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Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods.Methods: We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow-up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously-developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies.Results: CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P < 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P < 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low-risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes.Conclusions: These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information. [ABSTRACT FROM AUTHOR]

The clinical utility of the 70-gene signature (MammaPrint®) to guide chemotherapy use in T1-3N0-1M0 breast cancer was demonstrated in the Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) study. One thousand four ninety seven of 3356 (46.2%) enrolled patients with high clinical risk (in accordance with the modified Adjuvant! Online clinical-pathological assessment) had a low-risk 70-gene signature. Using patient-level data from the MINDACT trial, the cost-effectiveness of using the 70-gene signature to guide adjuvant chemotherapy selection for clinical high risk, estrogen receptor positive (ER+), human epidermal growth factor 2 negative (HER2-) patients was analysed. A hybrid decision tree-Markov model simulated treatment strategies in accordance with the 70-gene signature with clinical assessment versus clinical assessment alone, over a 10-year time horizon. Primary outcomes were quality-adjusted life years (QALYs), country-specific costs and incremental cost-effectiveness ratios (ICERs) for six countries: Belgium, France, Germany, Netherlands, UK and the US. Treatment strategies guided by the 70-gene signature result in more QALYs compared with clinical assessment alone. Costs of the 70-gene signature strategy were lower in five of six countries. This led to dominance of the 70-gene signature in Belgium, France, Germany, Netherlands and the US and to a cost-effective situation in the UK (ICER £22,910/QALY). Annual national cost savings were €4.2M (Belgium), €24.7M (France), €45.1M (Germany), €12.7M (Netherlands) and $244M (US). UK budget increase was £8.4M. Using the 70-gene signature to safely guide chemotherapy de-escalation in clinical high risk patients with ER+/HER2- tumours is cost-effective compared with using clinical assessment alone. Long-term follow-up and outcomes from the MINDACT trial are necessary to address uncertainties in model inputs. • The 70-gene signature is cost-effective compared with clinical assessment alone • Minimal survival differences are balanced against quality of life gains • Results are consistent amongst the five studied countries [ABSTRACT FROM AUTHOR]

The great potential for reducing the cancer burden and cancer disparities through prevention and early detection is unrealized at the population level. A new community-based coalition, the San Francisco Cancer Initiative (SF CAN), focuses on the city and county of San Francisco, where cancer is the leading cause of death. SF CAN is an integrated, cross-sector collaboration launched in November 2016. It brings together the San Francisco Department of Public Health; the University of California, San Francisco; major health systems; and community coalitions to exert collective impact. Its goals are to reduce the burden of five common cancers--breast, lung and other tobacco-related, prostate, colorectal, and liver--for which there are proven methods of prevention and detection, while reducing known disparities. We describe the infrastructure, coalition building, and early progress of this initiative, which may serve as a model for other municipalities. [ABSTRACT FROM AUTHOR]

Summary: Background: Adjuvant! is a web-based program that calculates individualised 10-year survival probabilities and predicted benefit of adjuvant systemic therapy. The Adjuvant! model has not been validated in any large European series. The aim of our study was to validate Adjuvant! in Dutch patients, investigating both its calibration and discriminatory accuracy. Methods: Patients who were at least partly treated at the Netherlands Cancer Institute for breast cancer between 1987 and 1998 were included if they met the following criteria: tumour size T1 (≤2 cm), T2 (2–5 cm), or T3 (>5 cm), invasive breast carcinoma, with information about involvement of axillary lymph nodes available, no distant metastases, primary surgery, axillary staging, and radiotherapy according to national guidelines. Clinicopathological characteristics and adjuvant treatment data were retrieved from hospital records and medical registries and were entered into the Adjuvant! (version 8.0) batch processor with blinding to outcome. Endpoints were overall survival and the proportion of patients that did not die from breast cancer (breast-cancer-specific survival [BCSS]). Findings: 5380 patients were included with median follow-up of 11·7 years (range 0·03–21·8). The 10-year observed overall survival (69·0%) and BCSS (78·6%) and Adjuvant! predicted overall survival (69·1%) and BCSS (77·8%) were not statistically different (p=0·87 and p=0·18, respectively). Moreover, differences between predicted and observed outcomes were within 2% for most relevant clinicopathological subgroups. In patients younger than 40 years, Adjuvant! overestimated overall survival by 4·2% (p=0·04) and BCSS by 4·7% (p=0·01). The concordance index, which indicates discriminatory accuracy at the individual level, was 0·71 for BCSS in the entire cohort. Interpretation: Adjuvant! accurately predicted 10-year outcomes in this large-scale Dutch validation study and is of use for adjuvant treatment decision making, although the results may be less reliable in some subgroups. Funding: Dutch National Genomics Initiative-Cancer Genomics Center, Dutch Cancer Society-KWF. [Copyright &y& Elsevier]

