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1.
J Skin Cancer ; 2022: 4046554, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35959144

RESUMO

Public access to genetic information is increasing, and community dermatologists may progressively encounter patients interested in genetic testing for melanoma risk. Clarifying potential utility will help plan for this inevitability. We determined interest and uptake of genetic risk feedback based on melanocortin receptor gene (MC1R) variants, immediate (two weeks) responses to risk feedback, and test utility at three months in patients (age ≥ 18, with a history of nonmelanoma skin cancer). Participants (N = 50) completed a baseline survey and were invited to consider MC1R testing via the study website. Testing interest and uptake were assessed through registration of test decision, request of a saliva test kit, and kit return (all yes/no). Immediate responses to risk feedback included feedback-relevant thoughts, emotions, communication, and information seeking after result receipt; test utility outcomes included family and physician communication and information seeking. Results indicated good retention at both time points (76%; 74%). Half (48%) logged onto the study website, and of these, most (92%) chose testing and (95%) returned a saliva sample. After two weeks, most (94%) had read all the risk feedback information and distress was low (M = 8.81, 7-28, SD = 2.23). Many (69%) had talked with their family about the results. By three months, most had spoken with family (92%) and physicians (80%) about skin cancer risk. Physician communication was higher (70%) in those tested versus those not tested (40%, p = 0.02). The substantial interest and promising outcomes associated with MC1R genetic testing in dermatology patients inform intervention strategies to enhance benefits and minimize risks of skin cancer genetic testing.

2.
Clin Cancer Res ; 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35833951

RESUMO

PURPOSE: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied. EXPERIMENTAL DESIGN: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed. RESULTS: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts (12% [12/99] vs. 8.7% [10/115], p=0.4). In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, p=0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/LP variants in DNA damage response (DDR) genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in NMIBC patients not receiving BCG, P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG. CONCLUSIONS: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of the initial tumor stage. Therapeutic strategies that target impaired DNA repair may benefit patients with high-grade NMIBC.

3.
JAMA Netw Open ; 5(7): e2224296, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35900758

RESUMO

Importance: 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. Objective: 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. Design, Setting, and Participants: 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. Exposure: Positive test result for SARS-CoV-2. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: 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.


Assuntos
COVID-19 , Neoplasias , COVID-19/epidemiologia , COVID-19/terapia , Teste para COVID-19 , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias , Estudos Prospectivos , SARS-CoV-2 , Tempo para o Tratamento , Estados Unidos/epidemiologia
4.
Br J Cancer ; 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882941

RESUMO

BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (ntotal = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10-4) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, Pheterogeneity < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.

5.
Haematologica ; 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-35770528

RESUMO

We aim to identify predictors of therapy-related myeloid neoplasms (t-MN) in patients with breast cancer (BC) and cytopenias to determine the timing of bone marrow biopsy (BMBx). Patients with BC and cytopenias who were referred for BMBx between 2002-2018 were identified using the Memorial Sloan Kettering Cancer Center institutional database. Characteristics associated with the risk of t-MN were evaluated by multivariable logistic regression and included in a predictive model. The average area under the receiver operating characteristic curve (AUC) was estimated by 5-fold cross-validation. Of the 206 BC patients who underwent BMBx included in our study, 107 had t-MN. By multivariable analysis, white blood cell count 4-11 K/mcL, absolute neutrophil count (ANC) ≥1.5 K/mcL, hemoglobin ≥12.2 g/dL, red cell distribution width 11.5-14.5%, the presence of bone metastasis and a time from BC diagnosis to BMBx <15 months significantly decreased the likelihood of t-MN. The average AUC was 0.88. We stratified our cohort by bone metastasis and by findings on peripheral smear. In both the subset without bone metastasis (n= 159) and in the cohort with no blasts or dysplastic cells on peripheral smear (n= 96) our variables had similar effects on the risk of t-MN. Among the 47 patients with bone metastasis, an ANC ≥1.5 K/mcL was the only variable associated with a decreased risk of t-MN. Our findings show that in patients with BC and unexplained cytopenias, clinical and laboratory parameters can predict t-MN and assist clinicians in determining the timing of a BMBx.

6.
Ann Surg Oncol ; 29(9): 5821-5825, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35604619

RESUMO

Risk-reducing mastectomy is considered a safe and effective surgical procedure in high-risk individuals with BRCA1/2 germline mutations. Multigene panels identify women with alterations in breast cancer susceptibility genes other than BRCA1/2. International guidelines classify these genes as high-, moderate-, and low-penetrance based on their associated relative risk for breast cancer. Classification of specific genes is not always concordant among guidelines, and the indications for risk-reducing mastectomy are not defined. In this opinion paper, we review some considerations to clarify these controversial points.


