In cell and mouse models, miR-181a showed promise as a biomarker for early stage ovarian cancer and may help make immunotherapy treatment more effective.
“There are two major challenges in ovarian cancer,” says senior study author Analisa DiFeo, Ph.D., associate professor of pathology and of obstetrics and gynecology at Michigan Medicine. “It is usually detected at a later stage, when treating the disease is much more difficult. And even when we do treat them, most of the cancers will come back — with few good additional options for patients.”
Ovarian cancer is the fifth-leading cause of cancer death for women, with a five-year survival rate under 50%, according to National Cancer Institute statistics. Recent research suggests that most high grade serous ovarian carcinomas actually originate in the cells of the fallopian tubes, where early detection methods could help doctors eliminate precursor lesions before they progress and turn deadly.
“The hope was, if we can find a microRNA that regulates several significant pathways driving ovarian cancer progression, that could make a great biomarker and/or a therapeutic target,” DiFeo says. “MicroRNAs tend to be stable in serum and blood plasma, so finding the microRNAs involved in the earliest stages of ovarian cancer could potentially allow us to detect those pre-cancerous lesions.”
The current study is the first to show that a microRNA can drive the transformation of a fallopian tube secretory cell toward becoming a tumor cell while simultaneously suppressing the intrinsic immune response that is supposed to detect and clean up unhealthy cells.
This ability to block the body’s defenses against unstable cells is what makes miR-181a an attractive drug target to potentially help overcome a tumor’s resistance to immunotherapy, DiFeo says.
“The hope was, if we can find a microRNA that regulates several significant pathways driving ovarian cancer progression, that could make a great biomarker and/or a therapeutic target.” – Analisa DiFeo, Ph.D.
For immune check-point inhibitors to work, a tumor must be “hot” — that is, visible to the immune system. MiR-181a regulates a protein called STING, which plays an important role in innate immunity, and thus it may aid in making these tumors more responsive to immunotherapy.
“We’re currently working with collaborators in U-M’s drug discovery cores to identify small-molecules that might be able to modulate miR-181a, and therefore turn these ‘cold’ tumors ‘hot,’” she says.
Additionally, the findings may have relevance for other types of cancer, including breast cancer, prostate cancer and lung cancer, DiFeo notes. An analysis of more than 10,000 tumors across 38 different cancers in The Cancer Genome Atlas found higher levels of miR-181a were associated with worse outcomes for patients.
“This is significant because we found that miR-181a overexpression alone is sufficient to promote transformation of cells into cancer cells and to form tumors in mouse models,” DiFeo says.
The research continues in laboratory models with the goal of ultimately identifying drug compounds to advance toward human clinical trials.
High-grade serous ovarian cancer (HGSOC) is characterized by a high level of intrinsic heterogeneity in the tumor-immune microenvironment that is modified by chemotherapy, according to findings published in Nature Genetics.
HGSOC, a common and aggressive histologic subtype of epithelial ovarian cancer, frequently presents with disease metastases at multiple sites. Previous genomic studies have revealed the presence of mutational intratumoral heterogeneity, as well as characteristics, such as a few somatic point mutations, often associated with low levels of immunogenicity in the setting of HGSOC. Nevertheless, the authors of this study noted that many questions remain regarding “the extent of [tumor microenvironment] heterogeneity, its underlying mechanisms and its impact on therapeutic response.”
In this study, HGSOC samples from 2 cohorts of patients were subjected to systematic immunogenomic analyses using whole-genomic sequencing (WES), immunofluorescence staining (IF), as well as analyses of the transcriptome, including mRNA-based assessments of tumor cellularity. In addition, some of the samples were also evaluated using T-cell receptor (TCR) sequencing.
Patient cohort 1 included 10 treatment-naive patients from whom 49 tumor samples were collected from the primary tumor, omentum, or other location during cytoreductive surgery that were selected based on presurgical MRI and positron emission tomography (PET)/computed tomography (CT) imaging analyses. Patient cohort 2 included 40 patients from whom 80 paired tumor specimens were collected before and after the administration of neoadjuvant chemotherapy with a platinum and taxane-based chemotherapy.
