Outcome without any adjuvant systemic treatment in stage I ER+/HER2- breast cancer patients included in the MINDACT trial.

BACKGROUND: Adjuvant systemic treatments (AST) reduce mortality, but have associated short- and long-term toxicities. Careful selection of patients likely to benefit from AST is needed. We evaluated outcome of low-risk breast cancer patients of the EORTC 10041/BIG 3-04 MINDACT trial who received no AST. PATIENTS AND METHODS: Patients with estrogen receptor-positive, HER2-negative, lymph node-negative tumors ≤2 cm who received no AST were matched 1 : 1 to patients with similar tumor characteristics treated with adjuvant endocrine therapy (ET), using propensity score matching and exact matching on age, genomic risk (70-gene signature) and grade. In a post hoc analysis, distant metastasis-free interval (DMFI) and overall survival (OS) were assessed by Kaplan-Meier analysis and hazard ratios (HR) by Cox regression. Cumulative incidences of locoregional recurrence (LRR) and contralateral breast cancer (CBC) were assessed with competing risk analyses. RESULTS: At 8 years, DMFI rates were 94.8% [95% confidence interval (CI) 92.7% to 96.9%] in 509 patients receiving no AST, and 97.3% (95% CI 95.8% to 98.8%) in 509 matched patients who received only ET [absolute difference: 2.5%, HR 0.56 (95% CI 0.30-1.03)]. No statistically significant difference was seen in 8-year OS rates, 95.4% (95% CI 93.5% to 97.4%) in patients receiving no AST and 95.6% (95% CI 93.8% to 97.5%) in patients receiving only ET [absolute difference: 0.2%, HR 0.86 (95% CI 0.53-1.41)]. Cumulative incidence rates of LRR and CBC were 4.7% (95% CI 3.0% to 7.0%) and 4.6% (95% CI 2.9% to 6.9%) in patients receiving no AST versus 1.4% (95% CI 0.6% to 2.9%) and 1.5% (95% CI 0.6% to 3.1%) in patients receiving only ET. CONCLUSIONS: In patients with stage I low-risk breast cancer, the effect of ET on DMFI was limited, but overall significantly fewer breast cancer events were observed in patients who received ET, after the relatively short follow-up of 8 years. These benefits and side-effects of ET should be discussed with all patients, even those at a very low risk of distant metastasis.

Methodological guidance for the evaluation and updating of clinical prediction models: a systematic review.

BACKGROUND: Clinical prediction models are often not evaluated properly in specific settings or updated, for instance, with information from new markers. These key steps are needed such that models are fit for purpose and remain relevant in the long-term. We aimed to present an overview of methodological guidance for the evaluation (i.e., validation and impact assessment) and updating of clinical prediction models. METHODS: We systematically searched nine databases from January 2000 to January 2022 for articles in English with methodological recommendations for the post-derivation stages of interest. Qualitative analysis was used to summarize the 70 selected guidance papers. RESULTS: Key aspects for validation are the assessment of statistical performance using measures for discrimination (e.g., C-statistic) and calibration (e.g., calibration-in-the-large and calibration slope). For assessing impact or usefulness in clinical decision-making, recent papers advise using decision-analytic measures (e.g., the Net Benefit) over simplistic classification measures that ignore clinical consequences (e.g., accuracy, overall Net Reclassification Index). Commonly recommended methods for model updating are recalibration (i.e., adjustment of intercept or baseline hazard and/or slope), revision (i.e., re-estimation of individual predictor effects), and extension (i.e., addition of new markers). Additional methodological guidance is needed for newer types of updating (e.g., meta-model and dynamic updating) and machine learning-based models. CONCLUSION: Substantial guidance was found for model evaluation and more conventional updating of regression-based models. An important development in model evaluation is the introduction of a decision-analytic framework for assessing clinical usefulness. Consensus is emerging on methods for model updating.

Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer.

