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Although it is uncommon in general, breast cancer is the most commonly diagnosed cancer during pregnancy. While treatment for pregnant patients should adhere to treatment guidelines for non-pregnant patients, there exist specific considerations concerning diagnosis, staging, oncological treatment, and obstetrical care. Imaging and staging are preferably performed using breast ultrasound and mammography. Other ionizing radiation imaging modalities, including computed tomography (CT) and Positron Emission Tomography/ Computed Tomography (PET/CT), can be selectively performed when the estimated benefit for the mother outweighs the risks to the foetus, e.g., when the results will change clinical management. MRI is appropriate to stage for distant disease on the indication. Breast cancer during pregnancy is less often hormone receptor-positive and more frequently triple-negative breast cancer compared to age-matched controls. The basic principle is that women should receive state-of-the-art oncological treatment without delay if possible and that the pregnancy should be maintained as long as possible. Treatment strategy should be multidisciplinary defined, carefully weighing the selection, sequence, and timing of treatment modalities depending on patient-, tumour-, and pregnancy-related characteristics, as well as patient preferences. Initiating cancer treatment during pregnancy often decreases the risks of early delivery and prematurity. Breast cancer surgery is possible during all trimesters. Radiotherapy is possible during pregnancy in the first half of pregnancy. Chemotherapy can be safely administered starting from 12 weeks of gestational age, but endocrine and HER2 targeted therapy are contraindicated throughout the whole pregnancy. Importantly, foetal growth should be monitored and long-term follow-up of the children is encouraged in dedicated centres., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Many patients and physicians remain concerned about the potential detrimental effects of pregnancy after breast cancer (BC) in terms of reproductive outcomes and maternal safety. This systematic review and meta-analysis aimed at providing updated evidence on these topics., Methods: A systematic literature review was conducted to identify studies including patients with a pregnancy after BC (PROSPERO number CRD42020158324). Likelihood of pregnancy after BC, their reproductive outcomes, and maternal safety were assessed. Pooled relative risks, odds ratios (ORs), and hazard ratios (HRs) with 95% CIs were calculated using random effects models., Results: Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis. BC survivors were significantly less likely to have a subsequent pregnancy compared with the general population (relative risk, 0.40; 95% CI, 0.32 to 0.49). Risks of caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88), and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33) were significantly higher in BC survivors, particularly in those with previous chemotherapy exposure, compared with the general population. No significantly increased risk of congenital abnormalities or other reproductive complications were observed. Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68). Similar results were observed after correcting for potential confounders and irrespective of patient, tumor, and treatment characteristics, pregnancy outcome, and timing of pregnancy., Conclusion: These results provide reassuring evidence on the safety of conceiving in BC survivors. Patients' pregnancy desire should be considered a crucial component of their survivorship care plan., Competing Interests: Matteo LambertiniConsulting or Advisory Role: Roche, Novartis, Lilly, AstraZenecaSpeakers' Bureau: Theramex, Takeda, Roche, Lilly, Novartis, Pfizer, Sandoz Richard A. AndersonHonoraria: Merck, IBSAConsulting or Advisory Role: NeRRe Therapeutics, Roche Diagnostics, SojournixResearch Funding: Roche Diagnostics Evandro de AzambujaHonoraria: Roche/Genentech, SeaGen, Zodiac PharmaConsulting or Advisory Role: Roche/Genentech, Novartis, Libbs, Pierre FabreResearch Funding: Roche/Genentech, AstraZeneca, Servier/Pfizer, GlaxoSmithKline/NovartisTravel, Accommodations, Expenses: Roche/Genentech, GlaxoSmithKline Philip D. PoorvuOther Relationship: Medscape Cynthia Villarreal-GarzaConsulting or Advisory Role: Roche, Novartis, Pfizer, LillySpeakers' Bureau: Roche, Myriad Genetics, NovartisResearch Funding: AstraZeneca, RocheTravel, Accommodations, Expenses: Roche, MSD Oncology, Pfizer Barbara PistilliConsulting or Advisory Role: Puma Biotechnology, Pierre Fabre, Novartis, Myriad Genetics, AstraZenecaResearch Funding: Pfizer, Puma Biotechnology, Merus, Daiichi-SankyoTravel, Accommodations, Expenses: Pfizer, AstraZeneca, MSD Oncology, Novartis Ines Vaz-LuisHonoraria: AstraZeneca, Amgen, Pfizer Cristina SauraConsulting or Advisory Role: AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Roche, Exeter Pharmaceuticals, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, Puma Biotechnology, Sanofi/Aventis, SeaGen, ZymeworksResearch Funding: Genentech, AstraZeneca, Roche, Macrogenics, Novartis, Pfizer, Puma Biotechnology, Synthon, PiqurTravel, Accommodations, Expenses: Pfizer, Novartis, Roche, AstraZeneca, Genomic Health, Puma Biotechnology Kathryn J. RuddyResearch Funding: MedtronicPatents, Royalties, Other Intellectual Property: Spouse and Mayo Clinic have filed patents related to the application of artificial intelligence to the electrocardiogram for diagnosis and risk stratification, and Spouse and Mayo Clinic are involved in a potential equity or royalty relationship with AliveCor Hatem A. Azim JrEmployment: Innate PharmaStock and Other Ownership Interests: Innate PharmaHonoraria: NovartisConsulting or Advisory Role: DiaacurateSpeakers' Bureau: GlaxoSmithKlineTravel, Accommodations, Expenses: Novartis Frederic AmantConsulting or Advisory Role: Clovis Oncology, AstraZeneca, Samsung Bioepis Isabelle DemeestereConsulting or Advisory Role: RocheResearch Funding: Roche DiagnosticTravel, Accommodations, Expenses: Ferring Lucia Del MastroHonoraria: Roche, Novartis, Lilly, MSD OncologyConsulting or Advisory Role: Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Lilly, Seattle Genetics, Eisai, Pierre Fabre, Daiichi SankyoTravel, Accommodations, Expenses: Roche, Pfizer, Celgene Ann H. PartridgePatents, Royalties, Other Intellectual Property: I receive small royalty payments for coauthoring the breast cancer survivorship section of UpToDateTravel, Accommodations, Expenses: Novartis Olivia PaganiConsulting or Advisory Role: Pfizer, Roche, Novartis, Takeda, Lilly, Debiopharm Group Fedro A. PeccatoriConsulting or Advisory Role: Roche Molecular Diagnostics, IpsenNo other potential conflicts of interest were reported.

