At AstraZeneca our aim is to help improve the outcomes of breast cancer patients with the ambition to one day eliminate cancer as a cause of death. Throughout our history, our innovative science has led to potential practice-changing medicines for patients with breast cancer, and although we have come so far, there is still much to be done. We are committed to furthering our research to redefine the breast cancer treatment paradigm.皇冠注册平台
Breast cancer remains the most common cancer in women around the world1 and is the leading cause of cancer death in women.2 Men are susceptible to breast cancer, although at a far lower rate than women.3 It can begin in various parts of the organ, including the ducts, the lobules (which make milk), or the tissue in between.4皇冠注册平台
Breast cancer care has transformed over the last 50 years5皇冠注册平台
The introduction of mastectomy (a surgery to remove the entire breast6) and chemotherapy into clinical practice, as well as advancements in screening and diagnosis, namely mammography, and increased disease awareness have significantly improved the survival of people living with breast cancer.4,7皇冠注册平台
With progress in molecular biology, systems biology and genome sciences in recent years, we have expanded our understanding of breast cancer at the cellular, molecular and genomic levels.4皇冠注册平台
Today we can classify and help to treat those living with breast cancer by their hormone receptor or HER2 expression status, as well as whether they have a BRCA mutation. But as our understanding of the different factors fuelling breast cancer grows, so will our ability to develop potential medicines for new subtypes of patients.
Breast cancer classification – hormone receptors皇冠注册官网地址
Hormones are the driving factor in the development of breast tissue, so it’s no surprise they also play a critical role in the development of cancerous tissue in the breasts as well - in fact, their role in tumour formation has been well documented for over a century.8 The growth and proliferation of female breast tissue occurs during puberty when hormonal stimulation triggers cellular differentiation. The changes in puberty are heavily influenced by the steroid hormones, oestrogen9 and progesterone, which act as the ‘master regulators’ of the development of regular functions of the breasts.10皇冠注册平台
The two steroid hormones bind to cellular receptors and stimulate growth. Unfortunately, this exact mechanism is exploited by tumour cells which also use oestrogen and progesterone to fuel their growth.11皇冠注册平台
The presence of oestrogen receptors (ER) and/or progesterone receptors (PR) on tumour cells is used as one of the main classification methods of breast cancer. To be labelled as hormone receptor (HR)-positive, over 1% of breast cancer cells must express ER, or both.12 The cancer is labelled as hormone receptor (HR)-negative when less than 1% possess these receptors (if any receptors at all) and it is unlikely the cause of tumour growth.13皇冠注册平台
The role of hormones in breast cancer has been well understood for some time, and as a result some of the first medicines designed specifically for breast cancer were hormone therapies. 皇冠注册平台
Oestrogen receptors are far more prevalent than progesterone receptors in breast cancer, with approximately 80% of all breast cancers being hormone-dependent and oestrogen receptor-positive (ER+).14 Cases of tumours being oestrogen receptor-negative/progesterone receptor-positive (ER-/PR+) are extremely rare15 and, therefore, treatments often target pathways involving oestrogen – these are often called endocrine inhibitors.皇冠注册平台
The role in guiding treatment opinions: Aromatase inhibitors (AIs), for example, prevent oestrogen from being produced by certain tissues (other than the ovaries), while other therapies known as selective oestrogen receptor modulators (SERMs) compete with oestrogen to bind to the receptor, thereby blocking the effects of oestrogen.16皇冠注册平台
Another method of targeting HR+ breast cancer is to selectively degrade the oestrogen receptor with the use of selective oestrogen receptor degraders (SERDs).17 By degrading the oestrogen receptor, the ER signalling pathway is broken and the cancer cells ability to use oestrogen is snatched away. SERDs are often used in metastatic disease18 - where the cancer has spread to other parts of the body - and are increasingly used in combinations with other agents to potentially overcome resistance to endocrine therapies.19,20皇冠注册平台
