Genetic and Preventive Services for Hereditary Breast and Ovarian Cancer in the Czech Republic

The majority of hereditary breast and ovarian cancers can be accounted for by germline mutations in the BRCA1 and BRCA2 genes. Genetic counselling and testing in high-risk patients in the Czech Republic began in 1997 in two centres (Masaryk Memorial Cancer Institute in Brno, MMCI, and the General University Hospital plus the First Faculty of Medicine, Charles University in Prague, 1FMUK). Health insurance covers testing in MMCI, whereas testing at 1FMUK is covered by research grants. The spectrum of mutations in the BRCA1 gene is similar in the Bohemian (western) and Moravian (eastern) regions of the country but the mutation spectrum observed in the BRCA2 gene is completely different. There are three BRCA1 gene mutations that are responsible for 69% and 70.4% of all BRCA1 mutations identified in women reporting to the Brno and Prague centres, respectively. The two most frequent mutations in the BRCA2 gene, which comprises 41.5% of all detected BRCA2 mutations in Brno, were not found in women tested in the Prague centre. The testing of BRCA1/BRCA2 or other possible predisposition genes for hereditary breast/ovarian cancer is determined by medical geneticists after genetic counselling. Predictive testing is offered to persons older than 18 years of age. Genetic counselling centres are easily accessible to all inhabitants in the country. Specialized preventive care is mostly organized by MMCI and the General University Hospital in Prague; however, some patients and their family members are under the care of other oncology departments and clinics. The quality of preventive care in different hospitals is currently being investigated.     

Clinical Outcome of Hereditary Breast Cancer in the Lithuanian Population

Breast cancer family history has been known to be one of the main cancer risk factors. Members of high-risk families should be given recommendations which may improve prophylaxis, early diagnosis and treatment. Detection of high-risk families is possible by identification of mutations in cancer susceptibility genes like BRCA1 and BRCA2 as well as by family history showing breast and/or ovary cancer aggregation. In a group of 521 breast cancer patients we identified 26 patients with hereditary breast cancer who fulfilled the following criteria: one more relative with breast cancer, vertical transmission, at least one breast cancer patient affected at the age under 50 years. 8 patients of these developed second primary breast cancer. We also compared the frequency of hereditary cancers in stage I-III with the frequency of respective cancers with negative family history. Hereditary breast cancers were diagnosed less frequently in stage I and more frequently in stage II and III (RR = 0.49, RR = 1.39, RR = 1.62, respectively). Because of importance of family history as well as genetic testing for breast cancer susceptibility genes (BRCA1/2), it is necessary to create a nationwide network of hereditary cancer clinics for proper diagnosis, treatment, and prophylaxis of these patients.     

Advocate's Viewpoint on Hereditary Breast/Ovarian Cancer

This paper discusses the presentation I held at the symposium on genetics during the 4^th European Breast Cancer Conference held in Hamburg in March 2004.Primarily, the goals and working methods of the advocacy group specialised in Hereditary Breast/Ovarian Cancer of the Dutch Breast Cancer Patient Organisation known as BorstkankerVereniging Nederland (BVN) are explained. Furthermore, some specific individual problems that mutation carriers might encounter before and after BRCA1/2 susceptibility testing are discussed. These include: dilemmas in choosing preventive interventions, dealing with the psychological impact of knowing you are a mutation carrier, dealing with the social implications of being genetically at risk, an example of insurance discrimination. In addition, some controversial social and ethical issues that are currently under debate are highlighted, such as the issue of the European patenting of the breast cancer susceptibility genes BRCA1 and BRCA2. Since this topic could also become relevant for other gene-related diseases, society as a whole has to consider the ethical and social implications related to the patenting of human genes in general. Another ethical area of debate is the controversial issue of prenatal BRCA testing and the choice of pregnancy termination.Finally, the Working Party pleads for the international co-operation and exchange of data and experience among professionals as well as patients. It appears that professionals in different European countries tend to advise on different risk management strategies and treatments and as such, the Working Party strongly advocates the international standardisation of risk management and treatment of mutation carriers. In this respect, specific attention should be given to a group that has had a non-informative or negative BRCA test result, because this group is still considered to be at high risk to develop the disease.     