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy., Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women., Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates., Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients., Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

In a previous longitudinal diffusion tensor imaging (DTI) study, we observed cerebral white matter (WM) alterations (reduced fractional anisotropy (FA)) related to decreased cognitive performance 3-5 months after chemotherapy-treatment (t2) when compared to baseline (t1) (Deprez et al. in Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30(3), 274-281. doi:10.1200/JCO.2011.36.8571, 2012). The current study investigates the evolution and the nature of these previously observed microstructural changes. Twenty-five young women with early-stage breast cancer who received chemotherapy treatment (C+), 14 who did not receive chemotherapy (C-) and 15 healthy controls (HC) previously studied, underwent reassessment 3-4 years after treatment (t3). We assessed (1) longitudinal changes of cognitive performance and FA and (2) cross-sectional group differences in myelin-water-imaging and multishell diffusion MRI metrics at t3. MRI metrics were assessed on a voxel-by-voxel basis and in regions-of-interest (ROI) in which previous WM injury was detected. Longitudinal results: Mixed-effects modeling revealed significant group-time interactions for verbal memory and processing speed (p < 0.05) reflecting regained performance in the C+ group at t3. Furthermore, in chemotherapy-treated patients, FA returned to baseline levels at t3 in all ROIs (p < 0.002), whereas no FA changes were seen in controls. Additionally, FA increase from t2 to t3 correlated with time since treatment in two of the four regions (r = 0.40, p < 0.05). Cross-sectional results: Advanced diffusion MRI and myelin-water imaging metrics in the ROIs did not differ between groups. Similarly, no whole-brain voxelwise differences were detected. Initial WM alterations and reduced cognitive performance following chemotherapy-treatment were found to recover in a group of young breast cancer survivors three to four years after treatment.

