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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations. METHODS: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed. RESULTS: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344). CONCLUSIONS: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors.
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OBJECTIVE: Genetic testing for ovarian cancer (OC) patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) allowing patients to have a same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). METHODS: The GTS was implemented December 2018 and operated through February 2020. Gynecologic Oncologists offered ovarian cancer patients a same-day GTS visit with a GCA. The patient received education via videos designed by GCs and then provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a GC. Patients were retrospectively identified by querying the medical record for OC patients seen 12 months prior to and 18 months after GTS implementation. RESULTS: A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.4% (p = 0.012) after implementation, primarily in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral for genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. Time to obtaining results was 21 days in the GTS group (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. CONCLUSIONS: The GTS reduces barriers to care and facilitates discussion of precision treatment within a timely fashion while optimizing GC clinic time. Access improvement remains integral to improving uptake of genetic testing.
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PURPOSE: Germline testing for men with prostate cancer (PCa) poses numerous implementation barriers. Alternative models of care delivery are emerging, but implementation outcomes are understudied. We evaluated implementation outcomes of a hybrid oncologist- and genetic counselor-delivered model called the genetic testing station (GTS) created to streamline testing and increase access. METHODS: A prospective, single-institution, cohort study of men with PCa referred to the GTS from October 14, 2019, to October 14, 2021, was conducted. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, we described patients referred to GTS (Reach), the association of GTS with germline testing completion rates within 60 days of a new oncology appointment in a pre- versus post-GTS multivariable logistic regression (Effectiveness), Adoption, Implementation, and Maintenance. Because GTS transitioned from an on-site to remote service during the COVID-19 pandemic, we also compared outcomes for embedded versus remote GTS. RESULTS: Overall, 713 patients were referred to and eligible for GTS, and 592 (83%) patients completed germline testing. Seventy-six (13%) patients had ≥ 1 pathogenic variant. Post-GTS was independently associated with higher odds of completing testing within 60 days than pre-GTS (odds ratio, 8.97; 95% CI, 2.71 to 29.75; P < .001). Black race was independently associated with lower odds of testing completion compared with White race (odds ratio, 0.35; 95% CI, 0.13 to 0.96; P = .042). There was no difference in test completion rates or patient-reported decisional conflict for embedded versus remote GTS. GTS has been adopted by 31 oncology providers across four clinics, and implementation fidelity was high with low patient loss to follow-up, but staffing costs are a sustainability concern. CONCLUSION: GTS is a feasible, effective model for high-volume germline testing in men with PCa, both in person and using telehealth. GTS does not eliminate racial disparities in germline testing access.
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COVID-19 , Neoplasias da Próstata , Telemedicina , Masculino , Humanos , Estudos de Coortes , Pandemias , Estudos Prospectivos , Testes Genéticos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Células Germinativas/patologiaRESUMO
BACKGROUND: Germline genetic testing is universally recommended for patients with pancreatic cancer, but testing remains infrequent. In May 2018, we implemented a systematic patient intake workflow featuring an in-clinic genetic testing station (GTS) at the University of California San Francisco (UCSF) to expedite genetic counseling and facilitate sample collection. We sought to determine the impact of this innovation on rates of genetic counseling and testing. METHODS: Medical records, patient intake records, and genetic test reports were retrospectively reviewed for new patients with pancreatic cancer eligible for germline testing at UCSF from May 2018 to May 2019. Primary outcomes included the rate of offered genetic counseling and confirmed germline testing. Data were compared for periods before and after GTS implementation. Associations between demographic characteristics and testing rates were assessed. RESULTS: Genetic counseling/testing was offered to 209 (94%) of 223 eligible patients, and 158 (71%) completed testing (135 at UCSF, 23 elsewhere). Compared with a traditional referral-based genetic counseling model, confirmed testing increased from 19% to 71%, patient attrition between referral and genetics appointment decreased from 36% to 3%, and rate of pathogenic variant detection increased from 20% to 33%. Patients who were younger, identified as non-Hispanic White, and spoke English as a primary language were more likely to complete testing. CONCLUSIONS: Implementation of a systematic patient intake workflow and in-clinic GTS resulted in the highest reported real-world rate of germline testing for patients with pancreatic cancer. Health care disparities were identified and will guide future innovation. This report provides a model for other centers to create a similar testing infrastructure. IMPLICATIONS FOR PRACTICE: This study demonstrates that a systematic patient intake workflow and associated in-clinic genetic testing station improve delivery of genetic counseling and completion of germline testing for patients with pancreatic cancer. This study achieved, to the authors' knowledge, the highest real-world rate of confirmed genetic testing in this patient population. This article describes this innovation in detail to guide replication at other medical centers and facilitate guideline-concordant care for patients with pancreatic cancer. This infrastructure can also be applied to other cancers for which germline testing is recommended.
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Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Testes Genéticos , Células Germinativas , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments. RESULTS: 41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408). CONCLUSIONS: Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.
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Hemiplegia , ATPase Trocadora de Sódio-Potássio , Humanos , Mutação , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
BACKGROUND: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood-based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. PATIENTS AND METHODS: Provista-001 and Provista-002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor-associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista-001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista-002 cohort one (validation set). RESULTS: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow-up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow-up, a 67% reduction in FPs (P < .00001). CONCLUSIONS: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC.
