Ovarian Cancer Study Provides Painstaking Look At Inner Workings Of Tumors

Ovarian Cancer Study Provides Painstaking Look At Inner Workings Of TumorsIn what is believed to be the largest study of its kind, scientists at the Pacific Northwest National Laboratory, Johns Hopkins University and their collaborators from institutions across the nation have examined the collections of proteins in the tumors of 169 ovarian cancer patients to identify critical proteins present in their tumors.

By integrating their findings about the collection of proteins (the proteome) with information already known about the tumors’ genetic data (the genome), the investigators report the potential for new insights into the progress of the most malignant form of the disease. The work is published June 29, 2016, in the advance online edition of Cell.

The researchers say their achievement illustrates the power of combining genomic and proteomic data – an approach known as proteogenomics – to yield a more complete picture of the biology of a cancer that accounts for three percent of all cancers in women and is the fifth leading cause of cancer deaths among women in the United States.

“Historically, cancer’s been looked at as a disease of the genome,” said Karin Rodland, a senior author of the study and chief scientist for biomedical research at PNNL, a U.S. Department of Energy laboratory. “But that genome has to express itself in functional outcomes, and that’s what the proteomic data adds, because proteins do the actual work of the genome.”

Daniel W. Chan, the study’s other senior author, who led the team at the Johns Hopkins University School of Medicine, said, “Correlating our data with clinical outcomes is the first step toward the eventual ability to predict outcomes that reflect patient survival, with potential applications for precision medicine and new targets for pharmaceutical interventions. But just like anything in medicine, clinical validation will be a long and rigorous process.”

The authors say that with the findings, researchers expect to be better able to identify the biological factors defining the 70% of ovarian cancer patients who suffer from the most malignant form of ovarian cancer, called high-grade serous carcinoma. Currently, only one in six such patients lives five or more years beyond diagnosis.

The Power Of Collaboration

The work draws on the efforts of physicians, scientists and patients who have worked together to understand ovarian cancer. The investigators say the effort requires collaboration among physicians as well as patients willing to take part in research to benefit others with the disease or even to prevent others from ever developing cancer.

Under the leadership of the National Cancer Institute, scientists around the nation have worked together to create the Cancer Genome Atlas (TCGA), a collaborative effort to map cancer’s genetic mutations. The task for ovarian cancer was completed in 2011. In the current study, the PNNL and JHU teams each studied subsets of 169 high-grade serous carcinoma tissue samples and accompanying genomic and clinical data drawn from that study.

The Johns Hopkins team initially selected 122 of the samples based on those tumors’ ability to repair damaged DNA – known as homologous recombination deficiency – and characterized by changes in genes including BRCA1, BRCA2 and PTEN, mutations long linked to increased cancer risk and severity.

“We chose to examine these samples because patients with changes in these genes already are benefiting from a specific drug regimen for breast cancer, so if we could find similar changes in ovarian cancer genomes and proteomes, those patients would likely benefit from the same regimen,” said Chan, a professor of pathology and oncology at JHU. Chan is one of the inventors of the OVA1 ovarian cancer detection test, which is licensed to Vermillion Inc. of Austin, Texas.

The PNNL team initially selected 84 samples based on overall patient survival times. “We examined the data for the shortest-surviving patients and the longest-surviving patients hoping to pinpoint biological factors associated with extremely short survival or better-than-average, longer survival,” said Rodland.

Then, through their participation in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), another program of the National Cancer Institute which funded both teams, the two groups combined their efforts.

Using protein measurement and identification techniques based on mass spectrometry, the teams identified 9,600 proteins in all the tumors, and pursued study on 3,586 proteins common to all 169 tumor samples.

Beyond The Genome

While many people are familiar with the role our genes play in the development of cancer, the genes are often just a starting point, for patients and researchers alike. Genes are transcribed into RNA, the genetic material that makes proteins, which are the workhorses of cells. The activity of the proteins varies dramatically, with many undergoing changes that affect their impact and interactions with other proteins.

A detailed look at the activity of proteins in cancer biology gives researchers insight into specific molecular events that would otherwise remain unknown.

A hallmark of cancer, and particularly high grade serous carcinoma, is when genetic instructions go awry. One form is the appearance of more copies of certain regions of the genome. These so-called copy number alterations can lead to changes in protein abundance. When the researchers compared known regions of copy number alterations, they found that parts of chromosomes 2, 7, 20 and 22 led to changes in abundance of more than 200 proteins. A more careful study of those 200 proteins revealed that many are involved in cell movement and immune system function, both processes implicated in cancer progression, the researchers said.

