooled nested case–control analysis in 3 cohorts (Prostate, Lung, Colorectal, and Ovarian Cancer Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study-II), with 758 cases (435 current smokers) and 1,052 controls (531 smokers) matched by cohort, age, sex, race, blood draw date and follow-up time. We used conditional logistic regression adjusted for age, smoking, diabetes, and body mass index to calculate ORs and 95% confidence intervals (CI).
Results: Circulating C-peptide concentration was not associated with PDA in never or former smokers, but was inversely associated with PDA in current smokers (per SD OR = 0.67; 95% CI, 0.54–0.84; Pinteraction = 0.005). HMW adiponectin was inversely associated with PDA in never smokers (OR = 0.43; 95% CI, 0.23–0.81), not associated in former smokers, and positively associated in smokers (OR = 1.23; 95% CI, 1.04–1.45; Pinteraction = 0.009). Total adiponectin was not associated with PDA in nonsmokers or current smokers.
Conclusions: Associations of biomarkers of insulin secretion and sensitivity with PDA differ by smoking status. Smoking-induced pancreatic damage may explain the associations in smokers while mechanisms related to insulin resistance associations in nonsmokers.
Impact: Future studies of these biomarkers and PDA should examine results by smoking status. Cancer Epidemiol Biomarkers Prev; 26(6); 914–22. ©2017 AACR.
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Comparison of Triage Strategies for HPV-Positive Women: Canadian Cervical Cancer Screening Trial Results
Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment.
Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30–69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated.
Results: A strategy referring all women HPV16/18+ and HPV16/18–, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%–91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%–75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%–45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%–95.6%), positive predictive value (41.5%; 95% CI, 28.1%–55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities.
Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage.
Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923–9. ©2017 AACR.
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Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study
Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk.
Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case–control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations.
Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24–4.61; Ptrend < 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P < 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant (P = 0.25, 0.71, and 0.61, respectively).
Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer.
Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945–52. ©2017 AACR.
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Nut Consumption and Lung Cancer Risk: Results from Two Large Observational Studies
Background: Epidemiologic evidence on the association between nut consumption and lung cancer risk is limited.
Methods: We investigated this relationship in the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, a population-based case–control study, and the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study, a prospective cohort. We identified 2,098 lung cases for EAGLE and 18,533 incident cases in AARP. Diet was assessed by food frequency questionnaire for both studies. Multivariable ORs and HRs and respective 95% confidence intervals (CI) were calculated using unconditional logistic regression and Cox proportional hazards regression for EAGLE and AARP, respectively.
Results: Higher frequency of intake of nut consumption was inversely associated with overall lung cancer risk (highest vs. lowest quintile, OREAGLE = 0.74; 95% CI, 0.57–0.95; HRAARP = 0.86; 95% CI, 0.81–0.91), regardless of smoking status. Results from the prospective cohort showed similar associations across histologic subtypes and a more pronounced benefits from nut consumption for those who smoked 1 to 20 cigarettes/day (OREAGLE = 0.61; 95% CI, 0.39–0.95; HRAARP = 0.83; 95% CI, 0.74–0.94).
Conclusions: Nut consumption was inversely associated with lung cancer in two large population-based studies, and associations were independent of cigarette smoking and other known risk factors.
Impact: To our knowledge, this is the first study that examined the association between nut consumption and lung cancer risk by histologic subtypes and smoking intensity. Cancer Epidemiol Biomarkers Prev; 26(6); 826–36. ©2017 AACR.
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Estimating TP53 Mutation Carrier Probability in Families with Li-Fraumeni Syndrome Using LFSPRO
Background: Li–Fraumeni syndrome (LFS) is associated with germline TP53 mutations and a very high lifetime cancer risk. Algorithms that assess a patient's risk of inherited cancer predisposition are often used in clinical counseling. The existing LFS criteria have limitations, suggesting the need for an advanced prediction tool to support clinical decision making for TP53 mutation testing and LFS management.
Methods: Based on a Mendelian model, LFSPRO estimates TP53 mutation probability through the Elston–Stewart algorithm and consequently estimates future risk of cancer. With independent datasets of 1,353 tested individuals from 867 families, we evaluated the prediction performance of LFSPRO.
Results: LFSPRO accurately predicted TP53 mutation carriers in a pediatric sarcoma cohort from MD Anderson Cancer Center in the United States, the observed to expected ratio (OE) = 1.35 (95% confidence interval, 0.99–1.80); area under the receiver operating characteristic curve (AUC) = 0.85 (0.75–0.93); a population-based sarcoma cohort from the International Sarcoma Kindred Study in Australia, OE = 1.62 (1.03–2.55); AUC = 0.67 (0.54–0.79); and the NCI LFS study cohort, OE = 1.28 (1.17–1.39); AUC = 0.82 (0.78–0.86). LFSPRO also showed higher sensitivity and specificity than the classic LFS and Chompret criteria. LFSPRO is freely available through the R packages LFSPRO and BayesMendel.
Conclusions: LFSPRO shows good performance in predicting TP53 mutations in individuals and families in varied situations.
Impact: LFSPRO is more broadly applicable than the current clinical criteria and may improve clinical management for individuals and families with LFS. Cancer Epidemiol Biomarkers Prev; 26(6); 837–44. ©2017 AACR.
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Longitudinal Changes in Volumetric Breast Density with Tamoxifen and Aromatase Inhibitors
Background: Reductions in breast density with tamoxifen and aromatase inhibitors may be an intermediate marker of treatment response. We compare changes in volumetric breast density among breast cancer cases using tamoxifen or aromatase inhibitors (AI) to untreated women without breast cancer.
Methods: Breast cancer cases with a digital mammogram prior to diagnosis and after initiation of tamoxifen (n = 366) or AI (n = 403) and a sample of controls (n = 2170) were identified from the Mayo Clinic Mammography Practice and San Francisco Mammography Registry. Volumetric percent density (VPD) and dense breast volume (DV) were measured using Volpara (Matakina Technology) and Quantra (Hologic) software. Linear regression estimated the effect of treatment on annualized changes in density.
Results: Premenopausal women using tamoxifen experienced annualized declines in VPD of 1.17% to 1.70% compared with 0.30% to 0.56% for controls and declines in DV of 7.43 to 15.13 cm3 compared with 0.28 to 0.63 cm3 in controls, for Volpara and Quantra, respectively. The greatest reductions were observed among women with ≥10% baseline density. Postmenopausal AI users had greater declines in VPD than controls (Volpara P = 0.02; Quantra P = 0.03), and reductions were greatest among women with ≥10% baseline density. Declines in VPD among postmenopausal women using tamoxifen were only statistically greater than controls when measured with Quantra.