One of the key findings from investigations of patient cohort 1, which allowed for analyses of multiple tumor samples from the same patient, was that there was a high level of intrapatient variation between samples, with differences in the extent of T-cell infiltration into tumor ranging from 1% to over 10%.
Furthermore, immune-related and stromal gene signatures were more common in samples characterized by low tumor cellularity, whereas Myc and Wnt signaling were more common in high cellularity tumors. Specifically, across all patients in cohort 1, significant negative and positive associations between Myc and Wnt signaling were observed in low (P =.001) and high cellularity tumors (P =.006), respectively.
“These observations suggest that high Myc and Wnt signaling could be considered to be at least partially independent of tumor proliferation and may contribute to immune cell exclusion, as suggested by previous studies,” the study authors noted.
Immunogenomic analyses of matched pre- and post-chemotherapy tumor samples from patient cohort 2 revealed that chemotherapy was associated with TCR clonal expansions, and that the number of shared TCRs increased following chemotherapy suggesting that “chemotherapy may have induced or unmasked preexisting common (neo)antigens in these patients.”
Specifically, multivariate analyses comparing pre- and post-chemotherapy samples showed an increase in natural killer cells and the cytotoxic gene set following exposure to neoadjuvant chemotherapy only in samples that were site-matched, but not site-unmatched samples.
In commenting on these results, the authors stated that “the induced immunogenicity following [neoajduvant chemotherapy] was only unmasked after taking into account the [tumor microenvironment] heterogeneity, which acts as a confounding variable.”
“The tumor–immune microenvironment of advanced HGSOC is intrinsically heterogeneous” and “chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors,” the authors concluded. Nevertheless, they added that such intrinsic heterogeneity presents “an important challenge for the successful application of therapies that target the [tumor microenvironment], such as checkpoint blockade immunotherapy.”
A study presented at the AACR Virtual Annual Meeting II showed a significant decrease in mortality rate for patients with epithelial ovarian cancer when treated with lipophilic statins, supporting the further evaluation of statins to treat ovarian cancer in randomized clinical trials.
By Matthew Fowler
Lipophilic statins were associated with decreased mortality rates of patients with ovarian cancer, according to a study presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting II.
More, the results found in this study support the evaluation of specific lipophilic statins like atorvastatin and simvastatin in a randomized clinical trial to treat patients with ovarian cancer.
“Our results consistently show that among women with epithelial ovarian cancer statin users compared to never users have a significant reduction in ovarian cancer specific mortality, particularly those taking lipophilic statins,” wrote author Kala Visvanathan, MD, MHS, of the John Hopkins School of Public Health and Sidney Kimmel Comprehensive Cancer Center, in the study’s presentation.
Overall, the ovarian cancer mortality rate was reduced in the ever statin use population by 40% (HR, 0.60; 95% CI, 0.54-0.66) with a similar 5-year reduction as well (HR, 0.63; 95% CI, 0.56-0.70). More, a subgroup analysis revealed a 43% reduction in overall mortality with women who used lipophilic statins compared to never use statins (HR, 0.57; 95% CI, 0.43-0.76). Specifically, reductions were observed in women who used simvastatin and atorvastatin versus never use statin, both of which are forms of lipophilic statins.
By tumor characteristic, there was a 40% reduction in ovarian cancer mortality rate (95% CI, 32%-47%). Overall, for all of the different subgroups, there was a reduction in mortality among patients.
The study’s population of 10,062 women aged 18 or older was collected from the Finnish National Cancer Registry and the National Prescription Claims Database. A series of complex analyses were utilized to minimize bias amongst the research.
Of the 2,621 women who used statins, 80% of them used lipophilic statins as treatment. The median age of the population was 62 years, with a median age for statin users of 67 years.
“Our results provide further evidence in support of the clinical evaluation of lipophilic statins as part of the treatment of ovarian cancer,” Visvanathan said in a press release. “These drugs are appealing as they are widely used, inexpensive, and well tolerated in most patients. The associated reduction in ovarian cancer mortality is promising.”