“Adding the information about the proteome on top of the genome provides an entirely new dimension of information that has enabled the discovery of new biological insights to ovarian cancer, while creating a valuable resource that the scientific community can use to generate new hypotheses about the disease, and how to treat it,” said Rodland.

“High grade serous carcinoma is such a challenging disease, requiring complex clinical care to achieve long-term survival. This new knowledge gives us new directions to test in the lab and clinic,” said study author Douglas A. Levine, director of gynecologic oncology at the Laura and Isaac Perlmutter Cancer Center of NYU Langone Medical Center. “This proteogenomic analysis will help us improve patient outcomes and quality of life.”

In addition to large teams of scientists from PNNL and Johns Hopkins, contributors included colleagues from Stanford University School of Medicine, Vanderbilt University School of Medicine, University of California at San Diego, New York University School of Medicine, Virginia Tech, the National Cancer Institute’s Office of Cancer Clinical Proteomics Research, as well as CPTAC investigators.

The proteomic analyses performed by the PNNL team were done at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility.

To read this full article on Medical Xpress, click here.


TESARO’s Niraparib Significantly Improved Progression-Free Survival for Patients With Ovarian Cancer in Both Cohorts of the Phase 3 NOVA Trial

TESARO’s Niraparib Significantly Improved Progression-Free Survival for Patients With Ovarian Cancer in Both Cohorts of the Phase 3 NOVA TrialTESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, today announced that the Phase 3 NOVA trial of niraparib successfully achieved its primary endpoint of progression-free survival (PFS). This trial demonstrated that niraparib significantly prolonged PFS compared to control among patients who are germline BRCA mutation (gBRCAmut) carriers, among patients who are not germline BRCA mutation (non-gBRCAmut) carriers but who have homologous recombination deficient (HRD) tumors as determined by the Myriad myChoice® HRD test, and overall in patients who are not germline BRCA mutation carriers.

NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled more than 500 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. There is currently no therapy approved by the U.S. Food and Drug Administration for maintenance treatment of patients with recurrent ovarian cancer following response to platinum.

“We are extremely grateful to the patients, caregivers, and investigators who participated in the NOVA trial. The results of this study, which is the first successful, prospectively designed, randomized, well-controlled Phase 3 study of a PARP inhibitor, demonstrate that a single, daily, oral dose of niraparib is superior to control in prolonging PFS in women with recurrent ovarian cancer,” said Mary Lynne Hedley, Ph.D., President and COO of TESARO. “Importantly, these results show activity of niraparib in a population of ovarian cancer patients beyond those with germline BRCA mutations. In keeping with our mission of responsible drug development, NOVA was designed to define those patients most likely to benefit from niraparib treatment and, in so doing, optimize the benefit/risk profile for patients. We believe we have achieved that goal and look forward to presentation of the full data set from this study at the European Society for Medical Oncology (ESMO) congress in October.”

Statistically Significant PFS Results in the gBRCAmut Cohort

Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27. The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p < 0.0001).

Statistically Significant PFS Results in non-gBRCAmut Cohort for Patients with HRD Positive Tumors

For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice® HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38. The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p < 0.0001).

Statistically Significant PFS Results in the Overall non-gBRCAmut Cohort

Niraparib also showed statistical significance in the overall non-germline BRCA mutant cohort, which included patients with both HRD-positive and HRD-negative tumors. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p < 0.0001).

The most common (≥10%) treatment-emergent grade 3/4 adverse events among all patients treated with niraparib were thrombocytopenia (28.3%), anemia (24.8%) and neutropenia (11.2%). Adverse events were generally managed via dose modifications. The discontinuation rate was 14.7% for niraparib treated patients and 2.2% for control. The rates of MDS/AML in the niraparib (1.3%) and control (1.2%) arms were similar. There were no deaths among patients during study treatment.

“The majority of women who are diagnosed with advanced ovarian cancer will experience a relapse of their disease, even if they respond to their initial chemotherapy,” said Dr. Tom Herzog, M.D., Clinical Director, University of Cincinnati Cancer Institute and Professor, Department of Obstetrics and Gynecology at the University of Cincinnati. “New treatment options are needed to extend the time in between cycles of platinum-based chemotherapy for these patients, and the results from the NOVA study suggest that niraparib could represent an important new treatment option for many patients with ovarian cancer.”

