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Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non‐consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array‐CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.

Background. Identifying and understanding modifiable factors for the well-being of cancer patients is critical in survivorship research. We studied variables associated with the exercise habits of breast cancer patients and investigated if the achievement of exercise recommendations was associated with enhanced quality of life and/or psychological well-being. Material and Methods. 311 women from Finland, Portugal, Israel, and Italy receiving adjuvant therapy for stage I–III breast cancer answered questions about sociodemographic factors and physical exercise. Quality of life was assessed by the EORTC C30 and BR23 questionnaires. Anxiety and depression were evaluated using the HADS scale. Results. At the beginning of adjuvant therapy and after twelve months, 32% and 26% of participants were physically inactive, 27% and 30% exercised between 30 and 150 minutes per week, while 41% and 45% exercised the recommended 150 minutes or more per week. Relative to other countries, Finnish participants were more likely to be active at baseline and at twelve months (89% vs. 50%, p < 0.001 and 87% vs. 64%, p < 0.001 ). Participants with stage I cancer were more likely to be active at twelve months than those with a higher stage (80% vs. 70%, p < 0.05 ). The inactive participants reported more anxiety ( p < 0.05 ) and depression ( p < 0.001 ), lower global quality of life ( p < 0.001 ), and more side effects ( p < 0.05 ) than the others at twelve months. Accordingly, those who remained inactive or decreased their level of exercise from baseline to twelve months reported more anxiety ( p < 0.01 ) and depression ( p < 0.001 ), lower global quality of life ( p < 0.001 ), and more side effects ( p < 0.05 ) than those with the same or increased level of exercise. Conclusion. For women with early breast cancer, exercise was associated with a better quality of life, less depression and anxiety, and fewer adverse events of adjuvant therapy. Trial registration number: NCT05095675. Paula Poikonen-Saksela on behalf of Bounce consortium (https://www.bounce-project.eu/).

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

Breast cancer is the most frequent event in Li-Fraumeni syndrome associated with germline TP53 variants. Some studies have shown that breast cancers in women with Li-Fraumeni syndrome are commonly HER2-positive, suggesting that HER2 amplification or over-expression in a young woman may be a useful criterion to test for germline variants in the TP53 gene. We assessed the prevalence of germline TP53 variants by Sanger sequencing or next-generation sequencing in 149 women with HER2-positive breast cancer diagnosed until age 40. The pattern of HER2 amplification was evaluated with dual-probe FISH in a subset of breast carcinomas from patients with germline TP53 variants as compared with those of noncarriers. Among 149 women tested, three presented a deleterious TP53 germline variant (2%), with one patient diagnosed at age 31 and the other two with bilateral breast cancer at ages 29/33 and 28/32, respectively. Three of the 36 patients (8.3%) with the first breast cancer diagnosed at age 31 or younger presented a pathogenic TP53 variant. Additionally, all TP53 deleterious variant carriers had a first degree relative diagnosed with different early-onset cancers (frequently not belonging to the Li-Fraumeni syndrome tumor spectrum) diagnosed at age 45 or younger. Higher levels of HER2 amplification were found in breast carcinomas of TP53 pathogenic variant carriers than in those of noncarriers. Deleterious germline TP53 variants account for a small proportion of early-onset HER2-positive breast cancers, but these seem to have higher HER2 amplification ratios. All TP53 pathogenic variant carriers found in this study had the first breast carcinoma diagnosed at age 31 or younger and a first-degree relative with early-onset cancer. Further studies are needed to clarify if HER2 status in early-onset breast cancer patients, in combination with other personal and/or familial cancer history, is useful to update the TP53 testing criteria.