Background: Gene-expression–profiling studies of primary breast tumors performed by different laboratories have resulted in the identification of a number of distinct prognostic profiles, or gene sets, with little overlap in terms of gene identity. Methods: To compare the predictions derived from these gene sets for individual samples, we obtained a single data set of 295 samples and applied five gene-expression–based models: intrinsic subtypes, 70-gene profile, wound response, recurrence score, and the two-gene ratio (for patients who had been treated with tamoxifen). Results: We found that most models had high rates of concordance in their outcome predictions for the individual samples. In particular, almost all tumors identified as having an intrinsic subtype of basal-like, HER2-positive and estrogen-receptor–negative, or luminal B (associated with a poor prognosis) were also classified as having a poor 70-gene profile, activated wound response, and high recurrence score. The 70-gene and recurrence-score models, which are beginning to be used in the clinical setting, showed 77 to 81 percent agreement in outcome classification. Conclusions: Even though different gene sets were used for prognostication in patients with breast cancer, four of the five tested showed significant agreement in the outcome predictions for individual patients and are probably tracking a common set of biologic phenotypes. N Engl J Med 2006;355:560-9. [ABSTRACT FROM AUTHOR]

Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial., Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction., Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease., Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted., (©2023 American Association for Cancer Research.)

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer., Competing Interests: Competing interests statement:V.B. and L.L. have filed two patents on ENPP1 inhibitors (PCT/US2020/015968 and PCT/US2018/050018) that are licensed to Angarus Therapeutics. L.L. is a co-founder of Angarus Therapeutics. L.A.G. has filed patents on CRISPR technologies and is a co-founder of Chroma Medicine. All other authors have no additional financial interests.

Background: Early changes in breast intratumor heterogeneity during neoadjuvant chemotherapy may reflect the tumor's ability to adapt and evade treatment. We investigated the combination of precision medicine predictors of genomic and MRI data towards improved prediction of recurrence free survival (RFS)., Methods: A total of 100 women from the ACRIN 6657/I-SPY 1 trial were retrospectively analyzed. We estimated MammaPrint, PAM50 ROR-S, and p53 mutation scores from publicly available gene expression data and generated four, voxel-wise 3-D radiomic kinetic maps from DCE-MR images at both pre- and early-treatment time points. Within the primary lesion from each kinetic map, features of change in radiomic heterogeneity were summarized into 6 principal components., Results: We identify two imaging phenotypes of change in intratumor heterogeneity (p < 0.01) demonstrating significant Kaplan-Meier curve separation (p < 0.001). Adding phenotypes to established prognostic factors, functional tumor volume (FTV), MammaPrint, PAM50, and p53 scores in a Cox regression model improves the concordance statistic for predicting RFS from 0.73 to 0.79 (p = 0.002)., Conclusions: These results demonstrate an important step in combining personalized molecular signatures and longitudinal imaging data towards improved prognosis., (© 2023. The Author(s).)

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers., (© 2021. The Author(s).)

