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1.  Lymph Node Staging in Invasive Breast Cancer 
Breast Care  2014;9(3):211-214.
doi:10.1159/000365315
PMCID: PMC4132218  PMID: 25177263
2.  Subsequent risk of ipsilateral and contralateral invasive breast cancer after treatment for ductal carcinoma in situ: incidence and the effect of radiotherapy in a population-based cohort of 10,090 women 
Purpose
To assess the effect of different treatment strategies on the risk of subsequent invasive breast cancer (IBC) in women diagnosed with ductal carcinoma in situ (DCIS).
Methods
Up to 15-year cumulative incidences of ipsilateral IBC (iIBC) and contralateral IBC (cIBC) were assessed among a population-based cohort of 10,090 women treated for DCIS in the Netherlands between 1989 and 2004. Multivariable Cox regression analyses were used to evaluate associations of treatment with iIBC risk.
Results
Fifteen years after DCIS diagnosis, cumulative incidence of iIBC was 1.9 % after mastectomy, 8.8 % after BCS+RT, and 15.4 % after BCS alone. Patients treated with BCS alone had a higher iIBC risk than those treated with BCS+RT during the first 5 years after treatment. This difference was less pronounced for patients <50 years [hazard ratio (HR) 2.11, 95 % confidence interval (CI) 1.35–3.29 for women <50, and HR 4.44, 95 % CI 3.11–6.36 for women ≥50, P interaction < 0.0001]. Beyond 5 years of follow-up, iIBC risk did not differ between patients treated with BCS+RT or BCS alone for women <50. Cumulative incidence of cIBC at 15 years was 6.4 %, compared to 3.4 % in the general population.
Conclusions
We report an interaction of treatment with age and follow-up period on iIBC risk, indicating that the benefit of RT seems to be smaller among younger women, and stressing the importance of clinical studies with long follow-up. Finally, the low cIBC risk does not justify contralateral prophylactic mastectomies for many women with unilateral DCIS.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-016-3973-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-016-3973-y
PMCID: PMC5021731  PMID: 27624164
Ductal carcinoma in situ; Invasive breast cancer; Surgery; Radiotherapy; Population-based cohort study
3.  Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer 
Couch, Fergus J. | Kuchenbaecker, Karoline B. | Michailidou, Kyriaki | Mendoza-Fandino, Gustavo A. | Nord, Silje | Lilyquist, Janna | Olswold, Curtis | Hallberg, Emily | Agata, Simona | Ahsan, Habibul | Aittomäki, Kristiina | Ambrosone, Christine | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Lars | Beckmann, Matthias W. | Benitez, Javier | Blank, Stephanie V. | Blomqvist, Carl | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Burwinkel, Barbara | Buys, Saundra S. | Caldes, Trinidad | Caligo, Maria A. | Canzian, Federico | Carpenter, Jane | Chang-Claude, Jenny | Chanock, Stephen J. | Chung, Wendy K. | Claes, Kathleen B. M. | Cox, Angela | Cross, Simon S. | Cunningham, Julie M. | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Darabi, Hatef | de la Hoya, Miguel | Devilee, Peter | Diez, Orland | Ding, Yuan C. | Dolcetti, Riccardo | Domchek, Susan M. | Dorfling, Cecilia M. | dos-Santos-Silva, Isabel | Dumont, Martine | Dunning, Alison M. | Eccles, Diana M. | Ehrencrona, Hans | Ekici, Arif B. | Eliassen, Heather | Ellis, Steve | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Försti, Asta | Fostira, Florentia | Foulkes, William D. | Friebel, Tara | Friedman, Eitan | Frost, Debra | Gabrielson, Marike | Gammon, Marilie D. | Ganz, Patricia A. | Gapstur, Susan M. | Garber, Judy | Gaudet, Mia M. | Gayther, Simon A. | Gerdes, Anne-Marie | Ghoussaini, Maya | Giles, Graham G. | Glendon, Gord | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Gunter, Marc | Haeberle, Lothar | Haiman, Christopher A. | Hamann, Ute | Hansen, Thomas V. O. | Hart, Steven | Healey, Sue | Heikkinen, Tuomas | Henderson, Brian E. | Herzog, Josef | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hooning, Maartje J. | Hoover, Robert N. | Hopper, John L. | Humphreys, Keith | Hunter, David J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Jakubowska, Anna | James, Paul | Janavicius, Ramunas | Jensen, Uffe Birk | John, Esther M. | Jones, Michael | Kabisch, Maria | Kar, Siddhartha | Karlan, Beth Y. | Khan, Sofia | Khaw, Kay-Tee | Kibriya, Muhammad G. | Knight, Julia A. | Ko, Yon-Dschun | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kwong, Ava | Laitman, Yael | Lambrechts, Diether | Lazaro, Conxi | Lee, Eunjung | Le Marchand, Loic | Lester, Jenny | Lindblom, Annika | Lindor, Noralane | Lindstrom, Sara | Liu, Jianjun | Long, Jirong | Lubinski, Jan | Mai, Phuong L. | Makalic, Enes | Malone, Kathleen E. | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Martens, John W. M. | McGuffog, Lesley | Meindl, Alfons | Miller, Austin | Milne, Roger L. | Miron, Penelope | Montagna, Marco | Mazoyer, Sylvie | Mulligan, Anna M. | Muranen, Taru A. | Nathanson, Katherine L. | Neuhausen, Susan L. | Nevanlinna, Heli | Nordestgaard, Børge G. | Nussbaum, Robert L. | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Osorio, Ana | Park, Sue K. | Peeters, Petra H. | Peissel, Bernard | Peterlongo, Paolo | Peto, Julian | Phelan, Catherine M. | Pilarski, Robert | Poppe, Bruce | Pylkäs, Katri | Radice, Paolo | Rahman, Nazneen | Rantala, Johanna | Rappaport, Christine | Rennert, Gad | Richardson, Andrea | Robson, Mark | Romieu, Isabelle | Rudolph, Anja | Rutgers, Emiel J. | Sanchez, Maria-Jose | Santella, Regina M. | Sawyer, Elinor J. | Schmidt, Daniel F. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Schumacher, Fredrick | Scott, Rodney | Senter, Leigha | Sharma, Priyanka | Simard, Jacques | Singer, Christian F. | Sinilnikova, Olga M. | Soucy, Penny | Southey, Melissa | Steinemann, Doris | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Swerdlow, Anthony | Szabo, Csilla I. | Tamimi, Rulla | Tapper, William | Teixeira, Manuel R. | Teo, Soo-Hwang | Terry, Mary B. | Thomassen, Mads | Thompson, Deborah | Tihomirova, Laima | Toland, Amanda E. | Tollenaar, Robert A. E. M. | Tomlinson, Ian | Truong, Thérèse | Tsimiklis, Helen | Teulé, Alex | Tumino, Rosario | Tung, Nadine | Turnbull, Clare | Ursin, Giski | van Deurzen, Carolien H. M. | van Rensburg, Elizabeth J. | Varon-Mateeva, Raymonda | Wang, Zhaoming | Wang-Gohrke, Shan | Weiderpass, Elisabete | Weitzel, Jeffrey N. | Whittemore, Alice | Wildiers, Hans | Winqvist, Robert | Yang, Xiaohong R. | Yannoukakos, Drakoulis | Yao, Song | Zamora, M Pilar | Zheng, Wei | Hall, Per | Kraft, Peter | Vachon, Celine | Slager, Susan | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Monteiro, Alvaro A. N. | García-Closas, Montserrat | Easton, Douglas F. | Antoniou, Antonis C.
Nature Communications  2016;7:11375.