“While the identification of mutations in the BRCA genes was a significant advancement, ovarian cancer remains the deadliest of gynecologic cancers, and new diagnostic and therapeutic options are needed,” said David Barley, Chief Executive Officer of the National Ovarian Cancer Coalition. “The results of the NOVA trial are encouraging for patients and their families, and we look forward to seeing the full results of this study this fall.”

About the Phase 3 NOVA Clinical Trial of Niraparib

NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that planned to enroll 490 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. Patients were enrolled into one of two independent cohorts based on germline BRCA mutation status. One cohort enrolled patients who were germline BRCA mutation carriers (gBRCAmut), and the second cohort enrolled patients who were not germline BRCA mutation carriers (non-gBRCAmut). The non-gBRCAmut cohort included patients with HRD-positive tumors, including those with somatic BRCA mutations and other HR defects, and patients with HRD-negative tumors. Within each cohort, patients were randomized 2:1 to receive niraparib or placebo and were treated continuously with placebo or 300 milligrams of niraparib, dosed as three 100 milligram tablets once per day, until progression. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints include patient-reported outcomes, chemotherapy-free interval length, PFS2, overall survival, and other measures of safety and tolerability. More information about this trial is available at http://clinicaltrials.gov/show/NCT01847274.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA or any other regulatory agencies.

About Homologous Recombination Deficiency (HRD)

Homologous recombination deficiency (HRD) is a defect in high-fidelity, double-strand DNA repair. HRD results from a variety of causes, including mutations in BRCA and other genes involved in DNA repair, as well as other unidentified causes.  In cells with HRD, such as BRCA1 and BRCA2 mutant cells, lack of functional DNA repair pathways, including PARP, leads to irreparable double-strand breaks, genomic instability, and ultimately cell death. Because HRD-positive cells are sensitive to DNA-damaging processes, they are reliant upon proper DNA repair by other pathways, including PARP-dependent pathways.

Comprehensive assessment of HRD status includes both tBRCA mutational analysis and assessment of genomic instability through the combined analysis of HRD biomarker components LOH, TAI, and LST. myChoiceHRD® is a registered trademark of Myriad Genetics, Inc.

About Niraparib

Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes the Phase 3 trial in patients with ovarian cancer (the NOVA trial) as described above; a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); a Phase 3 trial for the treatment of patients with BRCA-positive breast cancer (the BRAVO trial); and a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial). Several collaborator-sponsored studies are also underway, including combination trials of niraparib plus pembrolizumab and bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

About Ovarian Cancer

Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and nearly 80% are diagnosed after the disease has become symptomatic and has progressed to a late stage. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, 90% of patients will experience recurrence within two years. If approved, niraparib may address the difficult “watchful waiting” periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

To read this entire article on GlobeNewsWire.com, click here.

Ovarian Cancer Risk Factors Show Substantial Heterogeneity Across Histologic Subtypes

Ovarian Cancer Risk Factors Show Substantial Heterogeneity Across Histologic SubtypesA large, prospective analysis showed that risk factors for ovarian cancer demonstrate substantial heterogeneity in their associations with histologic subtypes of the disease. The heterogeneity has implications for prevention and risk prediction in ovarian cancer.

“Most ovarian cancers are detected at a late stage and have a poor prognosis,” wrote study authors led by Nicolas Wentzensen, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, adding that two large trials failed to show any reduction in mortality with available screening techniques. “An understanding of the etiologic heterogeneity of ovarian cancer is critical for development of new prevention strategies.”

The new study evaluated associations of 14 key risk factors with invasive epithelial ovarian cancer risk both overall and by histologic subtype, based on data from the Ovarian Cancer Cohort Consortium (OC3). It included 5,584 cases, from more than 1.3 million women in 21 clinical trial cohorts. The results were published online ahead of print in the Journal of Clinical Oncology.

Most cases of ovarian cancer were serous (73.7%) histology, followed by endometrioid (13.2%), mucinous (7.2%), and clear cell (5.9%).

