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Although outcomes are similar following breast-conserving surgery (BCS) or mastectomy among sporadic breast cancer patients, data are mixed for women with a germline BRCA mutation. We sought to compare outcomes among a modern cohort of BRCA mutation carriers undergoing BCS versus mastectomy.Women with a BRCA mutation and an index breast cancer from 2006-2015 were retrospectively identified from institutional databases. Factors, including date of genetic testing, clinicopathologic details, and treatment characteristics, were identified. Subsequent locoregional recurrence (LRR), distant recurrence, contralateral breast cancer (CBC), breast cancer-specific survival (BCSS), and overall survival (OS) events were compared between groups.A total of 395 BRCA mutation carriers with 424 cancers were identified. Surgical treatment included BCS for 99 cancers and mastectomy for 325 cancers. Patients choosing mastectomy were more likely to have bilateral breast cancer, be younger/premenopausal, and be aware of their genetic status before surgery, and were less likely to receive radiation therapy (p0.001). At 7.9 years median follow-up, LRR, distant recurrence, BCSS, and OS rates did not differ between groups. CBC occurred in 5 versus 0 women treated with unilateral versus bilateral surgery, respectively, resulting is a 10-year estimated CBC risk of 14% among unilateral breast surgery patients (p0.001).With nearly 8 years follow-up, we report no difference in LRR, BCSS, and OS among BRCA mutation carriers who underwent BCS or mastectomy; however, we report a higher incidence of CBC among those undergoing unilateral breast surgery. These data support BCS as an option for BRCA mutation carriers willing to continue high-risk screening.

When BRCA1 and BRCA2 were first identified, the initial models for delivering testing were shaped by concepts of genetic exceptionalism and a lack of data regarding therapeutic implications and the effectiveness of risk reduction. Since then, interventions have been effective, and treatment implications have become clear. The sensitivity of guideline-based testing is incomplete, leading to calls for universal testing. Completely universal testing, however, is not necessary to identify the great majority of BRCA1 or BRCA2 variants. Broader testing (both in terms of eligibility and genes tested) will identify more variants, particularly in moderate penetrance genes, but the clinical implications remain less clear for these variants.

INTRODUCTION: Organophosphate (OP) insecticides, including chlorpyrifos, have been linked with numerous harmful health effects on maternal and child health. Limited data are available on the biological mechanisms and endogenous pathways underlying the toxicity of chlorpyrifos exposures on pregnancy and birth outcomes. In this study, we measured a urinary chlorpyrifos metabolite and used high-resolution metabolomics (HRM) to identify biological perturbations associated with chlorpyrifos exposure among pregnant women in Thailand, who are disparately exposed to high levels of OP insecticides. METHODS: This study included 50 participants from the Study of Asian Women and their Offspring’s Development and Environmental Exposures (SAWASDEE). We used liquid chromatography-high resolution mass spectrometry to conduct metabolic profiling on first trimester serum samples collected from participants to evaluate metabolic perturbations in relation to chlorpyrifos exposures. We measured 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos and chlorpyrifos-methyl, in first trimester urine samples to assess the levels of exposures. Following an untargeted metabolome-wide association study workflow, we used generalized linear models, pathway enrichment analyses, and chemical annotation to identify significant metabolites and pathways associated with urinary TCPy levels. RESULTS: In the 50 SAWASDEE participants, the median urinary TCPy level was 4.36 μg TCPy/g creatinine. In total, 691 unique metabolic features were found significantly associated with TCPy levels (p < 0.05) after controlling for confounding factors. Pathway analysis of metabolic features associated with TCPy indicated perturbations in 24 metabolic pathways, most closely linked to the production of reactive oxygen species and cellular damage. These pathways include tryptophan metabolism, fatty acid oxidation and peroxisome metabolism, cytochromes P450 metabolism, glutathione metabolism, and vitamin B3 metabolism. We confirmed the chemical identities of 25 metabolites associated with TCPy levels, including glutathione, cystine, arachidic acid, itaconate, and nicotinamide adenine dinucleotide. DISCUSSION: The metabolic perturbations associated with TCPy levels were related to oxidative stress, cellular damage and repair, and systemic inflammation, which could ultimately contribute to health outcomes, including neurodevelopmental deficits in the child. These findings support the future development of sensitive biomarkers to investigate the metabolic underpinnings related to pesticide exposure during pregnancy and to understand its link to adverse outcomes in children.

