Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.

Radiotherapy for ductal carcinoma in situ.

AIMS: The introduction of breast screening mammography has led to an increase in the diagnosis of ductal carcinoma in situ (DCIS). Mastectomy gives high rates of local control. However, most cases are suitable for local excision. The aim of this article is to review the role of radiotherapy in the treatment of DCIS after breast conserving surgery. MATERIAL AND METHODS: A review of the literature relating to radiotherapy and DCIS RESULTS: The published trials show that adjuvant radiotherapy after breast conserving surgery halves the ipsilateral recurrence rates of DCIS and invasive cancer. No subgroups have been reliably identified that do not benefit from adjuvant radiotherapy. Risk factors for recurrence are discussed. DISCUSSION: All patients with DCIS have potential benefit to gain from adjuvant radiotherapy. However, radiotherapy also has adverse effects and represents over-treatment from many women. Support should be given to current trials which are assessing endocrine treatment of DCIS, and whether radiotherapy can reasonably be omitted in lower risk disease.

Lymphopenic infectious mononucleosis.

Lymphopenic IM is a real phenomenon. It is likely to appear as a more severe clinical illness and, in contrast to the benign course to typical IM, may have a poorer prognosis. The clinical spectrum of IM should be extended to included to include lymphopenic patients if their diagnosis is supported by appropriate heterophil and EBV antibody titers.

Morbidity of tamoxifen-perceptions of patients and healthcare professionals.

There is little published data comparing patients' and doctors' perceptions of tamoxifen-related morbidity and toxicity, in particular in terms of side-effects which are not medically serious but which disrupt quality of life. We undertook a questionnaire-based study of 210 randomly selected, disease-free pre- and post-menopausal breast cancer patients to assess perceived morbidity whilst taking tamoxifen. We also questioned 143 healthcare professionals, including nurses, GPs and oncologists, on their opinions of tamoxifen-related side-effects. This study suggests that patients experience significant morbidity while taking adjuvant tamoxifen but will tolerate this for the sake of anticipated benefits. Healthcare professionals particularly hospital-based doctors and specialist nurses tend to overestimate the prevalence and severity of tamoxifen-associated symptoms.

Cancer knowledge of the general public in the United Kingdom: survey in a primary care setting and review of the literature.

The likelihood of cure from cancer is usually dependent on the stage of disease at diagnosis. Some patients attend their general practitioner with a long preceding history of cancer symptoms. This may be due in part to a lack of recognition of the seriousness of the symptoms. We have conducted a survey of 406 adult patients in a two-centre primary care practice to determine their awareness of risk factors, presenting symptoms, treatments and support services for cancer. The two health centres are located in areas covering different socio-economic groups--one located in an affluent residential area, and the other a deprived inner-city population. Significant deficiencies were identified in the cancer knowledge of respondents. Personal or family history of cancer, younger age and female sex were associated with improved cancer awareness. A review is also presented of the previous published literature on the cancer knowledge of the general public in the U.K. The results suggest that overall the public knowledge of cancer is poor and greater attempts should be made to raise awareness.

Open access follow-up for lung cancer: patient and staff satisfaction.

The majority of patients with lung cancer have incurable disease from presentation and a survival measured in months. Treatments offered to these patients are aimed at the palliation of symptoms with either radiotherapy or chemotherapy, or with supportive measures. It has been traditional to offer regular outpatient follow-up after initial palliative treatment. Further treatment options, which may be limited, are usually reserved for the recurrence of troublesome symptoms. A pilot 'open access' lung cancer clinic has been set up. Rather than have regular follow-up at the hospital, patients who have completed initial palliative treatments are discharged to the community with follow-up by their general practitioner and Macmillan nurse. Review at the open access clinic can be arranged at short notice if requested by the patient, carers, general practitioner or Macmillan nurse. The outcomes and level of satisfaction of patients, their relatives and staff to this method of follow-up were found to be positive. Open access follow-up may be useful for many patients after the completion of initial palliative treatment.

Thalidomide in the treatment of cancer.

Thalidomide caused severe malformations in babies born to mothers taking the drug for morning sickness in the late 1950s and early 1960s. It is now known that these teratogenic effects are due to potent anti-angiogenic and immunomodulatory actions. These properties have lead to the testing of thalidomide in a number of infective, inflammatory and malignant conditions. Promising activity has been reported in myeloma, AIDS-related Kaposi's sarcoma, renal cell carcinoma and glioblastoma multiforme. A review is presented of the history of thalidomide and its recent development with an emphasis on applications in malignant disease.

Optimum anthracycline-based chemotherapy for early breast cancer.

Adjuvant chemotherapy improves the overall survival of women treated after surgery for early breast cancer. Several trials have suggested that anthracycline-containing regimens are more effective than those that do not contain anthracyclines. A modest overall benefit has also been confirmed by the Early Breast Cancer Trialists' Collaborative Group overview. Newer agents, such as the taxanes, are now being tested in the adjuvant setting in randomised trials. The control group of such studies should receive the optimum standard treatment. There are several anthracycline-based regimens in common use, varying in terms of the type of anthracycline used, the dose, and drug scheduling. We review the available evidence and consider whether the optimum anthracycline-containing chemotherapy schedule has now been identified.