The impact of circulating protein levels identified by affinity proteomics on short-term, overall breast cancer risk.

OBJECTIVE: Current breast cancer risk prediction scores and algorithms can potentially be further improved by including molecular markers. To this end, we studied the association of circulating plasma proteins using Proximity Extension Assay (PEA) with incident breast cancer risk. SUBJECTS: In this study, we included 1577 women participating in the prospective KARMA mammographic screening cohort. RESULTS: In a targeted panel of 164 proteins, we found 8 candidates nominally significantly associated with short-term breast cancer risk (P < 0.05). Similarly, in an exploratory panel consisting of 2204 proteins, 115 were found nominally significantly associated (P < 0.05). However, none of the identified protein levels remained significant after adjustment for multiple testing. This lack of statistically significant findings was not due to limited power, but attributable to the small effect sizes observed even for nominally significant proteins. Similarly, adding plasma protein levels to established risk factors did not improve breast cancer risk prediction accuracy. CONCLUSIONS: Our results indicate that the levels of the studied plasma proteins captured by the PEA method are unlikely to offer additional benefits for risk prediction of short-term overall breast cancer risk but could provide interesting insights into the biological basis of breast cancer in the future.

PREDICT validity for prognosis of breast cancer patients with pathogenic BRCA1/2 variants.

We assessed the PREDICT v 2.2 for prognosis of breast cancer patients with pathogenic germline BRCA1 and BRCA2 variants, using follow-up data from 5453 BRCA1/2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC). PREDICT for estrogen receptor (ER)-negative breast cancer had modest discrimination for BRCA1 carrier patients overall (Gönen & Heller unbiased concordance 0.65 in CIMBA, 0.64 in BCAC), but it distinguished clearly the high-mortality group from lower risk categories. In an analysis of low to high risk categories by PREDICT score percentiles, the observed mortality was consistently lower than the expected mortality, but the confidence intervals always included the calibration slope. Altogether, our results encourage the use of the PREDICT ER-negative model in management of breast cancer patients with germline BRCA1 variants. For the PREDICT ER-positive model, the discrimination was slightly lower in BRCA2 variant carriers (concordance 0.60 in CIMBA, 0.65 in BCAC). Especially, inclusion of the tumor grade distorted the prognostic estimates. The breast cancer mortality of BRCA2 carriers was underestimated at the low end of the PREDICT score distribution, whereas at the high end, the mortality was overestimated. These data suggest that BRCA2 status should also be taken into consideration with tumor characteristics, when estimating the prognosis of ER-positive breast cancer patients.

Adherence to endocrine therapy in early breast cancer in relation to Cytochrome P450 2D6 genotype: a comparison between pharmacy dispensation data and medical records.

PURPOSE: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been described. The main aim of this study was to investigate the consistency between pharmacy dispensation data and medical records on adherence to AET. METHODS: Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate ≥ 80%. Subgroup analyses were performed based on menopausal status, recurrence risk and CYP2D6 activity. RESULTS: In 86% of the 1235 included patients the consistency between the two sources of information was within 80-125%. Poor consistency, < 80%, was most frequent in the premenopausal/ high-risk group and CYP2D6 Poor Metabolizers (PMs). Among 899 patients with at least 4.5 years follow up, 72% were adherent to tamoxifen based on pharmacy dispensation data, compared with 77% as reported by medical records. When including patients who switched to aromatase inhibitors after tamoxifen, adherence increased to 82% and 88%, respectively. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PMs had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). CONCLUSIONS: There was a good consistency between medical records and pharmacy dispensing data on the use of AET. Adherence to AET was adequate, especially when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a likely reduced risk of side effects according to previous data.

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1-25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10-11), 11q22.3 (OR 2.4; p 5.2 × 10-9), 15q11.2 (OR 3.6; p 2.3 × 10-8), 16q24.1 (OR 3; p 3 × 10-8) and Xq21.31 (OR 3.3; p 1.7 × 10-8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

Estrogen therapy after breast cancer diagnosis and breast cancer mortality risk.