A reduction in mortality was observed among all stage, treatment and epithelial ovarian cancer subtypes at varying magnitudes. Given the smaller sample size for post and pre diagnostic statin groups, the results are less robust.
As for statins, about 28% of United States adults over the age of 40 take the drugs for cholesterol control. While some studies have examined statin use for ovarian cancer, they have shown mixed results due to a small sample size.
While promising, Visvanathan explained that these results need to first be confirmed in randomized clinical trials and studied in broader populations before becoming a part of the disease’s standard of care.
Because of the disease’s low survival rate, epithelial ovarian cancer is hard to study over a long-term study. This study benefitted from the ability to evaluate data over a number of years and high-quality data as a whole.
While ovarian cancer only accounts for 1.3% of new cancer diagnoses in 2019, only 47.6% of patients survive for 5 years or longer. More, since there are no early detection tests for ovarian cancer, most patients are diagnosed at an advanced stage of the cancer when the disease is difficult to effectively treat.
“Our results also reinforce the value of examining existing therapies that are well tolerated and inexpensive to reduce global cancer burden,” explained Visvanathan in the study’s presentation.
Inhibiting the JAK/STAT pathway could represent a potential treatment for high-grade serous ovarian cancer, according to a single-cell analysis.
Researchers led by the Broad Institute’s Aviv Regev used single-cell RNA sequencing (scRNA-seq) to analyze about 11,000 cells from ascites from ovarian cancer patients. About a third of ovarian cancer patients have ascites — a build up of abdominal fluid — at diagnosis, and it is associated with drug resistance and a poor prognosis. Recurrent ovarian cancer is associated with a median survival of about a year.
While the researchers uncovered inter-patient variability in the makeup and function of the cells in the ascites samples, they also noted the shared expression of inflammatory programs. As they reported in Nature Medicine on Monday, the researchers further found that an inhibitor targeting the JAK/STAT pathway, which is expressed in both malignant and cancer-associated fibroblast cells (CAFs), had antitumor activity in cell cultures and patient-derived xenografts.
“Our work contributes to resolving the [high-grade serous ovarian cancer] landscape and provides a resource for the development of novel therapeutic approaches,” Regev and her colleagues wrote in their paper. Regev is slated to join Genentech as head of research and early development in August.
The researchers collected 22 ascites samples from 11 high-grade serous ovarian cancer patients. The ascites samples were split to undergo droplet-based scRNA-seq or plate-based scRNA-seq following antibody staining and cell sorting. A third group of three ascites and two primary tumor samples from the Human Tumor Atlas Pilot Project served as a validation set. In parallel, the researchers developed patient-derived cell cultures and mouse xenografts.
By analyzing the genes expressed, the researchers found that the makeup and functional programs of ascites cells varied from patient to patient. Droplet-based scRNA-seq revealed 18 different cell clusters, ranging from epithelial cells to macrophages and from cancer-associated fibroblasts to erythrocytes.
They noted further variation within macrophages and CAFs. Some CAF cell subpopulations expressed immune-related genes, suggesting an immunomodulatory role for them, while macrophages separated into groups that expressed HLA genes or complement factors.
They then confirmed this variability within the FACS-enriched sample, finding eight clusters, and that malignant cells clustered by patient of origin, underscoring the inter-patient variability.
For the malignant cells, the clusters lined up with two of The Cancer Genome Atlas subtypes. Six of the malignant cell custers expressed the differentiated signature and one expressed the proliferative signature. There was weak or no expression of the mesenchymal and immunoreactive signatures among the cancer cell clusters, but those signatures were found among the CAF and macrophage clusters. This suggests that bulk RNA profile-based subtypes reflect the tumor ecosystem, not solely cancer cells, the researchers noted.
Though the malignant cells exhibited diverse functions, as based on their expression programs, some programs were shared across patients. Three immune-associated programs in particular were shared among different patients: an inflammatory cytokines module, an MHC class II antigen presentation module, and an interferon-response module.
