Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Syndrome

Polycystic Ovary Syndrome

Hyperandrogenism

Anovulation

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Disorders of Sex Development

46, XX Disorders of Sex Development

Congenital Abnormalities

Urogenital Abnormalities

Adrenal Hyperplasia, Congenital

Adrenogenital Syndrome

Male Urogenital Diseases

Congenital Adrenal Hyperplasia

21-hydroxylase Deficiency

Izhar Ben-Shlomo, MD

Background: Infertility affects up to 15% of married couples. About half are attributable to female factors, among which anovulation is the leading cause. Some 5% of all women of reproductive age are anovulatory due to the polycystic ovarian syndrome (PCOS). PCOS causes also major health and cosmetic problems and significantly affects quality of life. PCOS is associated with cardiovascular morbidity and Type 2 diabetes mellitus, but it is unclear whether these are caused by the ovarian dysfunction or result from a common denominator.

Working hypothesis and aims: Whole genome analysis of multigenerational families in which at least one woman is affected by PCOS may significantly reduce the numbers needed to verify the specific genes, involved in the causation of PCOS.

Methods: Registration of multigenerational families and production of personal files with full workup for the presence of PCOS or its absence (in the women participants). Drawing of blood, extraction and preservation of DNA. Analysis of all informative SNPs in the genomes of the participants on a specific microarray chip. Statistical analysis of the results.

Expected results: Verification of the loci and putative genes, associated with the appearance of PCOS.

Importance: Elucidation of the specific genes underlying the pathology of PCOS. Probable implications to Medicine: Paving the way for targeted treatment of the problems, associated with PCOS, based on the clear knowledge of its underlying cause(s).

1. Working Hypothesis The recent trend in GWA has been the comparison of large numbers of DNA samples from affected individuals and large pools of unrelated individuals (Wellcome Trust Case Control Consortium). Whenever the control group came from family members, the number of patients needed to be sampled has been consistently smaller (Dempfle a et al 2006; The Japanese Schizophrenia Sib-Pair Linkage Group 2005), due to less degrees of freedom in the statistical analysis (Chen WM \& Abecasis GR 2007).
2. Specific Aims

   1. What are the specific informative SNPs, associated with PCOD?
   2. What are the specific genes located in the vicinity of these SNPs, which could contribute to the development of the clinical syndrome? Detailed description of the proposed research Clinical data collection and patient recruitment Patients

   Women will be diagnosed as suffering from PCOD based on the Rotterdam criteria ():
   1. Oligo- and/or anovulation
   2. Clinical and/or biochemical signs of hyperandrogenism
   3. Polycystic ovaries, and exclusion of other aetiologies (congenital adrenal hyperplasias, androgen-secreting tumours, Cushing's syndrome) Routine testing of serum levels for the relevant sex hormones will be performed at the 3rd day of the menstrual cycle. Glucose and insulin levels will be measured at the fasting state. The individual data collection page is presented as Appendix 1.

   Controls Sisters, mothers, fathers, aunts and grandmothers of affected women will be asked to disclose their relevant clinical history and donate a single blood test for both DNA extraction and hormonal tests, which will be taken at the 3rd day of menstruation, where applicable.

   The population that is served by Mayanei Hayeshua hospital is characterized by a short generation interval, due to the mean early age at marriage and the desire to bear children right after marriage. This should allow the formation of genealogy trees that are very informative.

   Data security and terms of use of samples Recruitment of family members will be only through the index cases, and each participant will receive a complete explanation of possible personal implication of the study results to herself and family (none). Overall, all included women, patients and family members alike, will be notified as to the secrecy of the data and its use only for the declared purpose of research. They will also be made aware that no personal benefit or harm can be derived from this data to them. In addition, all participants will be informed that if in the future there will arise a new reason to re-analyze their samples, a specific address will be made to each and every one of them to obtain a new permission for this use. Upon request each participant will receive a full explanation of the storage system and the hierarchy of responsibility for the samples and data security.
3. Compliance to the definition of a feasibility study The funds requested herein are meant to enable the formation of DNA bank and family trees, which in turn will serve as the basis for an application to receive the full funding for whole genome analysis, from larger funding resources. Towards this we have teamed up with the future participants of a worldwide consortium on this topic (letter of intention from Bart Fauser, the leading person of this consortium, is attached). Our most pronounced advantage within the consortium, is the availability of multigenerational families, members of which we treat in Bnei Brak.
4. Potential Implications to Medicine and contribution of the expected outcome to society Paving the way for targeted treatment of the problems, associated with PCOS, based on the clear knowledge of its underlying cause(s).

