Publications by authors named "Cecile Laurent"

56 Publications

Patterns and Factors Associated With Adherence to Lung Cancer Screening in Diverse Practice Settings.

JAMA Netw Open 2021 Apr 1;4(4):e218559. Epub 2021 Apr 1.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill.

Importance: For lung cancer screening to confer mortality benefit, adherence to annual screening with low-dose computed tomography scans is essential. Although the National Lung Screening Trial had an adherence rate of 95%, current data are limited on screening adherence across diverse practice settings in the United States.

Objective: To evaluate patterns and factors associated with adherence to annual screening for lung cancer after negative results of a baseline examination, particularly in centralized vs decentralized screening programs.

Design, Setting, And Participants: This observational cohort study was conducted at 5 academic and community-based sites in North Carolina and California among 2283 individuals screened for lung cancer between July 1, 2014, and March 31, 2018, who met US Preventive Services Task Force eligibility criteria, had negative results of a baseline screening examination (American College of Radiology Lung Imaging Reporting and Data System category 1 or 2), and were eligible to return for a screening examination in 12 months.

Exposures: To identify factors associated with adherence, the association of adherence with selected baseline demographic and clinical characteristics, including type of screening program, was estimated using multivariable logistic regression. Screening program type was classified as centralized if individuals were referred through a lung cancer screening clinic or program and as decentralized if individuals had a direct clinician referral for the baseline low-dose computed tomography scan.

Main Outcomes And Measures: Adherence to annual lung cancer screening, defined as a second low-dose computed tomography scan within 11 to 15 months after baseline screening.

Results: Among the 2283 eligible individuals (1294 men [56.7%]; mean [SD] age, 64.9 [5.8] years; 1160 [50.8%] aged ≥65 years) who had negative screening results at baseline, overall adherence was 40.2% (n = 917), with higher adherence among those who underwent screening through centralized (46.0% [478 of 1039]) vs decentralized (35.3% [439 of 1244]) programs. The independent factor most strongly associated with adherence was type of screening program, with a 2.8-fold increased likelihood of adherence associated with centralized screening (adjusted odds ratio [aOR], 2.78; 95% CI, 1.99-3.88). Another associated factor was age (65-69 vs 55-59 years: aOR, 1.38; 95% CI, 1.07-1.77; 70-74 vs 55-59 years: aOR, 1.47; 95% CI, 1.10-1.96).

Conclusions And Relevance: After negative results of a baseline examination, adherence to annual lung cancer screening was suboptimal, although adherence was higher among individuals who were screened through a centralized program. These results support the value of centralized screening programs and the need to further implement strategies that improve adherence to annual screening for lung cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.8559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087957PMC
April 2021

Girls' Pubertal Timing and Tempo and Mental Health: A Longitudinal Examination in an Ethnically Diverse Sample.

J Adolesc Health 2021 Feb 23. Epub 2021 Feb 23.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.

Purpose: Earlier timing and faster tempo of puberty have been linked to adolescents' poor mental health. Previous research rarely adjusted for childhood mental health, did not use physical examination to assess puberty, and excluded Latinas and Asian Americans. This study addressed these limitations.

Methods: We followed 822 girls, recruited at ages 6-8, for 8 years. Breast and pubic hair development and anxiety and depressive symptoms were assessed prospectively and repeatedly. Structural equation models tested whether pubertal timing and tempo were associated with adolescent mental health symptoms and whether associations varied by ethnicity. Models were adjusted for childhood mental health symptoms, body mass index, and family income.

Results: Earlier breast development was associated with higher depressive symptoms among whites (β = -.19; p < .01) and higher anxiety symptoms among Latinas (β = -.26; p < .05), but lower depressive symptoms among Asians (β = .24, p < .05). Later pubic hair development (b = .24; p < .05) and faster pubic hair tempo (β = .26; p < .01) were associated with higher anxiety symptoms among Latinas. Faster pubic hair tempo was associated with lower depressive symptoms among Asians (β = -.34; p < .05). Tempo of breast development showed no associations.

Conclusions: Findings confirmed that earlier breast development was associated with higher mental health symptoms for Latina and white girls but was protective among Asians. Results for pubic hair and pubertal tempo were inconsistent, requiring future examination. While targeted interventions to prevent mental health problems among early-maturing girls are critical, there is variability among who might benefit most.
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http://dx.doi.org/10.1016/j.jadohealth.2021.01.020DOI Listing
February 2021

The Adolescent and Young Adult (AYA) Horizon Study: An AYA Cancer Survivorship Cohort.

Cancer Epidemiol Biomarkers Prev 2021 May 22;30(5):857-866. Epub 2021 Feb 22.

Division of Research, Kaiser Permanente Northern California, Oakland, California.

Background: In the United States, >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the United States.

Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the five most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g., miscarriage, live birth) and birth (e.g., birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data.

Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall ( = 1,679), and notably lower among minority groups compared with non-Hispanic white women.

Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements.

Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102328PMC
May 2021

A prospective study of lifestyle factors and bone health in breast cancer patients who received aromatase inhibitors in an integrated healthcare setting.

J Cancer Surviv 2021 Feb 9. Epub 2021 Feb 9.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Purpose: Fracture and osteoporosis are known side effects of aromatase inhibitors (AIs) for postmenopausal hormone receptor positive (HR+) breast cancer (BC) patients. How modifiable lifestyle factors impact fracture risk in these patients is relatively unknown.

Methods: We conducted a prospective cohort study to examine the association of lifestyle factors, focusing on physical activity, with risk of incident major osteoporotic fracture and osteoporosis in 2152 HR+ BC patients diagnosed from 2006 to 2013 at Kaiser Permanente Northern California and who received AIs. Patients self-reported lifestyle factors at study entry and at 6-month follow-up. Fracture and osteoporosis outcomes were prospectively ascertained by physician-adjudication and bone mineral density (BMD) values, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable proportional hazards regression. Models were adjusted for age, menopausal status, race/ethnicity, body mass index (BMI), AJCC stage, breast cancer treatment, prior osteoporosis, and prior major fracture.

Results: Over a median 6.1 years of follow-up after AI initiation, 165 women experienced an incident osteoporotic fracture and 243 women had osteoporosis. No associations were found between overall moderate-vigorous physical activity and fracture risk, although < 150 min/week of aerobic exercise in the 6 months after BC diagnosis was associated with increased fracture risk (HR=2.42; 95% CI: 1.34, 4.37) compared with ≥ 150 min/week (meeting physical activity guidelines). Risk was also higher for never or infrequently engaging in aerobic exercise (HR=1.90; 95% CI: 1.05, 3.44). None or infrequent overall moderate-vigorous physical activity in the 6 months before BC diagnosis was associated with increased risk of osteoporosis (HR=1.94; 95% CI: 1.11; 3.37).

Conclusions: Moderate-vigorous physical activity during the immediate period after BC diagnosis, particularly aerobic exercise, was associated with lower risk of major osteoporotic fractures in women on AI therapy.

Implications For Cancer Survivors: Findings may inform fracture prevention in women on AI therapy through non-pharmacologic lifestyle-based strategies.
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http://dx.doi.org/10.1007/s11764-021-00993-0DOI Listing
February 2021

Urinary polycyclic aromatic hydrocarbons in relation to anthropometric measures and pubertal development in a cohort of Northern California girls.

Environ Epidemiol 2020 Aug 6;4(4):e0102. Epub 2020 Jul 6.

Environmental Health Investigations Branch, California Department of Public Health, Richmond, California.

Background: Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous, environmental chemicals that may have endocrine disrupting capabilities. We investigated whether childhood exposure to PAHs was associated with adiposity and pubertal timing in a longitudinal study of 404 girls enrolled in the Northern California site of the Breast Cancer and the Environment Research Program cohort.

Methods: Baseline urinary samples from girls aged 6-8-years-old were assayed for 2-naphthol, fluorene metabolites, phenanthrene metabolites, 1-hydroxypyrene, and sum of PAH metabolites. Mixed-effects linear models were used to estimate how concentrations of PAH metabolites were related to changes in girl's body mass index (BMI) and waist-to-height ratio from age 7 through 16 years old. Accelerated failure time models were used to estimate age of pubertal onset (Tanner stages 2 or higher for breast and pubic hair development).

Results: Higher adiposity measurements among high tertiles of baseline PAH metabolites were evident at age 7 years old and increased thereafter (i.e., BMI for all PAH metabolites, waist-to-height ratio for fluorene and phenanthrene metabolites) or leveled off (i.e., waist-to-height ratio for 2-naphthol, 1-hydroxypyrene, sum of PAHs). Among girls overweight/obese at baseline, median age of breast development onset for high tertiles was 9.1-9.4 years old compared with 10-10.2 years old for low tertiles for all PAH metabolites; in contrast, found no association or slightly later onset of breast development for girls with normal weight at baseline.

Discussion: These results suggest that exposure to specific PAHs during childhood may influence adiposity throughout adolescence and effect pubertal timing.
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http://dx.doi.org/10.1097/EE9.0000000000000102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423521PMC
August 2020

Streamlining genetic testing for women with ovarian cancer in a Northern California health care system.

Gynecol Oncol 2020 10 7;159(1):221-228. Epub 2020 Aug 7.

Kaiser Permanente Northern California, Division of Research, Oakland, CA, United States of America.

Objective: Referral to Genetics for pre-testing counseling may be inefficient for women with ovarian cancer. This study assesses feasibility of gynecologic oncologists directly offering genetic testing.

