New Targeted therapy

The antibody–drug conjugate targeting ROR1, NBE-002, is active in high-grade serous ovarian cancer preclinical models

https://tinyurl.com/2h8jthp9

New pre-clinical research from Sydney Australia has shown a possible new therapy for ovarian cancer. The research identifies the effectiveness of inhibition of a cell membrane receptor named the receptor tyrosine kinase orphan receptor 1 (ROR1). This receptor becomes more active with ovarian cancer. Usually, ROR1 has an important part in early embryonic development and is suppressed later. In the presence of cancer increased ROR1 activity promotes cancer growth and spread.

An antibody/drug combination labelled NBE 002 has been shown to block the receptor with restriction of cell metabolism causing cell death. This early study showed about half the cell types used which had been previously grown from human ovarian cancer had increased ROR1 activity.

If the therapeutic effect can be reproduced in human clinical trials, this drug combination may be yet another example of the possible benefits of targeted cancer treatment.

Biosynthetic Taxol

New method of Taxol production has the potential to greatly reduce the cost

https://tinyurl.com/3hrrx7x4

Since 1996 Taxol, a growth suppressant has been used, together with carboplatin, a cytotoxic, in the initial chemo treatment of ovarian cancer. Originally extracted from the bark of the Pacific Yew tree, Taxol is the most expensive in terms of raw ingredients of any drug in common use.

The original process required the bark from two trees for each individual treatment killing the tree which took 100 years to mature. Subsequently it has been extracted from the harvested Yew needles at a cost of US$20000/ Kg. These too are in short supply.

Now a biosynthetic process using cloned yeast cells has been developed, thereby ensuring an adequate supply at much less cost. Hopefully this will make this essential treatment more readily available, especially in third world countries.

FDA approval

FDA Approves New Treatment for KRAS-Mutated Recurrent Low-Grade Serous Ovarian Cancer

https://tinyurl.com/4t7up48w

Low Grade Serous Ovarian Cancer (LGSOC) is rare, comprising about 5% of all ovariancancer and difficult to treat. Usually, patients with LGSOC have better survival than other forms of ovarian cancer. However, recurrence is common, eight out of ten women with LGSOC will have a recurrence of the cancer.

Recurrent LGSOC is resistant, meaning chemo used as the first-line treatment is no longer effective. Women with LGSOC are often younger than the usual ovarian cancer patients, the opportunity cost is greater when recurrence occurs.

The new targeted therapy using the antibody drug combination Avutometinib plus Defactinib is a welcome addition to LGSOC recurrence management. FDA approval for this drug follows encouraging results from the RAMP-201 clinical trial. 

The target for this new therapy is mutation of the KRAS gene with consequent damage to DNA repair. About 50% of women with LGSOC carry this mutation. This is the second FDA approval of an antibody drug combination for ovarian cancer, suggesting these drugs will have an important role in the future.

Ascites near death

Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer

https://tinyurl.com/yc4ssp65

Free fluid in the abdominal cavity is called ascites. When ascites occurs in patients with ovarian cancer it has always been recognised as an ominous sign of near death. Some understanding of why is now becoming clear. Previously it was thought that the loss of protein and general debility that occurs with ascites was responsible. This research suggests that the immune response to cancer is suppressed by fat content in the fluid.

The immune response to ovarian cancer is generated by a cellular mechanism via lymphocytes. There are two main types; T cells which are specific to the cancer cell antigen and Natural Killer (NK) cells which are non-specific and have a protective function by reducing metastasis of cancer and causing cell death.

In the presence of ascites, the immune response is suppressed. Using an experimental model with NK cells in ascitic fluid, the protection was impaired. This damage to lymphocyte function was not seen when the NK cells were placed in peritoneal fluid obtained from subjects who did not have cancer.

Further analysis of the components of ascites showed the active component causing impairment is the presence of phospho-lipids. These fats surround the NK cells, attaching to the cell membrane and preventing the normal cytotoxic action.

Sometimes size doesn’t matter

Ovarian cancer survival by residual disease following cytoreductive surgery: a nationwide study in Norway

https://tinyurl.com/59v8kavu

It is well known that one of the most important predictors of cure with ovarian cancer is the completeness of the initial surgery. This retrospective survey of 2608 women with ovarian cancer from the Norwegian Cancer registry looked at survival after surgery compared to the amount of residual tumour left behind.

Unsurprisingly those women who had apparently complete removal with no residual tumour did best. When only a small fragment of tumour remained (1-4 mm diameter) survival decreased two-fold. 

For those women with larger residual tumour the risk of death was three times greater. This level of risk was constant for all tumours larger than 4mm, with some measuring 20mm or more. Whether or not women with no residual cancer had neoadjuvant therapy did not change the chance of survival.

Risk management

Large-scale analysis to identify risk factors for ovarian cancer

https://tinyurl.com/2sfbv5nw

The UK Biobank recruited 500,000 participants during the period 2006-2010. A questionnaire and blood and urine tests together with physical exam provide base-line information looking for biomarkers of subsequent disease.

