A Look at Glucose Metabolism in Ovarian Cancer

A Look at Glucose Metabolism in Ovarian CancerA new study of non-diabetic women with ovarian cancer reveals a potential correlation and area for further study regarding the expression of the GLUT1 glucose transporter receptor at the cancer tissue level (J Cell Physiol 2017; doi:10.1002/jcp.26023).

GLUT1 is a receptor protein involved in the absorption of glucose in the bloodstream and across membranes in the body. Physiologically, GLUT1 is not traceable in the ovaries. However, in patients diagnosed with ovarian cancer, use of immunohistochemical methods revealed the presence of this receptor, which tends to be intensely expressed in the most aggressive cases.

“Ovarian cancer is the leading cause of death among gynecological cancers. Despite remarkable achievements in terms of diagnoses and therapeutics, patient outcomes in terms of survival rates have remained largely unchanged. This is largely due to our limited understanding of the underlying mechanisms and pathways,” said Maddalena Barba, PhD, researcher at the IRCCS Regina Elena National Cancer Institute of Rome, Central Italy.

“This study revealed a higher expression of the glucose transporter 1 in cancer samples of patients with lower glucose levels in non-diabetic women. These findings provide evidence in support of our prior results from this same study population. Indeed, we have recently observed an association between cancer stage at diagnosis and circulating levels of fasting glucose,” explained Patrizia Vici, MD, clinical researcher at the Division of Medical Oncology 2 of the IRCCS Regina Elena National Cancer Institute.

The study included 40 randomly-selected patients from a larger cohort of 147 women diagnosed with high-grade, advanced-stage ovarian cancer.

“The findings from the immunohistochemical assessment of this population are key to understanding a variety of factors and determinants related to glucose metabolism in ovarian cancer. In addition, our findings establish a link between fasting glucose, and the expression of the glucose transporter GLUT1. We thus provide support to the hypothesis stated in our prior work within this same pipeline and, at the same time, ascertain the existence of a relation between a systemic and a local tissue biomarker related to energy metabolism. If confirmed in future studies, this may translate into the identification and characterization of innovative drug targets in ovarian cancer patients,” concluded Antonio Giordano, MD, PhD, Director of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia.

To read this full article on journals.lww.com, please click here.

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Niraparib Maintains Quality of Life in Recurrent Ovarian Cancer

Niraparib Maintains Quality of Life in Recurrent Ovarian CancerAdministering niraparib to patients with recurrent ovarian cancer after a complete response (CR) or partial response (PR) to platinum-based chemotherapy may allow patients to continuously maintain their quality of life (QOL) during treatment, according to a study presented at the European Society for Medical Oncology (ESMO) 2017 Congress.

The ENGOT-OV16/NOVA trial (ClinicalTrials.gov Identifier: NCT01847274) previously demonstrated that niraparib significantly prolonged progression-free survival (PFS) in patients with recurrent ovarian cancer following CR or PR.

Study authors analyzed patient-reported outcomes (PROs) associated with QOL, and the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L) were used to evaluate individual patient-reported symptoms in the niraparib and placebo groups.

A mixed-effect growth-curve adjusted for 3 stratification factors and baseline demographics was formed to reflect the relationship between the PRO scores and treatment for each measure. Health status and PRO associations were determined by a cross-sectional analysis of adjusted EQ-5D-5L health utility index (HUI) scores.

Results of the study showed no significant difference in mean PRO scores between the niraparib and placebo arms. The adjusted HUI scores were comparable at baseline in both study arms, but average adjusted HUI scores prior to progression trended higher for the niraparib arm (0.812 vs 0.803 in gBRCAmut cohort; 0.845 vs 0.828 in non-gBRCAmut cohort).

Patients’ overall health utility was not negatively impacted by hematologic toxicities.

To read this entire article in Oncology Nurse Advisor, please click here.

New Data Confirms Standard Dosing of Chemotherapy in Ovarian Cancer Treatment

New Data Confirms Standard Dosing of Chemotherapy in Ovarian Cancer TreatmentWomen with ovarian cancer can safely stick to the standard 3-week dosing schedule for paclitaxel rather than boosting up to a weekly dose-dense regimen, according to results of the phase III ICON8 trial to be presented at the ESMO 2017 Congress in Madrid (Abstract 929O_PR).

“The results clearly demonstrate that, although well-tolerated, using weekly scheduling to achieve dose-intensification of paclitaxel as part of the first-line treatment of epithelial ovarian cancer does not extend progression-free survival in this population,” said study investigator Andrew Clamp, PhD, from The Christie NHS Foundation Trust and The University of Manchester, U.K. “Therefore, this approach cannot be recommended as a standard-of-care treatment option for this population.”