Conclusions: Automated software can detect volumetric breast density changes among women on tamoxifen and AI.
Impact: If declines in volumetric density predict breast cancer outcomes, these measures may be used as interim prognostic indicators. Cancer Epidemiol Biomarkers Prev; 26(6); 930–7. ©2017 AACR.
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Trends in Radiation Therapy among Cancer Survivors in the United States, 2000-2030
Background: Although the number of cancer survivors has increased substantially over the past several decades, the composition of survivors treated with radiotherapy is not well defined. Radiotherapy carries unique long-term toxicity risks for cancer survivors. This study describes the current estimates and future projections of the epidemiology of 5-year cancer survivors who receive radiation therapy.
Methods: We used cancer incidence and survival data from the Surveillance, Epidemiology, and End-Results (SEER) database linked to U.S. Census data to estimate the number of 5-year cancer survivors treated with radiation between 2000 and 2030. Future projections assumed continuing incidence and survival trends based on historical rates.
Results: In 2016, there were an estimated 3.05 million cancer survivors treated with radiation, accounting for 29% of all cancer survivors. The number of radiation-treated cancer survivors is projected to reach 3.38 million by 2020 and 4.17 million by 2030. In 2016, breast (40%) and prostate cancer (23%) composed the majority of radiation-treated survivors, followed by head and neck cancer (5.8%), lymphoma (5.6%), uterine (3.9%), and rectal cancer (3.8%). The percentage of 70 years or older radiation-treated survivors steadily increased between 2000 and 2030.
Conclusions: The next several years are projected to see a large increase in the number of cancer survivors treated with radiation.
Impact: This group of cancer survivors has unique needs given the long-term risks of radiation, and increased research and awareness are required to optimize health of this growing population. Cancer Epidemiol Biomarkers Prev; 26(6); 963–70. ©2017 AACR.
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Diabetes, Abnormal Glucose, Dyslipidemia, Hypertension, and Risk of Inflammatory and Other Breast Cancer
Background: Obesity has been associated with substantially higher risk of inflammatory breast cancer (IBC) than other breast cancer. Here, we assess whether comorbidities of obesity, namely diabetes, abnormal glucose, dyslipidemia, and hypertension, are differentially related to risk of IBC and other breast cancers by tumor stage at diagnosis (localized/regional/distant/unstaged).
Methods: We used linked SEER-Medicare data, with female breast cancer cases ages 66+ years identified by SEER registries (years 1992–2011). We divided first breast cancers into IBC (N = 2,306), locally advanced non-IBC (LABC; N = 10,347), and other (N = 197,276). We selected female controls (N = 200,000) from a stratified 5% random sample of Medicare recipients alive and breast cancer free. We assessed exposures until 12 months before diagnosis/selection using Medicare claims data. We estimated odds ratios (OR) and 99.9% confidence intervals (CI) using unconditional logistic regression.
Results: Diabetes was associated with increased risk of distant IBC (98.5% of IBC cases; OR 1.44; 99.9% CI 1.21–1.71), distant (OR 1.24; 99.9% CI, 1.09–1.40) and regional (OR 1.29 (99.9% CI, 1.14–1.45) LABC, and distant (OR 1.23; 99.9% CI, 1.10–1.39) and unstaged (OR 1.32; 99.9% CI, 1.18–1.47) other breast cancers. Dyslipidemia was associated with reduced risk of IBC (OR 0.80; 95% CI, 0.67–0.94) and other breast cancers except localized disease. Results were similar by tumor estrogen receptor status. Abnormal glucose levels and hypertension had little association with risk of any tumor type.
Conclusions: Associations with diabetes and dyslipidemia were similar for distant stage IBC and other advanced tumors.
Impact: If confirmed, such findings could suggest avenues for prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 862–8. ©2017 AACR.
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Insurance Status and Racial Disparities in Cancer-Specific Mortality in the United States: A Population-Based Analysis
Background: Cancer-specific mortality (CSM) is known to be higher among blacks and lower among Hispanics compared with whites. Private insurance confers CSM benefit, but few studies have examined the relationship between insurance status and racial disparities. We sought to determine differences in CSM between races within insurance subgroups.
Methods: A population-based cohort of 577,716 patients age 18 to 64 years diagnosed with one of the 10 solid malignancies causing the greatest mortality over 2007 to 2012 were obtained from Surveillance, Epidemiology, and End Results. A Cox proportional hazards model for CSM was constructed to adjust for known prognostic factors, and interaction analysis between race and insurance was performed to generate stratum-specific HRs.
Results: Blacks had similar CSM to whites among the uninsured [HR = 1.01; 95% confidence interval (CI), 0.96–1.05], but higher CSM among the Medicaid (HR = 1.04; 95% CI, 0.01–1.07) and non-Medicaid (HR = 1.14; 95% CI, 1.12–1.16) strata. Hispanics had lower CSM compared with whites among uninsured (HR = 0.80; 95% CI, 0.76–0.85) and Medicaid (HR = 0.88; 95% CI, 0.85–0.91) patients, but there was no difference among non-Medicaid patients (HR = 0.99; 95% CI, 0.97–1.01). Asians had lower CSM compared with whites among all insurance types: uninsured (HR = 0.80; 95% CI, 0.76–0.85), Medicaid (HR = 0.81; 95% CI, 0.77–0.85), and non-Medicaid (HR = 0.85; 95% CI, 0.83–0.87).
Conclusions: The disparity between blacks and whites was largest, and the advantage of Hispanic race was absent within the non-Medicaid subgroup.
Impact: These findings suggest that whites derive greater benefit from private insurance than blacks and Hispanics. Further research is necessary to determine why this differential exists and how disparities can be improved. Cancer Epidemiol Biomarkers Prev; 26(6); 869–75. ©2017 AACR.
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Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC)
Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case–control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI.
Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls.
Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04–1.14; P = 0.007]. We observed significant heterogeneity by study design (P = 0.04), noting the BMI–multiple myeloma association only for population-based studies (Ptrend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m2; OR, 1.2; 95% CI, 1.1–1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI (Pinteraction <0.0001); we noted statistically significant associations with multiple myeloma for persons overweight (25–<30 kg/m2) or obese (30+ kg/m2) in both younger and usual adulthood (vs. individuals consistently <25 kg/m2), but not for those overweight or obese at only one time period.
Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood.
Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876–85. ©2017 AACR.
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Family History of Breast Cancer, Breast Density, and Breast Cancer Risk in a U.S. Breast Cancer Screening Population
Background: The utility of incorporating detailed family history into breast cancer risk prediction hinges on its independent contribution to breast cancer risk. We evaluated associations between detailed family history and breast cancer risk while accounting for breast density.
Methods: We followed 222,019 participants ages 35 to 74 in the Breast Cancer Surveillance Consortium, of whom 2,456 developed invasive breast cancer. We calculated standardized breast cancer risks within joint strata of breast density and simple (1st-degree female relative) or detailed (first-degree, second-degree, or first- and second-degree female relative) breast cancer family history. We fit log-binomial models to estimate age-specific breast cancer associations for simple and detailed family history, accounting for breast density.
Results: Simple first-degree family history was associated with increased breast cancer risk compared with no first-degree history [Risk ratio (RR), 1.5; 95% confidence interval (CI), 1.0–2.1 at age 40; RR, 1.5; 95% CI, 1.3–1.7 at age 50; RR, 1.4; 95% CI, 1.2–1.6 at age 60; RR, 1.3; 95% CI, 1.1–1.5 at age 70). Breast cancer associations with detailed family history were strongest for women with first- and second-degree family history compared with no history (RR, 1.9; 95% CI, 1.1–3.2 at age 40); this association weakened in higher age groups (RR, 1.2; 95% CI, 0.88–1.5 at age 70). Associations did not change substantially when adjusted for breast density.
Conclusions: Even with adjustment for breast density, a history of breast cancer in both first- and second-degree relatives is more strongly associated with breast cancer than simple first-degree family history.
Impact: Future efforts to improve breast cancer risk prediction models should evaluate detailed family history as a risk factor. Cancer Epidemiol Biomarkers Prev; 26(6); 938–44. ©2017 AACR.
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A Comparison of the Natural History of HPV Infection and Cervical Abnormalities among HIV-Positive and HIV-Negative Women in Senegal, Africa
Background: There is evidence of an interaction between HIV and human papillomavirus (HPV) resulting in increased HPV-associated morbidity and cancer mortality among HIV-positive women. This study aims to determine how the natural history of cervical HPV infection differs by HIV status.
Methods: A total of 1,320 women (47% were positive for HIV-1 and/or HIV-2) were followed for an average of two years in Senegal, West Africa between 1994 and 2010. Cytology (with a sub-sample of histology) and HPV DNA testing were performed at approximately 4-month intervals yielding data from over 7,900 clinic visits. Competing risk modeling was used to estimate rates for transitioning between three clinically relevant natural history stages: Normal, HPV, and HSIL (high-grade squamous intraepithelial lesions). Among HIV-positive women, exploratory univariate analyses were conducted examining the impact of HPV type, infection with multiple HPV types, HIV type, CD4+ count, and age.
Results: HIV-positive women had higher rates of progression and lower rates of regression compared with HIV-negative women (i.e., adverse transitions). HIV-positive women had a 2.55 [95% confidence interval (CI), 1.69–3.86; P < 0.0001] times higher rate of progression from HPV to HSIL than HIV-negative women (with 24-month absolute risks of 0.18 and 0.07, respectively). Among HIV-positive women, HPV-16/18 infection and CD4+ count <200/mm3 were associated with adverse transitions.
Conclusions: Adverse HIV effects persist throughout HPV natural history stages.
Impact: In the limited-resource setting of sub-Saharan Africa where cervical cancer screening is not widely available, the high-risk population of HIV-positive women may be ideal for targeted screening. Cancer Epidemiol Biomarkers Prev; 26(6); 886–94. ©2017 AACR.
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Cancer Risk in Women Treated with Fertility Drugs According to Parity Status--A Registry-based Cohort Study
Background: Long-term safety of assisted reproductive techniques (ART) is of interest as their use is increasing. Cancer risk is known to be affected by parity. This study examined the risk of cancer after fertility treatment, stratified by women's parity.
Methods: Data were obtained from all women (n = 1,353,724) born in Norway between 1960 and 1996. Drug exposure data (2004–2014) were obtained from the Norwegian Prescription Database (drugs used in ART and clomiphene citrate). The Medical Birth Registry of Norway provided parity status. HRs were calculated for all site cancer, breast, cervical, endometrial, ovarian, colorectal, central nervous system, thyroid cancer, and malignant melanoma.
Results: In 12,354,392 person-years of follow-up, 20,128 women were diagnosed with cancer. All-site cancer risk was 1.14 [95% confidence interval (95% CI), 1.03–1.26] and 1.10 (95% CI, 0.98–1.23) after clomiphene citrate and ART exposure, respectively. For ovarian cancer, a stronger association was observed for both exposures in nulliparous (HR, 2.49; 95% CI, 1.30–4.78; and HR, 1.62; 95% CI, 0.78–3.35) versus parous women (HR, 1.37; 95% CI, 0.64–2.96; and HR, 0.87; 95% CI, 0.33–2.27). Elevated risk of endometrial cancers was observed for clomiphene citrate exposure in nulliparous women (HR, 4.49; 95% CI, 2.66–7.60 vs. HR, 1.52; 95% CI, 0.67–3.42). Risk was elevated for breast cancer in parous women exposed to clomiphene citrate (HR, 1.26; 95% CI, 1.03–1.54) for thyroid cancer and among nulliparous women after ART treatment (HR, 2.19; 95% CI, 1.08–4.44).
Conclusions: Clomiphene citrate appears associated with increased risk of ovarian and endometrial cancer. Elevations in risks of breast and thyroid cancer were less consistent across type of drug exposure and parity.
Impact: Continued monitoring of fertility treatments is warranted. Cancer Epidemiol Biomarkers Prev; 26(6); 953–62. ©2017 AACR.
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Measured Adiposity in Relation to Head and Neck Cancer Risk in the European Prospective Investigation into Cancer and Nutrition
Background: Emerging evidence from cohort studies indicates that adiposity is associated with greater incidence of head and neck cancer. However, most studies have used self-reported anthropometry which is prone to error.