The Prevention of Hereditary Breast and Ovarian Cancer: A Personal View

Options for the prevention of hereditary breast and ovarian cancer include screening, preventive surgery and chemoprevention. Screening studies with magnetic resonance imaging of the breast are promising but the technology is not widespread and MRI is unlikely to be available as a screening tool in the near future. Prophylactic oophorectomy and mastectomy are effective preventive measures and are gaining in acceptance by patients and physicians. Preventive mastectomy is effective against both primary and contralateral breast cancer. Oophorectomy prevents ovarian cancer, and if done prior to menopause, will prevent breast cancer as well. Tamoxifen has been shown to prevent contralateral breast cancers in BRCA1 and BRCA2 carriers but is not widely accepted as a means of primary prevention. Oral contraceptives and tubal ligation will reduce the risk of hereditary ovarian cancer and should be considered in women who wish to retain ovarian function.     

Hereditary Genes and SNPs Associated with Breast Cancer

Breast cancer is the most common cancer among women affecting up to one third of tehm during their lifespans.Increased expression of some genes due to polymorphisms increases the risk of breast cancer incidence. Sincemutations that are recognized to increase breast cancer risk within families are quite rare, identification of theseSNPs is very important. The most important loci which include mutations are; BRCA1, BRCA2, PTEN, ATM,TP53, CHEK2, PPM1D, CDH1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, BRIP1, RAD50,RAD51C, STK11 and BARD1. Presence of SNPs in these genes increases the risk of breast cancer and associateddiagnostic markers are among the most reliable for assessing prognosis of breast cancer. In this article we reviewedthe hereditary genes of breast cancer and SNPs associated with increasing the risk of breast cancer that wererecently were reported from candidate gene, meta-analysis and GWAS studies. SNPs of genes associated withbreast cancer can be used as a potential tool for improving cancer diagnosis and treatment planning.     

Hereditary Colorectal Cancer (CRC) Program in Latvia

Introduction

The aim of the study is to evaluate the incidence and phenotype - genotype characteristics of hereditary colorectal cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by these syndromes.

Materials and methods

From 02/1999-09/2002 in several hospitals in Latvia cancer family histories were collected from 865 patients with CRC. In families suspected of having a history consistent with a hereditary colorectal cancer syndrome, DNA testing for MLH1, MSH2 and MSH6 genes was performed. In addition immunohistochemical (IH) examination of the normal and cancer tissue from large bowel tumors for MSH2 and MSH6 protein expression was performed prior to DNA analysis.

Results

From the 865 CRC cases only 3 (0.35%) pedigrees fulfilled the Amsterdam II criteria of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and 15 cases (1.73%) were suspected of HNPCC. In 69 cases (8%) with a cancer family aggregation (CFA) were identified. Thus far 27 IH analyses have been performed and in 3 cancers homogenous lack of MSH2 or MSH6 protein expression was found. In one of these cases a mutation in MSH6 was identified. In 18 patients suspected of HNPCC or of matching the Amsterdam II criteria, denaturing high performance liquid chromatography (DHPLC) followed by DNA sequencing of any heteroduplexes of the 35 exons comprising both MLH1 and MSH2 was performed revealing 3 mutations.For all of kindreds diagnosed definitively or with a high probability of being an HNPCC family appropriate recommendations concerning prophylactic measures, surveillance and treatment were provided in written form.

Conclusions

Existing pedigree/clinical data suggest that in Latvia the frequency of HNPCC is around 2% of consecutive colorectal cancer patients. It is crucial that genetic counseling is an integral part of cancer family syndrome management.