Taking into account that these programs may be downstream from the JAK/STAT pathway, that cells like the CAFs secrete ligands that activate the JAK/STAT pathway, and that parts of the JAK/STAT pathway appear to be highly expressed in malignant and non-malignant cells, the researchers explored the effect of a JAK/STAT inhibitor on these cells. Through a drug screen, they homed in on JSI-124 as an inhibitor of cell viability in an ovarian cancer cell line. Further, in patient-derived cell culture and xenograft models, JSI-124 additionally reduced disease burden, they reported.
“Together, these results suggest that JAK/STAT inhibition may be a potent therapeutic option for patients with HGSOC, through action on malignant cells, non-malignant cells, or both,” Regev and her colleagues wrote in their paper.
The researchers noted, though, that larger studies and studies of stratified clinical cohorts are needed.
University of British Columbia (UBC) researchers have led an international team in developing a new test to better diagnose different types of ovarian cancer, a tool that could one day guide and improve treatment options for women diagnosed with the most common and deadliest form of the disease.
The development and validation of the test are outlined in a new study, published today in Clinical Cancer Research, a journal of the American Association for Cancer Research. The study—led by researchers at UBC’s faculty of medicine, University of New South Wales, Huntsman Cancer Institute, Peter MacCallum Cancer Centre and Mayo Clinic—is one of the largest ovarian cancer investigations to date, involving data compiled by more than 50 research institutes and involving more than 3,800 ovarian cancer patients worldwide.
“With this new test, we’ll be able to give researchers, clinicians and patients more insight into the disease, which could pave the way for more targeted treatment down the road,” says the study’s senior author, Dr. Michael Anglesio, a molecular biologist, assistant professor in UBC’s department of obstetrics and gynecology, investigator at the Vancouver Coastal Health Research Institute (VCHRI) and scientist at OVCARE, B.C.’s multidisciplinary gynecological cancer research team.
The new test, known as PrOTYPE (Predictor of high-grade serous Ovarian carcinoma molecular subTYPE), is specifically designed to analyze and classify high-grade serous ovarian cancer, the most common and lethal form of ovarian cancer. Principal investigators validated the test in laboratories at BC Cancer and Vancouver General Hospital.
Using PrOTYPE, researchers and clinicians alike will be able to further classify an individual patient’s tumor into one of four known molecular subtypes, each with its distinct biological features believed to respond differently to treatment options.
“Right now, high-grade serous ovarian cancer patients are all treated the same, but by knowing what subtype their tumor falls into, we can begin to explore how certain treatments may prove more beneficial for individual patients,” says the study’s lead author Dr. Aline Talhouk, a translational data scientist, assistant professor in UBC’s department of obstetrics and gynecology, VCHRI investigator and OVCARE scientist.
Prior to the development of PrOTYPE, subtyping tests using gene expression analysis for high-grade serous ovarian cancer relied on the aggregation of large patient cohorts and the examination of all of the genes in the genome at once—a situation that made them impractical for use in clinical settings, says Anglesio.
“Doctors will never see a few hundred patients walk through their clinic door at one time. It’s just not the reality,” says Anglesio.
With PrOTYPE, which was designed for clinical use, a small amount of information—55 informative genes from a small tissue sample—can quickly determine the tumor subtype with more than 95 percent accuracy. The researchers also developed a corresponding web tool, enabling clinicians to print out a report that can be added to a patient’s records.
“We’ve developed a push-button solution. All that’s needed is the tumor from the patient in question and a common reference to compare the data to. Before this test, no one could do that,” says Anglesio. “We now have a robust way of figuring out which of the four subtypes a patient fits into.”
The researchers see great potential for the test to one day guide patient care. The test is already being used in ongoing clinical trials investigating whether certain subtypes are more sensitive to particular treatments among women with recurrent high-grade serous ovarian cancer.
“This test has opened up new opportunities and treatment avenues to explore. It will be important to re-evaluate treatment options and test new targets for therapeutics in light of this new ability,” says Talhouk.
