Periodic Reporting for period 4 - BRCA-ERC (Understanding cancer development in BRCA 1/2 mutation carriers for improved Early detection and Risk Control)
Reporting period: 2022-05-01 to 2023-05-31
Cancer represents a growing burden on society and tackling this growing burden requires a multifactorial approach including understanding the fundamental drivers of cancer development; improving methods for detecting earlier those forms of cancer with the worst prognosis; predicting a person’s risk of developing cancer; and identifying appropriate targets for preventing cancer. Indeed, one of the biggest obstacles in identifying tailored cancer prevention strategies is a lack of surrogate readout markers reflecting and integrating an individual’s response to the cancer-initiating and cancer-promoting factors that they are exposed to during their lifetime.
The BRCA-ERC programme aimed to better understand the factors contributing to increased risk for breast and ovarian cancer in BRCA1/2 germline mutation carriers. Tissue specific disease penetrance of the BRCA1/2 mutation remains partly understood and we aimed to learn more through the study of multiple body systems, specifically examining the contribution of factors which have an indirect impact on cancer development in women with BRCA1/2 mutations with a specific focus on epigenetic processes. The insights developed samples from these women at high risk will be more broadly applicable in a disease area that represents a growing burden for society, particularly in younger women.
Our ultimate aim was to uncover novel insights into the systemic contributors of heightened risk in BRCA1/2 mutation carriers that can then be targeted to advance preventive measures.
The BRCA-ERC programme aimed to better understand the factors contributing to increased risk for breast and ovarian cancer in BRCA1/2 germline mutation carriers. Tissue specific disease penetrance of the BRCA1/2 mutation remains partly understood and we aimed to learn more through the study of multiple body systems, specifically examining the contribution of factors which have an indirect impact on cancer development in women with BRCA1/2 mutations with a specific focus on epigenetic processes. The insights developed samples from these women at high risk will be more broadly applicable in a disease area that represents a growing burden for society, particularly in younger women.
Our ultimate aim was to uncover novel insights into the systemic contributors of heightened risk in BRCA1/2 mutation carriers that can then be targeted to advance preventive measures.
Breast cancer is an increasingly common disease, particularly amongst younger women. Although new treatments developed over the past few decades mean that most survive the disease, for women with some types of breast cancer, such as triple negative breast cancer, the prognoses remain poor. Women with a germline mutation in the BRCA1 genes have an excessively high risk of developing breast cancer and the majority of these cancers are triple negative breast cancers. Their risk of ovarian cancer is also high. Risk reducing surgery through removal of both breasts, ovaries and fallopian tubes, is currently the only option available to these women at the highest risk as it is not currently possible to predict which women with a mutation will develop cancer.
Role of progesterone in cancer formation
Previous studies in mice have shown that increased progesterone levels trigger increases in the protein RANKL in breast tissue and leads more frequent cell division in non-hormone responsive luminal progenitor cells. This more frequent division of the luminal progenitor cells drives cancer formation.
We studied daily progesterone levels in saliva and urine samples from women with and without BRCA mutations. We found that the progesterone levels were higher throughout the menstrual cycle in women with a BRCA1 mutation compared to controls, particularly during the luteal (post-ovulation) phase. Hence, blocking progesterone signalling in women at high risk of breast cancer could prevent of the disease.
We developed an epigenetic signature in breast tissue – the WID-Breast29 – that identifies the proportion of luminal progenitor cells that have undergone a high number of divisions (or in other words, cells with a high replicative age) and showed that the WID-Breast29 is much higher in breast cancer tissue compared to normal tissue.
Our in vitro studies also highlight the role of progesterone in controlling the cytotoxicity of NK cells in BRCA1 mutation carriers and the role of hypoxia in cancer development.
Mifepristone for breast cancer prevention
Mifepristone is a drug that stops progesterone from binding to its receptor and thereby should interfere with the cascade of events involving RANKL leading to an increased number of luminal progenitor cells and cancer. In our studies, we showed that mifepristone reduced the number of luminal progenitor cells with a high replicative age, as measured with the WID Breast29.
Precision prevention
These new data, as well as the wider literature, support the use of mifepristone for breast cancer prevention. Clinical trials are warranted, but are challenging to perform due to the long-term follow up required to demonstrate the preventive effect.
Our studies show that monitoring breast cancer risk in tissue using the WID-Breast29 could indicate whether breast cancer prevention with mifepristone is working or whether risk reducing surgery would be needed. However, regular tissue sampling is invasive and it would be preferable to monitor risk in a surrogate tissue, such as a cervical sample or cheek swab.
Evidence generated during the BRCA-ERC study support the hypothesis that epigenetic signatures in easy-to-access, hormone sensitive, cervical tissue are reflective of cancer field defects at distant sites, such as in the breast. These data complement other data in surrogate tissue generated during the project for example showing that a tissue-independent epigenetic clock measured in cervical samples (the WID-relative epigenetic age) reflects changes in breast tissue from pre-menopausal women with a BRCA mutation; and a signature in cervical cells – the WID-qtBC – that combines information on methylation status and underlying genetic risk (single nucleotide polymorphisms) identifies women at increased risk for breast cancer. Both the WID-REA and the WID-qtBC indicated a reduction breast cancer risk after treatment with mifepristone.
