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Purpose Caveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer. Methods A cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments). Results Only one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome. Conclusion CAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.

After a diagnosis of unilateral breast cancer, increasing numbers of patients are requesting contralateral prophylactic mastectomy (CPM), the surgical removal of the healthy breast after diagnosis of unilateral breast cancer. It is important for the community of breast cancer specialists to provide meaningful guidance to women considering CPM. This manifesto discusses the issues and challenges of CPM and provides recommendations to improve oncological, surgical, physical and psychological outcomes for women presenting with unilateral breast cancer: (1) Communicate best available risks in manageable timeframes to prioritise actions; better risk stratification and implementation of risk-assessment tools combining family history, genetic and genomic information, and treatment and prognosis of the first breast cancer are required; (2) Reserve CPM for specific situations; in women not at high risk of contralateral breast cancer (CBC), ipsilateral breast-conserving surgery is the recommended option; (3) Encourage patients at low or intermediate risk of CBC to delay decisions on CPM until treatment for the primary cancer is complete, to focus on treating the existing disease first; (4) Provide patients with personalised information about the risk:benefit balance of CPM in manageable timeframes; (5) Ensure patients have an informed understanding of the competing risks for CBC and that there is a realistic plan for the patient; (6) Ensure patients understand the short- and long-term physical effects of CPM; (7) In patients considering CPM, offer psychological and surgical counselling before surgery; anxiety alone is not an indication for CPM; (8) Eliminate inequality between countries in reimbursement strategies; CPM should be reimbursed if it is considered a reasonable option resulting from multidisciplinary tumour board assessment; (9) Treat breast cancer patients at specialist breast units providing the entire patient-centred pathway.

Purpose Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. MethodsA total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical pathologic characteristics, survival and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. Results The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years-old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, pBRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. ConclusionOur study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Beta-blockers have shown anti-neoplastic effects in laboratory studies but epidemiologic evidence in relation to contralateral breast cancer (CBC) is sparse. We investigated post-diagnosis beta-blocker use and risk of CBC in a cohort of 52 723 women with breast cancer by using nationwide Danish health registers and the Danish Breast Cancer Group database. We defined post-diagnosis beta-blocker use as a time-varying covariate starting one year after a second prescription was redeemed. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with beta-blocker use compared with non-use. We identified 1444 women with CBC of whom 209 women were beta-blocker users. We found an overall HR of 1.08 (95% CI: 0.93-1.27) for beta-blocker use and risk of CBC with no substantial variation according to cumulative amount, intensity or selectivity of beta-blocker use. Hence, our cohort study of women with breast cancer did not sustain a protective effect of beta-blocker use on risk of CBC, irrespective of beta-blocker type.

Peer reviewed: True, Funder: UK Medical Research Council PhD pro-gramme, Simple Summary: As the treatment for breast cancer continues to improve and more women survive their initial diagnosis, there is an increasingly large number of women who are at risk of a second new breast cancer in their lifetimes. However, the hereditary causes of these second breast cancers are not well understood. In this study, we used the latest genetic sequencing technologies to investigate hereditary causes for the second breast cancer in individuals who are known not to have alterations in one of the three main breast cancer genes (BRCA1, BRCA2 and PALB2). We analyzed the genetic profiles of selected participants from the WECARE study, one of the largest studies looking at second breast cancers in women. By comparing the genetic profiles of women who have had one breast cancer to similarly matched women who went on to have a second breast cancer, we found that younger women (under 50) with second breast cancers had a higher number of inherited gene alterations compared with those women with one breast cancer. We did not see the same effect in the older women. The results from this study improve our understanding of the hereditary contribution to second breast cancers. Abstract: Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. Methods: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC). Results: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2–5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7–2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1). Conclusion: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.

To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a “texture risk score” using pre-treatment mammograms in a case–control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01–1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.

Women with Li–Fraumeni Syndrome (LFS) often consider risk-reducing mastectomy (RRM) due to extremely high risk of breast cancer at early ages. Data on uptake of RRM in LFS are scarce, and are inferred from experience in women with pathogenic variants (PVs) in BRCA1/2, despite differences in cancer risks. This study evaluated RRM uptake in a cohort of women with LFS. Women (n = 205) with LFS enrolled in NCI’s LFS study reported lifetime cancer diagnoses and mastectomies and completed questionnaires regarding reproductive history, cancer worry and risk perceptions. A subset of women participating in an annual cancer screening study received counseling regarding RRM. 65% (n = 71) of women diagnosed with presumed unilateral breast cancer (n = 109) underwent contralateral RRM over their lifetime. Nearly half (49%, n = 25) of the women who did not complete contralateral RRM within one year of their breast cancer diagnosis (n = 51) developed contralateral breast cancer (median interval = 6 years). Only 18.5% (n = 15) of women without breast cancer history (n = 81) underwent bilateral RRM. Median age at bilateral RRM of 39 years was sub-optimal for breast cancer risk reduction. Contralateral RRM was associated with early genetic diagnosis, participation in the screening study, and fewer prior cancers. Bilateral RRM uptake was associated with having had children, having breastfed, and high cancer worry. Uptake of contralateral RRM is high in women with LFS. The frequency of contralateral breast cancer necessitates active discussion of benefits of contralateral RRM and counseling regarding bilateral RRM should be tailored to the early age at risk of breast cancer onset in LFS. There is a need for research into the survival and long-term benefits of RRM in LFS.

Background Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I-III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular (n = 8903), lobular mixed with other types (n = 3512), versus ductal (n = 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause-specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04-1.33) for lobular and 1.37 (95% CI: 1.16-1.63) for lobular mixed versus ductal PBC. Ten-year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.

Women with breast cancer often wonder whether they should have their other breast removed as well, to prevent a potential tumor from developing there. The exact risks vary significantly per person. We used information about patients, breast cancer characteristics and treatments, and rare and common genetic variant correlated with a higher or lower risk of developing breast cancer in the other breast in large datasets to develop and validate statistical models to predict each patient’s risk of developing a tumor. We investigated whether and how these models might be clinically useful to better inform patients and physicians to tailor clinical decision making about potential strategies to prevent or early detect a tumor in the opposite breast. We discussed statistical aspects about model development and validation, and we provided frameworks about how to develop and assess prediction performance of risk prediction models using motivating examples in breast cancer.

