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1.  Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: prospectively patient-reported outcome measures in breast cancer patients 
Introduction
This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy.
Method
Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted of (on average) 47 sessions. In total, 80 min of 100 % O2 was administered under increased pressure of 2.4 ATA. Quality of life was assessed before and after treatment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23, and a NRS pain score.
Results
Fifty-seven women were available for evaluation before and after treatment. Before HBOT, patients had severe complaints of pain in the arm/shoulder (46 %), swollen arm/hand (14 %), difficulty to raise arm or move it sideways (45 %), pain in the area of the affected breast (67 %), swollen area of the affected breast (45 %), oversensitivity of the affected breast (54 %), and skin problems on/in the area of the affected breast (32 %); post HBOT, severe complaints were still experienced in 17, 7, 22, 15, 13, 15, and 11 % of the women, respectively. Differences were all significant. The NRS pain score improved at least 1 point (range 0–10) in 81 % of the patients (p < 0.05).
Conclusion
In these breast cancer patients treated with HBOT for LRITT, the patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible.
doi:10.1186/s13014-016-0700-0
PMCID: PMC5041335  PMID: 27682427
Breast cancer; Radiotherapy; Radiation toxicity; Fibrosis; Pain
2.  Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent 
Guo, Yan | Warren Andersen, Shaneda | Shu, Xiao-Ou | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Garcia-Closas, Montserrat | Milne, Roger L. | Schmidt, Marjanka K. | Chang-Claude, Jenny | Dunning, Allison | Bojesen, Stig E. | Ahsan, Habibul | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bogdanova, Natalia V. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brand, Judith | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Casey, Graham | Chenevix-Trench, Georgia | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Devilee, Peter | Dörk, Thilo | Dumont, Martine | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Fostira, Florentia | Gammon, Marilie | Giles, Graham G. | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hooning, Maartje J. | Hopper, John L. | Jakubowska, Anna | Jasmine, Farzana | Jenkins, Mark | John, Esther M. | Johnson, Nichola | Jones, Michael E. | Kabisch, Maria | Kibriya, Muhammad | Knight, Julia A. | Koppert, Linetta B. | Kosma, Veli-Matti | Kristensen, Vessela | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lindblom, Annika | Luben, Robert | Lubinski, Jan | Malone, Kathi E. | Mannermaa, Arto | Margolin, Sara | Marme, Frederik | McLean, Catriona | Meijers-Heijboer, Hanne | Meindl, Alfons | Neuhausen, Susan L. | Nevanlinna, Heli | Neven, Patrick | Olson, Janet E. | Perez, Jose I. A. | Perkins, Barbara | Peterlongo, Paolo | Phillips, Kelly-Anne | Pylkäs, Katri | Rudolph, Anja | Santella, Regina | Sawyer, Elinor J. | Schmutzler, Rita K. | Seynaeve, Caroline | Shah, Mitul | Shrubsole, Martha J. | Southey, Melissa C. | Swerdlow, Anthony J. | Toland, Amanda E. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Ursin, Giske | Van Der Luijt, Rob B. | Verhoef, Senno | Whittemore, Alice S. | Winqvist, Robert | Zhao, Hui | Zhao, Shilin | Hall, Per | Simard, Jacques | Kraft, Peter | Pharoah, Paul | Hunter, David | Easton, Douglas F. | Zheng, Wei
PLoS Medicine  2016;13(8):e1002105.
Background
Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
Methods
We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
Results
In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10−8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
Conclusions
BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Using Mendelian randomization analysis, Wei Zheng and colleagues probe potentially causal associations between BMI and breast cancer risk in both pre- and postmenopausal women.
Author Summary
Why Was This Study Done?
Body mass index (BMI) has been linked to breast cancer risk in conventional population studies.
In these studies, high BMI is associated with reduced risk of breast cancer in premenopausal women but with increased risk in postmenopausal women. These changed risks may be caused by BMI or caused by environmental factors that are associated with BMI.
We sought to use a research tool from the genetics field to understand BMI’s causal role in breast cancer.
What Did the Researchers Do and Find?
We took advantage of previously identified genetic sequence variations that are associated with BMI in European populations and used these variants to predict BMI. These variants are set at birth and are not affected by environmental factors; thus, outcomes associated with high BMI as predicted by genetic variants are more likely to be caused by high BMI itself rather than by environmental factors that are associated with high BMI.
Using databases containing individual genetic sequences and breast cancer diagnoses in a European population, we tested whether genetically predicted BMI was associated with diagnosis of breast cancer in either pre- or postmenopausal women.