The study aims to perform a whole genome analysis for the detection of genes, associated with the polycystic ovary syndrome. Therefore, the main clinical effort is the diagnosis of index cases and recruitment of family members to give DNA samples.

Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome

Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome - a Study on Multigenerational Families

Maaynei Hayesha Medical Center

Izhar Ben-Shlomo

Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Robert Zeiser, MD

The objective of this study is to investigate whether the SNP rs2910164 in the pre-miR-146a gene is associated with outcome and toxicity of immune checkpoint inhibitor therapy.

The single nucleotide polymorphism (SNP) rs2910164 within the gene for microRNA-146a (miR-146a) reduces miR-146a expression. Previous studies of the investigators demonstrated that this SNP was associated with increased acute GvHD severity in patients undergoing allogeneic hematopoietic stem cell transplantation. In this prospective, observational study the investigators aim to analyze, whether SNP rs2910164 is associated with severity of immune-related adverse events of immune checkpoint inhibitor therapy. Moreover, association of rs2910164 with outcome parameters will be studied.

The rs2910164 genotype will be assessed using DNA isolated from peripheral blood samples and Taqman realtime PCR assays.

The Role of SNP rs2910164 in Patients Treated With Immune Checkpoint Inhibitors

A Single-Center, Prospective, Observational Trial to Analyze the Relationship Between Single Nucleotide Polymorphism rs2910164 and the Efficacy and Safety of Immune Checkpoint Inhibitor Therapy

University of Freiburg

Head of Department of Tumorimunnology and Immunoregulation

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases, Male

Prostatic Diseases

Matthew Parliament, MD

Prostate cancer is the most common malignancy in males, and radiotherapy is a commonly chosen treatment option for patients with localized disease. Technical innovations such as three-dimensional conformal radiotherapy (3D CRT) and intensity-modulated radiotherapy permit radiation dose escalation and possibly better disease outcomes, but escalated doses may be accompanied by long-term complications. This study will examine, for the first time, the independent contribution of a patient's own genetic makeup to the development of post-radiation complications, permitting the future development of predictive tests to avoid radiation injury. To do this, the investigators will examine gene markers and blood proteins in a series of approximately 100 prostate cancer survivors who have received three-dimensional conformal radiotherapy between 1996 and 2000 at the Cross Cancer Institute.

OBJECTIVES: Major innovations in radiotherapy (RT) delivery (3D conformal RT, intensity modulated RT) now permit RT dose escalation to be tested as a means of improving control of localized prostate cancer. With delivery innovations, severe toxicity occurs rarely, but significant bladder and rectal toxicity is common. The investigators have studied a cohort of 98 patients who received dose-escalated 3D-CRT and have obtained evidence of dosimetric factors underlying rectal toxicity. They posit that the late radiation toxicity disease state has significant genetic determinants. These determinants are neither understood nor accounted for in selection of treatment, and the investigators propose to study the above well-characterized cohort, who are clinically well from a disease control perspective, given that comprehensive dosimetric and outcome information is available on all.

HYPOTHESIS: Comprehensive analysis of the genomic, proteomic, and dosimetric characteristics of patients with prostate cancer will provide a novel understanding of the genetic predisposition of cellular and tissue responses to irradiation which result in the clinical occurrence of significant chronic rectal and bladder injury after 3D-CRT.

APPROACH: For a thorough understanding of the molecular processes underlying tissue responses to radiation damage, the investigators propose a genomic analysis. Their working hypothesis is that rectal and bladder toxicity will be correlated to patient genetics as measured by single nucleotide polymorphisms (SNPs) in a select group of genes. The criteria for selecting SNPs will be based on evidence for the various genes implicated or demonstrated in DNA repair pathways and radiation-induced tissue damage. In addition, since radiation injury can be considered a phenotypic tissue response to RT in genetically predisposed individuals, the investigators will examine the protein profile "signature" in sera from patients who have suffered significant toxicity. Analysis of these data will be unique in that the investigators will use both statistically based bioinformatics approaches, and biophysical modeling. This proposal represents the most comprehensive exploration to date of the concept of a molecular "signature" of normal tissue radiation injury of which the applicants are aware.

