Suspicions confirmed

Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data

https://tinyurl.com/wzaxy5w5

Anecdotal experience has suggested that cancer is becoming more common for younger patients. This suggests that lifestyle changes and environmental effects are causing more cancer. Using data from population-based cancer registry this study looks at the increase in cancer risk for younger cohorts.

Information is available from this huge study with data from more than 23 million patients, of whom more than 7 million developed cancers. Comparing cancer rates from 5-year birth cohorts showed that for 9 of the 34 different cancers included in the study there was an increase for patients born in the 1990 cohort compared to the 1955 cohort. The mortality has decreased, with better treatment options.

Some cancers notably smoking affected cancers such as lung cancer, show a decrease due to changed lifestyle. Ovarian cancer also is less, probably due to medical intervention with hormonal contraception.

Understanding of these changes suggest a need for modification of lifestyle and environmental factors with more research into underlying causes.

Liquid Biopsy beats CA125

The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care

https://tinyurl.com/5dy6escn

For some time, the presence of circulating tumour DNA (ctDNA) has been shown as a useful marker for many cancers including breast and colon. Testing for ctDNA is readily available by a polymerase chain reaction (PCR), the use of which became commonplace during the Covid pandemic.

Previous studies have shown ctDNA to be present in ovarian cancer. This study looks at whether using ctDNA liquid biopsy improves the management of the cancer, by confirming adequate surgery and earlier detection of recurrence.

Currently the standard marker of active disease is the cancer antigen CA125. There are problems with this in that there is a significant time lag, with persisting elevation of test scores for CA125 after treatment, and delay in a rise to mark recurrence.

ctDNA does clear rapidly from the circulation after complete clearance of cancer, making it a good indicator of adequate surgery, which remains the most significant factor for long survival. Also, in this small group of women (22), ctDNA increase after recurrence was detected several months earlier than CA125 elevation or changes in imaging.

There is a logistic issue due to cost and access, but the use of ctDNA liquid biopsy does offer some promise of improved management for ovarian cancer.

Is there a “gut feeling” for OC?

Ovarian cancer symptoms in pre-clinical invasive epithelial ovarian cancer – An exploratory analysis nested within the UK Collaborative Trial of Ovarian Cancer Screening 

https://tinyurl.com/2nj7cv48

Ovarian cancer is hard to diagnose, no screening test has so far been shown to be effective. Because of this difficulty women are advised to look out for subtle changes thought to be predictors of later disease. These include bowel symptoms such as bloating, dyspepsia and altered bowel habit.

It seems that this advice is intuitive rather than objective, this study aims to use the mass of data from the UKCTOCS trial to determine the importance of such advice.

UKCTOCS was a huge trial over 15 years involving more than 200000 women which ultimately failed to show any increase in survival from ovarian cancer when an array of screening tests was used. As part of the information sought at commencement the women were asked about bowel symptoms. 

Of the 202 women who were actively screened and developed ovarian cancer, 35% had previously described bowel symptoms. For the non-screened 874 women who developed ovarian cancer, only 9% had previously described bowel symptoms.

It seems that once again there is no accurate discriminator for ovarian cancer outside the known high-risk groups. Some caution when interpreting these results should be exercised,as this is use of data for a purpose other than originally intended.

Is there a reason for BRCA?

Conditional loss of Brca1 in oocytes causes reduced litter size, ovarian reserve depletion and impaired oocyte in vitro maturation with advanced reproductive age in mice

https://tinyurl.com/5cdrru74

Darwin’s theory of evolution includes the concept that a mutation persists because of biological advantage. Meaning that there must be some benefit for women who carry the BRCA mutation.

This fundamental research, using mice who have BRCA knockout (mutation), looked at the fertility and fecundity for these mice compared to non BRCA affected mice. No change in fertility was observed with normal follicle production and fertile lifespan.

However, the size of the litter with fewer infant mice was shown to be significantly smaller for mice which are BRCA positive.

This finding suggests a possible advantage, fewer offspring may mean better maternal care and more likely survival. 

Anti-ageing not all good

Common drug could extend women's fertility by as much as 5 years

https://tinyurl.com/ycyzc6ej

There is much research currently looking at anti-ageing drugs. One such is Rapamycin; this is an immunosuppressant drug currently used to prevent transplant rejection. There is experimental evidence that Rapamycin extends the lifecycle of mice and fruit flies. This has led to a trial using Rapamycin to extend ovarian function.

Results from the study suggest that fertility could be prolonged by up to 5 years. 