Methods: Among 363,094 participants in the European Prospective Investigation into Cancer and Nutrition study (EPIC) with measured anthropometry, there were 837 incident cases of head and neck cancer. Head and neck cancer risk was examined in relation to body mass index (BMI) [lean: <22.5 kg/m2, normal weight (reference): 22.5–24.9 kg/m2, overweight 25–29.9 kg/m2, obese: ≥30 kg/m2], waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) using Cox proportional hazards models.
Results: Among men, a BMI < 22.5 kg/m2 was associated with higher head and neck cancer risk [HR 1.62; 95% confidence interval (CI), 1.23–2.12)]; BMI was not associated with head and neck cancer among women. WC and WHR were associated with greater risk of head and neck cancer among women (WC per 5 cm: HR, 1.08; 95% CI, 1.02–1.15; WHR per 0.1 unit: HR, 1.64; 95% CI, 1.38–1.93). After stratification by smoking status, the association for WHR was present only among smokers (Pinteraction = 0.004). Among men, WC and WHR were associated with head and neck cancer only upon additional adjustment for BMI (WC per 5 cm: HR 1.16; 95% CI, 1.07–1.26; WHR per 0.1 unit: HR, 1.42; 95% CI, 1.21–1.65).
Conclusions: Central adiposity, particularly among women, may have a stronger association with head and neck cancer risk than previously estimated.
Impact: Strategies to reduce obesity may beneficially impact head and neck cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(6); 895–904. ©2017 AACR.
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Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI
The American Association for Cancer Research convened a meeting of international pediatric oncologists, geneticists, genetic counselors, and radiologists expert in childhood cancer predisposition syndromes (CPS) in October 2016 to propose consensus surveillance guidelines. Imaging plays a central role in surveillance for most, though not all, syndromes discussed. While encompassing the full gamut of modalities, there is increasing emphasis on use of nonionizing radiation imaging options such as magnetic resonance imaging (MRI) in children and adolescents, especially in the pediatric CPS population. In view of rapid evolution and widespread adoption of whole-body MRI (WBMRI), the purpose of our review is to address WBMRI in detail. We discuss its place in the surveillance of a range of pediatric CPS, the technical and logistical aspects of acquiring and interpreting these studies, and the inherent limitations of WBMRI. We also address issues associated with sedation and use of gadolinium-based contrast agents in MRI in children. Clin Cancer Res; 23(11); e6–e13. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the TP53 tumor suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS. Clin Cancer Res; 23(11); e38–e45. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders
DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal-recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Notably, all patients have elevated risks of syndrome-associated cancers, and many of these cancers present in childhood. Although it is clear that the risk of cancer is increased, there are limited data defining the true incidence of cancer and almost no evidence-based approaches to cancer surveillance in patients with DNA repair disorders. This article is the product of the October 2016 AACR Childhood Cancer Predisposition Workshop, which brought together experts from around the world to discuss and develop cancer surveillance guidelines for children with cancer-prone disorders. Herein, we focus on the more common of the rare DNA repair disorders: ataxia telangiectasia, Bloom syndrome, Fanconi anemia, dyskeratosis congenita, Nijmegen breakage syndrome, Rothmund–Thomson syndrome, and Xeroderma pigmentosum. Dedicated syndrome registries and a combination of basic science and clinical research have led to important insights into the underlying biology of these disorders. Given the rarity of these disorders, it is recommended that centralized centers of excellence be involved directly or through consultation in caring for patients with heritable DNA repair syndromes. Clin Cancer Res; 23(11); e23–e31. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions
Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when Li-Fraumeni syndrome was linked to TP53 mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia-predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes. Clin Cancer Res; 23(11); e14–e22. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion
Purpose: Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Host lymphodepletion is associated with favorable ACT therapy outcomes, but it may cause detrimental effects in humans. We tested the hypothesis that IL15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL15 in vivo comprises a stable complex of the IL15 chain with the IL15 receptor alpha chain (IL15Rα), termed heterodimeric IL15 (hetIL15).
Experimental Design: We evaluated the effects of the combination regimen ACT + hetIL15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice.
Results: hetIL15 treatment delayed tumor growth by promoting infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells into the tumor. In contrast, persistence of Pmel-1 cells was severely reduced following irradiation in comparison with mice treated with hetIL15. Importantly, we found that hetIL15 treatment led to the preferential enrichment of Pmel-1 cells in B16 tumor sites in an antigen-dependent manner. Upon hetIL15 administration, tumor-infiltrating Pmel-1 cells showed a "nonexhausted" effector phenotype, characterized by increased IFN secretion, proliferation, and cytotoxic potential and low level of PD-1. hetIL15 treatment also resulted in an improved ratio of Pmel-1 to Treg in the tumor.
Conclusions: hetIL15 administration improves the outcome of ACT in lymphoreplete hosts, a finding with significant implications for improving cell-based cancer immunotherapy strategies. Clin Cancer Res; 23(11); 2817–30. ©2016 AACR.
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Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood
Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair–deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32–e37. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data
Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.
Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a meta-analysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.
Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37–0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38–0.73, P < 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72–0.92;P = 0.0007) and OS (HR 0.84; 95% CI, 0.75–0.94; P = 0.02) only in univariate analysis.
Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702–12. ©2016 AACR.
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Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study
Purpose: To provide proof of principle of safety, breast tumor–specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab–IRDye800CW targeting VEGF-A in patients with breast cancer.
Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab–IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.
Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.
Conclusions: Our study shows that systemic administration of the bevacizumab–IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730–41. ©2016 AACR.
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E6 and E7 Antibody Levels Are Potential Biomarkers of Recurrence in Patients with Advanced-Stage Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma
Purpose: There is a paucity of biomarkers to predict failure in human papillomavirus–positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) following curative therapy. E6/E7 viral oncoproteins are constitutively expressed in HPV+ tumors and highly immunogenic, resulting in readily detected serum antibodies. The purpose of this study is to determine whether serum E6 and E7 antibody levels can potentially serve as a biomarker of recurrence in patients with HPV+OPSCC.
Experimental Design: We evaluated E6/E7 antibody levels in patients with previously untreated, advanced stage (III, IVa-b), HPV+OPSCC receiving definitive chemoradiation under a uniform protocol from 2003 to 2010. Baseline and longitudinal serum samples were obtained from our archived repository. E6/E7 serum levels were measured using a glutathione-S-transferase capture ELISA and quantified by approximating the area under the dilution curve, and were analyzed using ANOVA and linear mixed model for longitudinal analysis.