Background We sought to estimate the annual risk and 25-year cumulative risk of contralateral breast cancer among women with stage 0-III unilateral breast cancer. Methods We identified 812,851 women with unilateral breast cancer diagnosed between 1990 and 2015 in the SEER database and followed them for contralateral breast cancer for up to 25 years. Women with a known bilateral mastectomy were excluded. We calculated the annual risk of contralateral breast cancer by age at diagnosis, by time since diagnosis and by current age. We compared risks by ductal carcinoma in situ (DCIS) versus invasive disease, by race and by oestrogen receptor (ER) status of the first cancer. Results There were 25,958 cases of contralateral invasive breast cancer diagnosed (3.2% of all patients). The annual risk of contralateral breast cancer over the 25-year follow-up period was 0.37% and the 25-year actuarial risk of contralateral invasive breast cancer was 9.9%. The annual risk varied to a small degree by age of diagnosis, by time elapsed since diagnosis and by current age. The 25-year actuarial risk was similar for DCIS and invasive breast cancer patients (10.1 versus 9.9%). The 25-year actuarial risk was higher for black women (12.7%) than for white women (9.7%) and was lower for women with ER-positive breast cancer (9.5%) than for women with ER-negative breast cancer (11.2%). Conclusions Women with unilateral breast cancer experience an annual risk of contralateral breast cancer ~0.4% per year, which persists over the 25-year follow-up period.

The uptake of contralateral prophylactic mastectomy (CPM) has increased steadily over the last twenty years in women of all age groups and breast cancer stages. Since contralateral breast cancer is relatively rare and the breast cancer guidelines only recommend CPM in a small subset of patients with breast cancer, the drivers of this trend are unknown. This review aims to evaluate the evidence for and acceptability of CPM, data on patient rationales for choosing CPM, and some of the factors that might impact patient preferences. Based on the evidence, future recommendations will be provided. First, data on contralateral breast cancer risk and CPM rates and trends are addressed. After that, the evidence is structured around four main patient rationales for CPM formulated as questions that patients might ask their surgeon: Will CPM reduce mortality risk? Will CPM reduce the risk of contralateral breast cancer? Can I avoid future screening with CPM? Will I have better breast symmetry after CPM? Also, three different guidelines regarding CPM will be reviewed. Studies indicate a large gap between patient preferences for radical risk reduction with CPM and the current approaches recommended by important guidelines. We suggest a strategy including shared decision-making to enhance surgeons’ communication with patients about contralateral breast cancer and treatment options, to empower patients in order to optimize the use of CPM incorporating accurate risk assessment and individual patient preferences., Highlights • Contralateral prophylactic mastectomy rates have increased over the last 20 years. • Patients may want CPM to reduce risk of contralateral breast cancer and mortality. • Patients do not always have the tools available to make a well-informed decision. • Patient and surgeon’s shared decision-making could optimize the use of CPM.

Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually matched, case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1521 CBC cases and 2212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2008 aged younger than 55 years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms, and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR = 1.00, 95% CI = 0.89 to 1.14; continuous RT dose with years smoked: RR = 1.00, 95% CI = 0.99 to 1.01; and continuous RT dose with lifetime pack-years: RR = 1.00, 95% CI = 0.99 to 1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history.

OBJECTIVE: To evaluate the prognosis, the patient and tumor characteristics, and the treatment of bilateral breast cancer (BBC) and to compare synchronous (sBBC) and metachronous BBC (mBBC). MATERIALS AND METHODS: For this retrospective study, data from 123 consecutive BBC patients (56 sBBC and 67 mBBC) that were presented at the Sion Hospital tumor board between 2007 and 2018 were collected retrospectively. RESULTS: Mean follow-up was 85 months. 2(nd) tumors in both groups were more often diagnosed radiologically. Mean time interval between mBBC was 115 months. A shorter interval was positively correlated with a negative hormonal receptor (HR) status and higher grade for the 2(nd) tumor. There was no difference in overall survival (OS) and relapse-free survival (RFS) between sBBC and mBBC. OS was longer if both tumors were hormonal receptor (HR) positive. mBBC exhibited a higher local recurrence rate than sBBC (p=0.03). CONCLUSION: sBBC and mBBC patients did not show any difference in OS or RFS, although mBBC patients were more prone to local relapses.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina Introdução: Nas últimas duas décadas, verificou-se a prática crescente da mastectomia contralateral redutora de risco (MCRR), apesar das complicações documentadas e da evidência limitada dos seus benefícios. Constitui ainda um desafio discernir quais os fatores que conduzem as mulheres à realização desta intervenção e qual o seu benefício em termos de sobrevivência. Materiais e métodos: Foi realizada uma pesquisa de publicações entre 2010 e 2021 na base de dados PubMed, utilizando os termos MeSH “prophylactic mastectomy”, “unilateral breast neoplasms”, “contralateral mastectomy” e “breast neoplasms”.Resultados: Observa-se uma sobrestimação do risco de cancro da mama contralateral por parte das mulheres com cancro da mama unilateral, sendo fundamental a determinação correta desse risco, tendo em conta fatores modificadores como a história familiar e a presença de mutações em genes de suscetibilidade para o cancro da mama. O interesse na MCRR acentuou-se com a divulgação pelas figuras públicas de experiências com a cirurgia mamária profilática, com o desenvolvimento das técnicas de sequenciação genética, da reconstrução mamária e dos meios complementares imagiológicos. O aumento para o dobro do risco de complicações, a maior necessidade de re-intervenções precoces, o aumento do tempo de internamento, o atraso na terapêutica adjuvante, o impacto negativo no bem-estar físico, emocional e sexual são possíveis consequências associadas à realização da MCRR. A melhoria da sobrevivência com a MCRR é verificada apenas nas mulheres portadoras de mutação BRCA.Conclusão: A escolha da MCRR assenta numa interligação de fatores psicossociais, crenças e sentimentos. Por se tratar de uma intervenção extensa e com riscos associados, importa fazer-se uma abordagem multidisciplinar e adaptada a cada doente, permitindo a seleção das que realmente beneficiam da MCRR. Palavras-chave: mastectomia profilática redutora de risco, mastectomia bilateral, cancro da mama unilateral, cancro da mama contralateral, BRCA, reconstrução mamária. Introduction: The last two decades have seen the increasing practice of risk-reducing contralateral mastectomy, despite documented complications and limited evidence of its benefits. It is still a challenge to discern which factors lead women to undergo this intervention and its benefit in terms of survival.Methods: Research of articles published between 2010 and 2021 was conducted in PubMed database using the MeSH terms "prophylactic mastectomy", "unilateral breast neoplasms", "contralateral mastectomy" and "breast neoplasms".Results: An overestimation of contralateral breast cancer risk is observed in women with unilateral breast cancer, and its correct determination is essential, considering modifying factors such as family history and the presence of mutations in breast cancer susceptibility genes. Risk-reducing contralateral mastectomy interest has increased with the dissemination of celebrities´s experiences with prophylactic breast surgery, the development of genetic sequencing techniques, breast reconstruction and breast imaging. A twofold increase in the risk of complications, increased need for early re-interventions, longer hospital stays, delay in adjuvant therapy, and negative impact on physical, emotional, and sexual well-being are possible consequences associated with performing risk-reducing contralateral mastectomy. Improved survival with this intervention is only seen in women carrying BRCA mutation.Conclusion: The choice of risk-reducing contralateral mastectomy is based on an interconnection of psychosocial factors, beliefs, and feelings. Because it is an extensive surgery with associated risks, it is important to take a multidisciplinary and tailored approach to each patient, allowing the selection of those who really benefit from this intervention. Keywords: prophylactic risk-reducing mastectomy, bilateral mastectomy, unilateral breast cancer, contralateral breast cancer, BRCA, breast reconstruction.

