Study could help recommend the best treatment for women with early-stage mucinous ovarian cancer

This is an edited version of an article reviewed by Emilie Henderson, B.Sc., and published on News-Medical.Net  Oct. 12, 2022

A global study into mucinous ovarian cancer could help oncologists recommend the best treatment for women who are diagnosed early with the condition.

By looking down a microscope for two different 'patterns of invasion' – the way that cancer cells invade ovarian tissue – oncologists can better predict which patients may have better or worse prognoses and can target treatment accordingly. The finding was reported in a paper published today in Clinical Cancer Research, a journal of the American Association for Cancer Research.

"Mucinous ovarian cancer is a rare type of ovarian cancer. It actually has more in common with gastrointestinal cancers, and can be hard to diagnose and hard to treat once it has spread beyond the ovaries," says lead author Nicki Meagher, who has just completed her PhD in the Molecular Oncology group, University of New South Wales School of Clinical Medicine.

She says that observing which of the two types of invasion patterns that the cancer cells form could help specialists decide on treatment strategies.

The two patterns of invasion are defined by the way the cancer cells organize themselves when viewed under a microscope. The infiltrative pattern of invasion associated with poorer health outcomes shows cancer cells spreading in an uneven, haphazard way through the ovarian tissue. The other pattern is known as expansile, where cells expand through tissue in a more orderly manner, and is associated with better prognoses.

Up until now, other studies had suggested that the infiltrative pattern of invasion was associated with poorer patient outcomes, but no study had large enough numbers of patients with early-stage cancer to reach statistical significance.

But the current study, that involved more than 100 researchers in Australia, UK, Canada, Asia, Europe and the US, was able to test this hypothesis in much larger numbers by examining the tissue of 604 patients. The researchers also looked for the expression of 19 genes including THBS2 and TAGLN in addition to the patterns of invasion.

Professor Susan Ramus who oversaw the global study and heads the Ovarian Tumour Tissue Analysis consortium says that guidelines on how to treat women with early-stage mucinous ovarian cancer have differed around the world due to limited data on infiltrative patterns of invasion associated with survival rates.

"For example, in some parts of the world, an infiltrative pattern was acknowledged as an important feature and determined what treatment those women receive," Professor Ramus says.

"Whereas in others, all patients are recommended for the same pathway of treatment. We hope that after this large study treatment guidelines can be aligned and that we can target treatment for women who may have these more serious indicators, even if they are diagnosed in early stages."

The researchers also noted that women with higher expression of two genes, THBS2 and TAGLN in their tumors, had poorer overall survival.

"We're hoping that this may be able to help explain some of the biology potentially down the track," says Ms Meagher.

"Another avenue could be that knowledge of expression of these genes could assist in developing targeted drugs."

The researchers are part of a wide network of experts who plan to carry out a validation study to further investigate these genomic markers as the basis for a targeted treatment strategy.

Two New Studies Help Improve the Understanding of Ovarian Cancer

 This is an edited version of an article reviewed Emilie Henderson, B.Sc., and published on News-Medical.Net  Oct. 11, 2022

Two new discoveries led by Cedars-Sinai Cancer investigators help improve the understanding of what drives the development of ovarian cancer and why some women's tumors do not respond to therapy. 

Scientists identify mutations tied to increase risk of ovarian cancer

The first study, published today in the Journal of the National Cancer Institute, identified four new regions of the human genome that harbor genetic variants or mutations that put women at an increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer.

"When it comes to ovarian cancer, prevention is how we're really going to impact mortality," said Michelle Jones, PhD, a research scientist in the Center for Bioinformatics and Functional Genomics and corresponding author of the study. "This study helps us accurately identify women who carry cancer-causing mutations, which can help physicians develop preventive strategies for these women."

To pinpoint the mutations, the team of investigators used new methods to analyze the structural variation of the genome, which is made up of 23 pairs of chromosomes where an individual's genetic code is stored.

