Jan Lubinski
Prof. Jan Lubinski M.D.
Pomeranian Academy of Medicine, Szczecin
Topic
Milestone improvements on prevention and treatment of cancers based on knowledge of patients' genetic changes
Abstract
Special emphasis will be devoted to:
1)Platins in the treatment of BRCA1-dependent breast cancers
2)SELINA - clinical trial on lowering the risk of malignancies by optimizing selenium levels in females from families with hereditary breast cancer
3)Arsenic as prognostic and risk factor of cancers.
Ad 1)
Aim. To evaluate in a contemporary cohort the impacts of chemotherapy and oophorectomy on survival for breast cancer patients with a BRCA1 mutation.
Method. We reviewed the pathology reports and medical records of 372 women with breast cancer and a BRCA1 mutation, diagnosed from 2005 to 2017, between the ages of 25 and 65 and followed them for death from all causes and death from breast cancer. Death was ascertained through the Poland vital statistics registry. We performed survival analysis to evaluate the impacts of chemotherapy (including neoadjuvant cisplatinum) and of oophorectomy on survival.
Results. After a mean follow-up of 5.6 years (median 5.2), 66 of the 372 women died; 56 of the deaths were from breast cancer and 6 were from ovarian cancer. 127 women received neoadjuvant cisplatinum and 245 women received other chemotherapies. Cisplatinum (versus all other therapies) was associated with a hazard ratio of 0.42 (95%CI 0.20-0.87) on breast cancer-specific survival. The 10-year actuarial all-cause survival for women who had both cisplatinum and an oophorectomy was 94.4%. The 10-year all-cause survival for women who had neither cisplatinum nor an oophorectomy was 65.4% (p < 0.01).
Conslusions. Cisplatinum and oophorectomy are effective therapies for women with breast cancer and a BRCA1 mutation.
Ad 2)
Aim. Prospective observational studies showed that blood selenium (Se) levels associated with significantly lower risk of cancers can be identified in Polish females from families with hereditary breast cancers (HBC). For BRCA1 mutation carriers it is: 70-89 µg/l at age <50 yrs (OR~12) and 95-120 µg/l at age ≥50 yrs (OR~4). For females without detected BRCA1 mutation but from families with pedigree/clinical features of HBC it is 98-108 µg/l (OR~5).
The main goal of SELINA is validation of hypothesis that optimization of Se level by supplementation or diet changes can decrease the risk of malignancies in groups described above.
Method. 7000 females (including 1200 BRCA1 carriers) from families with HBC and deficiency or excess of Se will be recruited and randomly qualified to one of the following arms: “placebo”, prospective observational, supplement (Sodium Selenite) or diet modification. Blood Se level will be systematically measured using ICP-MS and appropriately optimized. Follow-up will take 5 yrs.
Results. At present we are performing recruitment. It is planned to close it at the end of 2019.
Conclusion. SELINA is the first clinical trial aimed to decrease the risk of cancers by active control of blood selenium levels . All interested scientists/institutions are welcome for collaboration.
Project - INNOMED/I/16NCBR/2014 - sponsored by National Center of Research and Development and Read-Gene SA.
Ad 3)
Background. Inherited mutations of high risk can explain only a few percent of cases of breast carcinoma. Environmental factors like exposure on metals may play role in such cases. Arsenic (As) is known as a potent carcinogen. Knowledge of chronic low level exposure is limited to a few studies.
Aim. Authors aim was to determine if blood arsenic level may reflect cancer risk among women in Poland.
Method. Cohort of 1702 healthy women, aged 40 and above was set. Only women without BRCA1 mutations were enrolled. Blood arsenic level was determined by inductively coupled plasma mass spectrometry. Statistical analysis was performed using Cox regression model for equal quartiles of arsenic levels.
Results. Over an average of 4.5 years (range 0.7 to 7.3) of follow-up and 7,731 person-years, there were 110 incident cases of cancer diagnosed in the cohort. Annual breast cancer incidence rate is was 4.9 times greater than the expected risk based on Polish statistics. Women in the highest quartile of arsenic had a highly significant 12-fold increased risk of developing breast cancer compared to women in the lowest quartile (HR = 12.72; 95%CI 3.89-41.57). Cumulative incidence was 0.7% for quartile 1, 3.8% for quartile 2, 4.2% for quartile 3 and 9.5% for quartile 4. Results were similar in the analysis including all incident cancers (HR quartile 4 vs. quartile 1 = 13.14; 95%CI 4.72-36.51).
Conclusions. Unexpectedly, the blood arsenic level may be particularly strong marker of low/high cancer risk in women.
Biography
Education
Pomeranian Academy of Medicine, Szczecin
M.D. 1971-1977 Medicine
Ph.D. 1980 Pathology Habilitation
1989 Pathology-Molecular Genetics
Specialisation
1980, 1985 Surgical Pathology
1989 Clinical and Molecular Genetics of Hereditary Cancer
2003 Clinical Genetics
2007 Medical Laboratory Genetics
Research and professional experience:
1977-1985 Assistant, Dept Pathomorphology, Pomeranian Academy of Medicine, Szczecin
1981-1982 Visiting Scientist, French Government Fellowship, Pasteur Institute, Paris
1985-1989 Assistant Professor, Dept. Tumour Pathology, Pomeranian Academy of Medicine, Szczecin.
