scholarly journals The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Bernard Pereira ◽  
Suet-Feung Chin ◽  
Oscar M. Rueda ◽  
Hans-Kristian Moen Vollan ◽  
Elena Provenzano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Driver Mutations ◽  
Breast Cancers ◽  
Tumour Heterogeneity ◽  
Driver Genes ◽  
Genomic Landscape ◽  
Er Positive ◽  
Low Levels

Abstract The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13–14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13–14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

scholarly journals Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

2013 ◽  
Vol 31 (19) ◽  
pp. 2382-2387 ◽  
Author(s):  
Kevin S. Hughes ◽  
Lauren A. Schnaper ◽  
Jennifer R. Bellon ◽  
Constance T. Cirrincione ◽  
Donald A. Berry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Distant Metastasis ◽  
Early Stage ◽  
Breast Cancer Specific Survival ◽  
Cancer Specific Survival ◽  
Er Positive ◽  
Long Term Follow Up

Purpose To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer. Patients and Methods Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) –positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer–specific survival, time to distant metastasis, and overall survival (OS). Results Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer–specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. Conclusion With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.

Early breast cancer: evaluation of the prognostic role of the site of the primary tumor.

1998 ◽  
Vol 16 (4) ◽  
pp. 1363-1366 ◽  
Author(s):  
R Zucali ◽  
L Mariani ◽  
E Marubini ◽  
R Kenda ◽  
L Lozza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Distant Metastases ◽  
Breast Cancers ◽  
Prognostic Role ◽  
Long Term Follow Up ◽  
Internal Mammary

PURPOSE The prognostic role of the site of the primary breast cancer has not been clarified. This study aimed to gather more information about this issue from a large series of patients with long-term follow-up data. PATIENTS AND METHODS Data from 2,396 patients treated for early breast cancer with a conservative approach were reviewed (1973 to 1989). In 1,619 patients, the tumor had a lateral site, while in 777 cases, it was situated in the internal/central quadrants. The characteristics of the two groups were well balanced, apart from axillary nodal metastases, which were more frequent for lateral tumors (38.1% v 26.3%). RESULTS Analysis of distant metastases indicated that the regression coefficient associated with tumor site was significant and the hazards ratio estimate was 1.291, which indicates the risk of distant metastases was increased by approximately 30% for internal/central tumors. The analysis of overall survival yielded a significant coefficient and a hazards ratio of 1.192, which indicates an approximately 20% increase of mortality for internal/central tumors. CONCLUSION Early breast cancers situated in central/ internal quadrants have a worse prognosis compared with those in lateral quadrants, in terms of distant metastases and survival. Irradiation of the internal mammary chain for internal/medial tumors could be suggested, but, to date, the therapeutic strategy is still controversial.

scholarly journals Guidelines for Follow-Up of Women at High Risk for Inherited Breast Cancer: Consensus Statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer

1999 ◽  
Vol 15 (1-3) ◽  
pp. 207-211 ◽  
Author(s):  
P. Møller ◽  
G. Evans ◽  
N. Haites ◽  
H. Vasen ◽  
M. M. Reis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Early Diagnosis ◽  
Brca1 Mutation ◽  
Breast Cancers ◽  
Management Options ◽  
Detection Rates ◽  
Inherited Breast Cancer

Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention.

scholarly journals Utilisation of Prophylactic Mastectomy in 10 European Centres

1999 ◽  
Vol 15 (1-3) ◽  
pp. 148-151 ◽  
Author(s):  
D. G. R. Evans ◽  
E. Anderson ◽  
F. Lalloo ◽  
H. Vasen ◽  
M. Beckmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Psychological Assessment ◽  
Prophylactic Mastectomy ◽  
Prophylactic Surgery ◽  
Breast Cancers ◽  
Screening Service ◽  
Long Term Follow Up ◽  
Extended Group

Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25–80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae.

scholarly journals Risk factors for breast cancer development by tumor characteristics among women with benign breast disease

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jonine D. Figueroa ◽  
Gretchen L. Gierach ◽  
Máire A. Duggan ◽  
Shaoqi Fan ◽  
Ruth M. Pfeiffer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Fold Increase ◽  
Tumor Grade ◽  
Breast Disease ◽  
Breast Cancers ◽  
Increased Risk ◽  
Er Positive ◽  
Proliferative Bbd

Abstract Background Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. Methods Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models. Results Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14–14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21–3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size. Conclusion Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

scholarly journals Microcalcification-Associated Breast Cancer: Presentation, Successful First Excision, Long-Term Recurrence and Survival Rate

Breast Care ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. 380-385 ◽  
Author(s):  
Marga B. Rominger ◽  
Carolin Steinmetz ◽  
Ronny Westerman ◽  
Annette Ramaswamy ◽  
Ute-Susann Albert
Keyword(s):  
Breast Cancer ◽  
Survival Rate ◽  
Breast Imaging ◽  
Breast Conservation ◽  
Breast Conserving Therapy ◽  
Cancer Center ◽  
Breast Cancers ◽  
Term Survival