Cancer isn’t waiting for Covid-19 to go away. Neither is Karen Howley.
Diagnosed two years ago with advanced ovarian cancer, Howley started on a new experimental drug in mid-March, just as coronavirus case counts were soaring in Massachusetts. Her treatment, part of a clinical trial at Dana-Farber Cancer Institute in Boston, began with a four-week hospital stay, and since then, she’s been returning every Monday for infusions.
While the study drug dripped into her body, she heard the hospital staff apprehensively discussing the coming surge of cases. Howley felt safe on a floor devoted to cancer patients, where there was no shortage of personal protective gear for the medical workers, but she still wiped down her tray each time a a meal was delivered to her bedside.
Ambulance sirens wailing endlessly outside her window made her anxious. The hospital’s no-visitor policy made her lonely. But Howley, who has faced her cancer with both humor and realism, never considered quitting the clinical trial.
“I don’t think it occurred to me,” Howley, 56, said during an infusion appointment last week that she wryly called her “spa day.”
“Treatment for me is prolonging my life at this point. And if I do get Covid, I do.”
Around the world, Covid-19 has disrupted all types of clinical trials, decreasing by 74% the number of new patients enrolling. In cancer, the number of new patients entering Phase 2 and 3 cancer trials in the U.S. plummeted by about 46% to 48% in the last two weeks of March, said Margaret Mooney, associate director of the Cancer Therapy Evaluation Program in the Division of Cancer Treatment and Diagnosis at the National Cancer Institute. By the last week of May and first week of June, the cliff wasn’t so steep, moderating to a 25% to 30% decline.
Some medical centers put certain research trials on hold, stretched too thin by the needs of treating Covid-19 patients. Others continued their cancer trials by taking advantage of NCI-modified protocols allowing patient consent by phone or delivery of oral drugs to patients’ homes. “Depending on where an individual site was located, they made local decisions that were best for their patients and their patient population in terms of clinical trials,” Mooney said.
At Dana-Farber, Ursula Matulonis, chief of gynecologic oncology and Howley’s oncologist, recalled patients feeling frightened and doctors feeling uncertain about exactly how they would carry on in the early days of the pandemic — but no one ever doubted that they would.
“We said, look, we’ve got to go in to see our patients because they’ve got cancer. They want to continue to be treated in the same way,” she said. “We have a job to do and we have to continue to do that job.”
Doing that job at Dana-Farber means patients are screened for symptoms when they enter the cancer center and at each step along the way. Howley answers the same set of questions — Any fever? Any cough? Any contact with anyone who has Covid-19? — when she has her vitals checked, gets her blood drawn, sees her doctor, receives her infusion.
She’s used to the waiting-room chairs zip-tied in opposite directions to keep single patients (no more friends or family) from getting too close. She expects to park her own car rather than turn it over to a valet. Because she’s enrolled in a research trial, there are more blood samples taken for analysis and for tracking her response to the drug, but the entire visit moves along more quickly now, streamlined to reduce waiting times so no patient is exposed longer than necessary to other people.
Howley goes through a final Covid-19 screening before her medicine infusion. – KAYANA SZYMCZAK FOR STAT
Andrew Wagner, an oncologist who is leading Dana-Farber’s efforts to keep patients safe and on treatment during Covid-19, said in consultation with study sponsors, some tissue biopsies were canceled, or for some patients chemotherapy was adjusted from every week to every three weeks. Physician visits to discuss imaging scans moved from in-person to video. Dana-Farber had zero telemedicine before March, but virtual visits now account for just under half of patient appointments, holding lessons for the future.
“It’s been hard in oncology, of course. Such a large part of what we do is the emotional care of patients and their families,” Wagner said. “Being able to hold someone’s hand is really hard to do through telemedicine, but certainly the video aspect of it is much better than just the telephone. You’re able to express yourself empathically.”
Patient visits to Dana-Farber plunged by 40% in the course of one week in mid-March but chemotherapy appointments slipped by only 10% to 15% over that same week. Now doctors are encouraging patients to come back in. “We think that it’s very safe here. We are certainly safer than in the grocery store,” Wagner said. “Cancer is not going to wait for Covid to go away.”