PURPOSE: Studies have shown that screen detection by national screening programs is independently associated with better prognosis of breast cancer. The aim of this study is to evaluate the association between tumor biology according to the 70-gene signature (70-GS) and survival of patients with screen-detected and interval breast cancers. METHODS: All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041/BIG3-04) accrued 2007-2011, who participated in the national screening program (biennial screening, ages 50-75) were included (n = 1102). Distant Metastasis-Free Interval (DMFI) was evaluated according to the 70-GS for patients with screen-detected (n = 754) and interval cancers (n = 348). RESULTS: Patients with screen-detected cancers had 8-year DMFI rates of 98.2% for 70-GS ultralow-, 94.6% for low-, and 93.8% for high-risk tumors (p = 0.4). For interval cancers, there was a significantly lower 8-year DMFI rate for patients with 70-GS high-risk tumors (85.2%) compared to low- (92.2%) and ultralow-risk tumors (97.4%, p = 0.0023). Among patients with 70-GS high-risk tumors, a significant difference in 8-year DMFI rate was observed between interval (85.2%, n = 166) versus screen-detected cancers (93.8%, n = 238; p = 0.002) with a HR of 2.3 (95%CI 1.2-4.4, p = 0.010) adjusted for clinical-pathological characteristics and adjuvant systemic treatment. CONCLUSION: Among patients with 70-GS high-risk tumors, a significant difference in DMFI was observed between screen-detected and interval cancers, suggesting that method of detection is an additional prognostic factor in this subgroup and should be taken into account when deciding on adjuvant treatment strategies.

Suspended mid-infrared waveguides for Stimulated Brillouin Scattering.

We theoretically investigate a new class of silicon waveguides for achieving Stimulated Brillouin Scattering (SBS) in the mid-infrared (MIR). The waveguide consists of a rectangular core supporting a low-loss optical mode, suspended in air by a series of transverse ribs. The ribs are patterned to form a finite quasi-one-dimensional phononic crystal, with the complete stopband suppressing the transverse leakage of acoustic waves, confining them to the core of the waveguide. We derive a theoretical formalism that can be used to compute the opto-acoustic interaction in such periodic structures, and find forward intramodal-SBS gains up to 1750 m-1W-1, which compares favorably with the proposed MIR SBS designs based on buried germanium waveguides. This large gain is achieved thanks to the nearly complete suppression of acoustic radiative losses.

The role of Indonesian patients' health behaviors in delaying the diagnosis of nasopharyngeal carcinoma.

BACKGROUND: With an estimated 13,000 newly diagnosed patients per year, nasopharyngeal carcinoma (NPC) is one of the most common types of cancer in males in Indonesia. Moreover, most patients are diagnosed at an advanced stage of the disease. This study aimed to explore the health behaviors of patients diagnosed with NPC and the possible causes of patient delay in NPC diagnosis. METHODS: A qualitative research method was used to gain better insight into patient behaviors. Twelve patients were interviewed using semi-structured interview guidelines. All interviews were recorded, transcribed verbatim and analyzed according to a standard content analysis framework. RESULTS: Most patients had limited knowledge regarding NPC and its causes. Fifty percent of the patients had a delay of six months from the onset of symptoms to diagnosis. The main reason for this delay was the lack of awareness among the patients, which was influenced by their environment, economic status, family, culture, and religion. The perceived barriers to seeking medical help included direct non-medical costs not covered by health insurance, complex and time-consuming insurance and referral systems, and negative experiences in the past. Health insurance did motivate people to seek medical help. CONCLUSION: This study provides additional insight into patients' motivations to delay seeking medical help and can facilitate the design of NPC education programs. To improve awareness of the abovementioned causes for delay, community-based education programs are highly warranted and should focus on the recognition of NPC symptoms and possible solutions to overcome the main barriers at an earlier disease stage.

Long-term impact of the 70-gene signature on breast cancer outcome.

Several studies have validated the prognostic value of the 70-gene prognosis signature (MammaPrint(R)), but long-term outcome prediction of these patients has not been previously reported. The follow-up of the consecutively treated cohort of 295 patients (<53 years) with invasive breast cancer (T1-2N0-1M0; n = 151 N0, n = 144 N1) diagnosed between 1984 and 1995, in which the 70-gene signature was previously validated, was updated. The median follow-up for this series is now extended to 18.5 years. A significant difference is seen in long-term distant metastasis-free survival (DMFS) for the patients with a low- and a high-risk 70-gene signature (DMFS p < 0.0001), as well as separately for node-negative (DMFS p < 0.0001) and node-positive patients (DMFS p = 0.0004). The 25-year hazard ratios (HRs) for all patients for DMFS and OS were 3.1 (95 % CI 2.02-4.86) and 2.9 (95 % CI 1.90-4.28), respectively. The HRs for DMFS and OS were largest in the first 5 years after diagnosis: 9.6 (95 % CI 4.2-22.1) and 11.3 (95 % CI 3.5-36.4), respectively. The 25-year HRs in the subgroup of node-negative patients for DMFS and OS were 4.57 (95 % CI 2.31-9.04) and 4.73 (95 % CI 2.46-9.07), respectively, and for node-positive patients for DMFS and OS were 2.24 (95 % CI 1.25-4.00) and 1.83 (95 % CI 1.07-3.11), respectively. The 70-gene signature remains prognostic at longer follow-up in patients <53 years of age with stage I and II breast cancer. The 70-gene signature's strongest prognostic power is seen in the first 5 years after diagnosis.