We found that genetically predicted high BMI was associated with decreased breast cancer risk, in both cancer databases. Unexpectedly, this was true for both pre- and postmenopausal women.
What Do These Findings Mean?
Our results from postmenopausal women contradict prior findings from population studies, which used measured, rather than genetically predicted, BMI.
BMI predicted using genetic variants identified to date may be more closely related to body weight in early life or midlife, which is negatively associated with risk of breast cancer. Measured high BMI later in life may be influenced by environmental factors that are associated with increased risk of breast cancer.
More research is needed on the interrelationship of genetic factors, environment, and BMI in the risk of breast cancer.
doi:10.1371/journal.pmed.1002105
PMCID: PMC4995025  PMID: 27551723
3.  Extent of ductal carcinoma in situ according to breast cancer subtypes: a population-based cohort study 
Ductal carcinoma in situ (DCIS) is a precursor of invasive breast carcinoma (IBC). The DCIS component is often more extensive than the invasive component, which affects local control. The aim of our study was to analyze features of DCIS within different IBC subtypes, which may contribute to the optimization of personalized approaches for patients with IBC. Patients with IBC reported according to the synoptic reporting module in the Netherlands between 2009 and 2015 were included. Data extraction included characteristics of the invasive component and, if present, several features of the DCIS component. Resection margin status analyses were restricted to patients undergoing breast-conserving surgery (BCS). Differences between subtypes were tested by a Chi-square test, spearman’s Rho test or a one-way ANOVA test. Overall, 36.937 cases of IBC were included. About half of the IBCs (n = 16.014; 43.4 %) were associated with DCIS. Her2+ IBC (irrespective of ER status) was associated with a higher prevalence of adjacent DCIS, a larger extent of DCIS and a higher rate of irradicality of the DCIS component as compared to ER+/Her2− and triple-negative subtypes (P < 0.0001 for all variables). The prevalence of DCIS in triple-negative IBC on the other hand was lowest. In this large population-based cohort study, we showed significant differences between the prevalence and extent of DCIS according to IBC subtypes, which is also reflected in the resection margin status in patients treated with BCS. Our data provide important information regarding the optimization of local therapy according to IBC subtypes.
doi:10.1007/s10549-016-3862-4
PMCID: PMC4937080  PMID: 27318854
Breast cancer subtypes; Ductal carcinoma in situ; Prevalence
4.  Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer 
Kabisch, Maria | Lorenzo Bermejo, Justo | Dünnebier, Thomas | Ying, Shibo | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Peeters, Stephanie | Weltens, Caroline | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Purrington, Kristen | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Johnson, Nichola | Fletcher, Olivia | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Hogervorst, Frans B.L. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Burwinkel, Barbara | Marmé, Frederik | Yang, Rongxi | Bugert, Peter | González-Neira, Anna | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose I. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Kriege, Mieke | Koppert, Linetta B. | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slettedahl, Seth | Toland, Amanda E. | Vachon, Celine | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Ruebner, Matthias | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Swerdlow, Anthony | García-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Radice, Paolo | Peterlongo, Paolo | Scuvera, Giulietta | Fortuzzi, Stefano | Bogdanova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Zheng, Wei | Shrubsole, Martha J. | Cai, Qiuyin | Torres, Diana | Anton-Culver, Hoda | Kristensen, Vessela | Bacot, François | Tessier, Daniel C. | Vincent, Daniel | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Simard, Jacques | Chenevix-Trench, Georgia | Hall, Per | Pharoah, Paul D.P. | Dunning, Alison M. | Easton, Douglas F. | Hamann, Ute
Carcinogenesis  2015;36(2):256-271.
Summary
This is the first study investigating the contribution of inherited variants in core genes of the chromosomal passenger complex to breast cancer susceptibility. It was found that several INCENP variants are associated with the risk of ER-negative breast cancer in the European population.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
doi:10.1093/carcin/bgu326
PMCID: PMC4335262  PMID: 25586992
5.  Oncological safety of prophylactic breast surgery: skin-sparing and nipple-sparing versus total mastectomy 
Gland Surgery  2015;4(6):467-475.
