New Options Now Available For Ovarian Cancer

New Options Now Available For Ovarian CancerOvarian cancer is estimated to affect more than 22,000 women each year and is the fifth leading cause of cancer deaths among women, according to American Cancer Society.

Unlike other gynecologic cancers, there are no screening tests for ovarian cancer. While some women diagnosed with ovarian cancer have elevated levels of the CA 125 protein, the associated blood test is not accurate enough for ovarian cancer screening, as many noncancerous conditions can increase the CA 125 level.

Ovarian cancer is hard to detect in its early stages due to its vague symptoms. Women may experience constipation, bloating, early satiety after eating and back pain. While ovarian cancer tends to occur in post-menopausal women, anyone can be at risk. A number of factors, including smoking, endometriosis, polycystic ovary disease and obesity, can raise a woman’s risk for the disease.

About 20 percent of all ovarian cancers are caused by a genetic mutation. The genes most likely to increase the risk of ovarian cancer are BRCA1 and BRCA2. These genes also affect a woman’s risk of breast cancer. Genetic mutations that cause Lynch syndrome, an inherited condition associated with colon cancer, also raise a woman’s risk of ovarian cancer.

Over the past two decades, there were few options to treat ovarian cancer other than surgery and chemotherapy. And recurrence of the disease was common.

“Ovarian cancer, thankfully, does respond really nicely to surgery and chemotherapy. But unfortunately, in roughly 70 percent of patients, we do see recurrence,” says Dr. Andrea Wahner Hendrickson, a Mayo Clinic oncologist.

But thanks to research by Wahner Hendrickson and her colleagues, patients now have additional – and sometimes more effective – options for treatment, including individualized medical therapy and immunotherapy.

Currently, there are more than 1,350 clinical trials for ovarian cancer, including a vaccine trial aimed at preventing recurrence.

Since not all tumors respond to every treatment, Dr. Wahner Hendrickson recommends all ovarian cancer patients undergo genetic testing to see which therapy might work best or them.

“Thanks to the innovations, I think there’s a lot of promise and hope in the treatment of ovarian cancer,” says Wahner Hendrickson.

She encourages women of all ages to see their physician if they experience abnormal signs or symptoms.

To read the full article by Albuquerque Journal, please click here.


Trabectedin Plus PLD Shows Benefit in Real-Life Ovarian Cancer Setting

Trabectedin Plus PLD Shows Benefit in Real-Life Ovarian Cancer SettingThe combination of trabectedin and pegylated liposomal doxorubicin (PLD) offered clinical benefit and was reasonably well tolerated in a real-life setting of patients with previously treated platinum-sensitive recurrent ovarian cancer, according to a new study.

“Thus far no prospective, non-interventional study with trabectedin plus PLD had been performed in a routine clinical setting, with a more diverse patient population with platinum-sensitive recurrent ovarian cancer than that recruited in clinical trials,” wrote study authors led by Ingo B. Runnebaum, MD, of Jena University Hospital in Germany. “Such an observational study can provide useful insights of the real-world toxicity, efficacy, and management of patients receiving trabectedin plus PLD.”

The OVA-YOND trial included 77 patients with platinum-sensitive recurrent ovarian cancer who had been previously treated with at least one platinum-containing regimen. Patients received a median of 6 cycles of trabectedin plus PLD; 50.6% received 6 or more cycles. The median treatment duration was 4.2 months, and 88.3% of patients were treated on an outpatient basis. The results of the analysis were published in the Journal of Cancer Research and Clinical Oncology.

Five patients (6.5%) achieved a complete response to the treatment, and another 19 patients (24.7%) achieved a partial response, for an overall response rate of 31.2% and a median duration of response of 6.25 months. Another 16 patients had disease stabilization, for a disease control rate of 52.0%.

The median progression-free survival was 6.3 months, and 77.2% of patients were free from progression at 3 months; at 6 months, that rate was 50.3%. The median time to progression was 7.3 months. The median overall survival was 16.4 months, and 58.3% of patients were alive 12 months after treatment.

Just over half of the cohort (57.1%) had at least one trabectedin-related adverse event (AE) of any grade. The most common grade 3/4 AEs included leukopenia (18.2% of patients), neutropenia (15.6%), and thrombocytopenia (9.1%).

With regard to PLD-related AEs, 63.6% of the study population experienced at least one AE of any grade. The most common grade 3/4 AEs related to PLD again included neutropenia (18.2%), leukopenia (15.6%), and thrombocytopenia (10.4%). There were no deaths attributed to drug-related AEs.