Aim: To assess the outcomes of 737 consecutive patients with DCIS, with particular attention to the type of recurrences, other malignancies and causes of deaths. Material and Methods: A retrospective analysis of 737 consecutive DCIS patients treated in one institution in the years 1996–2011 was carried out. The cumulative recurrence risk, DFS, OS depending on the method of treatment (mastectomy, breast-conserving treatment (BCT), breast-conserving surgery (BCS)) and cause of death were assessed. Results: Sixty-six recurrences (42% DCIS, 58% invasive) were reported: 61 in the breast and 5 outside the breast. The cumulative recurrence risk after a 15-year observation after mastectomy, BCT and BCS was 3.2%, 19.5% and 31.2%, respectively (p < 0.001). The 15-year DFS after mastectomy, BCT and BCS was 72%, 65% and 48%, respectively (p < 0.001). The 15-year OS after mastectomy, BCT and BCS was 75%, 83% and 70%, respectively (p = 0.329). Deaths due to DCIS progression were reported in four (0.5%) of the overall patients and in 10.5% of patients with invasive recurrences. The majority of deaths were linked to the age of the patients or other diseases, including other neoplasms, but not DCIS. Conclusions: The highest number of recurrences was reported in patients after BCS, despite the fact that it was the lowest-risk group. In total, 79% of local recurrences were true recurrences and 58% were invasive recurrences. Local recurrences were effectively treated without an influence on the OS. The percentage of deaths due to DCIS was low and mainly concerned patients with locoregional and distant failure.

Due to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors associated with CBC. We observed significant associations for a polygenic risk score of common germline variants (PRS313) and for different adjuvant systemic therapy regimens with (subtype-specific) CBC risk. These factors may be incorporated in CBC risk prediction models together with other known and available risk factors. For support of clinical decision making more biological information is needed to understand CBC development in women with invasive breast cancer and DCIS. As a first step towards implementation of a risk prediction model, we performed an exploratory interview study, which showed that patients had varying preferences for graphical presentation of probabilities in a CBC prediction model. In future studies, the prediction model should be incorporated in a decision support tool and implemented in clinical practice. This tool can then help to better identify women at high risk of CBC who may benefit from prophylactic surgery, while the estimates can also be used to reassure patients who are at low risk of developing CBC.

Due to the increased incidence of breast cancer and improved survival, more women are at risk of developing contralateral breast cancer (CBC). The aim of this thesis was to explore risk factors associated with CBC. We observed significant associations for a polygenic risk score of common germline variants (PRS313) and for different adjuvant systemic therapy regimens with (subtype-specific) CBC risk. These factors may be incorporated in CBC risk prediction models together with other known and available risk factors. For support of clinical decision making more biological information is needed to understand CBC development in women with invasive breast cancer and DCIS. As a first step towards implementation of a risk prediction model, we performed an exploratory interview study, which showed that patients had varying preferences for graphical presentation of probabilities in a CBC prediction model. In future studies, the prediction model should be incorporated in a decision support tool and implemented in clinical practice. This tool can then help to better identify women at high risk of CBC who may benefit from prophylactic surgery, while the estimates can also be used to reassure patients who are at low risk of developing CBC.

Background Women with unilateral breast cancer are at an increased risk for the development of contralateral breast cancers. We hypothesis that combined breast MRI would detect more contralateral synchronous breast cancer than conventional imaging alone, and resulted in less contralateral metachronous breast cancer during follow-up. Methods We retrospectively collected two groups of breast cancer patients diagnosed from 2009 to 2013 for evaluating the effectiveness and value of adding pre-operative breast MRI to conventional breast images (mammography and sonography) for detection of contralateral synchronous breast cancer. The new metachronous contralateral breast cancer diagnosed during follow-up was prospectively evaluated and compared. Results Group A (n = 733) comprised patients who underwent conventional preoperative imaging and group B (n = 735) combined with MRI were enrolled and compared. Seventy (9.5%) of the group B patients were found to have contralateral lesions detected by breast MRI, and 65.7% of these lesions only visible with MRI. The positive predictive value of breast MRI detected contralateral lesions was 48.8%. With the addition of breast MRI to conventional imaging studies, more surgical excisions were performed in contralateral breasts (6% (44/735) versus 1.4% (10/733), P< 0.01), more synchronous contralateral breast cancer detected (2.9% (21/735) versus 1.1% (8/733), P = 0.02), and resulted in numerical less (2.2% (16/714) versus 3% (22/725), p = 0.3) metachronous contralateral breast cancer during a mean follow-up of 102 months. Conclusions Our study provides useful estimates of the pre-operative breast MRI for the increased detection of contralateral synchronous breast cancer and less subsequent contralateral metachronous breast cancer.