However, he added “it remains appropriate to continue to offer weekly dose-dense paclitaxel as a treatment option to Japanese women.”

The conflicting recommendations stem from the fact that findings from ICON8 contrast with those of JGOG3016, a previously reported study of Japanese ovarian cancer patients that showed significantly increased median progression-free survival (PFS) and overall survival (OS) in those treated with dose-dense weekly paclitaxel compared to the standard 3-weekly schedule.

To evaluate for a similar effect from weekly paclitaxel, ICON8 randomised 1,566 predominantly European patients to receive six cycles of either the standard 3-week dosing regimen (carboplatin AUC 5/6-paclitaxel 175 mg/mq; Arm 1), compared to two different regimens that included once-weekly dose-dense paclitaxel (carboplatin AUC 5/6+paclitaxel 80 mg/mq weekly, Arm 2; and carboplatin AUC2+paclitaxel 80 mg/mq weekly, Arm 3). All patients entered ICON8 after immediate primary surgery, or received neoadjuvant chemotherapy with planned delayed primary surgery.

The study found no benefit to either of the once-weekly regimens. PFS was 24.4 months with standard dosing, compared to 24.9 months and 25.3 months in Arms 2 and 3, respectively. In terms of toxicity, there was a slight increase in grade 3-4 toxicity in Arms 2 and 3 compared to Arm 1 (63% vs. 53% vs. 42%, respectively), although this increase was predominantly due to uncomplicated hematological toxicity.

Noting that the study was “robust and appropriately powered,” Clamp said it is “not entirely clear” why ICON8 and JGOG3016 showed contrasting results. “Both were well-conducted trials and achieved the goal of increasing paclitaxel dose-intensity. We know the histological profile of ovarian cancer is slightly different between Japanese and Caucasian women, but I think it is unlikely that this accounts for the difference. It is more likely that there are pharmacogenomic differences between these two ethnic groups that account for the different results seen.”

Commenting for ESMO, Domenica Lorusso, MD, PhD, from Fondazione IRCCS National Cancer Institute of Milan, Chair of the Gynecological Tumors track at ESMO 2017, said: “The trial confirms that carboplatin-paclitaxel every 3 weeks is the standard first-line treatment in ovarian cancer, a standard which has remained unmodified in the last 20 years, at least in the Caucasian population.”

Lorusso agreed that success with weekly dosing in the Japanese population “is possibly due to genetic differences. According to the  5th Ovarian Cancer Consensus Conference, standard options to be discussed with the patients for first-line ovarian cancer treatment include carboplatin-paclitaxel every 3 weeks, as well as the dose-dense schedule (at least in the Japanese populations).​

To read this full article on Oncology Times, please click here.

Another Win for PARP Inhibition in Ovarian Cancer

Another Win for PARP Inhibition in Ovarian CancerWomen with recurrent, platinum-sensitive ovarian cancer lived twice as long without disease progression when they received maintenance therapy with the PARP inhibitor rucaparib (Rubraca), a randomized trial showed.

Overall, patients treated with rucaparib had a median progression-free survival of 10.8 months compared with 5.4 months for the placebo group. The magnitude of the benefit tripled for patients with BRCA-mutant ovarian cancer — 16.6 versus 5.4 months for placebo-treated patients.

A subgroup analysis showed a consistent treatment effect of the PARP inhibitor across all prespecified patient groups, as reported here at the European Society for Medical Oncology congress.

“The results of the ARIEL3 trial demonstrate the benefit of rucaparib maintenance treatment for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy,” said Jonathan Ledermann, MD, of University College London.

“Rucaparib maintenance treatment significantly improved progression-free survival versus placebo in the nested BRCA-mutant, homologous recombination-deficient cohorts, and in the overall intention-to-treat population,” he added. “Several patients with measureable residual disease at baseline had further reduction in tumor burden with rucaparib maintenance treatment. The most common side effects were gastrointestinal, asthenia, and anemia, consistent with prior studies of rucaparib.”

The results added to a growing volume of evidence supporting the use of PARP to treat recurrent ovarian cancer.

Earlier this year, the ARIEL2 trial of rucaparib established efficacy across a broad range of patients with recurrent, platinum-sensitive ovarian cancer. Results of another randomized trial showed almost a fourfold improvement in PFS in patients with platinum-sensitive ovarian cancer treated with olaparib (Lynparza) maintenance therapy. Late last year, a randomized trial of niraparib (Zejula) maintenance therapy showed a PFS benefit, regardless of BRCA mutation status.

