D. G. Evans

Familial Breast Cancer

Since the localization and discovery of the first high‐risk breast cancer (BC) genes in 1990, there has been a substantial progress in unravelling its familial component. Increasing numbers of women at risk of BC are coming forward requesting advice on their risk and what they can do about it. Three groups of genetic predisposition alleles have so far been identified with high‐risk genes conferring 40–85% lifetime risk including BRCA1, BRCA2 and TP53. Moderate risk genes (20–40% risk) including PALB1, BRIP, ATM and CHEK2, and a host of low‐risk common alleles identified largely through genome‐wide association studies. Currently, only BRCA1, BRCA2 and TP53 are used in clinical practice on a wide scale, although testing of up to 50–100 gene loci may be possible in the future utilizing next‐generation technology.

Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

IntroductionBreast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.MethodsMore than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.ResultsThe 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.ConclusionsWith resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

Lynch syndrome or hereditary non‐polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first‐degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty‐four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high‐risk clinic.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Study Type – Diagnostic (validating cohort)
Level of Evidence 1b

Familial breast cancer.

#### Summary points There is now unequivocal evidence that a small proportion of breast cancer cases, perhaps 4-5%, are due to highly penetrant dominant genes.*RF 1-4* The recent publicity surrounding breast cancer in general, the national screening programme,5 and trials of prevention have heightened awareness in families where the disease has already occurred. This has led to demands for advice about risks and what to do about them. Women wish to know not only their own risks but also the risks to their daughters. The needs of these women are being met by general practitioners, surgeons, oncologists, and an increasing number of specialist cancer family history clinics. Access to such clinics is now possible in most regions. In this article we consider how best to give advice and what to do with regard to prevention and screening for women at high risk of developing cancer. The new potential for precise genetic diagnosis in some families raises important additional psychological and ethical issues. From studies of the pattern of distribution of breast and other cancers in families it has been known for some time that inheritance is usually dominantly transmitted.6,7 To find the defective gene …

Neurofibromatosis/Noonan phenotype: A variable feature of type 1 neurofibromatosis

Since January 1989 we have ascertained patients with neurofibromatosis type 1 (NFl) as part of our genetic register in the North West of England. This register has now identified 453 affected cases from 235 families. The first 94 individuals were specifically examined for features of the Noonan phenotype. This was present in 12/94 sequentially identified individuals with NFl, including six individuals from three families. However, three cases occurred in a further family, where Noonan syndrome appeared to segregate separately from NFl. We have provided evidence for the chance association of Noonan syndrome and NFl and that the Noonan phenotype occurs as a feature in some NFl families. However, there is now little evidence of a separate NFl/Noonan syndrome entity or of NFl features occurring in classical Noonan syndrome.

Screening by mammography, women with a family history of breast cancer

The aim of this study was to describe the experience of screening women under the age of 50 years with a family history of breast cancer. 1259 women attended the Family History Clinic in Manchester for their first and subsequent consultations between 30 September 1992 and 30 April 1997. All women were under the age of 50 years at the initial consultation and had a lifetime risk of breast cancer of 1 in 6 or greater. Seven prevalent, seven incident and two interval cancers were detected. The number of invasive cancers expected to occur if this high risk population had not been screened was 8.45 (in 2722 person years at risk). 12 invasive cancers were detected, giving a ratio of 1.42 (95% confidence interval 0.73-2.48). The overall cancer detection rates in this young, at risk population were similar to those in older women in the National Health Service Breast Screening Programme. The number of cancers detected in the study was greater than expected in this population. As the numbers were small, a national trial needs to be undertaken to confirm these results and to determine the long term effects of screening.

Risk assessment and management of high risk familial breast cancer

The demand for genetic services by women with a family history of breast cancer has increased exponentially over the last few years. It is important that risks to women are accurately assessed and that processes are in place for appropriate counselling and management. The classification of risk into average, moderate, and high, depending upon the assessed lifetime risk of breast cancer, allows for the management of moderate risk women within cancer units and high risk women within the regional genetic centres. Management of high risk women includes discussion of options including screening, chemoprevention, and preventive surgery. The majority of these options are still unproven in the long term and continuing research is needed for their evaluation. Mutation screening and predictive testing are now a reality for a minority of families, allowing for a more informed basis for decisions regarding management options.

Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer

Triple negative breast cancer (TNBC) is a term that reflects lack of immunostaining for oestrogen, progesterone, and HER2 receptors. It is a relatively uncommon subgroup of breast cancers, accounting for approximately 15% of all types, and overlaps substantially with basal tumours (defined by gene expression pattern) that are the predominant tumour that develops in BRCA1 mutation carriers.1 TNBCs usually have a worse prognosis and no clear options for receptor targeted treatment.2 The recent development of drugs that target the homologous recombination repair deficiency typical of BRCA-null cancer cells has led to an increased referral of women who have developed TNBC to genetic services for (rapid) genetic testing.3 We have tested 63 isolated cases of TNBC <41 years and only eight (12.7%) had a BRCA1 mutation. The decision to test women affected with breast cancer for BRCA mutations has traditionally been based on clinical utility (clarifying the future risks of contralateral breast cancer/ovarian cancer for the index case). Equally importantly the result may help develop a genetic test for the wider family facilitating their risk assessment and management. However, recently the utility of testing to the oncologist treating the cancer in the index case has come sharply into focus with the advent of treatments such as the PARP (poly ADP ribose polymerase) inhibitors.3 Despite the fact that treatment with PARP inhibitors is still only available through research trials, our experience in the genetic clinic is of unrealistically high expectations about the likelihood of an underlying BRCA1 mutation …

Risk of breast cancer in male BRCA2 carriers

The risk of breast cancer for unaffected men who test positive for a BRCA2 mutation is based on very few retrospective studies. We have used both retrospective and prospective analysis in 321 families with pathogenic BRCA2 mutations. Three breast cancers occurred in male first-degree relatives after family ascertainment in 4140 years of follow-up suggesting a risk of breast cancer to 80 years of 8.9%. A second analysis excluding index cases identified 16 breast cancers in 905 first-degree male relatives on which Kaplan–Meier analysis was performed after assigning carrier status. This analysis confirmed that breast cancer risk in men was 7.1% (SE 5.2–8.6%) by age 70 years and 8.4% (SE 6.2–10.6%) by age 80 years.