The main purpose of this study was to build a prediction model for patients with contralateral breast cancer (CBC) using competing risks methodology. The aim is to help clinicians predict the probability of CBC in breast cancer (BC) survivors. We reviewed data from the Surveillance, Epidemiology, and End Results database of 434,065 patients with BC. Eligible patients were used to quantify the association between the development of CBC and multiple characteristics of BC patients using competing risk models. A nomogram was also created to facilitate clinical visualization and analysis. Finally, the stability of the model was verified using concordance index and calibration plots, and decision curve analysis was used to evaluate the clinical utility of the model by calculating the net benefit. Four hundred thirty-four thousand sixty-five patients were identified, of whom 6944 (1.6%) developed CBC in the 10 years follow-up. The 10-year cumulative risk of developing CBC was 2.69%. According to a multivariate competing risk model, older patients with invasive lobular carcinoma who had undergone unilateral BC surgery, and whose tumor was better differentiated, of smaller size and ER-negative/PR-positive, had a higher risk of CBC. The calibration plots illustrated an acceptable correlation between the prediction by nomogram and actual observation, as the calibration curve was closed to the 45° diagonal line. The concordance index for the nomogram was 0.65, which indicated it was well calibrated for individual risk of CBC. Decision curve analysis produced a wide range of risk thresholds under which the model we built would yield a net benefit. BC survivors remain at high risk of developing CBC. Patients with CBC have a worse clinical prognosis compared to those with unilateral BC. We built a predictive model for the risk of developing CBC based on a large data cohort to help clinicians identify patients at high risk, which can then help them plan individualized surveillance and treatment.

Purpose To extend the functionality of the existing INFLUENCE nomogram for locoregional recurrence (LRR) of breast cancer toward the prediction of secondary primary tumors (SP) and distant metastases (DM) using updated follow-up data and the best suitable statistical approaches. Methods Data on women diagnosed with non-metastatic invasive breast cancer were derived from the Netherlands Cancer Registry (n = 13,494). To provide flexible time-dependent individual risk predictions for LRR, SP, and DM, three statistical approaches were assessed; a Cox proportional hazard approach (COX), a parametric spline approach (PAR), and a random survival forest (RSF). These approaches were evaluated on their discrimination using the Area Under the Curve (AUC) statistic and on calibration using the Integrated Calibration Index (ICI). To correct for optimism, the performance measures were assessed by drawing 200 bootstrap samples. Results Age, tumor grade, pT, pN, multifocality, type of surgery, hormonal receptor status, HER2-status, and adjuvant therapy were included as predictors. While all three approaches showed adequate calibration, the RSF approach offers the best optimism-corrected 5-year AUC for LRR (0.75, 95%CI: 0.74–0.76) and SP (0.67, 95%CI: 0.65–0.68). For the prediction of DM, all three approaches showed equivalent discrimination (5-year AUC: 0.77–0.78), while COX seems to have an advantage concerning calibration (ICI Conclusions INFLUENCE 2.0 is a flexible model to predict time-dependent individual risks of LRR, SP and DM at a 5-year scale; it can support clinical decision-making regarding personalized follow-up strategies for curatively treated non-metastatic breast cancer patients.

Purpose Patients who have ductal carcinoma in situ (DCIS) are undergoing bilateral mastectomy at increasing rates. One of the reasons is to minimize contralateral breast cancer (CBC) risk. The purpose of this study is to determine the rate of and risk factors associated with CBC in women treated for DCIS. Methods A retrospective study was performed of women with DCIS at surgery from 2007 to 2014 who had at least five-year follow-up. Patient attributes, imaging findings, histopathology results, and surgical and long-term outcomes were collected. Features associated with a CBC were assessed with multivariable logistic regression models. Results 613 women (mean 56 years, range 30–87) with DCIS underwent breast-conserving surgery (BCS) (n = 426), unilateral mastectomy (n = 101), or bilateral mastectomy (n = 86), with mean follow-up of 7.9 years. Of the 527 women who had BCS or unilateral mastectomy, 7.4% (n = 39) developed a CBC (DCIS in 12 and invasive cancer in 27). 4.1% (5/122) of women treated with adjuvant endocrine therapy developed a CBC, compared to 8.4% (34/405) who were not treated (p = .11). Features associated with CBC risk were younger age at menarche (adjusted odds ratio [aOR] of 0.76, p = .03) and low nuclear grade of DCIS (aOR of 5.43 for grade 1 versus 3, p = .01). Conclusion In women treated for DCIS, the overall rate of CBC was low at 7.4%. Younger age at menarche and low nuclear grade of DCIS had significant associations with higher CBC risk.

Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

Objectives The objective of this study was to evaluate patient compliance with management recommendations given by a breast cancer multidisciplinary team (MDT), assess for reasons for noncompliance, and perform an exploratory assessment on breast cancer outcomes in noncompliant patients. Materials and methods A retrospective analysis of prospectively collected data was undertaken for patients selected by their primary clinician to be discussed at the MDT of Breast Cancer Research Centre-WA in Perth between 1st March 2011 and the 28th February 2016. The primary objective was the rate of compliance with MDT management recommendations. Secondary objectives included factors associated with noncompliance, rate of clinical trial uptake, and impact of treatment noncompliance on breast cancer events in a subgroup of early breast cancer (EBC) patients. Results and conclusion A total of 2614 MDT management recommendations were made for 925 patients. Overall, 92% were compliant with all recommendations given. Clinical trial recruitment was successful in 84.1%. The reasons given for treatment noncompliance were fear of toxicity, choosing an alternative treatment, and treatment inconvenience. In a subset of 337 EBC patients, there was a significantly higher rate of contralateral breast cancer, distant recurrence, and breast cancer-specific death, P = .0016, in those who were noncompliant. Our study demonstrates a high rate of MDT treatment recommendation compliance and clinical trial recruitment. In a subgroup of EBC patients, noncompliance was associated with significantly worse outcomes. Attention to educating patients to minimize their fear of treatment toxicity and ensuring their understanding of evidence-based treatment may lead to lower rates of noncompliance.