Methods: A prospective pilot study was conducted at two gynecologic oncology hubs in an integrated healthcare system from May 1 to November 6, 2019. Gynecologic oncologists offered multigene panel testing to women with newly diagnosed ovarian cancer, followed by selective genetic counseling. Outcomes were compared between study participants and women from other hubs in the health system.

Results: Of ovarian cancer patients at study sites, 40 participated and all underwent genetic testing. Of 101 patients diagnosed at other sites, 85% were referred to genetics (p = .0061 compared to pilot participants) and 67% completed testing (p < .0001). The time from diagnosis to blood draw and notification of result was 18.5 and 34 days for the pilot group compared to 25.5 and 53 days at other sites. Panel testing detected 9 (22.5%) and 7 (10.3%, p = .08) pathogenic mutations in each group, respectively. Patients and providers were highly satisfied with the streamlined process.

Conclusion: Genetic testing performed at the gynecologic oncology point of care for patients with ovarian cancer is feasible, increases uptake of testing, and improves time to results.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.027DOI Listing
October 2020

Obesity and related conditions and risk of inflammatory breast cancer: a nested case-control study.

Breast Cancer Res Treat 2020 Sep 20;183(2):467-478. Epub 2020 Jul 20.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: Inflammatory breast cancer (IBC) is a rare, poorly understood and aggressive tumor. We extended prior findings linking high body mass index (BMI) to substantial increased IBC risk by examining BMI associations before and after adjustment for well-characterized comorbidities using medical record data for diabetes, insulin resistance, and disturbances of cholesterol metabolism in a general community healthcare setting.

Methods: We identified 247 incident IBC cases diagnosed at Kaiser Permanente Northern California between 2005 and 2017 and 2470 controls matched 10:1 on birth year and geographic area and with ≥ 13 months of continuous enrollment prior to diagnosis/index date. We assessed exposures from 6 years up to one year prior to the diagnosis/index date, using logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Results: Before adjustment for comorbidities, ORs (95% CIs) for BMI of 25-< 30, 30-< 35, and ≥ 35 compared to < 25 kg/m were 1.5 (0.9-2.3), 2.0 (1.2-3.1), and 2.5 (1.4-4.4), respectively. After adjustment for pre-diabetes/diabetes, HDL-C and triglyceride levels, and dyslipidemia, corresponding ORs were 1.3 (0.8-2.1), 1.6 (0.9-2.9), and 1.9 (1.0-3.5). The OR for HDL-C levels < 50 mg/dL compared to ≥ 65 mg/dL was 2.0 (1.2-3.3) in the adjusted model. In a separate model the OR for a triglyceride/HDL-C ratio ≥ 2.50 compared to < 1.62 was 1.7 (1.1-2.8) after adjustment for BMI, pre-diabetes/diabetes, and dyslipidemia. Results did not differ significantly by estrogen receptor status.

Conclusions: Obesity and measures of insulin resistance independently increased IBC risk as did obesity and low HDL-C levels. These findings, if confirmed, have implications for IBC prevention.
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http://dx.doi.org/10.1007/s10549-020-05785-1DOI Listing
September 2020

Targeted deep sequencing reveals clonal and subclonal mutational signatures in Adult T-cell leukemia/lymphoma and defines an unfavorable indolent subtype.

Leukemia 2021 03 17;35(3):764-776. Epub 2020 Jun 17.

Service d'Hématologie Adultes, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, 149-161 rue de Sèvres, 75015, Paris, France.

Adult T-cell leukemia/lymphoma (ATL) carries a poor prognosis even in indolent subtypes. We performed targeted deep sequencing combined with mapping of HTLV-1 proviral integration sites of 61 ATL patients of African and Caribbean origin. This revealed mutations mainly affecting TCR/NF-kB (74%), T-cell trafficking (46%), immune escape (29%), and cell cycle (26%) related pathways, consistent with the genomic landscape previously reported in a large Japanese cohort. To examine the evolution of mutational signatures upon disease progression while tracking the viral integration architecture of the malignant clone, we carried out a longitudinal study of patients who either relapsed or progressed from an indolent to an aggressive subtype. Serial analysis of relapsing patients identified several patterns of clonal evolution. In progressing patients, the longitudinal study revealed NF-kB/NFAT mutations at progression that were present at a subclonal level at diagnosis (allelic frequency < 5%). Moreover, the presence in indolent subtypes of mutations affecting the TCR/NF-kB pathway, whether clonal or subclonal, was associated with significantly shorter time to progression and overall survival. Our observations reveal the clonal dynamics of ATL mutational signatures at relapse and during progression. Our study defines a new subgroup of indolent ATLs characterized by a mutational signature at high risk of transformation.
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http://dx.doi.org/10.1038/s41375-020-0900-3DOI Listing
March 2021

Adjuvant endocrine therapy for breast cancer patients: impact of a health system outreach program to improve adherence.

