Who misses out on best care?

Barriers and Breakthroughs in Precision Oncology: A National Registry Study of BRCA Testing and PARP Inhibitor Uptake in Women from the National Gynae-Oncology Registry (NGOR)

https://tinyurl.com/2dw5xwdj

Australia is a wealthy nation with universal health care. Despite this some women with ovarian cancer do not receive best care. This prospective study using the National Gynae-Oncology Registry (NGOR), looks at the extent of genetic testing of the BRCA variant and the subsequent chance of PARP inhibitor (PARPi) therapy.

Survival for women with ovarian cancer has been significantly improved with the introduction of PARPi. This treatment of defective DNA repair is recommended for the approximately 50% of women, who demonstrate this on genetic or biomarker testing. Data from the NGOR show a disparity in testing, with older women and women from regional communities being less likely to be tested.

About 70% of women with ovarian cancer in Australia have genetic testing, which is good by international standards. However, for women aged 80 or more the likelihood of them having genetic testing is reduced to half that of younger patients. Living in a non-metropolitan location (about 1/3rd of the group) reduced the testing rate also, to about 60%.

Of women likely to benefit from PARPi, about half start therapy. This outcome is similar in other countries such as the US. Why this is so is unclear, other factors may be important, with women of higher socio-economic status being more likely to progress to PARPi. The authors suggest the findings indicate a need for better management of ovarian cancer.

Childhood obesity and OC

Association between childhood adiposity and gynaecologic cancers: a mendelian randomisation analysis

https://tinyurl.com/mr2nah45

Obesity is a major health problem throughout the developed world. Previous studies have shown increased risks of cancer associated with obesity and being obese means worse survival for those affected.

Determining the level of risk is difficult because of multiple other factors which may mask the effect. This study using the UK genome-wide association study data, sought to determine the association between obesity for girls aged 10 or less with later development of gynaecological cancers of the ovary, endometrium, and cervix. This was achieved by a process known as mendelian randomisation which seeks to use genetic information in a non-biased randomised way, like an RCT.

Findings from the data showed increased risk of ovarian and endometrial cancer but not for cervical cancer. The latter finding is not surprising in that cervical cancer has been shown to be strongly associated with human papilloma virus infection.

The risk of developing ovarian cancer was increased by about 20% for those women who had been obese at the age of 10 or younger. It remains uncertain as to why this is so. However, childhood obesity is associated with early puberty and more lifetime menstrual cycles. Also, obesity causes inflammation. Both these factors are known to increase ovarian cancer risk.

Natural selection causing drug resistance

Tracking clonal evolution during treatment in ovarian cancer using cell-free DNA

https://tinyurl.com/2xtv64nx

Drug resistance is the major cause of death from ovarian cancer. Why this occurs is problematic and varies with individuals. This study looks at the evolving genetic mutations which cause previously effective chemo to lose its ability to control the cancer.

Using new sequence genetic profiling of circulating tumour DNA, this prospective study followed the course of disease for 18 women with ovarian cancer from diagnosis to recurrence. The main finding was that the genetic clones which disabled the chemo response were present at diagnosis for all these women. This suggests that evolutional preselection is occurring, whereby the environment of chemo promotes the increase in effectiveness of harmful genetic clones.

The authors suggest that understanding this evolutionary effect should lead to a change in management, alter the environment, and prevent the preselection. It seems that drug resistance is due to selective expansion of a small set of genetic clones with reduction of normal clone diversity. Early detection would allow personalisation of chemotherapy.

Recurrent OC subtypes

Myeloid cell networks govern re-establishment of original immune landscapes in recurrent ovarian cancer

https://tinyurl.com/47mcxyde

Women unfortunate enough to develop a recurrence of ovarian cancer show a range of responses to repeat chemo. This study looks at the immune response to the cancer and the survival outcomes.

About half of these women show the presence of tumour infiltrating lymphocytes, (TIL), suggesting an active cell-mediated immune response. This is associated with better survival. Most of those women also display defective DNA repair with Homologous Recombination Deficiency (HRD). The immune response is stimulated by increased antigens such as PD-1, which suggest that immunotherapy with immune checkpoint inhibitors could be of benefit. However, in practice this has not seen to be true.

To understand why this is the case the authors reviewed the immune status of abut 600 patients with ovarian cancer using digital pathology. They subdivided the immune response into 4 groups from high to low.