Polymorphisms in the PER3 gene have been associated with several human disease phenotypes, including sleep disorders and cancer. In particular, the long allele of a variable number of tandem repeat (VNTR) polymorphism has been previously linked to an increased risk of breast cancer. Here we carried out a combined germline and somatic genetic analysis of the role of the PER3 VNRT polymorphism in breast cancer. The combined data from 8284 individuals showed a non-significant trend towards increased breast cancer risk in the 5-repeat allele homozygous carriers (OR = 1.17, 95% CI: 0.97-1.42). We observed allelic imbalance at the PER3 locus in matched blood and tumor DNA samples, showing a significant retention of the long variant (risk) allele in tumor samples, and a preferential loss of the short repetition allele (p = 0.0005). Gene co-expression analysis in healthy and tumoral breast tissue samples uncovered significant associations between PER3 expression levels with those from genes which belong to several cancer-associated pathways. Finally, relapse-free survival (RFS) analysis showed that low expression levels of PER3 were linked to a significant lower RSF in luminal A (p = 3 × 10 -12 ) but not in the rest of breast cancer subtypes., (© 2021. The Author(s).)

The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients., Competing Interests: Declaration of interests L. Pusztai has received consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Bristol-Myers Squibb Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Clovis, Syndax, H3Bio, and Daiichi, and Nanostring research support to his institution from AstraZeneca, Pfizer, Merck, Seagen, and Bristol Myers Squibb. H.S. Han: research funding to institution from GlaxoSmithKline, Abbvie, Prescient, G1 Therapeutics, Marker Therapeutics, Novartis, Horizon Pharma, Quantum Leap Healthcare Collaborative, Pfizer, Seattle Genetics, Arvinas, Zymeworks; grants from the Department of Defense, Speaker’s Bureau - Lilly. E. String-Reasor: Consulting Lilly; Susan G. Komen, BCRFA, V Foundation research funding. J.C. Boughey: research funding from Eli Lilly. A.J. Chien: institutional research funding from Seagen, Merck, Amgen, and Puma. R. Nanda: research funding from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics/Gilead, Merck, OBI Pharm, Inc., Odonate Therapeutics, OncoSec, Pfizer, Taiho, SeaGen. A.S. Clark: research funding from Novartis. K. Kalinsky has disclosed advisory/consulting funding from Eli-Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, OncoSec, 4D Pharma, DaicchiSankyo, and Cyclocel. Dr. Kalinsky also reports financial disclosures for his spouse (stock): Grail, Array BioPharma and Pfizer (prior employee). C. Isaacs has received consulting fees from Seattle Genetics, Genentech, AstraZeneca, Novartis, PUMA, Pfizer, and Esai. A. Thomas declares research support (paid to the institution) from Seattle Genetics, Sanofi; stock ownership in Johnson and Johnson, Bristol Myers Squibb, Pfizer, and Gilead; and participation in DSMB (BeyondSpring Pharmaceuticals; and royalties from Up-to-Date). A. Forero-Torres became a Seattle Genetics employee in 2018, and holds stock option from this employment. M.C. Liu received clinical trial research support from Eisai, Genentech, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro. M. Melisko received research funding to the institution from AstraZeneca, Novartis, KCRN Research, and Puma, and consulting fees from Biotheranostics, their spouse received honoraria from Genentech and has stock ownership in Merrimack. E.F. Petricoin: leadership roles in Perthera, Ceres Nanosciences; stock and other ownership interests in Perthera, Ceres Nanosciences, Avant Diagnostics; consulting or advisory roles in Perthera, Ceres Nanosciences, AZGen, Avant Diagnostics; research funding from Ceres Nanosciences (Inst), GlaxoSmithKline (Inst), Abbvie (Inst), Symphogen (Inst), Genentech (Inst); patents, royalties, other intellectual property (National Institutes of Health patents licensing fee distribution/royalty; co-inventor on filed George Mason University–assigned patents related to phosphorylated HER2 and EGFR response predictors for HER family-directed therapeutics, as such can receive royalties and licensing distribution on any licensed IP; travel, accommodations, and expenses from Perthera, Ceres Nanosciences. J.D. Wulfkuhle received honoraria from DAVA Oncology and consults for Baylor College of Medicine, and has disclosed stock ownership in Theralink Technologies, Inc. H.S. Rugo has received research support for clinical trials through the University of California from Pfizer, Merck, Novartis, Lilly, Genentech, Odonate, Daiichi, Seattle Genetics, Eisai, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, and Immunomedics; and Honoraria from Puma, Mylan, and Samsung. L.J. van’t Veer is employed by and a stockholder of Agendia NV. L.J. Esserman is an unpaid member of the board of directors of Quantum Leap Healthcare Collaborative, and received grant funding from QLHC for the I-SPY TRIAL; and is a member of the Blue Cross/Blue Shield Medical Advisory Panel and receives reimbursement for her time and travel. She has a grant from Merck for an Investigator initiated trial of DCIS. The following authors declare no competing interests: C.Y., D.M.W., L.D., A.M.W., A.D., E.H.B., K.S.A., R. Shatsky, L.S., S.M.A., A.W., R. Singhrao, L.S., G.L.H., S.M.B., A.A., J.P., R.B.S., D.Y., N.M.H., K. Kemmer, T.L.H., A.S., J.B.M., W.F.S., A.M.D., and D.A.B., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