     

BRCA1, BRCA2 and CHEK2 (1100 del C) Germline Mutations in Hereditary Breast and Ovarian Cancer Families in South India

Cancer of the breast is the second most common cancer seen among Indian women. This study describes the use ‍of DHPLC for mutation analysis for BRCA1, BRCA2 and CHEK2 (1100delC) in 22 patients with a family history of ‍breast and/or ovarian cancer and early onset breast cancer (<35 years of age). Three of the 22 patients were found to ‍have a non-sense mutation or a deletion, resulting in a premature stop codon, potentially leading to a truncated ‍protein. Two of these were in BRCA1 (one was a novel 5 base deletion) and one in the BRCA2 gene. No patient was ‍found in our series to have the CHEK2 (1100delC) mutation. DNA from a healthy blood donor and all but one of the ‍22 patients, demonstrated polymorphisms in BRCA1 and/or BRCA2 genes. This is the first study from South India, ‍on BRCA1, BRCA2 & CHEK2 (1100 del C) mutations in patients with a family history of breast and/or ovarian ‍cancer and early onset breast/ovarian cancer, using the sensitive DHPLC approach.     

遗传性乳腺癌的筛查与预防研究进展

摘 要：遗传性乳腺癌是指由乳腺癌易感基因致病性种系突变所致的恶性肿瘤。BRCA1/2等易感基因突变与乳腺癌终生风险升高密切相关。乳腺癌筛查技术和方法的不断革新,为早期发现乳腺癌和预防干预提供了可能;早期识别高危风险人群已经成为遗传性乳腺癌筛查与预防工作的重要突破点。全文综述国内外遗传性乳腺癌筛查与预防现状,重点探讨了遗传性乳腺癌的风险评估、基因检测和遗传咨询。     

Prevalence of Pathogenic Germline Mutations in 13 Hereditary Cancer-Related Genes in Breast Cancer Patients in Narathiwat Province,Thailand

Background: BRCA1 and BRCA2 genes are known to increase breast cancer’s lifetime risk. Early identification of women with this inherited risk can potentially reduce the risk of breast and/or ovarian cancer and, together with early screening, decrease the mortality rate. Objective: This study explored the frequency and distribution of genetic variants in consecutive cases of breast cancer in Narathiwat province, one of the three provinces in the southernmost Thai border. Material & Method: A series of 64 consecutive breast cancer patients who underwent treatment in two general hospitals in the province during the period from the year 2021 to 2022. Genotyping studies were performed using a whole exome sequencing platform. Moderate to high penetrance variants recommended by the National Comprehensive Cancer Network (NCCN) guidelines 2022 (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53) were annotated and filtered for pathogenic, likely pathogenic, or high-impact variants. Results: Pathogenic germline variants were found in 8/64 cases (12.5%), namely BRCA1 in 3 (4.7%), BRCA2 in 4 (6.3%), ATM in 1 (1.6%), and PALB2 in 1 (1.6%). One patient had two concomitant germline mutations in BRCA2 and ATM. Conclusion: This is the first study on the frequency of germline mutations in BRCA1/2 and other breast cancer-predisposing genes in the southernmost provinces of Thailand. At least one pathogenic germline mutation was identified in 12.5% of the study patients, which suggests that genetic testing in this population has a high potential to provide benefits.     

Evaluation of Psychosocial Effects of Pre-Symptomatic Testing for Breast/Ovarian and Colon Cancer Pre-Disposing Genes: A 12-Month Follow-Up

A prospective study of psychosocial consequences following predictive testing for inherited mutations in breast/ovarian and colon cancer susceptibility genes BRCA1, BRCA2, MLH1, and MSH2 was performed. Eighty-seven healthy women were tested for known family mutations and self-assessment scales were used to evaluate anxiety, depression and quality of life. Extensive pre- and post-test information was given. Questionnaires were responded before testing and four times after during the following year. A statistically significant decrease in anxiety mean scores over time was observed among the studied participants. The levels of depression in cancer genes carriers decreased over time while, surprisingly the levels in non-carriers increased. Compared to a normative Swedish sample all women tested showed similar levels of anxiety but women tested for breast cancer genes showed statistically lower levels of depression. Vitality dropped initially after disclosure of the testing of colon cancer genes carriers, followed by increasing levels. No change in vitality or in other quality of life parameters was seen in the other groups and the levels were similar to Swedish norm data. Most tested individuals were satisfied with the testing procedure including genetic counselling and testing and all of them but one would redo the testing. Healthy self-referred women going through predictive breast/ovarian or colon cancer gene testing, including extensive pre- and post-test information and support, in general, will not experience adverse psychological consequences.     