PURPOSE: The safety of local estrogen therapy in patients on adjuvant endocrine treatment is questioned, but evidence on the issue is scarce. This nested case-control registry-based study aimed to investigate whether estrogen therapy affects breast cancer mortality risk in women on adjuvant endocrine treatment. METHODS: In a cohort of 15,198 women diagnosed with early hormone receptor (HR)-positive breast cancer and adjuvant endocrine treatment, 1262 women died due to breast cancer and were identified as cases. Each case was matched with 10 controls. Exposure to estrogen therapy with concurrent use of aromatase inhibitors (AIs), tamoxifen, or both sequentially, was compared between cases and controls. RESULTS: No statistically significant difference in breast cancer mortality risk was seen in patients with exposure to estrogen therapy concurrent to endocrine treatment, neither in short-term or in long-term estrogen therapy use. CONCLUSIONS: The study strengthens current evidence on local estrogen therapy use in breast cancer survivors, showing no increased risk for breast cancer mortality in patients on adjuvant AIs or tamoxifen.

Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer: Results from the Randomized PREDIX HER2 Trial.

PURPOSE: PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors. PATIENTS AND METHODS: In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of TILs [digital TILs (DTIL)] was performed in digitized full-face sections. RESULTS: After a median follow-up of 5.21 years, there was no difference between the two treatment groups in terms of EFS [HR = 1.26; 95% confidence interval (CI), 0.54-2.91], RFS (HR = 0.69; 95% CI, 0.24-1.93), or OS (HR = 0.52; 95% CI, 0.09-2.82). Higher SUVmax at cycle 2 (C2) predicted lower pCR (ORadj = 0.65; 95% CI, 0.48-0.87; P = 0.005) and worse EFS (HRadj = 1.27; 95% CI, 1.12-1.41; P < 0.001). Baseline TILs and DTILs provided additional prognostic information to clinical parameters and C2 SUVmax. CONCLUSIONS: Long-term outcomes following neoadjuvant T-DM1 were similar to neoadjuvant THP. SUVmax after two cycles of neoadjuvant therapy for HER2-positive breast cancer may be an independent predictor of both short- and long-term outcomes. Combined assessment with TILs may facilitate early selection of poor responders for alternative treatment strategies.

Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction.

Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.

PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients.

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.

Real World Evaluation of the Prosigna/PAM50 Test in a Node-Negative Postmenopausal Swedish Population: A Multicenter Study.

Molecular signatures to guide decisions for adjuvant chemotherapy are recommended in early ER-positive, HER2-negative breast cancer. The objective of this study was to assess what impact gene-expression-based risk testing has had following its recommendation by Swedish national guidelines. Postmenopausal women with ER-positive, HER2-negative and node negative breast cancer at intermediate clinical risk and eligible for chemotherapy were identified retrospectively from five Swedish hospitals. Tumor characteristics, results from Prosigna® test and final treatment decision were available for all patients. Treatment recommendations were compared with the last version of regional guidelines before the introduction of routine risk signature testing. Among the 360 included patients, 41% (n = 148) had a change in decision for adjuvant treatment based on Prosigna® test result. Out of the patients with clinical indication for adjuvant chemotherapy, 52% (n = 118) could avoid treatment based on results from Prosigna® test. On the contrary, 23% (n = 30) of the patients with no indication were escalated to receive adjuvant chemotherapy after testing. Ki67 could not distinguish between the Prosigna® risk groups or intrinsic subtypes and did not significantly differ between patients in which decision for adjuvant therapy was changed based on the test results. In conclusion, we report the first real-world data from implementation of gene-expression-based risk assessment in a Swedish context, which may facilitate the optimization of future versions of the national guidelines.

Time to Mammographic Density Decrease After Exposure to Tamoxifen.

Mammographic density change has proven to be a reliable proxy for tamoxifen therapy response. The primary aim of this study was to identify time to tamoxifen-induced mammographic density change. We also analyzed side effects and adherence to therapy. In all, 42 women were randomized to 10 or 20 mg of daily oral tamoxifen. Mammograms were taken at baseline, 3, 6, and 9 months. Mammographic density change was measured using the automated STRATUS tool. Adverse events were monitored through a web-based questionnaire based on the FACT-ES tool. Nine out of the 42 (21%) participants discontinued therapy due to adverse events leaving 33 women in the study. A significant decrease in density was seen after 3 months of therapy. Dose did not seem to affect density change, side effects or adherence. Given the size of the study, additional studies are needed to confirm our data.