Parous women had a reduced risk of all subtypes compared with nulliparous women; the strongest association was seen in clear cell carcinomas, with a relative risk (RR) of 0.35 (95% CI, 0.27–0.47), and serous cancers had the least risk reduction with an RR of 0.81 (95% CI, 0.73–0.90). There was significant heterogeneity by subtype (P value for heterogeneity [Phet] < .001), and similar patterns were seen for number of children (with more children, risk decreased).

Age at menopause was significantly associated with risk of endometrial and clear cell carcinomas, but not with serous or mucinous tumors (Phet = .009). Tubal ligation was associated with reduced risk of endometrioid and clear cell histology but not the others (Phet < .001), and hysterectomy was associated with only clear cell carcinomas (Phet = .006). Oral contraceptive use was associated with reduced risk of all ovarian cancers, though the association was only significant for serous and clear cell carcinomas.

Non-hormonal or reproductive risk factors also showed heterogeneity in their associations with risk. First-degree family history of breast or ovarian cancer showed significant associations with increased risk of serous tumors, while a family history of breast cancer was associated with endometrioid carcinomas. Ever smoking was associated with an increased risk of mucinous carcinomas, but no other histologic subtype.

“The substantial heterogeneity of individual risk factor associations across ovarian cancer subtypes supports that subtypes are indeed different diseases and underscores the importance of evaluating risk factors and biomarkers by ovarian cancer subtypes,” the authors wrote. They suggested exploring potential risk factors specifically for high-grade serous cancers, which showed the weakest associations for the established risk factors.

To read this full article on CancerNetwork.com, click here.

June 2016 ASCO Highlights

ASCO 2016Since the first time I attended ASCO I have seen the number of abstracts presented about ovarian cancer increase significantly as understanding of the disease has expanded.  No longer do we hear the one size fits all approach to ovarian cancer; ovarian cancer is a heterogeneous disease with several subtypes.  It has become quite clear that low-grade and high-grade ovarian cancer present differently and respond to treatment differently.  A potential therapeutic target may be present in high-grade serous ovarian cancer but not in clear cell ovarian cancer. Researchers are focusing on these differences and similarities.  A few years ago the push was for one screening test, one silver bullet.  Now we know that the questions are far more complex.

Another significant development has been the increasing focus on survivorship and quality of life.  Recognizing that patients are living longer, the questions of how best to care for this population was the topic of great discussion.  Survivors need to be advocates in their own care asking about potential long-term side effects of treatment, recommended surveillance and follow-up when treatment is completed, as well as other quality of life issues.  Additionally survivors should consider lending their voice to the larger discussion.  The patient perspective will continue to move the field of survivorship forward.

Clinical trial design and ways to improve patient accrual continue to take center stage.  The patient voice is critical to understanding these issues.  This was very apparent in a meeting of patient advocates and FDA patient representatives during which FDA officials asked for our input on what patients want and need from clinical trials.    The take-away message is get involved and bring the patient voice to the table.

Intraperitoneal chemotherapy for Ovarian Cancer: Trials and Tribulations: Following the presentation of GOG252, a phase III trial, at the SGO annual meeting, many questions lingered and the presenters of this session attempted to offer some clarity.  GOG252 compared intraperitoneal and intravenous chemotherapy.  There were three trial arms, and patients in all three arms received IV bevacizumab.  Arm 1: IV carboplatin AUC (area under the curve) 6/IV weekly paclitaxel at 80 mg/m2.  Arm 2: IP carboplatin AUC 6/IV weekly paclitaxel at 80 mg/m2.  Arm 3: IV paclitaxel at 135 mg/m2 on day 1/IP cisplatin at 75 mg/m2 on day 8.

Dr. Helen Mackay of the Princess Margaret Hospital in Canada noted that progression free survival (PFS) was similar for all three study arms.  Although, IP chemo studied in GOG 172 had shown amazing results of 60.4 months PFS, in GOG 252 PFS was 33.8 months.  Why the marked difference?  Some questions include:

  • All patients in GOG252 underwent 6-month CT scans (not done in GOG 172).  Was PFS influenced by the results of the scans?
  • Did dose reduction of paclitaxel and cisplatin and patient cross over from the IP arm to the IV arm confound the results?
  • Did the introduction of bevacizumab negate the IP results seen previously?

