Search

Your search keyword '"Thompson, Alastair"' showing total 144 results
Start Over Author "Thompson, Alastair" Database Supplemental Index
144 results on '"Thompson, Alastair"'

1. Normal breast tissues harbour rare populations of aneuploid epithelial cells

Author

Lin, Yiyun, Wang, Junke, Wang, Kaile, Bai, Shanshan, Thennavan, Aatish, Wei, Runmin, Yan, Yun, Li, Jianzhuo, Elgamal, Heba, Sei, Emi, Casasent, Anna, Rao, Mitchell, Tang, Chenling, Multani, Asha S., Ma, Jin, Montalvan, Jessica, Nagi, Chandandeep, Winocour, Sebastian, Lim, Bora, Thompson, Alastair, and Navin, Nicholas

Abstract

Aneuploid epithelial cells are common in breast cancer1,2; however, their presence in normal breast tissues is not well understood. To address this question, we applied single-cell DNA sequencing to profile copy number alterations in 83,206 epithelial cells from the breast tissues of 49 healthy women, and we applied single-cell DNA and assay for transposase-accessible chromatin sequencing co-assays to the samples of 19 women. Our data show that all women harboured rare aneuploid epithelial cells (median 3.19%) that increased with age. Many aneuploid epithelial cells (median 82.22%) in normal breast tissues underwent clonal expansions and harboured copy number alterations reminiscent of invasive breast cancers (gains of 1q; losses of 10q, 16q and 22q). Co-assay profiling showed that the aneuploid cells were mainly associated with the two luminal epithelial lineages, and spatial mapping showed that they localized in ductal and lobular structures with normal histopathology. Collectively, these data show that even healthy women have clonal expansions of rare aneuploid epithelial cells in their breast tissues.

Published
2024
Full Text
View/download PDF

2. Application of deep learning on mammographies to discriminate between low and high-risk DCIS for patient participation in active surveillance trials.

Author

Alaeikhanehshir, Sena, Voets, Madelon M., van Duijnhoven, Frederieke H., lips, Esther H., Groen, Emma J., van Oirsouw, Marja C. J., Hwang, Shelley E., Lo, Joseph Y., Wesseling, Jelle, Mann, Ritse M., Teuwen, Jonas, Thompson, Alastair, Nik-Zainal, Serena, Sawyer, Elinor J., Davies, Helen, Futreal, Andrew, Navin, Nicholas, Hwang, E. Shelley, Jonkers, Jos, and Rheenen, Jacco van

Published
2024
Full Text
View/download PDF

3. Application of deep learning on mammographies to discriminate between low and high-risk DCIS for patient participation in active surveillance trials.

Author

Alaeikhanehshir, Sena, Voets, Madelon M., van Duijnhoven, Frederieke H., lips, Esther H., Groen, Emma J., van Oirsouw, Marja C. J., Hwang, Shelley E., Lo, Joseph Y., Wesseling, Jelle, Mann, Ritse M., Teuwen, Jonas, Thompson, Alastair, Nik-Zainal, Serena, Sawyer, Elinor J., Davies, Helen, Futreal, Andrew, Navin, Nicholas, Hwang, E. Shelley, Jonkers, Jos, and Rheenen, Jacco van

Published
2024
Full Text
View/download PDF

4. Locoregional Breast Cancer Recurrence in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT Trial: Analysis of Risk Factors Including the 70-Gene Signature.

Author

Alaeikhanehshir, Sena, Ajayi, Taiwo, Duijnhoven, Frederieke H., Poncet, Coralie, Olaniran, Ridwan O., Lips, Esther H., van 't Veer, Laura J., Delaloge, Suzette, Rubio, Isabel T., Thompson, Alastair M., Cardoso, Fatima, Piccart, Martine, and Rutgers, Emiel J.T.

Published
2024
Full Text
View/download PDF

5. Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.

Author

Goodwin, Pamela J., Chen, Bingshu E., Gelmon, Karen A., Whelan, Timothy J., Ennis, Marguerite, Lemieux, Julie, Ligibel, Jennifer A., Hershman, Dawn L., Mayer, Ingrid A., Hobday, Timothy J., Bliss, Judith M., Rastogi, Priya, Rabaglio-Poretti, Manuela, Thompson, Alastair M., Rea, Daniel W., Stos, Paul M., Shepherd, Lois E., Stambolic, Vuk, and Parulekar, Wendy R.

Published
2023
Full Text
View/download PDF

7. A spatially resolved single-cell genomic atlas of the adult human breast

Author

Kumar, Tapsi, Nee, Kevin, Wei, Runmin, He, Siyuan, Nguyen, Quy H., Bai, Shanshan, Blake, Kerrigan, Pein, Maren, Gong, Yanwen, Sei, Emi, Hu, Min, Casasent, Anna K., Thennavan, Aatish, Li, Jianzhuo, Tran, Tuan, Chen, Ken, Nilges, Benedikt, Kashikar, Nachiket, Braubach, Oliver, Ben Cheikh, Bassem, Nikulina, Nadya, Chen, Hui, Teshome, Mediget, Menegaz, Brian, Javaid, Huma, Nagi, Chandandeep, Montalvan, Jessica, Lev, Tatyana, Mallya, Sharmila, Tifrea, Delia F., Edwards, Robert, Lin, Erin, Parajuli, Ritesh, Hanson, Summer, Winocour, Sebastian, Thompson, Alastair, Lim, Bora, Lawson, Devon A., Kessenbrock, Kai, and Navin, Nicholas

Abstract

The adult human breast is comprised of an intricate network of epithelial ducts and lobules that are embedded in connective and adipose tissue1–3. Although most previous studies have focused on the breast epithelial system4–6, many of the non-epithelial cell types remain understudied. Here we constructed the comprehensive Human Breast Cell Atlas (HBCA) at single-cell and spatial resolution. Our single-cell transcriptomics study profiled 714,331 cells from 126 women, and 117,346 nuclei from 20 women, identifying 12 major cell types and 58 biological cell states. These data reveal abundant perivascular, endothelial and immune cell populations, and highly diverse luminal epithelial cell states. Spatial mapping using four different technologies revealed an unexpectedly rich ecosystem of tissue-resident immune cells, as well as distinct molecular differences between ductal and lobular regions. Collectively, these data provide a reference of the adult normal breast tissue for studying mammary biology and diseases such as breast cancer.

Published
2023
Full Text
View/download PDF

8. Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226)

Author

Bergqvist, Mattias, Nordmark, Adrian, Williams, Amy, Paoletti, Costanza, Barlow, William, Cobain, Erin F., Mehta, Rita S., Gralow, Julie R., Hortobagyi, Gabriel N., Albain, Kathy S., Pusztai, Lajos, Sharma, Priyanka, Godwin, Andrew K., Thompson, Alastair M., Hayes, Daniel F., and Rae, James M.

Abstract

AbstractBackgroundSome patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum®TKa highlighting differences vs. a Research Use Only version is reported.Methods1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum®unit of Activity) is adopted.ResultsA DiviTum®TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals.ConclusionsDiviTum®TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET.Trial registration: NCT00075764

Published
2023
Full Text
View/download PDF

9. Exploring locoregional treatment reporting in neoadjuvant systemic breast cancer treatment studies: A systematic review.

Author

Jiang, Michael, Avery, Kerry, Ahmed, Rosina, de Boniface, Jana, Chatterjee, Sanjoy, Dodwell, David, Dubsky, Peter, Finestone, Sandy, Iwata, Hiroji, Lee, Han-Byoel, MacKenzie, Mairead, Meyn, Anne, Poulakaki, Fiorita, Richardson, Andrea L., Sepulveda, Karla, Spillane, Andrew, Thompson, Alastair M., Werutsky, Gustavo, Wright, Jean L., and Zdenkowski, Nicholas

Subjects
NEOADJUVANT chemotherapy, BREAST cancer, TREATMENT effectiveness, CANCER treatment, DESCRIPTIVE statistics, RADIOTHERAPY
Abstract

Accurate information about locoregional treatments in breast cancer neoadjuvant systemic therapy (NST) trials is vital to support surgical decision-making and allow meaningful interpretation of long-term oncological outcomes. This systematic review (PROSPERO registration CRD42023470891) aimed to describe the current practice of outcome reporting in NST studies. A systematic search identified primary research studies published 01/01/2018-08/09/2023 reporting outcomes in patients receiving NST for breast cancer followed by locoregional treatment. Included were randomised controlled trials (RCTs) and non-randomised studies (NRS) with >250 participants reporting at least one locoregional treatment outcome. Outcomes were extracted verbatim and categorised using content analysis. Descriptive statistics were used to summarise results. Of the 3111 abstracts screened, 137 studies (22 RCTs and 115 NRS) reporting at least one locoregional outcome in 575,531 patients were included. The 137 studies reported a total of 510 surgical outcomes with a median of 3 (range 1–12) per study. No single outcome was reported in all studies. Type of breast (n = 129, 94.2 %) and axillary (n = 86, 62.8 %) surgery were reported most frequently. Only 34 % (n = 47) studies reported how treatment response was assessed and if/how this informed surgical decision-making. Only a fifth (n = 28) reported outcomes relating to surgical de-escalation. Only 72 studies (52.6 %) reported any radiation therapy (RT)-related outcome, most frequently whether RT had been received (n = 63/72, 87.5 %). Current reporting of locoregional treatment outcomes in NST studies is poor, inconsistent and urgently needs to be improved. A core outcome set and reporting guidelines may improve the quality and value of future research. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

10. Learning to distinguish progressive and non-progressive ductal carcinoma in situ

Author

Casasent, Anna K., Almekinders, Mathilde M., Mulder, Charlotta, Bhattacharjee, Proteeti, Collyar, Deborah, Thompson, Alastair M., Jonkers, Jos, Lips, Esther H., van Rheenen, Jacco, Hwang, E. Shelley, Nik-Zainal, Serena, Navin, Nicholas E., and Wesseling, Jelle

Abstract

Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients.

Published
2022
Full Text
View/download PDF

11. Unresected screen-detected ductal carcinoma in situ: Outcomes of 311 women in the Forget-Me-Not 2 study.

Author

Maxwell, Anthony J., Hilton, Bridget, Clements, Karen, Dodwell, David, Dulson-Cox, Joanne, Kearins, Olive, Kirwan, Cliona, Litherland, Janet, Mylvaganam, Senthurun, Provenzano, Elena, Pinder, Sarah E., Sawyer, Elinor, Shaaban, Abeer M., Sharma, Nisha, Stobart, Hilary, Wallis, Matthew G., and Thompson, Alastair M.

