Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Diseases and Abnormalities at or Before Birth

Symptoms and General Pathology

Rare Diseases

Adenocarcinoma

Pancreatic Neoplasms

Congenital Abnormalities

Disease Susceptibility

Genetic Predisposition to Disease

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Pancreatic Cancer

This group will comprise of patients with pancreatic cancer who carry pathogenic mutations in genes associated with a predisposition to cancer.

This group will comprise of patients with pancreatic cancer who did not carry pathogenic mutations in any of the genes tested, that have been previously shown to be associated with a predisposition to cancer.

Mutations

This study will assess the hereditary component of pancreatic cancer in the largest series of patients up to date through the parallel analysis of 62 cancer-associated genes. The investigators will obtain germline DNA from blood samples that have been collected from 2000 to 2019 from patients with pancreatic cancer. The investigators plan to analyze germline DNA for mutations and single nucleotide polymorphisms (SNPs) in genes that have been previously linked to a predisposition towards cancer.

The outcome can provide useful insight on the overall understanding of pancreatic pathogenesis while possible associations with age of diagnosis, tumor stage and other cancer types might arise. In addition to that, it can lead to the characterization of new variants or even new genes that predispose to pancreatic cancer.

Confirmed deleterious mutations in established cancer genes can provide valuable clinical information that can lead to effective, individualized patient management. Furthermore, family relatives of the individuals found to carry mutations can also benefit from established screening protocols for various cancer types, such as frequent colonoscopies in the case of an MMR mutation predisposing for Lynch syndrome, or preventative surgeries in the case of a deleterious BRCA1 or BRCA2 mutation. In addition to that, specific therapies that have been previously shown to be effective in breast or ovarian cancer patients with BRCA1 \& BRCA2 mutations, such as platinum-based chemotherapy and PARP inhibitors can be also effective in mutations carriers with pancreatic cancer.

Background Pancreatic ductal adenocarcinoma has poor prognosis mainly highlighted by the low 5-year survival rate, which is estimated to be around 6%. Although pancreatic cancer incidence is approximately 0.5% in the general population, it has a high-mortality rate. It is being registered as the fourth leading cause of cancer-related deaths in the United States. Poor prognosis is mainly attributed to the lack of efficient treatment options.

With the majority of pancreatic adenocarcinoma cases being sporadic, familial clustering (defined by the presence of at least two first degree relatives with pancreatic cancer) is observed in \~20% of the cases, whereas a clear genetic cause is identified in approximately half of these cases. Pancreatic cancer is known to occur in a range of cancer predisposing syndromes, such as hereditary breast and ovarian cancer, Peutz-Jeghers, familial adenomatous polyposis, Lynch, Li-Fraumeni and familial atypical multiple mole syndromes, while there have been clear associations with loss-of-function mutations in non-syndromic cancer genes, such as PALB2 and ATM. In addition, individuals carrying mutations in PRSS1 gene that predisposes for hereditary pancreatitis are also considered to be at high-risk for pancreatic cancer. It is therefore clear that pancreatic cancer is not related with a single cancer predisposition gene, but with numerous known and probably yet to be discovered, cancer susceptibility genes.

On the other hand, the accurate fraction of genetic predisposition in pancreatic cancer hasn't been determined. Previous studies have evaluated the prevalence of loss-of-function mutations in known cancer predisposition genes in pancreatic cancer patients through the use of multi-gene panels. The mutation yield ranged from 3.8% to 9.7% in genes that were previously found relevant to pancreatic cancer predisposition.

Through these studies, it has been highlighted that family history and stage of pancreatic cancer or age at diagnosis is not always a predictor of an underlying genetic factor, while phenotypic heterogeneity is usually associated with mutation status. The search for novel predisposition genes in pancreatic cancer patients without family history is ongoing through candidate genes analysis or through whole exome sequencing.

Research methodology Clinicopathological characteristics

Genomic DNA from pancreatic cancer patients will be retrospectively and prospectively collected from the Hellenic Cooperative Oncology Group (HeCOG) Tumor Repository, through years 2000-2019. Written informed consent has already been obtained from all patients for the use and storage of their biologic material along with their approval for their participation in research studies. The study will be in agreement with the 1975 Helsinki statement, revised in 1983.

Clinicopathologic characteristics of patients with pancreatic cancer will be retrieved form their medical record. Diagnosis will be confirmed through pathology reports, which will also provide information about grade, proliferation rate, histological subtype and lymphovascular invasion. From the patient medical record, tumor size, nodal involvement as well as metastatic lesions (TNM staging) will be reported. Importantly, detailed family history will be collected. The collection of these information will be in compliance with the regulations of the Bioethics committees of participating hospitals. Clinicopathological characteristics will be correlated with the different genomic abnormalities identified by sequencing.

Germline DNA extraction

Blood samples will be collected from patients with pancreatic cancer. Germline DNA from white blood cells will be isolated using a commercially available blood DNA extraction kit. Germline DNA will then be subjected to mechanical fragmentation via sonication to reach a DNA size of approximately 200-250 bp for downstream next-generation sequencing (NGS) analysis.

