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1.  Cost-Benefit Analysis of Endocrine Therapy in the Adjuvant Setting for Postmenopausal Patients with Hormone Receptor-Positive Breast Cancer, Based on Survival Data and Future Prices for Generic Drugs in the Context of the German Health Care System 
Breast Care  2011;6(5):381-389.
Cost-effectiveness analyses have focused on aromatase inhibitors (AIs), but the results are inconsistent and disease-free survival has often been extrapolated to overall survival. The present study calculates the cost-effectiveness of 5 years of letrozole versus tamoxifen versus anastrozole in the context of the German health care system, using survival data from the Breast International Group (BIG) 1–98 study and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) study and generic prices.
Materials and Methods
A hybrid model was developed that incorporates recurrence rates, overall survival, treatment costs and treatment-associated adverse events and the resulting costs. The basic assumption was that generic anastrozole would lead to a price reduction to 75% of the original price. Further analyses were carried out with 50% and 25% of the original prices for anastrozole and letrozole.
The cost-benefit model showed a gain of 0.3124 or 0.0659 quality-adjusted life years (QALYs) for letrozole or anastrozole. Incremental costs of € 29,375.15/QALY for letrozole (100% of original price) were calculated and € 94,648.03/QALY for anastrozole (75% of original price). Marked increases in cost-effectiveness are observed with further decreases in price (anastrozole: 50% price € 54,715.17/QALY, 25% price € 14,779.57/QALY; letrozole 75% price € 20,988.59/QALY, 50% price € 12,602.03/QALY, 25% price € 4,215.46/QALY).
The present model including the inverse probability of censoring weighted analysis (IPCW) for letrozole and generic prices for both AIs shows that letrozole is cost effective.
PMCID: PMC3357170  PMID: 22619649
Letrozole; Anastrozole; Tamoxifen; Cost-effectiveness; QALY; BIG 1–98; ATAC
2.  Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer 
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
PMCID: PMC3098608  PMID: 20635389
risk of ovarian cancer; polymorphism; association studies
3.  A Genome-Wide Association Study Identifies Susceptibility Loci for Ovarian Cancer at 2q31 and 8q24 
Goode, Ellen L. | Chenevix-Trench, Georgia | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Lawrenson, Kate | Widschwendter, Martin | Vierkant, Robert A. | Larson, Melissa C. | Kjaer, Susanne K. | Birrer, Michael J. | Berchuck, Andrew | Schildkraut, Joellen | Tomlinson, Ian | Kiemeney, Lambertus A. | Cook, Linda S. | Gronwald, Jacek | Garcia-Closas, Montserrat | Gore, Martin E. | Campbell, Ian | Whittemore, Alice S. | Sutphen, Rebecca | Phelan, Catherine | Anton-Culver, Hoda | Pearce, Celeste Leigh | Lambrechts, Diether | Rossing, Mary Anne | Chang-Claude, Jenny | Moysich, Kirsten B. | Goodman, Marc T. | Dörk, Thilo | Nevanlinna, Heli | Ness, Roberta B. | Rafnar, Thorunn | Hogdall, Claus | Hogdall, Estrid | Fridley, Brooke L. | Cunningham, Julie M. | Sieh, Weiva | McGuire, Valerie | Godwin, Andrew K. | Cramer, Daniel W. | Hernandez, Dena | Levine, Douglas | Lu, Karen | Iversen, Edwin S. | Palmieri, Rachel T. | Houlston, Richard | van Altena, Anne M. | Aben, Katja K.H. | Massuger, Leon F.A.G. | Brooks-Wilson, Angela | Kelemen, Linda E. | Le, Nhu D. | Jakubowska, Anna | Lubinski, Jan | Medrek, Krzysztof | Stafford, Anne | Easton, Douglas F. | Tyrer, Jonathan | Bolton, Kelly L. | Harrington, Patricia | Eccles, Diana | Chen, Ann | Molina, Ashley N. | Davila, Barbara N. | Arango, Hector | Tsai, Ya-Yu | Chen, Zhihua | Risch, Harvey A. | McLaughlin, John | Narod, Steven A. | Ziogas, Argyrios | Brewster, Wendy | Gentry-Maharaj, Aleksandra | Menon, Usha | Wu, Anna H. | Stram, Daniel O. | Pike, Malcolm C. | Beesley, Jonathan | Webb, Penelope M. | Chen, Xiaoqing | Ekici, Arif B. | Thiel, Falk C. | Beckmann, Matthias W. | Yang, Hannah | Wentzensen, Nicolas | Lissowska, Jolanta | Fasching, Peter A. | Despierre, Evelyn | Amant, Frederic | Vergote, Ignace | Doherty, Jennifer | Hein, Rebecca | Wang-Gohrke, Shan | Lurie, Galina | Carney, Michael E. | Thompson, Pamela J. | Runnebaum, Ingo | Hillemanns, Peter | Dürst, Matthias | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Butzow, Ralf | Heikkinen, Tuomas | Stefansson, Kari | Sulem, Patrick | Besenbacher, Sören | Sellers, Thomas A. | Gayther, Simon A. | Pharoah, Paul D.P.