Subjects
CARCINOMA in situ, DUCTAL carcinoma, CANCER invasiveness, MEDICAL screening, WATCHFUL waiting, EARLY detection of cancer, BREAST exams
Abstract

The natural history of ductal carcinoma in situ (DCIS) is poorly understood. The aim of this cohort study was to determine the outcomes of women who had no surgery for screen-detected DCIS in the 6 months following diagnosis. English breast screening databases were retrospectively searched for women diagnosed with DCIS without invasive cancer at screening and who had no record of surgery within 6 months of diagnosis. These were cross-referenced with cancer registry data. Details of the potentially eligible women were sent to the relevant breast screening units for verification and for completion of data forms detailing clinical, radiological and pathological findings, non-surgical treatment and subsequent clinical course. Data for 311 eligible women (median age 62 years) were available. 60 women developed invasive cancer, 56 ipsilateral and 4 contralateral. Ipsilateral invasion risk increased approximately linearly with time for at least 10 years. The 10-year cumulative risk of ipsilateral invasion was 9% (95% CI 4–21%), 39% (24–58%) and 36% (24–50%) for low, intermediate and high grade DCIS respectively and was higher in younger women, in those with larger DCIS lesions and in those with microinvasion. Most invasive cancers that developed were grade 2 or 3. The findings suggest that active surveillance may be a reasonable alternative to surgery in patients with low grade DCIS but that women with intermediate or high grade disease should continue to be offered surgery. This highlights the importance of reproducible grading of DCIS to ensure patients receive appropriate treatment. • >1/3 women with intermediate/high grade DCIS developed invasive cancer within 10 years. • Approximately 10% of women with low grade DCIS developed invasion within 10 years. • Most invasive cancers that developed were grade 2 or 3. • The risk of invasion was age-dependent and higher in younger women. • Invasion risk was higher in larger DCIS lesions. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

12. A pre-operative prognostic model predicting all cause and cause specific mortality for women presenting with invasive breast cancer.

Author

Wang, Huan, Donnan, Peter, Macaskill, E. Jane, Jordan, Lee, Thompson, Alastair, and Evans, Andy

Subjects
PROGNOSTIC models, CANCER invasiveness, WOMEN'S mortality, BREAST cancer, CHRONIC kidney failure
Abstract

The aim of this study is to develop a pre-operative prognostic model based on known pre-operative factors. A database of ultrasound (US) lesions undergoing biopsy documented US lesion size, stiffness, and patient source prospectively. Women with invasive cancer presenting between 2010 and 2015 were the study group. Breast and axillary core results and ER, PR and HER receptor status were collected prospectively. Assessment of US skin thickening, US distal enhancement and presence of chronic kidney disease (CKD) was performed retrospectively. Patient survival and cause of death were ascertained from computer records. Predictive models for (i) all-cause mortality (ACM) and (ii) breast cancer death (BCD) were built and then validated using bootstrap k -fold cross-validation. A comparison of predictive performance was made between a full cause-specific Cox model, a sub cause-specific Cox model, and a full Fine-Gray sub-distribution hazard model. 1136 patients were included in the study. The median follow-up time was 6.2 years. 125 (11%) women died from breast cancer and 155 (14%) died from other causes. For the prediction of BCD, the cause-specific Cox sub-model performed the best. The time dependent AUC begins above 0.91 in year one to 3 reducing to 0.83 in year 6. The factors included in the Cox sub model were tumour size, skin thickening, source of detection, tumour grade, ER status, pre-operative nodal metastasis and CKD. We have shown that a model based on preoperative factors can predict BCD. Such prediction if externally validated and incorporating treatment data could be useful for treatment planning and patient counselling. • Known preoperative prognostic indicators can be combined to give a prognostic model. • Such a model performs well with an area under the curve above 0.80 for the first 5 years. • In the future, if treatment data is added, a model could be used to guide decisions regarding NACT and patient counselling. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

13. BI-RADS Ultrasound Lexicon Descriptors and Stromal Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Author

Candelaria, Rosalind P., Spak, David A., Rauch, Gaiane M., Huo, Lei, Bassett, Roland L., Santiago, Lumarie, Scoggins, Marion E., Guirguis, Mary S., Patel, Miral M., Whitman, Gary J., Moulder, Stacy L., Thompson, Alastair M., Ravenberg, Elizabeth E., White, Jason B., Abuhadra, Nour K., Valero, Vicente, Litton, Jennifer, Adrada, Beatriz E., and Yang, Wei T.

Abstract

Purpose: Increased levels of stromal tumor-infiltrating lymphocytes (sTILs) have recently been considered a favorable independent prognostic and predictive biomarker in triple-negative breast cancer (TNBC). The purpose of this study was to determine the relationship between BI-RADS (Breast Imaging Reporting and Data System) ultrasound lexicon descriptors and sTILs in TNBC.Materials and Methods: Patients with stage I-III TNBC were evaluated within a single-institution neoadjuvant clinical trial. Two fellowship-trained breast radiologists used the BI-RADS ultrasound lexicon to assess pretreatment tumor shape, margin, echo pattern, orientation, posterior features, and vascularity. sTILs were defined as low <20 or high ≥20 on the pretreatment biopsy. Fisher's exact tests were used to assess the association between lexicon descriptors and sTIL levels.Results: The 284 patients (mean age 52 years, range 24-79 years) were comprised of 68% (193/284) with low-sTIL tumors and 32% (91/284) with high-sTIL tumors. TNBC tumors with high sTILs were more likely to have the following features: (1) oval/round shape than irregular shape (p = 0.003), (2) circumscribed or microlobulated margins than spiculated, indistinct, or angular margins (p = 0.0005); (3) complex cystic and solid pattern than heterogeneous pattern (p = 0.006); and (4) posterior enhancement than shadowing (p = 0.002). There was no significant association between sTILs and descriptors for orientation and vascularity (p = 0.06 and p = 0.49, respectively).Conclusion: BI-RADS ultrasound descriptors of the pretreatment appearance of a TNBC tumor can be useful in discriminating between tumors with low and high sTIL levels. Therefore, there is a potential use of ultrasound tumor characteristics to complement sTILs when used as stratification factors in treatment algorithms for TNBC. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

14. Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer

Author

Lips, Esther H., Kumar, Tapsi, Megalios, Anargyros, Visser, Lindy L., Sheinman, Michael, Fortunato, Angelo, Shah, Vandna, Hoogstraat, Marlous, Sei, Emi, Mallo, Diego, Roman-Escorza, Maria, Ahmed, Ahmed A., Xu, Mingchu, van den Belt-Dusebout, Alexandra W., Brugman, Wim, Casasent, Anna K., Clements, Karen, Davies, Helen R., Fu, Liping, Grigoriadis, Anita, Hardman, Timothy M., King, Lorraine M., Krete, Marielle, Kristel, Petra, de Maaker, Michiel, Maley, Carlo C., Marks, Jeffrey R., Menegaz, Brian A., Mulder, Lennart, Nieboer, Frank, Nowinski, Salpie, Pinder, Sarah, Quist, Jelmar, Salinas-Souza, Carolina, Schaapveld, Michael, Schmidt, Marjanka K., Shaaban, Abeer M., Shami, Rana, Sridharan, Mathini, Zhang, John, Stobart, Hilary, Collyar, Deborah, Nik-Zainal, Serena, Wessels, Lodewyk F. A., Hwang, E. Shelley, Navin, Nicholas E., Futreal, P. Andrew, Thompson, Alastair M., Wesseling, Jelle, and Sawyer, Elinor J.

Abstract

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.

Published
2022
Full Text
View/download PDF

15. Phase 2 study of neoadjuvant enzalutamide and paclitaxel for luminal androgen receptor-enriched TNBC: Trial results and insights into “ARness”

Author

Lim, Bora, Seth, Sahil, Yam, Clinton, Huo, Lei, Fujii, Takeo, Lee, Jangsoon, Bassett, Roland, Nasser, Sara, Ravenberg, Lisa, White, Jason, Clayborn, Alyson, Guerra, Gil, Litton, Jennifer K., Damodaran, Senthil, Layman, Rachel, Valero, Vicente, Tripathy, Debasish, Lewis, Michael, Dobrolecki, Lacey E., Lei, Jonathan, Candelaria, Rosalind, Arun, Banu, Rauch, Gaiane, Zhao, Li, Zhang, Jianhua, Ding, Qingqing, Symmans, W. Fraser, Chang, Jeffrey T., Thompson, Alastair M., Moulder, Stacy L., and Ueno, Naoto T.

Abstract

Luminal androgen receptor (LAR)-enriched triple-negative breast cancer (TNBC) is a distinct subtype. The efficacy of AR inhibitors and the relevant biomarkers in neoadjuvant therapy (NAT) are yet to be determined. We tested the combination of the AR inhibitor enzalutamide (120 mg daily by mouth) and paclitaxel (80 mg/m2weekly intravenously) (ZT) for 12 weeks as NAT for LAR-enriched TNBC. Eligibility criteria included a percentage of cells expressing nuclear AR by immunohistochemistry (iAR) of at least 10% and a reduction in sonographic volume of less than 70% after four cycles of doxorubicin and cyclophosphamide. Twenty-four patients were enrolled. Ten achieved a pathologic complete response or residual cancer burden-I. ZT was safe, with no unexpected side effects. An iAR of at least 70% had a positive predictive value of 0.92 and a negative predictive value of 0.97 in predicting LAR-enriched TNBC according to RNA-based assays. Our data support future trials of AR blockade in early-stage LAR-enriched TNBC.

Published
2024
Full Text
View/download PDF

17. The impact of patient characteristics and lifestyle factors on the risk of an ipsilateral event after a primary DCIS: A systematic review.

Author

Alaeikhanehshir, Sena, Engelhardt, Ellen G., van Duijnhoven, Frederieke H., van Seijen, Maartje, Bhairosing, Patrick A., Pinto, Donna, Collyar, Deborah, Sawyer, Elinor, Hwang, Shelley E., Thompson, Alastair M., Wesseling, Jelle, Lips, Esther H., and Schmidt, Marjanka K.

Subjects
META-analysis, BREAST cancer, DUCTAL carcinoma, DATA extraction
Abstract

The majority of 'low-risk' (grade I/II) Ductal Carcinoma In Situ (DCIS) may not progress to invasive breast cancer during a women's lifetime. Therefore, the safety of active surveillance versus standard surgical treatment for DCIS is prospectively being evaluated in clinical trials. If proven safe and selectively implemented in clinical practice, a significant group of women with low-risk DCIS may forego surgery and radiotherapy in the future. Identification of modifiable and non-modifiable risk factors associated with prognosis after a primary DCIS would also enhance our care of women with low-risk DCIS. To identify modifiable and non-modifiable risk factors for subsequent breast events after DCIS, we performed a systematic literature search in PUBMED, EMBASE and Scopus. Six out of the 3870 articles retrieved were included for final data extraction. These six studies included a total of 4950 patients with primary DCIS and 640 recorded subsequent breast events. There was moderate evidence for an association of a family history of breast cancer, premenopausal status, high BMI, and high breast density with a subsequent breast cancer or further DCIS. There is a limited number of recent studies published on the impact of modifiable and non-modifiable risk factors on subsequent events after DCIS. The available evidence is insufficient to identify potential targets for risk reduction strategies, reflecting the relatively small numbers and the lack of long-term follow-up in DCIS, a low-event condition. • Need for risk management strategies for untreated DCIS patients. • Limited evidence for association between lifestyle factors and prognosis after DCIS. • Positive family history, premenopausal status, high breast density associated with prognosis. [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

18. Neoadjuvant Talazoparib for Patients With Operable Breast Cancer With a Germline Pathogenic Variant.

Author

Litton, Jennifer K., Scoggins, Marion E., Hess, Kenneth R., Adrada, Beatriz E., Murthy, Rashmi K., Damodaran, Senthil, DeSnyder, Sarah M., Brewster, Abenaa M., Barcenas, Carlos H., Valero, Vicente, Whitman, Gary J., Schwartz-Gomez, Jill, Mittendorf, Elizabeth A., Thompson, Alastair M., Helgason, Thorunn, Ibrahim, Nuhad, Piwnica-Worms, Helen, Moulder, Stacy L., and Arun, Banu K.