Purpose: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer., Patients and Methods: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week., Results: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform)., Conclusion: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

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.

This corrects the article DOI: 10.1038/ncomms5999.

To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer., Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis., Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95)., Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Purpose: Early-stage hormone-receptor positive breast cancer is treated with endocrine therapy and the recommended duration of these treatments has increased over time. While endocrine therapy is considered less of a burden to patients compared to chemotherapy, long-term adherence may be low due to potential adverse side effects as well as compliance fatigue. It is of high clinical utility to identify subgroups of breast cancer patients who may have excellent long-term survival without or with limited duration of endocrine therapy to aid in personalizing endocrine treatment., Methods: We describe a new ultralow risk threshold for the 70-gene signature (MammaPrint) that identifies a group of breast cancer patients with excellent 20 year, long-term survival prognosis. Tumors of these patients are referred to as "indolent breast cancer." We used patient series on which we previously established and assessed the 70-gene signature high-low risk threshold., Results: In an independent validation cohort, we show that patients with indolent breast cancer had 100% breast cancer-specific survival at 15 years of follow-up., Conclusions: Our data indicate that patients with indolent disease may be candidates for limited treatment with adjuvant endocrine therapy based on their very low risk of distant recurrences or death of breast cancer.

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach., (©2015 American Association for Cancer Research.)

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Background: The analytical performance of multigene signatures depends on many parameters, including precision, repeatability, reproducibility and intratumor heterogeneity. Indicators such as sensitivity, specificity, positive predictive value and negative predictive value are typically used to define the clinical performance of a diagnostic test., Aim: Here we study these performance characteristics of the MammaPrint ® (Agendia NV, Amsterdam, The Netherlands) 70-gene signature using the US FDA-recommended guidelines, as well as predetermined acceptance criteria., Results: The clinical and analytical performance characteristics show that MammaPrint is a robust, reproducible, precise test, with a maximum variation of 5% in multiple samplings of the same tissue., Conclusion: MammaPrint is a reliable indicator of distant metastasis in early-stage breast cancer patients of all ages and is well suited for personalized medical care.