Introduction: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤ 40 years., Methods and Analysis: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle., Ethics and Dissemination: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (). Forms are available on request from the corresponding author. Authors declare the following: SCL reports grants from The Netherlands Organization for Health Research and Development (ZonMW) and A Sister’s Hope during the conduct of the study. SCL also received non-financial support from AstraZeneca, grants from AstraZeneca,Roche and Genentech and other from Novartis, Cergentis, PhilipsHealth BV, Roche and Astra Zeneca outside the submitted work. In addition, SCL has two patents pending (WO/2015/080585,PCT/NL2014/050813). AR reports grants, personal fees and non-financial support from Pfizer, grants and personal fees from Roche, Astra Zeneca, MSD, BMS, Merck and grants from Boehringer Ingelheim and Novartis outside the submitted work. NS reports grants from University Medical Centre Utrecht during the conduct of the study. SMW reports grants and personal fees from Roche, Pfizer, AstraZeneca and personal fees from MSD outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Breast cancer during pregnancy (BCP), although rare, is becoming more common and treatment should be as similar as possible to that for nonpregnant young patients with breast cancer. A group of specialists convened to review current guidelines and provide guidance on how recent advances in breast cancer diagnosis and treatment can be adapted for pregnant patients. The majority of patients with BCP will be considered for treatment during the pregnancy. Premature delivery should be avoided whenever possible. Most treatments, including sentinel lymph node biopsy, systemic therapy with taxanes, platinum agents, or dose-dense treatment can be safely given during pregnancy, after careful risk/benefit assessment for mother and child. Chemotherapy is contraindicated during the first trimester because of a higher risk of fetal malformations but is feasible in the second and third trimesters. Other treatments such as radiation therapy or anti-human epidermal growth receptor 2 treatment are in general not indicated during pregnancy but might be considered in some instances. Patient data should be collected in a systematic way whenever possible.

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types., (© 2015 Society for Endocrinology.)

Diagnosis of breast cancer in young women poses a threat to fertility. Due to a recent trend of delaying pregnancy, an increasing number of breast cancer patients in reproductive age wish to bear children. Health care providers have the responsibility to know how to manage fertility issues in cancer survivors. Oncofertility counseling is of great importance to many young women diagnosed with cancer and should be managed in a multi-disciplinary background. Most of young breast cancer patients are candidate to receive chemotherapy, which could lead to premature ovarian failure. A baseline evaluation of ovarian reserve may help in considering the different fertility preservation options. The choice of the suitable strategy depends also on age, type of chemotherapy, partner status and patients' motivation. Various options are available, some established such as embryo and oocyte cryopreservation, some still experimental such as ovarian tissue cryopreservation and ovarian suppression with GnRHa during chemotherapy. An early referral to a reproductive specialist should be offered to patients at risk of infertility who are interested in fertility preservation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Completion axillary lymph node dissection (cALND) is the golden standard if breast cancer involves the sentinel lymph node (SLN). However, most non-sentinel lymph nodes (NSLN) are not involved, cALND has a considerable complication rate and does not improve outcome. We here present and validate our predictive model for positive NSLNs in the cALND if the SLN is positive. Consecutive early breast cancer patients from one center undergoing cALND for a positive SLN were included. We assessed demographic and clinicopathological variables for NSLN involvement. Uni- and multivariate analysis was performed. A predictive model was built and validated in two external centers. 21.9% of 470 patients had at least one involved NSLN. In univariate analysis, seven variables were significantly correlated with NSLN involvement: tumor size, grade, lymphovascular invasion (LVI), number of positive and negative SLNs, size of SLN metastasis and intraoperative positive SLN. In multivariate analysis, LVI, number of negative SLNs, size of SLN metastasis and intraoperative positive pathological evaluation were independent predictors for NSLN involvement. The calculated risk resulted in an AUC of 0.76. Applied to the external data, the model was accurate and discriminating for one (AUC = 0.75) and less for the other center (AUC = 0.58). A discriminative predictive model was constructed to calculate the risk of NSLN involvement in case of a positive SLN. External validation of our model reveals differences in performance when applied to data from other institutions concluding that such a predictive model requires validation prior to use., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To examine whether cognitive complaints after treatment for breast cancer are associated with detectable changes in brain activity during multitasking., Patients and Methods: Eighteen patients who were scheduled to receive chemotherapy performed a functional magnetic resonance imaging multitasking task in the scanner before the start of treatment (t1) and 4 to 6 months after finishing treatment (t2). Sixteen patients who were not scheduled to receive chemotherapy and 17 matched healthy controls performed the same task at matched intervals. Task difficulty level was adjusted individually to match performance across participants. Statistical Parametric Mapping 8 (SPM8) software was used for within-group, between-group, and group-by-time interaction image analyses., Results: Voxel-based paired t tests revealed significantly decreased activation (P < .05) from t1 to t2 at matched performance in the multitasking network of chemotherapy-treated patients, whereas no changes were noted in either of the control groups. At baseline, there were no differences between the groups. Furthermore, in contrast to controls, the chemotherapy-treated patients reported a significant increase in cognitive complaints (P < .05) at t2. Significant (P < .05) correlations were found between these increases and decreases in multitasking-related brain activation. Moreover, a significant group-by-time interaction (P < .05) was found whereby chemotherapy-treated patients showed decreased activation and healthy controls did not., Conclusion: These results suggest that changes in brain activity may underlie chemotherapy-induced cognitive complaints. The observed changes might be related to chemotherapy-induced damage to the brain or reduced connectivity between brain regions rather than to changes in effort or changes in functional strategy. To the best of our knowledge, this is the first longitudinal study providing evidence for a relationship between longitudinal changes in cognitive complaints and changes in brain activation after chemotherapy., (© 2014 by American Society of Clinical Oncology.)