Published
2020
Full Text
View/download PDF

19. Validation of the DNA Damage Immune Response Signature in Patients With Triple-Negative Breast Cancer From the SWOG 9313c Trial.

Author

Sharma, Priyanka, Barlow, William E., Godwin, Andrew K., Parkes, Eileen E., Knight, Laura A., Walker, Steven M., Kennedy, Richard D., Harkin, Denis P., Logan, Gemma E., Steele, Christopher J., Lambe, Shauna M., Badve, Sunil, Gökmen-Polar, Yesim, Pathak, Harsh B., Isakova, Kamilla, Linden, Hannah M., Porter, Peggy, Pusztai, Lajos, Thompson, Alastair M., and Tripathy, Debu

Published
2019
Full Text
View/download PDF

20. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.

Author

Hurvitz, Sara A., Martin, Miguel, Jung, Kyung Hae, Huang, Chiun-Sheng, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Fasching, Peter A., Afenjar, Karen, Spera, Gonzalo, Lopez-Valverde, Vanesa, Song, Chunyan, Trask, Peter, Boulet, Thomas, Sparano, Joseph A., Symmans, W. Fraser, and Thompson, Alastair M.

Published
2019
Full Text
View/download PDF

21. eEF1A2 promotes PTEN-GSK3β-SCF complex-dependent degradation of Aurora kinase A and is inactivated in breast cancer

Author

Treekitkarnmongkol, Warapen, Solis, Luisa M., Sankaran, Deivendran, Gagea, Mihai, Singh, Pankaj K., Mistry, Ragini, Nguyen, Tristian, Kai, Kazuharu, Liu, Jiajun, Sasai, Kaori, Jitsumori, Yoshimi, Liu, Jianwen, Nagao, Norio, Stossi, Fabio, Mancini, Michael A., Wistuba, Ignacio I., Thompson, Alastair M., Lee, Jonathan M., Cadiñanos, Juan, Wong, Kwong-Kwok, Abbott, Catherine M., Sahin, Aysegul A., Liu, Suyu, Katayama, Hiroshi, and Sen, Subrata

Abstract

The translation elongation factor eEF1A promotes protein synthesis. Its methylation by METTL13 increases its activity, supporting tumor growth. However, in some cancers, a high abundance of eEF1A isoforms is associated with a good prognosis. Here, we found that eEF1A2 exhibited oncogenic or tumor-suppressor functions depending on its interaction with METTL13 or the phosphatase PTEN, respectively. METTL13 and PTEN competed for interaction with eEF1A2 in the same structural domain. PTEN-bound eEF1A2 promoted the ubiquitination and degradation of the mitosis-promoting Aurora kinase A in the S and G2 phases of the cell cycle. eEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. Genetic ablation of Eef1a2or Ptenin mice resulted in a greater abundance of Aurora-A and increased cell cycling in mammary tumors, which was corroborated in breast cancer tissues from patients. Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.

Published
2024
Full Text
View/download PDF

22. Three-Year Outcomes With Hypofractionated Versus Conventionally Fractionated Whole-Breast Irradiation: Results of a Randomized, Noninferiority Clinical Trial.

Author

Shaitelman, Simona F., Lei, Xiudong, Thompson, Alastair, Schlembach, Pamela, Bloom, Elizabeth S., Arzu, Isidora Y., Buchholz, Daniel, Chronowski, Gregory, Dvorak, Tomas, Grade, Emily, Hoffman, Karen, Perkins, George, Reed, Valerie K., Shah, Shalin J., Stauder, Michael C., Strom, Eric A., Tereffe, Welela, Woodward, Wendy A., Amaya, Diana N., and Shen, Yu

Published
2018
Full Text
View/download PDF

24. Risk factors for the development of invasive cancer in unresected ductal carcinoma in situ.

Author

Maxwell, Anthony J., Clements, Karen, Hilton, Bridget, Dodwell, David J., Evans, Andrew, Kearins, Olive, Pinder, Sarah E., Thomas, Jeremy, Wallis, Matthew G., and Thompson, Alastair M.

Subjects
CANCER invasiveness, CANCER risk factors, DUCTAL carcinoma, NEEDLE biopsy, SURGICAL excision
Abstract

Background The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. Methods Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for ≥1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed. Results Eighty-nine women with DCIS diagnosed 1998–2010 were identified. The median age at diagnosis was 75 (range 44–94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12–180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12–144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades ( p = .0016, log-rank test). Invasion was more frequent in lesions with calcification as the predominant feature (23/50 v. 5/25; p = .042) and in younger women ( p = .0002). Endocrine therapy was associated with a lower rate of invasive breast cancer ( p = .048). Conclusions High cytonuclear grade, mammographic microcalcification, young age and lack of endocrine therapy were risk factors for DCIS progression to invasive cancer. Surgical excision of high grade DCIS remains the treatment of choice. Given the uncertain long-term natural history of non-high grade DCIS, the option of active surveillance of women with this condition should be offered within a clinical trial. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

25. Variability in diagnostic threshold for comedo necrosis among breast pathologists: implications for patient eligibility for active surveillance trials of ductal carcinoma in situ

Author

Harrison, Beth T., Hwang, E.Shelley, Partridge, Ann H., Thompson, Alastair M., and Schnitt, Stuart J.

Abstract

Active surveillance trials for low-risk ductal carcinoma in situ (DCIS) are in progress in the United States and Europe. In some of these trials, the presence of comedo necrosis in the DCIS has been an exclusion criterion for trial entry. However, the minimum amount of necrosis required by pathologists for a diagnosis of comedo necrosis is not well-defined. We surveyed 35 experienced breast pathologists to assess their diagnostic threshold for comedo necrosis. Pink circles representing necrosis ranging in extent from 10 to 80% of the duct diameter were superimposed on eight replicate histologic images of a single duct involved by low nuclear grade, solid pattern DCIS. These images were circulated by e-mail to the participating pathologists who were asked to select the image that represents the minimum amount of necrosis that they require for a diagnosis of comedo necrosis. Among the 35 participants, the minimum extent of the duct diameter required for a diagnosis of comedo necrosis was 10% for 4 pathologists, 20% for 5, 30% for 11, 40% for 7, 50% for 6, 60% for 1 and 70% for 1. There was no single threshold about which more than one-third of the pathologists agreed met the minimal criteria for comedo necrosis. We conclude that even among experienced breast pathologists, the threshold for comedo necrosis is highly variable. Our findings highlight the need for a standardized definition of comedo necrosis as a trial criterion, and more generally where it may be used as a marker of increased risk of recurrence for therapeutic decision making.

Published
2019
Full Text
View/download PDF

26. Variability in diagnostic threshold for comedo necrosis among breast pathologists: implications for patient eligibility for active surveillance trials of ductal carcinoma in situ

Author

Harrison, Beth, Hwang, E., Partridge, Ann, Thompson, Alastair, and Schnitt, Stuart

Abstract

Active surveillance trials for low-risk ductal carcinoma in situ (DCIS) are in progress in the United States and Europe. In some of these trials, the presence of comedo necrosis in the DCIS has been an exclusion criterion for trial entry. However, the minimum amount of necrosis required by pathologists for a diagnosis of comedo necrosis is not well-defined. We surveyed 35 experienced breast pathologists to assess their diagnostic threshold for comedo necrosis. Pink circles representing necrosis ranging in extent from 10 to 80% of the duct diameter were superimposed on eight replicate histologic images of a single duct involved by low nuclear grade, solid pattern DCIS. These images were circulated by e-mail to the participating pathologists who were asked to select the image that represents the minimum amount of necrosis that they require for a diagnosis of comedo necrosis. Among the 35 participants, the minimum extent of the duct diameter required for a diagnosis of comedo necrosis was 10% for 4 pathologists, 20% for 5, 30% for 11, 40% for 7, 50% for 6, 60% for 1 and 70% for 1. There was no single threshold about which more than one-third of the pathologists agreed met the minimal criteria for comedo necrosis. We conclude that even among experienced breast pathologists, the threshold for comedo necrosis is highly variable. Our findings highlight the need for a standardized definition of comedo necrosis as a trial criterion, and more generally where it may be used as a marker of increased risk of recurrence for therapeutic decision making.

Published
2019
Full Text
View/download PDF

27. Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma

Author

Atkinson, Aithne, Renziehausen, Alexander, Wang, Hexiao, Lo Nigro, Cristiana, Lattanzio, Laura, Merlano, Marco, Rao, Bhavya, Weir, Lynda, Evans, Alan, Matin, Rubeta, Harwood, Catherine, Szlosarek, Peter, Pickering, J Geoffrey, Fleming, Colin, Sim, Van Ren, Li, Su, Vasta, James T., Raines, Ronald T., Boniol, Mathieu, Thompson, Alastair, Proby, Charlotte, Crook, Tim, and Syed, Nelofer

Abstract

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1and Leprel2is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor suppressor function, ectopic expression of Leprel1and Leprel2inhibits melanoma proliferation, whereas P4HA2and P4HA3increase proliferation, and particularly invasiveness, of melanoma cells. Pharmacological inhibition with multiple selective collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells.

Published
2019
Full Text
View/download PDF

28. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Author

Renziehausen, Alexander, Wang, Hexiao, Rao, Bhavya, Weir, Lynda, Nigro, Cristiana Lo, Lattanzio, Laura, Merlano, Marco, Vega-Rioja, Antonio, del Carmen Fernandez-Carranco, Maria, Hajji, Nabil, Matin, Rubeta, Harwood, Catherine, Li, Su, Sim, Van Ren, O’Neill, Kevin, Evans, Alan, Thompson, Alastair, Szlosarek, Peter, Fleming, Colin, Stebbing, Justin, Proby, Charlotte, Tzakos, Andreas G., Syed, Nelofer, and Crook, Tim

Abstract

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1CpG island in metastatic melanoma implying that AGTR1encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.

Published
2019
Full Text
View/download PDF

29. Outcomes of complex oncoplastic breast surgery in older women. Analysis of data from the Age Gap cohort study.

Author

Quddus, Ratul, Banks, Jessica, Morgan, Jenna L., Martin, Charlene, Reed, Malcolm WR., Walters, Stephen, Cheung, Kwok Leung, Todd, Annaliza, Audisio, Riccardo, Green, Tracy, Revell, Deirdre, Gath, Jacqui, Horgan, Kieran, Holcombe, Chris, Parmeshwar, Rishi, Thompson, Alastair, and Wyld, L.