Introduction and objectives TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. Methods TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. Results The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P .0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ± 7.65 mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. Conclusions TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Patients with estrogen receptor-positive (ER +) early breast cancer (EBC) are at a continuous risk for distant relapse despite 5 years of standard endocrine therapy, even after 10–15 years after primary diagnosis. Hence, large randomized clinical trials were conducted to evaluate the role of extended endocrine treatment (ET) with the primary goal to prevent or at least delay distant relapse. Two very large trials of extended tamoxifen (TAM), the ATLAS and the aTTom trial, proved the efficacy of prolonged TAM particularly important after 10 years due to the carry-over effect of the five initial years. Additionally, the extended use of AIs after 5 years of tamoxifen, also proved to be efficacious in preventing late distant relapses. For letrozole (LET) it was shown in the MA.17 trial that it also improves overall survival (OS) in node-positive BC patients. There are many options and still unanswered questions related to extended ET, which are discussed in this review. The most important issue in deciding prolonged duration of ET is undoubtfully how to identify ER+ patients who benefit most from this approach. With this purpose, not only classical pathological factors have been studied, but also molecular profiles of individual tumors, which might help us in the near future to better tailor ET. Not only efficacy, but also toxicity of such prolonged treatment is essential for optimal use, particularly maintained compliance in a routine clinical practice. These issues are discussed in this review.

Background Cancer and its treatment represent major stressors requiring that patients make multiple adaptations. Despite evidence that poor adaptation to stressors is associated with more distress and negative affect (NA), neuroimmune dysregulation and poorer health outcomes, current understanding is very limited of how NA covaries with central nervous system changes to account for these associations. Methods NA was correlated with brain metabolic activity using 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) in several regions of interest in 61 women with metastatic breast cancer. Patients underwent 18 F-FDG PET/CT and completed an assessment of NA using the Brief Symptom Inventory. Results Regression analyses revealed that NA was significantly negatively correlated with the standardized uptake value ratio of the insula, thalamus, hypothalamus, ventromedial prefrontal cortex, and lateral prefrontal cortex. Voxel-wise correlation analyses within these 5 regions of interest demonstrated high left-right symmetry and the highest NA correlations with the anterior insula, thalamus (medial and ventral portion), lateral prefrontal cortex (right Brodmann area 9 [BA9], left BA45, and right and left BA10 and BA8), and ventromedial prefrontal cortex (bilateral BA11). Conclusions The regions of interest most strongly negatively associated with NA represent key areas for successful adaptation to stressors and may be particularly relevant in patients with metastatic breast cancer who are dealing with multiple challenges of cancer and its treatment.

Introduction: Thyroid hormones have an important role in the regulation of lipid metabolism. Higher levels of TSH could be associated with impaired lipid profile and cardiovascular disease, even with normal levels of free thyroxine (FT4). The aim of this study was to investigate the association between TSH levels and lipid profile in patients with primary hypothyroidism. Materials and methods: Retrospective evaluation of patients with primary hypothyroidism treated with levothyroxine (LT4), with normal levels of FT4. Patients with known dyslipidemia were excluded. Thyroid function, total cholesterol (TC), triglycerides (Tg), HDL-cholesterol (HDL) and LDL-cholesterol (LDL) were studied. Patients were divided according to their TSH levels: 0.05) and lower mean LDL levels (96.3mg/dL vs 106.7mg/dL, p>0.05). TSH values positively correlated with higher TC levels (r=0.319, p

IntroductionPseudohypoparathyroidism is a genetically heterogeneous condition characterized by hypocalcemia and hyperphosphatemia resulting from end-organ resistance to parathyroid hormone (PTH). It is classified into several distinct entities (type Ia, Ib, Ic, type II), according to the molecular causes and clinical features of the patients.Case reportWe report a symptomatic case of a pediatric patient with hypocalcaemia, hyperphosphatemia, hypomagnesaemia and an elevated serum PTH level that presented with tetany. The molecular genetic test revealed a GNAS gene methylation defect of the A/B promoter, which confirms the diagnosis of a sporadic form of pseudohypoparathyroidism type Ib.