“The findings of this non-interventional, prospective real-life study consistently support that trabectedin plus PLD confers clinically meaningful long-term benefits to pretreated patients with platinum-sensitive recurrent ovarian cancer,” the authors concluded. “Large randomized trials are warranted to show that platinum-free combinations in platinum-sensitive disease may effectively allow patients’ recovery from previous platinum-associated adverse effects with similar or improved oncological outcome.”

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Scientists Identify Why Some People May Be Resistant To PARP Inhibitor Drugs

Scientists Identify Why Some People May Be Resistant To PARP Inhibitor DrugsA team of scientists from the Institute of Cancer Research in London has identified DNA mutations which makes cancer cells resistant to a new class of drugs called PARP inhibitors, used for the treatment of breast and ovarian cancers.

The research published today in Nature Communications used the CRISPR/Cas9 gene editing system to artificially make different DNA mutations in the PARP1 gene, then testing the effect of these mutations on the sensitivity of cancer cells to PARP inhibitors. These included olaparib (marketed by AstraZeneca as Lynparza), which achieved FDA approval for treating a particular type of breast cancer in January of this year after approval for some types of ovarian cancer last year and Pfizer’s talazoparib, which has shown promising results in recent clinical trials.

Lead author of the study, Dr Stephen Pettitt, Staff Scientist in Cancer Genomics at The Institute of Cancer Research, London, said: “Our study has discovered one of the reasons why resistance to PARP inhibitors such as olaparib might occur. Testing for the mutations we have identified could offer even more personalized treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib should be used.”

PARP1 is part of a family of proteins which are responsible for repairing damaged DNA. In healthy cells, this is a good thing but in cancer cells, especially with patients who have mutations in other DNA repair genes, the PARP system may actually help the cell survive. By using PARP inhibitors, this process can be blocked, leading to the death of cancer cells.

PARP inhibitors are particularly effective in people with inherited DNA mutations in BRCA genes, the hereditary disorder that means women have a much-increased risk of breast and ovarian cancers, which hit the headlines a few years ago after Angelina Jolie had a preventative mastectomy.

The researchers stress more work is needed to look for actual PARP1 mutations found in human patients rather than made artificially in the lab, but in the future, they hope that testing for these DNA mutations can help guide clinicians to prescribe the best treatment for patients.

Baroness Delyth Morgan, Chief Executive at Breast Cancer Now, which helped to fund the study, said: Resistance to breast cancer drugs is a major hurdle that we must overcome if we are to stop women dying from this devastating disease. Studies like this could help take us a step closer to an even more personalized approach to treating the disease.’

To read this full article on FORBES, please click here.

Is Adjuvant Chemo Warranted In Stage I Ovarian Clear Cell Carcinoma?

Is Adjuvant Chemo Warranted In Stage I Ovarian Clear Cell Carcinoma?In patients with stage I ovarian clear cell carcinoma, the use of adjuvant chemotherapy was associated with superior overall survival (OS), according to results of a large, retrospective cohort study.

The finding, published in Gynecologic Oncology, provides further evidence that adjuvant chemotherapy may provide a survival advantage for patients with this relatively common epithelial ovarian cancer subtype.

However, not all data to date point toward a benefit of adjuvant chemotherapy. “Its utility has yet to be established, especially for patients with stage IA disease,” wrote Dimitrios Nasioudis, MD, and his coauthors in the department of obstetrics and gynecology, Hospital of the University of Pennsylvania, Philadelphia.

In one recent large population-based study, chemotherapy was not associated with superior OS in patients with stage I disease, whereas two smaller retrospective studies suggested that chemotherapy may improve progression-free survival in that setting, noted Dr. Nasioudis and his colleagues.

Their study included data on 2,325 patients in the National Cancer Data Base diagnosed with stage I ovarian clear cell carcinoma between 2004 and 2014. That is the largest cohort of patients with stage I ovarian clear cell carcinoma with adequate staging reported to date in the medical literature, the investigators noted.

The rate of OS at 5 years was 89.2% for patients receiving adjuvant chemotherapy, versus 82.6% for those who did not (P less than .001). Furthermore, adjuvant chemotherapy was associated with improved OS after the researchers controlled for medical comorbidities, age, race, disease substage, and hospital type (hazard ratio, 0.59; 95% confidence interval, 0.45-0.78).