In the presence of HRD, cell-mediated immunity is increased with inflammation. When treated with chemo and PARP inhibitors, prostaglandin E prevents TIL activity by cell death called ferroptosis. Using a mouse model the researchers were able to prevent this using ant-inflammatories and restore the immune response.

New knowledge about OC

Kinesin superfamily proteins in ovarian cancer: from molecular mechanisms to clinical applications

https://tinyurl.com/3d9f6z4v

Understanding the cellular changes that occur in ovarian cancer is essential for developing a cure. This review examines the action of microtubule motor proteins, which are crucial for controlling cell division and maintaining normal cell function.

In ovarian cancer, one of these motor proteins, called Kinesin, is disrupted. This disruption leads to uncontrolled cell division, metastasis, and chemoresistance.

The review highlights that increased intracellular amounts of Kinesin-like proteins are associated with a more aggressive clinical course and a lower survival rate for women with ovarian cancer. The authors suggest that this change in microtubular activity could be a valuable target for precision therapy.

Better informed consent needed

Navigating dual risks: Ovarian cancer prevention and cardiovascular health in patients with hereditary cancer syndromes

https://tinyurl.com/3z46f2tp

Premature menopause is a health hazard. It has long-term implications for the quality of life and health including adverse effects on cardiovascular well-being.

For women with inherited genetic mutations such as BRCA1&2 this means a dilemma. They have a choice of reducing the risk of ovarian cancer by surgical resection of Fallopian tubes and ovaries but need to understand the possible long-term adverse effects.

This review article shows the benefits of risk reduction surgery with a decreased risk of ovarian cancer of up to 96%. After surgery there is an immediate menopause. This has been shown to significantly increase the likelihood of cardiovascular disease which is the leading cause of death for women. The risk has been shown to be 2 to 3 times greater when compared to women who experience a normal menopause at the usual age.

Other side effects of premature menopause such as osteoporosis, dementia, and loss of libido are well known. Cardiovascular adverse effect does not have the same prominence and has only recently been acknowledged by the American College of Cardiology as a “risk enhancing factor”. This lack of understanding has resulted in poor informed consent, with many women not being told of the risk before surgery.

Ethnic disparity of care

Homologous recombination deficiency and survival in ovarian high-grade serous carcinoma by self-reported race

https://tinyurl.com/5e7mf9cb

The benefits of personalised chemo for women with ovarian cancer are obvious. However, this benefit is not being applied equally to all ethnic groups, with black women being less likely to have genetic testing and personalised chemo using PARP inhibitors.

Initially used for women with the BRCA mutation, PARP inhibitors are effective in improving survival for all women who have the metabolic defect of Homologous Recombination Deficiency (HRD).

This study compares survival for women with HRD (about 50% of all ovarian cancer), to those without. The subgroups of HRD women were divided into self-reported race. All women with HRD have a better survival chance, white women survival is improved by 62%, black women do less well with a 32% reduction in death from ovarian cancer.

The authors suggest a difference in genetic mutation for black women, who show more variations of unknown significance, and lower rates of testing, leading to disparity of care.

It’s not just your genotype

Exploring causal relationships between brain imaging-derived phenotypes and ovarian cancer risk: a bidirectional Mendelian randomization

https://tinyurl.com/yhfkpwyb

One of the perplexing aspects of ovarian cancer is why there is individual variation between those who do have cancer and those who don’t. It would be expected that women with high risk due to genetic mutation such as BRCA2 would all eventually succumb to breast or ovarian cancer. However, many (about 20%), do not. This study suggests that brain structure and function may be part of the reason this is so.

Magnetic Resonance Imaging (MRI) is able in a non-invasive way to identify different brain shapes and anatomy. Using data from the UK Biobank study it has been possible to identify 12 distinct varieties of brain anatomy which have an influence on ovarian cancer. Further investigation suggested distinct areas of brain cortex variation, with the right medial cortex being protective, and the right pre-central gyrus being harmful.

Why this is so remains unclear, different areas of the brain have various immunological and psychological effects. Ovarian cancer is more likely for women with immune compromise or depression. There is uncertainty as to whether these changes represent cause or effect, but the findings suggest new variables in cancer study.

What women with OC want

What do Ovarian Cancer Patients expect from treatment?

https://tinyurl.com/mr3rbbxy

Increasingly medicine is being consumer driven. There is now an expectation that any course of treatment should actively involve the patient. However, this is not always the case and this survey of women with ovarian cancer shows their expectations and hopes about treatment and how the reality is different.