Other cancer centers made similar adjustments. At the Ohio State University Comprehensive Cancer Center in Columbus, where close to 1,000 clinical trials are typically underway, Ohio Gov. Mike DeWine’s March 23 stay-at-home policy kept 200 research nurses and other staffers away from their duties. That meant only trials with a critical therapeutic outcome, extremely modest staffing needs, or time-sensitive enrollment targets continued, said Raphael Pollock, director of the cancer center.
Now that Ohio’s stay-at-home policy has been lifted and the research machinery is gearing up again, he expects trial participation to tick back up, too. “Cancer didn’t take time off,” Pollock said. “We’ll be quite busy by the mid- to late summer.”
And at Memorial Sloan Kettering Cancer Center in New York City, the U.S. epicenter of the pandemic, no therapeutic trials were put on hold, but in-clinic volume in March and April did drop by about 75%. Telemedicine helped, said Paul Sabbatini, an oncologist and deputy physician-in-chief for clinical research. “We and most centers have developed processes to rationally deal with the Covid risk as best we can so [clinical trials] can proceed now.”
Now patients are coming back.
“While it was prudent for patients to avoid the medical setting when the pandemic was at peak, enough time has elapsed that many of those patients clearly now have a benefit/risk ratio in favor of care,” Sabbatini said. “Clinical trials remain the only way we evaluate and ultimately approve new therapies for patients with cancer.”
NCI’s Mooney believes some good may come from adjustments made to ensure the safety of patients participating in studies and medical staff. But it’s still a work in progress, as hotspots rise and fall.
“I think we’re learning more as we go along,” she said. “Some of the adaptations we’ve made have made all of us realize that perhaps there is better use we can make of technology — telemedicine or technologies like that — to take care of the patient. That’s a benefit to everyone, and they may be things that we can continue into the future once the public health emergency, as we all hope, has been resolved.”
At Dana-Farber, Howley is enrolled in a Phase 1 trial of REGN4018, a bispecific antibody developed by the biotech company Regeneron. It grabs onto cancer cells at two points connected by a bridge. One side targets MUC16, a gene mutated in ovarian cancer and previously known as CA125 (which is still the name for the biomarker measured in diagnostic blood tests). The other side of the antibody binds to a T cell receptor that can then kill the cancer cell, the theory goes.
“You realize this [Covid-19] is temporary and one day we will be back. For me, it’s like, I don’t know how long I have.”
When patients are hospitalized at the outset of the trial, which at this early phase is designed to test safety and dosing, it’s not an easy time for them with or without a pandemic. They are waiting for the drug to provoke their immune systems into killing their cancers. Howley felt savage pain across her abdomen and the wrath of a cytokine storm, the massive inflammatory response that also occurs in some Covid-19 patients whose immune systems go into overdrive.
“We believe that the best antibodies you can get are the specific antibodies that travel to the sites of tumors. And that’s what causes the abdominal pain,” Matulonis, her oncologist, said.
From the beginning, Howley’s treatment path has not been easy. After initial surgery to remove her tumor, she endured peritoneal delivery of the chemotherapy drug cisplatin directly to her abdomen, which was both painful and ultimately ineffective. She went on a standard drug called Doxil, but her cancer still progressed. Next she started a clinical trial that combined three drugs: one immunotherapy drug, one drug that blocks new blood vessel growth, and one PARP inhibitor that interferes with how cancer cells repair DNA damage. It was an aggressive regimen designed to expose the cancer to three agents it had never seen before, Matulonis said.
But one drug caused a bowel perforation, a known side effect. She continued to take the immunotherapy and the PARP inhibitor, but by November her cancer was progressing, measured by blood tests gauging her CA125 levels and imaging scans that spot metastasis.
The new trial, of the bispecific antibody, started in February.
“I think for her, I’ve always wanted to go beyond standard chemotherapy,” Matulonis said. “You can see that the tumor was a harder nut to crack. We really have to think outside the box to treat her.”