SPECIFIC AIM 1:

* To create a database of SNPs among long-term prostate cancer survivors who have been treated with 3D-CRT, and for whom detailed toxicity, quality of life and dosimetric information are available;
* To assess the feasibility of using bioinformatics approaches with this database to examine the possibility that specific SNPs, in the context of known dosimetric factors, can predict occurrence of late rectal or bladder toxicity;
* To perform a proteomic analysis of serum samples from a cohort of 25 patients experiencing higher levels of ongoing late toxicity and 50 patients with no ongoing late toxicity.

SPECIFIC AIM 2:

* To utilize biophysical approaches to modelling clinical complication data, using the concept of generalized mean biological effective dose (GMBED) and the critical volume model.

SUMMARY: This proposal will be the first comprehensive retrospective analysis of genomic, proteomic and dosimetric determinants of late radiation injury in prostate cancer. The investigators have assembled a broad array of expertise from the CCI PolyomX program (the only high throughput SNP facility in western Canada), the NCI/FDA Clinical Proteomics Program at Bethesda, MD, and the unique biophysical modeling capability of CBIAR researchers to reach these goals.

Exploring Genomic, Proteomic and Dosimetric Determinants of Late Toxicity After Three Dimensional Conformal Radiotherapy (RT) for Prostate Cancer

Exploring Genomic, Proteomic and Dosimetric Determinants of Late Toxicity After Three Dimensional Conformal RT for Prostate Cancer

AHS Cancer Control Alberta

Blood and Lymph Conditions

Immune System Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Lymphosarcoma

Hyoung Jin Kang, MD. PhD.

This study is to find out distribution of genetic polymorphisms and genes related to the chemotherapeutic drugs of ALL.

Cure rate of pediatric ALL dramatically improved over 80%. Resistance to drug and hematologic relapse are remaining problem in ALL treatment. One of the explanations of drug resistance and toxicities is the pharmacogenetic effect. Germline polymorphisms in genes that code for proteins involved in the pharmacokinetics and pharmacodynamics of antileukemic agents are various, and inter-patient variability is the main factor for pharmacogenetic difference. Since multiple chemotherapeutic agents are involved in treating ALL, many genes related to the metabolic pathways of those drugs have an effect on the pharmacokinetics of patients with ALL. In Korea, pharmacogenetic study including multiple genetic loci for pediatric ALL has not been reported.In this study, the distribution of genetic polymorphisms and genes related to antileukemic drugs were analyzed, and their relations to the outcome of treatment and relapse rates were assessed.

1. Candidate genes exhibit polymorphisms and encodes proteins that are involved in the pharmacokinetics and pharmacodynamics of antileukemic agents

   * Priority was given to polymorphism that were demonstrated to be associated with phenotypes in both clinical and preclinical studies.
   * Candidate genes : CYP3A4\*1B, CYPA5\*3, GSTM1 deletion, GSTP1 313, GSTT1 deletion, MDR exon 21, MDR exon 26, MTHFR 677, MTHFR 1298, NR3C1 1088, RFC 80, TPMT-1 238, TPMT-1 460, TPMT-1 719, VDR intron 8, VDR FokI, ITPA
2. Blood sample at complete remission→DNA extraction
3. Total-Plex (multiplex) PCR amplification
4. Luminex system analysis

Pharmacogenetic Analysis of Korean Pediatric Patients With Acute Lymphoblastic Leukemia

* The distribution of each genetic polymorphism is descriped.
* The differences in genetic polymorphism between risk groups (high vs. standard) are analyzed using the chi-square test or Fisher's exact test.

• The differences in genetic polymorphism between other populations (Korean vs. Western or Japanese) are analyzed using the chi-square test or Fisher's exact test.

- Event-free and overall survival are estimated using Kaplan-Meier analysis, and the survival differences according to different genetic polymorphisms and prognostic variables are analyzed by log-rank test.

- Multivariate analysis is conducted with Cox proportional hazards regression model to analyze predictive factors. For the multivariate analysis, all significant univariate variables are entered in a stepwise, forward-selection protocol.

Seoul National University Hospital

MD. Ph D., Professor

Patients were diagnosed as adult acute lymphoblastic leukemia.