Challenges and Considerations on Risk-Reducing Surgery in BRCA1/2 Patients with Advanced Breast Cancer

Cancer survivors harboring inherited pathogenic variants in the breast cancer (BC) susceptibility genes BRCA1 or BRCA2 are at increased risk of ovarian cancer (OC) and also of contralateral BC. For these women, risk-reducing surgery (RRS) may contribute to risk management. However, women with locally advanced or metastatic breast cancer (ABC) were excluded from clinical trials evaluating the benefit of these procedures in the BRCA1/2 carriers, and thus, current guidelines do not recommend RRS in this specific setting. Although ABC remains an incurable disease, recent advances in treatment have led to increased survival, which, together with improvement in RRS techniques, raise questions about the potential role of RRS in the management of BRCA1/2 ABC patients. When should RRS be discussed as an option for BRCA1/2 patients diagnosed with ABC? To address this issue, we report two clinical cases that reflect new challenges in routine oncology practice. Team experience and patient motivations may shape multidisciplinary decisions in the absence of evidence-based data. A wise rationale may be the analysis of the competing risks of death by a previous ABC against risk of death by a secondary BC or OC, tailored to patient preferences.     

日本乳腺癌和卵巢癌死亡率的特点

目的：对1947年－1997年日本的乳腺癌与卵巢癌死亡情况及居民食物变化特点进行研究分析，为我国的肿瘤防治措施借鉴。方法：从“日本死亡统计数据库（Vital Statistics of Japan)”中，收集自1947年至1997年以来日本乳腺癌和卵巢癌年龄别死亡人数和5岁年龄组人口数，用世界标准人口对死亡率进行标化。所有资料输入计算机，用SPSS软件对其标化死亡率进行分析研究；从日本文部省收集1946年－1997年国民营养调查资料，对几种有关的食物进行动态分析。结果：乳腺癌和卵巢癌的死亡率分别增加了2和6倍，以50岁以上年龄组增加最明显；乳腺癌死亡率模型与卵巢癌相似，但卵巢癌随时间变化增加较迅速。出生队列研究发现，出生越晚，死亡率越高，这是两者的共同特点；居民营养调查发现，从1947年到1997年的50年内，动物性食物的消费量明显增加，其中以牛奶增加最为显著。结论：近50年来日本乳腺癌和卵巢癌的死亡率在不断升高，可能与膳食的结构变化有关。     

565例双侧原发性乳腺癌临床病理特征分析

目的探讨原发性双侧乳腺癌（bilateral primary breast cancer,BPBC）患者的临床病理特征。方法收集1971年1月-2011年11月间我院诊治的565例双乳癌患者临床资料。对比分析同时性双乳癌（bilateral synchronous breastcancer）和异时性双乳癌（bilateral asynchronous breast cancer）在发病年龄、发病间隔、月经情况、家族史、肿瘤体积、临床分期、淋巴结数目、激素受体等临床病理特征的差异。结果异时性双乳癌首发癌年龄要早于同时性双乳癌（P<0.05）。同时性/异时性双乳癌在家族史、肿瘤体积、临床分期、腋淋巴结数目方面的差异均无统计学意义（P>0.05）。同时性双乳癌两侧病灶内分泌受体表达一致率高于异时性双乳癌(P<0.01)。无论同时性或异时性双乳癌其第二癌的肿瘤体积、临床分期和腋淋巴结情况都优于第一癌。同时性双乳癌与异时性双乳癌5年无病生存率与10年总生存率之间的差异有统计学意义(P<0.01)。 结论双侧原发性乳腺癌第二癌与第一癌可视为两个完全不同的癌灶。单侧发生乳癌之后对侧乳癌发生的累积危险度逐年增加,应建立完善的随访制度。异时性双乳癌的5年无病生存率与10年总生存率均高于同时性双乳癌。     