The term breast cancer covers many different conditions, whose clinical course ranges from indolent to aggressive. However, current practice in breast cancer prevention and care, and in breast cancer epidemiology, does not take into account the heterogeneity of the disease. A comprehensive understanding of the etiology and progression of different breast cancer subtypes would enable a more patient-centered approach to breast health care: assessing an individual's risk of getting specific subtypes of the disease, providing risk-based screening and prevention recommendations, and, for those diagnosed with the disease, tailored treatment options based on risk and timing of progression and mortality. The Athena Breast Health Network is an initiative of the five University of California medical and cancer centers to prototype this approach and to enable the development of a rapid learning system-connecting risk and outcome information from a heterogeneous patient population in real time and using new knowledge from research to continuously improve the quality of care. The Network is based on integrating clinical and research processes to create a comprehensive approach to accelerating patient-centered breast health care. Since its inception in 2009, the Network has developed a multi-site, transdisciplinary collaboration that enables the learning system. The five-campus collaboration has implemented a shared informatics platform, standardized electronic patient intake questionnaires, and common biospecimen protocols, as well as new clinical programs and multi-center research projects. The Athena Breast Health Network can serve as a model of a rapid learning system that integrates epidemiologic, behavioral, and clinical research with clinical care improvements.

Invasive lobular carcinoma (ILC) has been reported to be less responsive to neoadjuvant chemotherapy (NAC) than invasive ductal carcinoma (IDC). We sought to determine whether ILC histology indeed predicts poor response to NAC by analyzing tumor characteristics such as protein expression, gene expression, and imaging features, and by comparing NAC response rates to those seen in IDC after adjustment for these factors. We combined datasets from two large prospective NAC trials, including in total 676 patients, of which 75 were of lobular histology. Eligible patients had tumors ≥3 cm in diameter or pathologic documentation of positive nodes, and underwent serial biopsies, expression microarray analysis, and MRI imaging. We compared pathologic complete response (pCR) rates and breast conservation surgery (BCS) rates between ILC and IDC, adjusted for clinicopathologic factors. On univariate analysis, ILCs were significantly less likely to have a pCR after NAC than IDCs (11 vs. 25 %, p = 0.01). However, the known differences in tumor characteristics between the two histologic types, including hormone receptor (HR) status, HER2 status, histological grade, and p53 expression, accounted for this difference with the lowest pCR rates among HR+/HER2- tumors in both ILC and IDC (7 and 5 %, respectively). ILC which were HR- and/or HER2+ had a pCR rate of 25 %. Expression subtyping, particularly the NKI 70-gene signature, was correlated with pCR, although the small numbers of ILC in each group precluded significant associations. BCS rate did not differ between IDC and ILC after adjusting for molecular characteristics. We conclude that ILC represents a heterogeneous group of tumors which are less responsive to NAC than IDC. However, this difference is explained by differences in molecular characteristics, particularly HR and HER2, and independent of lobular histology.

Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP inhibitors can act as chemosensitizers, or operate on the principle of synthetic lethality when used as single agent. Clinical trials have shown drugs in this class to be promising for BRCA mutation carriers. We postulated that inability to demonstrate response in non-BRCA carriers in which BRCA is inactivated by other mechanisms or with deficiency in homologous recombination for DNA repair is due to lack of molecular markers that define a responding subpopulation. We identified candidate markers for this purpose for olaparib (AstraZeneca) by measuring inhibitory effects of nine concentrations of olaparib in 22 breast cancer cell lines and identifying features in transcriptional and genome copy number profiles that were significantly correlated with response. We emphasized in this discovery process genes involved in DNA repair. We found that the cell lines that were sensitive to olaparib had a significant lower copy number of BRCA1 compared to the resistant cell lines (p value 0.012). In addition, we discovered seven genes from DNA repair pathways whose transcriptional levels were associated with response. These included five genes (BRCA1, MRE11A, NBS1, TDG, and XPA) whose transcript levels were associated with resistance and two genes (CHEK2 and MK2) whose transcript levels were associated with sensitivity. We developed an algorithm to predict response using the seven-gene transcription levels and applied it to 1,846 invasive breast cancer samples from 8 U133A/plus 2 (Affymetrix) data sets and found that 8-21 % of patients would be predicted to be responsive to olaparib. A similar response frequency was predicted in 536 samples analyzed on an Agilent platform. Importantly, tumors predicted to respond were enriched in basal subtype tumors. Our studies support clinical evaluation of the utility of our seven-gene signature as a predictor of response to olaparib.