Dong Hwan Kim, M.D.,Ph.D.

Dong Hwan Kim, M.D., Ph. D.

Acute lymphoblastic leukemia (ALL) is not a single disease, but a composite of heterogeneous subgroup. Accordingly, more sophisticated classification in ALL is essential to achieve further improvement of treatment outcomes. However, only a few genetic markers are revealed to have significant prognostic implications in ALL patients. The current study is designed to stratify the ALL patients according to their prognosis and to predict their outcomes by a pharmacogenetic approach. A predictive model will be generated from 130 genotypes in adult ALL patients diagnosed at the Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine, Seoul,Korea between 1994 and 2008. The validation of the predictive model will be performed using an independent external cohort of ALL patients.

1. Definition of the cohort: two hundred ALL patients from the SMC as a test set, another 100 patients from the SMC as a first validation set, and another 150 independent external patients as second external validation set. DNAs will be extracted and stored from patients' samples collected at the time of diagnosis.
2. In the test set, genotypes will be determined using a MALDI-TOF based platform (Sequenom, San Diego, CA, USA) for 130 SNPs of the candidate genes involved in DNA repair pathway, drug metabolism/transport pathway and folate metabolism pathway.
3. Bioinformatic analyses will be performed to identify around 13 genotypes (10%) having strongest predictive significance out of these 130 SNPs in terms of their treatment outcomes, drug toxicity and prognosis in the test set.
4. These 13 genotypes will be validated in the first cohort of 100 ALL patients using a multivariate Cox's proportional hazard model.
5. The predictive model will be built up based on Cox's proportional hazard model derived from 13 candidate genotypes and clinical risk factors.
6. The predictive model based on pharmacogenetic information will be validated again in the second, independent external cohort of 150 ALL patients.

Definite prognostic value was not established for genetic or molecular markers in acute lymphoblastic leukemia (ALL) except BCR/ABL fusion gene. The current study attempts to build up a predictive model based on single nucleotide polymorphisms (SNPs) with pharmacogenetic approach using 130 genotypes in the multiple candidate pathways such as DNA repair pathway, drug metabolism / transport pathway and folate metabolism pathway. The predictive model based on SNPs will be generated and validated with respect to treatment outcomes, drug toxicity and prognosis in adult ALL patients.

The present study will demonstrate that: 1) Pharmacogenetic information derived from SNPs involved in the DNA repair pathway, drug metabolism/transport pathway and folate metabolism pathway, is helpful to predict the treatment outcomes, drug toxicity and prognosis in ALL patients; 2) Predictive model derived from pharmacogenetic information will be effective and reasonable approach to stratify ALL patients according to their clinical outcomes; 3) The SNP-based predictive model could be reasonably applied to the treatment of ALL patients, thus becoming a basis for further improvement of treatment outcome; 4) Finally, this project will enhance and facilitate the pharmacogenetic research in the hematology area, thus make the team to lead the pharmacogenetic research in the world.

Stored bone marrow specimens of patients with acute lymphoblastic leukemia

Genome-wide Single Nucleotide Polymorphism (SNP) Array-based Approach to Predict Chemoresponse and Survival in Patients With Acute Lymphoblastic Leukemia

Samsung Medical Center

Dong Hwan (Dennis) Kim/Assistant professor

Digestive System Diseases

Infections

Stomach Neoplasms

Communicable Diseases

Stomach Cancer

Anti-Infective Agents

Gastrointestinal Agents

Amoxicillin

Anti-Bacterial Agents

Esomeprazole

Levofloxacin

Ofloxacin

Antibiotics, Antitubercular

Clarithromycin

All enrolled subjects received chemoprevention with Helicobacter pylori eradication

For subjects who received the first-line treatment, the costs included the initial 13C-UBT, one-week triple therapy (esomeprazole 40mg once daily, amoxicillin 1g twice daily, and clarithromycin 500mg twice daily), and the confirmatory 13C-UBT. For subjects in whom the initial treatment failed, the costs further included the re-treatment consisting of ten-day triple therapy (esomeprazole 40mg once daily, amoxicillin 1g twice daily, and levofloxacin 500mg once daily), and the confirmatory 13C-UBT.

The first round of study was between 2004 and 2005, the second round was between 2008 and 2009, and the third round was between 2012 and 2013.