Breast Cancer Res Treat 2020 Feb 23;180(1):219-226. Epub 2020 Jan 23.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: Reports suggest that up to 50% of women with hormone receptor-positive (HR+) breast cancer (BC) do not complete the recommended 5 years of adjuvant endocrine therapy (AET). We examined the impact of an outreach program at Kaiser Permanente Northern California (KPNC) on adherence and discontinuation of AET among patients who initiated AET.

Methods: We assembled a retrospective cohort of all KPNC patients diagnosed with HR+, stage I-III BC initiating AET before (n = 4287) and after (n = 3580) implementation of the outreach program. We compared adherence proportions and discontinuation rates before and after program implementation, both crude and adjusted for age, race/ethnicity, education, income, and stage. We conducted a pooled analysis of data from six Cancer Research Network (CRN) sites that had not implemented programs for improving AET adherence, using identical methods and time periods, to assess possible secular trends.

Results: In the pre-outreach period, estimated adherence in years 1, 2, and 3 following AET initiation was 75.2%, 71.0%, and 67.3%; following the outreach program, the estimates were 79.4%, 75.6%, and 72.2% (p-values < .0001 for pairwise comparisons). Results were comparable after adjusting for clinical and demographic factors. The estimated cumulative incidence of discontinuation was 0.22 (0.21-0.24) and 0.18 (0.17-0.19) at 3 years for pre- and post-outreach groups (p-value < .0001). We found no evidence of an increase in adherence between the study periods at the CRN sites with no AET adherence program.

Conclusion: Adherence and discontinuation after AET initiation improved modestly following implementation of the outreach program.
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http://dx.doi.org/10.1007/s10549-020-05539-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035197PMC
February 2020

Serum bone markers and risk of osteoporosis and fragility fractures in women who received endocrine therapy for breast cancer: a prospective study.

Breast Cancer Res Treat 2020 Feb 7;180(1):187-195. Epub 2020 Jan 7.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: Osteoporosis and fragility fracture are major bone toxicities of aromatase inhibitors (AIs) for postmenopausal hormone receptor-positive breast cancer. Except for a few small studies on bone turnover markers and reduced bone mineral density after AI treatment, data on the associations of bone markers and risk of osteoporosis or fracture from prospective studies are lacking.

Methods: In a prospective study of 1709 women on AIs, two bone turnover markers, BALP and TRACP, and two bone regulatory markers, RANKL and OPG, were measured and examined in relation to risk of osteoporosis and fragility fractures during a median follow-up time of 6.1 years.

Results: Higher levels of BALP and TRACP were both associated with increased risk of osteoporosis and higher BALP/TRACP ratios were associated with lower risk of osteoporosis, but no associations were observed for fracture risk. Higher levels of OPG were associated with increased risk of fracture, whereas higher levels of RANKL were associated with lower risk. As a result, OPG/RANKL ratios were positively associated with fracture risk [hazard ratio (HR) = 2.49, 95% confidence interval (CI) 1.34-4.61]. After controlling for age and fracture history, the associations became non-significant but a suggestive trend remained (HR = 1.80, 95% CI 0.96-3.37).

Conclusion: Our study provides suggestive evidence for the potential utility of OPG/RANKL ratios in predicting risk of fracture in women treated with AIs for breast cancer. Further validation may be warranted.
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http://dx.doi.org/10.1007/s10549-019-05518-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171589PMC
February 2020

Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.

Blood 2020 01;135(5):360-370

Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France.

The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
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http://dx.doi.org/10.1182/blood.2019001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059458PMC
January 2020

Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data.

PLoS One 2019 7;14(11):e0224143. Epub 2019 Nov 7.

MINES ParisTech, PSL Research University, CBIO-Centre for Computational Biology, Paris, France.

Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage. Those subclonal populations can be sensitive or resistant to different treatments, and provide information about tumor aetiology and future evolution. Hence, it is important to be able to assess the level of heterogeneity of tumors with high reliability for clinical applications. In the past few years, a large number of methods have been proposed to estimate intra-tumor heterogeneity from whole exome sequencing (WES) data, but the accuracy and robustness of these methods on real data remains elusive. Here we systematically apply and compare 6 computational methods to estimate tumor heterogeneity on 1,697 WES samples from the cancer genome atlas (TCGA) covering 3 cancer types (breast invasive carcinoma, bladder urothelial carcinoma, and head and neck squamous cell carcinoma), and two distinct input mutation sets. We observe significant differences between the estimates produced by different methods, and identify several likely confounding factors in heterogeneity assessment for the different methods. We further show that the prognostic value of tumor heterogeneity for survival prediction is limited in those datasets, and find no evidence that it improves over prognosis based on other clinical variables. In conclusion, heterogeneity inference from WES data on a single sample, and its use in cancer prognosis, should be considered with caution. Other approaches to assess intra-tumoral heterogeneity such as those based on multiple samples may be preferable for clinical applications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837753PMC
March 2020

Decentralization of Next-Generation RNA Sequencing-Based MammaPrint® and BluePrint® Kit at University Hospitals Leuven and Curie Institute Paris.

