SPEAKERS are lining up for the fifth breast cancer forum, to be held at the royal society of medicine, London, 14 September 2018.
The programme will feature a session on the breast cancer-associated risks of pregnancy, to be delivered by Neha Tabassum, part of professor Justin Stebbing’s research team at Imperial College, Hammersmith hospital. For full details, please see below.
The conference will have a focus on the causes and cures of breast cancer, with speakers including professors Virginia Kaklamani, Gareth Evans, Mitch Dowsett, Christopher Twelves and miss Leena Chagla, and will have a separate session on pathology with the royal college of pathology.
Summary of the pregnancy research project:
Breast cancer is one of the most commonly diagnosed cancer in the world, with more than 50,000 cases diagnosed in the UK in a year. Early full-term pregnancy decreases long-term chances of developing breast cancer, while leading to temporary increase in the chances of having cancer diagnosed soon after pregnancy. On the contrary, women bearing a child at a later age are more at risk in developing cancer compared to the women who never gave birth (nulliparous women).
The correlation between age of first full term pregnancy and exposure to the chances in developing breast cancer at a molecular level have not been fully understood yet. By analysing low frequencies genomic DNA mutations (rare changes in the DNA, which may have a deleterious effect) in the normal and cancerous breast tissue, we will be able to follow how mutated cells can divide or die during different time points in the reproductive years of parous and nulliparous age-matched women pregnancy.
By creating for the first time a model of growth and expansion of mutated cells in the normal breast, we aim to explain pregnancy-associated cancer risk by confirming how pregnancy at different ages can change the probability these mutated cells in the breast, which could lead to cancer. We believe this will be clinically significant in the long term as the patient group falling under high risk categories can make an informed choice when planning their first child. This will also help us in early diagnosis and much more effective treatment.
Details of the study:
Over the years, the diagnosis of BC has increased in the most developed areas of the world, but this increase cannot only be attributed to better diagnostic techniques (1). While a variety of risk factors, including age, family history, genetic factors and personal history have always been in the centre of scientific attention to improve early diagnosis and surveillance, less focus has been applied to pregnancy and reproductive history (2) (3) (4). However, previous population based scientific studies have observed a correlation between delay in child-bearing and the chances of developing BC (2) (3) (4).
These studies indicate that there is no significant difference in the likelihood of developing cancer at the age of 50, between women who never bear a child and women who have a first full-term pregnancy (FFTP) at the age of 35 or above (Figure 1). But, it was also observed that the chances of developing cancer in majority of the women in these groups increased to 35% when compared to younger mothers, who had their FFTP before 24 years of age (5) (6) (3) (Figure 1). Finally, in any FFPE age groups, a temporary increase in the trend of developing the cancer is seen for the next 10 years following pregnancy, due do the enormous changes in the breast at the molecular level (Figure 1). (7) (3) Collectively, this data indicates that pregnancy may exert a dual role as both promoter and suppressor of cancer, and that age of pregnancy is what indeed defines this trend.
Up to date, only few studies have looked into the molecular basis of pregnancy in breast cancer. During pregnancy, the breast, in preparation for breastfeeding, undergoes significant changes in size. The cells in the mammary gland increase in number and during this process any mutation the cells have they will be carried over and expanded in frequency. If these mutations are deleterious, they may eventually lead to cancer.
Studies focussing on the role of pregnancy in breast cancer should therefore consider understanding the normal breast at a molecular level, to see how a normal cell changes into cancerous cell with the involvement of pregnancy at different ages.
During the course of the project, 60 normal breast samples from healthy women between 18 and 50 years of age who underwent breast surgery were collected from Komen tissue bank (USA).This tissue bank is the only tissue bank in the world, which recruits healthy volunteers to donate their breast and help in the scientific research to fight cancer.
Different time points in the reproductive age were considered for normal tissue collection:
- Younger than 24 year old (nulliparous women)
- During pregnancy (both early and late pregnancies, thus before 24 or after 35 years of age) and age-matched nulliparous women
- 1-5 years after early/late pregnancy and age-matched nulliparous women
- More than 10 year after early/late pregnancy and age-matched nulliparous women
Patients with multiple pregnancies were excluded from this study. The usage of contraceptive pill is recorded and kept into consideration in the study.
The breast cells from the normal tissue samples are isolated individually and collected using specialised microscope in the lab, PALM Laser capture microdissection microscope from Zeiss (Figure 2).
The DNA is extracted from the cells to analyse the samples at a molecular level using novel genome based technique such as sequencing, which will identify the low frequency mutations in the normal sample, which might play a role in cancer development. The huge amount of data resulting from the sequencing will be analysed using bio informatics tools in the lab and also, the results will be validated using laboratory techniques.
Finally, with all the analysed data resulted from the study we will create a mathematical model comparing normal breast growth in women who have had children, and women who have not (taking into account the different ages of FFTP over the reproductive years of a woman). This will provide future patients, in particular from at risk categories, with an informed choice when deciding to plan a pregnancy. If the age of the patient is deemed at higher risk for developing breast cancer, a surveillance programme could be implemented to closely monitor any changes in the breast after a late pregnancy and improve early cancer detection. Early diagnosis is very often key to successful cancer treatment.
Work in progress
Currently, we are close to sending the preliminary set of samples for whole genome sequencing. The next steps would be
To analyse the huge amount of data coming up with the sequencing, using bioinformatic tools (Figure 3) and validation of results in the laboratory.
To create for the first time, the model of growth and expansion of the normal breast during the reproductive years of the women, this will allow us to predict the chances of developing cancer with different ages at FFTP.
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- Hinkula M, Pukkala E, Kyyronen P, Kauppila A. Grand multiparity and the risk of breast cancer: population-based study in Finland. Cancer causes & control : CCC. 2001;12(6):491-500.
- Ma H, Henderson KD, Sullivan-Halley J, Duan L, Marshall SF, Ursin G, et al. Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort. Breast cancer research : BCR. 2010;12(3):R35.
- Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Wactawski-Wende J, Kuller LH, et al. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. Journal of the National Cancer Institute. 2011;103(6):470-7.
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- Lord SJ, Bernstein L, Johnson KA, Malone KE, McDonald JA, Marchbanks PA, et al. Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2008;17(7):1723-30.
- Schedin P. Pregnancy-associated breast cancer and metastasis. Nature reviews Cancer. 2006;6(4):281-91.