Helicobacter pylori eradication

Pan-Chyr Yang, PHD

Yi-Chia Lee, MD, MSc

Jaw-Town Lin, MD, PhD

Tony Hsiu-Hsi Chen, PhD

Based on a universal eradication of H. pylori in an offshore island (Matsu) with a high prevalence of gastric cancer as well as premalignant gastric lesion, we first examined the infection rate of H. pylori. Secondly, we evaluated the efficacy of clarithromycin-based triple therapy with a levofloxacin-based rescue treatment. And thirdly, we tested the hypothesis that whether the cure of H. pylori can reverse the premalignant gastric lesion. Fourth, we determine the cost-effectiveness of this intervention. The gene-environment interaction will be addressed regarding gastric cancer carcinogenesis. Finally, the incident rate of gastric cancer would be followed in this cohort.

Despite the decline of global incidence, gastric cancer still affects public health substantially due to the considerable medical burden in the treatment of disease at the symptomatic stage. This fact has prompted clinicians to extend their attention from the multidisciplinary therapies to the design of preventive strategies. Gastric cancer development follows a carcinogenic process from non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and eventually to the adenocarcinoma. Helicobacter pylori (H. pylori) infection triggers this carcinogenic cascade and its eradication is currently the most reliable regimen to arrest the histologic progression in order to prevent gastric cancer. Emerging data have suggested that the benefit of H. pylori treatment earlier in the course of infection is larger and cannot be outweighed by a disfavored discount rate as a result of different time horizons between early treatment and later benefit of averting advanced cancer.

In the Asia-Pacific area, however, virulent strains of H. pylori infection are highly prevalent and premalignant gastric lesions may have already developed at the take-off age of active intervention. Our current knowledge remains limited in answering whether H. pylori eradication can regress these premalignant lesions and if so, what determinant can contribute to a positive response is unknown. The concept of "a point of no return" suggests that the benefit of H. pylori eradication may diminish at later stages when many types of molecular damage become irreversible. Several population-based studies, in contrast, found that the premalignant gastric lesions were potentially reversible given a sufficiently long duration free from infection. The inconsistence may reflect the facts that studies with adequate sample size and long enough follow-up are rarely available and that some important factors, such as the variation in host susceptibility to disease and dietary exposure to carcinogens, are difficult to be measured but they are likely to confound the results.

Therefore, the present study was to:

1. Determine the efficacy of a novel regimen to treat the H. pylori infection in the general population.
2. To address the question whether the premalignant gastric lesion could be reversed following the cure of infection.
3. To simulate the cost-effectiveness of this chemoprevention.
4. To use individual data to empirically calculate the cost-effectiveness of this intervention.
5. To address the host genetic susceptibility to gastric cancer development.
6. To follow-up the gastric cancer incidence following the eradication of H. pylori.

Community-based Helicobacter Pylori Eradication

Community-based Helicobacter Pylori Eradication With Two Sequential Antibiotic Regimens for the Residents and Migrants From a High-risk Area for Gastric Cancer

National Taiwan University Hospital

Skin and Connective Tissue Diseases

Breast Neoplasms

Nausea

Vomiting

Postoperative Nausea and Vomiting

Signs and Symptoms, Digestive

Breast Diseases

Skin Diseases

Postoperative Complications

Central Nervous System Depressants

Anesthetics

Liangcheng Zhang, Ph.D

Postoperative nausea and vomiting ( PONV ) is one of the common complications after general anesthesia while genetic factors may play an important role in Postoperative nausea and vomiting. In this study, the investigators investigated the relationship between gene polymorphism ( such as single nucleotide polymorphism ) of the gene HTR3A ( 5-hydroxytryptamine receptor 3A ), HTR3B ( 5-hydroxytryptamine receptor 3B ), HTR3C ( 5-hydroxytryptamine receptor 3C ) and TACR1 ( tachykinin receptor 1 ) etc. with nausea and vomiting after general anesthesia. Simultaneously, the investigators explored the influencing factors of nausea and vomiting.

Materials and methods:

Demographic data and risk factors responsible for PONV, including the history of PONV and motion sickness, were collected preoperatively by interviewing participants the day before anesthesia.