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥ 3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.

The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a "more aggressive phenotype" gene expression profile. There was no evidence of such an effect on survival within the TP53-mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations.

Phosphorylation of estrogen receptor α at serine 305 (ERαS305-P) by protein kinase A (PKA) or p21-activated kinase 1 (PAK1) has experimentally been associated with tamoxifen sensitivity. Here, we investigated the clinical application of this knowledge to predict tamoxifen resistance in ER-positive breast cancer patients. Using immunohistochemistry, a score including PAK1 and co-expression of PKA and ERαS305-P (PKA/ERαS305-P) was developed on a training set consisting of 103 patients treated with tamoxifen for metastatic disease, and validated on 231 patients randomized between adjuvant tamoxifen or no treatment. In the training set, PAK1 levels were associated with tumor progression after tamoxifen (HR 1.57, 95% CI 0.99-2.48), as was co-expression of PKA and ERαS305-P (HR 2.00, 95% CI 1.14-3.52). In the validation set, a significant tamoxifen benefit was found among the 73% patients negative for PAK1 and PKA/ERαS305-P (HR 0.54, 95% CI 0.34-0.87), while others (27%) were likely to have no benefit from tamoxifen (HR 0.88, 95% 0.42-1.82). The test for interaction showed a significant difference in recurrence-free survival between groups defined by PAK1 and PKA/ERαS305-P (P = 0.037). Elevated PAK1 and PKA/ERαS305-P appeared to influence tamoxifen sensitivity. Both PAK1 and PKA/ERαS305-P levels were associated with sensitivity to tamoxifen in breast tumors and the combination of these variables should be considered in predicting tamoxifen benefit.

Objective: To predict clinical outcome by classification of peritoneal metastases (PM) of colorectal or appendiceal origin., Background: This study investigates whether standardized histological classification can predict outcome for PM of colorectal or appendiceal origin treated with cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: Histology of PM (n = 269) was evaluated by analysis of mitotic activity, atypia, cellularity, and mucinous component. For overall survival (OS) and disease-free survival (DFS) Cox proportional-hazard models were constructed. Covariates included tumor, patient, and treatment characteristics., Results: PM could be categorized into four groups: low-grade, well-differentiated mucinous tumor (DPAM); intermediated-grade mucinous carcinoma (PMCA-i); high-grade mucinous carcinoma (PMCA); and high-grade nonmucinous carcinoma (PCA). Multivariate analysis showed that histological classification, gender, number of segments affected, completeness of cytoreduction, and HIPEC as primary treatment were significant related to OS and DFS. The 5-year OS was 64% in the DPAM group, 36% in the PMCA group, and 24% in the PCA group. Of PM originating from an appendix tumor, 29% were of non-DPAM type. Of primary colorectal tumors, 37% resulted in mucinous PM, and another 26% of PM of colorectal origin had partly mucinous histology., Conclusion: Histology is a significant predictive factor of OS and DFS in PM treated with surgical cytoreduction and HIPEC. Low-grade PM (DPAM) should be regarded as a separate entity because of its clearly different clinical course. High-grade mucinous PM has significant better prognosis than nonmucinous PM and should thus be distinguished.