Neoadjuvant therapy (NT) has become a valuable research tool for the incorporation of alternative cytotoxic agents, as well as new biological therapies, into anthracycline and taxane chemotherapy-based regimens. Her-2-positive disease is predictive of higher pathological complete response (pCR) to neoadjuvant chemotherapy and trastuzumab. Benefits were also seen for the combination of trastuzumab with lapatinib or pertuzumab, suggesting that dual blockage of the HER-2 will probably emerge as the new standard. Triple-negative phenotype is also predictive of high pCR to NT, but the prognosis of patients whose tumours do not achieve a pCR after neoadjuvant chemotherapy with anthracyclines and taxanes is dismal. Currently, it is recommended to use the same chemotherapy regimens as in non-triple-negative disease. The suggested benefit of neoadjuvant platinum, mainly in BRCA1-related cancers, needs to be confirmed in large randomized trials. Bevacizumab combined with neoadjuvant chemotherapy yields increased pCR compared with non-bevacizumab treatment, in large randomized data recently published. One study suggested higher benefit in triple-negative tumours. Long-term follow-up of these trials is needed to understand the role of bevacizumab treatment in BC and its important to find predictive biomarkers of response to this drug.

Margaret Hutka1,*, Berta Sousa2, Felipe Ades3, Joost van de Vorst4, Pierluigi Bonomo5, Leticia De Mattos-Arruda6 1 Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK 2 Breast Unit, Champalimaud Cancer Center, Lisbon, Portugal 3 Breast Unit, Institut Jules Bordet, Universite Libre de Bruxelles, Belgium 4 Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands 5 Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy 6 Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

Background and objectives: Bevacizumab, used in combination with chemotherapy has demonstrated efficacy in randomized trials in MBC. Hypertension, congestive heart failure and cardiomyopathy have been reported in trials of bevacizumab in breast cancer. The aim of this systematic review and meta analysis is to determine the overall risk of grade 3-4 hypertension (HTN), left ventricular dysfunction (LVD) and venous (VT) and arterial thromboembolic events (ATE) related to Bevacizumab in patients with MBC. Methods: We selected randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC as first or second line therapy. Data extraction was carried out from results published in the literature or from conference proceedings of the selected studies. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. We collected all grade 3-4 events reported in these trials in relation to cardiovascular events: HTN, LVD, congestive heart failure, cardiomyopathy, VT and ATE. Results: Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2 and Miller et al study (capecitabine alone or plus bevacizumab in previously treated MBC). In total 2126 patients received chemotherapy in combination with bevacizumab and 1444 chemotherapy alone. When there was tendency for heterogeneity, random-effects models were used. Thromboembolic events were pooled together as VT and ATE as information was not clear in some of the reported studies. CHF and cardiomyopathy were considered for LVD events in the Miller study as LVD was not reported. Patients treated with bevacizumab-containing regimens had a RR for HTN of 10.32 (95% CI, 4.23- 24.79; p Conclusion: HTN is a recognized side effect of bevacizumab therapy. The risk of LVD is also significantly higher with bevacizumab therapy (RR 2.58) as shown in this pooled analysis, but the risk of thrombotic events is not increased. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-01.

Context: Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. Objective: The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome. Results: We report the detailed phenotype of two males and one female patient, 26–34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well. Conclusions: We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.

Growth factors are important mediators of proliferation. Deregulation in growth factor mechanisms as well as in its receptors will contribute to cancer development. One of the most important is the epidermal growth factor (EGF), which is encoded by EGF gene. A functional polymorphism at position 61 (A/G) is associated with increased expression of EGF. Thus, we proposed to assess genotype frequencies in a case-control study and appraise their association to breast cancer risk. Using the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) we analyzed DNA from 883 women (500 controls and 383 breast cancer patients). Our results suggested that carriers of G homozygous genotype had a lower risk for developing breast cancer (odds ratio = 0.68; 95% confidence intervals, 0.46-1.01). Further, we showed that the waiting time for onset of breast cancer in G homozygous patients for EGF genotypes (55 years) was significantly lower in comparison to A-allele carriers (59 years) (log-rank test: p = 0.038). EGF is produced in mammary tissue and acts in the mammalian development. A lower risk for breast cancer in GG carriers might be explained through EGF receptor internalization promoted by EGF.