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
doi:10.1038/ncomms11375
PMCID: PMC4853421  PMID: 27117709
4.  An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors 
Rudolph, Anja | Milne, Roger L. | Truong, Thérèse | Knight, Julia A. | Seibold, Petra | Flesch-Janys, Dieter | Behrens, Sabine | Eilber, Ursula | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Munday, Hannah R. | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Olson, Janet | Vachon, Celine M. | Hallberg, Emily | Castelao, J. Esteban | Carracedo, Angel | Torres, Maria | Li, Jingmei | Humphreys, Keith | Cordina-Duverger, Emilie | Menegaux, Florence | Flyger, Henrik | Nordestgaard, Børge G. | Nielsen, Sune F. | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Engelhardt, Ellen G. | Broeks, Annegien | Rutgers, Emiel J. | Glendon, Gord | Mulligan, Anna Marie | Cross, Simon | Reed, Malcolm | Gonzalez-Neira, Anna | Perez, José Ignacio Arias | Provenzano, Elena | Apicella, Carmel | Southey, Melissa C. | Spurdle, Amanda | Investigators, kConFab | Group, AOCS | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | McLean, Catriona | Baglietto, Laura | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Brüning, Thomas | Hamann, Ute | Ko, Yon-Dschun | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Mannermaa, Arto | Swerdlow, Anthony | Giles, Graham G. | Brenner, Hermann | Fasching, Peter A. | Chenevix-Trench, Georgia | Hopper, John | Benítez, Javier | Cox, Angela | Andrulis, Irene L. | Lambrechts, Diether | Gago-Dominguez, Manuela | Couch, Fergus | Czene, Kamila | Bojesen, Stig E. | Easton, Doug F. | Schmidt, Marjanka K. | Guénel, Pascal | Hall, Per | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Chang-Claude, Jenny
A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC.
Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator.
Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4).
In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
doi:10.1002/ijc.29188
PMCID: PMC4289418  PMID: 25227710
gene-environment interaction; breast cancer; risk factor; genetic susceptibility
5.  Discordant assessment of tumor biomarkers by histopathological and molecular assays in the EORTC randomized controlled 10041/BIG 03-04 MINDACT trial breast cancer 
Accurate identification of breast cancer patients most likely to benefit from adjuvant systemic therapies is crucial. Better understanding of differences between methods can lead to an improved ER, PgR, and HER-2 assessment. The purpose of this preplanned translational research is to investigate the correlation of central IHC/FISH assessments with microarray mRNA readouts of ER, PgR, and HER-2 status in the MINDACT trial and to determine if any discordance could be attributed to intratumoral heterogeneity or the DCIS and normal tissue components in the specimens. MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early breast cancer for adjuvant chemotherapy (n = 6694 patients). Gene-expression data were obtained by TargetPrint; IHC and/or FISH were assessed centrally (n = 5788; 86 %). Macroscopic and microscopic evaluation of centrally submitted FFPE blocks identified 1427 cases for which the very same sample was submitted for gene-expression analysis. TargetPrint ER had a positive agreement of 98 %, and a negative agreement of 95 % with central pathology. Corresponding figures for PgR were 85 and 94 % and for HER-2 72 and 99 %. Agreement of mRNA versus central protein was not different when the same or a different portion of the tumor tissue was analyzed or when DCIS and/or normal tissue was included in the sample subjected to mRNA assays. This is the first large analysis to assess the discordance rate between protein and mRNA analysis of breast cancer markers, and to look into intratumoral heterogeneity, DCIS, or normal tissue components as a potential cause of discordance. The observed difference between mRNA and protein assessment for PgR and HER-2 needs further research; the present analysis does not support intratumoral heterogeneity or the DCIS and normal tissue components being likely causes of the discordance.