1987-1988 Visiting Scientist, Fulbright Fellowship. The Wistar Institute, Philadelphia
IV-VII 1989 and 1991 Visiting Scientist, The Fels Institute for Cancer Research and Molecular Biology, Temple University, Jefferson Cancer Institute, Philadelphia
1989 Associate Professor, Head of Dept. of Genetics and Pathology, Pomeranian Academy of Medicine
1992 Professor
1992 Organiser and head of Regional Hereditary Cancer Centre, Szczecin
1993-1999 Rector for Science, Pomeranian Academy of Medicine, Szczecin
I-II 1994 Visiting Scientist, Jefferson Centre Institute, Philadelphia
1998 Author and coordinator of project on development of Polish Network of Hereditary Cancer Centres.
1998 – 2011 National Consultant of Clinical Genetics
1999 Author and coordinator of project on development of cancer family syndrome registries in Eastern Europe
2003 - Head of International Hereditary Cancer Center of Pomeranian Medical University
2003 - Founder and one of editors-in-chief of the journal Hereditary Cancer in Clinical Practice
2005 - Polish representative for the Contact Group to ETP Innovative Medicine, European Commission
2005 Doctor Honoris Causa of Rīga Stradiņš University, Rīga, Latvia
2005 - Head of Polish Technology Platform for Innovative Medicine
2006 - 2011 European Society of Human Genetics Board Member
2010 - Clinical Genetics - Member of Editorial Board
2010 - 2014 Member of Scientific Council of the National Center for Research and Development
2015 – 2018 Member of Scientific Council of the Institute of Human Genetics, Polish Academy of Sciences
Number of publications: ~650
Hirsch-index: 59, no of citations: 13.795, without self-citations: 12.542
List of patents granted:
9 international patents granted:
1. Determining a predisposition to cancer - Patent No. 7,851,162 B2 (USA), EP05704666.6 (European).
2. Determining a predisposition to cancer (CHEK2) - Patent No. 7,407,755 B2 (USA),
3. Determining a predisposition to cancer (NBS1) - Patent No. 7,319,007 B2 (USA),
4. Determining a predisposition to cancer (NBS1) - Patent No. 7,745,133 (USA),
5. Fast assignment of adequate neoadjuvant chemotherapy for breast cancer patients based on the identification of constitutional BRCA1 mutations – patent no 2008/10173 (South Africa)
6. Method for determining reduced predisposition to cancer based on genetic profile - Patent 61/069,403 (USA)
7. Pharmaceutical composition and methods for the prevention of breast and ovarian cancer - Patent No. 2006/02081 (South Africa),
8. Polymorphism in the human NBS1 gene useful in diagnostic of inherited predisposition to cancer - Patent No. 011608 (Euroasia),
9. Polymorphism in the human NBS1 gene useful in diagnostics of inherited predisposition to prostate cancer and lobular invasive breast cancer - patent no 93344 (Ukraine).
15 Polish patents granted
Summarisation of the most important achievements:
1. Creation of International Hereditary Cancer Centre and Department of Genetics and Pathology of Pomeranian Medical University with significant international position due to achievements mainly on diagnosis and prophylactics of hereditary cancers elaborated in Poland in collaboration with scientists from other countries.
2. Publication together with his team around 200 publications on hereditary cancers during the last 10 years. Most of them are papers published in SCI journals including JAMA (Impact Factor 23,33), Journal of the National Cancer Institute (Impact Factor 15,171), American Journal of Human Genetics (Impact Factor 12,649), Journal of Clinical Oncology (Impact Factor 11,81), PNAS (Impact Factor 10,231), Lancet Oncology (Impact Factor 7,855), Cancer Research (Impact Factor 7,616).
3. Realisation of numerous international collaborative studies. Prof. Lubinski has been an author and coordinator of the projects:
MZ/NIH-96-287 – Genomic deletions as markers for renal carcinoma diagnosis; U.S.-Poland Maria Sklodowska–Curie Joint Fund II.
ERB 3510-PL-92-2713 – Molecular genetic analyses in diagnosis of renal cell carcinoma – EC project;
MZ/HHS-91–75 - Molecular genetic analyses in tumour diagnosis; U.S.-Poland Maria Sklodowska–Curie Joint Fund II.
QLRI-CT-1999-00063 - Development of network of cancer family syndrome registries in Eastern Europe 5th Framework Programme of European Union
MTKD-CT-2004-510114 - Identification of new cancer susceptibility genes by linkage analyses in Polish families with aggregation of breast or colorectal cancers, 6th Framework Programme of European Union
4. Co-authorship of numerous international patent applications.
5. Population screening for familial cancers – family doctors and nurses performed screening for cancer family history of all inhabitants – population of 1.5 million, of West-Pomeranian Region in Poland. Programme of entire population screening for all types of familial cancer is, according to our knowledge, the first in the world.
6. Publication under auspices of UICC peer-reviewed journal Hereditary Cancer in Clinical Practice (since 2008 on SCI list), editors-in-chief: J. Lubinski, R. Scott, R. Sijmons.
7. Development of registry unique at worldwide scale of cancer family syndromes with the following parameters:
- almost 5,000 of diagnosed and registered BRCA1 mutation carriers – the largest number in the world,
- more than 32,000 registered families with other cancer family syndromes or strong aggregation of malignancies with biological samples available from at least 1 affected relative,
- more than 274,000 DNAs from cancer patients or their relatives,
- almost 7,000 cell lines from BRCA1 mutation carriers,
- pedigree data from 1,258,000 persons – more than 80% of Regional Health Care Company collected during realisation of 1st worldwide project for inherited cancer prevention.
8. The first world-wide demonstration of genetic contribution to all cancers using the model of breast cancers from homogenous Polish population (Breast Cancer Res Treat 2008)