Background: Little is known about the treatment of breast cancer during pregnancy. We aimed to determine whether treatment for breast cancer during pregnancy is safe for both mother and child., Methods: We recruited patients from seven European countries with a primary diagnosis of breast cancer during pregnancy; data were collected retrospectively if the patient was diagnosed before April, 2003 (when the registry began), or prospectively thereafter, irrespective of the outcome of pregnancy and the type and timing of treatment. The primary endpoint was fetal health for up to 4 weeks after delivery. The registry is ongoing. The study is registered with ClinicalTrials.gov, number NCT00196833., Findings: From April, 2003, to December, 2011, 447 patients were registered, 413 of whom had early breast cancer. Median age was 33 years (range 22-51). At the time of diagnosis, median gestational age was 24 weeks (range 5-40). 197 (48%) of 413 women received chemotherapy during pregnancy with a median of four cycles (range one to eight). 178 received an anthracycline, 15 received cyclophosphamide, methotrexate, and fluorouracil, and 14 received a taxane. Birthweight was affected by chemotherapy exposure after adjustment for gestational age (p=0·018), but not by number of chemotherapy cycles (p=0·71). No statistical difference between the two groups was observed for premature deliveries before the 37th week of gestation. 40 (10%) of 386 infants had side-effects, malformations, or new-born complications; these events were more common in infants born before the 37th week of gestation than they were in infants born in the 37th week or later (31 [16%] of 191 infants vs nine [5%] of 195 infants; p=0·0002). In infants for whom maternal treatment was known, adverse events were more common in those who received chemotherapy in utero compared with those who were not exposed (31 [15%] of 203 vs seven [4%] of 170 infants; p=0·00045). Two infants died; both were exposed to chemotherapy and delivered prematurely, but both deaths were thought not to be related to treatment. Median disease-free survival for women with early breast cancer was 70·6 months (95% CI 62·1-105·5) in women starting chemotherapy during pregnancy and 94·4 months (lower 95% CI 64·4; upper 95% CI not yet reached) in women starting chemotherapy after delivery (unadjusted hazard ratio 1·13 [95% CI 0·76-1·69]; p=0·539)., Interpretation: Although our data show that infants exposed to chemotherapy in utero had a lower birthweight at gestational age than did those who were unexposed, and had more complications, these differences were not clinically significant and, since none of the infants was exposed to chemotherapy in the first trimester, were most likely related to premature delivery. Delay of cancer treatment did not significantly affect disease-free survival for mothers with early breast cancer. Because preterm birth was strongly associated with adverse events, a full-term delivery seems to be of paramount importance., Funding: BANSS Foundation, Biedenkopf, Germany and the Belgian Cancer Plan, Ministry of Health, Belgium., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To uncover the neural substrate of cognitive impairment related to adjuvant chemotherapy, we studied cerebral white matter (WM) integrity before and after chemotherapy by using magnetic resonance diffusion tensor imaging (DTI) in combination with detailed cognitive assessment., Patients and Methods: Thirty-four young premenopausal women with early-stage breast cancer who were exposed to chemotherapy underwent neuropsychologic testing and DTI before the start of chemotherapy (t1) and 3 to 4 months after treatment (t2). Sixteen patients not exposed to chemotherapy and 19 age-matched healthy controls underwent the same assessment at matched intervals. In all groups, we used paired t tests to study changes in neuropsychologic test scores and whole-brain voxel-based paired t tests to study changes in WM fractional anisotropy (FA; a DTI measure that reflects WM tissue organization), with depression scores and intelligence quotient as included covariates. We correlated changes of neuropsychologic test scores with the mean change of FA for regions that survived the paired t tests in patients treated with chemotherapy., Results: In contrast to controls, the chemotherapy-treated group performed significantly worse on attention tests, psychomotor speed, and memory at t2 compared with t1 (P < .05). In the chemotherapy-treated group, we found significant decreases of FA in frontal, parietal, and occipital WM tracts after treatment (familywise error P < .05), whereas for both control groups, FA values were the same between t1 and t2. Furthermore, performance changes in attention and verbal memory correlated with mean regional FA changes in chemotherapy-treated patients (P < .05)., Conclusion: We report evidence of longitudinal changes in cognitive functioning and cerebral WM integrity after chemotherapy as well as an association between both.

Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11,928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer.

Purpose: To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS)., Patients and Methods: The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively., Results: In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer-related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI - PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group., Conclusion: The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.

Aims: To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status., Methods: 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER(-)PR(-)HER-2(-) (NNN; triple negative), ER(-)PR(-)HER-2(+) (NNP), ER(+)PR(-)HER-2(-) (PNN), ER(+)PR(-)HER-2(+) (PNP), ER(+)PR(+)HER-2(- )(PPN), ER(+)PR(+)HER-2(+) (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio chi(2)-tests were used for univariate analysis and logistic regression for multivariate analysis., Results: Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P<0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490-3.156)., Conclusion: Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.

Purpose: The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR+) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure., Materials and Methods: Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR+ advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily., Results: A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane (n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate (7.4% v 6.7%; P = .736) and clinical benefit rate (32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant., Conclusion: Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Objective: Arthralgia, skeletal and muscle pain have been reported in postmenopausal women under treatment with third generation aromatase inhibitors (AIs). However, the pathogenesis and anatomic correlate of musculoskeletal pains have not been thoroughly evaluated. Moreover, the impact of AI-induced musculoskeletal symptoms on normal daily functioning needs to be further explored., Patients and Methods: We examined 12 consecutive non-metastatic breast cancer patients who reported severe musculoskeletal pain under a third generation AI; 11 were on letrozole and 1 on exemestane. Clinical rheumatological examination and serum biochemistry were performed. Radiological evaluation of the hand/wrist joints were performed using ultrasound (US) and/or magnetic resonance imaging (MRI)., Results: The most common reported symptom was severe early morning stiffness and hand/wrist pain causing impaired ability to completely close/stretch the hand/fingers and to perform daily activities and work-related skills. Six patients had to discontinue treatment due to severe symptoms. Trigger finger and carpal tunnel syndrome were the most frequently reported clinical signs. US showed fluid in the tendon sheath surrounding the digital flexor tendons. On MRI, an enhancement and thickening of the tendon sheath was a constant finding in all 12 patients., Conclusions: Musculoskeletal pains in breast cancer patients under third generation AIs can be severe, debilitating, and can limit compliance. Characteristic tenosynovial, and in some patients joint changes on US and MRI were observed in this series and have not been reported before.

In oestrogen receptor-positive (ER+) breast cancer, HER-2/neu and the progesterone receptor (PR) are inversely associated. This explains a lower response to anti-oestrogens if ER+ breast cancers are HER-2/neu positive. One randomized study however, showed that premenopausal women with an ER+ breast cancer respond to anti-oestrogens independent of HER-2/neu. We therefore hypothesized an age-related association between HER-2/neu and PR in ER+ breast cancers. Receptors for ER, PR and HER-2/neu were analysed by immunohistochemistry (IHC). A uni- and multivariate analyses was carried out to assess this relationship in 1104 women with an ER+ breast cancer. We observed an inverse association between HER-2/neu and PR only after age 45. There were 173 women of age45 years. In multivariate analysis, only tumour grade (p=0.005) but not PR status was associated with HER-2/neu in women age45 years group, both PR status (p=0.001) and tumour grade (p=0.001) were independently associated with HER-2/neu. In ER+ breast cancers from women age>45, PR was positive in 76.9% if HER-2/neu negative but in 53.4% if HER-2/neu positive (p<0.001) and the median quantitative PR levels are 150 and 75 respectively in HER-2/neu negative and HER-2/neu positive tumours (p=0.002). This age effect of HER-2/neu on the PR status was not seen in women age45 years but not in women age