Background Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. Methods A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients’ cancer type were investigated. Results 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient’s current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. Conclusions Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.

The COVID-19 pandemic led to disruptions in delivery of cancer treatments; factors associated with treatment delay among patients with cancer who contract COVID-19 need further characterization.To assess the associations of patient factors, social determinants of health, severity of COVID-19, and timing of COVID-19 diagnosis with the risk of treatment delay.This prospective cohort study was conducted from March 2020 through July 2021 at 60 academic and community medical practices in the United States. Participants included patients with any cancer diagnosis who were scheduled for treatment and contracted COVID-19. Data were analyzed in February 2022.Positive test result for SARS-CoV-2.The main outcomes were treatment delay, defined as more than 14 days between the date originally planned for treatment and the date of initiation of therapy, or discontinuation of therapy. Multivariable analyses were used to assess outcomes.A total of 3028 patients (1470 patients [49%] aged ≥65 years; 1741 [58%] women) were included in the registry. With 962 of 2103 patients (46%) experiencing anticancer drug delay or discontinuation, delays were higher among Black patients compared with White patients (odds ratio [OR], 1.87; 95% CI, 1.40-2.51), Hispanic or Latino patients compared with non-Hispanic or Latino patients (OR, 1.91; 95% CI, 1.34-2.72), patients with 2 or more comorbidities compared with patients with 0 to 1 (OR, 1.23; 95% CI, 1.00-1.53), patients with metastatic disease rather than locoregional disease (OR, 1.63; 95% CI, 1.29-2.05), and patients who experienced COVID-19 complications compared with those who did not (OR, 1.52; 95% CI, 1.24-1.86). Residing in an area with a higher proportion of residents reporting Hispanic or Latino ethnicity (OR, 0.76; 95% CI, 0.60-0.95) and contracting COVID-19 later in the pandemic, compared with those who were infected in March to June 2020, (eg, January to March 2021: OR, 0.38; 95% CI, 0.26-0.53) were associated with lower likelihood of drug therapy delay. A total of 95 of 202 patients (47%) experienced delay or discontinuation of radiation treatment, with having 2 or more comorbidities associated with delay (OR, 2.69; 95% CI, 1.20-6.20). Higher local-area median household income was associated with lower likelihood of radiation treatment delay (OR, 0.41; 95% CI, 0.17-0.94). There were 89 of 125 patients (71%) who experienced surgical treatment delay, and delays were higher among patients in the South compared with those in the Midwest (OR, 9.66; 95% CI, 2.14-52.3). Interestingly, patients with 2 or more comorbidities, compared with those with 0 to 1, experienced lower likelihoods of surgical treatment delay (OR, 0.26; 95% CI, 0.07-0.88).Our findings suggest that individual patient factors, social determinants of health, and COVID-19 severity and diagnosis date were associated with exacerbated health disparities during the pandemic in regards to cancer treatment delay.

PURPOSE An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors. CLINICAL CONTEXT An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection. PROVISIONAL CLINICAL OPINION Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel–based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase ( NTRK) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker–linked options relative to other approved or investigational treatments. Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines .

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit. (C) 2019 Published by Elsevier Ltd.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.

Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10(−76)), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10(−3)), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10(−3)), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10(−2)). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10(−3)). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline.To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results.We retrospectively reviewedA total of 1666The 2018 guideline eliminated

Purpose The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

There has been no indication to test for BRCA1/2 in children (with the rare exception of Fanconi anemia) as screening begins in adult years and there is a potential to induce anxiety related to adult-onset cancers. However, in the setting of pediatric cancer, with increasing utility and frequency of companion tumor-normal sequencing without regard for phenotype and with BRCA1/2 included in tumor profiling panels, germline mutations in BRCA1/2 and other DNA damage repair genes have been found. When mutations in these genes are revealed, there are implications for immediate family members. Here we present two children in whom BRCA2 mutations identified through tumor sequencing prompted parental genetic testing and medical action. These cases illustrate the potential importance of including a matched normal DNA sample when performing tumor profiling of pediatric cancer patients to ensure optimal care.