“We have data from three PARP inhibitors in the same setting, and we have no data to say that one is better than the others,” said invited discussant Sandro Pignata, MD, of the University of Naples in Italy.

Instead, adverse events might prove to be the distinguishing feature of the agents. Rucaparib is the only one of the three drugs in the class associated with liver toxicity. Niraparib is associated with substantially more thrombocytopenia and leukopenia as compared with rucaparib and olaparib. Fatigue, nausea, and anemia occur with similar frequency across the three drugs.

Rucaparib and niraparib are associated with higher rates of treatment interruption, dose reduction, and discontinuation due to adverse events.

“These are clinical factors. What happens in clinical practice?” said Pignata. “I think we need to collect data from real-life studies to see how dose adjustments can be performed and how the toxicity affects our patients, and mainly, we need to learn how to treat the side effects.”

“Peak toxicity probably is not the best way to describe safety,” he added. “The duration [of toxicity] and changes after dose adjustment probably are more important.”

The ARIEL3 trial continued the line of clinical investigation that helped to define patients who benefit from treatment with rucaparib. Previous studies in patients with recurrent ovarian cancer demonstrated rucaparib efficacy in patients with BRCA mutations and those with tumors harboring a higher percentage of loss of heterozygosity (LOH), a marker of homologous repair deficiency (HRD).

ARIEL3 investigated rucaparib in a population of patients with high-grade recurrent ovarian cancer that had responded to second-line or later platinum-based chemotherapy. Patients were randomized 2:1 to rucaparib or placebo maintenance therapy and followed until disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS). In addition to an intention-to-treat analysis, investigators assessed rucaparib efficacy in patients with BRCA-mutant disease and with tumors exhibiting HRD.

Data analysis comprised 564 patients, 196 of whom had BRCA-mutant ovarian cancer. The HRD cohort comprised 354 patients (including the BRCA-mutant subgroup).

An intention-to-treat (ITT) analysis of the primary endpoint showed that treatment with rucaparib reduced the hazard for progression or death by 64% compared with placebo (95% CI 0.30-0.45, P<0.0001). Patients with BRCA-mutant disease had a 77% reduction in the hazard ratio when treated with rucaparib (95% CI 0.16-0.34, P<0.0001). The subgroup with HRD had a median PFS of 13.6 months with rucaparib versus 5.4 months with placebo, representing 68% reduction in the hazard ratio (95% CI 0.24-0.42, P<0.0001).

Review of PFS by a blinded independent committee found even larger PFS benefits for patients treated with rucaparib and a similar consistency of effect across the three key subgroups: median PFS of 26.8 versus 5.4 months for the BRCA-mutant subgroup (HR 0.20, 95% CI 0.13-0.32, P<0.0001); 22.9 versus 5.5 months for the HRD subgroup (HR 0.34, 95% CI 0.24-0.47, P<0.0001); and 13.7 versus 5.4 months for the ITT analysis (HR 0.35, 95% CI 0.28-0.45, P<0.0001).

Maintenance Rucaparib Highly Effective Across Ovarian Cancer Subtypes

Maintenance Rucaparib Highly Effective Across Ovarian Cancer SubtypesMaintenance treatment with the PARP inhibitor rucaparib (Rubraca) improved median progression-free survival (PFS) by 11.2 months compared with placebo for patients with BRCA-mutant platinum-sensitive ovarian cancer, according to findings from the phase III ARIEL3 trial presented at the 2017 ESMO Congress.

For patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34; P <.0001). Moreover, the median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) compared with 5.4 months for placebo (95% CI, 3.4-6.7). Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency (HRD) or low to high loss of heterozygosity (LOH).

“The improvement in progression-free survival was greatest in the BRCA-mutated group, who had a 77% increase, but it was seen across three subgroups that were evaluated,” lead investigator Jonathan Ledermann, MD, professor of Medical Oncology, UCL Cancer Institute, London, UK, said in a statement. “These results reinforce rucaparib’s potential to provide an enduring and significant clinical benefit in women with advanced ovarian cancer, regardless of their tumor genetics.”

In the ARIEL3 trial, patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer were randomized in a 2:1 ratio to receive rucaparib or placebo. Endpoints were prospectively assessed across 3 cohorts. In the first, patients had BRCA-positive tumors, including both germline and somatic alterations (n = 196). In the second group, patients were HRD-positive, which could include BRCA-mutant or wild-type with a high LOH (n = 354). A third group assessed all-comers in the intent-to-treat population (n = 564).