Other panel participants including Dr. Charlie Gourley of the University of Edinburgh agreed with the need for further clarification of these results while emphasizing that previous trials (GOG 104, 114, and 172) resulted in longer PFS using intraperitoneal compared to intravenous chemotherapy and stating that BRCA1/2 patients could benefit from the use of IP.  All agreed that there are unresolved issues regarding the use of IP chemotherapy and much work remains to better understand the microenvironment and biology of ovarian cancer and the role of IP chemotherapy in treatment.

Overall survival (OS) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: An interim analysis.

Dr. Jonathan Ledermann from the United Kingdom summarized findings to date of a phase II trial that found patients who received maintenance olaparib after responding to platinum therapy demonstrated an overall survival advantage.  BRCA mutation and platinum sensitive relapsed serous ovarian cancer showed a significant progression free survival benefit from olaparib maintenance monotherapy, both with BRCA germline and somatic mutations.

Hormonal maintenance therapy for women with low-grade serous carcinoma of the ovary or peritoneum.
Dr. David Gershenson of MD Anderson explained that while low-grade serous carcinoma (LGSC) has been shown to be relatively chemoresistant, postoperative platinum-based chemotherapy remains the standard of care for women newly diagnosed with this subtype.  Newly diagnosed patients with stage II-IV LGSC who had undergone treatment primary treatment with cytoreductive surgery followed by platinum-based chemotherapy and at least two years of follow-up who had not recurred were randomized to surveillance or hormonal maintenance therapy (letrozole, tamoxifen, anastrozole or leuprolide acetate).  Women who received HMT had a statistically significant improvement in progression free survival compared to women in the surveillance arm of the study (34 months PFS versus 29.9 months).

Multicenter phase II study of intraperitoneal carboplatin plus intravenous dose-dense paclitaxel in patients with suboptimally debulked epithelial ovarian or primary peritoneal carcinoma.

Dr. Kosei Hasegawa of Japan reported on a multicenter phase II prospective trial conducted to evaluate the efficacy and safety of intraperitoneal carboplatin in combination with dose-dense paclitaxel and carboplatin (ddTCip) in patients with stage II-IV ovarian or primary peritoneal carcinoma suboptimally debulked at primary cytoreductive surgery.  The trial results suggest that frontline chemotherapy with this regimen is safe and effective for those who are suboptimally debulked at initial surgery.  A phase III randomized trial comparing ddTCip and ddTC (dose dense paclitaxel and carboplatin) is currently ongoing.

The MITO8 phase III international multicenter randomized study testing the effect on survival of prolonging platinum-free interval (PFI) in patients with ovarian cancer recurring between 6 and 12 months after previous platinum-based chemotherapy: A collaboration of MITO, MANGO, AGO, BCOG, ENGOT, and GCIG.
This study addressed the question of whether introducing a non-platinum based chemotherapy and prolonging the platinum-free interval would improve sensitivity to platinum.   The trial concluded that prolonging the platinum-free interval by introducing a non-platinum based agent does not improve and even worsens efficacy outcomes in patients with partially platinum sensitive recurrent ovarian cancer.

Baseline quality of life (QOL) as a predictor of stopping chemotherapy early, and of overall survival, in platinum-resistant/refractory ovarian cancer (PRROC); The GCIC symptom benefit study (SBS).

Dr. Felicia Roncolato, of St. George Hospital in Sydney Australia, reported that assessing baseline quality of life in women with PRR-ROC might help identify which patients are unlikely to benefit from palliative chemotherapy.  The SBS showed that Global Health status, physical function, role function and abdominal/GI symptoms were independent predictors for overall survival, and were significantly associated with stopping chemotherapy early.  The worse the symptoms, the shorter the survival.

Association of ovarian cancer risk with mutations detected by multiple-gene germline sequencing in 96,561 women.

Dr. Alison Kurlan of Stanford presented the results of this study to attempt to assess ovarian cancer risk for genes on one commercially available panel of 25 genes.  Multivariable regression analysis was used to examine the association between pathogenic/suspected pathogenic mutations and a personal history of ovarian cancer.  Personal histories were also collected.  Among nearly 100,000 women, multiple-gene sequencing detected ovarian cancer associated mutations in 11 genes.

Read more about ASCO 2016 by clicking here.