Mammographic screening detects low-risk tumor biology breast cancers.

Overdiagnosis of breast cancer, i.e. the detection of slow-growing tumors that would never have caused symptoms or death, became more prevalent with the implementation of population-based screening. Only rough estimates have been made of the proportion of patients that are overdiagnosed and identification of those patients is difficult. Therefore, the aim of this study is to evaluate whether tumor biology can help identify patients with screen-detected tumors at such a low risk of recurrence that they are likely to be overdiagnosed. Furthermore, we wish to evaluate the impact of the transition from film-screen mammography (FSM) to the more sensitive full-field digital mammography (FFDM) on the biology of the tumors detected by each screening-modality. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041) accrued 2007-2011, who participated in the national screening program (biennial screening ages 50-75) were included (n = 1,165). We calculated the proportions of high-, low- and among those the ultralow-risk tumors according to the 70-gene signature for patients with screen-detected (n = 775) and interval (n = 390) cancers for FSM and FFDM. Screen-detected cancers had significantly more often a low-risk tumor biology (68 %) of which 54 % even an ultralow-risk compared to interval cancers (53 % low-, of which 45 % ultralow-risk (p = 0.001) with an OR of 2.33 (p < 0.0001; 95 % CI 1.73-3.15). FFDM detected significantly more high-risk tumors (35 %) compared to FSM (27 %) (p = 0.011). Aside from favorable clinico-pathological factors, screen-detected cancers were also more likely to have a biologically low-risk or even ultralow-risk tumor. Especially for patients with screen-detected cancers the use of tools, such as the 70-gene signature, to differentiate breast cancers by risk of recurrence may minimize overtreatment. The recent transition in screening-modalities led to an increase in the detection of biologically high-risk cancers using FFDM.

Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms.

Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70-gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction.

Polarization control of metal-enhanced fluorescence in hybrid assemblies of photosynthetic complexes and gold nanorods.

Fluorescence imaging of hybrid nanostructures composed of a bacterial light-harvesting complex LH2 and Au nanorods with controlled coupling strength is employed to study the spectral dependence of the plasmon-induced fluorescence enhancement. Perfect matching of the plasmon resonances in the nanorods with the absorption bands of the LH2 complexes facilitates a direct comparison of the enhancement factors for longitudinal and transverse plasmon frequencies of the nanorods. We find that the fluorescence enhancement due to excitation of longitudinal resonance can be up to five-fold stronger than for the transverse one. We attribute this result, which is important for designing plasmonic functional systems, to a very different distribution of the enhancement of the electric field due to the excitation of the two characteristic plasmon modes in nanorods.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Outcome of BRCA1- compared with BRCA2-associated ovarian cancer: a nationwide study in the Netherlands.

BACKGROUND: Recent studies suggested an improved overall survival (OS) for BRCA2- versus BRCA1-associated epithelial ovarian cancer (EOC), whereas the impact of chemotherapy is not yet clear. In a nationwide cohort, we examined the results of primary treatment, progression-free survival (PFS), treatment-free interval (TFI), and OS of BRCA1 versus BRCA2 EOC patients. METHODS: Two hundred and forty-five BRCA1- and 99 BRCA2-associated EOC patients were identified through all Dutch university hospitals. Analyses were carried out with the Pearson's Chi-square test, Kaplan-Meier, and Cox regression methods. RESULTS: BRCA1 patients were younger at EOC diagnosis than BRCA2 patients (51 versus 55 years; P < 0.001), without differences regarding histology, tumor grade, and International Federation of Gynecology and Obstetrics (FIGO) stage. Complete response rates after primary treatment, including chemotherapy, did not differ between BRCA1 (86%) and BRCA2 patients (90%). BRCA1 versus BRCA2 patients had a shorter PFS (median 2.2 versus 3.9 years, respectively; P = 0.006), TFI (median 1.7 versus 2.8 years; P = 0.009), and OS (median 6.0 versus 9.7 years; P = 0.04). Differences could not be explained by age at diagnosis, FIGO stage or type of treatment. CONCLUSIONS: PFS and OS were substantially longer in BRCA2- than in BRCA1-associated EOC patients. While response rates after primary treatment were similarly high in both groups, TFI, as surrogate for chemosensitivity, was significantly longer in BRCA2 patients.