When the researchers looked at disease substage, women with stage IA or IB disease had superior OS with chemotherapy versus no chemotherapy, while in women with stage IC disease, there was a trend toward better OS with chemotherapy that did not reach statistical significance.

“The administration of adjuvant chemotherapy was associated with a survival benefit, even for those with stage IA disease,” the researchers wrote.

Ovarian clear cell carcinoma is the third most common subtype of epithelial ovarian carcinoma, accounting for up to 25% of new diagnoses, they said. Current U.S. and European clinical practice guidelines recommend adjuvant chemotherapy for all women with stage I disease because of a high risk of relapse associated with this subtype.

Observation could be acceptable for patients with surgical stage IA disease, in light of excellent survival rates, the Gynecologic Cancer Intergroup has suggested.

While the present study suggests a survival benefit associated with chemotherapy in stage I ovarian clear cell carcinoma, the investigators had no information on morbidity, cost, or quality-of-life impacts associated with treatment, which limit the findings.

“International collaboration, such as the creation of ovarian clear cell carcinoma registry, is greatly needed to further elucidate the optimal management of those patients,” they wrote.

Dr. Nasioudis and his coauthors had no conflicts of interest to report.

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National Survey Examines Oncologists’ Practices, Beliefs on Medical Marijuana Use

National Survey Examines Oncologists' Practices, Beliefs on Medical Marijuana UseData from a new survey show that as many as 80% of oncologists have discussed medical marijuana use with their patients. According to the authors, this is the first nationally representative survey to examine oncologists’ practices and beliefs on the subject since the implementation of state medical marijuana laws. The research was published by Braun et al in the Journal of Clinical Oncology.

“Our study shows that medical marijuana is a salient topic in cancer care today, and the majority of oncologists think it may have utility for certain patients,” said study author Ilana Braun, MD, Chief of the Division of Adult Psychosocial Oncology at the Dana-Farber Cancer Institute. “While this topic is common, however, data on medical marijuana use is less so. We need to bridge this gap so oncologists have the unbiased information they need to assist with decision-making related to medical marijuana use.”

California enacted the United States’ first medical marijuana law in 1996, and today, its use is legal in more than 30 states, almost all of which list cancer as a qualifying condition. In the 22 intervening years, however, no randomized clinical trial has investigated the utility of whole-plant medical marijuana to alleviate symptoms such as pain, insomnia, or nausea and vomiting in patients with cancer.

Many studies have explored the use of pharmaceutical cannabinoids—highly refined, quality-controlled products consisting of one or two active ingredients and available through a pharmacy. Nonpharmaceutical medical marijuana, however, is often whole-plant, containing hundreds of active ingredients, and thus cannot easily be compared to pharmaceutical cannabinoids.

Recent clinical practice guidelines from ASCO recognize knowledge gaps about medical marijuana use in oncology. The guidelines note insufficient evidence to recommend medical marijuana for the initial management of chronic pain in cancer survivors, although evidence suggests it is worthy of consideration as an adjuvant analgesic and for managing pain conditions that are difficult to treat. Evidence also remains insufficient to recommend medical marijuana for the prevention of nausea and vomiting in patients with cancer who receive chemotherapy or radiation therapy.

About the Study

Researchers mailed a survey to 400 practicing oncologists in the United States, randomly selected from a national database of board-certified medical oncologists. Of the 237 participants who responded, more than half (55%) practice in states where medical marijuana is legal.

The survey asked oncologists about their discussions with patients, recommendations they provided, and their knowledge of medical marijuana. Respondents were also asked about their views on the effectiveness of medical marijuana for cancer-related symptoms such as pain, nausea and vomiting, depression, anxiety, poor appetite, poor sleep, and general coping, as well as its risks compared with other treatments.

Key Findings

Researchers found that most oncologists surveyed had encountered questions about medical marijuana, and many expressed research and education needs to better inform the care they provide to patients with cancer. Specifically:

  • Physician discussions: 80% reported discussing medical marijuana with patients, and 78% reported these conversations were most frequently initiated by patients and their families.
  • Education: Less than 30% felt knowledgeable enough about medical marijuana to make recommendations.
  • Recommendations: Nearly half (46%) recommended medical marijuana use to patients in the past year.
  • Beliefs on potential benefit: More than two-thirds (67%) believed medical marijuana to be a helpful treatment for alleviating pain when used together with standard therapies, and a majority viewed it as presenting a lower risk than opioids for overdose death (75%) and addiction (52%). Nearly two-thirds (65%) also viewed it as equally or more effective than standard treatments for poor appetite and extreme weight loss. When evaluating its effectiveness for other conditions, however, many oncologists responded, “I do not know,” from 29% for nausea and vomiting to 45% for poor sleep.