All study subjects received a standardized anesthesia regimen. General anesthesia was induced by midazolam 0.04 mg/kg, propofol 1.5 mg/kg, sufentanil 0.4 μg/kg, and cisatracurium 0.2 mg/kg (to facilitate tracheal intubation) given intravenously.Participants' lungs were ventilated with 50% oxygen in air.

During general anesthesia, concentration of sevoflurane maintained 1.0% to 3.0% at the discretion of anesthetist who was not involved in the study. General anesthesia also uses propofol 1 mg kg-1 h-1 and sufentanil 0.1 μg kg-1 h-1 by continuous intravenous infusion. An Entropy index monitor was used to maintain the appropriate anesthesia depth by 40-60. Participants received a repeated bolus of sufentanil 0.1 μg/kg or cisatracurium intravenously on demand.

After surgery the investigators recorded the data such as Anesthesia duration, doses of sufentanil and propofol and so on.

At the end of surgery and after returning to the ward, flurbiprofen axetil 50 mg injection i.v. was administered as an analgesic therapy, respectively. Cholinesterase inhibitor-based neuromuscular reversal drugs and vitamine B6 were not administered after surgery. Bucinnazine hydrochloride 100 mg intramuscular injection (i.m.) as a rescue medication was administered to any participant whose visual analogue scale/score (VAS) was \> 3.

Ondansetron was given intravenously to the participants if necessary or requested . Unaware of the genotypes of the subjects, the investigators collected the participants' data including nausea, vomiting and pain.

Relationship Between Genetic Polymorphism and Postoperative Nausea and Vomiting in Chinese Han Population

Relationship Between Genetic Polymorphism and Postoperative Nausea and Vomiting Undergoing Breast Surgery With General Anesthesia in Chinese Han Population

Nausea was defined as a feeling of wanting to throw up or about to throw up.

Vomiting was defined as the discharge of the stomach contents, while retching as an involuntary attempt to vomit that did not produce stomach contents. Retching was considered as vomiting.

The level of participants' nausea was rated on four-point scales: 0=no nausea; 1=mild nausea with activities; 2=mild nausea at rest; and 3=se-vere nausea at rest.

The investigators defined an emetic episode as a single occurrence of vomiting/retching or as a series of immediately successive vomiting/retching. However, vomiting/retching had to be separated by at least 1 minute to be classified as a single emetic episode.

Fujian Medical University Union Hospital

Hypersensitivity

Primary Ovarian Insufficiency

Menopause, Premature

Patients will be genotyped for single nucleotide polymorphism previously found to be associated with age at natural menopause

Blood sample for genetic test

at each visit : 2x7ml. At the end of the study hormonal measurements (AMH, P4, LH, FSH, E25)

Blood sample for hormonal measurement

Ovarian ultrasound scan at follow up visits (Y1,Y1.5, Y2.5 Y3.5 Y4.5 Y5.5)

Ovarian ultrasound scan

Charlotte SONIGO, MD

Michael Grynberg, MD, PhD

Over the past decade, advances in diagnosis and treatments have dramatically increased the rates of cure for young patients with cancer. As a consequence, a new population of cancer survivors has emerged whose fertility is compromised after cancer therapy. Indeed, gonadotoxicity is a well-known long-term side effect of cancer treatment in young patients having survived malignant diseases. More than 80% of women of childbearing age, treated for breast cancer with standard protocol of neoadjuvant (4 cycles of 5-fluorouracile - epirubicin- cyclophosphamide (FEC) and 4 cycles of docetaxel) or adjuvant chemotherapy (3 FEC and 3 docetaxel), show an alteration of their ovarian reserve 2 years after completion of the treatment, as a result of chemotherapy-related follicular loss. Therefore, according to the extent of the follicular damages, the gonadal function may vary from moderate to severe diminished ovarian reserve (DOR) and possibly to the ultimate stage of premature ovarian insufficiency (POI).

Investigators propose a multicentric and prospective study of a cohort of young women with breast cancer to evaluate whether genetic polymorphisms, previously identified as being correlated with age at menopause in the healthy population, are associated with the intensity of the follicular decline following chemotherapy in young breast cancer survivors.