Breast cancer classification – HER2 receptors皇冠注册官网地址
In the early 1980s, the human epidermal growth factor 2 (HER2) gene, which helps maintain a healthy cell lifecycle, was found to fuel excessive cancer cell growth and proliferation in breast cancer cells when there is overexpression of the HER2 gene or protein.21皇冠注册平台
High levels of HER2 protein expression is found in approximately 20% of breast cancers and is associated with aggressive disease, high recurrence rate, and increased mortality.22皇冠注册平台
The role in guiding treatment options: Although traditionally HER2+ breast cancer is associated with poor prognosis23, this has improved meaningfully as monoclonal anti-HER2 antibodies, tyrosine kinase inhibitors and antibody-drug conjugates (ADCs) have been developed to target the oncogenic driver.24皇冠注册平台
ADCs consist of two cancer-fighting medicines in one, a cytotoxic agent, also known as chemotherapy or the “payload”, and a monoclonal antibody (that binds to a specific target expressed on cancer cells) joined together by a linker. This enables the highly targeted delivery of a cytotoxic agent, which is known for having poor specificity towards cancer cells, directly into the cancer cell thereby potentially sparing normal cells.25 To learn more about ADCs, click here皇冠注册平台
Breast cancer classification – Triple-Negative Breast Cancer (TNBC)皇冠注册官网地址
Triple-negative breast cancers (TNBC) do not express oestrogen receptors, progesterone receptors and do not have high levels of HER2 overexpression, so they are considered ‘negative’ for all three. TNBC accounts for 10-15% of all breast cancers and is more common in women under 40. This specific form of breast cancer is known to be particularly aggressive and fast growing, with a high risk of metastasis and, unfortunately, is more likely to recur after treatment than other breast cancers.26,27皇冠注册平台
The role in guiding treatment options: The number of treatment options available for TNBC is significantly less than that of other forms of breast cancer due to the lack of known actionable biomarker targets. As with most breast cancers, if the disease has not yet metastasised, surgery is usually employed with chemotherapy used to either shrink the tumour before surgery or reduce the chance of the cancer coming back following surgery. In some circumstances, women with TNBC may also be eligible for immunotherapy where the body’s own immune system is harnessed to fight the cancer.26 皇冠注册平台
Breast cancer classification – BRCA mutations皇冠注册官网地址
Developments within genomics identified further biomarkers which can be actioned to target breast cancer, specifically, the two BReast CAncer susceptibility (BRCA) genes – BRCA1 and BRCA2.28皇冠注册平台
The two BRCA genes are considered ‘tumour suppressors’ and repair damage caused to our DNA in a process known as the DNA Damage Response (DDR), specifically in homologous recombination repair (HRR), which is just one of the pathways to do so. It’s worth noting that also part of DDR, a family of enzymes known as PARPs (Poly(ADP-Ribose) Polymerases) helps to repair damage through another pathway.29,30皇冠注册平台
When the BRCA genes are mutated, they cannot perform their function and the risk of developing cancer increases.31 On average, a woman with a BRCA1 or BRCA2 gene mutation has up to a 7 in 10 chance of acquiring breast cancer by age 80.32皇冠注册平台
The role in guiding treatment options: At a cellular level, mutated BRCA genes lead to dysfunctional HRR pathways and to survive, the cell must rely on other pathways. This is what can be exploited through targeted therapy. PARP inhibitors trap the PARP enzyme and prevent single-stranded DNA breaks from being repaired. This leads to increases in double-stranded DNA breaks, which cannot be repaired by the dysfunctional HRR pathway. The cell, then must rely on a back-up pathway that is less accurate and prone to error at which point the level of DNA damage goes beyond the manageable limit and leads to cancer cell death.33皇冠注册平台
AstraZeneca is committed to investigating the potential of DDR inhibition in breast cancer. To learn more about DDR, including other molecules involved and how inhibition of DDR pathways can results in a targeted treatment approach, click here皇冠注册平台
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Veeva ID: Z4-24315
Date of Preparation: 14/05/2020
Date of Expiry: 14/05/2022