Nature genetics  2010;42(10):874-879.
Ovarian cancer (OC) accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance OC susceptibility genes, we conducted a genome-wide association study (GWAS) of 507,094 SNPs in 1,768 cases and 2,354 controls, with follow-up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (BNC2)1. Here, we report on nine additional candidate loci (p≤10-4), identified after stratifying cases by histology, genotyped in an additional 4,353 cases and 6,021 controls. Two novel susceptibility loci with p≤5×10-8 were confirmed (8q24, p=8.0×10-15 and 2q31, p=3.8×10-14); two additional loci were also identified that approached genome-wide significance (3q25, p=7.1×10-8 and 17q21, p=1.4×10-7). The associations with serous OC were generally stronger than other subtypes. Analysis of HOXD1, MYC, TiPARP, and SKAP1 at these loci, and BNC2 at 9p22, supports a functional role for these genes in OC development.
PMCID: PMC3020231  PMID: 20852632
4.  Common variants at 19p13 are associated with susceptibility to ovarian cancer 
Bolton, Kelly L. | Tyrer, Jonathan | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Jones, Chris | Sher, Tanya | Gentry-Maharaj, Aleksandra | Wozniak, Eva | Tsai, Ya-Yu | Weidhaas, Joanne | Paik, Daniel | Van Den Berg, David J. | Stram, Daniel O. | Pearce, Celeste Leigh | Wu, Anna H. | Brewster, Wendy | Anton-Culver, Hoda | Ziogas, Argyrios | Narod, Steven A. | Levine, Douglas A. | Kaye, Stanley B. | Brown, Robert | Paul, Jim | Flanagan, James | Sieh, Weiva | McGuire, Valerie | Whittemore, Alice S. | Campbell, Ian | Gore, Martin E. | Lissowska, Jolanta | Yang, Hannah | Medrek, Krzysztof | Gronwald, Jacek | Lubinski, Jan | Jakubowska, Anna | Le, Nhu D. | Cook, Linda S. | Kelemen, Linda E. | Brook-Wilson, Angela | Massuger, Leon F.A.G. | Kiemeney, Lambertus A. | Aben, Katja K.H. | van Altena, Anne M. | Houlston, Richard | Tomlinson, Ian | Palmieri, Rachel T. | Moorman, Patricia G. | Schildkraut, Joellen | Iversen, Edwin S. | Phelan, Catherine | Vierkant, Robert A. | Cunningham, Julie M. | Goode, Ellen L. | Fridley, Brooke L. | Kruger-Kjaer, Susan | Blaeker, Jan | Hogdall, Estrid | Hogdall, Claus | Gross, Jenny | Karlan, Beth Y. | Ness, Roberta B. | Edwards, Robert P. | Odunsi, Kunle | Moyisch, Kirsten B. | Baker, Julie A. | Modugno, Francesmary | Heikkinenen, Tuomas | Butzow, Ralf | Nevanlinna, Heli | Leminen, Arto | Bogdanova, Natalia | Antonenkova, Natalia | Doerk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Thompson, Pamela J. | Carney, Michael E. | Goodman, Marc T. | Lurie, Galina | Wang-Gohrke, Shan | Hein, Rebecca | Chang-Claude, Jenny | Rossing, Mary Anne | Cushing-Haugen, Kara L. | Doherty, Jennifer | Chen, Chu | Rafnar, Thorunn | Besenbacher, Soren | Sulem, Patrick | Stefansson, Kari | Birrer, Michael J. | Terry, Kathryn L. | Hernandez, Dena | Cramer, Daniel W. | Vergote, Ignace | Amant, Frederic | Lambrechts, Diether | Despierre, Evelyn | Fasching, Peter A. | Beckmann, Matthias W. | Thiel, Falk C. | Ekici, Arif B. | Chen, Xiaoqing | Johnatty, Sharon E. | Webb, Penelope M. | Beesley, Jonathan | Chanock, Stephen | Garcia-Closas, Montserrat | Sellers, Tom | Easton, Douglas F. | Berchuck, Andrew | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A.