With 48 763 new cases in 2012, breast cancer represents the first female cancer in France. Although the incidence of this malignancy peaks after the age of 60 years, nearly 2500 of reproductive-age women are diagnosed with breast cancer every year. Recent advances in cancer therapy markedly improved the rates of cure for young adult suffering from cancers. Over the past decade, the mortality rates in breast cancer patients has decreased by more than 1.6% per year. The five year survival rate for women under 45 with breast cancer is now approaching 80%. As a consequence, a new population of young cancer survivors has emerged whose fertility is compromised after cancer therapy. Thus, the question of fertility preservation (FP) in young cancer patients has become a major issue in the care-personalized path. Indeed, information regarding the risks of infertility and FP counselling may contribute to improving the quality of life and the coping of patients with the burden of cancer treatment. Therefore, oncofertility counselling by a specialist is now recommended for all young cancer patients having to undergo treatment that may reduce the fertility potential.

Gonadotoxicity is a well-known long-term side effect of cancer treatment in young patient having survived malignant diseases. Neoadjuvant or adjuvant chemotherapy usually combining alkylating agent and taxane, is often recommended for young women presenting with breast cancer. However, alkylating agents, such as cyclophosphamide have been shown to cause extensive dose-dependent loss of primordial follicles in cancer patients. Beside a enhancement of apoptosis, cyclophosphamide might induce a follicular loss through an activation of the primordial follicle recruitment: the "burnout" phenomenon.

Moreover, the extent of ovarian damages depends not only on the nature and dose of chemotherapy but also on age and ovarian reserve before treatment. Women age at chemotherapy administration is one of the most predictive risk factor of follicular depletion after the end of treatment. Therefore, according to the extent of the follicular damages, the gonadal function may vary from moderate to severe diminished ovarian reserve (DOR) and possibly to the ultimate stage of premature ovarian insufficiency (POI).

Currently, patients' age and the values of markers of the follicular ovarian status (serum anti-Müllerian hormone (AMH) levels and ultrasonographic antral follicle count (AFC), measured before the initiation of gonadotoxic treatment, are considered the most accurate predictive factors of post chemotherapy ovarian function. However, they may have some limitations since important inter-individual variations in the ovarian reserve two years after completion of treatment are reported in patients displaying similar age, AMH as well as AFC. This observation suggests that, besides environmental and pathologic variables, genetic variations, inducing different ovarian sensitivity to chemotherapy, might be at play.

Indeed, in healthy women, age at natural menopause varies from 40 to 55 years and is characterized by a strong familial concordance. Many studies of large genome-wide association (GWAS) found a link between the age and variants of some genes involved in DNA repair, DNA maintenance and folliculogenesis as initial follicular recruitment. Since these genes may have an influence on the ovarian reserve (together with the effects of gonadotoxic treatment regimens), investigators hypothesize that genetic polymorphisms known to be associated with age at menopause (BRSK1 (rs1 172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827), TNF (rs909253), AMH (rs10407022) and AMHR2 (rs2002555) could be linked to the intensity of the follicular depletion after chemotherapy.

The primary objective is to evaluate whether genetic polymorphisms, previously identified as being correlated with age at menopause onset in the healthy population, are associated with the intensity of the follicular decline following chemotherapy in young breast cancer survivors.

The secondary objectives are to evaluate the association between genetic polymorphisms and other parameters related to female fertility, as menstrual cycle profile, pregnancy rate, serum anti-mullerian hormone (AMH) levels and ultrasonographic antral count (AFC) after chemotherapy such as the menstrual cycle profile and pregnancy rates.

Eligible subjects followed in the different participating centers will be included in this study. Informed consent will be obtained from all participating individuals before blood sample collection and molecular studies. AMH measurement and AFC will be performed before the cancer treatment randomly during the menstrual cycle phase. In the same time, blood samples will be taken for the genotyping. All patients will receive adjuvant or neoadjuvant chemotherapy containing cyclophosphamide, epirubicin, 5-FU and docetaxel. Patients will be evaluated 12 and 24 months after the end of the treatment. A clinical (menstrual cyclicity) and hormonal (AMH, FSH) evaluation associated with ultrasound evaluation of AFC of enrolled patients will be performed. Thus, association between genetic polymorphism and the depth of ovarian decline (classified as: normal ovarian reserve, moderate DOR, severe DOR or POI) after healing will be evaluated.