During the follow up 1441 cases of ovarian cancer were detected. Data from the initialsurvey was collected and compared retrospectively with the other 220,201 women who did not have ovarian cancer. There is a huge amount of data with 2920 items for everyone involved.  Statistical adjustment attempted to separate cause from effect.

Results from the survey supported the known association with obesity and the protective effect of hormonal contraception and childbirth. Some blood factors suggest causal effects. The authors conclude avoiding obesity and limiting the number of menstrual cycles should be promoted. To this extent, the risk of ovarian cancer may be reduced by lifestyle modification.

Adverse visual effects with Elahere

Ocular Events with Mirvetuximab Show No Impact on QoL in Ovarian Cancer

https://tinyurl.com/4zbpp67k

One of the more exciting developments in ovarian cancer treatment has been the FDA approval of an antibody drug combination called Elahere in the treatment of platinum resistant ovarian cancer. This group of patients are especially difficult to treat with a poor disease-free survival of around 4 months. Results from the MIRASOL trial suggest an increase to 6 months.

Elahere is a targeted treatment for women with ovarian cancer which demonstrate Folate Receptor 𝛂 expression (about 80%). One of the important adverse effects is loss of visual acuity. This is seen in 50% of patients, it develops within 4 to 5 weeks of commencing treatment. The cause is inflammatory change due to local action of the drug and subsequent chronic formation of microcysts in the cornea, usually this adverse effect is reversible.

This prospective study of the Quality of Life for women participants in the MIRASOL trial showed no deterioration for those women who experienced eye complications. The suggestion is that the use of Elahere extends life and does not decrease the enjoyment, meaning the benefit is greater than the risk.

Not for everyone

Risk-Reduction Surgery Benefit in Non-BRCA Ovarian Cancer

https://tinyurl.com/2mnd5c9y

Risk reduction surgery has been promoted as a means of avoiding ovarian cancer. Most studies have concentrated on removal of fallopian tubes for women who are at high risk, especially those who carry the BRCA or Lynch mutation. Some centres have extended this for all women and suggested that additional surgery, to remove the fallopian tubes, be added to other abdominal surgical procedures. Any extra intervention will increase operative risk.

This prospective study of 142 non-BRCA women at low risk, looks at the surgical specimen, and compares the evidence, of pre-cancer change with a similar control group of 388 women, who had the same surgery for risk reduction, in the presence of a hazardous mutation.

Results from the study show similar rates of normal appearance at about 95%. No evidence of pre-cancer change was found in non BRCA women whereas 3% of specimen removed from BRCA +ve women did show abnormality which might lead to subsequent ovarian cancer.

The author states that the number of cases  suggest that the procedure is commonly being performed on low-risk women, and that though the benefit is yet to be established the potential for harm is great.

Putting cancer to sleep

Scientists Discover How To Reactivate Cancer’s Dormant “Kill Switch”

https://tinyurl.com/yeytv4es

Ovarian cancer presents late. The peak incidence is at age 75 which is about 10 years later than most cancers.  Theories about why this is so suggested that there is a period of dormancy, and that the cancer becomes overt because of some unexplained change.

This research suggests that many aggressive and hard to treat cancers including ovarian cancer hijack normal protective functions that would otherwise limit cancer invasion. This protective mechanism limits cellular metabolism by blocking DNA and RNA transcription,with consequent reduction in enzyme and protein activity which would otherwise promote cancer growth.

When this process is hijacked, the protection is lost. This research suggests that the protective mechanism can be restored using synthetic RNA fragments to alter cellular metabolism.

This discovery has the potential to provide a new target for precision therapy by restoring cancer dormancy.

We’ve been looking in the wrong place

Aged and BRCA mutated stromal cells drive epithelial cell transformation

https://tinyurl.com/mxs7nz32

Ovarian cancer is different, the commonest type called serous cancer presents late with metastasis. It has been known for some time that the most likely site of origin for this cancer is the fallopian tube as a precursor abnormality of the epithelium occurs known as a serous tubal intraepithelial cancer (STIC) lesion.

These lesions have a high risk of conversion to invasive cancer with subsequent spread to ovary, meaning that ovarian cancer is always advanced at the time of presentation.

It seemed logical that STIC lesions would develop in the epithelium as a result of conversion from adaptable stem cells. This research from the US suggests that the initial change occurs in cells from the sub-epithelial layer known as the stroma. The responsible cells are called mesenchymal stem cells (MSC). Usually, these cells assist in repair of tubal tissues. Women with known increased risk of ovarian cancer such as those with the BRCA mutation have increased numbers of MSC, which are present before ovarian cancer develops.

Further understanding of the role of the fallopian tube in the cause of ovarian cancer supports the role of preventative surgery for high-risk women.

Alarming weight loss

Adipose tissue loss during neoadjuvant chemotherapy: a key prognostic factor in advanced epithelial ovarian cancer

https://tinyurl.com/55ykwrm4

Early understanding of probable poor survival may be useful in planning the management of ovarian cancer. This study looks at changes in body composition that occur after chemo prior to surgery (neoadjuvant chemo).