Purpose Absorbable retaining thread (ART) needle localization utilizes a guiding needle with a thread; this technique was invented to reduce patient discomfort and wire migration. We investigated the feasibility of ultrasound (US)-guided ART needle localization for nonpalpable breast lesions. Methods ART needle localization was performed for 26 nonpalpable breast lesions in 26 patients who were scheduled to undergo surgical excision the day after localization. Seventeen breast lesions were initially diagnosed as invasive ductal carcinoma, six as ductal carcinomas in situ, and one as fibrocystic change. The other two cases without an initial pathologic diagnosis had suspicious US features, and excision was planned concomitantly with contralateral breast cancer surgery. The primary outcome was the technical success rate of ART needle localization confirmed by US immediately after the procedure, and the secondary outcomes were the percentage of clear margins on pathology and the complication rate of ART needle localization. Results The technical success rate of ART needle localization was 96.2% (25 of 26 patients), and the ART was located 1 cm away from the mass in one patient (3.8%). The lesions were successfully removed with clear margins in all 26 patients. No significant complications related to ART needle localization were observed. Conclusion ART needle localization can be an alternative to wire needle localization for nonpalpable breast lesions.

Background Factors associated with the decision to pursue unilateral mastectomy (UM) versus contralateral prophylactic mastectomy (CPM) in unilateral breast cancer (UBC) patients, and satisfaction with this decision, remain to be elucidated. Methods UBC patients who underwent mastectomy were surveyed regarding factors affecting their surgical decision and satisfaction with the same. Results Both UM (n = 46) and CPM (n = 55) patients were satisfied with their surgical decision (mean 4.72 and 4.85 out of 5 on Satisfaction With Decision scale, respectively, p = 0.078). Most CPM patients cited the desire to lower their risk of contralateral breast cancer (96.4%) and the desire for peace of mind (94.5%) as “very important” drivers of their decision; whereas most UM patients felt not wanting to remove a normal breast (67.4%) was a “very important” driver for their decision. Conclusions Both UM and CPM patients reported high satisfaction with their surgical decisions, despite differing reasons for their respective surgeries.

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

Background Radiation therapy (RT) for women with ductal carcinoma in situ (DCIS) undergoing breast‐conserving surgery (BCS) may be overtreatment for some, especially for those in which DCIS is eradicated, and ipsilateral breast tumor recurrence (IBTR) risk approaches the contralateral breast cancer (CBC) level. The aim of this study was to clarify whether the polygon method, a new systematic method of en face (tangential, shaved) margin assessment, can identify a subset of DCIS that can be safely treated by BCS alone. Methods A key tool of the polygon method is an adjustable mold that prevents the “pancake phenomenon” (flattening) of breast tissue after surgical removal so that the specimen is fixed in the shape of a polygonal prism. This preanalytical procedure enables us to command a panoramic view of entire en face margins 3‐5‐mm deep from the real peripheral cut surfaces. Competing risk analysis was used to quantify rates of IBTR and CBC and to evaluate risk factors. Results From 2000 to 2013, we identified 146 DCIS patients undergoing BCS with a contralateral breast at risk. In 100 DCIS patients whose margin was negative by the polygon method, 5 IBTR (3 DCIS and 2 invasive ductal carcinoma [IDC]) and 10 CBC (6 DCIS and 4 IDC) cases were identified during a median follow‐up of 7.6 years (range, 0.9‐17.4). Five‐ and 10‐year cumulative incidence rates were 3.0% and 5.3% for IBTR, and 7.1% and 13.3% for CBC, respectively. Thus, patients with a negative margin consistently showed at least twofold lower IBTR than CBC despite omission of RT. Conclusions Japanese women classified with a negative margin by the polygon method show a very low risk of IBTR and account for approximately half of CBC cases. In this subset of DCIS patients, additional RT is not beneficial.

Background Breast cancer patients are at significant risk of a second contralateral, breast cancer (CBC). Identification of women at high or low CBC risk could improve patient management decisions. Previous research has shown that breast cancer-associated single nucleotide polymorphisms (SNPs) summarized in a polygenic risk score (PRS) predict the risk of a first breast cancer with an odds ratio (OR) per 1 SD of 1.55 (95% confidence interval (95%CI)=1.52-1.58) (77-SNP PRS). The aim of this study was to evaluate the association between a recently developed PRS and CBC risk. Methods We identified 19 studies from the Breast Cancer Association Consortium (BCAC) with follow-up information on participating patients and at least 10 patients diagnosed with CBC. This included 38,228 females of European ancestry diagnosed with first invasive breast cancer since 1990. Genotyping was done using the iCOGS array or OncoArray, with genotypes for SNPs not on the arrays estimated by imputation. We used a 313-SNP PRS, optimized for prediction of overall (first) breast cancer in the BCAC dataset. Metachronous CBC risk by PRS was quantified using univariable and multivariable Cox regression analyses stratified by country and adjusted for multiple patient, tumor, and treatment characteristics. We assessed PRS interaction with age, family history, adjuvant systemic therapy, and ER-status. Results Median time to develop a CBC (N=1,046) after a first breast cancer was 5.8 years (range 0.3-21.9). Higher PRS was associated with increased CBC risk: hazard ratio (HR) per 1 SD=1.31 (95%CI=1.23-1.39). Patients in the highest and lowest 5% of the PRS had 1.95 fold and 0.67 fold risks of CBC, respectively, compared with patients in the middle quintile. Adjustments for age, year of diagnosis, family history, tumor size, nodal status, ER-status, or treatment (chemotherapy, endocrine therapy, radiotherapy) did not substantially alter these results. We found an interaction with age at first breast cancer diagnosis (Pinteraction=.002); the PRS was associated with an increased CBC risk for patients aged ≥40 years (HR=1.37, 95%CI=1.28-1.47), but not for patients Conclusion The PRS is predictive for the development of CBC in patients ≥40 years at first breast cancer diagnosis. For this group, the PRS could be incorporated in CBC risk prediction models to help define high and low risk patients, and hence optimize screening and treatment strategies. Citation Format: Kramer I, Hooning MJ, Breast Cancer Association Consortium (BCAC), Mavaddat N, Canisius S, Keeman R, van den Broek AJ, Steyerberg E, Hauptmann M, Pharoah PD, Easton DF, Hall P, Schmidt MK. Association between a breast cancer polygenic risk score and contralateral breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-04.