Subjects
BREAST surgery, OLDER women, MAMMAPLASTY, COHORT analysis, DATA analysis, MASTECTOMY
Abstract

Breast cancer, mastectomy, breast conserving surgery, post-mastectomy reconstruction, older women, quality of life. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

30. Atypia detected during breast screening and subsequent development of cancer: observational analysis of the Sloane atypia prospective cohort in England

Author

Freeman, Karoline, Jenkinson, David, Clements, Karen, Wallis, Matthew G, Pinder, Sarah E, Provenzano, Elena, Stobart, Hilary, Stallard, Nigel, Kearins, Olive, Sharma, Nisha, Shaaban, Abeer, Kirwan, Cliona Clare, Hilton, Bridget, Thompson, Alastair M, and Taylor-Phillips, Sian

Abstract

ObjectiveTo explore how the number and type of breast cancers developed after screen detected atypia compare with the anticipated 11.3 cancers detected per 1000 women screened within one three year screening round in the United Kingdom.DesignObservational analysis of the Sloane atypia prospective cohort in England.SettingAtypia diagnoses through the English NHS breast screening programme reported to the Sloane cohort study. This cohort is linked to the English Cancer Registry and the Mortality and Birth Information System for information on subsequent breast cancer and mortality.Participants3238 women diagnosed as having epithelial atypia between 1 April 2003 and 30 June 2018.Main outcome measuresNumber and type of invasive breast cancers detected at one, three, and six years after atypia diagnosis by atypia type, age, and year of diagnosis.ResultsThere was a fourfold increase in detection of atypia after the introduction of digital mammography between 2010 (n=119) and 2015 (n=502). During 19 088 person years of follow-up after atypia diagnosis (until December 2018), 141 women developed breast cancer. Cumulative incidence of cancer per 1000 women with atypia was 0.95 (95% confidence interval 0.28 to 2.69), 14.2 (10.3 to 19.1), and 45.0 (36.3 to 55.1) at one, three, and six years after atypia diagnosis, respectively. Women with atypia detected more recently have lower rates of subsequent cancers detected within three years (6.0 invasive cancers per 1000 women (95% confidence interval 3.1 to 10.9) in 2013-18 v24.3 (13.7 to 40.1) in 2003-07, and 24.6 (14.9 to 38.3) in 2008-12). Grade, size, and nodal involvement of subsequent invasive cancers were similar to those of cancers detected in the general screening population, with equal numbers of ipsilateral and contralateral cancers.ConclusionsMany atypia could represent risk factors rather than precursors of invasive cancer requiring surgery in the short term. Women with atypia detected more recently have lower rates of subsequent cancers detected, which might be associated with changes to mammography and biopsy techniques identifying forms of atypia that are more likely to represent overdiagnosis. Annual mammography in the short term after atypia diagnosis might not be beneficial. More evidence is needed about longer term risks.

Published
2024
Full Text
View/download PDF

31. Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement.

Author

Correa, Candace, Harris, Eleanor E., Leonardi, Maria Cristina, Smith, Benjamin D., Taghian, Alphonse G., Thompson, Alastair M., White, Julia, and Harris, Jay R.

Abstract

Purpose To update the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy (IORT) for partial breast irradiation in early-stage breast cancer, based on published evidence complemented by expert opinion. Methods and materials A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles; 44 articles were selected. The authors synthesized the published evidence and, through a series of conference calls and e-mails, reached consensus regarding the recommendations. Results The new recommendations include lowering the age in the “suitability group” from 60 to 50 years and in the “cautionary group” to 40 years for patients who meet all other elements of suitability (Table 1). Patients with low-risk ductal carcinoma in situ, as per Radiation Therapy Oncology Group 9804 criteria, were categorized in the “suitable” group. The task force agreed to maintain the current criteria based on margin status. Recommendations for the use of IORT for breast cancer patients include: counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation; the need for prospective monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up; and restriction of IORT to women with invasive cancer considered “suitable.” Conclusion These recommendations will provide updated clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

33. From the lab to the clinic: Lessons learned from a translational working group.

Author

Lynch, Thomas, Basila, Desiree, Schnitt, Stuart J., Marks, Jeffrey R, Strand, Siri H, Hyslop, Terry, Badve, Sunil S., Watson, Mark A, Le-Petross, Huong T., Grimm, Lars, West, Robert B., Weiss, Anna, Rapperport, Anna, King, Lorraine, Factor, Rachel E., Ryser, Marc D, Partridge, Ann H., Hwang, Eun-Sil Shelley, Thompson, Alastair Mark, and Collyar, Deborah E.

Published
2023
Full Text
View/download PDF

34. Comparing the prognostic and predictive utility of serum thymidine kinase 1 and CA 15-3 in patients with hormone receptor positive metastatic breast cancer starting first-line endocrine therapy in SWOG S0226.

Author

Cobain, Erin Frances, Barlow, William E., Paoletti, Costanza, Bergqvist, Mattias, Williams, Amy, Ritzen, Hanna, Mehta, Rita S., Gralow, Julie R., Hortobagyi, Gabriel N., Albain, Kathy S., Pusztai, Lajos, Sharma, Priyanka, Godwin, Andrew K., Thompson, Alastair Mark, Hayes, Daniel F., and Rae, James M.