Introduction: In this study we evaluated mammographic, histological and immunohistochemical findings for microcalcification-associated breast cancer with regards to breast-conserving therapy, recurrence and survival rate. Patients and Methods: We retrospectively analyzed 99 consecutive, non-palpable and microcalcification-associated breast cancers (94 women) that were treated surgically between January 2002 and December 2003 at a national academic breast cancer center. Calcifications were classified according to the Breast Imaging Reporting and Data System (BI-RADS). Descriptors, surgical outcome and histological findings were assessed. Recurrences and survival rates were evaluated based on medical records, standardized patient questionnaires and/or contacting the physician. Results: 42 of the 99 lesions (42.4%) were invasive carcinomas, 57 (57.6%) were pure ductal carcinoma in situ (DCIS). 6 out of 99 (6.1%) lesions were triple negative, and 29 (29.3%) were HER2/neu positive. Successful first excision rate was 76/99 lesions (76.8%). Breast conservation was achieved in 73.7% (73/99). 10 women showed local recurrences without negatively impacting survival. The recurrences included round/punctate, amorphous, fine pleomorphic, and fine linear or fine-linear branching descriptors. The breast cancer-specific long-term survival rate was 91/94 (96.8%) for a mean follow-up of 81.4 months. The 3 patients who died due to breast carcinoma showed fine pleomorphic calcifications, and had nodal-positive invasive carcinoma at diagnosis. Conclusion: Microcalcification-associated breast cancers are frequently treated with breast-conserving therapy. Continuous clinical and mammographic follow-up is recommended for all descriptors.

scholarly journals BRCA1-Associated Breast Cancers Present Differently From BRCA2-Associated and Familial Cases: Long-Term Follow-Up of the Dutch MRISC Screening Study

2010 ◽  
Vol 28 (36) ◽  
pp. 5265-5273 ◽  
Author(s):  
Adriana J. Rijnsburger ◽  
Inge-Marie Obdeijn ◽  
Reinoutje Kaas ◽  
Madeleine M.A. Tilanus-Linthorst ◽  
Carla Boetes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca2 Mutation ◽  
Risk Groups ◽  
Long Term Results ◽  
Breast Cancers ◽  
Moderate Risk ◽  
Mutation Carriers ◽  
Screening Study

Purpose The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. Patients and Methods Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). Results Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P < .00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis ≤ 1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n = 43). Conclusion Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

scholarly journals Annual mammographic screening to reduce breast cancer mortality in women from age 40 years: long-term follow-up of the UK Age RCT

2020 ◽  
Vol 24 (55) ◽  
pp. 1-24
Author(s):  
Stephen Duffy ◽  
Daniel Vulkan ◽  
Howard Cuckle ◽  
Dharmishta Parmar ◽  
Shama Sheikh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Confidence Interval ◽  
Relative Rate ◽  
Intervention Group ◽  
Mammographic Screening ◽  
Control Group ◽  
Breast Cancers ◽  
National Programme

Background There remains disagreement on the long-term effect of mammographic screening in women aged 40–49 years. Objectives The long-term follow-up of a randomised controlled trial that offered annual mammography to women aged 40–49 years. The estimation of the effect of these mammograms on breast cancer and other-cause mortality, and the effect on incidence, with implications for overdiagnosis. Design An individually randomised controlled trial comparing offering annual mammography with offering usual care in those aged 40–48 years, and thus evaluating the effect of annual screening entirely taking place before the age of 50 years. There was follow-up for an average of 23 years for breast cancer incidence, breast cancer death and death from other causes. We analysed the mortality and incidence data by Poisson regression and estimated overdiagnosis formally using Markov process models. Setting Twenty-three screening units in England, Wales and Scotland within the NHS Breast Screening Programme. Participants Women aged 39–41 years were recruited between 1990 and 1997. After exclusions, a total of 53,883 women were randomised to undergo screening (the intervention group) and 106,953 women were randomised to have usual care (the control group). Interventions The intervention group was invited to an annual breast screen with film mammography, two view at first screen and single view thereafter, up to and including the calendar year of their 48th birthday. The control group received no intervention. Both groups were invited to the National Programme from the age of 50 years, when screening is offered to all women in the UK. Main outcome measures The main outcome measures were mortality from breast cancers diagnosed during the intervention phase of the trial (i.e. before the first National Programme screen at 50 years), mortality from all breast cancers diagnosed after randomisation, all-cause mortality, mortality from causes other than breast cancer, and the incidence of breast cancer. Results There was a statistically significant 25% reduction in mortality from breast cancers diagnosed during the intervention phase at 10 years’ follow-up (relative rate 0.75, 95% confidence interval 0.58 to 0.97; p = 0.03). No reduction was observed thereafter (relative rate 0.98, 95% confidence interval 0.79 to 1.22). Overall, there was a statistically non-significant 12% reduction (relative rate 0.88, 95% confidence interval 0.74 to 1.03; p = 0.1). The absolute benefit remained approximately constant over time, at one death prevented per 1000 women screened. There was no effect of intervention on other-cause mortality (relative rate 1.02, 95% confidence interval 0.97 to 1.07; p = 0.4). The intervention group had a higher incidence of breast cancer than the control group during the intervention phase of the trial, but incidence equalised immediately on the first National Programme screen at the age of 50–52 years. Limitations There was 31% average non-compliance with screening and three centres had to cease screening for resource and capacity reasons. Conclusions Annual mammographic screening at the age of 40–49 years resulted in a relative reduction in mortality, which was attenuated after 10 years. It is likely that digital mammography with two views at all screens, as practised now, could improve this further. There was no evidence of overdiagnosis in addition to that which already results from the National Programme carried out at later ages. Future work There is a need for research on the effects of modern mammographic protocols and additional imaging in this age group. Trial registration Current Controlled Trials ISRCTN24647151. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 55. See the NIHR Journals Library website for further project information. Other funding in the past has been received from the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, the US National Cancer Institute and the American Cancer Society.

