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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3037-3037
    Abstract: 3037 Background: Less than 20% of cancers are diagnosed as a result of standard-of-care (SOC) screening in the US. MCED tests may expand screening to more cancers, but the long-term outcomes of MCED test-detected cancers are unknown. DETECT-A was the first large prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK and was evaluated in 9,911 women without history of cancer ( Science 369:6499, 2020). CancerSEEK, coupled with diagnostic PET-CT, safely identified cancers including those not detected by SOC screening, the majority of which were localized or regional. This follow-up observational study evaluated longitudinal clinical outcomes of cancers diagnosed as a result of an abnormal CancerSEEK test with a median follow up of 4.4 (IQR:4.1-4.6) years from initial CancerSEEK testing. Methods: Nine cancer types were diagnosed in 26 participants whose cancers were first detected by CancerSEEK. Information on cancer diagnosis, treatment, treatment response, remission status, recurrence, secondary cancer diagnoses, and mortality (cancer-related and all-cause) was extracted from electronic medical records through November 2022. Data collection for living participants took place a median of 3.7 years following cancer diagnosis (IQR: 3.3-3.9) and a median of 4.3 years (IQR: 4.1-4.7) following initial CancerSEEK screen. Results: Fourteen (53.8%) participants underwent surgery; 5 had surgery alone, 9 had surgery with adjuvant and/or neoadjuvant chemotherapy, radiation, or hormone therapy. Twelve of 14 (85.7%) surgically treated participants were in remission as of November 2022, including 10 with localized or regional disease at diagnosis. Among patients whose treatment was non-surgical (11) or unknown (1), 1 (8.3%) was in remission (stage I at diagnosis), 9 (75.0%) were deceased (all stage III or IV at diagnosis), and 2 (16.7%) were in surveillance or ongoing treatment (stage II and stage III at diagnosis). Overall, 13 of 26 (50%) participants were in remission [ovarian (4), thyroid (1), uterus (2), breast (1), colorectal (2), and lung (3)] ; 7 of these 13 (54%) had cancers without recommended SOC screening modalities. Eleven of 17 (64.7%) participants with localized or regional disease (stage I, II, or III) were in remission, whereas 2 of 9 (22.2%) with stage IV disease at diagnosis were in remission. Conclusions: CancerSEEK detected cancers earlier in patients who, when treated subsequently with conventional methods, achieved long-term survival. Half of all patients with a CancerSEEK-detected cancer remain cancer-free after treatment 〉 4 years (median) after their initial CancerSEEK test. This includes 7 patients with cancer types for which no SOC screening option exists. Additional biomarkers, new analytic methods and algorithms are being incorporated in the development of the next generation of the MCED test.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2628-2628
    Abstract: Pancreatic ductal adenocarcinoma (PDA) affects over 44,000 people in the United States every year and carries a dismal prognosis, with a 5-year survival rate of just 5%. A subset of these patients (5-10%) report a familial history of the disease. The genetic etiology in these familial cases is poorly defined, with known susceptibility genes, such as: BRCA2, PALB2, CDKN2A, BRCA1, PRSS1 and STK11, accounting for only 10-15% of familial pancreatic cancer. In an effort to identify previously unappreciated pancreatic cancer susceptibility genes, we used next generation sequencing technology to evaluate the whole genome and whole exome sequences of 16 (6 families) and 22 individuals (10 families) respectively. All of these families enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology (PacGene) Consortium, all had at least three members with PDA, and DNA was available from at least two affected members in each kindred. Using this approach, we identified heterozygous, inactivating, ATM mutations in two kindreds with familial pancreatic cancer (c.8266A & gt;AT; p.K2756X and c.170G & gt;GA; p.W57X). These mutations were previously reported as disease causing variants in patients with ataxia-telangiectasia, an autosomal recessive condition resulting from bi-allelic deleterious mutations of ATM. Interestingly, heterozygotes of deleterious ATM mutations have an increased risk of breast cancer. However, there have been no previous reports of deleterious ATM mutations in the germline of familial PDA patients. In our study, mutations segregated with disease in both kindreds and tumor analysis demonstrated Loss of heterozygosity (LOH) of the wild-type allele. Sequence analysis of the entire ATM gene in an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene (c.3214G & gt;GT; p.E1072X, c.6095G & gt;GA; p.R2032K, IVS41-1G & gt;GT and c.3801delG), while no deleterious mutations were identified in 190 spouse controls (p=0.046). When considering only the mostly severely affected families, those with three or more pancreatic cancer cases, four deleterious mutations were found in 87 families (P=0.009). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition and have significant implications in the management of affected individuals and the risk assessment of family members. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2628. doi:1538-7445.AM2012-2628
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 8 ( 2009-04-15), p. 3681-3688
    Abstract: Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced & gt;750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer. [Cancer Res 2009;69(8):3681–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 14 ( 2009-07-15), p. 4674-4679
    Abstract: Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. Results: When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (≥4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. Conclusions: SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3039-3039
    Abstract: 3039 Background: Recommended standard of care (SOC) early detection tests are solely available for four cancer types and fewer than 20% of incident cancers in the US are being diagnosed as a result of screening. Advances in detection of tumor-derived analytes in the blood are enabling the development of MCED tests that may expand early cancer detection. While MCED tests are being designed with high specificity, false positive (FP) results remain a concern for clinicians and patients alike, as no long-term outcomes of individuals with a FP MCED test have been reported. DETECT-A was the first prospective interventional clinical trial to evaluate an MCED blood test. The test used was an early version of CancerSEEK, evaluated in 9,911 women without history of cancer ( Science, 369:6499, 2020). This prospectively planned analysis evaluates cancer incidence among DETECT-A participants with FP results, with the intention of providing key long-term data on test effectiveness. Methods: This analysis included 98 DETECT-A participants with FP results, where a FP was defined as a positive CancerSEEK result with subsequent PET-CT and clinical evaluation with no evidence of cancer within 1 year of the initial CancerSEEK test. Sixty-three of 98 participants had no follow-up procedure performed after imaging, and 35 subjects had noninvasive/minimally invasive follow-up procedures performed. Electronic medical records were analyzed from January 2020 through November 2022 for cancer diagnosis, treatment, remission, recurrence, and mortality. Results: Ninety-six of 98 participants with a FP result remained free of cancer with a median follow-up of 4.3 years (IQR: 3.9-4.9) from the initial CancerSEEK test. One stage I breast cancer and one stage III ovarian cancer were diagnosed 2.7 and 2.9 years respectively from the initial CancerSEEK test. Conclusions: Patients with a negative PET-CT and initial clinical evaluation after a positive CancerSEEK test had low ( 〈 1% per year) risk for cancer in the ensuing four years after the initial CancerSEEK test. If confirmed, this result should prove reassuring to clinicians and to patients who have no evidence of cancer on comprehensive imaging following a positive MCED test. Further, these results provide preliminary support for the recommendation that patients who participate in MCED testing and receive a FP result can safely return to routine care after comprehensive anatomic and functional imaging and clinical evaluation reveal no suspicion of cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 13 ( 2014-07-01), p. 3381-3389
    Abstract: Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts. Cancer Res; 74(13); 3381–9. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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