Purpose: Following a diagnosis of breast cancer, BRCA mutation carriers face an increased risk of developing a second (contralateral) cancer in the unaffected breast. It is important to identify predictors of contralateral cancer in order to make informed decisions about bilateral mastectomy. The impact of bilateral salpingo-oophorectomy (i.e., oophorectomy) on the risk of developing contralateral breast cancer is unclear. Thus, we conducted a prospective study of the relationship between oophorectomy and the risk of contralateral breast cancer in 1781 BRCA1 and 503 BRCA2 mutation carriers with breast cancer. Methods: Women were followed from the date of diagnosis of their first breast cancer until the date of diagnosis of a contralateral breast cancer, bilateral mastectomy, date of death, or date of last follow-up. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of contralateral breast cancer associated with oophorectomy. Oophorectomy was included as a time-dependent covariate. We performed a left-censored analysis for those women who reported a primary breast cancer prior to study entry (i.e., from completion of baseline questionnaire). Results: After an average of 9.8years of follow-up, there were 179 (7.8%) contralateral breast cancers diagnosed. Oophorectomy was not associated with the risk of developing a second breast cancer (HR 0.92; 95% CI 0.68–1.25). The relationship did not vary by BRCA mutation type or by age at diagnosis of the first breast cancer. There was some evidence for a decreased risk of contralateral breast cancer among women with an ER-positive primary breast cancer, but this was based on a small number of events (n = 240). Conclusion: Overall, our findings suggest that oophorectomy has little impact on the risk of contralateral breast cancer

Simple Summary In this study we report the outcome of salvage mastectomy and reconstruction in 11 BRCA mutation carrier patients that participated in a clinical trial of prophylactic contralateral breast irradiation and suffered reoccurrences of breast cancer in either the ipsilateral or contralateral breast or elected to have the procedure for risk reduction. Patients’ satisfaction and physicians’ assessment of the cosmetic outcome were not inferior for previously irradiated compared to non-irradiated breasts. These results are encouraging and support continuing research as well as a discussion of risk-reduction alternatives besides mastectomy, including prophylactic breast irradiation, in BRCA1/2 mutation carriers. Abstract Risk-reducing mastectomy (RRM) is often advocated for BRCA1/2 mutation carriers who face a heightened lifetime risk of breast cancer. However, many carrier patients seek alternative risk-reducing measures. In a phase II nonrandomized trial, we previously reported that prophylactic irradiation to the contralateral breast among BRCA carriers undergoing breast-conserving treatment significantly reduced subsequent contralateral breast cancer. Herein, we report the outcome of salvage mastectomy and reconstruction in 11 patients that suffered reoccurrences of breast cancer in either the ipsilateral or contralateral breast or elected to have the procedure for risk reduction during the eight-year follow-up period. Patients’ satisfaction with the procedure and physicians’ assessment of the cosmetic outcome were not inferior for previously irradiated compared to non-irradiated breasts. Although the numbers are small, the results are encouraging and sustain hope in a challenging population. Our findings support continuing research as well as a discussion of risk-reduction alternatives besides mastectomy, including prophylactic breast irradiation, in BRCA1/2 mutation carriers.

Simple Summary In this survey study, we examined survey responses from 397 women with stage 0 to III unilateral breast cancer and found that partners, physicians, and the media were significant relative to the patient’s own influence in their decision to undergo a CPM. The findings of this study may inform policy by highlighting the need for educational aids, programs, or tools that help women with unilateral breast cancer make informed, evidence-based decisions regarding CPM efficacy. Abstract (1) Background: The relatively high rate of contralateral prophylactic mastectomy (CPM) among women with early stage unilateral breast cancer (BC) has raised concerns. We sought to assess the influence of partners, physicians, and the media on the decision of women with unilateral BC to undergo CPM and identify clinicopathological variables associated with the decision to undergo CPM. (2) Patients and Methods: Women with stage 0 to III unilateral BC who underwent CPM between January 2010 and December 2017. Patients were surveyed regarding factors influencing their self-determined decision to undergo CPM. Partner, physician, and media influence factors were modeled by logistic regressions with adjustments for a family history of breast cancer and pathological stage. (3) Results: 397 (29.6%) patients completed the survey and were included in the study. Partners, physicians, and the media significantly influenced patients’ decision to undergo CPM. The logistic regression models showed that, compared to self-determination alone, overall influence on the CPM decision was significantly higher for physicians (p = 0.0006) and significantly lower for partners and the media (p < 0.0001 for both). Fifty-nine percent of patients’ decisions were influenced by physicians, 28% were influenced by partners, and only 17% were influenced by the media. The model also showed that patients with a family history of BC had significantly higher odds of being influenced by a partner than did those without a family history of BC (p = 0.015). (4) Conclusions: Compared to self-determination, physicians had a greater influence and partners and the media had a lower influence on the decision of women with unilateral BC to undergo CPM. Strong family history was significantly associated with a patient’s decision to undergo CPM.

Second breast cancers after breast-conserving therapy (BCT) include ipsilateral breast tumor recurrence (IBTR) and metachronous contralateral breast cancer (CBC). Each IBTR is further classified as true recurrence (TR) or new primary tumor (NP). We aim to compare survival outcomes of TR, NP and CBC, and explore the optimal treatments.168,427 patients with primary breast cancer who underwent BCT between 1990 and 2005 were identified in the SEER database. The risks of IBTR and CBC were estimated by annual hazard rate. The breast cancer-specific survival (BCSS) were assessed using multivariable Cox regression analysis.With median follow-up of 13 years after BCT, 5413 patients developed an IBTR and 4050 patients had a CBC. The risk of IBTR peaked between 10 and 15 years after BCT, while the risk of CBC distributed evenly. 45.9% of IBTRs were classified as a TR and 54.1% as an NP. The time interval from primary breast cancer to NP was longer than to TR and CBC (P 0.001). Patients with TR had a poorer BCSS than NP (P = 0.003) and CBC (P = 0.002). There was no difference in BCSS between mastectomy and repeat BCT for treating TR (P = 0.584) or NP (P = 0.243). The BCSS of CBCs treated with BCT was better than mastectomy (P = 0.010). Chemotherapy didn't improve the survival of patients with TR (P = 0.058). However, TRs with grade III or negative hormone receptors benefited from chemotherapy significantly.Patients with TR had a poorer BCSS than NP and CBC. Classifying IBTR may provide clinical significance for treatments.