Background: Mammographic screening and increased awareness has led to an increase in the detection of T1 breast tumors that are generally estimated as having low risk of recurrence after locoregional treatment. However, even small tumors can metastasize, which leaves us with the question for the necessity of adjuvant treatment. Therefore, additional prognostic markers are needed to tailor adjuvant systemic treatment for these relatively low-risk patients. The aim of our study was to evaluate the accuracy of the 70-gene MammaPrint signature in T1 breast cancer., Materials and Methods: We selected 964 patients from previously reported studies with pT1 tumors (

Annexin A1 (AnxA1) is a candidate regulator of the epithelial- to mesenchymal (EMT)-like phenotypic switch, a pivotal event in breast cancer progression. We show here that AnxA1 expression is associated with a highly invasive basal-like breast cancer subtype both in a panel of human breast cancer cell lines as in breast cancer patients and that AnxA1 is functionally related to breast cancer progression. AnxA1 knockdown in invasive basal-like breast cancer cells reduced the number of spontaneous lung metastasis, whereas additional expression of AnxA1 enhanced metastatic spread. AnxA1 promotes metastasis formation by enhancing TGFbeta/Smad signaling and actin reorganization, which facilitates an EMT-like switch, thereby allowing efficient cell migration and invasion of metastatic breast cancer cells.

BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR(low versus never) = 0.93, 95%CI = 0.60-1.43; HR(medium versus never) = 0.81, 95%CI = 0.51-1.29; HR(high versus never) = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR(medium versus low) = 0.60, 95%CI = 0.38-0.96; HR(high versus low) = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.

The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant treatment decisions. The aim of this study was to assess its value to predict chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of stage II-III patients prior to neoadjuvant chemotherapy and classified the prognosis-signatures. Pathological complete remission (pCR) was used to measure chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%) a good prognosis-signature. None of the good prognosis-signature patients achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38) had a poor prognosis-signature. Within the non triple-negative subgroup, the response of the primary tumor remained associated with the classification of the prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.

In a large retrospective cohort of breast cancer patients, BRCA1 and BRCA2 germline mutations were analysed in DNA isolated from residual paraffin-embedded tissue samples. Because it was not feasible to ask individual for informed consent, a data and DNA coding protocol, based on the Dutch 'Code of Conduct', was developed. The corner stone of the protocol is that a trusted third party, in our case a notary, keeps the coding keys of clinical data and DNA. Because (re)linkage of the combined coded clinical and genotyping data (BRCA1/2) is only possible through the notary's keys, these can be considered to be comparable to anonymised data at the level of the researcher. Issues around retrospective genotyping of allegedly high-risk mutations and the coding procedure itself are discussed. Our protocol is an appropriate solution to safeguard the privacy of patients when using residual tissue or DNA of patients. Importantly, the coding procedure also allows re-linkage of new genotyping data or extended patient follow-up data to the valuable coded dataset.

Purpose: The 70-gene prognosis-signature has shown to be a valid prognostic tool in node-negative breast cancer. Although axillary lymph node status is considered to be one of the most important prognostic factors, still 25-30% of node-positive breast cancer patients will remain free of distant metastases, even without adjuvant systemic therapy. We therefore investigated whether the 70-gene prognosis-signature can accurately identify patients with 1-3 positive lymph nodes who have an excellent disease outcome., Methods: Frozen tumour samples from 241 patients with operable T1-3 breast cancer, and 1-3 positive axillary lymph nodes, with a median follow-up of 7.8 years, were selected from 2 institutes. Using a customized microarray, tumour samples were analysed for the 70-gene tumour expression signature. In addition, we reanalysed part of a previously described cohort (n = 106) with extended follow-up., Results: The 10-year distant metastasis-free (DMFS) and breast cancer specific survival (BCSS) probabilities were 91% (SE 4%) and 96% (SE 2%), respectively for the good prognosis-signature group (99 patients), and 76% (SE 4%) and 76% (SE 4%), respectively for the poor prognosis-signature group (142 patients). The 70-gene signature was significantly superior to the traditional prognostic factors in predicting BCSS with a multivariate hazard ratio (HR) of 7.17 (95% CI 1.81 to 28.43; P = 0.005)., Conclusions: The 70-gene prognosis-signature outperforms traditional prognostic factors in predicting disease outcome in patients with 1-3 positive nodes. Moreover, the signature can accurately identify patients with an excellent disease outcome in node-positive breast cancer, who may be safely spared adjuvant chemotherapy.