doi:10.1007/s10549-016-3690-6
PMCID: PMC4764628  PMID: 26820652
Breast cancer; ER; PgR; HER2; Concordance; Tumor heterogeneity; Hormone receptor; IHC/FISH; Gene expression; TargetPrint
6.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
7.  Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants 
Mavaddat, Nasim | Pharoah, Paul D. P. | Michailidou, Kyriaki | Tyrer, Jonathan | Brook, Mark N. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Peto, Julian | dos-Santos-Silva, Isabel | Dudbridge, Frank | Johnson, Nichola | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J. | Figueroa, Jonine | Chanock, Stephen J. | Brinton, Louise | Lissowska, Jolanta | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine | Pankratz, Vernon S. | Lambrechts, Diether | Wildiers, Hans | Van Ongeval, Chantal | van Limbergen, Erik | Kristensen, Vessela | Grenaker Alnæs, Grethe | Nord, Silje | Borresen-Dale, Anne-Lise | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen M. | Hunter, David J. | Lindstrom, Sara | Tamimi, Rulla M. | Kraft, Peter | Rahman, Nazneen | Turnbull, Clare | Renwick, Anthony | Seal, Sheila | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Bernstein, Leslie | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofyeva, Darya | Takhirova, Zalina | Meindl, Alfons | Schmutzler, Rita K. | Sutter, Christian | Yang, Rongxi | Schürmann, Peter | Bremer, Michael | Christiansen, Hans | Park-Simon, Tjoung-Won | Hillemanns, Peter | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Pensotti, Valeria | Hopper, John L. | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Sigurdson, Alice J. | Doody, Michele M. | Hamann, Ute | Torres, Diana | Ulmer, Hans-Ulrich | Försti, Asta | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Marie Mulligan, Anna | Chenevix-Trench, Georgia | Balleine, Rosemary | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Lindblom, Annika | Margolin, Sara | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Eilber, Ursula | Wang-Gohrke, Shan | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Koppert, Linetta B. | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Karina Dieffenbach, Aida | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Offit, Kenneth | Vijai, Joseph | Robson, Mark | Rau-Murthy, Rohini | Dwek, Miriam | Swann, Ruth | Annie Perkins, Katherine | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Eccles, Diana M. | Tapper, William J. | Rafiq, Sajjad | John, Esther M. | Whittemore, Alice S. | Slager, Susan | Yannoukakos, Drakoulis | Toland, Amanda E. | Yao, Song | Zheng, Wei | Halverson, Sandra L. | González-Neira, Anna | Pita, Guillermo | Rosario Alonso, M. | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Simard, Jacques | Hall, Per | Easton, Douglas F. | Garcia-Closas, Montserrat
Background:
Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
Methods:
We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
Results:
There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
Conclusions:
The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
doi:10.1093/jnci/djv036
PMCID: PMC4754625  PMID: 25855707
8.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
9.  Cardiovascular Morbidity and Mortality After Treatment for Ductal Carcinoma In Situ of the Breast 
Background
Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients.
Methods
Data on all incident DCIS case patients in the Netherlands between 1989 and 2004 who were diagnosed before the age of 75 years were obtained (n = 10468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within-cohort comparisons were based on multivariable competing-risk regression.
Results
Compared with the general population, 5-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] = 0.97 to 1.11) but a lower risk of dying of CVD (SMR = 0.77; 95% CI = 0.67 to 0.89). No difference in CVD risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs right-sided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32). In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005, we were able to account for history of CVD and did not observe a risk difference between treatment groups (left-sided vs right-sided radiotherapy: HR = 0.94; 95% CI = 0.68 to 1.29).
Conclusions
After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS. Compared with the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment.
doi:10.1093/jnci/dju156
PMCID: PMC4151854  PMID: 25128694
10.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
11.  Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 
Annals of Oncology  2013;24(9):2206-2223.
The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and ‘triple-negative’ disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints.
doi:10.1093/annonc/mdt303
PMCID: PMC3755334  PMID: 23917950
surgery; radiation therapy; systemic adjuvant therapies; early breast cancer; St Gallen Consensus; subtypes
12.  Breast density as indicator for the use of mammography or MRI to screen women with familial risk for breast cancer (FaMRIsc): a multicentre randomized controlled trial 
BMC Cancer  2012;12:440.
Background
To reduce mortality, women with a family history of breast cancer often start mammography screening at a younger age than the general population. Breast density is high in over 50% of women younger than 50 years. With high breast density, breast cancer incidence increases, but sensitivity of mammography decreases. Therefore, mammography might not be the optimal method for breast cancer screening in young women. Adding MRI increases sensitivity, but also the risk of false-positive results. The limitation of all previous MRI screening studies is that they do not contain a comparison group; all participants received both MRI and mammography. Therefore, we cannot empirically assess in which stage tumours would have been detected by either test.
The aim of the Familial MRI Screening Study (FaMRIsc) is to compare the efficacy of MRI screening to mammography for women with a familial risk. Furthermore, we will assess the influence of breast density.