Results: We compared 22 HPV+OPSCC patients who developed recurrence with 30 patients who remained disease-free. There were no differences in T classification, N classification, disease subsite, or smoking status between the groups. In a longitudinal analysis, recurrent patients had significantly higher E6 and E7 serum antibody levels than the nonrecurrent patients over the follow-up period (P = 0.02 and P = 0.002, respectively). Patients who recurred had a lower clearance of E7 antibody than patients who remained disease-free (P = 0.0016).
Conclusions: Patients with HPV+OPSCC whose disease recurs have a lower clearance of E6 and E7 antibodies than patients who do not have recurrence. The ratio of E7 antibody at disease recurrence compared with baseline is potentially a clinically significant measurement of disease status in HPV+OPSCC. Clin Cancer Res; 23(11); 2723–9. ©2016 AACR.
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microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma
Purpose: MYCN is one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to how MYCN mediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR-221 has been reported as one of the upregulated miRNAs, the interplay between miR-221 and MYCN-mediated neuroblastoma progression remains largely elusive.
Experimental Design: The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid-in situ hybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined both in vitro and in vivo.
Results: miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells.
Conclusions: This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma. Clin Cancer Res; 23(11); 2905–18. ©2016 AACR.
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Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers
Purpose: The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.
Experimental Design: We performed in vitro studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and TP53 expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
Results: We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents in vitro, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy in vivo. We show that anti-miR-155-DOPC can be considered non-toxic in vivo. We further demonstrate that miR-155 and TP53 are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of TP53 is significantly associated with shorter survival in lung cancer.
Conclusions: Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death. Clin Cancer Res; 23(11); 2891–904. ©2016 AACR.
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Drug-Repositioning Screens Identify Triamterene as a Selective Drug for the Treatment of DNA Mismatch Repair Deficient Cells
Purpose: The DNA mismatch repair (MMR) pathway is required for the maintenance of genome stability. Unsurprisingly, mutations in MMR genes occur in a wide range of different cancers. Studies thus far have largely focused on specific tumor types or MMR mutations; however, it is becoming increasingly clear that a therapy targeting MMR deficiency in general would be clinically very beneficial.
Experimental Design: Based on a drug-repositioning approach, we screened a large panel of cell lines with various MMR deficiencies from a range of different tumor types with a compound drug library of previously approved drugs. We have identified the potassium-sparing diuretic drug triamterene, as a novel sensitizing agent in MMR-deficient tumor cells, in vitro and in vivo.
Results: The selective tumor cell cytotoxicity of triamterene occurs through its antifolate activity and depends on the activity of the folate synthesis enzyme thymidylate synthase. Triamterene leads to a thymidylate synthase-dependent differential increase in reactive oxygen species in MMR-deficient cells, ultimately resulting in an increase in DNA double-strand breaks.
Conclusions: Conclusively, our data reveal a new drug repurposing and novel therapeutic strategy that has potential for the treatment of MMR deficiency in a range of different tumor types and could significantly improve patient survival. Clin Cancer Res; 23(11); 2880–90. ©2016 AACR.
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Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis
Purpose: Although autophagy plays important roles in malignant pathogenesis and drug resistance, there are few clinical agents that disrupt this pathway, and the potential therapeutic benefit of autophagy inhibition remains undetermined. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation.
Experimental Design: ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC) with HCQ serving as a comparator. Markers of autophagy inhibition and cell death were evaluated in tumor specimens.
Results: ROC-325 exhibited superior in vitro anticancer effects compared with the existing autophagy inhibitor hydroxychloroquine (HCQ) in 12 different cancer cell lines with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition, including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, was significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivo.
Conclusions: Our findings demonstrate that ROC-325 has superior preclinical anticancer activity compared with HCQ and support the clinical investigation of its safety and preliminary efficacy in patients with RCC and other autophagy-dependent malignancies. Clin Cancer Res; 23(11); 2869–79. ©2016 AACR.
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Dual ALK and CDK4/6 Inhibition Demonstrates Synergy against Neuroblastoma
Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy.
Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug–drug interactions.
Results: The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P = 0.008) and synergy scores (P = 0.006) in cell lines with ALK mutations as compared with cell lines lacking mutations or alterations in ALK. Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.
Conclusions: This preclinical combination drug screen with in vivo validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. Clin Cancer Res; 23(11); 2856–68. ©2016 AACR.
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Gas6/AXL Signaling Regulates Self-Renewal of Chronic Myelogenous Leukemia Stem Cells by Stabilizing {beta}-Catenin
Purpose: Quiescent leukemia stem cells (LSC) are important resources of resistance and relapse in chronic myelogenous leukemia (CML). Thus, strategies eradicating CML LSCs are required for cure. In this study, we discovered that AXL tyrosine kinase was selectively overexpressed in primary CML CD34+ cells. However, the role of AXL and its ligand Gas6 secreted by stromal cells in the regulation of self-renewal capacity of LSCs has not been well investigated.
Experimental Design: The function of CML CD34+ cells was evaluated by flow cytometer, CFC/replating, long-term culture-initiating cells (LTC-IC), CML mouse model driven by human BCR-ABL gene and NOD-scid-IL2Rg–/– (NSI) mice.
Results: AXL was selectively overexpressed in primary CML CD34+ cells. AXL knockdown reduced the survival and self-renewal capacity of human CML CD34+ cells. Pharmacologic inhibition of AXL reduced the survival and self-renewal capacity of human CML LSCs in vitro and in long-term grafts in NSI mice. Human CML CD34+ cells conscripted bone marrow–derived stromal cells (BMDSC) and primary mesenchymal stem cells (MSC) to secrete Gas6 to form a paracrine loop that promoted self-renewal of LSCs. Suppression of AXL by shRNA and inhibitor prolonged survival of CML mice and reduced the growth of LSCs in mice. Gas6/AXL ligation stabilizes β-catenin in an AKT-dependent fashion in human CML CD34+ cells.
Conclusions: Our findings improve the understanding of LSC regulation and validate Gas6/AXL as a pair of therapeutic targets to eliminate CML LSCs. Clin Cancer Res; 23(11); 2842–55. ©2016 AACR.