This raises the important question as to whether the risk for ovarian cancer will be increased for these women. This risk increases in proportion to the number of menstrual cycles.Ovarian cancer incidence has been decreasing as a side effect of hormonal contraception, which decreases the number of menstrual cycles.

As is often the case, the benefits of one course of action may be offset by unexpected consequences. It seems wise to proceed with caution.

Surprise benefit

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: Lower rates for 5 years post chemotherapy

https://tinyurl.com/5fm8d9um

For women who have had successful treatment of ovarian cancer it may seem logical to undergo risk reduction surgery to prevent breast cancer as a second primary disease, especially women who carry the BRCA mutation. This review suggests that such surgery may not be urgent due to associated benefits from current cancer therapy.

Retrospective analysis of the incidence of breast cancer after ovarian cancer was collected for women from the UK who had shown the presence of BRCA mutation and compared to a control group known to be BRCA positive but without ovarian cancer.

Results from the survey showed that in the 10- year period following diagnosis of ovarian cancer there is a lower likelihood of breast cancer, this is more for BRCA1 mutations that BRCA2. It is speculated that this reduction is a beneficial side effect of chemotherapy for ovarian cancer. Those women who have early- stage ovarian cancer who do not receive chemo show no similar reduction of breast cancer risk.

Understanding HRD

Limitations of homologous recombination status testing and poly (ADP-ribose) polymerase inhibitor treatment in the current management of ovarian cancer

https://tinyurl.com/ca67pusw

Recognition of the importance of defective DNA repair (DDR) as the cause for most ovarian cancer has radically changed the prospects for survival. Initially demonstrated as the basis for hereditary breast and ovarian cancer through the BRCA genetic mutation, DDR is the target for personalised therapy with enzyme inhibition using PARPi.

It is now realised that DDR is much more common and the basic defect is described as homologous recombination deficiency (HRD), which is not confined to the BRCA mutation. It is possible to test directly for HRD and this has increased the number of women who have been assigned personalised therapy.

However, there are problems; not all HRD women respond to PARPi, many develop resistance to the drug and it is unclear whether overall survival is improved. 

Partly this is due to the inaccuracies of HRD testing, the current test produces a score for homologous proficiency (HRP). It seems that HRP is complex with partial genetic penetration. There is more to learn about HRD.

What reduces OC risk?

Prospective analysis of circulating biomarkers and ovarian cancer risk in the UK Biobank

https://tinyurl.com/4p825ens

As an interesting variation of the use of biomarkers in the prediction of ovarian cancer, this article looks at the serum biomarkers which make ovarian cancer less likely.

The data for this analysis is taken from the UK Biobank. This is a remarkable source of information. Established in 2013, there are 500,000 participants in the UK, who underwent genetic and phenotypic testing, looking for strategies to reduce cancer and other diseases.

For this study, the presence of 20 biomarkers was compared to the risk of later development of ovarian cancer for more than 230,000 women. From the analysis it is shown that high levels of three of these markers (IGF-1, HbA1-c, and alanine aminotransferase) are protective in that the incidence of ovarian cancer is reduced for these women.

Once again, the value of the Biobank is demonstrated. The foresight and preparedness to allocate resources to this valuable project is commendable and will show valuable insight into disease as the years go by.

Basic, better, best

Accuracy of ultrasound, magnetic resonance imaging and

intraoperative frozen section in the diagnosis of ovarian

tumors: data from a London tertiary centre

https://tinyurl.com/4f74v2sa

Sometimes it can be difficult to differentiate between benign and malignant masses found in the ovary. For best management of ovarian tumors, it is crucial to identify cancer before surgery so that the correct technique can be used.

This study looked at 156 ovarian masses which were surgically removed. The final diagnosis, obtained by pathological examination was compared to the pre-operative diagnosis obtained by ultrasound MRI or intraoperative frozen section.

Results from the study showed that frozen section was the best at determining the presence of borderline and malignant tumors. Ultrasound and MRI have high specificity at diagnosing benign tumors but both these modalities have low predictive values when diagnosing borderline or malignant pathology.

The inference from this study is that pre-operative diagnosis is unreliable and that frozen section tissue analysis is required for best management.

Predicting blood transfusion needs

A pre-operative scoring model to estimate the risk of blood transfusion over an ovarian cancer debulking surgery (BLOODS score)

https://tinyurl.com/y37f76dh

Surgical procedures required for the initial treatment of ovarian cancer are complex and lengthy, frequently involving blood loss. Meaning transfusion of donated blood is necessary. Previous studies have shown that blood transfusion occurs in 40 –70% of initial ovarian cancer debulking surgical procedures.