Various Aspects,Patterns and Risk Factors in Breast Cancer Patients of Balochistan

Purpose: Breast cancer is the commonest malignancy of females throughout the world with one million newcases each year. In Pakistan, the burden of breast cancer disease is high with late stage presentation being acommon feature, more than half being stage III or stage IV. The objective of this study was to study variousaspects, patterns and risk factors in breast cancer patients of Balochistan. Method: Present study was performedon 134 patients of breast cancer who were registered in CENAR. The patients were interviewed by providing aquestionnaire. Informed consent was taken from all the patients who took part in this study after explanation ofthe study aims. Body mass index (BMI) was calculated andbiopsy reports were obtained from patients files. Allthe cases were classified with respect to age, gender, ethnic group (Baloch, Pashtoon, Punjabi, Afghani, Hazara)BMI, cancer type, cancer grade, hormonal status, side of the cancer, fertility and marital status. Results: Outof 134 patients, the most common ethnic group was Pashtoon with a total of 42 and the common age group was41-50 years with a total of 51. Invasive ductal carcinoma (IDC) was the most common type, accounting for in128 patients (95.5%) followed by invasive lobular carcinoma (ILC). Conclusion: Pashtoon was the most commonethnic group, IDC was common type and most of the patients had an ER/PR positive hormonal status.     

新疆地区三阴性乳腺癌临床特征及预后分析

探讨新疆地区三阴性乳腺癌与非三阴性乳腺癌患者临床特征及预后。方法：选取2002年1月至2003年12月本院收治的可手术切除并经病理证实的333例乳腺癌患者,依据ER、PR、Her-2的表达状况将其分为两组,三者表达均为阴性即为三阴性乳腺癌,另一组即为非三阴性乳腺癌,比较两组临床特征、复发转移情况及5年无瘤生存率。结果：333例乳腺癌患者中,三阴性乳腺癌82例,占24.62%,其淋巴结阳性率为41.5%,截止至随访日期,82例三阴性乳腺癌复发转移21例（25.61%）,251例非三阴乳腺癌复发转移38例（15.14%）,与非三阴性乳腺癌相比,其远处转移的危险比为2.041（P=0.015）,肺转移的危险比为2.551（P=0.036）,手术后3年内复发转移风险危险比为1.948（P=0.042）,生存分析显示三阴性乳腺癌5年无瘤生存率为74.4%,非三阴性乳腺癌为84.9%,两组曲线比较P=0.027。结论：三阴性乳腺癌淋巴结阳性率较非三阴乳腺癌高,其复发转移风险高于非三阴组,主要是远处转移风险较高,具体表现为肺转移风险高于非三阴组,并在术后的3年内复发转移风险高,且5年无瘤生存率低于非三阴性乳腺癌,临床预后差。     

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome

Background

Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.

Methods

We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).

Results

All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.

Conclusions

Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.     

乳腺卵巢双原发癌21例临床分析

[目的]探讨乳腺与卵巢双原发癌的临床特点。[方法]分析21例乳腺卵巢双原发癌患者的发病年龄、两癌发病间隔、病理类型、分期、家庭史和生存期。[结果]21例患者的中位生存期为69个月，2、5年生存率分别为40.0%和13.3%。两癌发病间隔≥5年者7例（占33.3%）。卵巢癌的中位发病年龄为49岁，55岁前发病者占61.9%；病理类型以浆液性腺癌最常见（占72.6%），Ⅲ期71.4%，低分化者61.9%。[结论]乳腺与卵巢双原发癌的卵巢癌发病年龄比散发者早，多数为晚期，病理类型以低分化为主。手术为主要治疗手段。     

Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8–70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1–56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9–20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9–29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2–19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8–6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6–31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4–12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2–5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.