Inferior survival for young patients with contralateral compared to unilateral breast cancer: a nationwide population-based study in the Netherlands.

To compare overall survival between women with unilateral breast cancer (UBC) and contralateral breast cancer (CBC). Women with UBC (N = 182,562; 95 %) and CBC (N = 8,912; 5 %) recorded in the Netherlands Cancer Registry between 1989 and 2008 were included and followed until 2010. We incorporated CBC as a time-dependent covariate to compute the overall mortality rate ratio between women with CBC and UBC. Prognostic factors for overall death were examined according to age at first breast cancer. Women with CBC exhibited a 30 % increase in overall mortality (Hazard Ratio (HR), 95 % Confidence Interval: 1.3, 1.3-1.4) compared with UBC, decreasing with rising age at diagnosis of first breast cancer (<50 years: 2.3, 2.2-2.5 vs. ≥70 years: 1.1, 1.0-1.1). Women older than 50 years at CBC diagnosis and diagnosed 2-5 years after their first breast cancer exhibited a 20 % higher death risk (1.2, 1.0-1.3) compared to those diagnosed within the first 2 years. In women younger than 50 years, the HR was significantly lower if the CBC was diagnosed >5 years after the first breast cancer (0.7, 0.5-0.9). The prognosis for women with CBC significantly improved over time (2004-2008: 0.6, 0.5-0.7 vs. 1989-1993). Women with CBC had a lower survival compared to women with UBC, especially those younger than 50 years at first breast cancer diagnosis. A tailored follow-up strategy beyond current recommendations is needed for these patients who, because of their age and absence of known familial risk, are currently not invited for population-based screening.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Dielectric antennas--a suitable platform for controlling magnetic dipolar emission.

Plasmonic nanoparticles are commonly used to tune and direct the radiation from electric dipolar emitters. Less progress has been made towards understanding complementary systems of magnetic nature. However, it has been recently shown that high-index dielectric spheres can act as effective magnetic antennas. Here we explore the concept of coupling dielectric magnetic antennas with either an electric or magnetic dipolar emitter in a similar fashion to the purely electric systems reported previously. We investigate the enhancement of radiation from systems comprising admixtures of these electric and magnetic elements and perform a full study of its dependence on the distance and polarization of the emitter with respect to the antenna. A comparison to the plasmon antennas reveals remarkable symmetries between electric and magnetic systems, which might lead to novel paradigms in the design of nanophotonic devices that involve magnetic activity.

Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk.

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.

BACKGROUND: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-like(CGH) classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. PATIENTS AND METHODS: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). RESULTS: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-like(CGH) tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04-0.43] compared with patients with non-BRCA1-like(CGH) tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50-1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-like(CGH) tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). CONCLUSION: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.

The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age.

BACKGROUND: The majority of breast cancer patients are postmenopausal women who are increasingly being offered adjuvant chemotherapy. Since the beneficial effect of chemotherapy in postmenopausal patients predominantly occurs in the first 5 years after diagnosis, a prognostic marker for early events can be of use for adjuvant treatment decision making. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis signature for early events in postmenopausal patients. METHODS: Frozen tumor samples from 148 patients aged 55-70 years were selected (T1-2, N0) and classified by the 70-gene prognosis signature (MammaPrint) into good or poor prognosis. Eighteen percent received hormonal therapy. RESULTS: Breast cancer-specific survival (BCSS) at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036). The 70-gene prognosis signature was a significant and independent predictor of BCCS during the first 5 years of follow-up with an adjusted hazard ratio of 14.4 (95% confidence interval 1.7-122.2; P = 0.01) at 5 years. CONCLUSION: The 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.

A trial of consent procedures for future research with clinically derived biological samples.