This chapter is a review of the current evidence for managing metastatic breast cancer. The treatment of metastatic disease is a complex one when compared to the early setting for which there is clear and high level of evidence. There has been a constant effort to improve survival in metastatic patients, but the incurable nature of the disease, its heterogeneity in terms of presentation and biology, the lack of well-designed clinical trials and the lack of acceptable endpoints have render it difficult. The fast introduction of new drugs makes the comparative standard arms used in most trials outdated, being difficult to generalise their results. A better understanding of the biology of disease is driving the development of new targeted agents as well as new methodologies for diagnosis and assessment of metastatic disease. This is shaping the design of new clinical trials in the metastatic setting with the aim of increasing the efficacy and tolerability of treatments. It is also an important goal in research how to best assess the psychosocial impact of this disease in patients and relatives life as well as the development of specific tools to measure quality of life in advance cancer.

The treatment of early breast cancer (EBC) is becoming increasingly complex, but also more effective as a better understanding of cancer biology is achieved with evolving research. Longer follow-up of prospective trials is crucial to evaluate the impact of current standard treatments in long-term outcome and safety. In this review we will summarise the current evidence for optimal treatment of EBC.

Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90 % of young patients with BC are symptomatic. Women

Male breast cancer is a rare disease for which treatment has been based on the evidence available from female breast cancer. The new genomic tools can better characterize the biology of breast cancer. It is hoping that these will help to clarify possible differences of breast cancer behaviour in male patients, which will have a major impact on treatment strategies and on the conduct of clinical trials in this setting. In this review we will summarize available information on epidemiology, risk factors for breast cancer in men, the new insights of the biology of this disease, current recommendations for treatment and insights for future research.

Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

We performed a phase II trial to test whether a cyclooxygenase (COX-2) inhibitor, celecoxib, added to standard first-line combination chemotherapy (CT) and as maintenance therapy would improve outcomes in extensive-stage (ES) small-cell lung cancer (SCLC). This was a multicenter trial in CT-naive patients with ES-SCLC. They received standard cisplatin and etoposide (EP) up to 6 cycles and celecoxib 400 mg PO bid continuously until disease progression. Primary end points were response rate (RR), time to progression (TTP), and toxicity. Secondary were overall survival (OS) and quality of life. Of 74 expected patients, only 24 were enrolled and the study stopped earlier because of the published safety concerns about celecoxib. The patients, all male, were between 38 and 74 years. A total of 130 cycles of CT were administered. Toxicity associated with celecoxib was minimal. The RR was 56.5%. Median TTP and OS were 8.6 and 11.3 months, respectively. These data suggest that celecoxib may safely be combined with EP for treatment of ES-SCLC. This combination showed a promising activity and, despite the safety concerns regarding celecoxib, it would be interesting to further evaluate this regimen.

Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY). A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation-positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice-site mutations (8%). The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.