A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16.

(1) Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2) Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1−25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 × 10−8), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2−25 and 113 risk haplotypes of window size 50 at p < 5 × 10−8 on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4) Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

Impact of systemic adjuvant therapy and CYP2D6 activity on mammographic density in a cohort of tamoxifen-treated breast cancer patients.

PURPOSE: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. METHODS: Swedish breast cancer patients (n = 699)  operated 2006-2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. RESULTS: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. CONCLUSION: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial.

PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms. PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis. RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group. CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer.

PURPOSE: To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer. PATIENTS AND METHODS: We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. We investigated whether metabolizer status was associated with tamoxifen discontinuation and prognosis for breast cancer using Cox regression analysis. RESULTS: The 6-month discontinuation rates of tamoxifen among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 7.1%, 7.6%, 6.7%, and 18.8%, respectively. A U-shaped association was found between CYP2D6 metabolizer status and breast cancer-specific mortality, with adjusted hazard ratios of 2.59 (95% CI, 1.01 to 6.67) for poor, 1.48 (95% CI, 0.72 to 3.05) for intermediate, 1 (reference) for normal, and 4.52 (95% CI, 1.42 to 14.37) for ultrarapid CYP2D6 metabolizers. CONCLUSION: Both poor and ultrarapid CYP2D6 metabolizers of tamoxifen have a worse prognosis for breast cancer compared with normal metabolizers after receiving a standard dose of tamoxifen. This U-shaped association might call for individualized tamoxifen dosage.

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation.

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.

Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer.

INTRODUCTION: Heritage is the most important risk factor for breast cancer. About 15-20% of breast cancer is familial, referring to affected women who have one or more first- or second-degree relatives with the disease. The heritable component in these families is substantial, especially in families with aggregation of breast cancer with low age at onset. Identifying breast cancer susceptibility genes: Since the discovery of the highly penetrant autosomal dominant susceptibility genes BRCA1 and BRCA2 in the 1990s, several more breast cancer genes that confer a moderate to high risk of breast cancer have been identified. Furthermore, during the last decade, advances in genomic technologies have led to large scale genotyping in genome-wide association studies that have identified a considerable amount of common low penetrance loci. In total, the high risk genes, BRCA1, BRCA2, TP53, STK11, CD1 and PTEN account for approximately 20% of the familial risk. Moderate risk variants account for up to 5% of the inherited familial risk. The more than 180 identified low-risk loci explain 18% of the familial risk. Altogether more than half of the genetic background in familial breast cancer remains unclear. Other genes and low risk loci that explain a part the remaining fraction will probably be identified. Clinical aspects and future perspectives: Definitive clinical recommendations can be drawn only for carriers of germline variants in a limited number of high and moderate risk genes for which an association with breast cancer has been established. Future progress in evaluating previously identified breast cancer candidate variants and low risk loci as well as exploring new ones can play an important role in improving individual risk prediction in familial breast cancer.

Cognitively active older adults' comprehension and metacomprehension of negated text.

Background/Study context: Previous research has demonstrated that negated text is universally difficult to understand, and while readers are aware of the difficulty, they are not always able to direct this awareness to improve their comprehension of negation. The present research aimed to determine whether this holds true for older adults, even while maintaining good cognitive function through reading activity. METHODS: The study used an online paradigm, where young (age range 19-24) and older (age range 60-87) adults read passages, rated their comprehension, and answered questions about what they read. Data analysis included analysis of variance for comprehension accuracy and metacomprehension judgment as well as gamma correlation analysis for the relationship between these two variables to determine accuracy of metacomprehension judgments. RESULT: . Older readers, who took part in library activities and book discussion groups, had better comprehension than young adults overall and were also better able to judge their own comprehension of negative text. CONCLUSION: These results suggested that remaining cognitively active may help older adults not only maintain their ability to understand text but may also enhance their ability to assess their own comprehension of that text. In addition, these readers were likely able to use their experience with reading to compensate for any working memory deficits that may occur with age and which may detrimentally affect their ability to understand complex text constructions, such as negation.

Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer.

PURPOSE: Although adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs. METHODS: The SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18-65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up. RESULTS: A total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up. CONCLUSIONS: In this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.