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Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr
The prevalence of childhood cancer attributable to genetic predisposition was generally considered very low. However, recent reports suggest that at least 10% of pediatric cancer patients harbor a germline mutation in a cancer predisposition gene. Although some of these children will have a family history suggestive of a cancer predisposition syndrome, many others will not. Evidence from recent pediatric studies suggests that surveillance and early detection of cancer in individuals carrying a germline cancer predisposing mutation may result in improved outcomes. However, there is a lack of consistency in the design of cancer surveillance regimens across centers both nationally and internationally. To standardize approaches, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop, during which consensus screening recommendations for children with the most common cancer predisposition syndromes were developed. In general, we considered a 5% or greater chance of developing a childhood cancer to be a reasonable threshold to recommend screening. Conditions for which the cancer risk was between 1% to 5% were addressed individually. In a series of manuscripts accompanying this article, we provide recommendations for surveillance, focusing on when to initiate and/or discontinue specific screening measures, which modalities to use, and the frequency of screening. Points of controversy are also reviewed. We present the outcome of our deliberations on consensus screening recommendations for specific disorders in 18 position articles as Open Access publications, which are freely available on an AACR-managed website. Clin Cancer Res; 23(11); e1–e5. ©2017 AACR.
See all articles in the online-only CCR Pediatric Oncology Series.
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Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response
Purpose: Epigenetic silencing of tumor suppressor genes (TSG) is an acquired abnormality observed in cancer and is prototypically linked to DNA methylation. We postulated that pretreatment (priming) with 5-azacitidine would increase the efficacy of chemotherapy by reactivating TSGs. This study was conducted to identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients with locally advanced esophageal/gastric adenocarcinoma (EGC).
Experimental Design: Eligible patients had untreated, locally advanced, resectable EGC, ECOG 0–2, and adequate organ function. 5-Azacitidine (V, 75 mg/m2) was given subcutaneously for 3 (dose level, DL 1) or 5 (DL 2) days prior to each 21-day cycle of EOX (E, 50 mg/m2; O, 130 mg/m2; X, 625 mg/m2 twice daily for 21 days). Standard 3+3 methodology guided V dose escalation. DNA methylation at control and biomarker regions was measured by digital droplet, bisulfite qPCR in tumor samples collected at baseline and at resection.
Results: All subjects underwent complete resection of residual tumor (R0). Three of the 12 patients (25%) achieved a surgical complete response and 5 had partial responses. The overall response rate was 67%. The most common toxicities were gastrointestinal and hematologic. Hypomethylation of biomarker genes was observed at all dose levels and trended with therapeutic response.
Conclusions: Neoadjuvant VEOX was well-tolerated with significant clinical and epigenetic responses, with preliminary evidence that priming with V prior to chemotherapy may augment chemotherapy efficacy. The recommended phase II trial schedule is 5-azacitidine 75 mg/m2 for 5 days followed by EOX chemotherapy every 21 days. Clin Cancer Res; 23(11); 2673–80. ©2016 AACR.
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Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study
Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).
Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1–5, 8–10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).
Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0–19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.
Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691–701. ©2016 AACR.
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Circulating Tumor Cells Expressing Markers of Tumor-Initiating Cells Predict Poor Survival and Cancer Recurrence in Patients with Pancreatic Ductal Adenocarcinoma
Purpose: Circulating tumor cells (CTCs) have been identified in the blood of patients with pancreatic adenocarcinoma (PDAC), but little is known about the exact phenotype of these cells. We assessed expression of aldehyde dehydrogenase (ALDH), CD133, and CD44 as markers of CTCs with a tumor-initiating cell (TIC) phenotype in patients with PDAC and the relationship of this expression to patient outcomes.
Experimental Design: Peripheral blood from 60 consecutive patients with PDAC undergoing surgical resection was obtained and processed using the Isolation by Size of Epithelial Tumor (ISET) method. Immunofluorescence was used to identify CTCs expressing cytokeratin, CD133, CD44, and ALDH.
Results: Forty-seven patients (78%) had epithelial CTCs staining positive for pan-cytokeratin and at least one TIC marker. Forty-six patients (77%) had epithelial CTCs that labeled with antibodies to cytokeratin and ALDH. By separate analysis, 34 (57%) had cytokeratin-positive, CD133-positive, and CD44-positive (triple-positive) CTCs, whereas 40 (67%) had cytokeratin-positive, CD133-positive, CD44-negative CTCs. The remaining 13 patients did not have CTCs, as defined by cytokeratin expression. ALDH-positive CTCs and triple-positive CTCs were significantly associated with worse survival by univariate analysis, even when accounting for other significant prognostic factors (all, P ≤ 0.01). ALDH-positive CTCs, triple-positive CTCs, and dual cytokeratin- and CD133-positive CTCs were independent predictors of tumor recurrence by logistic regression analysis and associated with decreased disease-free survival (all, P ≤ 0.03).
Conclusions: CTCs labeling with one or more markers of TICs are found in a majority of patients with PDAC and are independently predictive of decreased disease-free and overall survival. Clin Cancer Res; 23(11); 2681–90. ©2016 AACR.
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Integrative Analysis Identifies a Novel AXL-PI3 Kinase-PD-L1 Signaling Axis Associated with Radiation Resistance in Head and Neck Cancer
Purpose: The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach.
Experimental Design: We utilized human papilloma virus (HPV)-negative cell lines rendered radiation-resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.
Results: RR cell lines exhibited upregulation of several proteins compared with controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70%, and 50% compared with 20%, 25%, and 20% in the PD-L1–low expression group (P = 0.01, 1.9 x 10–3, and 9 x 10–4, respectively). This finding remained significant on multivariate analysis in all groups. Additionally, patients with PD-L1 low/CD8+ tumor-infiltrating lymphocytes high had no local failure or death due to disease (P = 5 x 10–4 and P = 4 x 10–4, respectively).
Conclusions: Taken together, our data point to a targetable Axl–PI3 kinase–PD-L1 axis that is highly associated with radiation resistance. Clin Cancer Res; 23(11); 2713–22. ©2017 AACR.