The article by Hackshaw et al that accompanies this editorial includes important data on the long-term benefits of 5 years versus 2 years of tamoxifen use from a large randomized trial of women more than 50 years of age with early breast cancer. The median follow-up in this study is 10.1 years; 25% of the women were observed for more than 14 years. The trial results were last reported in 1996. Follow-up strategies included matching trial subjects with death data from the British National Health Service Information Center. This extensive follow-up revealed 1,103 recurrences, including 876 recurrences that were followed by death, and 621 cardiovascular events that included 236 cardiovascular deaths. This study, like others, shows the long-term positive effects of 5 years of tamoxifen use compared with 2 years, with effects on recurrence that continue for up to 10 years and on breast cancer deaths that continue beyond 10 years. Extended follow-up data from studies such as this one are crucial for describing the long-term history of early breast cancer treated with tamoxifen, but also for assessing other potential long-term effects of such breast cancer treatment. Perhaps because of the long follow-up period, the use of British National Health Service cause of death data, and the 50 years of age required for enrollment onto this trial, the investigators were also able to report a trend toward overall reduction in cardiovascular events (hazard ratio [HR], 0.90; P .18) and a nearly statistically significant reduction in cardiovascular deaths (HR, 0.79; P .08) when tamoxifen was used for 5 years compared with 2 years of use. Furthermore, the women who were between 50 and 59 years of age when they were enrolled onto the study were found to have an even greater reduction in cardiovascular events (HR, 0.65; P .005; P .046 for interaction between age and treatment group) and in cardiovascular deaths (HR, 0.41; P .02; P .11 for interaction) for 5 years versus 2 years of tamoxifen use. The effects of long-term tamoxifen use on cardiovascular events and deaths were as great as or greater than the effects on breast cancer. Although neither the cardiovascular death event and survival analysis nor subanalyses by decades of age were preplanned, and should therefore be regarded with some caution, these data are still of considerable interest. Tamoxifen was initially postulated in the 1970s to potentially have a major beneficial effect on cardiovascular events and deaths, given that it is known to reduce blood lipid levels, including cholesterol and lipoprotein A and B, and to affect endothelial function. Furthermore, other studies, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-14, a trial from the Scottish Breast Cancer Group, and the 2005 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis, have suggested reduction in cardiovascular deaths with tamoxifen treatment. However, this was not seen in the NSABP Breast Cancer Prevention Trial, perhaps because of the large proportion of younger women who were enrolled. Interestingly, one of the first studies to show a relationship between reduced cardiac events and deaths and the use of tamoxifen also used the technique of matching patients from clinical trials with national data registry causes of death. Similar use of this technique in Sweden produced the first definitive reports of the association between endometrial cancer and tamoxifen; information on endometrial cancer incidence and death was obtained from the national registry in relation to a large study of women who were randomly assigned to receive tamoxifen versus a control years earlier. It may well be that this technique represents a more powerful methodology for ascertaining this type of secondary end point. Furthermore, depending on the availability of the registry data, its accuracy with regard to the end points being sought, and the costs and ethical issues involved in linking patients from randomized clinical trials with such registries, this methodology may also prove less costly. Thus, long-term follow-up data from studies such as the trial described by Hackshaw et al add to pre-existing data that suggests that long-term therapy with tamoxifen may be beneficial in reducing cardiac events and deaths as well as breast cancer recurrence and death. The results of the EBCTCG tamoxifen overview for 2010 (in preparation) will contribute additional data. However, only those individual studies in which long-term follow-up and accurate cause of death ascertainment have been performed can contribute to a metaanalysis of secondary medical effects of tamoxifen such as cardiovascular events and deaths. Given that breast cancer is increasingly treated effectively in the adjuvant setting, the secondary effects of drugs used in its long-term treatment will become increasingly important. We now know from a variety of randomized trials that cardiovascular events and perhaps cardiovascular deaths are higher in women who are randomly assigned to receive aromatase inhibitors (AIs) as compared with tamoxifen, although lipid levels and cardiovascular events seem little affected in trials of AIs versus placebos. It may be that women can be selected for therapy with tamoxifen or AIs on the basis of their underlying risk of cardiovascular disease and the use of other cardioprotective approaches. However, data to guide us can only be obtained with long-term follow-up from ongoing and future adjuvant trials. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 13 MAY 1 2011