This prospective study looked at 53 patients with advanced ovarian cancer who received three cycles of chemo before surgery. Using CT scans before and after chemo the muscle and fat volumes were measured. All patients showed loss of muscle and fat. This was greater for those women who were obese before treatment.

Loss of muscle volume did not alter survival. Loss of fat however was a marker of poor survival especially when the fat loss was visceral within the abdomen rather than subcutaneous. This was even more marked when the weight loss was rapid. The authors suggest that nutritional support to avoid weight loss may be beneficial for ovarian cancer patients undergoing neoadjuvant chemo.

A catchy title

Leader cells promote immunosuppression to drive ovarian cancer progression in vivo

https://tinyurl.com/myym6w6v

In medical research having a catchy name for any recent findings is a good tool to promote visibility and attract funding. A recent article from the Hudson Institute demonstrates this.

Ovarian cancer presents late with metastasis having already occurred for 75% of cases at the time of diagnosis. This study looks at a feature of aggressive ovarian cancer, whereby cells at the margins of the cancer known as “Leader cells”, develop invasive outgrowths formed of keratin-14, a protein similar to skin and hair proteins.

The presence of these leader cells promotes invasion of surrounding tissues, the exact nature of why this occurs is unclear but studies in mice ovarian cancer cells show immune suppression. As a result, the normal protective immune reaction to invasion, mediated by T cell lymphocytes is inactivated.

Caution about the significance of these results is expressed by the authors who suggest this study is limited and further investigation is warranted. Despite this caution the term “Leader cells” seems to have caught the attention of the popular press.

Robots are the future

Feasibility of Robotic Surgical Approach in Peritoneal Carcinomatosis

https://tinyurl.com/4h24fnfr

Complete clearance of ovarian cancer at the time of the first surgery remains the most important factor in a cure. Sometimes with advanced cancer the distant spread to the lining of the abdomen, (peritoneal carcinomatosis), makes clearance difficult if not impossible.

New surgical techniques using robotic assistance are becoming commonplace for some surgical procedures, notably prostate cancer. Robotic surgery is safer with less morbidity and mortality, there is better visualisation of small structures and is more likely to achieve complete clearance.

This retrospective study of 16 patients, 9 of whom had ovarian surgery, showed that robotic surgery is feasible and safe. Because of the cost and due to limited resources, randomised prospective clinical trials, looking for better outcomes will be required before this technique becomes more readily available.

Indicators of survival

The impact of preoperative immuno-nutritional status on prognosis in ovarian cancer: a multi-centre real-world study

https://tinyurl.com/yeyspm3c

Two relatively simple indices of health may be obtained prior to surgery for ovarian cancer. These are the Prognostic nutritional Index (PNI) which is measured using the serum albumen and the Systemic Immune-inflammation Index (SII) calculated as a ratio of platelets to white cells in circulating blood.

This prospective survey looked at survival after surgery for women with ovarian cancer and the correlation to pre-operative health.

Results obtained from the study showed that those women with good nutritional health (high PNI) had better progress free survival and overall survival. Women whose immune status was good before surgery (high SII) had good progress free survival but slightly worse overall survival.

For those women whose nutritional and immune status were not good there was more platinum resistance and poor outcomes. Use of these markers gives important prognostic information and may alter management.

Vigil, partial FDA approval

The US FDA grants RMAT Designation to Gradalis’ Vigil for Advanced Ovarian Cancer

https://tinyurl.com/46bdjj7v

For women with ovarian cancer who don’t respond to maintenance therapy using PARP inhibitors there is new hope. The FDA has enabled fast access through the Regenerative Medicine Advanced Therapy, (RMAT) designation to a targeted treatment called Vigil, which is intended for use in patients who do not have defective DNA repair.

RMAT designation is used to speed the approval process of drugs which have shown encouraging impact on otherwise untreatable illness. Vigil is a new form of immunotherapy whereby cells from the patient’s own cancer are infected with a bacterial DNA fragment (a plasmid), and then injected back in to the donor, to promote an immune reaction similar to a vaccine.

Although this drug is only in a phase II clinical trial, early responses have shown promising improvements in progress free and overall survival.

The clinical trial titled VITAL is not recruiting currently and there are no Australian candidates. Following the FDA approval, phase III trials are expected soon.

More about survival

Role of pre-diagnostic reproductive factors on long-term (10 years or greater) survival of epithelial ovarian cancer: The Extreme study

https://tinyurl.com/3hft7xmy

It is well known that the risk of ovarian cancer is reduced by reproductive factors such as, previous pregnancy, breast feeding, and oral contraception.

This retrospective study, using information from the Danish health system, looks at survival after ovarian cancer for almost 12,000 women and sought to relate the chance of survival to previous gynaecological history.

Results from the study suggest that a previous history of childbirth, endometriosis, and infertility are protective with between 8% and 17% better survival respectively.

A history of previous hysterectomy or salpingectomy showed no survival benefit. The authors make no suggestion as to why this is so but suggest further research may be indicated.