Breast cancer genetics: 20 years later

Clinical, epidemiological and linkage studies have convincingly indicated for at least past 30 years that a significant proportion of common malignancies, including breast cancer, are due to monogenetic disorders that are associated with a very high risk of cancer. We believed so much in the new opportunities afforded to oncology and genetics as a consequence the identification of cancer predisposition genes that we started to organize the logistics of our medical and research system to cover this new aspect of cancer. In 1992 we established the first Polish Cancer Genetics Outpatient Clinics aimed at identifying cancer family syndromes and to offer intensive surveillance programs for persons from such families. We developed laboratories that are able to perform efficiently all manner of DNA molecular diagnostics including mutation detection within genes known to be associated with a high risk of disease. In 1998 we established and got acceptance of our approach from the Ministry of Health for a national programme of diagnostics and family management where there was a strong aggregation of malignancies. Finally, we successfully established an European Union (EU) funded research project collaborating with 11 countries to develop cancer family syndrome registries in Eastern Europe. We joined international organizations with other recently established networks on hereditary cancers such as the UICC and ICG-HNPCC. As a result of our initial activities, we accumulated and developed huge resources, however, their practical clinical value was actually limited. Especially hopeless was the situation of families with aggregations of breast and/or ovarian cancers – despite the use of mammography and ultrasound almost all cancers have been diagnosed at advanced clinical stage. We understood, that the best possible research was needed to seriously address the clinical problems raised by inherited predispositions to breast and/or ovarian cancer. In order to realize the potential of our centre for studies conducted at a world-class level we made a careful search for scientists who could efficiently contribute in addressing our common efforts. Finally, mainly for studies on colorectal cancers we invited Rodney Scott and for studies on breast cancers – Steven Narod (following suggestions of Henry Lynch). It was a great achievement. During a seminar at our centre in July 1999, S. Narod demonstrated to us the value of finding founder mutations. Since 1994 the time that BRCA1 was cloned, we started to search for constitutional mutations using indirect techniques – mainly SSCP followed by DNA sequencing. Methodology used in initial reports on BRCA1 sequencing included errors in the description of experimental conditions used to study exon 20. This problem was solved once we redefined the milestones of our research programme by assuming that potential founder effects in Poland existed. As a result, by October 1999 we had found that 5382insC is the ‘golden’ mutation for our country and that only a few mutations constitute approximately 90% of all BRCA1 pathological changes in Poland (1, 2). Later it was confirmed to be valid for all Slavic countries. Once founder mutations had been identified it became possible to perform inexpensive (50 euro instead of 3000), simple and rapid DNA testing for detecting BRCA1 carrier females. We started to perform population screenings. The most impressive was the screening program in collaboration with family doctors and nurses performed in the West-Pomeranian region of Poland. During 2000–2001 we collected questionnaires from almost 1.3 million (more than 75%) inhabitants. All females with at least one breast or ovarian cancer among relatives have been invited for BRCA1 testing. To date our registry includes >1000 carriers from West Pomerania and additionally approximately 4000 from other regions of Poland. Finding of founder mutations was also a milestone for the development of studies on clinical – genetic associations. S. Narod shared with us the project on incident breast cancers. We established cohort of approximately 7000 consecutive breast cancers diagnosed at <50 years of age. After 10 years of follow-up we have been able to prove that adnexectomy reduces the risk of death by 70% (! ) in BRCA1 mutation carriers diagnosed with breast cancer (3). Using the same cohort we were able to prove that taxanes have no therapeutic role in the neo-adjuvant setting for women harbouring a BRCA1 mutation and having breast cancer (4). In the next stage of our neoadjuvant project we have been convinced by S. Narod that, as a result of cell-line studies and single clinical reports, we should explore the efficacy of cis-platinum in such women. The result of this aspect of our endeavours is outstanding and it is fantastic to see how many breast cancers in carriers are just disappearing (5, 6). Today we can see that our patients (n = 38) treated by cis-platinum and adnexectomy show 100% survival after 4-year follow-up! This seems to be an unequivocal result and we are rapidly coming to the conclusion that our dream will be to find BRCA1 mutations among