Transl Oncol 2019 Dec 9;12(12):1557-1565. Epub 2019 Sep 9.

Agendia, Department of Research and Development, Medical Affairs, Amsterdam, The Netherlands.

A previously developed and centrally validated MammaPrint® (MP) and BluePrint® (BP) targeted RNA next-generation sequencing (NGS) kit was implemented and validated in two large academic European hospitals. Additionally, breast cancer molecular subtypes by MP and BP RNA sequencing were compared with immunohistochemistry (IHC). Patients with early breast cancer diagnosed at University Hospitals Leuven and Curie Institute Paris were prospectively included between September 2017 and January 2018. Formalin-fixed paraffin-embedded tissue sections were analyzed with MP and BP NGS technology at the beta sites and with both NGS and microarray technology at Agendia. Raw NGS data generated on Illumina MiSeq instruments at the beta sites were interpreted and compared with NGS and microarray data at Agendia. MP and BP NGS molecular subtypes were compared to surrogate IHC breast cancer subtypes. Equivalence of MP and BP indices was determined by Pearson's correlation coefficient. Acceptable limits were defined a priori, based on microarray data generated at Agendia between 2012 and 2016. The concordance, the Negative Percent Agreement and the Positive Percent Agreement were calculated based on the contingency tables and had to be equal to or higher than 90%. Out of 124 included samples, 48% were MP Low and 52% High Risk with microarray. Molecular subtypes were BP luminal, HER2 or basal in 82%, 8% and 10% respectively. Concordance between MP microarray at Agendia and MP NGS at the beta sites was 91.1%. Concordance of MP High and Low Risk classification between NGS at the beta sites and NGS at Agendia was 93.9%. Concordance of MP and BP molecular subtyping using NGS at the beta sites and microarray at Agendia was 89.5%. Concordance between MP and BP NGS subtyping, and IHC was 71.8% and 76.6%, for two IHC surrogate models. The MP/BP NGS kit was successfully validated in a decentralized setting.
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http://dx.doi.org/10.1016/j.tranon.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742807PMC
December 2019

Associations of Maternal Gestational Weight Gain and Obesity With the Timing of Pubertal Onset in Daughters.

Am J Epidemiol 2019 07;188(7):1262-1269

Kaiser Permanente Division of Research, Oakland, California.

Early puberty is associated with adverse health outcomes, but little is known regarding early-life determinants influencing pubertal timing. We examined the associations between maternal gestational weight gain (GWG) and the timing of the onset of breast development (thelarche) and pubic hair development (pubarche) in a cohort of 2,070 girls born in a Kaiser Permanente Northern California facility between 2005 and 2006. Using Weibull regression models accommodating interval censoring and adjusting for important confounders, we found that excess GWG was associated with increased risk of early thelarche (hazard ratio (HR) = 1.50, 95% confidence interval (CI): 1.26, 1.78) and early pubarche (HR = 1.35, 95% CI: 1.10, 1.66). Inadequate GWG was associated with early thelarche (HR = 1.36, 95% CI: 1.08, 1.71). The associations between excess or inadequate GWG and risk of earlier thelarche were stronger if mothers were obese before or at the beginning of pregnancy (body mass index ≥30 kg body weight per m height squared) (HR = 2.01, 95% CI: 1.53, 2.63; HR = 2.08, 95% CI: 1.45, 2.98, respectively). Similar associations were found for pubarche outcome. Inclusion of girls' prepubertal body mass index slightly attenuated these associations, but they remained significant. Monitoring of maternal weight before and throughout pregnancy might help prevent early pubertal onset and subsequent negative health outcomes.
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http://dx.doi.org/10.1093/aje/kwz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601524PMC
July 2019

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.

Int J Cancer 2019 10 4;145(7):1902-1912. Epub 2019 Apr 4.

Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie Research Center, Paris, France.

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.
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http://dx.doi.org/10.1002/ijc.32266DOI Listing
October 2019

Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2.

Sci Rep 2019 02 28;9(1):2990. Epub 2019 Feb 28.

Institut Curie, PSL Research University, CNRS, INSERM, Orsay, France.

Uveal melanoma (UM) is an aggressive tumor in which approximately 50% of patients develop metastasis. Expression of the PTP4A3 gene, encoding a phosphatase, is predictive of poor patient survival. PTP4A3 expression in UM cells increases their migration in vitro and invasiveness in vivo. Here, we show that CRMP2 is mostly dephosphorylated on T514 in PTP4A3 expressing cells. We also demonstrate that inhibition of CRMP2 expression in UM cells expressing PTP4A3 increases their migration in vitro and invasiveness in vivo. This phenotype is accompanied by modifications of the actin microfilament network, with shortened filaments, whereas cells with a inactive mutant of the phosphatase do not show the same behavior. In addition, we showed that the cell cytoplasm becomes stiffer when CRMP2 is downregulated or PTP4A3 is expressed. Our results suggest that PTP4A3 acts upstream of CRMP2 in UM cells to enhance their migration and invasiveness and that a low level of CRMP2 in tumors is predictive of poor patient survival.
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http://dx.doi.org/10.1038/s41598-019-39643-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395723PMC
February 2019

Author Correction: New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels.