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Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Carcinoma in Situ/diagnóstico , Carcinoma Lobular/diagnóstico , Proteoma/análise , Proteômica/métodos , Adulto , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico por imagem , Carcinoma in Situ/sangue , Carcinoma in Situ/diagnóstico por imagem , Carcinoma Lobular/sangue , Carcinoma Lobular/diagnóstico por imagem , Feminino , Seguimentos , Humanos , Mamografia/métodos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Prognóstico , Estudos ProspectivosRESUMO
Despite significant advances in breast imaging, the ability to accurately detect Breast Cancer (BC) remains a challenge. With the discovery of key biomarkers and protein signatures for BC, proteomic technologies are currently poised to serve as an ideal diagnostic adjunct to imaging. Research studies have shown that breast tumors are associated with systemic changes in levels of both serum protein biomarkers (SPB) and tumor associated autoantibodies (TAAb). However, the independent contribution of SPB and TAAb expression data for identifying BC relative to a combinatorial SPB and TAAb approach has not been fully investigated. This study evaluates these contributions using a retrospective cohort of pre-biopsy serum samples with known clinical outcomes collected from a single site, thus minimizing potential site-to-site variation and enabling direct assessment of SPB and TAAb contributions to identify BC. All serum samples (n = 210) were collected prior to biopsy. These specimens were obtained from 18 participants with no evidence of breast disease (ND), 92 participants diagnosed with Benign Breast Disease (BBD) and 100 participants diagnosed with BC, including DCIS. All BBD and BC diagnoses were based on pathology results from biopsy. Statistical models were developed to differentiate BC from non-BC (i.e., BBD and ND) using expression data from SPB alone, TAAb alone, and a combination of SPB and TAAb. When SPB data was independently used for modeling, clinical sensitivity and specificity for detection of BC were 74.7% and 77.0%, respectively. When TAAb data was independently used, clinical sensitivity and specificity for detection of BC were 72.2% and 70.8%, respectively. When modeling integrated data from both SPB and TAAb, the clinical sensitivity and specificity for detection of BC improved to 81.0% and 78.8%, respectively. These data demonstrate the benefit of the integration of SPB and TAAb data and strongly support the further development of combinatorial proteomic approaches for detecting BC.
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Autoanticorpos/genética , Autoanticorpos/metabolismo , Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Proteômica/normas , Área Sob a Curva , Neoplasias da Mama/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Análise Multivariada , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (TbetaRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TbetaRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.
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Proteínas Morfogenéticas Ósseas/fisiologia , Metaloproteinase 2 da Matriz/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteína Smad1/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Humanos , Mesoderma/citologia , Mesoderma/fisiologia , Invasividade Neoplásica , Neoplasias Pancreáticas/patologia , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad1/genética , Regulação para CimaRESUMO
Transforming growth factor beta (TGF-beta) superfamily signaling pathways are ubiquitous and essential regulators of cellular processes including proliferation, differentiation, migration, and survival, as well as physiological processes, including embryonic development, angiogenesis, and wound healing. Alterations in these pathways, including either germ-line or somatic mutations or alterations in the expression of members of these signaling pathways often result in human disease. Appropriate regulation of these pathways is required at all levels, particularly at the ligand level, with either a deficiency or an excess of specific TGF-beta superfamily ligands resulting in human disease. TGF-beta superfamily ligands and members of these TGF-beta superfamily signaling pathways also have emerging roles as diagnostic, prognostic or predictive markers for human disease. Ongoing studies will enable targeting of TGF-beta superfamily signaling pathways for the chemoprevention and treatment of human disease.
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Doença , Ligantes , Transdução de Sinais , Fator de Crescimento Transformador beta/fisiologia , Biomarcadores , Doenças Cardiovasculares/genética , Aberrações Cromossômicas , Feminino , Doenças Genéticas Inatas/genética , Humanos , Doenças Musculoesqueléticas/genética , Mutação , Neoplasias/genética , Gravidez , Complicações na Gravidez/genética , Prognóstico , Fator de Crescimento Transformador beta/genéticaRESUMO
Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion.
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Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Regulação da Expressão Gênica , Mesoderma/patologia , Neoplasias Pancreáticas/patologia , Proteoglicanas/fisiologia , Receptores de Fatores de Crescimento Transformadores beta/fisiologia , Animais , Células COS , Linhagem Celular Tumoral , Movimento Celular , Chlorocebus aethiops , Progressão da Doença , Humanos , Modelos Biológicos , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Proteoglicanas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
The TGF-beta signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression. TbetaRIII expression decreased during breast cancer progression, and low TbetaRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TbetaRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TbetaRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TbetaRIII, which binds and sequesters TGF-beta to decrease TGF-beta signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TbetaRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.
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Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/prevenção & controle , Proteoglicanas/fisiologia , Receptores de Fatores de Crescimento Transformadores beta/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Mamárias Animais/genética , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Proteoglicanas/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de SinaisRESUMO
Breast carcinoma has the potential for widespread dissemination. Spread to the lower gastrointestinal tract is infrequent, often multifocal, occurs in association with spread to other sites, and most commonly develops from lobular carcinoma. Solitary colorectal metastasis as the first and sole manifestation of spread is a rare occurrence and can be confused with primary intestinal malignancy. We present a case of metastatic papillary breast carcinoma presenting as a perforated primary colon cancer. Identity of the lesion was confirmed by direct histologic comparison of the resected tumor with prior breast specimen, cytokeratin expression, and the presence of estrogen receptors.