Presurgery Chemotherapy May Make Advanced Ovarian Cancers Responsive To Immunotherapy

Presurgery Chemotherapy May Make Advanced Ovarian Cancers Responsive To ImmunotherapyMetastatic ovarian cancer patients treated with chemotherapy prior to surgery had altered immune cells in their tumors, and specific alterations identified suggest that immunotherapy given after chemotherapy may help in preventing the cancer from coming back, reports Frances R. Balkwill, PhD, professor of cancer biology at Barts Cancer Institute in Queen Mary University of London, United Kingdom. The work is published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“We are studying a type of ovarian cancer called high-grade serous ovarian cancer (HGSC), which is quite difficult to treat for two main reasons: first, it is often detected after it has spread quite extensively in the body; and second, although the disease can respond well to the first chemotherapy treatments, it often relapses and becomes more difficult to treat. Therefore we need to find other treatment options after the initial treatment is given,” said Balkwill.

Prior preclinical research in mice suggests that when chemotherapy destroys cancer cells, it also stimulates immune cells in the cancer that can kill cancer cells, she explained. “We wanted to study whether this was also true in cancer patients, and whether it occurred with the chemotherapy used to treat women with ovarian cancer,” Balkwill added.

Balkwill and colleagues collected pre- and post-chemotherapy biopsies and blood samples from 54 patients with advanced-stage HGSC who underwent platinum-based neoadjuvant (given prior to surgery) chemotherapy, and from six patients who underwent surgery without prior chemotherapy.

The researchers analyzed the samples using immunohistochemistry and RNA sequencing to study the changes in the tumor immune microenvironment of patients who received and did not receive chemotherapy, and changes before and after chemotherapy. Patients were categorized into those who had a good response and those who had a poor response to chemotherapy, based on a recently approved chemotherapy response score that correlates with progression-free and overall survival.

They found that in patients who received chemotherapy, there was evidence of activation of certain types of T cells that can fight cancer cells, while the number of a type of T cell that suppresses the immune system decreased. The results were more pronounced in those who had a good response to chemotherapy, compared with those who had a poor response to chemotherapy.

The team also found that chemotherapy reduced the blood levels of certain cytokines–inflammatory molecules that promote cancer growth–often back to normal levels in the patients. “This could help immunotherapies work better,” Balkwill noted.

“Our study showed that chemotherapy altered the immune cells called T cells that are found in metastatic ovarian cancer samples in a way that suggested they were better able to fight the cancer after the treatment. Our research provides evidence that immunotherapy may be more effective if given straight after chemotherapy,” Balkwill said.

“Although we found that chemotherapy activated the T cells, the levels of the protein PD-L1 [to which the immune checkpoint molecule PD-1 binds to disable T cells and prevent them from recognizing and destroying the cancer cells] remained the same or increased. However, immune checkpoint blockade therapies [such as pembrolizumab and nivolumab] can stop this from happening, so we suggest that immune checkpoint blockade might be a suitable form of immunotherapy to give to ovarian cancer patients after chemotherapy,” she added.

“The chemotherapies, carboplatin and paclitaxel, given in our study are also used to treat many different cancer types. It will, therefore, be very interesting and potentially promising if similar effects are seen in other cancer types, such as lung cancer,” Balkwill noted.

To read the full article on ScienceDaily.com, click here.

Exercise May Help Thwart Ovarian Cancer

Exercise May Help Thwart Ovarian CancerLack of exercise is associated with an increased risk of ovarian cancer and of death from the disease, two new studies suggest.

“Women may be overwhelmed with mixed messages about physical activity or exercise recommendations and opt to be inactive because they feel that they cannot meet the recommended amount of physical activity,” said Kirsten Moysich, senior author of both studies.

“Our findings suggest that any amount of regular, weekly recreational physical activity may reduce the risk for and improve survival from ovarian cancer, while a lack of regular exercise throughout adulthood is associated with an increased risk of developing and dying from ovarian cancer,” Moysich, a professor of oncology at Roswell Park Cancer Institute, in Buffalo, N.Y., said in an institute news release.

In one study, the researchers analyzed data from more than 8,300 ovarian cancer patients and more than 12,600 women without ovarian cancer. Those who said they had done no recreational physical activity during their lives were 34 percent more likely to develop ovarian cancer than those who exercised regularly, the researchers found.

The link between inactivity and a higher risk of ovarian cancer was seen in both normal-weight women and those who were overweight or obese, according to the study. The findings were recently published online in the journal Cancer Epidemiology, Biomarkers & Prevention.

The other study of more than 6,800 ovarian cancer patients found that women who were inactive in the years before the diagnosis were 22 percent to 34 percent more likely to die of the disease than those who had done at least some regular weekly exercise. Again, this was true in both normal-weight women and those who were overweight or obese.