Evaluation of Individual Sensitivity to the Gonadotoxicity of Chemotherapy in Young Patients With Breast Cancer

is an aggregated measure of FSH, AMH serum level, Antral Follicle Count and menstrual profile :

* Normal ovarian reserve: persistence of menstrual cycle, FSH\<40 IU/L and AMH\>1.1 ng/mL or AFC\>7 follicles
* Moderate diminished ovarian reserve : persistence of menstrual cycle, FSH\<40 IU/L and 0.5≤AMH≤1.1 ng/mL or 5≤AFC≤7 follicles
* Severe diminished ovarian reserve : persistence of menstrual cycle and AMH\<0.5 ng/mL or AFC\<5 follicles
* Premature ovarian insufficiency is defined by amenorrhea above four months and FSH level ≥40 IU/L in women before 40 years.

AMH serum levels and ultrasonographic evaluation of AFC will be evaluated FIVEyears after the end of chemotherapy.

To evaluate the association between genetic polymorphisms and other parameters related to female fertility after chemotherapy such as the menstrual cycle profile. These data will be obtained from clinical interrogatory performed by medical doctors.

These data will be obtained from clinical interrogatory performed by medical doctors.

To assess the evolution of ovarian reserve tests at the end of chemotherapy AMH level will be performed before the initiation of chemotherapy and 6, 12, 24, 36, 48, 60 months following the end of chemotherapy.

To assess the evolution of ovarian reserve tests at the end of chemotherapy Measurements of ultrasonographic AFC will be performed before the initiation of chemotherapy and 6, 12, 24, 36, 48, 60 months following the end of chemotherapy.

A follicular decline will be defined as a moderate/severe DOR or a POI

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome	NCT00665171	Anovulation Hyperandrogenis... Polycystic Ovar... Single Nucleoti...		-	Maaynei Hayesha Medical Center
The Role of SNP rs2910164 in Patients Treated With Immune Checkpoint Inhibitors	NCT04038996	Cancer		18 Years - 99 Years	University of Freiburg
The Role of SNP rs2910164 in Patients Treated With Immune Checkpoint Inhibitors	NCT04038996	Cancer		18 Years - 99 Years	University of Freiburg
Exploring Genomic, Proteomic and Dosimetric Determinants of Late Toxicity After Three Dimensional Conformal Radiotherapy (RT) for Prostate Cancer	NCT00122265	Prostate Cancer		-	AHS Cancer Control Alberta
Pharmacogenetic Analysis of Korean Pediatric Patients With Acute Lymphoblastic Leukemia	NCT01556386	Acute Lymphobla...		- 21 Years	Seoul National University Hospital
Genome-wide Single Nucleotide Polymorphism (SNP) Array-based Approach to Predict Chemoresponse and Survival in Patients With Acute Lymphoblastic Leukemia	NCT01079507	Acute Lymphobla...		18 Years -	Samsung Medical Center
Community-based Helicobacter Pylori Eradication	NCT00155389	Helicobacter Py...	Helicobacter py...	30 Years -	National Taiwan University Hospital
Community-based Helicobacter Pylori Eradication	NCT00155389	Helicobacter Py...	Helicobacter py...	30 Years -	National Taiwan University Hospital
Pharmacogenetic Analysis of Korean Pediatric Patients With Acute Lymphoblastic Leukemia	NCT01556386	Acute Lymphobla...		- 21 Years	Seoul National University Hospital
Relationship Between Genetic Polymorphism and Postoperative Nausea and Vomiting in Chinese Han Population	NCT03705026	Breast Neoplasm... Anesthesia, Gen...		18 Years - 80 Years	Fujian Medical University Union Hospital
The Role of SNP rs2910164 in Patients Treated With Immune Checkpoint Inhibitors	NCT04038996	Cancer		18 Years - 99 Years	University of Freiburg
Evaluation of Individual Sensitivity to the Gonadotoxicity of Chemotherapy in Young Patients With Breast Cancer	NCT03731845	Breast Cancer	Blood sample fo... Blood sample fo... Ovarian ultraso...	18 Years - 36 Years	Assistance Publique - Hôpitaux de Paris
Whole Genome Analysis for the Detection of Key Genes in the Polycystic Ovary Syndrome	NCT00665171	Anovulation Hyperandrogenis... Polycystic Ovar... Single Nucleoti...		-	Maaynei Hayesha Medical Center

Spots Global Cancer Trial Database for single nucleotide polymorphism