Aim: MC (continuous administration of low doses of conventional chemotherapeutics) is characterized by an excellent therapeutic index. In fact, we recently demonstrated that 24% of patients with ABC receiving daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP) achieved clinical benefit with minimal toxicity. While there are no predictive markers of response to MC, circulating miRNAs have a high potential to serve as easy accessible biomarkers. Hence we sought to generate a predictive plasma miRNA signature of response to dalCMP. Methods: We analyzed pre-treatment plasma samples from top-responders versus patients with dalCMP refractory ABC (n = 6 each) using the nCounter® miRNA expression assay (NanoString Technologies). Candidate miRNAs were validated by qRT-PCR. Results: Of 800 human miRNAs of miRBase v18.0, we identified 210 miRNAs expressed in all patient samples. Of these, the average expression of 24 miRNAs displayed a > 2-fold change in either direction in responders to dalCMP (mean ± SD time to tumor progression 65.6 ± 13.9 weeks) versus non-responders (3.2 ± 1.0 weeks). Student t-testing followed by Benjamini–Hochberg correction revealed 6 miRNAs significantly upregulated in non-responders: miR-451a, miR-122-5p, miR-142-3p, miR-548ai, miR-150-5p, and miR-342-3p. Using qRT-PCR, we confirmed the differential expression pattern of miR-451a, miR-122-5p, miR-142-3p, and miR-548ai. In contrast to our findings, miR-451a overexpression has been found by others to exert in vitro chemosensitizing properties, whereas miR-122-5p, miR-142-3p and miR-548ai have not been associated with chemosensitivity modulation to date. Conclusions: We describe the first candidate miRNA signature predicting response to MC (i.e. dalCMP), currently being validated in the original and extension dalCMP study populations (n = 92). This signature may become a helpful tool to select patients with ABC suitable for dalCMP, and to possibly predict response to other MC regimens as well as to MC used for other tumor types. Disclosure: All authors have declared no conflicts of interest.

Background Although the activity of cytochrome P450 2D6 (CYP2D6), the enzyme responsible for conversion of tamoxifen (TAM) to its most important active metabolite endoxifen, varies significantly with genotype. Routine genotype testing in patients on TAM has recently been discouraged. Conflicting results in publications regarding the prognostic utility of this test remain unexplained. Confounding factors could be lack of predicted correlation between CYP2D6 genotype and TAM active metabolites, or variability of patient compliance Methods: Consecutive breast cancer patients on TAM were asked to enroll in a study to examine the relationship between CYP 2D6 phenotype, patient-reported treatment adherence, and TAM metabolites levels. Patients were genotyped for CYP2D6 polymorphisms using long-range PCR allele-specific amplification and single-nucleotide primer extension assay. From the genotypes, four phenotype groups were defined: Ultra rapid Metabolizer (UM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM) and Poor Metabolizer (PM). Plasma was collected after at least 6 weeks of TAM (20 mg daily). The parent drug TAM, as well as 4-hydroxy N-desmethyl tamoxifen (endoxifen), 4 hydroxy tamoxifen (4OHtam) and N-desmethyl-tamoxifen (NDtam), were determined by Liquid Chromatography tandem mass-spectrometry (LC-MS/MS). Patients also completed a questionnaire about ethinicity, side effects, concurrent medications and tamoxifen adherence. Correlation between metabolite/TAM ratio and phenotype was tested by Spearman correlation test. Relationship between metabolite levels and adherence was tested by Wilcoxon rank sum test. Chi square test was used to compare proportions. Results: Of the 100 patients enrolled there were 62 Caucasians, 25 Asians, 4 Africans and 6 Unknown. We found a strong correlation between ratio of endoxifen/TAM and phenotype (p 5times (2 missing data). In EM group we found significantly lower levels of TAM (p Conclusions: Our data suggests the predicted association between endoxifen levels and genotype. However, non-adherence may have a significant confounding effect. Prospective studies to evaluate the prognostic impact of CYP2D6 variants for patients on adjuvant tamoxifen should be done but results could be confounded by variable drug adherence if this is not measured concurrently. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-04.

1152 Background: We recently published data on 41 patients (pts) treated with DalCMP (JCO 2009). We have now accrued additional pts to further compare responses in pts treated or not with prior anthracycline (A) and taxane (T) based regimens. Methods: Pts with measurable MBC received daily sc dalteparin (5,000UI), po cyclophosphamide (50mg), twice weekly po methothrexate (2.5mg BID) and daily po prednisone (5mg). Primary study endpoint was clinical benefit rate (CBR) (i.e., complete response [CR] + partial response [PR] + prolonged stable disease for ≥ 24 weeks [pSD]). Secondary endpoints included time to progression (TTP), duration of response (DOR), and overall survival (OS). Pts were in group 1 (no prior chemotherapy for metastatic disease) or group 2 (prior A and T for metastatic disease, or prior adjuvant A and T if relapse < 1 year, or prior adjuvant A and prior T for metastatic disease). Adverse events were assessed by common toxicity criteria version 2 (CTCAE). Kaplan-Meier methods and log rank te...