Background The current standard of care (SOC) for whole breast radiotherapy (WBRT) in the US is conventional tangential photon fields. Advanced WBRT techniques may provide similar tumor control and better normal tissue sparing, but it is controversial whether the medical benefits of an advanced technology are significant enough to justify its higher cost. Objective To analyze the cost-effectiveness of six advanced WBRT techniques compared with SOC. Methods We developed a Markov model to simulate health states for one cohort of women (65-year-old) with early-stage breast cancer over 15 years after WBRT. The cost effectiveness analyses of field-in-field (FIF), hybrid intensity modulated radiotherapy (IMRT), full IMRT, standard volumetric modulated arc therapy (STD-VMAT), multiple arc VMAT (MA-VMAT), non-coplanar VMAT (NC-VMAT) compared with SOC were performed with both tumor control and radiogenic side effects considered. Transition probabilities and utilities for each health state were obtained from literature. Costs incurred by payers were adopted from literature and Medicare data. Quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to evaluate the impact of uncertainties on the final results. Results FIF has the lowest ICER value of 1,511 $/QALY. The one-way analyses show that the cost-effectiveness of advanced WBRT techniques is most sensitive to the probability of developing contralateral breast cancer. PSAs show that SOC is more cost effective than almost all advanced WBRT techniques at a willingness-to-pay (WTP) threshold of 50,000 $/QALY, while FIF, hybrid IMRT and MA-VMAT are more cost-effective than SOC with a probability of 59.2%, 72.3% and 72.6% at a WTP threshold of 100,000 $/QALY, respectively. Conclusions FIF might be the most cost-effective option for WBRT patients at a WTP threshold of 50,000 $/QALY, while hybrid IMRT and MA-VMAT might be the most cost-effective options at a WTP threshold of 100,000 $/QALY.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neuroectodermal disorder associated with increased risk for several neural and non-neural malignancies. The link between NF1 and breast cancer has recently been established, with patients with NF1 being at higher risk for developing breast cancer, more likely to get breast cancer at a younger age, and more likely to have their breast cancer present with more adverse prognostic factors. Although rare, several cases of NF1 patients with contralateral breast cancer have been mentioned in the literature. We report the case of one such patient who developed contralateral breast cancer 40 years after her initial breast cancer diagnosis.

Objective: Despite little survival benefit and potential for harm, contralateral prophylactic mastectomy (CPM) rates are increasing amongst early-stage breast cancer patients at low contralateral breast cancer risk. We developed a CPM decision aid (DA) and conducted a pilot implementation. Methods: Surgeons and oncologists recruited eligible patients considering CPM. Consenting patients re-ceived the DA, completed a questionnaire and participated in a semi-structured interview. Clinicians were interviewed at study close. Results: Eleven clinicians and 31 patients participated. Three themes emerged: perceived utility and impact of the DA, disagreement regarding timing of delivery and target population, and implementation strategies. Both women and clinicians found the DA valuable, indicating it confirmed rather than changed preferences. Women (all of whom raised CPM themselves), preferred offering the DA early in treatment discussions whilst clinicians favoured targeting women who enquired about CPM. Conclusion: A DA about CPM is feasible and acceptable, but questions remain about the role of DAs in these types of decisions where one option has limited medical benefit. Practice implications: Some women have a high need to make an informed choice about CPM. Tools to support this could include a DA with a clear recommendation against CPM and an explanation why. (c) 2021 Published by Elsevier B.V.

Background Estimates of contralateral breast cancer (CBC) risk in the modern treatment era by year of diagnosis and characteristics of the first breast cancer are needed to assess the impact of recent advances in breast cancer treatment and inform clinical decision making. Methods We examined CBC risk among 419,818 women (age 30–84 years) who were diagnosed with a first unilateral invasive breast cancer and survived ≥ 1 year in the US Surveillance, Epidemiology, and End Results program cancer registries from 1992 to 2015 (follow-up through 2016). CBC was defined as a second invasive breast cancer in the contralateral breast ≥ 12 months after the first breast cancer. We estimated standardized incidence ratios (SIRs) of CBC by year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. Cumulative incidence of CBC was calculated for women diagnosed with a first breast cancer in the recent treatment era (2004–2015, follow-up through 2016). Results Over a median follow-up of 8 years (range 1–25 years), 12,986 breast cancer patients developed CBC. Overall, breast cancer patients had approximately twice the risk of developing cancer in the contralateral breast when compared to that expected in the general population (SIR = 2.21, 95% CI = 2.17–2.25). SIRs for CBC declined by year of first diagnosis, irrespective of age at diagnosis and estrogen receptor (ER) status (p-trends Conclusion Declines in CBC risk are consistent with continued advances in breast cancer treatment. The updated estimates of cumulative incidence inform breast cancer patients and clinicians on the risk of CBC and may help guide treatment decisions.

Background: Chronic encapsulated seroma following breast cancer surgery is a rare entity, and management is challenging. We present clinical and pathologic findings in a patient with extensive history of bilateral refractory breast seroma successfully treated with capsulectomy. Case presentation: A 71-year-old woman with previous early BRCA2 associated, node-negative breast cancer, developed late onset seroma following endocrine therapy, unilateral breast-conserving surgery, and completion of adjuvant radiotherapy. Non-simultaneous bilateral mastectomy was later performed to treat infection and reduce risk of contralateral breast cancer. Each surgery was followed by chronic seroma. After six years of ineffective treatment attempts with repeated aspirations, the patient successfully underwent bilateral capsulectomy. She remains seroma-free nine months from time of capsulectomy. Conclusion: This is the first report of late onset bilateral encapsulated breast seroma following mastectomy without axillary dissection. When managing breast seroma refractory to conventional treatment encapsulated seroma and prompt capsulectomy should be considered.