Published
2023
Full Text
View/download PDF

35. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Author

Dennis, Martin, Mead, Gillian, Forbes, John, Graham, Catriona, Hackett, Maree, Hankey, Graeme J, House, Allan, Lewis, Stephanie, Lundström, Erik, Sandercock, Peter, Innes, Karen, Williams, Carol, Drever, Jonathan, Mcgrath, Aileen, Deary, Ann, Fraser, Ruth, Anderson, Rosemary, Walker, Pauli, Perry, David, Mcgill, Connor, Buchanan, David, Chun, Yvonne, Dinsmore, Lynn, Maschauer, Emma, Barugh, Amanda, Mikhail, Shadia, Blair, Gordon, Hoeritzauer, Ingrid, Scott, Maggie, Fraser, Greig, Lawrence, Katherine, Shaw, Alison, Williamson, Judith, Burgess, David, Macleod, Malcolm, Morales, Dan, Sullivan, Frank, Brady, Marian, French, Ray, Van Wijck, Frederike, Watkins, Caroline, Proudfoot, Fiona, Skwarski, Joanna, Mcgowan, Diane, Murphy, Rachael, Burgess, Seona, Rutherford, William, Mccormick, Katrina, Buchan, Ruaridh, Macraild, Allan, Paulton, Ruth, Fazal, Adnan, Taylor, Pat, Parakramawansha, Ruwan, Hunter, Neil, Perry, Jack, Bamford, John, Waugh, Dean, Veraque, Emelda, Bedford, Caroline, Kambafwile, Mary, Idrovo, Luis, Makawa, Linetty, Smalley, Paula, Randall, Marc, Thirugnana-Chandran, Tharani, Hassan, Ahamad, Vowden, Richard, Jackson, Joanne, Bhalla, Ajay, Rudd, Anthony, Tam, Chi Kai, Birns, Jonathan, Gibbs, Charlotte, Lee Carbon, Leonie, Cattermole, Elizabeth, Marks, Katherine, Cape, Angela, Hurley, Lisa, Kullane, Sagal, Smyth, Nigel, Eglinton, Charlotte, Wilson, Jennifer, Giallombardo, Elio, Frith, Angela, Reidy, Paul, Pitt, Matthew, Sykes, Lucy, Dellafera, Deborah, Croome, Victoria, Kerwood, Lauriane, Hancevic, Mirea, Narh, Christina, Merritt, Carley, Duffy, John, Cooke, Duncan, Willson, Juliet, Ali, Ali, Naqvi, Aaizza, Kamara, Christine, Bowler, Helen, Bell, Simon, Jackson, Tracy, Harkness, Kirsty, Stocks, Kathy, Duty, Suzanna, Doyle, Clare, Dunn, Geoffrey, Endean, Keith, Claydon, Fiona, Richards, Emma, Howe, Jo, Lindert, Ralf, Majid, Arshad, Dakin, Katy, Maatouk, Ahmad, Barron, Luke, Meegada, Madana, Rana, Pratap, Nair, Anand, Brighouse-Johnson, Christine, Greig, Jill, Kyu, Myint, Prasad, Sanjeev, Robinson, Matthew, Alam, Irfan, Mclean, Belinda, Greenhalgh, Lindsay, Ahmed, Zenab, Roffe, Christine, Brammer, Susan, Beardmore, Carole, Finney, Kay, Barry, Adrian, Hollinshead, Paul, Grocott, Jeanette, Maguire, Holly, Natarajan, Indira, Chembala, Jayan, Sanyal, Ranjan, Lijko, Sue, Abano, Nenette, Remegoso, Alda, Ferdinand, Phillip, Stevens, Stephanie, Varquez, Resti, Causley, Chelsea, Butler, Adrian, Whitmore, Philip, Stephen, Caroline, Carpio, Racquel, Hiden, Joanne, Muddegowda, Girish, Denic, Hayley, Sword, Jane, Curwen, Ross, James, Martin, Mudd, Paul, Hall, Fiona, Cageao, Julie, Keenan, Samantha, Roughan, Caroline, Kingwell, Hayley, Hemsley, Anthony, Lohan, Christoph, Davenport, Sue, Bowring, Angela, Chapter, Tamika, Hough, Max, Strain, David, Gupwell, Karin, Miller, Keniesha, Goff, Anita, Cusack, Ellie, Todd, Shirley, Partridge, Rebecca, Jennings, Georgiana, Thorpe, Kevin, Stephenson, Jacquelyn, Littlewood, Kelly, Barber, Mark, Brodie, Fiona, Marshall, Steven, Esson, Derek, Coburn, Irene, Mcinnes, Caroline, Ross, Fiona, Bowie, Emma, Barcroft, Heather, Withers, Victoria, Miller, Laura, Willcoxson, Paul, Donninson, Michelle, Evans, Richard, Daniel, Di, Coyle, John, Keeling, Michael, Wanklyn, Peter, Elliott, Mark, Wightman, John, Iveson, Elizabeth, Dyer, Natasha, Porteous, Anne-Marie, Haritakis, Monica, Ward, Mandy, Doughty, Lucy, Carr, Lisa, O Neill, Mark, Anazodo, Cosmas, Wood, Paul, Cottrell, Poppy, Donne, Cheryl, Rodriguez, Romina, Mir, Ruhail, Westmoreland, Jax, Bell, Judith, Emms, Christopher, Wright, Lorraine, Clark Brown, Pearl, Bamford, Elizabeth, Stanners, Andrew, Carpenter, Mike, Datta, Prabal, Davey, Richard, Needle, Ann, Eastwood, Marjorie Jane, Razik, Fathima Zeena, Ghouri, Imran, Bateman, Gavin, Archer, Judy, Balasubramanian, Venkatesh, Bowers, Richard, Ball, Julie, Benton, Louise, Jackson, Linda, Ellam, Julie, Norton, Kate, Guyler, Paul, Dowling, Terry, Tysoe, Sharon, Harman, Paula, Kundu, Ashish, Omodunbi, Ololade, Loganathan, Thayalini, Chandler, Stuart, Noor, Shanas, Siddiqui, Anwer, Siddiqui, Amber, Kunhunny, Swapna, Sinha, Devesh, Sheppard, Martin, Rashmi, Sindhu, France, Elena, Orath Prabakaran, Rajalakshmi, Wilson, Laura, Ropun, Amiirah, Kelavkar, Shyam, Ng, Kheng Xiong, Kamuriwo, Lucy, Shah, Sweni, Mangion, David, Constantin, Camen, De Michele Hock, Luigi, Hardwick, Anne, Borley, Jayne, Markova, Skarlet, Netherton, Kimberley, Lawrence, Tara, Fletcher, Jo, Spencer, Rebecca, Palmer, Helen, Cullen, Claire, Hamill, Dolores, Durairaj, Ramesh, Mellor, Zoe, Fluskey, Tanya, Wood, Diane, Keeling, Alison, Hankin, Victoria, Peters, Jennifer, Shackcloth, Daniela, Hlaing, Thant, Tangney, Rebecca, Ewing, Jordan, Harrison, Melanie, Stevenson, Sarah, Sutton, Victoria, Soliman, Mohamed, Hindle, Julia, Watson, Elizabeth, Hewitt, Claire, Borley, Jayne, Butler, Susie, Wahishi, Ibrahim, Arif, Sarwat, Fields, Amy, Sharma, Jagdish, Brown, Rose, Taylor, Caroline, Bell, Sarah, Leach, Simon, Patterson, Chris, Khan, Sophia, Wilson, Helen, Price, Joanne, Ramadan, Hawraman, Maguire, Stuart, Bellfield, Ruth, Hooley, Michaela, Hamid, Umair, Gaba, Waqar, Ghulam, Robina, Masters, Leslie, Quinn, Outi, Sekaran, Lakshmanan, Tate, Margaret, Mohammed, Niaz, Bharaj, Kiranjit, Justin, Frances, Pattni, Rajan, Alwis, Lanka, Sethuraman, Sakthivel, Robinson, Rianne, Eldridge, Lianne, Mintias, Susan, Chauhan, Meena, Tam, Chi-Kai, Palmones, Jeremias, Holmes, Clare, Guthrie, Lucy Belle, Osborn, Mairead, Ball, Lindsay, Caine, Sarah, Steele, Amy, Murphy, Peter, Devitt, Nikki, Leonard, Jayne, Patel, Ronak, Penwarden, Ian, Dodd, Emily, Holloway, Amy, Baker, Pauline, Clarke, Samantha, Williams, Sandra, Dow, Lindsey, Wynn-Williams, Roland, Kennedy, James, Teal, Rachel, Schulz, Ursula, Ford, Gary, Mathieson, Philip, Reckless, Ian, Deveciana, Ana, Mccann, Paige, Cluckie, Gillian, Howell, Geoffrey, Ayer, Jonathan, Moynihan, Barry, Ghatala, Rita, Clarke, Brian, Cloud, Geoffrey, Patel, Bhavini, Khan, Usman, Al-Samarrai, Nia, Trippier, Sarah, Chopra, Neha, Adedoyin, Temi, Watson, Fran, Jones, Val, Zhang, Liqun, Choy, Lillian, Williams, Rebecca, Clarke, Natasha, Blight, Adrian, Kennedy, Kate, Dainty, Alice, Selvarajah, Johann, Kalladka, Dheeraj, Cheripelli, Bharath, Smith, Wilma, Moreton, Fiona, Welch, Angela, Huang, Xuya, Douglas, Elizabeth, Lush, Audrey, Day, Nicola, El Tawil, Salwa, Montgomery, Karen, Hamilton, Helen, Ritchie, Doreen, Ramachandra, Sankaranarayanan, Mcleish, Kirsty, Thavanesan, Kamy, Loganathan, Sathyabama, Roberts, Josh, Cox, Chantel, Orr, Sarah, Hogan, Alison, Tiwari, Divya, Hann, Gail, Longland, Barbara, David, Owen, Bell, Jo, Ovington, Catherine, Rogers, Emily, Bower, Rachel, Keltos, Marketa, Cohen, David, Devine, Joseph, Alwis, Lankantha, Southworth, Lucy, Burgess, Laura, Lang, Matilda, Badiani, Bhavna, Guo, Fenglin, Oshodi, Anne, Owoyele, Emmanuelle, Epie, Norah, David, Anette, Mpelembue, Mushiya, Bathula, Rajaram, Abdul-Saheb, Mudhar, Chamberlain, Angela, Sudkeo, Varthi, Rashed, Khalid, Wood, Diane, Williams-Yesson, Barbara, Board, Joanne, De Bruijn, Sarah, Buckley, Clare, Board, Sarah, Allison, Joanna, Keeling, Elizabeth, Duckett, Tracey, Donaldson, Dave, Vickers, Carinna, Barron, Claire, Balian, Linda, Wilson, Jodhi, Edwards, Adam, England, Timothy, Hedstrom, Amanda, Bedford, Elizabeth, Harper, Margaret, Melikyan, Elina, Abbott, Wendy, Subramanian, Kashmira, Goldsworthy, Marie, Srinivasan, Meena, Yeomans, Angela, Donaldson, Denise, Hurford, Frances, Chapman, Riquella, Shahzad, Sana, David, Owen, Motherwell, Nicki, Tonks, Louise, Young, Rachel, Ghani, Usman, Mukherjee, Indranil, Dutta, Dipankar, Obaid, Mudhar, Brown, Pauline, Davis, Fiona, Ward, Deborah, Turfrey, Jennifer, Cartwright, Bethan, Topia, Bilal, Spurway, Judith, Collins, Kayleigh, Bakawala, Rehana, Hughes, Chloe, Oconnell, Susan, Hill, Linda, Chatterjee, Kausik, Webster, Tim, Haider, Syed, Rushworth, Pamela, Macleod, Fiona, Nallasivan, Arumugam, Perkins, Charlotte, Burns, Edel, Leason, Sandra, Carter, Tom, Seagrave, Samantha, Sami, Eman, Armstrong, Lisa, Naqvi, Syed Naseem, Hassan, Muhammad, Parkinson, Sharron, Mawer, Samantha, Darnbrook, Gillian, Booth, Carl, Hairsine, Brigid, Smith, Matthew, Williamson, Sue, Farquhar, Fiona, Esisi, Bernard, Cassidy, Tim, Mankin, Gavin, Mcclelland, Beverley, Bokhari, Maria, Sproates, David, Epstein, Elliot, Hurdowar, Steve, Blackburn, Ruth, Sukhdeep, Nazran, Razak, Saika, Osman, Khalid, Hashmi, Amina, Upton, Natasha, Harrington, Frances, Courtauld, Gillian, Schofield, Christine, Lucas, Linda, Adie, Katja, Bond, Kirsty, Mate, Abhijit, Skewes, Jo, James, Ali, Brodie, Carolyn, Johnson, Matthew, Allsop, Linda, Driver, Emma, Harris, Karina, Drake, Mark, Ellis, Sam, Maund, Bev, Thomas, Emma, Moore, Kimberley, Burn, Matthew, Hamilton, Adam, Mahalingam, Shageetha, Misra, Amulya, Reid, Farrah, Benford, Adrienne, Hilton, Derek, Hazell, Lorraine, Ofori, Keziah, Thomas, Anne Louise, Mathew, Moncy, Dayal, Sonia, Burn, Iona, Fotherby, Kenneth, Jennings-Preece, Karla, Willberry, Angela, Morgan, Debbie, Butler, Donna, Sahota, Gurminder, Kauldhar, Kelly, Ahmad, Nasar, Stevens, Angela, Das, Saugata, Bruce, David, Pai, Yogish, Nyo, Khin, Stephenson, Lynsey, Nendick, Richard, Rogers, Gill, Dhakal, Mahesh, Dima, Sofia, Brown, Ellen, Clayton, Susan, Gamble, Penny, Naeem, Muhammad, Hayman, Rachel, Burnip, Rachel, Earnshaw, Philip, Hargroves, David, Ransom, Barbara, Rudenko, Hannah, Balogun, Ibrahim, Griffiths, Kirsty, Mears, Kim, Webb, Tom, Cowie, Linda, Hammond, Tessa, Thomson, Audrey, Ceccarelli, Daniela, Chattha, Navraj, Beranova, Eva, Verrion, Anna, Gillian, Andrew, Schumacher, Natasha, Bahk, Anna, Walker, Susannah, Cvoro, Vera, Mccormick, Katrina, Chapman, Nicola, Pound, Susan, Cain, Rebecca, Mcauley, Sean, Couser, Mandy, Simpson, Maria, Tachtatzis, Athan, Ullah, Khalil, Sims, Don, Jones, Rachael, Smith, Jonathan, Tongue, Rebecca, Willmot, Mark, Sutton, Claire, Littleton, Edward, Khaira, Jattinder, Maiden, Susan, Cunningham, James, Green, Carole, Chin, Yin-May, Bates, Michelle, Ahlquist, Katherine, Kane, Ingrid, Breeds, Joanna, Sargent, Tenesa, Latter, Laura, Pitt Ford, Alexandra, Gainsborough, Nicola, Levett, Tom, Thompson, Philip, Barbon, Emma, Dunne, Angela, Hervey, Simon, Ragab, Suzanne, Sandell, Tracy, Dickson, Christine, Dube, Judith, Power, Sharon, Evans, Nick, Wadams, Beverley, Elitova, Savina, Aubrey, Beth, Garcia, Tatiana, Mcilmoyle, James, Jeffs, Carol, Dickinson, Christina, Ahmed, Anis, Kumar, Sanjeev, Frudd, Julie, Armer, Charlotte, Potter, Andrew, Donaldson, Stacey, Howard, Joanne, Jones, Kirsty, Dhar, Saikat, Collas, David, Sundayi, Saul, Denham, Lynn, Oza, Deepali, Walker, Elaine, Cunningham, James, Bhandari, Mohit, Ispoglou, Sissy, Evans, Rachel, Sharobeem, Kamel, Walton, Elaine, Shanu, Steven, Hayes, Anne, Howard-Brown, Jennifer, Billingham, Steven, Weir, Nic, Pressly, Vanessa, Wood, Emma, Sykes, Lucy, Howard, Gabriella, Burton, Holly, Crawford, Pam, Egerton, Shuna, Evans, Sue, Hakkak, Jasmine, Andrews, Janet, Lampard, Rebecca, Allen, Christopher, Walters, Ashleigh, Said, Rasha, Marigold, James