Using an on-line platform, (Patients Like Me) 30 women with ovarian cancer received a questionnaire seeking to determine their hopes and expectations at the beginning of their treatment and the actual experience of the process. In addition, information was sought about the impact of this experience on their quality of life.

Results from the survey showed little understanding about the nature of the disease and the side effects of treatment. Most women initially had a realistic expectation of complete cure. Only 20% of women thought they were completely cured after the first course of treatment. This expectation was little changed after subsequent treatment courses, more women after the second intervention focussed on a return to normal life and function rather than complete cure.

The impact on their quality of life was surprising: half of the women reported a positive effect with empowerment and clarity with an appreciation of family and inter-personal relationships. For those women whose experience was negative most reported isolation from work, friends and family, with loss of mobility and financial stress.

The authors suggest there is a lack of communication from care givers and that patients with ovarian cancer cope well when fully informed.

Premature menopause causes cognitive decline

Cognitive and brain health in women with early bilateral salpingo-oophorectomy: Implications for risk, resilience, and subjective cognitive decline

https://tinyurl.com/mwayffrf

Dementia and cognitive decline are twice as likely for women. It seems that oestrogen is neuro-protective and premature menopause which occurs after removal of fallopian tubes and ovaries accelerates this process.

It has been well known that dementia in the elderly has been associated with this surgical procedure. This article looks at younger women and measures the impact on their neurological status after surgery before the age of 49 by comparing the outcomes with age-matched controls and a group of BRCA positive women.

Standard testing for cognitive decline includes short-term memory tests, logical thought and depression.All participants had MRI brain imaging looking for decrease in brain volumes.

Results from the retrospective study showed loss of cognitive function for women who had early surgery when compared to both control groups. This was associated with decreased brain volumes. Many participants across all 3 groups reported subjective memory loss. Those women also had decreased brain volume especially in sub-occipital regions known to be important for cognitive function.

The results suggest a further need for full informed consent prior to possible life-changing surgery.

subjective memory loss. Those women also had decreased brain volume especially in sub-occipital regions known to be important for cognitive function.

The results suggest a further need for full informed consent prior to possible life-changing surgery.

Better use of PARP inhibitors

BRCA1 promoter methylation predicts PARPi response in ovarian cancer: insights from the KOMET study

https://tinyurl.com/556t49sr

For ovarian cancer patients who carry the BRCA mutation, the use of PARP inhibition (PARPi) has significantly improved survival. It has been noted that some women without the BRCA mutation benefit from PARPi. This has led to a push for PARPi treatment for all. However, the cost and side effects of PARPi precludes this.

As an attempt to determine which patients benefit from PARPi, additional genomic testing known as homologous recombination deficiency (HRD) analysis shows genomic instability. Use of this has shown that up to half of the women with ovarian cancer will benefit from PARPi.

HRD analysis is expensive and may be inconclusive, meaning that it’s use is restricted. In addition, some women who might benefit from PARPi do not have the typical chromosomal mutation which causes HRD but rather have an epigenetic change called promoter methylation which stimulates the BRCA gene.

Epigenetic change is potentially reversible damage to the genetic code. In this prospective study the epigenetic methylation status testing of 88 women with ovarian cancer showed an extra 19% (17 women) who would benefit from PARPi. The authors suggest that it is possible to further identify those women who should have PARPi and avoid inappropriate use.

How common is complete clearance?

Surgical and blood-based minimal residual disease in patients with ovarian cancer after frontline therapy: Clinical outcomes and translational opportunities

https://tinyurl.com/4698cc7c

In the treatment of ovarian cancer, the most important determinant of survival is the effectiveness of the initial surgical procedure. The aim is complete clearance and for about 80% of women no residual cancer can be detected either by CT scan or plasma CA 125 levels. Despite this only about 20% of women will have been cured suggesting that residual cancer is present despite evidence to the contrary.

This study shows the true rate of minimal residual disease (MRD), by measuring circulating tumour DNA (CT DNA), and by repeat “second look” laparoscopy after completion of surgery and chemo.

Findings from the study showed that of 95 patients thought to have had a complete clearance at initial surgery almost half had MRD with abnormal CT DNA or second look laparoscopy. These women had worse survival and earlier recurrent disease. The authors suggest that searching for occult MRD should be part of standard treatment to enable correct management.