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What Makes Muslim Women Entrepreneurs Successful? A Field Study Examining Religiosity and Social Capital in Tunisia
Abstract
The present study sheds light upon critical factors that help explain the entrepreneurial success among Muslim women living in a democratic Tunisia, a Muslim-majority country considered by many to be the lone Arab Spring success story. We hypothesized that successful entrepreneurs need social capital, including the capital that comes from marriage and high levels of wasta (the Arabic concept of having personal connections with influential others). Moreover, given the lack of empirical attention paid to the role of the culture, language, and customs associated with Islam on women's empowerment, we examine whether religiosity is related to entrepreneurial performance among Tunisian women. Data collected with 84 female entrepreneurs participating in entrepreneurship training programs across Tunisia reveal that two forms of social capital, marital status and wasta, are related to training center directors' ratings of women entrepreneurs' performance, suggesting that social capital is a critical asset for Muslim women entrepreneurs. Religiosity, on the other hand, had no statistically significant relationship with entrepreneurial performance. Our study contributes to research on entrepreneurship by identifying wasta as a form of social capital that may be necessary for women entrepreneurs to succeed in the Middle East and North Africa and by taking an initial step towards better understanding the empirical (and controversial) relationship between religiosity and career success among Muslim women. We recommend that training organizations supporting entrepreneurs directly assist women in the development of social capital and acknowledge, rather than ignore, that nepotism and wasta are linked to entrepreneurial success in some cultures.
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Effects of sesamin on chondroitin sulfate proteoglycan synthesis induced by interleukin-1beta in human chondrocytes
Numerous studies have reported on the health benefits of sesamin, a major lignin found in sesame (S. indicum) seeds. Recently, sesamin was shown to have the ability to promote chondroitin sulfate proteoglycan syn...
http://ift.tt/2spO2SY
TAM Receptor Tyrosine Kinases in Cancer Drug Resistance
Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 2775–8. ©2017 AACR.
http://ift.tt/2rdwxHQ
Multinuclear NMR and MRI Reveal an Early Metabolic Response to mTOR Inhibition in Sarcoma
Biomarkers predicting rapalog responses in sarcomas where PI3K and mTOR are often hyperactivated could improve the suitable recruitment of responsive patients to clinical trials. PI3K/mTOR pathway activation drives energy production by regulating anaerobic glycolysis in cancer cells, suggesting a route toward a monitoring strategy. In this study, we took a multimodality approach to evaluate the phenotypic effects and metabolic changes that occur with inhibition of the PI3K/mTOR pathway. Its central role in regulating glycolysis in human sarcomas was evaluated by short- and long-term rapamycin treatment in sarcoma cell lines. We observed an overall decrease in lactate production in vitro, followed by cell growth inhibition. In vivo, we observed a similar quantitative reduction in lactate production as monitored by hyperpolarized MRI, also followed by tumor size changes. This noninvasive imaging method could distinguish reduced cell proliferation from induction of cell death. Our results illustrate the use of hyperpolarized MRI as a sensitive technique to monitor drug-induced perturbation of the PI3K/mTOR pathway in sarcomas. Cancer Res; 77(11); 3113–20. ©2017 AACR.
http://ift.tt/2qIeVjL
Expression of Neuroendocrine Factor VGF in Lung Cancer Cells Confers Resistance to EGFR Kinase Inhibitors and Triggers Epithelial-to-Mesenchymal Transition
Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. Cancer Res; 77(11); 3013–26. ©2017 AACR.
http://ift.tt/2qIs9ND
Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer
IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 2779–83. ©2017 AACR.
http://ift.tt/2rdEoVD
A Squalene-Based Nanomedicine for Oral Treatment of Colon Cancer
Nanotechnology offers many possibilities to improve drug treatments, including with regard to drug pharmacology. The current study reports a simple approach to improve cisplatin efficacy in the treatment of colon cancer through the creation of orally administered squalenoylated nanoparticles loaded with cisplatin (SQ-CDDP NP). Cytotoxic effects of SQ-CDDP NP were assessed in human colonic cells and in mouse models of intestinal cancer. In cell culture, SQ-CDDP NP exhibited at least 10-fold greater cytotoxic potency compared with uncomplexed cisplatin, reflecting an enhancement in intracellular accumulation and DNA platination. Mechanistic investigations showed that SQ-CDDP NP stimulated ROS production, expression of heavy metal–inducible and stress-inducible genes, stress kinase cascades, and apoptosis. In ApcMin/+ mice, a model of intestinal tumorigenesis, oral administration of SQ-CDDP NP curtailed spontaneous tumor formation and azoxymethane-induced colon carcinogenesis with no apparent evidence of tissue toxicity. Our results offer preclinical validation of a nanocarrier formulation that can safely improve chemotherapeutic efficacy, address risks of drug resistance, and improve patient compliance by enabling oral administration. Cancer Res; 77(11); 2964–75. ©2017 AACR.
http://ift.tt/2qIjVVD
Widespread Use of Misidentified Cell Line KB (HeLa): Incorrect Attribution and Its Impact Revealed through Mining the Scientific Literature
Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 correct and 171 incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between correct and incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication. Cancer Res; 77(11); 2784–8. ©2017 AACR.
http://ift.tt/2rdCggD
Combination Therapy Targeting BCL6 and Phospho-STAT3 Defeats Intratumor Heterogeneity in a Subset of Non-Small Cell Lung Cancers
Oncogene-specific changes in cellular signaling have been widely observed in lung cancer. Here, we investigated how these alterations could affect signaling heterogeneity and suggest novel therapeutic strategies. We compared signaling changes across six human bronchial epithelial cell (HBEC) strains that were systematically transformed with various combinations of TP53, KRAS, and MYC—oncogenic alterations commonly found in non–small cell lung cancer (NSCLC). We interrogated at single-cell resolution how these alterations could affect classic readouts (β-CATENIN, SMAD2/3, phospho-STAT3, P65, FOXO1, and phospho-ERK1/2) of key pathways commonly affected in NSCLC. All three oncogenic alterations were required concurrently to observe significant signaling changes, and significant heterogeneity arose in this condition. Unexpectedly, we found two mutually exclusive altered subpopulations: one with STAT3 upregulation and another with SMAD2/3 downregulation. Treatment with a STAT3 inhibitor eliminated the upregulated STAT3 subpopulation, but left a large surviving subpopulation with downregulated SMAD2/3. A bioinformatics search identified BCL6, a gene downstream of SMAD2/3, as a novel pharmacologically accessible target of our transformed HBECs. Combination treatment with STAT3 and BCL6 inhibitors across a panel of NSCLC cell lines and in xenografted tumors significantly reduced tumor cell growth. We conclude that BCL6 is a new therapeutic target in NSCLC and combination therapy that targets multiple vulnerabilities (STAT3 and BCL6) downstream of common oncogenes, and tumor suppressors may provide a potent way to defeat intratumor heterogeneity. Cancer Res; 77(11); 3070–81. ©2017 AACR.
http://ift.tt/2qIjURz
BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer
Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.
http://ift.tt/2rdykwq
Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk
Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor–positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis. Cancer Res; 77(11); 2800–9. ©2017 AACR.