Assuntos
Neoplasias da Mama , Mastectomia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Mastectomia/métodos , Mutação , Penetrância
7.
Ann Surg Oncol ; 29(8): 4706-4713, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35585432

RESUMO

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 (p < 0.001). 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 (p < 0.001). CONCLUSIONS: 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.


Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Genes BRCA2 , Humanos , Mastectomia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos
8.
Cancer Epidemiol Biomarkers Prev ; 31(7): 1450-1459, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35477182

RESUMO

BACKGROUND: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer. METHODS: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes. RESULTS: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n = 54), CHEK2 (n = 30), and ATM (n = 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P = 1.7e-04). CONCLUSIONS: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer. IMPACT: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.


Assuntos
Predisposição Genética para Doença , Neoplasias Pulmonares , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Neoplasias Pulmonares/genética , Estudos Prospectivos
9.
NPJ Breast Cancer ; 8(1): 37, 2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35319017

RESUMO

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients' selection.

10.
Rocz Panstw Zakl Hig ; 73(1): 121-130, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35322964

RESUMO

Background: The Thai government has been developing its Eastern Economic Corridor (EEC), which spans three provinces, with the aim of improving connections with other Asian nations. Since this strategic development, the number of trucks, private car, and passenger car registrations have continued to grow, with a corresponding increase in related to benzene, toluene, ethylbenzene, and xylene (BTEX). Objectives: This study aims to compare the levels of trans, trans-muconic acid (t, t MA); toluene (TU); mandelic acid (MA); and methyl hippuric acid (MHA) in the urine of gas station employees, considering demographic and occupational factors. Material and methods: These employees worked either near or away from the fuel dispenser, and there 100 people in each group. Data were collected using interviews and testing environmental air and urine samples for benzene, toluene, ethyl benzene, and xylene (BTEX). Results: The results showed that BTEX concentrations were just detectable in all 200 cases (100%). The mean (±SD) urine level of t, t MA was 449.28 (±213.32) µg/g creatinine, while the median (min-max) was 428.23 (95.58-1202.56) µg/g creatinine. The mean TU was 0.011 (0.001) mg/L, while the median (min-max) was 0.011 (0.010-0.013) mg/L. MA levels were higher inside the pollution control zone than they were outside the zone (p=.009). Employees who practiced poor personal hygiene had relatively high urinary toluene and MHA levels (p=.009) and those who did not wear personal protective equipment (PPE) had relatively high MA levels (p=.040). Conclusion: The results of this study revealed statistically significant biomarkers influencing the levels of t, t MA; TU; MA; and MHA in urine. The recommendations of this study are that employers should provide their employees with suitable PPE, check regularly to ensure that it is worn, and strongly encourage employees to take care of their sanitation. Employees should take appropriate breaks and days off to minimize their exposure to BTEX.


Assuntos
Exposição Ocupacional , Humanos , Rim/química , Estações do Ano , Tailândia , Xilenos/urina
11.
Cell ; 185(3): 563-575.e11, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35120664

RESUMO

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.


Assuntos
Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Especificidade de Órgãos/genética , Estudos Prospectivos
12.
JAMA Oncol ; 8(4): 587-596, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35175286

RESUMO

IMPORTANCE: Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women. OBJECTIVE: To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants. DESIGN, SETTING, AND PARTICIPANTS: This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985. INTERVENTIONS: Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years. MAIN OUTCOMES AND MEASURES: Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges. RESULTS: The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women. CONCLUSIONS AND RELEVANCE: This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.


Assuntos
Neoplasias da Mama , Mamografia , Adulto , Idoso , Proteínas Mutadas de Ataxia Telangiectasia/genética , Mama , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Detecção Precoce de Câncer/métodos , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade
13.
J Clin Oncol ; 40(11): 1231-1258, 2022 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-35175857

RESUMO

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.


Assuntos
Neoplasias , Biomarcadores Tumorais/genética , Testes Genéticos , Genômica , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptores Proteína Tirosina Quinases/genética
14.
JMIR Res Protoc ; 11(2): e31696, 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35129451