While most research focuses on analyzing the change in the sequence of the gene, the team looked at the number of copies of the gene an individual has-;known as a copy number variant.

When the genome gets copied, structural variation can occur, and stretches of the genome can get deleted, duplicated or rearranged to another position. These changes can lead to diseases, like cancer.

The researchers collaborated with scientists at the University of Cambridge to specifically look at deletions and duplications in 13,000 women with ovarian cancer and compared them to 17,000 women without ovarian cancer from the Ovarian Cancer Association Consortium to identify copy number variants that were associated with ovarian cancer risk.

They found significant deletions and duplications in the BRCA1 gene, BRCA2 gene, and RAD51C gene, all of which are known to harbor changes in a patient's DNA sequence that increase risk for ovarian cancer. Also found: four new genes that have not been previously linked to an increased risk for ovarian cancer.

The study, which is the largest to date to evaluate the contribution of copy number variants to ovarian cancer risk, will likely lead to more accurate genetic testing for women.

"We have the technology that can pick up these deletions and duplications, but it's not always done consistently in clinical genetic testing," said Jones. "We hope these findings highlight the value of looking at copy number variants in clinical genetic testing."

Gene expression unlikely to drive chemotherapy resistance in ovarian cancer

The second study, published in the Journal of Experimental & Clinical Cancer Research, gives investigators a deeper understanding as to how ovarian tumors develop resistance to chemotherapy, which occurs in about 80% of high-grade serous ovarian cancer patients and ultimately leads to their succumbing to the disease.

Previously, researchers believed that ovarian tumors evolve after they are exposed to chemotherapy, and that they change their gene expression to adapt and survive through the treatment.

However, using whole genome sequencing, they found for the first time that this is not the case. Instead, it seems more likely that most high-grade serous ovarian tumors have the capacity to survive chemotherapy from a very early stage, said Jones, who is also the co-first author on this study.

"This study has changed our understanding of how tumors respond to chemotherapy," Jones said. "Previously it was thought that we could probably find a way to treat chemo-resistant tumors with other drugs after they have been treated with the standard therapy, but this study suggests that may not be the best approach."

"By improving our understanding as to how tumors ... survive chemotherapy, and even continue growing throughout treatment, as well as finding vulnerabilities in the tumors, will give us an opportunity to design better drugs and save the lives of women with ovarian cancer," added Gayther....

Olaparib Plus Bevacizumab Maintenance Therapy Provides OS Benefit in Advanced HRD-Positive Ovarian Cancer

  This is an edited version of an article written by Kristie L. Kahl and published in OncLive Sept. 9, 2022

Maintenance olaparib (Lynparza) plus bevacizumab (Avastin) following first-line standard-of-care treatment improved overall survival (OS) in patients with newly diagnosed advanced ovarian cancer, particularly those with homologous recombination deficiency (HRD), according to final OS results from the phase 3 PAOLA-1/ENGOT-ov25 ... trial presented at the 2022 ESMO Congress.

“These data confirm the addition of olaparib to bevacizumab as a standard of care for HRD-positive patients in this setting and the importance of precision medicine and biomarker testing to guide treatment decisions,” Isabelle L. Ray-Coquard, MD, PhD, a medical oncologist at Centre Léon Berard Université Claude Bernard in Lyon, France, said during a presentation of the data....

Rucaparib Maintenance Elicits PFS Benefit in Newly Diagnosed Ovarian Cancer

 This is an edited version of an article written by Hayley Virgil and published in OncLive Sept. 11, 2022

Rucaparib (Rubraca) maintenance therapy improved progression-free survival (PFS) vs placebo in patients with newly diagnosed ovarian cancer, according to disease risk subgroup analyses from the phase 3 ATHENA–MONO study....

The goal of the ATHENA-MONO trial was for investigators to assess the PFS of rucaparib and placebo across subgroups of patients with newly diagnosed ovarian cancer, including surgical outcomes by surgeon’s assessment and by the response to first-line chemotherapy by radiographic scans....