Sci Rep 2018 Dec 13;8(1):17945. Epub 2018 Dec 13.

Residual Tumor & Response to Treatment Laboratory (RT2Lab), PSL Research University, Translational Research Department, F-75248, Paris, France.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-36812-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292849PMC
December 2018

Medullary Breast Carcinoma, a Triple-Negative Breast Cancer Associated with BCLG Overexpression.

Am J Pathol 2018 10 1;188(10):2378-2391. Epub 2018 Aug 1.

Department of Pathology, Institut Curie, PSL Research University, Paris, France; INSERM U934, Institut Curie, PSL Research University, Paris, France.

Medullary breast carcinoma (MBC) is a rare subtype of triple-negative breast cancer with specific genomic features within the spectrum of basal-like carcinoma (BLC). In this study of 19 MBCs and 36 non-MBC BLCs, we refined the transcriptomic and genomic knowledge about this entity. Unsupervised and supervised analysis of transcriptomic profiles confirmed that MBC clearly differs from non-MBC BLC, with 92 genes overexpressed and 154 genes underexpressed in MBC compared with non-MBC BLC. Immunity-related pathways are the most differentially represented pathways in MBC compared with non-MBC BLC. The proapoptotic gene BCLG (official name BCL2L14) is by far the most intensely overexpressed gene in MBC. A quantitative RT-PCR validation study conducted in 526 breast tumors corresponding to all molecular subtypes documented the specificity of BCLG overexpression in MBC, which was confirmed at the protein level by immunohistochemistry. We also found that most MBCs belong to the immunomodulatory triple-negative breast cancer subtype. Using pan-genomic analysis, it was found that MBC harbors more losses of heterozygosity than non-MBC BLC. These observations corroborate the notion that MBC remains a distinct entity that could benefit from specific treatment strategies (such as deescalation or targeted therapy) adapted to this rare tumor type.
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http://dx.doi.org/10.1016/j.ajpath.2018.06.021DOI Listing
October 2018

Urinary biomarkers of polycyclic aromatic hydrocarbons in pre- and peri-pubertal girls in Northern California: Predictors of exposure and temporal variability.

Environ Res 2018 08 14;165:46-54. Epub 2018 Apr 14.

Environmental Health Investigations Branch, California Department of Public Health, Richmond, CA, USA.

Background: Polycyclic aromatic hydrocarbons (PAHs), a class of chemicals produced as combustion by-products, have been associated with endocrine disruption. To understand exposure in children, who have been less studied than adults, we examined PAH metabolite concentrations by demographic characteristics, potential sources of exposure, and variability over time, in a cohort study of pre- and peri-pubertal girls in Northern California.

Methods: Urinary concentrations of ten PAH metabolites and cotinine were quantified in 431 girls age 6-8 years at baseline. Characteristics obtained from parental interview, physical exam, and linked traffic data were examined as predictors of PAH metabolite concentrations using multivariable linear regression. A subset of girls (n = 100) had repeat measures of PAH metabolites in the second and fourth years of the study. We calculated the intraclass correlation coefficient (ICC), Spearman correlation coefficients, and how well the quartile ranking by a single measurement represented the four-year average PAH biomarker concentration.

Results: Eight PAH metabolites were detected in ≥ 95% of the girls. The most consistent predictors of PAH biomarker concentrations were cotinine concentration, grilled food consumption, and region of residence, with some variation by demographics and season. After adjustment, select PAH metabolite concentrations were higher for Hispanic and Asian girls, and lower among black girls; 2-naphthol concentrations were higher in girls from lower income households. Other than 1-naphthol, there was modest reproducibility over time (ICCs between 0.18 and 0.49) and the concentration from a single spot sample was able to reliably rank exposure into quartiles consistent with the multi-year average.

Conclusions: These results confirm diet and environmental tobacco smoke exposure as the main sources of PAHs. Controlling for these sources, differences in concentrations still existed by race for specific PAH metabolites and by income for 2-naphthol. The modest temporal variability implies adequate exposure assignment using concentrations from a single sample to define a multi-year exposure timeframe for epidemiologic exposure-response studies.
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http://dx.doi.org/10.1016/j.envres.2017.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999561PMC
August 2018

Associations Between Maternal Obesity and Pregnancy Hyperglycemia and Timing of Puberty Onset in Adolescent Girls: A Population-Based Study.

Am J Epidemiol 2018 07;187(7):1362-1369

Kaiser Permanente Division of Research, Oakland, California.