Women with a BRCA1/2 gene mutation and others with a high breast cancer risk may opt for bilateral prophylactic mastectomy. To allow for immediate breast reconstruction the skin envelope is left in situ with or without the nipple-areola complex (NAC). Although possibly leading to a more natural aesthetic outcome than the conventional total mastectomy, so-called skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM) may leave some breast glandular tissue in situ. The oncological risk associated with remaining breast glandular tissue is unclear. We present a case of primary breast cancer after prophylactic mastectomy followed by a review of the literature on remaining breast glandular tissue after various mastectomy techniques and oncological safety of prophylactic mastectomies.
doi:10.3978/j.issn.2227-684X.2015.02.01
PMCID: PMC4647001  PMID: 26645001
Risk-reduction; skin-sparing mastectomy (SSM); nipple-sparing mastectomy (NSM); total mastectomy; primary breast cancer; breast glandular tissue; terminal duct lobular units
6.  Adjuvant radiotherapy for primary breast cancer in BRCA1 and BRCA2 mutation carriers and risk of contralateral breast cancer with special attention to patients irradiated at younger age 
The purpose of this study was to estimate the influence of adjuvant radiotherapy for primary breast cancer (BC) on the risk of contralateral BC (CBC) in BRCA1 or BRCA2(BRCA1/2) mutation carriers, with special attention to patients irradiated at age younger than 40 years. Additionally, tendencies in locoregional treatments and rates of contralateral risk-reducing mastectomy over time were explored. In this retrospective cohort study, 691 BRCA1/2-associated BC patients treated between 1980 and 2013 were followed from diagnosis until CBC or censoring event including ipsilateral BC recurrence, distant metastasis, contralateral risk-reducing mastectomy, other invasive cancer diagnosis, death, or loss to follow up. Hazard ratios (HR) for CBC associated with radiotherapy were estimated using Cox regression. Median follow-up time was 8.6 years [range 0.3–34.3 years]. No association between radiotherapy for primary BC and risk of CBC was found, neither in the total population (HR 0.82, 95 % CI 0.45–1.49) nor in the subgroup of patients younger than 40 years at primary diagnosis (HR 1.36, 95 % CI 0.60–3.09). During follow-up, the number of patients at risk decreased substantially since a large proportion of patients were censored after contralateral risk-reducing mastectomy or BC recurrence. Over the years, increasing preference for mastectomy without radiotherapy compared to breast-conserving surgery with radiotherapy was found ranging from less than 30 % in 1995 to almost 50 % after 2010. The rate of contralateral risk-reducing mastectomy increased over the years from less than 40 % in 1995 to more than 60 % after 2010. In this cohort of BRCA1/2-associated BC patients, no association between radiotherapy for primary BC and risk of CBC was observed in the total group, nor in the patients irradiated before the age of 40 years. The number of patients at risk after 10 and 15 years of follow-up, however, was too small to definitively exclude harmful effects of adjuvant radiotherapy.
doi:10.1007/s10549-015-3597-7
PMCID: PMC4621694  PMID: 26467044
Radiotherapy; BRCA mutation; Contralateral breast cancer; Risk-reducing mastectomy; Breast-conserving surgery
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.  Lower mitotic activity in BRCA1/2-associated primary breast cancers occurring after risk-reducing salpingo-oophorectomy 
Cancer Biology & Therapy  2014;15(4):371-379.
Risk-reducing salpingo-oophorectomy (RRSO) is associated with 50% reduction of BRCA1/2-associated breast cancer (BC) risk, possibly through decreased growth activity. In this pilot study, tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO were compared with those of PBCs originating without RRSO. From a cohort of 271 women with BRCA1/2-associated screen detected BC, we selected 20 patients with PBC detected ≥12 months after RRSO (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at diagnosis (± 2.5 y) and for BRCA1 or BRCA2 mutation. Pathology samples were revised for histological subtype, tumor differentiation grade, mitotic activity index (MAI), estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated from revised magnetic resonance and mammographic images. Median age at PBC diagnosis was 52 y (range 35–67). PBCs after RRSO had lower MAIs (12 vs. 22 mitotic counts/2 mm, P = 0.02), were smaller (11 vs. 17 mm, P = 0.01), and tend to be PR-positive more often than PBCs without RRSO (38% vs. 13%, P = 0.07). Differentiation grade, ER, and HER2 status were not different. Median DT was 124 d (range 89–193) in the RRSO group and 93 days (range 54–253) in the non-RRSO group (P = 0.47). BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological phenotype. When confirmed in larger series, this may have consequences for BC screening protocols after RRSO.
doi:10.4161/cbt.27628
PMCID: PMC3979814  PMID: 24423863
BRCA1/2; breast cancer; estrogen; mitotic activity; risk-reducing salpingo-oophorectomy; tumor characteristics; tumor growth
9.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
10.  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

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