Nature genetics  2010;42(10):880-884.
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world accounting for 4 percent of deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 EOC cases with available survival time data, and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P=5×10−4 and 6×10−4), but did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P=3×10−9 and 4×10−11 respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1 interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
PMCID: PMC3125495  PMID: 20852633
5.  A Genome-Wide Association Study Identifies A New Ovarian Cancer Susceptibility Locus On 9p22.2 
Song, Honglin | Ramus, Susan J. | Tyrer, Jonathan | Bolton, Kelly L. | Gentry-Maharaj, Aleksandra | Wozniak, Eva | Anton-Culver, Hoda | Chang-Claude, Jenny | Cramer, Daniel W. | DiCioccio, Richard | Dörk, Thilo | Goode, Ellen L. | Goodman, Marc T | Schildkraut, Joellen M | Sellers, Thomas | Baglietto, Laura | Beckmann, Matthias W. | Beesley, Jonathan | Blaakaer, Jan | Carney, Michael E | Chanock, Stephen | Chen, Zhihua | Cunningham, Julie M. | Dicks, Ed | Doherty, Jennifer A. | Dürst, Matthias | Ekici, Arif B. | Fenstermacher, David | Fridley, Brooke L. | Giles, Graham | Gore, Martin E. | De Vivo, Immaculata | Hillemanns, Peter | Hogdall, Claus | Hogdall, Estrid | Iversen, Edwin S | Jacobs, Ian J | Jakubowska, Anna | Li, Dong | Lissowska, Jolanta | Lubiński, Jan | Lurie, Galina | McGuire, Valerie | McLaughlin, John | Mędrek, Krzysztof | Moorman, Patricia G. | Moysich, Kirsten | Narod, Steven | Phelan, Catherine | Pye, Carole | Risch, Harvey | Runnebaum, Ingo B | Severi, Gianluca | Southey, Melissa | Stram, Daniel O. | Thiel, Falk C. | Terry, Kathryn L. | Tsai, Ya-Yu | Tworoger, Shelley S. | Van Den Berg, David J. | Vierkant, Robert A. | Wang-Gohrke, Shan | Webb, Penelope M. | Wilkens, Lynne R. | Wu, Anna H | Yang, Hannah | Brewster, Wendy | Ziogas, Argyrios | Houlston, Richard | Tomlinson, Ian | Whittemore, Alice S | Rossing, Mary Anne | Ponder, Bruce A.J. | Pearce, Celeste Leigh | Ness, Roberta B. | Menon, Usha | Kjaer, Susanne Krüger | Gronwald, Jacek | Garcia-Closas, Montserrat | Fasching, Peter A. | Easton, Douglas F | Chenevix-Trench, Georgia | Berchuck, Andrew | Pharoah, Paul D.P. | Gayther, Simon A.
Nature genetics  2009;41(9):996-1000.
Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk1. We performed a genome wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and ~2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P<10−8). The most significant SNP (rs3814113; P = 2.5 × 10−17) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls confirming its association (combined data odds ratio = 0.82 95% CI 0.79 – 0.86, P-trend = 5.1 × 10−19). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77 95% CI 0.73 – 0.81, Ptrend = 4.1 × 10−21).
PMCID: PMC2844110  PMID: 19648919

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