Blood transfusion is not without hazard. Those patients who require blood have increased risk of infection, altered immunity, and higher mortality, and morbidity. This article tests a scoring system which can assist by identifying patients likely to require transfusion prior to surgery. With this knowledge, it may be possible to reduce the need for transfusion by the use of blood-saving techniques.

The score is calculated using serum levels of CA125, albumen and hemoglobin, with clinical assessment of tumour size and spread. Retrospective assessment showed that the score predicts transfusion in three quarters of women who will require it as part of the operative clearance of ovarian cancer.

Why is ovarian cancer different?

Unlocking ovarian cancer heterogeneity: advancing immunotherapy through single-cell transcriptomics

https://tinyurl.com/2vpf36vp

Gradually the reasons why ovarian cancer is such a difficult challenge to treat, with high mortality, are becoming clear. This article uses new technology; single cell RNA sequencing to show the variation in the immune features of the individual cells, which make up ovarian cancer.

It is well known that ovarian cancer has great capacity to resist immunological challenge. Tumour micro-environments exist with protective features involving white cells and suppressor cells which enable cancer survival and progression.

Single cell sequencing reveals targets for new treatment such as check-point blockade, (which is important with mis-match DNA repair). Also, the new information may identify those women who will have a less effective response to standard treatment.

No longer number 1

Disparities in ovarian and uterine cancer in relation to the development of novel therapeutics. 

https://tinyurl.com/249mzrma

Ovarian cancer has always been shown to be the gynaecological cancer most likely to cause death. With the onset of targeted therapy, this no longer appears to be the case. As this article shows it is now more likely that women in the US will die of uterine cancer.

The number of deaths from ovarian and uterine cancer were compared for the periods 2001-2019, and 2015-2024, with estimated mortality for the latter period. During this time ovarian cancer deaths decreased by 1.1% per annum, and uterine cancer deaths increased by 3%.

Total numbers of deaths per annum for ovarian cancer at about 12750, are less in 2024 than for uterine cancer, being 13250. This is a reversal of previous ratios of 1.4 to 1. 

It is speculated that this change is due to improved treatment for ovarian cancer. New targets for personalised treatment have led to much interest by pharmaceutical companies in developing potentially highly profitable new treatments. Clinical trials of treatment of ovarian cancer are four times the number of those for uterine cancer. Uterine cancer is common for black women. This too is a thought to be a factor for the disparity in clinical trials.

The Viking Gene

Two founder variants account for 90% of pathogenic BRCA alleles in Orkney and Shetland

https://tinyurl.com/54pbt2jh

For most women, the chance of carrying the BRCA gene mutation is 1:400. In certain populations, notably the Ashkenazi Jews, Scandinavians from Norway, and the Shetlanders this risk increases to 1:40, making breast, ovarian and other cancers ten times more likely.

With next generation gene sequencing, it is now possible to identify variants of the BRCA genes which are responsible for this increased risk. Using genealogy, the origins of the mutations can be traced to a founder variant. 

Founder effect is increased when populations are small, with in-breeding. In Norway this followed the ravages of the bubonic plague, for the Ashkenazi the outside stimulus was the destruction of Jerusalem. Recent research has identified the founder family in the Shetlands as settlers on the island of Whalsay before 1750. Knowing the BRCA variant means that whole of population screening can be done more cheaply.

Too much of a good thing?

Cost-effectiveness of BRCA1 testing at time of obstetrical prenatal carrier screening for cancer prevention

https://tinyurl.com/5hb76d25

Pre-natal testing has become normal for all pregnant women in first world countries. With the availability of cheaper genetic testing, it may be possible to detect potentially lethal genetic mutations for mothers as well as the infant.

BRCA1/2 mutations are found in 1 in 400 women, these mutations increase the risk of breast, ovarian and other cancers. Early intervention has proved effective for prevention of cancer development for these women.

This study looks at the theoretical cost versus the benefit of doing prenatal testing and subsequent risk reduction. Retrospective analysis of almost 1.5 million women who had genetic screening for obstetric care suggested that, if BRCA1/2 and other autosomal dominant genetic mutations were included in the screen, there would be significant reduction in cancer.

However, whether the benefit of early knowledge of potential risk outweighs the adverse effects of increased anxiety, problems with employment and insurance, together with the reduced quality of life is not addressed. There is a cost-benefit advantage in terms of healthcare costs but there is a bigger picture.