Richard, Tsang, Sau-Mon, Creeden, Robyn, Cox, Chloe, Smith, Simon, Gartrell, Imogen, Smith, Fiona, Jenkins, Colin, Pryor, Joanna, Hedges, Andrew, Price, Fiona, Moseley, Linda, Mercer, Lily, Hughes, Claire, Mcgowan, Diane, Azim, Abul, White, Julie, Krasinska-Chavez, Milena, Chaplin, Shaun, Curtis, James, Singh, Deepwant, Imam, Javed, Nicolson, Anne, Alam, Sajid, Whitworth, Simon, Wood, Lisa, Warburton, Elizabeth, Kelly, Siobhan, Mcgee, Joanne, Markus, Hugh, Chandrasena, Denish, Hayden, Derek, Sesay, Juliana, Hayhoe, Helen, Bolton, Mark, Macdonald, Jane, Mitchell, Jenny, Farron, Charlotte, Amis, Elaine, Day, Diana, Culbert, Ainsley, Espanol, Ailene, Hannon, Niamh, Handley, Dominic, Finlay, Sarah, Crisp, Sarah, Whitehead, Lynne, Francis, Jobbin, Oconnell, Janice, Osborne, Emily, Beard, Rod, Krishnamurthy, Ramesh, Mokoena, Langanani, Sattar, Naweed, Myint, Min, Edwards, Michelle, Smith, Andrew, Corrigan, Paul, Byrne, Anthony, Blackburn, Joanne, Mcghee, Caroline, Smart, Amanda, Macleod, Malcolm, Donaldson, Fiona, Copeland, Claire, Wilson, Jill, Scott, Rhona, Fitzsimmons, Paul, Lopez, Paula, Wilkinson, Mark, Manoj, Aravindakshan, Cox, Penelope, Trainor, Leona, Fletcher, Glyn, Denny, Lisa, Kavanagh, Karen, Allsop, Hannah, Emsley, Hedley, Sultan, Sulaiman, Mcloughlin, Alison, Walmsley, Benjamin, Hough, Louise, Ahmed, Shakeel, Doyle, Donna, Gregary, Bindu, Raj, Sonia, Nagaratnam, Kirubananthan, Mannava, Neelima, Haque, Nyla, Shields, Norma, Preston, Kate, Mason, Geraldine, Short, Kirsty, Lumsdale, Gemma, Uitenbosch, Giulia, Sukys, Ugnius, Valentine, Stacey, Jarrett, David, Dodsworth, Kerry, Wands, Mary, Khan, Nisa, Tandy, Jane, Watkinson, Catrin, Golding, Wendy, Butler, Rebecca, Williams, Max, Davies, Yasmin, Yip, Keith, James, Claire, Suttling, Anne, Maney, Aditya, Gamble, Giles Edward, Hague, Adam, Charles, Bethan, Blane, Sujata, Duran, Beatriz, Lambert, Caroline, Stagg, Katherine, Whiting, Robert, Homan, Jane E, Brown, Sarah, Hussain, Malik, Harvey, Miriam, Graham, Libby, Foote, Leanne, Lane, Catherine, Kemp, Liz (Joan), Rowe, Joy, Durman, Helen, Foot, Jayne, Brotherton, Lucy, Hunt, Nicholas, Pawley, Corinne, Whitcher, Alison, Sutton, Patrick, Mcdonald, Susan, Pak, Denys, Wiltshire, Alison, Jagger, Jennifer, Metcalf, Anthony K, Healey, Gail Louise, Balami, Joyce, Self, Clare Marie, Crofts, Melissa, Chakrabarti, Annie, Hmu, Chit, Ravenhill, Garth, Grimmer, Charmaine, Soe, Thandar, Keshet-Price, Jocelyn, Langley, Margaret, Potter, Ian, Tam, Pui-Lin, Macleod, Mary Joan, Cooper, Patricia, Christie, Michael, Irvine, Janice, Annison, Faye, Christie, David, Meneses, Celia, Johnson, Amber, Joyson, Anu, Nelson, Sandra, Taylor, Vicky, Reid, John, Clarke, Rebecca, Furnace, Jacqueline, Gow, Heather, Abousleiman, Youssif, Beadling, Tania, Collins, Sally, Jones, Stuart, Purcell, Jessica, Bloom, Samantha, Goshawk, Shelly, Landicho, Marcial, Sangaralingham, Sivatharshini, Begum, Yasmin, Mutton, Sherree, Munuswamy Vaiyapuri, Elangovan, Allen, Jane, Lowe, Jemma, Hughes, Martin, Wiggam, Ivan, Cuddy, Sarah, Tauro, Suzanne, Wells, Brian, Mohd Nor, Azlisham, Eglinton, Charlotte, Persad, Nicola, Kalita, Maggie, Weatherby, Stuart, Brown, Claire, Pace, Adrian, Lashley, Daniel, Marner, Mike, Weinling, Marie, Wilmshurst, Natasha, Waugh, Darren, Mucha, Anna, Shah, Alex, Baker, John, Westcott, Jacqueline, Cowan, Richard, Vasileiadis, Evangelos, Mumani, Samira, Parry, Anthea, Mason, Cathy, Holden, Melinda, Petrides, Katerina, Nishiyama, Tomoko, Mehta, Hina, Krishnan, Manju, Lynne, Dacey, Thomas, Lisa, Lynda, Connor, Hughes, Catherine, Clements, Clare, Williams, Rhys, Anjum, Tal, Sharon, Storton, Tucker, Susan, Jones, Paul, Colwill, Deanne, Thompson Jones, Helen, Chadha, Dinesh, Fairweather, Mark, Walstow, Deborah, Fong, Rosanna, Johnston, Stuart, Almadenboyle, Christine, Ross, Sarah, Carson, Shona, Nair, Priya, Tenbruck, Emily, Stirling, Mairi, Pusalkar, Aparna, Beadle, Hannah, Chan, Kelly, Dangri, Puneet, Asokanathan, Asaipillai, Rana, Anita, Gohil, Sunita, Massyn, Mark, Aruldoss, Prabhu, Cook, Angela, Crabtree, Karen, Dabbagh, Sura, Black, Toby, Clarke, Caroline, Mead, Denise, Fennelly, Ruth, Anthony, Alpha, Nardone, Linda, Dimartino, Victoria, Tribbeck, Michele, Broughton, David, Tryambake, Dinesh, Dixon, Lynn, Skotnicka, Agnieszka, Thompson, Jane, Whitehouse, Sarah, Sigsworth, Andrew, Wong, Jason, Annamalai, Arunkumar, Pagan, Julie, Affley, Brendan, Sunderland, Caroline, Goldenberg, Lynda, Khan, Atif, Wilkinson, Peter, Nari, Raad, Abbott, Lucy, Young, Emma, Shakhon, Amritpal, Lock, Sally, Stewart, Jack, Pereira, Rita, Dsouza, Margaret, Dunn, Sally, Mckenna, Anne-Marie, Cron, Nina, Kidd, Michelle, Hull, Grace, Bunworth, Kerry, Drummond, Graham, Mahawish, Karim, Hayes, Nicola, Connell, Lynne, Simpson, Jennifer, Penney, Helen, Punekar, Shuja, Nevinson, Joanne, Wareing, William, Ward, Jacqueline, Greenwood, Richard, Austin, Duncan, Banaras, Azra, Hogan, Carolin, Corbett, Thomas, Oji, Nnebuife, Elliott, Emma, Brezitski, Maria, Passeron, Nathalie, Howaniec, Laura, Watchurst, Caroline, Patel, Krishna, Erande, Renuka, Shah, Rahi, Sengupta, Nabarun, Metiu, Maria, Gonzalez, Celia, Funnell, Sarah, Margalef, Jordi, Peters, Gillian, Chadbourn, Indra, Sivakumar, Ramachandran, Saksena, Rajesh, Ketley-O'donel, Jane, Needle, Richard, Chinery, Elaine, Wright, Alison, Cook, Sue, Ngeh, Joseph, Proeschel, Harald, Cook, Paige, Ashcroft, Pauline, Sharpe, Simon, Jones, Stephanie, Jenkinson, Damian, Kelly, Deborah, Bray, Holly, Gunathilagan, Gunaratnam, Griffiths, Kirsty, Mears, Kim, Gillian, Andrew, Jones, Sally, Tilbey, Sorrell, Abubakar, Saidu, Beranova, Eva, Vassallo, Joseph, Leonard, Dee, Orrell, Lucy, Hasan, Aziz, Khan, Asif, Qamar, Sulmaaz, Graham, Susan, Hewitt, Emma, Awolesi, Jennifer, Haque, Muhammad, Kent, Alissa, Bradshaw, Elizabeth, Cooper, Martin, Wynter, Inez, Rajapakse, Anoja, Janbieh, Joumana, Nasar, Abu M, Wade, Lynne, Otter, Linda, Haigh, Steve, Burgoyne, Jamie-Rae, Boulton, Rebecca, Boulton, Andrew, Rayessa, Rayessa, Clarkson, Emma, Rhian, Horne, Fleming, Amy, Mitchelson, Kim, Lowthorpe, Vicki, Abdul-Hamid, Ahmed, Jones, Phil, Duggan, Claire, Hynes, Abigail, Nurse, Emma, Raza, Syed Abid, Jones, Sarah, Pallikona, Udaya, Edwards, Bleddyn, Morgan, Geraint, Dennett, Kirsty, Tench, Helen, Loosley, Ronda, Trugeon-Smith, Toby, Jones, Rhian, Williams, Richard, Robson, Donna, Mavinamane, Sunanda, Meenakshisundaram, Sanjeevi, Ranga, Lalitha, Dealing, Sharon, Hill, Andrew, Hargreaves, Margaret, Smith, Tom, Bate, Julie, Harrison, Linda, Kirthivasan, Ramanathan, Cannon, Emma, Topliffe, Joanne, Keskeys, Rebecca, Williams, Sarah, Mcneela, Fiona, Cairns, Frances, James, Thomas, Lyle, Amanda, Shah, Sheela, Zachariah, George, Fergey, Lauren, Smolen, Susan, Cooper, Lucy, Bohannan, Elizabeth, Omer, Siddiq, Amlani, Sageet, Hunter, Nadia, Hawkes-Blackburn, Melissa, Gulli, Giosue, Peacocke, Alice, Amero, Justine, Burova, Maria, Speirs, Ottilia, Levy, Steph, Francis, Lynda, Holland, Susan, Brotheridge, Sean, Lyon, Helen, Hare, Christine, Jackson, Samantha, Stephenson, Lorraine, Al Hussayni, Samer, Featherstone, James, Bwalya, Agness, Singh, Arun, Goorah, M N, Walford, Jamie, Bell, Angela, Kelly, Christine, Rusk, Darren, Sutton, Deborah, Patel, Farzana, Duberley, Stephen, Hayes, Kathryn, Hunt, Lorraine, El Nour, Ahmed, Cottrell, Poppy, Westmoreland, Jax, Honour, Sacha, Box, Chloe, Wood, Paul, Haritakis, Monica, Dyer, Simon, Brown, Lynne, Elliott, Kerry, Temlett, Emma, Paterson, John, Furness, Rosie, Young, Shelli, Orugun, Enoch, Brewer, Chris, Thornthwaite, Sarah, Crowther, Hannah, Glover, Rachel, Sein, Moe, Haque, Kashif, Gibson, Elspeth, Wong, Sam, Rotchell, Karen, Burton, Karen, Brookes, Lisa, Bailey, Linda, Leonard, Dee, Lindley, Chris, Murray, Abbi, Waltho, Karen, Holland, Maureen, Kumar, Pradeep, Harlekar, Purnima, Booth, Laura, Culmsee, Charlotte, Drew, Jade, Khan, Mohammad, Mackenzie, Nicola, Thomas, Carmel, Ritchie, Jane, Barker, James, Haley, Michael, Cotterill, Donna, Lane, Lynne, Little, Christine, Simmons, Dawn, Saunders, Glenn, Dymond, Harvey, Kidd, Sarah, Warinton, Rachel, Neves-Silva, Yara, Nevajda, Branimir, Villaruel, Michael, Umasankar, Udayaraj, Patel, Seema, Man, Anna, Christmas, Natasha, Rangasamy, Ravi, Ladner, Richard, Butt, Georgina, Alvares, Wilson, Gadi, Narasimha, Power, Michael, Wroath, Belinda, Dynan, Kevin, Wilson, David, Crothers, Sarah, Leonard, Catherine, Hagan, Samantha, Douris, Geraldine, Vahidassr, Djamil, Thompson, Alastair, Gallen, Brian, Mckenna, Shirley, Edwards, Collette, Mcgoldrick, Clare, Bhattad, Murdi, Kawafi, Khalil, Morse, Deborah, Jacob, Patricia, Turner, Lisa, Saravanan, Narayanamoorti, Johnson, Linda, Humphrey, Sadie, Namushi, Robert, Patel, Ramesh, Mclaughlin, Jemma, Omahony, Paul, Osikominu, Esther, Orefo, Chukwuka, Mcdonald, Chisha, Jones, Val, Makanju, Esther, Khan, Tabindah, Appiatse, Grace, Stone, Helena, Augustin, Martia, Wardale, Alicia, Salehin, Maqsud, Bailey, Duncan, Garcia-Alen, Luciano, Kalathil, Latheef, Tinsley, Sarah, Jones, Taya, Amor, Kelly, Ritchings, Andrew, Margerum, Emma, Horton, Jane, Miller, Richard, Gautam, Nireekshana, Meir, Julie, Jones, Amaryl, Putteril, Janet, Lepore, Mirella, Makanju, Esther, Gallifent, Rachel, Arundell, Laura-Louise, Mcredmond, Catherine, Goulding, Alicia, Nadarajan, Vivek, Laurence, Julia, Fung Lo, Su, Melander, Sabina, Nicholas, Paul, Woodford, Elizabeth, Mckenzie, Gillian, Le, Vietland, Crause, Jacolene, Luder, Robert, Bhargava, Maneesh, Shah, Rahi, Bhome, Girish, Johnson, Venetia V, Chesser, Dara, Bridger, Hayley, Murali, Elodie, Scott, Jon, Morrison, Susan, Burns, Amy, Graham, Julie, Duffy, Madeline, Ali, Khalid, Sargent, Tenesa, Pitcher, Emma, Gaylard, Jane, Newman, Julie, Punnoose, Sunil, Besley, Sarah, Purohit, Kirtan, Rees, Amy, Davy, Mark, Chohan, Osman, Khan, Muhammad Fozan, Walker, Rachel, Murray, Vicky, Bent, Charlotte, Oakley, Susan, Blight, Adrian, Peixoto, Cassilda, Jones, Suzanne, Livingstone, Gaybrielle, Butler, Fiona, Bradfield, Sally, Gordon, Laura, Schmit, Jenneke, Wijewardane, Anika, Edmunds, Tineke, Wills, Rebecca, Medcalf, Catherine, Argandona, Lucia, Cuenoud, Larissa, Hassan, Hanna, Erumere, Esther, Ocallaghan, Aidan, Gompertz, Patrick, Redjep, Ozlem, Auld, Grace, Howaniec, Laura, Song, Anna, Tarkas, Tillana, Kabash, Hashim, and Hungwe, Rumbi