Breast cancer is the most commonly diagnosed cancer among women in Sweden, as well as worldwide. In Sweden, 8,288 women were diagnosed with invasive breast cancer in 2019, out of whom approximately 1.5% were younger than 35 years of age. Although breast cancer is relatively uncommon in young women, they tend to be diagnosed with more aggressive tumors at a more advanced stage, and have a poorer prognosis compared with older women. Young patients are also more likely to harbor a strong genetic predisposition for breast cancer.In paper I–III, women who were diagnosed with breast cancer at an age of 35 years or younger in the South Swedish Health Care Region were studied. In paper I, the concordance between self- and register-reported information regarding first-degree family history of cancer was evaluated. Almost perfect agreement between reports of family history of breast and ovarian cancers, but lesser agreement for other types of cancer, was observed. In addition, the frequencies of carriers and noncarriers of pathogenic variants and tumor characteristics for each of these group were described. Pathogenic variants were identified in BRCA1 (19%), BRCA2 (7%), and other genes, i.e., TP53, CHEK2, and PALB2 (4.5%). Compared with other groups, women with pathogenic variants in BRCA1 were more likely to be diagnosed with high grade, estrogen receptor-, progesterone receptor-, and triple-negative tumors. We also noted that even though all included women fulfilled the criteria for consideration of genetic counseling and testing, many had not been referred to the Oncogenetic Clinic in Lund. In paper II, we subsequently observed that both place of residence at breast cancer diagnosis and treating hospital were associated with the probability for a referral for genetic counseling and testing, and in paper III, most women stated that the main reason for not undergoing genetic testing when they were first diagnosed with breast cancer was that they had not received any information about genetic counseling and testing from their treating physicians.Among women who have previously been diagnosed with breast cancer, both young age and the identification of a pathogenic variant are associated with an increased risk for the development of a new primary breast cancer. The second breast cancer can occur ipsilaterally, i.e., in the same breast, but most occur in the contralateral breast. In paper IV, we evaluated how the incidence of contralateral breast cancer (CBC) has evolved in Sweden since the 1960s. A statistically significant increase in CBC incidence, within ten years from the first breast cancer diagnosis between the 1960s and 1980s, was observed. This increase was seen throughout all age groups, with the steepest increase in women younger than 40 years. However, a subsequent significant decrease in the incidence of invasive CBCs after the 1980s was also seen, in contrast to in situ CBCs, where the incidence stabilized in the years after.In paper III, a Traceback approach, i.e., a retrospective genetic outreach activity, was also evaluated by inviting all the women diagnosed with early-onset breast cancer, who had not previously been referred for genetic counseling, to an analysis of breast cancer predisposing genes. Pathogenic variants were identified in BRCA1 (n=2), CHEK2 (n=1), and ATM (n=1), i.e., in four (14%) of the participants. The Traceback pilot study procedure, with written pre-test information and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. Based on these results, we will initiate an enlarged Traceback study were all previously untested women diagnosed with breast cancer between the ages of 36 and 40 years will be invited.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:107 issue:5 pages:837-848 ispartof: location:United States status: published

Objective This study aimed to explore the potential of magnetic resonance imaging (MRI) radiomics-based machine learning to improve assessment and diagnosis of contralateral Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions in women with primary breast cancer. Materials and Methods A total of 178 contralateral BI-RADS 4 lesions (97 malignant and 81 benign) collected from 178 breast cancer patients were involved in our retrospective dataset. T1 + C and T2 weighted images were used for radiomics analysis. These lesions were randomly assigned to the training (n = 124) dataset and an independent testing dataset (n = 54). A three-dimensional semi-automatic segmentation method was performed to segment lesions depicted on T2 and T1 + C images, 1,046 radiomic features were extracted from each segmented region, and a least absolute shrinkage and operator feature selection method reduced feature dimensionality. Three support vector machine (SVM) classifiers were trained to build classification models based on the T2, T1 + C, and fusion image features, respectively. The diagnostic performance of each model was evaluated and tested using the independent testing dataset. The area under the receiver operating characteristic curve (AUC) was used as a performance metric. Results The T1+C image feature-based model and T2 image feature-based model yielded AUCs of 0.71 ± 0.07 and 0.69 ± 0.07 respectively, and the difference between them was not significant (P > 0.05). After fusing T1 + C and T2 imaging features, the proposed model’s AUC significantly improved to 0.77 ± 0.06 (P < 0.001). The fusion model yielded an accuracy of 74.1%, which was higher than that of the T1 + C (66.7%) and T2 (59.3%) image feature-based models. Conclusion The MRI radiomics-based machine learning model is a feasible method to assess contralateral BI-RADS 4 lesions. T2 and T1 + C image features provide complementary information in discriminating benign and malignant contralateral BI-RADS 4 lesions.

Objective To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC). Methods The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0, Highlights • Radiation treatment is associated with increased contralateral breast cancer risk in some women. • Reproductive status at the time of treatment may modify this relationship. • Some evidence that pregnancy after radiation treatment increases contralateral breast cancer risk.

Summary:. A deep inferior epigastric perforator (DIEP) flap is one of the gold standards for autologous breast reconstructions. However, this flap cannot be chosen again if asynchronous contralateral breast cancer occurs in the future. To solve this problem, we propose an idea and design for a hemi-abdominal DIEP flap. The patient was a 50-year-old woman who was suffering from right invasive ductal carcinoma. In using a hemi-abdominal DIEP flap, the poor postoperative appearance of the donor site might be a problem. To obtain a good donor site shape, we use a specific design to make the appearance of the donor site as good as possible. Specifically, we make an oblique spindle-shaped flap that can cover the deep inferior epigastric perforators, the superficial circumflex iliac artery, and the superficial inferior epigastric artery and avoid dog-ears, without passing over the median line. The flap weight was 800 g, the operating time was 6 hours and 22 minutes, and the bleeding amount was 110 ml. The patient had a minor wound infection in the donor site, and it was treated with a local wound treatment. The patient is satisfied with the result. We believe our flap design could minimize the unfavorable appearance of the donor site. This method might be suited to cases where the patients present with excess skin and fat on the abdomen, and half the abdominal tissue is enough to create the necessary volume of the breast. Although more cases and studies will be required to justify our technique, this case may show the possibility of a new option for breast reconstructions.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Background In patients with ductal carcinoma in situ (DCIS), the risk of developing contralateral breast cancer (CBC) and the role of adjuvant endocrine therapy (ET) in decreasing CBC risk is not well understood. Methods A retrospective review was performed on patients with DCIS who underwent a unilateral mastectomy (UM) from 2000 to 2010. CBC incidence, time to CBC and disease free survival were evaluated for women who took ET versus those who did not. Results 176 patients underwent a UM for DCIS, 72% were ER positive and 16% of patients took ET. At a median of 12 year follow up, 15 patients experienced CBC. Women over 63 years had highest incidence of CBC. CBC risk was not different between those who took ET versus those who did not. Conclusion The overall incidence of CBC was 9% in our DCIS cohort and was not significantly different among patients who took ET versus those who did not.

Background Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). Methods We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. Results The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. Conclusions Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making. ispartof: BREAST CANCER RESEARCH AND TREATMENT vol:181 issue:2 pages:423-434 ispartof: location:Netherlands status: published

This cohort study examines whether mammographic density is associated with an increased risk of contralateral breast cancer or ipsilateral breast tumor recurrence among women.