5594 Background: Cervical cancer (ICC) and squamous intraepitelial lesions of the cervix uteri (SIL) constitute serious health problems to women worldwide. ICC occupies the second place in the list of tumours afflicting women. Around 470,000 new cases are diagnosed annually, 80% of which in less developed countries and near half of them resulting in death of the women. MCP-1 chemokine is the main determinant of tumour associated macrophages (TAM) content in the squamous cell carcinoma of the uterine cervix. The aim of our study was the evaluation of the association between the -2518 MCP-1 polymorphism (a biallelic G/A functional polymorphism) and susceptibility to cervical intraepithelial lesions and cervical cancer development. Methods: We analyzed 898 samples of DNA, of which 420 corresponded to healthy women (control group), 130 to women with low and high-grade cervical intraepithelial lesions and 348 to women with cervical cancer. The analysis of the polymorphism and the evaluation of the corresponding genotypes were performed with the PCR-RFLP methodology. Analysis of data was performed using the computer software SPSS for windows. Results: The analysis of the genotipic frequencies of the -2518 MCP-1 genotypes indicates that women carrying genotypes with the G allele present a 29.2% protection for the development of intraepithelial lesions of the cervix uteri (OR=0.708; 95% CI: 0.503–0.998; P=0.048) and a 33.5% protection for the development of squamous cell carcinoma of the cervix uteri. It was also possible to observe an association between the waiting time to onset of cervical cancer and the polymorphism: 59 years for women carrying genotypes with the G allele (95% CI: 56–61years) and 53 years for women with the AA genotype (95% CI: 52–57 years; P=0.005). Also, women with genotypes carrying the G allele present a 2.5 fold higher risk for the progression from early stages of invasive cervical carcinoma (I/II) to clinically more advanced stages (III/IV) (OR=2.26; 95% CI: 1.09–4.67; P=0.026). Conclusions: These findings suggest a role of the -2518 MCP-1 polymorphism in the molecular mechanisms that lead to cervical cancer development and progression. No significant financial relationships to disclose.

Introduction McCune–Albright syndrome is a rare sporadic disease characterized by fibrous bone dysplasia, café-au-lait skin spots and variable hyperfunctional endocrinopathies. McCune–Albright syndrome is caused by somatic postzygotic activating mutations in the GNAS gene that produce a broad spectrum of effects. Case presentation We report a case of McCune–Albright syndrome with multi-organ manifestations in the neonatal period. A newborn preterm black girl was referred to our Neonatal Intensive Care Unit at the age of 17 days for suspected extrahepatic cholestasis. On clinical examination she presented failure to thrive, jaundice, hypertension, marked hypotonia and café-au-lait spots on her back and lower limbs. An abdominal ultrasound excluded extrahepatic causes of cholestasis but revealed bilateral serpiginous adrenal hyperplasia. These clinical findings suggested a diagnosis of McCune–Albright syndrome with multi-organ involvement. Laboratory data confirmed adrenocorticotropic hormone-independent Cushing’s syndrome, hyperthyroidism, cholestasis and elevated transaminases. Ventricular hypertrophy was demonstrated by echocardiography. The baby girl underwent medical treatment of Cushing’s syndrome with metyrapone which was followed by a rapid recovery. A mosaic activating GNAS gene mutation was found on DNA extracted from a buccal swab sample. However, she died at 4 months due to a respiratory infection. Conclusion In the neonatal period the diagnosis of McCune–Albright syndrome depends on having a high index of suspicion and café-au-lait spots may be the clue for the diagnosis.