All enrolled patients had received ≥2 prior platinum-based therapies, and continued to have platinum-sensitive ovarian cancer (defined as progression in ≥6 months on their last platinum-based therapy). Oral rucaparib was administered at 600 mg twice daily. In the BRCA-mutant group, 130 patients received rucaparib and 66 got placebo. In the HRD group, 236 got rucaparib and 118 received placebo. The intent-to-treat group contained those with BRCA-mutant and wild-type tumors and those with high, indeterminate, and low genomic LOH.

In the BRCA-mutant group, by blinded independent central review (BICR), which was a secondary endpoint, the median PFS with rucaparib was 26.8 months compared with 5.4 months for placebo (HR, 0.20; P <.0001). The objective response rate (ORR) was 38% for rucaparib versus 9% with placebo. There were 7 complete responses (CR) with the PARP inhibitor and none for placebo.

In the HRD group, the investigator assessed PFS was 13.6 versus 5.4 months for rucaparib and placebo, respectively (HR, 0.32; P <.0001). In the BICR assessment, the median PFS was 22.9 months with the PARP inhibitor versus 5.5 months with placebo (HR, 0.34; P <.0001). The ORRs were 27% (10 CRs) and 12% (0 CRs) for rucaparib and placebo, respectively.

In the intent-to-treat group, for rucaparib and placebo, respectively, the PFS was 10.8 versus 5.4 months by investigator assessment (HR, 0.36; P <.0001) and 13.7 versus 5.4 months by BICR (HR, 0.35; P <.0001). The ORR with rucaparib was 18% (10 CRs) versus 8% with placebo (1 CR).

An exploratory analysis looked at outcomes specifically in those with BRCA wild-type tumors with LOH high (n = 158) and low status (n = 161). In the LOH high group, the median PFS was 9.7 months with rucaparib versus 5.4 months with placebo (HR, 0.44; P <.0001). In the LOH low group, the medians were 6.7 and 5.4 months for rucaparib and placebo, respectively (HR, 0.58; P = .0049). By BICR, for rucaparib and placebo, respectively, the medians were 11.1 versus 5.6 months for the LOH high group (HR, 0.55; P = .0135) and 8.2 versus 5.3 months for the LOH low group (HR, 0.47; P = .0003).

“We had hoped that the LOH test would distinguish responders from non-responders but both high and low LOH groups benefitted,” said Ledermann. “However, the magnitude of progression-free survival benefit was greater in the BRCA wild type/LOH high patients.”

The most common grade ≥3 treatment-emergent adverse events (TEAEs) with rucaparib were anemia/decreased hemoglobin (19%), increase in ALT/AST (10%), neutropenia (7%), asthenia/fatigue (7%), thrombocytopenia (5%), vomiting (4%), and nausea (4%). TEAEs led to treatment discontinuation for 13.4% of patients in the rucaparib arm versus 1.6% for placebo. Three patients developed treatment-emergent myelodysplastic syndrome/acute myeloid leukemia with rucaparib versus none for placebo.

“It is both impressive and encouraging that rucaparib demonstrated improvements in key primary, secondary, and exploratory endpoints in all 3 ARIEL3 patient populations,” said Ledermann. “It is also clinically significant that rucaparib not only sustained patients’ most recent response to platinum, but in some trial participants also enhanced that response, including the radiological elimination of residual tumor.”

Rucaparib was initially approved by the FDA in December 2016 as a monotherapy for patients with ovarian cancer with a deleterious BRCA mutation following prior treatment with 2 or more chemotherapies. Based on findings from the ARIEL3 trial, Clovis Oncology, the company developing the drug, plans to submit a supplemental new drug application to the FDA for an expanded approval. This submission is planned for October 2017, according to the company.

“ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefitted, especially those with BRCA mutations but also HRD patients,” said ESMO spokesperson Andrés Poveda, MD, head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain. “Personalized medicine has arrived in high grade serious ovarian cancer. Further studies are needed to identify predictive biomarkers of response to PARP inhibitors. Specifically, we need to know whether there are non-HRD factors that predict response.

To read this full article on OncLive.com, please click here.

Tumor DNA in Blood Used to Detect Many Early-stage Ovarian

Tumor DNA in Blood Used to Detect Many Early-stage OvarianUsing a modern DNA sequencing technique, Johns Hopkins researchers have come one step closer to diagnosing early-stage cancer patients with a simple blood draw.

The method reads free circulating DNA in a patient’s blood and detects common cancer mutations. While further refinement is needed, it was able to identify three out of every five people with early-stage colorectal, ovarian, breast or lung cancer.

The study, “Direct detection of early-stage cancers using circulating tumor DNA,” published in the journal Science Translational Medicine, describes the noninvasive approach that may also help doctors in choosing appropriate and timely treatments for these patients.