Abstract

Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.

Published
2019
Full Text
View/download PDF

36. The circular RNome of primary breast cancer

Author

Smid, Marcel, Wilting, Saskia M., Uhr, Katharina, Rodríguez-González, F. Germán, de Weerd, Vanja, Prager-Van der Smissen, Wendy J.C., van der Vlugt-Daane, Michelle, van Galen, Anne, Nik-Zainal, Serena, Butler, Adam, Martin, Sancha, Davies, Helen R., Staaf, Johan, van de Vijver, Marc J., Richardson, Andrea L., MacGrogan, Gae¨ten, Salgado, Roberto, van den Eynden, Gert G.G.M., Purdie, Colin A., Thompson, Alastair M., Caldas, Carlos, Span, Paul N., Sweep, Fred C.G.J., Simpson, Peter T., Lakhani, Sunil R., Van Laere, Steven, Desmedt, Christine, Paradiso, Angelo, Eyfjord, Jorunn, Broeks, Annegien, Vincent-Salomon, Anne, Futreal, Andrew P., Knappskog, Stian, King, Tari, Viari, Alain, Børresen-Dale, Anne-Lise, Stunnenberg, Hendrik G., Stratton, Mike, Foekens, John A., Sieuwerts, Anieta M., and Martens, John W.M.

Abstract

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R< 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and REREin an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.

Published
2019
Full Text
View/download PDF

37. The radiological features, diagnosis and management of screen-detected lobular neoplasia of the breast: Findings from the Sloane Project.

Author

Maxwell, Anthony J., Clements, Karen, Dodwell, David J., Evans, Andrew J., Francis, Adele, Hussain, Monuwar, Morris, Julie, Pinder, Sarah E., Sawyer, Elinor J., Thomas, Jeremy, and Thompson, Alastair

Subjects
BREAST cancer diagnosis, CANCER radiotherapy, BREAST cancer treatment, CALCIFICATIONS of the breast, MASTECTOMY, AXILLA, SURGERY
Abstract

Objectives To investigate the radiological features, diagnosis and management of screen-detected lobular neoplasia (LN) of the breast. Materials and methods 392 women with pure LN alone were identified within the prospective UK cohort study of screen-detected non-invasive breast neoplasia (the Sloane Project). Demography, radiological features and diagnostic and therapeutic procedures were analysed. Results Non-pleomorphic LN (369/392) was most frequently diagnosed among women aged 50–54 and in 53.5% was at the first screen. It occurred most commonly on the left (58.0%; p = 0.003), in the upper outer quadrant and confined to one site (single quadrant or retroareolar region). No bilateral cases were found. The predominant radiological feature was microcalcification (most commonly granular) which increased in frequency with increasing breast density. Casting microcalcification as a predominant feature had a significantly higher lesion size compared to granular and punctate patterns (p = 0.034). 326/369 (88.3%) women underwent surgery, including 17 who underwent >1 operation, six who had mastectomy and six who had axillary surgery. Two patients had radiotherapy and 15 had endocrine treatment. Pleomorphic lobular carcinoma in situ (23/392) presented as granular microcalcification in 12; four women had mastectomy and six had radiotherapy. Conclusion Screen-detected LN occurs in relatively young women and is predominantly non-pleomorphic and unilateral. It is typically associated with granular or punctate microcalcification in the left upper outer quadrant. Management, including surgical resection, is highly variable and requires evidence-based guideline development. [ABSTRACT FROM AUTHOR]

Published
2016
Full Text
View/download PDF

38. Are There Alternative Strategies for the Local Management of Ductal Carcinoma in Situ?

Author

Rosso, Kelly J., Weiss, Anna, and Thompson, Alastair M.

Abstract

The management of ductal carcinoma in situ (DCIS) has traditionally followed the evidence base for invasive breast cancer using surgery, radiation therapy, and drug therapy to remove the DCIS from the breast and reduce the risk of recurrence for both DCIS and invasive breast cancer. Because of concerns regarding the overtreatment of DCIS, randomized controlled trials have been established to test the outcomes (invasive breast cancer outcomes and patient-reported outcome measures) of active surveillance compared with guideline-concordant care for low-risk (for progression) DCIS. These strategies are undergoing rigorous evaluation to evaluate alternatives to the current management of DCIS.

Published
2018
Full Text
View/download PDF

39. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial

Author

Coles, Charlotte E, Griffin, Clare L, Kirby, Anna M, Titley, Jenny, Agrawal, Rajiv K, Alhasso, Abdulla, Bhattacharya, Indrani S, Brunt, Adrian M, Ciurlionis, Laura, Chan, Charlie, Donovan, Ellen M, Emson, Marie A, Harnett, Adrian N, Haviland, Joanne S, Hopwood, Penelope, Jefford, Monica L, Kaggwa, Ronald, Sawyer, Elinor J, Syndikus, Isabel, Tsang, Yat M, Wheatley, Duncan A, Wilcox, Maggie, Yarnold, John R, Bliss, Judith M, Al Sarakbi, Wail, Barber, Sarah, Barnett, Gillian, Bliss, Peter, Dewar, John, Eaton, David, Ebbs, Stephen, Ellis, Ian, Evans, Philip, Harris, Emma, James, Hayley, Kirwan, Cliona, Kirk, Julie, Mayles, Helen, McIntyre, Anne, Mills, Judith, Poynter, Andrew, Provenzano, Elena, Rawlings, Christine, Sculpher, Mark, Sumo, Georges, Sydenham, Mark, Tutt, Andrew, Twyman, Nicola, Venables, Karen, Winship, Anna, Winstanley, John, Wishart, Gordon, and Thompson, Alastair

Abstract

Local cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy.

Published
2017
Full Text
View/download PDF

40. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures

Author

Davies, Helen, Glodzik, Dominik, Morganella, Sandro, Yates, Lucy R, Staaf, Johan, Zou, Xueqing, Ramakrishna, Manasa, Martin, Sancha, Boyault, Sandrine, Sieuwerts, Anieta M, Simpson, Peter T, King, Tari A, Raine, Keiran, Eyfjord, Jorunn E, Kong, Gu, Borg, Åke, Birney, Ewan, Stunnenberg, Hendrik G, van de Vijver, Marc J, Børresen-Dale, Anne-Lise, Martens, John W M, Span, Paul N, Lakhani, Sunil R, Vincent-Salomon, Anne, Sotiriou, Christos, Tutt, Andrew, Thompson, Alastair M, Van Laere, Steven, Richardson, Andrea L, Viari, Alain, Campbell, Peter J, Stratton, Michael R, and Nik-Zainal, Serena

Abstract

Approximately 1–5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1–5%) who could have selective therapeutic sensitivity to PARP inhibition.

Published
2017
Full Text
View/download PDF

41. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo

Author

Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B., Rahbari, Raheleh, Wedge, David C., Davies, Helen R., Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O’Meara, Sarah, Giri, Dilip D., Sauer, Torril, Pinder, Sarah E., Purdie, Colin A., Borg, Åke, Stunnenberg, Henk, van de Vijver, Marc, Tan, Benita K. T., Caldas, Carlos, Tutt, Andrew, Ueno, Naoto T., van ’t Veer, Laura J., Martens, John W. M., Sotiriou, Christos, Knappskog, Stian, Span, Paul N., Lakhani, Sunil R., Eyfjörd, Jórunn Erla, Børresen-Dale, Anne-Lise, Richardson, Andrea, Thompson, Alastair M., Viari, Alain, Hurles, Matthew E., Nik-Zainal, Serena, Campbell, Peter J., and Stratton, Michael R.

Abstract

Somatic cells acquire mutations throughout the course of an individual’s life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.

Published
2017
Full Text
View/download PDF

42. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author

Glodzik, Dominik, Morganella, Sandro, Davies, Helen, Simpson, Peter T, Li, Yilong, Zou, Xueqing, Diez-Perez, Javier, Staaf, Johan, Alexandrov, Ludmil B, Smid, Marcel, Brinkman, Arie B, Rye, Inga Hansine, Russnes, Hege, Raine, Keiran, Purdie, Colin A, Lakhani, Sunil R, Thompson, Alastair M, Birney, Ewan, Stunnenberg, Hendrik G, van de Vijver, Marc J, Martens, John W M, Børresen-Dale, Anne-Lise, Richardson, Andrea L, Kong, Gu, Viari, Alain, Easton, Douglas, Evan, Gerard, Campbell, Peter J, Stratton, Michael R, and Nik-Zainal, Serena

Abstract

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.

