C. Michael Steel

Screening for Familial Ovarian Cancer: Failure of Current Protocols to Detect Ovarian Cancer at an Early Stage According to the International Federation of Gynecology and Obstetrics System

PURPOSEnTo assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA-125 estimation) in detecting presymptomatic ovarian cancer in women at increased genetic risk.nnnPATIENTS AND METHODSnA cohort of 1,110 women at increased risk of ovarian cancer were screened between January 1991 and March 2004; 553 were moderate-risk individuals (4% to 10% lifetime risk) and 557 were high-risk individuals (> 10% lifetime risk). Outcome measurements include the number and stage of screen-detected cancers, the number and stage of cancers not detected at screening, the number of equivocal screening results requiring recall/repetition, and the number of women undergoing surgery for benign disease.nnnRESULTSnThirteen epithelial ovarian malignancies (12 invasive and one borderline), developed in the cohort. Ten tumors were detected at screening: three International Federation of Gynecology and Obstetrics (FIGO) stage I (including borderline), two stage II, four stage III, and one stage IV. Of the three cancers not detected by screening, two were stage III and one was stage IV; 29 women underwent diagnostic surgery but were found not to have ovarian cancer.nnnCONCLUSIONnAnnual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer is ineffective in detecting tumors at a sufficiently early stage to influence prognosis. With a positive predictive value of 17% and a sensitivity of less than 50%, the performance of ultrasound does not satisfy the WHO screening standards. In addition, the combined protocol has a particularly high false-positive rate in premenopausal women, leading to unnecessary surgical intervention.

Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy.

Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaN0) and 26% had cancer with spread (CaN+). Five‐year survival was 100% for CIS, 94% for CaN0 and 72% for CaN+ (p = 0.007). Thirty‐six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5‐year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaN0 patients, mutation carriers had 75% 5‐year disease‐free survival vs. 96% for noncarriers (p = 0.01). Twenty‐one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but 1 relapse occurred in the 15 who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.

Surveillance for familial breast cancer : Differences in outcome according to BRCA mutation status

Women with a family history of breast cancer are commonly offered regular clinical or mammographic surveillance from age 30. Data on the efficacy of such programmes are limited. Clinical, pathological and outcome data were recorded on all breast and ovarian cancers diagnosed within familial breast cancer surveillance programmes at collaborating centers in Norway and the UK up to the end of 2005. These have been analyzed according to the mutation status of the affected women (BRCA1+ve, BRCA2+ve or mutation‐negative). Breast cancer was diagnosed in 442 patients subsequently followed for a total of 2095 years. Eighty‐nine (20%) had BRCA1 mutations, 35 (8%) BRCA2 mutations and in 318 (72%) no mutation could be detected (“mut neg”). Five‐year survival in BRCA1 was 73% compared to 96% in BRCA2 and 92% in mut neg (p = 0.000). Among BRCA1 mutation‐carriers, 5‐year survival was 67% for cases diagnosed as carcinoma in situ, 84% for node‐negative invasive cancers and 58% for those with nodal involvement (p > 0.05). For BRCA2 mutation‐carriers the corresponding figures were 100, 100 and 90% (p > 0.05), while for mut neg women they were 100, 97 and 71% (p = 0.03). Regular surveillance in women at increased familial risk of breast cancer is associated with a good outcome if they carry BRCA2 mutations or no detectable mutation. Carriers of BRCA1 mutations fare significantly worse, even when their tumors are diagnosed at an apparently early stage. The differences in outcome associated with different genetic causes of disease were associated with demonstrated differences in tumor biology. The findings demonstrate the outcome for genetically different breast cancers detected within a programme for early diagnosis and treatment, which is relevant to genetic counseling when women at risk have to chose between the options for preventing death from inherited breast cancer.

Human MHC class II molecules as differentiation markers

DA6.231 and DA6.164 are mouse monoclonal antibodies that immunoprecipitate HLA-DR-like p34,29 glycoprotein dimers from surface- and metabolically-labeled cells. On lymphoblastoid cell lines the distribution of the 231 epitope is completely nonpolymorphic, while the 164 epitope is present on all cells except on those that are DR7 homozygous. Binding-inhibition studies show that the 231 and 164 epitopes are spatially close to each other when present on the same molecule. The mutual inhibition pattern and the absence of the 164 epitope from the 231+ cells of a few leukemia patients suggest, however, that 231 and 164 epitopes are not invariably present together. Most DR-positive cells possess 231− 164+ and 231+ 164− class 11 molecules in approximately a 2:1 ratio. This has been confirmed by immune depletion studies. Thus DA6.231 appears to define a supralocus epitope. The 164 epitope may be a marker for a subset of class 11 molecules exhibiting differential expression on various cell types immortalized by malignant transformation.

Efficacy of Early Diagnosis and Treatment in Women with a Family History of Breast Cancer

BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality. METHODS: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer. All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded. Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan—Meier survival plots. RESULTS: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations. For women under age 50 at diagnosis, this figure was 68%. Eighteen percent were mammographically negative, (23% in patients under age 50). At first (“prevalence”) round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+). Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+. Overall five-year survival was 89% and five-year event-free survival 86%. Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+. CONCLUSIONS: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50. Surveillance should include regular expert clinical examination and teaching of “breast awareness” as well as mammography. Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected. The trend towards earlier pathological stage in tumours detected during follow-up rounds and the preliminary findings on survival analysis suggest that this approach will prove to be of long-term benefit for breast cancer families.

Use of Cytology to Diagnose Inherited Breast Cancer

Pal Moller, Gareth Evans, Elaine Anderson, Lovise Maehle, Fiona Lalloo, Ketil R. Heimdal, and C. Michael Steel, in cooperation with The Biomed 2 Demonstration Programme on Inherited Breast Cancer Unit of Medical Genetics, The Norwegian Radium Hospital, Norway Family History Clinic, Centre for Cancer Epidemiology, Christie Hospital NHS Trust, Withington, Manchester, UK Edinburgh Breast Unit, Western General Hospital NHS Trust, Edinburgh, UK School of Biomedical Sciences, University of St Andrews, Fife and Edinburgh Healthcare NHS Trust, UK

The frequency of micronuclei in bone-marrow erythroblasts during the treatment of childhood acute lymphoblastic leukaemia

We scored the frequency of micronuclei in bone-marrow erythroblasts from 41 patients with childhood acute lymphoblastic leukaemia (childhood ALL) at diagnosis and during their 2-year treatment cycle in order to see whether there would be any variation in the cytogenetic damage induced by chemotherapy. We found that most patients showed the same trend in micronucleus frequency, with a progressive rise from the diagnostic slide through induction to pre-intensification and completion of treatment. The rise was attributed to damage to the erythroblasts occurring as a result of chemotherapy, and was judged not prognostically significant in this study.

Screening of Workshop “B” Series Antibodies by Radioimmunobinding to Human Leukocyte Cell Lines and to Cells from Human Lymphoid Tumors

The fifty-two monoclonal antibodies of the Workshop B series were received in April, 1984. They were allowed to thaw and were held at 8°C for the period of study (April–August, 1984). Aliquots of the original samples were diluted 1:20 with RPM1 1640 culture medium containing 5% fetal calf serum (FCS), 5% horse serum (HS), and 0.02% sodium azide. The diluted antibodies were then tested for binding to a panel of cells from human lymphoid lines or from lymphoid tumors. The phenotypes of the cells forming the panel had already been determined but additional monoclonal antibodies of known specificities were included to act as positive or negative controls in the binding assays.