Rucaparib (Rubraca) maintenance therapy improved progression-free survival (PFS) vs placebo in patients with newly diagnosed ovarian cancer, according to disease risk subgroup analyses from the phase 3 ATHENA–MONO study (NCT03522246).

Niraparib Maintenance Provides Durable Long-term Remission in High-Risk Advanced Ovarian Cancer

 This is an edited version of an article written by Kristi Rosa and published in OncLive Sept. 15, 2022

Maintenance treatment with niraparib (Zejula) produced a sustained and durable progression-free survival (PFS) benefit in patients with primary advanced ovarian cancer who responded to first-line platinum-based chemotherapy, spanning biomarker subgroups, according to updated data from the phase 3 PRIMA trial....

Data presented during the 2022 ESMO Congress showed that at a median follow-up of 3.5 years, which had a data cutoff date of November 17, 2021, the median progression-free survival (PFS) with niraparib was 24.5 months per investigator assessment vs 11.2 months with placebo in the homologous recombination deficiency (HRD) population....

In the overall population (n = 733), the median investigator-assessed PFS with niraparib was 13.8 months vs 8.2 months with placebo....

Treatment with niraparib boosted the duration of PFS vs placebo across the biomarker subgroups examined. The greatest benefit was observed in those with HRD tumors that were BRCA mutated....

“Sustained benefit was observed with long-term follow-up, with hazard ratios that were consistent with the primary analysis regardless of biomarker status,” lead study author Antonio González-Martin, of Medical Oncology Department, Clinica Universidad de Navarra, and colleagues, wrote in a poster on the data. “In the HRD and homologous recombination–proficient [HRp] populations, respectively, a clinically meaningful 48% and 35% reduction of the risk of progression or death was observed.”

The randomized, double-blind, placebo-controlled, phase 3 trial enrolled patients with newly diagnosed ovarian cancer who were at high risk for recurrence following response to frontline platinum-based chemotherapy....

Niraparib Maintenance Produces Long-Term Benefit in Advanced Ovarian Cancer, Irrespective of HRD Status

 This is an edited version of an article written by Ryan Scott and published in OncLive Oct. 12, 2022

Frontline niraparib (Zejula) maintenance sustained a progression-free survival (PFS) benefit in patients with advanced ovarian cancer, according to updated data from the phase 3 PRIMA trial presented at the 2022 ESMO Congress.

Notably, investigators observed a PFS benefit in patients who received niraparib irrespective of homologous recombination–deficient (HRD) status, according to Antonio González-Martín, MD, PhD.

At a median follow-up of 3.5 years, findings showed that patients in the overall population treated with niraparib (n = 484) achieved a median PFS of 13.8 months vs 8.2 months for patients treated with placebo.... Additionally, patients with HRD tumors treated with niraparib (n = 245) experienced a median PFS of 24.5 months vs 11.2 months for those treated with placebo.

"Our data are contributing to the body of evidence that PARP inhibitors are changing the natural history of patients with HRD [ovarian cancer] in the frontline," González-Martín said. “Our data confirm the sustained benefit of [niraparib] in this setting. This is an alternative as monotherapy for the maintenance of patients with HRD tumors.”

Pembrolizumab Delivers Promising Results in Advanced Clear Cell Gynecologic Cancer

 This is an edited version of an article written by Jason Ryan and published in OncLive Oct. 17, 2022

Pembrolizumab (Keytruda) monotherapy induced durable clinical outcomes in heavily pretreated patients with clear cell gynecologic cancer (CCGC), according to findings from the phase 2 PEACOCC trial (NCT03425565).

Forty-eight patients were included in the analysis. The progression-free survival (PFS) rate was 43.8% (n = 21/48; 90% CI, 31.5%-56.6%) at 12 weeks, exceeding the established lower bound of 15%. Eighteen (37.5%) patients had progressive disease, and 6 (12.5%) progressed and died.

Translational sample analysis is ongoing. Investigators said these results justify further evaluation of pembrolizumab as the new standard of care for advanced CCGC.