Methods/Design
This Dutch multicentre, randomized controlled trial, with balanced randomisation (1:1) has a parallel grouped design. Women with a cumulative lifetime risk for breast cancer due to their family history of ≥20%, aged 30–55 years are eligible. Identified BRCA1/2 mutation carriers or women with 50% risk of carrying a mutation are excluded. Group 1 receives yearly mammography and clinical breast examination (n = 1000), and group 2 yearly MRI and clinical breast examination, and mammography biennially (n = 1000).
Primary endpoints are the number and stage of the detected breast cancers in each arm. Secondary endpoints are the number of false-positive results in both screening arms. Furthermore, sensitivity and positive predictive value of both screening strategies will be assessed. Cost-effectiveness of both strategies will be assessed. Analyses will also be performed with mammographic density as stratification factor.
Discussion
Personalized breast cancer screening might optimize mortality reduction with less over diagnosis. Breast density may be a key discriminator for selecting the optimal screening strategy for women < 55 years with familial breast cancer risk; mammography or MRI. These issues are addressed in the FaMRIsc study including high risk women due to a familial predisposition.
Trial registration
Netherland Trial Register NTR2789
doi:10.1186/1471-2407-12-440
PMCID: PMC3488502  PMID: 23031619
Breast cancer; Familial risk; Screening; MRI; Breast density; Cost-effectiveness
13.  Role of Axillary Clearance After a Tumor-Positive Sentinel Node in the Administration of Adjuvant Therapy in Early Breast Cancer 
Journal of Clinical Oncology  2009;28(5):731-737.
Purpose
The After Mapping of the Axilla: Radiotherapy or Surgery? (AMAROS) phase III study compares axillary lymph node dissection (ALND) and axillary radiation therapy (ART) in early breast cancer patients with tumor-positive sentinel nodes. In the ART arm, the extent of nodal involvement remains unknown, which could have implications on the administration of adjuvant therapy. In this preliminary analysis, we studied the influence of random assignment to ALND or ART on the choice for adjuvant treatment.
Patients and Methods
In the first 2,000 patients enrolled in the AMAROS trial, we analyzed the administration of adjuvant systemic therapy. Multivariate analysis was used to assess variables affecting the administration of adjuvant chemotherapy. Adjuvant therapy was applied according to institutional guidelines.
Results
Of 2,000 patients, 566 patients had a positive sentinel node and were treated per random assignment. There was no significant difference in the administration of adjuvant systemic therapy. In the ALND and ART arms, 58% (175 of 300) and 61% (162 of 266) of the patients, respectively, received chemotherapy. Endocrine therapy was administered in 78% (235 of 300) of the patients in the ALND arm and in 76% (203 of 266) of the patients in the ART arm. Treatment arm was not a significant factor in the decision, and no interactions between treatment arm and other factors were observed. Multivariate analysis showed that age, tumor grade, multifocality, and size of the sentinel node metastasis significantly affected the administration of chemotherapy. Within the ALND arm, the extent of nodal involvement remained not significant in a sensitivity multivariate analysis.
Conclusion
Absence of knowledge regarding the extent of nodal involvement in the ART arm appears to have no major impact on the administration of adjuvant therapy.
doi:10.1200/JCO.2008.21.7554
PMCID: PMC2834391  PMID: 20038733
14.  Gene Expression Profiles from Formalin Fixed Paraffin Embedded Breast Cancer Tissue Are Largely Comparable to Fresh Frozen Matched Tissue 
PLoS ONE  2011;6(2):e17163.
Background and Methods
Formalin Fixed Paraffin Embedded (FFPE) samples represent a valuable resource for cancer research. However, the discovery and development of new cancer biomarkers often requires fresh frozen (FF) samples. Recently, the Whole Genome (WG) DASL (cDNA-mediated Annealing, Selection, extension and Ligation) assay was specifically developed to profile FFPE tissue. However, a thorough comparison of data generated from FFPE RNA and Fresh Frozen (FF) RNA using this platform is lacking. To this end we profiled, in duplicate, 20 FFPE tissues and 20 matched FF tissues and evaluated the concordance of the DASL results from FFPE and matched FF material.
