Easy testing for defective DNA repair

Easy testing for defective DNA repair

Olaparib, durvalumab, and cyclophosphamide, and a prognostic blood signature in platinum-sensitive ovarian cancer: the randomized phase 2 SOLACE2 trial

https://tinyurl.com/dmncvndv

Defective DNA repair causes about half of all ovarian cancer. For those women who develop this cancer, and are shown to have the defect, treatment with PARP inhibitors (PARPi) will extend progress-free survival (PFS). Identifying these women is costly and unreliable. A new finding obtained from an otherwise inconclusive clinical trial may lead to a cheaper and dependable test.

The Solace 2 trial sought over a 4-year period to prove that stimulating an immune response before starting conventional therapy would improve PFS for women with advanced high grade serous ovarian cancer (HGSOC). It is well known that HGSOC depresses immunity, and this accounts for the usual bad outcomes. The trial did not achieve the key indicator, which was 36-week PFS for two-thirds of the treatment group.

An unexpected finding from the trial was the effectiveness of a blood test for defective DNA repair. This test identifies T cell checkpoints found with this defect, meaning it may soon be possible to quickly and easily determine who will benefit from PARPi therapy.

All about theranostics

Australian ovarian cancer breakthrough enters human trials

https://tinyurl.com/ye245f8f

Medicine is full of new words or neologisms. Mostly these are produced by PR agencies looking for a memorable brand name for a new drug. Sometimes the new name marks a dramatic shift in medical care. One such is theranostics a complex noun first used in 1997 to name a marriage of therapy and diagnosis.

Theranostics are combinations of antibodies and radiopharmaceuticals currently being used in the treatment of prostate cancer and carcinoid. The radiopharmaceutical of choice is lutetium-177 which is an isotope with a short half-life and an intense Beta emitter. Beta radiation is of high energy with low penetration and highly toxic, Standard systemic brachytherapy with Beta emitters is likely to kill the patient before killing the cancer.

The antibody combination targets the radiation to the cancer cell meaning only a low non-fatal dose is required. The antibody is produced to bind to a specific cancer cell antigen receptor. The theranostic is used to identify which cancers show this antigen by PET scan. Prostate cancer exhibits an antigen called PSMA. 

This study describes a new antigen found with ovarian cancer called CDCP1. A clinical trial is commencing looking at whether PET scan using a new theranostic combination is effective in identifying ovarian cancer cells which show this antigen receptor. Hopefully this will lead to more effective treatment.

Understanding Cachexia

Molecular subtypes of human skeletal muscle in cancer cachexia

https://tinyurl.com/3y3dun9v

Cachexia is a grave indicator of near death for women with ovarian cancer. It is defined as a weight loss of more than 10% or a BMI of less than 20 in patients with ovarian cancer.

Why some patients become cachexic has been a mystery, the weight loss is predominately due to decrease of muscle bulk with associated weakness and impaired mobility.

This prospective study involved next-generation genetic sequencing, using muscle biopsy tissue, obtained from 84 patients with cancer, at the time of their initial surgery. The whole muscle RNA signature (RNAome) showed two distinct subtypes. Only subtype I patients progressed to cachexia with an inflammatory reaction causing muscle wasting.

This breakthrough in understanding suggests it may be possible to predict cachexia and employ treatment to prevent it. Also, the difference in the RNAome between the two groups may suggest a metabolic pathway of disease.

Best laid plans

P-POSSUM Falls Short: Predicting Morbidity in Ovarian Cancer (OC) Cytoreductive Surgery

https://tinyurl.com/mrypfj3j

Sometimes there are disappointments in the progress of treatment of ovarian cancer. One such is the realisation that predicting the outcome of surgery is more difficult than previously thought.

P-POSSUM (Physiologic and Operative Severity Score for the Study of Mortality and Morbidity) is a commonly used indicator of perioperative risk used for general surgery patients. Based on Age, Previous History of Disease and Blood Test, P-POSSUM has been shown to be a reasonable predictor of peri-operative morbidity and mortality.

This has led to a push for this to be used in the management of ovarian cancer seeking to avoid futile surgery for those most at risk. This retrospective study looked at data from 161 patients with ovarian cancer. Peri-operative morbidity occurred in 40% of these women. The predicted risk from the POSSUM score was higher at about 60%. Similarly, the score over-estimated the mortality. However, this may not be significant as the number of deaths occurring during the review period was small.

The authors suggest that POSSUM score is not applicable to ovarian cancer, other factors may need to be included when assessing risk.

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.