The study showed that the following factors contributed to significant differences in oncologists’ practices regarding medical marijuana:

  • Geographic location: Oncologists practicing in the Western United States were more likely to have discussed (95%) or recommended (84%) medical marijuana, and oncologists practicing in the South were least likely (69% and 35%, respectively).
  • Type of practice: Respondents practicing outside a hospital setting were more likely to recommend medical marijuana than hospital-based oncologists (54% vs 35%).
  • Size of practice: Oncologists who saw the most patients each week were more likely to have discussed medical marijuana than those who saw the fewest patients (89% vs 70%).

Next Steps

In the article, researchers call for clinical trials to address these gaps in knowledge regarding medical marijuana use. “I think we need to carry out comparative effectiveness studies of medical marijuana to clarify its role,” said Dr. Braun. “We also need to extend our survey to other specialties and to patients with cancer.”

This study received funding from the Hans and Mavis Lopater Foundation.

To read this entire post on The ASCO Post, please click here.

Microenvironment Heterogeneity May Contribute to Lack of Immunotherapy Success in High-Grade Serous Ovarian Cancer

Microenvironment Heterogeneity May Contribute to Lack of Immunotherapy Success in High-Grade Serous Ovarian CancerINTER- AND INTRAPATIENT heterogeneity of the tumor microenvironment may explain the limited success of checkpoint blockade thus far observed in patients with advanced high-grade serous ovarian cancer, according to Paulina Cybulska, MD, MSc, of Memorial Sloan Kettering Cancer Center in New York.

Aggressive surgical debulking in combination with platinum-based chemotherapy is the mainstay of treatment for this population. These interventions allow the majority of patients to achieve full clinical remission, but almost all will have a recurrence and develop platinum-resistant disease during subsequent treatment. Although immunotherapies have emerged as an important therapeutic modality for a broad range of cancers, their effect on ovarian cancer has been modest. A key factor contributing to this therapeutic failure and drug resistance is believed to be intra- and intertumoral heterogeneity.

Dr. Cybulska and her colleagues at Memorial Sloan Kettering conducted an internal analysis of patients with recurrent primary serous ovarian cancer treated with checkpoint blockade; they found that 66% of patients experienced a “mixed response.” That is, within the same patient, some tumors shrunk, some were stable, and others grew. “This incongruity between response rate and disease control rate is quite characteristic of immunotherapies,” she said at the 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.1

Research has shown that patients with metastatic ovarian cancer exhibit heterogeneity at the genomic level even prior to the initiation of treatment. The researchers sought to find out whether this genomic heterogeneity is mirrored by similar heterogeneity in the tumor microenvironment and whether multiple, distinct tumor microenvironments exist within the same patient. Further, they wanted to examine which cells contribute to the interpatient heterogeneity.

Complete, Distinct Microenvironments 

Tumor samples were collected prospectively from eight patients undergoing primary debulking surgery for advanced-stage disease, with a median of five sites sampled per patient. The investigators performed immunofluorescent staining and quantification of CD4-positive, CD8-positive, and regulatory T cells in at least 10 tumor regions in each sample. They found that patients had marked variability in infiltrating T cells, ranging from barely detectable to highly abundant. They also found clear differences in T-cell staining between various tumor deposits from the same patient.

“This multiregional analysis shows that high-grade serous cancers are characterized by the presence of heterogeneous tumor immune microenvironments across patients, anatomic sites, and even within the same individual and tumor deposit,” she said.

From the same eight patients, Dr. Cybulska and her colleagues analyzed the transcriptome of these primary metastatic tumors to look at how samples compared to one another and to the population. They found that, overall, the immune scores of the cohort fell within the expected range based on single-site samples from The Cancer Genome Atlas. They then compared scores across patients and found that the immune score varied substantially.

“Interestingly, some patients showed a level of immune score variation between their own tumor samples comparable to the variation observed across patients at the population level, indicating that even within a single individual, complete distinct immune microenvironments can coexist at the time of diagnosis,” Dr. Cybulska said.

Overall transcriptome analysis showed largely patient-specific, rather than site-specific, transcriptome-driven structure: Although each patient displayed intersite heterogeneity in gene expression, in most cases, all sites within a patient were more similar to each other than to any site from another patient, she reported.