Matulonis said Howley can stay on the current trial as long as she meets three conditions: She is benefiting from the drug, she is not having any significant toxicities, and she wants to continue. Howley’s CA125 has hit four figures in the past. Before last week’s blood test, her last reading was 499. She was both nervous and eager to know the latest, though she tries not to put too much stock in the biomarker. The reading can vary with inflammation and the drug she is on causes inflammation, irritating one hip so much that she wants to ask if a cortisone shot would be allowed under the trial’s rules.
Except for the cancer, she’ll tell you she’s healthy, and Matulonis agrees. Retired now from a career in client services, she lives with her husband in Sudbury, Mass., about a 40-minute drive to Boston. She walks three miles every morning, and she just got back to playing tennis. She ran the Falmouth Road Race last summer, astonishing a research nurse on her medical team who was volunteering on the sidelines.
Howley relaxes and looks at her mobile phone while getting her infusion. – KAYANA SZYMCZAK FOR STAT
For her visit last week, she wore a white, cowl-necked knit top — “port-friendly” for blood draws and drug infusions through an opening high on her chest. Her lively blue eyes were set off by sparkly deep-blue eye shadow, her dark hair accented with blond highlights. She’s been the woman in the waiting room with no hair or eyebrows and knows how it feels when people look at you. Now she jokes about reluctantly giving up her fashion-coordinated cloth face mask for the fresh paper one Dana-Farber offers each patient upon check-in.
Howley has dual motivations for participating in cancer research. One is to help other women with ovarian cancer. “Hopefully I’m a piece of that puzzle that’s going to give them a little insight,” she said. “They might have something here that’s going to be so critical down the road for others.”
Her other driving force is her 29-year-old daughter. She doesn’t worry about their sharing BRCA1 or BRCA2 mutations — her genetic tests were negative for those mutations — but she is concerned about being a role model.
“So much of my determination is just really providing an example to her,” she said. “I’m not saying I’ve got it down at all, but I try very hard to show her how to do it kind of gracefully. It doesn’t mean I’m going to do it. But I still try.”
Cancer has already narrowed how she thinks about the future. Six months is as far out as she’ll plan these days, and Covid-19 has cramped her dreams of traveling to one of her favorite places, Marco Island in Florida. “You realize this [Covid-19] is temporary and one day we will be back,” Howley said. “For me, it’s like, I don’t know how long I have.”
No one can tell her that, but she looks to Matulonis to see if her new CA125 number matches how good she’s felt, even if she “hit lousy” on the tennis court.
The number is still moving in the right direction, Matulonis tells her: 259, down from 499 a month ago. That could mean her cancer burden is diminishing, Matulonis said, but cautioned that imaging scans will have to confirm it.
Howley knows that.
“If it goes up 50 points, it doesn’t necessarily mean anything. But at the same time, I’m just blown away,” she said. “Today, it’s almost surreal to me, it’s going to take me a while to digest.”
She is still elated as she climbs into the infusion chair for her next dose of the trial drug.
Scientists have begun using berzosertib, a protein-targeting drug, as an accompaniment to chemotherapy for patients with ovarian cancer. The drug is currently in its second phase of trials with cancer patients and is showing promising results for how it can be used to target coronavirus antigens.
A recently published study reports phase two trials with high-grade serious ovarian cancer (HGSOC) patients being treated with berzosertib. Alongside chemotherapy, patients lived long before the disease worsened than those treated without the drug. This may lead to using berzosertib for the treatment of other cancers and even SARS-CoV-2.
Berzosertib is an inhibitor of the ataxia-telangiectasia and rad3-related kinase, or the ATR protein, which respond to damaged DNA. Tumor cells need constant repairs or the healing of broken DNA strands.
HGSOC and other types of cancer rely on the ATR protein to making those repairs. ATR protein dependency becomes greater when a patient is treated with chemotherapy, which impedes the cells’ ability to copy its DNA.