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Non

New and underutilized vaccines are becoming available to combat important public health challenges. Each year, rotavirus is estimated to cause approximately 111 million episodes of gastroenteritis, which requires home care, 25 million clinic visits, 2 million hospitalizations, and approximately 440,000 deaths in children younger than 5 years of age worldwide. Children in the poorest countries account for 82% of rotavirus deaths. An estimated 16,000 deaths by rotavirus-induced diarEditor’s note: The thoughtful article by Dr. Andrus and his colleagues in describing the utility of the Pan American Health Organization’s (PAHO’s) ProVac model1 reminds us of the startling childhood and adult disease statistics. Whether it is the 440,000 gastroenteritis annual deaths in children younger than age 5 or the 32,000 annual deaths from papillomavirus—with more than 80% in poor and developing countries—these numbers are staggering. Examples such as the experience in Mexico that was described by Santos et al.2 show the ProVac model can work very well. The authors suggest that three essential factors need to be addressed if agencies and governments are to attain a sustainable impact: decisions should be nationally based; evidence used to support the decisions must be broad-based; and infrastructure must be in place to support a nationally based process. The ProVac program objectives are rather aggressive, with just a five-year horizon to achieve a series of ambitious goals. At the same time, PAHO is honest: the organization recognizes it has little choice but to move in this direction. PAHO can serve as a model for the rest of the developing world. Lessons learned in the ProVac experience will serve many others well as they attempt a similar, if not more aggressive approach.

BACKGROUND Although BRCA1 and BRCA2 were identified in 1994 and 1995, respectively, to the authors' knowledge the optimal management of women with BRCA-associated breast carcinoma remains incompletely defined. The current study evaluates the appropriateness of breast-conserving therapy (BCT) in women with BRCA mutations. METHODS Between May 1992 and October 2003, 87 female participants in genetic testing protocols were identified who 1) were found to have deleterious germline BRCA mutations and 2) reported a history of invasive breast carcinoma that was treated with wide local excision and radiation therapy. Clinical records were reviewed and follow-up was updated. RESULTS The 87 subjects underwent BCT for 95 invasive breast tumors (8 women received BCT for metachronous bilateral tumors). In all 95 treated breasts, the 5-year and 10-year probabilities of metachronous ipsilateral breast carcinoma (MIBC) were 11.2% and 13.6%, respectively. Among the 87 subjects, the 5-year and 10-year probabilities of metachronous contralateral breast carcinoma (CBC) after treatment of the index tumor were 11.9% and 37.6%. No clinical factors were identified that were associated with either MIBC or CBC, including the use of tamoxifen or chemotherapy. CONCLUSIONS Women with BRCA-associated breast carcinoma who undergo BCT appear to have risks of MIBC that are similar to those reported for young women without known mutations. The indications for unilateral mastectomy in this group of women should be the same as those for women with nonhereditary carcinoma. However, significant risks of CBC and possibly late MIBC may prompt the serious consideration of bilateral mastectomy as a preventive measure. Cancer 2005. © 2004 American Cancer Society.

PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker–based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Author Summary BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer., Author Summary Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext

Early warning of the potential of mutagens or carcinogens caused by benzene exposure that might occur in gasoline station workers can be achieved by examining 2 major biomarkers: sister chromatid exchange (SCE) and trans, trans-muconic acid (t,t-MA), a urinary metabolite of benzene. The main objective of this study was to assess benzene exposure and monitor the genotoxic effect of gasoline station workers in Bangkok, Thailand. Blood and urine samples were collected from 33 gasoline station workers, working in Pathumwan district area, central Bangkok, Thailand, for SCE and t,t-MA analysis, from April to June 2009. Control samples were collected from 30 office workers and students in the same area at the same period. Our results indicated significantly higher frequencies of SCE in gasoline exposed workers were than in controls (p0.01), independent of gender. Urinary t,t-MA and t,t-MA/creatinine levels of gasoline exposed workers were also significantly higher than the control groups (p0.05) were significantly higher in women than men workers (p0.01). Calculated chromosomal damage relative risk (RR) of gasoline station workers was 3.00 (95% CI = 1.81 - 4.98, p0.001) compared to controls. The gasoline exposed workers had potentially higher risk of chromosomal damage and cancer development because of direct contact to benzene.