Next they performed single-sample gene set enrichment analysis and found that cancer-, immune-, and stroma-associated gene signatures could explain most of the gene set expression variation. Finally, they investigated which hallmark gene sets were differentially expressed between pure and impure tumors. As expected, immunostromal signatures were more highly enriched in infiltrated tumors.

“These data demonstrate that even before exposure to systemic therapy, a subset of high-grade serous ovarian cancers show substantial intra- and intersite heterogeneity,” said Dr. Cybulska. “Second, they underscore the importance of the activation of certain pathways—including MYC and WNT—to immune evasion.”

If generalizable, these findings pose challenges to the application of checkpoint blockade therapies in high-grade serous ovarian cancer, she said, suggesting that additional immunomodulation may be required to ensure that all sites of disease are effectively targeted by the immune system.

To read this entire article on The ASCO Post, please click here.

Why Ovarian Cancer Spreads and How We Might Stop It

Why Ovarian Cancer Spreads and How We Might Stop ItNew research has revealed exactly why ovarian cancer spreads to the peritoneal cavity. Existing drugs could be repurposed to stop this from happening.

In the United States, ovarian cancer is estimated to affect around 20,000 women every year.

In 2014, the Centers for Disease Control and Prevention (CDC) suggested that about 21,161 women received a diagnosis of ovarian cancer and 14,195 of these women died.

Ovarian cancer is the deadliest form of cancerof the reproductive system, but treatment is effective if the cancer is caught early.

Unfortunately, however, only 15 percent of patients present themselves with this form of cancer at an early stage, while 75 percent of cases are found when the tumor has already spread — or metastasized — to the peritoneal cavity.

How does metastasis occur and what can be done to stop it? This question prompted researcher Pamela Kreeger, a biomedical engineering professor at the University of Wisconsin-Madison, and her team to study the most aggressive type of ovarian cancer.

Prof. Kreeger and her colleagues examined the metastatic process in high-grade serous ovarian cancer, which is both the most prevalent form of ovarian cancer and the most difficult to stop.

Previous studies have demonstrated that in this form of cancer, having a high number of immune cells called macrophages is linked with a worse outcome. So, Prof. Kreeger and team looked at whether or not these immune cells enable cancer cells to spread and attach to the peritoneal cavity.

Their findings were published in the journal Cancer Research.

Secret To Ovarian Cancer Metastasis Unlocked

Cell culture experiments showed that a complex interplay between healthy and cancer cells helps to facilitate the spread of cancer.

Normally, the peritoneal cavity is lined with so-called mesothelial cells, which form the mesothelium — a slippery, non-sticky surface layer that lines the body’s cavities and internal organs, protecting them.

But in ovarian cancer, the new study revealed, macrophages transform these mesothelial cells into sticky cells that help cancer cells to attach.

“For me, that was one of those scientific ‘ah ha’ moments,” claims Prof. Kreeger. “[T]he interactions between the normal cells in our body can influence metastasis. In other words,” she adds, “it’s not all about the tumor cell.”

Next, the scientists needed to find out which proteins were responsible for this transformational effect.

Computational modeling revealed a chain reaction of proteins: macrophages secrete a protein called MIP-1β, which, in turn, causes mesothelial cells to produce a sticky protein called P-selectin, which then enables cancer cells to stick.

Further experiments with mice confirmed the results. Last but not least, the researchers examined human samples and found that people with ovarian cancer indeed had increased levels of both MIP-1β and P-selectin.

Existing Drugs Could Be Used To Stop It

The insights offered by this recent study might soon be turned into fruitful new treatments. There are already existing drugs that could be repurposed to inhibit the key aspects of the metastatic process revealed by this study.

For instance, an HIV drug called Maraviroc is known to block MIP-1β receptors, and two drugs for various blood disorders — which are still being trialed — are known to inhibit P-selectin.

“We’re interested in pursuing multiple avenues, because it’s possible one will work better than another,” says Prof. Kreeger. “It’s also possible one will have more tolerable side effects than another.”

First study author Molly Carroll, a postdoctoral fellow at the University of Wisconsin-Madison, also weighs in on the significance of the findings.

Prof. Kreeger and team have already been awarded a grant for conducting long-term experiments in mice. If these further confirm the findings, the scientists will soon begin preclinical tests of existing drugs to see if they cause significant toxicity.

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