Next-Generation Sequencing

Targeted capture enrichment NGS relies on in-solution hybridization of DNA libraries with TACS (Targeted Capture Enrichment Sequences) for the identification of germline mutations in cancer patients. First, TACS that target mutations associated with hereditary cancer (in a total of 62 cancer predisposing genes) are designed and prepared by PCR followed by biotinylation. Biotinylated TACS will then be immobilized on streptavidin coated magnetic beads for subsequent hybridisation with the DNA libraries. DNA libraries are prepared from patient derived-germline DNA that fulfill quality control criteria (DNA yield, DNA integrity and fragment size) according to established protocols. Library preparation involves the 3' end and 5' end adaptor ligation and each DNA library will be barcoded using unique oligonucleotide DNA sequences to allow subsequent discrimination after sequencing. Subsequent to barcoding, samples will undergo hybridization using custom made 5'-biotynylated TACS followed by PCR amplification. Finally, enriched DNA libraries will be normalised and pooled on a NGS platform prior to paired-end sequencing using manufacturer's protocols.

Bioinformatic and Data Analysis Sequence data from leucocyte (buffy coat) DNA will be demultiplexed and aligned to the human genome (hg19) using appropriate aligner algorithms (BWA) to generate a BAM file. A combination of variant calling algorithms will be used to call germline mutations. Local realignment will be performed for accurate detection of small insertions and deletions and appropriate algorithms to detect rearrangements. Bioinformatics tools for copy number alterations (CNAs) calling such as ASCAT-2, CNVkit or ANACONDA will be used for the assessment of focal gene amplification or deletion events. Read depth-based analysis will also be taken into consideration for assessment of gene-level CNAs. Appropriate variant annotators will be used to annotate the identified alterations to each gene. Germline variant databases such as ClinVar will be used for the classification of variants according to the ACMG guidelines.

Germline DNA from white blood cells will be isolated using a commercially available blood DNA extraction kit. Remaining germline DNA will be safely stored in HeCOG's repository.

Germline Mutations in Pancreatic Adenocarcinoma

Prevalence of Germline Pathogenic Mutations in Patients With Pancreatic Adenocarcinoma

Evaluation of overall survival in patients with pancreatic cancer, from the date of treatment start until verified disease progression, death from any cause or date of last contact whichever occurred first

Hellenic Cooperative Oncology Group

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Fibrocystic Breast Disease

Skin Diseases

Cases or Patients who underwent robotic nipple-sparing mastectomy and immediate reconstruction are enrolled in this arm. Robotic nipple-sparing mastectomy should be performed using robotic surgical systems. Robotic surgical systems include da Vinci S,Si, X, Xi, and SP systems. Axillary or lateral incisions are used for this procedure. Immediate reconstruction includes tissue expander insertion, direct-to-implant, latissimus dorsi flap, transverse abdominis rectus muscle flap, or deep inferior epigastric perforators flap. Cases with robotic mastectomy without immediate reconstruction are excluded.

Robotic or endoscopic nipple sparing mastectomy

Cases or Patients who underwent conventional mastectomy and immediate reconstruction are enrolled in this arm. Conventional mastectomy should not be performed using robotic or endoscopic surgical systems. Any incisions can be performed for this procedure. Conventional mastectomy includes also Nipple-sparing mastectomy and Skin sparing mastectomy. Immediate reconstruction includes tissue expander insertion, direct-to-implant, latissimus dorsi flap, transverse abdominis rectus muscle flap, or deep inferior epigastric perforators flap. Cases without immediate reconstruction are excluded.

Conventional mastectomy (including nipple sparing mastectomy, skin sparing mastectomy)

Hyung Seok Park, MD, PhD

Younju Lee, MD, PhD

Aeri Han, MD, PhD

Yeongwoo chang, MD, PhD

Hyukjai Shin, MD, PhD

Joo Heung Kim, MD

Hee Jun Choi, MD, PhD

Gusang Kim, MD,PhD

Jeeyeon Lee, MD, PhD

Young Joon Kang, MD, PhD

Ji Young You, MD, PhD

Honggyu Kim, MD, PhD

Jun-Hee Lee, MD, PhD

Sungjun Bae, MD,PhD

Jong-Ho Cheun, MD

Sanguk Woo, MD

Jai Min Ryu, MD, PhD

Sae Byeol Lee, MD, PhD

Robotic mastectomy and immediate reconstruction have been introduced in 2015. However, since robotic mastectomy is the latest surgical technique, there is a lack of studies prospectively comparing conventional mastectomy and immediate reconstruction with robotic mastectomy. For this reason, this study is designed to establish a single institution cohort study that prospectively collects patients undergoing mastectomy and reconstruction. This study was initially designed as a single institution study, however, currently, the study was extended to the multicenter study including 18 institutions over the country. Using the established prospective cohort data, a comparative study of robotic mastectomy with conventional mastectomy and reconstruction, and cost-effectiveness and satisfaction of robotic endoscopic surgery, and cost-effectiveness and satisfaction of reconstructive surgery are to be analyzed.