Published
2017
Full Text
View/download PDF

43. The Informatics Challenges Facing Biobanks: A Perspective from a United Kingdom Biobanking Network.

Author

Quinlan, Philip R., Groves, Martin, Jordan, Lee B., Stobart, Hilary, Purdie, Colin A., and Thompson, Alastair M

Abstract

The challenges facing biobanks are changing from simple collections of materials to quality-assured fit-for-purpose clinically annotated samples. As a result, informatics awareness and capabilities of a biobank are now intrinsically related to quality. A biobank may be considered a data repository, in the form of raw data (the unprocessed samples), data surrounding the samples (processing and storage conditions), supplementary data (such as clinical annotations), and an increasing ethical requirement for biobanks to have a mechanism for researchers to return their data. The informatics capabilities of a biobank are no longer simply knowing sample locations; instead the capabilities will become a distinguishing factor in the ability of a biobank to provide appropriate samples. There is an increasing requirement for biobanking systems (whether in-house or commercially sourced) to ensure the informatics systems stay apace with the changes being experienced by the biobanking community. In turn, there is a requirement for the biobanks to have a clear informatics policy and directive that is embedded into the wider decision making process. As an example, the Breast Cancer Campaign Tissue Bank in the UK was a collaboration between four individual and diverse biobanks in the UK, and an informatics platform has been developed to address the challenges of running a distributed network. From developing such a system there are key observations about what can or cannot be achieved by informatics in isolation. This article will highlight some of the lessons learned during this development process. [ABSTRACT FROM AUTHOR]

Published
2015
Full Text
View/download PDF

44. New approaches for improving outcomes in breast cancer in Europe.

Author

Di Leo, Angelo, Curigliano, Giuseppe, Diéras, Véronique, Malorni, Luca, Sotiriou, Christos, Swanton, Charles, Thompson, Alastair, Tutt, Andrew, and Piccart, Martine

Subjects
BREAST cancer treatment, MEDICAL care, BIOMARKERS, HEALTH outcome assessment, DRUG development, MOLECULAR pathology
Abstract

Considerable progress has been made in breast cancer treatment in Europe over the past three decades, yet survival rates for metastatic disease remain poor, underlining the need for further advances. While the use of predictive biomarkers for response to systemic therapy could improve drug development efficiency, progress in identifying such markers has been slow. The currently inadequate classification of breast cancer subtypes is a further challenge. Improved understanding of the molecular pathology of the disease has led to the identification of new targets for drug treatment, and evolving classifications should reflect these developments. Further ongoing challenges include difficulties in finding optimal combinations and sequences of systemic therapies, circumventing multidrug resistance and intra-tumor heterogeneity, problems associated with fragmentation in clinical trials and translational research efforts. Adoption of some of the strategies identified in this article may lead to further improvements in outcomes for patients with the disease. [ABSTRACT FROM AUTHOR]

Published
2015
Full Text
View/download PDF

45. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Author

Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B., Martin, Sancha, Wedge, David C., Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B., Morganella, Sandro, Aure, Miriam R., Lingjærde, Ole Christian, Langerød, Anita, Ringnér, Markus, Ahn, Sung-Min, Boyault, Sandrine, Brock, Jane E., Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc, Dronov, Serge, Fatima, Aquila, Foekens, John A., Gerstung, Moritz, Hooijer, Gerrit K. J., Jang, Se Jin, Jones, David R., Kim, Hyung-Yong, King, Tari A., Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong-Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O’Meara, Sarah, Pauporté, Iris, Pivot, Xavier, Purdie, Colin A., Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-González, F. Germán, Romieu, Gilles, Sieuwerts, Anieta M., Simpson, Peter T., Shepherd, Rebecca, Stebbings, Lucy, Stefansson, Olafur A., Teague, Jon, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert G., Vermeulen, Peter, Vincent-Salomon, Anne, Yates, Lucy, Caldas, Carlos, Veer, Laura van’t, Tutt, Andrew, Knappskog, Stian, Tan, Benita Kiat Tee, Jonkers, Jos, Borg, Åke, Ueno, Naoto T., Sotiriou, Christos, Viari, Alain, Futreal, P. Andrew, Campbell, Peter J., Span, Paul N., Van Laere, Steven, Lakhani, Sunil R., Eyfjord, Jorunn E., Thompson, Alastair M., Birney, Ewan, Stunnenberg, Hendrik G., van de Vijver, Marc J., Martens, John W. M., Børresen-Dale, Anne-Lise, Richardson, Andrea L., Kong, Gu, Thomas, Gilles, and Stratton, Michael R.

Abstract

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Published
2016
Full Text
View/download PDF

47. Association of DCIS size and margin status with risk of developing breast cancer post-treatment: multinational, pooled cohort study

Author

Schmitz, Renée S J M, van den Belt-Dusebout, Alexandra W, Clements, Karen, Ren, Yi, Cresta, Chiara, Timbres, Jasmine, Liu, Yat-Hee, Byng, Danalyn, Lynch, Thomas, Menegaz, Brian A, Collyar, Deborah, Hyslop, Terry, Thomas, Samantha, Love, Jason K, Schaapveld, Michael, Bhattacharjee, Proteeti, Ryser, Marc D, Sawyer, Elinor, Hwang, E Shelley, Thompson, Alastair, Wesseling, Jelle, Lips, Esther H, and Schmidt, Marjanka K

Abstract

ObjectiveTo examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer.DesignMultinational, pooled cohort study.SettingFour large international cohorts.ParticipantsPatient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both.Main outcome measuresThe main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed dataResultsThe 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS <20 mm (hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCIS <20 mm. No such association was found between involved margins and higher stage of ipsilateral invasive breast cancer. Associations between larger DCIS and hormone receptor negative and human epidermal growth factor receptor 2 positive ipsilateral invasive breast cancer and involved margins and hormone receptor negative ipsilateral invasive breast cancer were found.ConclusionsThe association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS.

Published
2023
Full Text
View/download PDF

49. Acute and Short-term Toxic Effects of Conventionally Fractionated vs Hypofractionated Whole-Breast Irradiation: A Randomized Clinical Trial

Author

Shaitelman, Simona F., Schlembach, Pamela J., Arzu, Isidora, Ballo, Matthew, Bloom, Elizabeth S., Buchholz, Daniel, Chronowski, Gregory M., Dvorak, Tomas, Grade, Emily, Hoffman, Karen E., Kelly, Patrick, Ludwig, Michelle, Perkins, George H., Reed, Valerie, Shah, Shalin, Stauder, Michael C., Strom, Eric A., Tereffe, Welela, Woodward, Wendy A., Ensor, Joe, Baumann, Donald, Thompson, Alastair M., Amaya, Diana, Davis, Tanisha, Guerra, William, Hamblin, Lois, Hortobagyi, Gabriel, Hunt, Kelly K., Buchholz, Thomas A., and Smith, Benjamin D.

Abstract

IMPORTANCE: The most appropriate dose fractionation for whole-breast irradiation (WBI) remains uncertain. OBJECTIVE: To assess acute and 6-month toxic effects and quality of life (QOL) with conventionally fractionated WBI (CF-WBI) vs hypofractionated WBI (HF-WBI). DESIGN, SETTING, AND PARTICIPANTS: Unblinded randomized trial of CF-WBI (n = 149; 50.00 Gy/25 fractions + boost [10.00-14.00 Gy/5-7 fractions]) vs HF-WBI (n = 138; 42.56 Gy/16 fractions + boost [10.00-12.50 Gy/4-5 fractions]) following breast-conserving surgery administered in community-based and academic cancer centers to 287 women 40 years or older with stage 0 to II breast cancer for whom WBI without addition of a third field was recommended; 76% of study participants (n = 217) were overweight or obese. Patients were enrolled from February 2011 through February 2014 and observed for a minimum of 6 months. INTERVENTIONS: Administration of CF-WBI or HF-WBI. MAIN OUTCOMES AND MEASURES: Physician-reported acute and 6-month toxic effects using National Cancer Institute Common Toxicity Criteria, and patient-reported QOL using the Functional Assessment of Cancer Therapy for Patients with Breast Cancer (FACT-B). All analyses were intention to treat, with outcomes compared using the χ2 test, Cochran-Armitage test, and ordinal logistic regression. RESULTS: Of 287 participants, 149 were randomized to CF-WBI and 138 to HF-WBI. Treatment arms were well matched for baseline characteristics, including FACT-B total score (HF-WBI, 120.1 vs CF-WBI, 118.8; P = .46) and individual QOL items such as somewhat or more lack of energy (HF-WBI, 38% vs CF-WBI, 39%; P = .86) and somewhat or more trouble meeting family needs (HF-WBI, 10% vs CF-WBI, 14%; P = .54). Maximum physician-reported acute dermatitis (36% vs 69%; P &lt; .001), pruritus (54% vs 81%; P &lt; .001), breast pain (55% vs 74%; P = .001), hyperpigmentation (9% vs 20%; P = .002), and fatigue (9% vs 17%; P = .02) during irradiation were lower in patients randomized to HF-WBI. The rate of overall grade 2 or higher acute toxic effects was less with HF-WBI than with CF-WBI (47% vs 78%; P &lt; .001). Six months after irradiation, physicians reported less fatigue in patients randomized to HF-WBI (0% vs 6%; P = .01), and patients randomized to HF-WBI reported less lack of energy (23% vs 39%; P &lt; .001) and less trouble meeting family needs (3% vs 9%; P = .01). Multivariable regression confirmed the superiority of HF-WBI in terms of patient-reported lack of energy (odds ratio [OR], 0.39; 95% CI, 0.24-0.63) and trouble meeting family needs (OR, 0.34; 95% CI, 0.16-0.75). CONCLUSIONS AND RELEVANCE: Treatment with HF-WBI appears to yield lower rates of acute toxic effects than CF-WBI as well as less fatigue and less trouble meeting family needs 6 months after completing radiation therapy. These findings should be communicated to patients as part of shared decision making. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01266642

Published
2015
Full Text
View/download PDF

50. Tissue confirmation of disease recurrence in breast cancer patients: Pooled analysis of multi-centre, multi-disciplinary prospective studies.

Author

Amir, Eitan, Clemons, Mark, Purdie, Colin A., Miller, Naomi, Quinlan, Phil, Geddie, William, Coleman, Robert E., Freedman, Orit C., Jordan, Lee B., and Thompson, Alastair M.

Abstract

Abstract: Background: Treatment decisions in recurrent breast cancer are usually based on the estrogen (ER), progesterone (PgR) and HER2 receptor status of the primary tumour. Retrospective studies suggest that discordance between receptor expression of primary and recurrent breast cancer exists. Methods: A pooled analysis of individual patient data from two large prospective studies comprising biopsy of recurrent lesions obtained from consenting patients was undertaken. Tissue was analyzed for ER, PgR by immunohistochemistry and HER2 by FISH. Receptor status of recurrent disease was compared with that of the primary tumour. Recruiting clinicians assessed whether or not receptor discordance affected subsequent systemic treatment. Results: Two hundred and eighty-nine patients underwent biopsy. Recurrent biopsy specimens were obtained from locoregional recurrence in 48.1% and from distant metastases in 51.9%. Distant sites included skin/soft tissue (25.0%), bone/bone marrow (19.2%) and liver (15.8%). Benign disease or second primary cancer was observed in 7.6% of biopsies. Discordance in ER, PgR or HER2 between confirmed primary and recurrent breast cancer was 12.6%, 31.2% and 5.5%, respectively (all p <0.001). Biopsy results altered management in 14.2% of patients undergoing biopsy (95% confidence intervals 10.4–18.8%, p ⩽0.0001). The duration between primary and recurrent disease, the site of recurrence and the receptor profile of the primary tumour did not affect discordance rates. Conclusions: There is substantial discordance in receptor status between primary and recurrent breast cancer. The number needed to biopsy in order to alter treatment was 7.1. Patients with recurrent breast cancer should have tissue confirmation of receptor status of recurrent disease. [Copyright &y& Elsevier]

Published
2012
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results