scholarly journals Risk factors for breast cancer development by tumor characteristics among women with benign breast disease

2020 ◽  
Author(s):  
Jonine Figueroa ◽  
Gretchen L. Gierach ◽  
Máire A. Duggan ◽  
Shaoqi Fan ◽  
Ruth M. Pfeiffer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Risk ◽  
Benign Breast Disease ◽  
Tumor Grade ◽  
Breast Disease ◽  
Breast Cancers ◽  
Er Positive ◽  
Proliferative Bbd ◽  
Er Status

Abstract Background: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. Methods: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk, and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971-2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models.Results: Breast cancers were predominantly ER-positive (86%), well- or moderately-differentiated (73%), small (74% <20mm) and stage I/II (91%). Having had an age at first birth <30 years was associated with reduced risk of ER-positive breast cancer (OR=0.69, 95%CI=0.49-0.98), but not of ER-negative disease (OR=1.08, 95%CI=0.51-2.30) p-heterogeneity=0.24. Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred higher risk for ER-positive (OR=5.48, 95%CI=2.14-14.01) than ER-negative disease (OR=1.52, 95%CI=0.18-13.05, with only one ER-negative case); p-heterogeneity=0.45. Presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with 1.5-fold risk for both ER-positive and ER-negative tumors, with a 2-fold risk (95%CI=1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size.Conclusion: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderate increased risk, independent of BBD histology, and irrespective of ER status.

Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention

2017 ◽  
Vol 17 (6) ◽  
pp. 676-695 ◽  
Author(s):  
Donald D. Muccio ◽  
Venkatram R. Atigadda ◽  
Wayne J. Brouillette ◽  
Kirby I. Bland ◽  
Helen Krontiras ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Prevention ◽  
Breast Cancer Prevention ◽  
Current Status ◽  
High Risk Population ◽  
Preclinical Studies ◽  
Breast Cancers ◽  
Phase 2 ◽  
Er Positive

This review focuses on our efforts to translate a low-toxicity retinoid X receptor-selective agonist, UAB30, to the clinic for the prevention of breast cancers. The review is divided into several sections. First, the current status of breast cancer prevention is discussed. Next, preclinical studies are presented that support translation of rexinoids to the clinic for cancer prevention. While current FDAapproved retinoids and rexinoids demonstrate profound effects in treating cancers, they lack sufficient safety for long term use in the high risk population that is otherwise disease free. The review stresses the need to identify cancer preventive drugs that are effective and safe in order to gain wide use in the clinic. Due to the heterogeneity of the disease, UAB30 is evaluated for the prevention of ER-positive and ER-negative mammary cancers. Since selective estrogen receptor modulators and aromatase inhibitors are used clinically to prevent and treat ER-positive breast cancers, preclinical studies also must demonstrate efficacy of UAB30 in combination with existing drugs under use in the clinic. To support an Investigational New Drug Application to the FDA, data on pharmacology and toxicity as well as mutagenicity is gathered prior to human trials. The review concludes with a discussion of the outcomes of human Phase 0/1 clinical trials that determine the safety and pharmacology of UAB30. These studies are essential before this agent is evaluated for efficacy in phase 2 trials. Success in phase 2 evaluation is critical before long-term and costly phase 3 trials are undertaken. The lack of surrogate biomarkers as endpoints for phase 2 evaluation of rexinoid preventive agents is discussed.

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