The study was published online June 14 in the British Journal of Cancer.

“While the current evidence regarding the association between different amounts of physical activity and ovarian cancer remains mixed, our findings demonstrate that chronic inactivity may be an important independent risk and prognostic factor for ovarian cancer,” said Rikki Cannioto, first author of both studies and a research affiliate at the cancer institute.

Less than 45 percent of ovarian cancer patients survive five years, the researchers said in background notes. While these studies can’t prove that exercise would prevent these cancer deaths, they suggest regular exercise could be of benefit.

To read this entire article on U.S. News & World Report Health Care, click here.

Neoadjuvant Chemotherapy May Render Advanced Ovarian Cancers Responsive to Immunotherapy

Neoadjuvant Chemotherapy May Render Advanced Ovarian Cancers Responsive to ImmunotherapyAlthough most patients with advanced ovarian cancer initially respond to platinum-based chemotherapy, they usually relapse. According to a study by Böhm et al published in Clinical Cancer Research, neoadjuvant chemotherapy seemed to alter the immune cells in the tumors of patients with stage III/IV high-grade serous ovarian cancer. The results suggest that the effects of immunotherapy might be enhanced if given after chemotherapy, possibly improving disease control. If confirmed in additional studies, the incorporation of immunotherapy into postchemotherapy treatment options may also benefit patients with other types of cancer.

Study Methodology

The researchers obtained pre- and post-treatment omental biopsies and blood samples from a total of 54 women with stage IIIC and stage IV tubo-ovarian high-grade serous carcinoma undergoing platinum-based neoadjuvant chemotherapy and 6 patients undergoing primary debulking surgery. They then measured T-cell density and phenotype, immune activation, and markers of cancer-related inflammation using immunohistochemistry, flow cytometry, electrochemiluminescence assays, and RNA sequencing and related their findings to the histopathologic treatment response.

Progression-free survival was calculated from the date of the first neoadjuvant chemotherapy to progression or death, whichever came first, using GCIG CA-125 criteria for biochemical progression. Overall survival was calculated from the date of the first neoadjuvant chemotherapy to death from the cancer. Survival functions were estimated using the Kaplan-Meier method, and the log-rank test was applied.

Study Findings

The researchers found evidence of T-cell activation in omental biopsies after neoadjuvant chemotherapy: CD4-positive T cells showed enhanced interferon-gamma production, and antitumor Th1 gene signatures were increased. T-cell activation was more pronounced with good response to neoadjuvant chemotherapy. The CD8-positive T-cell and CD45RO-positive memory cell density in the tumor microenvironment was unchanged after neoadjuvant chemotherapy, but biopsies showing a good therapeutic response had significantly fewer FoxP3-positive T regulatory (Treg) cells. This finding was supported by a reduction in a Treg cell gene signature in post- vs pre–neoadjuvant chemotherapy samples, which was more pronounced in good responders.

Plasma levels of proinflammatory cytokines decreased in all patients after neoadjuvant chemotherapy. However, a high proportion of T cells in biopsies expressed immune checkpoint molecules PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte–associated protein 4), and PD-L1 (programmed cell death ligand 1) levels were significantly increased after neoadjuvant chemotherapy.

“Our study showed that chemotherapy altered the immune cells called T cells that are found in metastatic ovarian cancer samples in a way that suggested they were better able to fight the cancer after the treatment,” said Frances R. Balkwill, PhD, Professor of Cancer Biology at Barts Cancer Institute in Queen Mary University of London in the United Kingdom, in a statement. “Our research provides evidence that immunotherapy may be more effective if given straight after chemotherapy. Although we found that chemotherapy activated the T cells, the levels of the protein PD-L1 remained the same or increased. However, immune checkpoint blockade therapies can stop this from happening, so we suggest that immune checkpoint blockade might be a suitable form of immunotherapy to give to ovarian cancer patients after chemotherapy.”

Study Limitations

According to Dr. Balkwill, a major limitation of the study was the small sample size, which also prevented the researchers from analyzing pre- and postchemotherapy samples from the same patient, in some cases because there was not enough material.

Funding for this study was provided by the Swiss Cancer League, the European Research Council, Cancer Research UK, Barts, and the London Charity.

The study authors reported no potential conflicts of interest.

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