RESUMO

BACKGROUND: Prenatal exposure to pesticides has been linked to adverse neurodevelopmental outcomes. Gaps exist in the current literature about the timing and magnitude of exposures that result in these adverse outcomes. OBJECTIVE: The Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE) cohort was established to investigate the impact of prenatal exposure to pesticides on early indicators of cognitive and motor skills, inhibitory control, emotion regulation, and memory that have been found to be important in the development of subsequent neurobehavioral and neurodevelopmental diseases. The overarching goal is to find earlier predictors of potential adverse neurologic outcomes in order to enable earlier interventions that could result in better outcome prognoses. METHODS: Recruitment of this prospective, longitudinal birth cohort began in July 2017 and was completed in June 2019 in Chom Thong and Fang, 2 farming districts in Chiang Mai Province in northern Thailand. Follow-up of the study participants is ongoing. During pregnancy, 7 questionnaires were administered. Time-resolved biospecimen samples were collected monthly (for urine) and during each trimester (for blood) during antenatal care visits. Medical records were abstracted. Infants were administered the NICU Network Neurobehavioral Scale (NNNS) test at 1 month of age. A total of 322 mother-child pairs completed the NNNS test. All children will be followed until 3 years of age and undergo a series of neurodevelopmental tests. We will complete several additional exposure related analyses. RESULTS: A total of 1298 women were screened, and of those, 394 (30.35%) women were enrolled. The mean gestational age at enrollment was 9.9 weeks (SD 2.6). Differences in literacy were observed between Chom Thong and Fang participants. In Fang, about 54 of 105 (51.4%) participants reported being able to read in Thai compared to about 206 of 217 (94.9%) participants in Chom Thong. The percentages were comparable for reporting to be able to write in Thai. CONCLUSIONS: This longitudinal birth cohort study will inform risk assessment standards for pregnant women in Thailand and other countries. Building awareness of how insecticide exposure during specific windows of pregnancy affects the neurodevelopmental trajectories of children in developing countries is a specific need recognized by the World Health Organization. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31696.

15.
Sci Rep ; 12(1): 499, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35017597

RESUMO

The objectives of the study were to evaluate the impact of pesticide exposure on farmer health during non-active rice farming and active rice farming periods and present the change in the individual cholinesterase activities (%reduction) on the geographic information system (GIS) mapping in Nakhon Ratchasima Province, Thailand. Acetyl- and butyryl-cholinesterase (AChE and BuChE) activities were monitored during both study periods using Test-mate ChE (Model 400). The location of paddy fields was specified using Garmin geographic positioning system MAP 62s. Fifty-eight farmers who participated in this study had an average age of 49.2 ± 6.9 years. Higher prevalence of all health symptoms was observed among farmer participants during the active rice farming period comparing to the non-active rice farming period (p < 0.01). Furthermore, farmers had significantly lower activities of AChE and BuChE during the active rice farming period comparing to the non-active rice farming period (p < 0.01). Our findings indicate that the GIS mapping indicate that the cases with a significant enzyme inhibition have dispersed across the agricultural and the nearby residential areas. This, investigation can be used to promote safer use of pesticides among farmers and mitigate pesticide exposure among residents living in close proximity to a rice field.


Assuntos
Sistemas de Informação Geográfica , Exposição Ocupacional/efeitos adversos , Oryza/crescimento & desenvolvimento , Praguicidas/toxicidade , Acetilcolinesterase/sangue , Adulto , Doenças dos Trabalhadores Agrícolas/sangue , Doenças dos Trabalhadores Agrícolas/enzimologia , Agricultura , Butirilcolinesterase/sangue , Fazendeiros/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tailândia
16.
Cancer Epidemiol Biomarkers Prev ; 31(2): 362-371, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34810208

RESUMO

BACKGROUND: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms. METHODS: Patients were prospectively consented (01/2013-02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants. RESULTS: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma-lung, lymphoma-uterine, breast-brain, and melanoma-lung pairs in women and prostate-mesothelioma, prostate-sarcoma, melanoma-stomach, and prostate-brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common. CONCLUSIONS: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities. IMPACT: If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.


Assuntos
Melanoma , Neoplasias Primárias Múltiplas , Segunda Neoplasia Primária , Neoplasias da Próstata , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/genética , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/genética , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/genética , Neoplasias da Próstata/genética
17.
Clin Cancer Res ; 28(2): 404-413, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34667028

RESUMO

PURPOSE: Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals. EXPERIMENTAL DESIGN: A retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA. RESULTS: A total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response. CONCLUSIONS: A subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.


Assuntos
Neoplasias da Mama , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL/genética , Estudos Retrospectivos
18.
Breast Cancer Res Treat ; 191(1): 31-38, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34642874

RESUMO

PURPOSE: Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance. METHODS: A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study. RESULTS: Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant. CONCLUSION: This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.


Assuntos
Neoplasias da Mama Masculina , Predisposição Genética para Doença , Penetrância , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Estudos de Coortes , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genes BRCA2 , Humanos , Masculino
19.
Genet Med ; 24(3): 564-575, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906490

RESUMO

PURPOSE: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs). METHODS: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years. RESULTS: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing. CONCLUSION: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Internet , Judeus/genética , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Estados Unidos
20.
Cancer Discov ; 12(4): 949-957, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34949653

RESUMO

Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. SIGNIFICANCE: Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873.


Assuntos
Neoplasias , Alelos , Desenvolvimento Embrionário/genética , Testes Genéticos , Humanos , Mutação , Neoplasias/genética
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