Augmenting our commitment in ovarian cancer
Ovarian cancer is a devastating disease which affects the primary reproductive organs for females. At birth the ovaries are rendered as body tissue, until very sophisticatedly, once a female reaches puberty and matures physically, so do her ovaries1,2
Despite advances in treatment, ovarian cancer is one of the most common female cancers3 and the eighth most common cause of death from cancer in women worldwide.4 The goals of front-line therapy have always been to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission - yet currently 70% of patients relapse within three years of initial treatment.5,6,7,8
These statistics show there is still much to be done for women with ovarian cancer and that there needs to be a clear and accessible understanding of the latest scientific advancements and novel therapies. At AstraZeneca we have focused our attention in this area. Our aim is to help improve the outcomes of these patients and our ambition is to one day eliminate cancer as a cause of death.
The functions of the ovaries – small but powerful
To understand ovarian cancer, we must first understand the evolving role of the ovaries. One function only starts at puberty; the ovaries secrete reproductive hormones, the most commonly known being oestrogen and progesterone, to drive the reproductive cycle and develop physical female characteristics. When a female goes through menopause, usually at the age of 45-55 years, the ovaries stop producing as much oestrogen and no longer release an egg each month1,9 – the menstrual cycle stops.
The amount of hormone secreted therefore changes not only throughout the menstrual cycle but also across a lifespan. There is also disparity in ovarian cancer across the ages; although younger women can develop ovarian cancer, it usually affects women who have reached menopause5 with almost 80% of diagnoses being women aged 50 and above.5
Why is the survival rate still so low?
There’s a reassuring link between early diagnosis of ovarian cancer and improved survival.10,11,12,13 Cancer progresses through four stages of development, from early (stages 1-2) to late (stages 3-4) and once it has become ‘advanced’, it may have spread from the ovaries to other parts of the body and can be more challenging to control.8,9,10,11
Up to four out of five women are diagnosed once the disease has already spread and chances of survival are greatly reduced.14,13 Despite this clear correlation between early diagnosis and survival, most ovarian cancers are diagnosed at a late stage15 – but why?
Part of the complexity comes from recognising early symptoms in order to diagnose the cancer at an early stage. Symptoms are non-specific, meaning they can often go unnoticed or may be misdiagnosed for another illness until the cancer is advanced.16 It is important to remember that the four most common symptoms, listed here, may also not indicate the presence of cancer.
Another reason is that unlike other cancers, there is still no reliable and effective screening method for ovarian cancer,2,17 further delaying the ability to diagnose. It is known that certain lifestyle18 and medical factors do indicate an increased risk of developing ovarian cancer which go beyond age, such as a lack of parity, endometriosis or a family history of ovarian, breast, or colorectal cancer.3,15,19 Beyond physical characteristics and lifestyle factors, a woman’s genetic makeup can also influence her risk of developing ovarian cancer…
Genetic pathways and gene mutations - have you HRD about them?
Every cell in the body suffers from DNA damage and undergoes a repair process in order to function normally20 .The Homologous Repair (HRR) pathway is just one genetic pathway which produces proteins, such as BRCA1/2, among others, to carry out this repair process via double-stranded breaks. PARPs (poly(ADP-Ribose) Polymerases) are an example of a family of enzymes vital to another genetic pathway, to repair single-stranded DNA breaks.21,22 This DNA damage response (DDR) shines a light on the connection between gene mutation and ovarian cancer.
HRD stands for Homologous Recombination Deficiency, a lack of functional components in one or more of the DNA repair pathways and a common trait of cancer cells, which have a high genetic mutation rate. One example is BRCA. Both men and women possess BRCA1 and BRCA2 proteins which, when functioning normally, act as tumour suppressors.23 Their role within the HRD pathway is to repair cell damage and prevent them from growing and dividing too quickly – mutated BRCA genes result in abnormal cells which grow uncontrollably24 and are just one of many HRDs. To find out more about BRCA within cancer watch this animation.
You can find out more about the DDR, HRD and other molecules involved here.
What is the importance of testing at diagnosis?
Genetic testing allows both clinicians and patients to make an informed decision when it comes to the treatment they receive. Conducting testing prior to or at the point of diagnosis can be important in improving patient care and enabling access to certain targeted therapies.25 By understanding the heritability of a woman’s cancer (if the mutation she possesses can be inherited) a patient’s family can also understand their risk of developing the disease – understanding the full picture has important implications for cancer risk assessment and prevention among relatives.26
What does this mean for treatment?
It’s one thing to know the link between genetic mutations and cancer development, another to leverage the science and target genetic vulnerability in order to optimise treatment. Targeted therapy for advanced ovarian cancer hinges on understanding the repair pathways and exploiting HRD by targeting PARPs. By inhibiting PARPs, the cells can’t repair single-stranded DNA breaks through its normal way and must rely on other pathways (such as HRR) to do so. Because cancer cells have HRD there are already fewer functional pathways; for BRCA mutations, there are fewer HRR pathways. This means cellular damage goes beyond the point of repair and results in cell death. Thus, the growth of abnormal cells is prevented.18
Our understanding of how to exploit HRD is evolving. We will continue our research in this pathway to further our understanding of how treatment options and combinations can achieve the best possible outcome.
Treatment falls into active and maintenance therapy. Active treatment includes surgery, chemotherapy and radiotherapy and maintenance therapy typically follows one round of active treatment. When a woman with ovarian cancer is in remission, she may have no treatment or otherwise undergo maintenance therapy to control the cancer. 27,28 Age may influence such treatment options.29
As leading pioneers, AstraZeneca has a portfolio of approved and potential treatment for advanced ovarian cancer including in newly diagnosed patients. Through our research, we have made progress in increasing the time that women can live without disease progression and improving quality of life. Our approach is based on using ground-breaking science to further our understanding of targeted therapy within ovarian cancer, focusing on patients with HRD and transferring our learnings to the wider patient population and paving the way to achieve the best possible outcomes for progression-free and overall survival.
Although progress has been made to understand the disease and novel therapies, there is still a very long way to go to expose the threat of ovarian cancer and help save more lives. Improvements in earlier diagnosis and accelerated access to the best available diagnostic testing and medicines are achievable goals which could help save countless lives.
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Veeva ID: Z4-24314
Date of Preparation: 14/05/2020