Early puberty is associated with adverse health outcomes. We investigated whether in utero exposure to maternal obesity is associated with daughters' pubertal timing using 15,267 racially/ethnically diverse Kaiser Permanente Northern California members aged 6-11 years with pediatrician-assessed Tanner staging (2003-2017). We calculated maternal body mass index (BMI; weight (kg)/height (m)2) during pregnancy from the electronic health record data. Using a proportional hazards model with interval censoring, we examined the associations between maternal obesity and girls' pubertal timing, as well as effect modification by race/ethnicity and mediation by prepubertal BMI. Maternal obesity (BMI ≥30) and overweight (BMI 25-29.9) were associated with earlier onset of breast development in girls (hazard ratio (HR) = 1.39 (95% confidence interval (CI): 1.30, 1.49) and HR = 1.21 (95% CI: 1.13, 1.29), respectively), after adjustment for girl's race/ethnicity, maternal age, education, parity, and smoking during pregnancy. There was interaction by race/ethnicity for associations between maternal obesity and girls' pubic hair onset: Associations were strongest among Asian and non-Hispanic white girls (HR = 1.53 (95% CI: 1.24, 1.90) and HR = 1.34 (95% CI: 1.18, 1.52), respectively) and absent for African-American girls. Adjustment for girl's prepubertal BMI only slightly attenuated associations. Our results suggest the importance of maternal metabolic factors during pregnancy in the timing of girls' puberty and potential differences in the associations by race/ethnicity.
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http://dx.doi.org/10.1093/aje/kwy040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030998PMC
July 2018

Capecitabine Efficacy Is Correlated with TYMP and RB1 Expression in PDX Established from Triple-Negative Breast Cancers.

Clin Cancer Res 2018 06 20;24(11):2605-2615. Epub 2018 Feb 20.

Translational Research Department, Institut Curie, PSL Research University, Paris, France.

Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of was performed by siRNA in a cell line established from a PDX. Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3490DOI Listing
June 2018

Girls' Sleep Trajectories Across the Pubertal Transition: Emerging Racial/Ethnic Differences.

J Adolesc Health 2018 04;62(4):496-503

Department of Epidemiology and Biostatistics, University of California, San Francisco, California.

Purpose: This study aims to examine the longitudinal association between puberty and sleep in a diverse sample of girls and explore racial/ethnic differences in this association.

Methods: Using latent growth curve modeling, the present study measured pubertal development (timing and rate) and sleep (wake time and bedtime) in 1,239 socioeconomically and ethnically diverse girls starting when they were 6-8 years old and followed longitudinally for up to 8 years. Pubertal assessment was conducted annually in clinic by physical examination, classified by sexual maturation stage for breast and pubic hair development by trained raters.

Results: In line with previous research, black girls had the earliest pubertal development, followed by Hispanic, white, and Asian girls. Black girls, on average, reported significantly shorter sleep duration than Hispanic (β = -.20, p < .001), Asian (β = -.29, p = .002), and white (β = -.35, p < .001) girls. In a series of dual-process models, we found that early pubertal timing predicted shorter sleep duration for early-maturing black girls (breast development: β = .13, p = .005; pubic hair development: β = .14, p = .012). There was no evidence of any association between pubertal rate and sleep. All models controlled for family socioeconomic status and body mass index.

Conclusion: Sleep is essential for many aspects of youth development, including emotional, cognitive, and physical functioning. Developmental changes associated with puberty may put some early maturing girls at risk of shorter sleep duration in adolescence and exacerbate racial/ethnic disparities in health and well-being.
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http://dx.doi.org/10.1016/j.jadohealth.2017.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866777PMC
April 2018

Changes in bone mineral density in women with breast cancer receiving aromatase inhibitor therapy.

Breast Cancer Res Treat 2018 Apr 16;168(2):523-530. Epub 2017 Dec 16.

Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA.

Purpose: We assessed bone mineral density (BMD) change with aromatase inhibitor (AI) treatment in a contemporary cohort of women with breast cancer treated in Kaiser Permanente Northern California.

Methods: Percent and estimated annual percent changes in BMD at the total hip and lumbar spine were examined in 676 women receiving AI therapy who had two serial BMD reports available (at least 1 year apart) before and after AI initiation (N = 317) or during continued AI therapy (N = 359). BMD changes were examined at the total hip and lumbar spine and compared by age and clinical subgroups.

Results: Women experienced BMD declines after AI initiation or continued therapy, with median annual percent change - 1.2% (interquartile range, IQR - 2.4 to - 0.1%) at the hip and - 1.0% (IQR - 2.3 to 0.1%) at the spine after AI initiation, and - 1.1% (IQR - 2.4 to 0.1%) at the hip and - 0.9% (IQR - 2.4 to 0.5%) at the spine during continued therapy. Higher levels of bone loss were observed among younger (< 55 years) compared with older (≥ 75 years) women at the hip (- 1.6% vs. - 0.8%) and at the spine (- 1.5% vs. - 0.5%) after AI initiation, and at the hip (- 1.4% vs. - 1.2%) and at the spine (- 2.4% vs. - 0.001%) during continued therapy.