Early cancer detection
Novel tests for the detection of women’s cancer complement our approach to prevention. Here, we expanded our findings on cell-free DNA methylation (cfDNAme) through analysis in diagnostic samples and early detection (preceding diagnosis; samples from the UK Familial Ovarian Cancer Screening Study). In the diagnostic set, the specificity of cfDNAme was 97.6%. High-risk cancers were detected with a sensitivity of 80%. Combination of cfDNAme and CA125 increased sensitivity to 94.4% for high-risk cancers. We also delivered new studies using an epigenetic test for uterine cancers (the WID-qEC), which outperformed imaging (ultrasound and MRI) in a cohort study.
Next steps
While our ultimate aim is to prevent cancers from occurring, early detection of cancer remains an important target and we have also generated new data on tests for ovarian, endometrial and cervical cancers during this project. Together these insights support clinical investigation of the antiprogestin mifepristone for breast and ovarian cancer prevention. Our ERC Proof of Concept award (BRCA-PREVENT; project number 101113534) will build the necessary consensus to take this forward.
Role of progesterone in cancer formation
Previous studies in mice have shown that increased progesterone levels trigger increases in the protein RANKL in breast tissue and leads more frequent cell division in non-hormone responsive luminal progenitor cells. This more frequent division of the luminal progenitor cells drives cancer formation.
We studied daily progesterone levels in saliva and urine samples from women with and without BRCA mutations. We found that the progesterone levels were higher throughout the menstrual cycle in women with a BRCA1 mutation compared to controls, particularly during the luteal (post-ovulation) phase. Hence, blocking progesterone signalling in women at high risk of breast cancer could prevent of the disease.
We developed an epigenetic signature in breast tissue – the WID-Breast29 – that identifies the proportion of luminal progenitor cells that have undergone a high number of divisions (or in other words, cells with a high replicative age) and showed that the WID-Breast29 is much higher in breast cancer tissue compared to normal tissue.
Our in vitro studies also highlight the role of progesterone in controlling the cytotoxicity of NK cells in BRCA1 mutation carriers and the role of hypoxia in cancer development.
Mifepristone for breast cancer prevention
Mifepristone is a drug that stops progesterone from binding to its receptor and thereby should interfere with the cascade of events involving RANKL leading to an increased number of luminal progenitor cells and cancer. In our studies, we showed that mifepristone reduced the number of luminal progenitor cells with a high replicative age, as measured with the WID Breast29.
Precision prevention
These new data, as well as the wider literature, support the use of mifepristone for breast cancer prevention. Clinical trials are warranted, but are challenging to perform due to the long-term follow up required to demonstrate the preventive effect.
Our studies show that monitoring breast cancer risk in tissue using the WID-Breast29 could indicate whether breast cancer prevention with mifepristone is working or whether risk reducing surgery would be needed. However, regular tissue sampling is invasive and it would be preferable to monitor risk in a surrogate tissue, such as a cervical sample or cheek swab.
Evidence generated during the BRCA-ERC study support the hypothesis that epigenetic signatures in easy-to-access, hormone sensitive, cervical tissue are reflective of cancer field defects at distant sites, such as in the breast. These data complement other data in surrogate tissue generated during the project for example showing that a tissue-independent epigenetic clock measured in cervical samples (the WID-relative epigenetic age) reflects changes in breast tissue from pre-menopausal women with a BRCA mutation; and a signature in cervical cells – the WID-qtBC – that combines information on methylation status and underlying genetic risk (single nucleotide polymorphisms) identifies women at increased risk for breast cancer. Both the WID-REA and the WID-qtBC indicated a reduction breast cancer risk after treatment with mifepristone.
Early cancer detection
Novel tests for the detection of women’s cancer complement our approach to prevention. Here, we expanded our findings on cell-free DNA methylation (cfDNAme) through analysis in diagnostic samples and early detection (preceding diagnosis; samples from the UK Familial Ovarian Cancer Screening Study). In the diagnostic set, the specificity of cfDNAme was 97.6%. High-risk cancers were detected with a sensitivity of 80%. Combination of cfDNAme and CA125 increased sensitivity to 94.4% for high-risk cancers. We also delivered new studies using an epigenetic test for uterine cancers (the WID-qEC), which outperformed imaging (ultrasound and MRI) in a cohort study.
Next steps
While our ultimate aim is to prevent cancers from occurring, early detection of cancer remains an important target and we have also generated new data on tests for ovarian, endometrial and cervical cancers during this project. Together these insights support clinical investigation of the antiprogestin mifepristone for breast and ovarian cancer prevention. Our ERC Proof of Concept award (BRCA-PREVENT; project number 101113534) will build the necessary consensus to take this forward.
The BRCA-ERC project has delivered significant new insight into why and how women with a BRCA mutation develop breast and ovarian cancer. We have learned that a large number of factors are altered by a germline BRCA mutation (i.e. hormonal balance, immune cells, microbiomial composition, etc.) and that these factors most likely affect the actual cells in the breast and Fallopian Tube, which eventually form breast and ovarian cancers, respectively. We now understand more about how these factors (i) contribute to cancer formation, (ii) can be modulated and tracked in non-invasive samples, and whether these insights also apply to women who develop these cancers in the absence of a BRCA mutation. The project has developed actionable clinical insights that will be explored in future clinical studies.