Methodology and Principal Findings
We show that after proper normalization, all FFPE and FF pairs exhibit a high level of similarity (Pearson correlation >0.7), significantly larger than the similarity between non-paired samples. Interestingly, the probes showing the highest correlation had a higher percentage G/C content and were enriched for cell cycle genes. Predictions of gene expression signatures developed on frozen material (Intrinsic subtype, Genomic Grade Index, 70 gene signature) showed a high level of concordance between FFPE and FF matched pairs. Interestingly, predictions based on a 60 gene DASL list (best match with the 70 gene signature) showed very high concordance with the MammaPrint® results.
Conclusions and Significance
We demonstrate that data generated from FFPE material with the DASL assay, if properly processed, are comparable to data extracted from the FF counterpart. Specifically, gene expression profiles for a known set of prognostic genes for a specific disease are highly comparable between two conditions. This opens up the possibility of using both FFPE and FF material in gene expressions analyses, leading to a vast increase in the potential resources available for cancer research.
doi:10.1371/journal.pone.0017163
PMCID: PMC3037966  PMID: 21347257
15.  Sentinel Node Identification Rate and Nodal Involvement in the EORTC 10981-22023 AMAROS Trial 
Annals of Surgical Oncology  2010;17(7):1854-1861.
Background
The randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement.
Methods
The first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed.
Results
In 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively.
Conclusions
With a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar—both were 18%.
doi:10.1245/s10434-010-0945-z
PMCID: PMC2889289  PMID: 20300966
16.  Feasibility of FDG PET/CT to monitor the response of axillary lymph node metastases to neoadjuvant chemotherapy in breast cancer patients 
Purpose
The aim of this study was to assess the accuracy of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to visualize lymph node metastases before the start of neoadjuvant chemotherapy and to determine how often the visualization is sufficiently prominent to allow monitoring of the axillary response.
Methods
Thirty-eight patients with invasive breast cancer of >3 cm and/or lymph node metastasis underwent FDG PET/CT before neoadjuvant chemotherapy. The results of the FDG PET/CT were compared with those from ultrasonography with fine-needle aspiration (FNA) cytology or sentinel node biopsy. Patients suitable for response monitoring of the axilla were defined as having either a maximum standardized uptake value (SUVmax) ≥ 2.5 or a tumour to background ratio ≥5 in the most intense lymph node.
Results
The sensitivity and specificity of FDG PET/CT in detecting axillary involvement were 97 and 100%, respectively. No difference existed between the SUVmax of the primary tumour and that from the related most intense lymph node metastasis. Moreover, the mean tumour to background ratio was 90% higher in the lymph nodes compared to the primary tumour (p = 0.006). Ninety-three per cent of the patients had sufficient uptake in the lymph nodes to qualify for subsequent response monitoring of the axilla. A considerable distinction in metabolic activity was observed between the different subtypes of breast cancer. The mean SUVmax in lymph node metastases of oestrogen receptor (ER)-positive, triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumours was 6.6, 11.6 and 6.6, respectively.
Conclusion
The high accuracy in visualizing lymph node metastases and the sufficiently high SUVmax and tumour to background ratio at baseline suggest that it is feasible to monitor the axillary response with FDG PET/CT, especially in triple-negative tumours.
doi:10.1007/s00259-009-1343-2
PMCID: PMC2869017  PMID: 20130860
Breast cancer; Axillary lymph node metastasis; FDG-PET/CT; Neoadjuvant chemotherapy
17.  History of sentinel node and validation of the technique 
Breast Cancer Research  2001;3(2):109-112.
Sentinel node biopsy is a minimally invasive technique to select patients with occult lymph node metastases who may benefit from further regional or systemic therapy. The sentinel node is the first lymph node reached by metastasising cells from a primary tumour. Attempts to remove this node with a procedure based on standard anatomical patterns did not become popular. The development of the dynamic technique of intraoperative lymphatic mapping in the 1990s resulted in general acceptance of the sentinel node concept. This hypothesis of sequential tumour dissemination seems to be valid according to numerous studies of sentinel node biopsy with confirmatory regional lymph node dissection. This report describes the history and the validation of the technique, with particular reference to breast cancer.
doi:10.1186/bcr281
PMCID: PMC139441  PMID: 11250756
history; lymphatic dissemination; review; sentinel node

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