Important questions for pediatric burn care specialists relate to the quality of life for those children who survive the most severe burn injuries. This study examines the psychological adjustment of 25 children who survived injuries > or = 80% total body surface area and the impact of such injury on the families. Data were analyzed from the most recent assessment, with the Child Behavior Checklist, Teacher Report Form, Piers-Harris Children's Self-Concept Scale, Parenting Stress Index, and a parental questionnaire designed by the authors. As a group, the children's behavioral problems as reported by both parents and teachers were within normal limits. Measures of parental stress, however, clearly differentiated the burn population. These parents attributed more stress to characteristics of their children. Children with > or = 80% TBSA burns develop positive feelings about themselves and appear no more troubled than a comparable group of nonburned children. The impact on the families is significant, however, and must be considered of consequence in the rehabilitation of the burned child. Language: en

As knowledge increases about the processes underlying cancer, it is becoming feasible to design "targeted therapies" directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through "synthetic lethality" if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in "triple-negative" breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

This article by Jiayou Luo et al. reminds us that even in countries with a large population, children with very traditional values end up being the victims of changes in work patterns, migration, and social norms. This article suggests that children who are attended by nonparents?either grandparents or other relatives?face less care and many nutrition problems, such as low intake of some nutrients and poor physical development related to nutritional status. The authors suggest that nutrition is the key factor and recommend nutritional intervention programs to improve the children's living conditions. However, in Spain, work by Bel et al.1 showed an important proportion of children with significant growth retardation upon entering a foster home, although significant catch-up growth was observed at the end of their stay. Growth failure in this population did not appear to be related to nutritional status.

Following the September 11 terrorist attacks, the vulnerability of the United States became apparent. It also became evident that there was a need for respiratory protection. The purpose of this study was to determine the prior knowledge and perceptions of emergency medical technicians with respect to bioterrorism and to enhance their current knowledge to better prepare them for possible future events. The study was also designed to create a certified pool of trainers who would be capable of fit-testing all squad members with N-100 respirators. Representatives were recruited from each of the Hunterdon County, New Jersey, rescue squads. Participants attended a train-the-trainer session. Before the session and after, they were tested on knowledge and perceptions about relevant bioterrorism issues and were given an educational presentation on bioterrorism, threatening agents, respiratory health, and proper protection, along with being introduced to the fit-test steps for N-100 respirator masks. The response rate for the training was 94 percent. The authors measured and compared responses on the pre-test and the post-test with respect to knowledge, behaviors, and perceptions, and the results indicated a change following the training. The study thus provided evidence that the train-the-trainer program is an effective method of providing public health preparedness training to members of community organizations and agencies.

To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL).A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later.This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York.Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable.The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times.Patients (mean age 68, range 65-84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (i.v.), methotrexate 40 mg/m2 i.v., 5-fluorouracil 600 mg/m2 i.v. every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL.Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

Risks of breast and ovarian cancer were determined for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 . We selected 1008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appear to be increasing with time: Breast cancer risk by age 50 among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset.

Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date.One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher's exact test and log-rank test.Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease.Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.