Conclusions: Small but consistent declines in total hip and lumbar spine BMD were present in breast cancer patients following AI therapy initiation or continued AI therapy. Although the overall rates of osteoporosis were low, greater estimated levels of annual bone loss were evident among women < 55 years.
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http://dx.doi.org/10.1007/s10549-017-4626-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534130PMC
April 2018

New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels.

Sci Rep 2017 11 9;7(1):15126. Epub 2017 Nov 9.

Residual Tumor & Response to Treatment Laboratory (RT2Lab), PSL Research University, Translational Research Department, F-75248, Paris, France.

One of the most challenging problems in the development of new anticancer drugs is the very high attrition rate. The so-called "drug repositioning process" propose to find new therapeutic indications to already approved drugs. For this, new analytic methods are required to optimize the information present in large-scale pharmacogenomics datasets. We analyzed data from the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia studies. We focused on common cell lines (n = 471), considering the molecular information, and the drug sensitivity for common drugs screened (n = 15). We propose a novel classification based on transcriptomic profiles of cell lines, according to a biological network-driven gene selection process. Our robust molecular classification displays greater homogeneity of drug sensitivity than cancer cell line grouped based on tissue of origin. We then identified significant associations between cell line cluster and drug response robustly found between both datasets. We further demonstrate the relevance of our method using two additional external datasets and distinct sensitivity metrics. Some associations were still found robust, despite cell lines and drug responses' variations. This study defines a robust molecular classification of cancer cell lines that could be used to find new therapeutic indications to known compounds.
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http://dx.doi.org/10.1038/s41598-017-14770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680301PMC
November 2017

Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer.

Cancer Causes Control 2017 Jun 27;28(6):557-562. Epub 2017 Mar 27.

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Purpose: Breast cancer patients can switch hormonal therapy (HT) regimens due to treatment side effects or menopausal status change. We describe HT class switching from aromatase inhibitor (AI) to tamoxifen (TAM), and vice versa.

Methods: In a cohort of 3,265 women diagnosed with hormone-receptor-positive breast cancer at Kaiser Permanente Northern California from 2005 to 2013, we analyzed prescription records, switching reasons, and treatment adherence post-switch by chart review, through 31 December 2014.

Results: There were 290 women who switched from AI to TAM (AI switchers), including 130 (45%) switchers during the first year of treatment; and 446 women who switched from TAM to AI (TAM switchers), including 120 (27%) switchers within the first year. After the switch, 136 (47%) AI switchers and 260 (58%) TAM switchers finished or remained on the planned therapy; 69 (24%) AI switchers and 99 (22%) TAM switchers discontinued therapy. AI side effects (73%), specifically joint pain/arthralgia and bone health issues, were the most common reasons for switching from AI to TAM, whereas from TAM to AI, it was menopausal status change (42%).

Conclusions: Study findings highlight the need for better ways to control patient symptoms from HT to prevent discontinuation, and thus ensure best prognosis.
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http://dx.doi.org/10.1007/s10552-017-0888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439523PMC
June 2017

A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in HER2-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways.

PLoS One 2016 22;11(12):e0167397. Epub 2016 Dec 22.

Institut Curie, PSL Research University, Translational Research Department, INSERM, U932 Immunity and Cancer, Residual Tumor & Response to Treatment Laboratory (RT2Lab), Paris, France.

Introduction: HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions.

Methods: We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset).

Results: We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the "Immunity" metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28-11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36-0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs).

Conclusion: The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167397PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5178998PMC
July 2017

Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis.

Breast Cancer Res Treat 2017 02 3;161(3):501-513. Epub 2016 Dec 3.

Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.

Purpose: The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy.

Methods: In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients' demographic, lifestyle, clinical tumor characteristics, as well as bone health history.

Results: The presence of bone metastases, prior bisphosphonate (BP) treatment, and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, several factors, including age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy, were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics were not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated.

Conclusions: Our findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer.
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http://dx.doi.org/10.1007/s10549-016-4068-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5243170PMC
February 2017

Upregulation of HLA Expression in Primary Uveal Melanoma by Infiltrating Leukocytes.

PLoS One 2016 20;11(10):e0164292. Epub 2016 Oct 20.

Department of Ophthalmology, LUMC, Leiden, the Netherlands.

Introduction: Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors should be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors.

Methods: 28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array.

Results: Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes, and their regulators.

Conclusion: Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164292PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072555PMC
June 2017

Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma.

Oncotarget 2016 Jun;7(23):33542-56

Laboratory of Preclinical Investigation, Department of Translational Research, PSL University, Institut Curie, Paris, France.

Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients.
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http://dx.doi.org/10.18632/oncotarget.9552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085101PMC
June 2016