This study is a multi-institution cohort study that prospectively collects patients undergoing mastectomy and reconstruction.

Patients' inclusion criteria is as below; adult women between the ages of 19 and 80, with breast cancer or high risk of breast cancer (patients with a BRCA1/2 mutation, TP53 mutation, PALB2 mutation, etc) scheduled for therapeutic or prophylactic mastectomy, and want immediate reconstruction.

Patients planned for breast-conserving surgery or who do not want immediate reconstruction will be excluded. Patients who planned for surgery on both sides in the different methods (e.g. right for RNSM and left for conventional open NSM) are also excluded. Meanwhile, cases with ipsilateral NSM and contralateral partial mastectomy or excision are included.

The goal number of enrolled patients is 2000.

Collecting data includes patients' clinicopathological factors including height, weight, etc. And also collecting surgical results, oncological results, cost-effectiveness, and satisfactions of patients to secure high-level data.

The satisfaction of patients using the Breast Q survey, basic characteristics like height, weight, etc, and patients' photos will be collected preoperatively.

Also, patients' data will be collected within 6 months after surgery including clinical-pathological factors, surgery results (drainage amount, removal date, complications), postoperative recovery evaluation, complications and adverse reactions, cost, etc.

Between 6 months and 1 year(Patients who have undergone skin sparing mastectomy can do within up to 3 years) after surgery, the results of surgery, recurrence, satisfaction survey, and postoperative photos will be collected.

Every 12 months thereafter, whether adjuvant therapy (chemotherapy, radiation therapy, targeted therapy, endocrine therapy) was implemented, surgical results, and recurrence will be investigated and collected until the end of the study period.

An interim analysis will be done after completing the recruitment of subjects by the 4th year after the start of the study and collecting data. Complete the follow-up observation and data collection of the subjects recruited in the 5-9 years and the final analysis will be conducted.

Categorial variables will be examined by the chi-square test or Fisher's exact test.

Continuous variables will be examined by t-test or ANOVA, and M-W test or K-W test if needed.

Survival analysis will be examined by Kaplan-Meier plot and log-rank test.

Prospective Study of MAstectomy With Reconstruction Including Robot Endoscopic Surgery

Prospective Cohort Study of Mastectomy With Reconstruction Including Robot Endoscopic Breast Surgery

Postoperative complication rates are calculated as total number of postoperative complication cases per total operation cases.

Clavien-Dindo grade of postoperative complications is evaluated. The highest grade of postoperative complications are used for the analysis.

Events of RFS includes locoregional recurrence, distant recurrence, and death. Contralateral breast cancer and second primary malignancy are considered to be censored data.

cancer incidence rate for those underwent prophylactic mastectomy

Reconstruction Expectations of Preoperative Short Form. In all scales, higher scores reflect a better outcome.

1. Mastectomy Module Pre-and Postoperative Scales Satisfaction with Breasts as assessed by BREAST-Q version 2.0. Higher scores reflect a better outcome.
2. Reconstruction Module Pre-and Postoperative Scales Satisfaction with abdomen as assessed by BREAST-Q version 2.0 (This scale should only be completed by the patient who has had reconstruction using a transverse rectus abdominis myocutaneous flap(TRAM flap) or deep inferior epigastric perforators flap(DIEP flap). Otherwise, skip it.) Satisfaction with Back as assessed by BREAST-Q version 2.0 (This scale should only be completed by the patient who has had reconstruction using a latissimus dorsi flap. Otherwise, skip it.) Satisfaction with Implants as assessed by BREAST-Q version 2.0 (This scale should only be completed by the patient who has had reconstruction using implants. Otherwise, skip it.) In all scales, higher scores reflect a better outcome.

Satisfaction of Surgery assessed by (Plastic)Surgeon(s) Items(1), Response Options(Overall symmetry, postoperative scar, nipple areolar complex symmetry, etc), Range(0-10) The higher scores are, the better an outcome is.

Cost-effectiveness evaluation according to the surgical method, by conducting a questionnaire survey on the subject 6 months to 1 year(Patients who have undergone skin sparing mastectomy up to 3 years) after the last surgery. Evaluation follows the EuroQol five-dimension scale(EQ5D, EQ5D-5L) Korean version questionnaire. In all scales, higher scores reflect a better outcome.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Germline Mutations in Pancreatic Adenocarcinoma	NCT03982446	Germline Mutati... Pancreatic Canc... Predisposition,... Hereditary Canc...	Mutations	18 Years - 90 Years	Hellenic Cooperative Oncology Group
Prospective Study of MAstectomy With Reconstruction Including Robot Endoscopic Surgery	NCT04585074	Breast Neoplasm... Germline BRCA1 ... Germline BRCA2 ... Benign Breast D... Germline Mutati...	Robotic or endo... Conventional ma...	19 Years - 80 Years	Severance Hospital

Spots Global Cancer Trial Database for germline mutation abnormality