Several studies to date have reported ovarian cancer risk due to inherited BRCA1 and BRCA2 mutations using familial data or population-based series of probands. Familial aggregation associated with both of these methods may result in a substantial ascertainment bias. To address this, we have used a case-control design that does not involve familial aggregation to estimate the lifetime penetrance of ovarian cancer due to BRCA1 and BRCA2 mutations.A total of 382 ovarian cancer cases self-identified as being Jewish with no prior diagnosis of breast cancer were derived from two hospital-based series. In the first series, all 197 invasive epithelial ovarian cancer cases self-identified as Jewish and without a prior history of breast cancer, diagnosed and treated at Memorial Sloan-Kettering Cancer Center between 1986 and 2000, were identified. In the second series, 185 Jewish invasive epithelial ovarian cancer patients without prior breast cancer were identified in a study conducted at 11 centers in North America and Israel from 1995 to 1996. Controls were 3434 Jewish women without any prior history of breast or ovarian cancer from a large study of genotyped volunteers of Jewish origin in the Washington, D. C. area recruited by investigators at the National Cancer Institute. The cases and controls were genotyped for three Ashkenazi Jewish founder mutations, namely 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. The lifetime penetrances were estimated using the odds ratios, mutation prevalence in the controls, and ovarian cancer incidence rates in the general American population obtained from the Surveillance, Epidemiology and End Results database adjusted for the incidence of ovarian cancer following breast cancer.Mutations were identified in 147 cases and 62 controls. The estimated penetrances at age 70 years were 37% (95% confidence interval, 25-71%) for a BRCA1 mutation and 21% (95% CI, 13-41%) for a BRCA2 mutation.The lifetime penetrances of BRCA1 mutations are lower than estimates obtained using familial data with multiple affected members but larger than estimates from some population-based proband series. The lifetime penetrance estimate of a BRCA2 mutation is in the range reported by some of the studies based on familial data. These results could have implications for clinical counseling, surgical interventions, and screening recommendations in women carrying these founder mutations.

In this study, we first sought to evaluate whether individuals heterozygous for ATM mutations may have an increased susceptibility to radiation-induced breast cancer (BC) after treatment for Hodgkin's disease (HD). We next sought to determine the frequency of ATM variants in patients with Hodgkin's lymphoma, regardless of coexisting BC, compared with healthy volunteers.Full sequence analysis of ATM was performed on cDNA from peripheral blood lymphocytes from 37 cases of BC after therapeutic radiation therapy for HD and 27 comparison cases with HD and no BC treated during the same time period. The frequency of ATM variants was analyzed in the total group of 64 cases of HD and compared to allele frequencies in 128 ethnically matched controls from the same geographical region.No protein-truncating ATM mutations were observed in cases with HD with or without BC. Missense mutations were more frequent in the cohort with HD compared with patients with BC following HD (P = 0.02). The median time from HD to the development of BC was 18 years in patients with ATM variants compared with 16 years in those with no ATM variants (P = 0.04). Multiple ATM variants, including one homozygous mutation, were observed in 9 HD cases.Heterozygous protein-truncating or missense mutations of ATM were not associated with increased radiation-associated risk of BC after HD. The observation of multiple germ-line mutations and a homozygote suggests that rare ATM variants may constitute cancer-susceptibility alleles in a subset of cases.

To review the available literature regarding the outcome of breast cancer arising in the setting of a germline BRCA1 mutation.Reports of relevant studies obtained from a search of MEDLINE and studies referenced in those reports were reviewed. In addition, data from a previously published study of breast conservation therapy among women of Ashkenazi descent were reanalyzed to discern the effect of germline BRCA1 status.Although BRCA1-associated breast cancers have been associated repeatedly with poor prognostic features, studies that examine the impact of germline BRCA1 status on outcome have not consistently shown an adverse effect of BRCA1 mutations. In part, this may result from methodologic limitations of earlier trials. Recent studies that examine relatively unselected groups of Ashkenazi women have indicated a negative prognostic effect of specific BRCA1 mutations. It remains to be determined, however, whether BRCA1 status is an independent prognostic factor and whether the findings can be generalized to other mutations.BRCA1-associated breast cancers present with histopathologic features that seem to confer an adverse prognosis, at least in certain subgroups. However, it is not clear whether BRCA1 status has an independent effect on outcome. Until further data become available, treatment for BRCA1-associated breast cancer should be determined by the same factors that influence therapy of nonhereditary disease.