BACKGROUND: The aims of this study were to determine which consent procedure patients prefer for use of stored tissue for research purposes and what the effects of consent procedures on actual consenting behaviour are. METHODS: We offered 264 cancer patients three different consent procedures: 'one-time general consent' (asked written informed consent), 'opt-out plus' (had the opportunity to opt out by a form), or the standard hospital procedure (control group). The two intervention groups received a specific leaflet about research with residual tissue and verbal information. The control group only received a general hospital leaflet including opt-out information, which is the procedure currently in use. Subsequently, all patients received a questionnaire to examine their preferences for consent procedures. RESULTS: In all, 99% of patients consented to research with their residual tissue. In the 'one-time consent' group 85% sent back their consent form. Patients preferred 'opt-out plus' (43%) above 'one-time consent' (34%) or 'opt-out' (16%), whereas 8% indicated that they did not need to receive information about research with residual tissues or be given the opportunity to make a choice. CONCLUSIONS: The 'opt-out plus' procedure, which places fewer demands on administrative resources than 'one-time consent', can also address the information needs of patients.

Breast cancer-related deaths according to grade in ductal carcinoma in situ: A Dutch population-based study on patients diagnosed between 1999 and 2012.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has drastically increased over the past decades. Because DCIS is resected after diagnosis similar to invasive breast cancer, the natural cause and behaviour of DCIS is not well known. We aimed to determine breast cancer-specific survival (BCSS) and overall survival (OS) according to grade in DCIS patients after surgical treatment in the Netherlands. PATIENTS AND METHODS: All DCIS patients diagnosed between 1999 and 2012 were selected from the Netherlands Cancer Registry. The cause of death was obtained from 'Statistics Netherlands'. BCSS and OS were estimated using multivariable Cox regression in the entire cohort and stratified for grades. RESULTS: In total, 12,256 patients were included, of whom 1509 (12.3%) presented with grade I, 3675 (30.0%) with grade II, 6064 (49.5%) with grade III and 1008 (8.2%) with an unknown grade. During a median follow-up of 7.8 years, 1138 (9.3%) deaths were observed, and 179 (1.5%) were breast cancer-related. Of these, 10 patients had grade I; 46 grade II; 95 grade III and 28 an unknown grade. After adjustment for confounding, grade II and III were related to worse BCSS than grade I with hazard ratios of 1.92 (95% confidence interval [CI]: 0.97-3.81) and 2.14 (95% CI: 1.11-4.12), respectively. No association between grades and OS was observed. CONCLUSION: BCSS and OS in DCIS patients were excellent. Because superior rates were observed for low-grade DCIS, it seems justified to investigate whether active surveillance may be a balanced alternative for conventional surgical treatment.

An association study of established breast cancer reproductive and lifestyle risk factors with tumour subtype defined by the prognostic 70-gene expression signature (MammaPrint®).

BACKGROUND: Reproductive and lifestyle factors influence both breast cancer risk and prognosis; this might be through breast cancer subtype. Subtypes defined by immunohistochemical hormone receptor markers and gene expression signatures are used to predict prognosis of breast cancer patients based on their tumour biology. We investigated the association between established breast cancer risk factors and the 70-gene prognostication signature in breast cancer patients. PATIENTS AND METHODS: Standardised questionnaires were used to obtain information on established risk factors of breast cancer from the Dutch patients of the MINDACT trial. Clinical-pathological and genomic information were obtained from the trial database. Logistic regression analyses were used to estimate the associations between lifestyle risk factors and tumour prognostic subtypes, measured by the 70-gene MammaPrint® signature (i.e. low-risk or high-risk tumours). RESULTS: Of the 1555 breast cancer patients included, 910 had low-risk and 645 had high-risk tumours. Current body mass index (BMI), age at menarche, age at first birth, age at menopause, hormonal contraceptive use and hormone replacement therapy use were not associated with MammaPrint®. In parous women, higher parity was associated with a lower risk (OR: 0.75, [95% confidence interval {CI}: 0.59-0.95] P = 0.018) and longer breastfeeding duration with a higher risk (OR: 1.03, [95% CI: 1.01-1.05] P = 0.005) of developing high-risk tumours; risk estimates were similar within oestrogen receptor-positive disease. After stratifying by menopausal status, the associations remained present in post-menopausal women. CONCLUSION: Using prognostic gene expression profiles, we have indications that specific reproductive factors may be associated with prognostic tumour subtypes beyond hormone receptor status.