http://ift.tt/2rdNYIf
SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer
Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990–3000. ©2017 AACR.
http://ift.tt/2qIn5sn
Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery
Massive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase–substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810–21. ©2017 AACR.
http://ift.tt/2rdyi7M
ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma
Defects in maintaining genome integrity are a hallmark of cancer. The DNA damage response kinase ATM is frequently mutated in human cancer, but the significance of these events to chemotherapeutic efficacy has not been examined deeply in whole organism models. Here we demonstrate that bi-allelic Atm deletion in mouse models of Kras-mutant lung adenocarcinoma does not affect cisplatin responses. In marked contrast, Atm-deficient tumors displayed an enhanced response to the topoisomerase-II poison etoposide. Moreover, Atm-deficient cells and tumors were sensitive to the PARP inhibitor olaparib. This actionable molecular addiction to functional PARP1 signaling was preserved in models that were proficient or deficient in p53, resembling standard or high-risk genetic constellations, respectively. Atm deficiency also markedly enhanced sensitivity to the ATR inhibitor VE-822. Taken together, our results provide a functional rationale to profile human tumors for disabling ATM mutations, particularly given their impact on PARP1 and ATR inhibitors. Cancer Res; 77(11); 3040–56. ©2017 AACR.
http://ift.tt/2qIdHF8
Variability in Chromatin Architecture and Associated DNA Repair at Genomic Positions Containing Somatic Mutations
Dynamic chromatin structures result in differential chemical reactivity to mutational processes throughout the genome. To identify chromatin features responsible for mutagenesis, we compared chromatin architecture around single-nucleotide variants (SNV), insertion/deletions (indels), and their context-matched, nonmutated positions. We found epigenetic differences between genomic regions containing missense SNVs and those containing frameshift indels across multiple cancer types. Levels of active histone marks were higher around frameshift indels than around missense SNV, whereas repressive histone marks exhibited the reverse trend. Accumulation of repressive histone marks and nucleosomes distinguished mutated positions (both SNV and indels) from the context-matched, nonmutated positions, whereas active marks were associated with substitution- and cancer type–specific mutagenesis. We also explained mutagenesis based on genome maintenance mechanisms, including nucleotide excision repair (NER), mismatch repair (MMR), and DNA polymerase epsilon (POLE). Regional NER variation correlated strongly with chromatin features; NER machineries exhibited shifted or depleted binding around SNV, resulting in decreased NER at mutation positions, especially at sites of recurrent mutations. MMR-deficient tumors selectively acquired SNV in regions with high active histone marks, especially H3K36me3, whereas POLE-deficient tumors selectively acquired indels and SNV in regions with low active histone marks. These findings demonstrate the importance of fine-scaled chromatin structures and associated DNA repair mechanisms in mutagenesis. Cancer Res; 77(11); 2822–33. ©2017 AACR.
http://ift.tt/2rdGeGc
The p53/p21 Complex Regulates Cancer Cell Invasion and Apoptosis by Targeting Bcl-2 Family Proteins
The tumor suppressor p53 binds prosurvival Bcl-2 family proteins such as Bcl-w and Bcl-XL to liberate Bax, which in turn exerts proapoptotic or anti-invasive functions depending on stress context. On the basis of our previous finding that p53 interacts with p21, we investigated the possible involvement of p21 in these functions. Here, we report that although p53 can bind Bcl-w alone, it requires p21 to liberate Bax to suppress cell invasion and promote cell death. p21 bound Bcl-w, forming a p53/p21/Bcl-w complex in a manner that maintained all pairwise p53/p21, p21/Bcl-w, and p53/Bcl-w interactions. This allowed Bax liberation from the complex. Accordingly, a p53 derivative incapable of binding p21 failed to mediate radiotherapy-induced tumor cell death in mice. Bcl-XL also served as a target of the cooperative action of p53 and p21. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple cell components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Cancer Res; 77(11); 3092–100. ©2017 AACR.
http://ift.tt/2qIdGB4
GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment–derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting. Cancer Res; 77(11); 2844–56. ©2017 AACR.
http://ift.tt/2rdmiTG
SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells
Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.
http://ift.tt/2rdGt4d
Targeting Autocrine CCL5-CCR5 Axis Reprograms Immunosuppressive Myeloid Cells and Reinvigorates Antitumor Immunity
The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5–CCR5 axis is a major regulator of immunosuppressive myeloid cells (IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of ccl5-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the ccl5-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8+ T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5–CCR5 axis is an excellent target for cancer immunotherapy. Cancer Res; 77(11); 2857–68. ©2017 AACR.
http://ift.tt/2rdCbcP
Prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan–Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32–3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31–2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.
Our study aims to investigate the prognostic value of Notch receptors in postsurgical patients with hepatitis B virus-related hepatocellular carcinoma. Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for overall survival (OS) in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.
http://ift.tt/2rma49V
Myeloid sarcoma identified on liquid-based cervical cytology samples: A report of two cases
The purpose of the Papanicolaou (Pap) smear is to detect primary squamous lesions of the uterine cervix. Although most successful at detection of squamous lesions, the Pap may also detect metastatic carcinomas, sarcomas, and melanomas. We report two rare cases of myeloid sarcoma (MS) of the uterine cervix identified on screening Pap smears with concurrent confirmatory cervical biopsies. The purpose of our study is to identify and report cytologic features of MS on Pap smears utilizing a liquid-based ThinPrep method, which has not been previously documented in literature. Two Pap smears were identified from the pathology laboratory information system, both with positive cervical biopsy findings of MS. Both women, age 40 and 39, presented with ureteral obstruction, hydronephrosis, and past medical histories significant for acute myeloid leukemia (AML). On imaging, cervical masses were identified, and subsequent work-up with Pap smears and biopsies were performed. Cytologic examination of the ThinPrep Pap smears were negative for squamous intraepithelial lesion. Atypical hematologic cells were seen in the background with irregular nuclear contours, increased nuclear to cytoplasmic ratios, variably prominent nucleoli, and variable amounts of agranular cytoplasm. The biopsy confirmed these findings to represent MS. MS is defined as a tumor mass of myeloblasts or immature myeloid cells occurring in an extramedullary site. This rarely involves the female genital tract, about 50 reported cases. Although very rare, MSs in the setting of a history of AML are able to be identified on liquid-based ThinPrep smears.
http://ift.tt/2rrrPXw
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