All cancers begin when one or more genes in a cell mutate, allowing the cell to proliferate excessively and to escape controls intended to kill abnormal cells. Identifying these early genetic changes could help to identify people as cancer starts to spread and the best therapeutic options for each of them.

Previous studies have shown that DNA from tumors cells can be detected in the blood stream. Now, a team of researchers at the Johns Hopkins Kimmel Cancer Center devised a strategy to see if they could detect circulating DNA marking early tumors.

The researchers analyzed blood samples from 44 healthy people and 200 patients with different types of cancer, including ovarian cancer, and at different disease stages.

The technique they used is called targeted “error correction sequencing” and is a method for “deep” DNA sequencing. This approach allows researchers to read a DNA sequence thousands of time,  greatly improving its sensitivity and allowing them to detect small DNA alterations.

With this technique, the team scanned the blood samples for mutations in 58 cancer-related genes. While healthy people had no tumor-derived mutations, 77 percent of patients with advanced cancers (stages 3 or 4) and 62 percent of those with stage 1 or 2 cancers had tumor-related DNA mutations.

Team members also investigated whether the amount of tumor DNA in circulation might predict how colorectal cancer patients will fare after surgery. They found high tumor DNA levels predicted poorer survival and a greater likelihood cancer recurrence in the patients.

“This study shows that identifying cancer early using DNA changes in the blood is feasible and that our high accuracy sequencing method is a promising approach to achieve this goal,” the study’s lead author, Victor Velculescu with the Hopkins center, said in a press release.

Overall, the findings “provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer,” the study concluded.

To read this entire article on Ovarian Cancer News Today, please click here.

Phase 1 Clinical Trial Is Assessing Cantrixil in Ovarian Cancer Patients Who Are Resistant to Chemo

Phase 1 Clinical Trial Is Assessing Cantrixil in Ovarian Cancer Patients Who Are Resistant to ChemoThree Australian and two American cancer centers are spearheading the first clinical trial of Cantrixil, Novogen’s therapy to restore ovarian cancer patients’ sensitivity to chemotherapy.

Associate Professor Jim Coward, an oncologist at Icon Cancer Care in South Brisbane, is directing the trial. In addition to Icon, the Australian trial locations are the Flinders Medical Center and Westmead Hospital in Sydney. The trial partners in the United States are the Peggy and Charles Stephenson Cancer Center and the Mary Crowley Cancer Research Center.

A key objective of the Phase 1 trial (NCT02903771), which began enrolling participants in August 2016, is to see if Cantrixil is safe for patients with recurring ovarian cancer. Researchers are administering it once a week through the peritoneum, or abdominal cavity.

Novogen is still recruiting patients for the study. In addition to ovarian cancer patients, it is encouraging women with cancer of the fallopian tubes or peritoneum to enroll.

Besides seeing whether Cantrixil is safe, the trial will allow researchers to determine the drug’s maximum tolerated dose.

“The survival rate for ovarian cancer is poor because of the high rate of relapse after standard-of-care treatment and the late stage at which the disease tends to be diagnosed,” Coward said in a press release. “The vast majority of patients who relapse will eventually become resistant to chemotherapy, so it’s imperative that we have a bigger portfolio of treatment options.”

He added that “we’ve seen massive developments in other types of cancer, but ovarian cancer has remained a challenge and, despite it being an unforgiving disease for women, treatment options have fallen behind as money and research are focused elsewhere.”

Recurring ovarian cancer means that during an initial round of treatment, a small group of cells is able to resist the chemotherapy. These slow-growing cells have stem-cell-like properties and are capable of repopulating the tumor.

Cantrixil is a first-in-class drug that goes after the vast range of cells that populate a tumor, including  cancer stem cells.

The therapy “could be a compelling treatment for patients with recurrent ovarian cancer because it has shown evidence in the laboratory of being able to target and kill the sub-population of cancer stem cells or tumor-initiating cells that are responsible for cancers originating, metastasizing [spreading to other parts of the body] and relapsing,” Coward said.

“This new treatment is being developed as an IP [intraperitoneal] chemotherapy that we hope will be used as both first-line and recurrent therapies in combination with carboplatin administered intravenously (IV) for epithelial ovarian cancer, which is the most common form of ovarian cancer, comprising 90 percent of cases,” he said. “We know that if a surgeon is able to remove all of the visible disease during an ovarian cancer patient’s initial operation, combination IP and IV therapy is associated with vastly superior outcomes.”

To read this entire article on Ovarian Cancer News Today, please click here.