Clinical Trials
Panagiotis Konstantinopoulos, MD, Ph.D., director of translational research, Gynecologic Oncology, at Dana-Farber explained that ‘The unbridled growth of cancer cells places enormous stress on the process of DNA replication.’
‘ATR helps them survive that stress: its job is to coordinate the halting of the cell cycle to check if the DNA is intact or needs repair. Drugs that inhibit ATR-that deprive tumor cells of such repair-have the potential to be particularly effective in some cancers.’
The study involved 11 centers in the US Experimental Therapeutics Clinical Trials Network with 70 patients. 36 were treated with gemcitabine alone, a chemotherapy drug, while 34 were given that plus berzosertib.
Those receiving standard chemotherapy alone were estimated to be stable for almost 14 weeks while the latter group averagely survived for 23 weeks. Those with the most platinum-resistant tumors showed a nine-week retreat or stability while the combination group has almost 28 weeks. There was only one side effect with adding berzosertib to their therapy; low blood platelet levels, also known as thrombocytopenia.
Treating Coronavirus
At the same time, since cancer blocks DNA strands from repairing, berzosertib selectively binds to the ATR protein and prevent ‘ATR-mediated signaling in the ATR-checkpoint kinase 1 (Chk1) signaling pathway. This is the same pathway that SARS-CoV-2 virus and other coronaviruses enter the body and multiply within host cells,
Vaithilingaraja Arumugaswami, a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, and his colleagues recognized the application of berzosertib for coronavirus by sifting through 430 types of cancer drugs. ‘Clinical trials have shown that Berzosertib blocks the DNA repair pathway in cancer cells, but has no effects on normal, healthy cells,’ he said.
The team has also seen how the anticancer drug, by targeting specific tumor cells, limits infection, prevents complications and has no significant side effects. Arumugaswami said that ‘clinical trials have shown that berzosertib blocks the DNA repair pathway in cancer cells, but has no effects on normal, healthy cells.’ Because of this, they believe that the drug is a promising treatment for coronavirus patients as well and ‘could be rapidly and safely be deployed in the clinic.’ They will design a clinical trial that can ‘bring the therapeutic benefit to a diverse population, especially to those in underserved communities.’
The FDA has approved pembrolizumab (Keytruda) to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden–high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options.
The FDA has approved pembrolizumab (Keytruda) to treat adult and pediatric patients with unresectable or metastatic solid tumors that are tissue tumor mutational burden–high (≥10 mutations/megabase) and have progressed following prior therapy and who have no satisfactory alternative treatment options.
The approval is based in part on the phase 2 KEYNOTE-158 trial, in which a link was established between TMB-high status and improved overall response rate (ORR) with the PD-1 inhibitor in patients with various solid tumors.
The multicenter, multicohort, nonrandomized, open-label KEYNOTE-158 trial accrued patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or small cell lung cancer. Patients had to have an ECOG performance status of 0 or 1 and have progressed on or be intolerant to at least 1 prior line of standard treatment. The investigators used the FoundationOne CDx™ assay to assess TMB in FFPE tumor samples, with 10 Mut/Mb used as the threshold for TMB-high status.
Overall, there were 755 patients with evaluable TMB, of whom 120 (15.9%) were TMB-high. Of these 120 patients, 15 (12.5%) were microsatellite instability-high (MSI-H). The investigators reported that baseline characteristics were comparable between patients with either TMB-high or -low status. The correlation was low between TMB and PD-L1 expression (P = .19).
Pembrolizumab was administered at 200 mg every 3 weeks for 35 cycles or until progressive disease, unacceptable toxicity, or physician/patient choice. The primary end point was ORR, with key secondary outcome measures being duration of response, progression-free survival (PFS), overall survival (OS), and safety.
For TMB-high patients, the ORR was 28.3% (95% CI, 20.5-37.3), including 24.8% (95% CI, 16.9-34.1) in non–MSI-H patients. In TMB-low patients the ORR was 6.5% (95% CI, 4.7-8.7). The median duration of response was not reached in either the TMB-high (range, 2.2+ to 28.8+) or TMB-low (4.1 to 30.6+) groups.
The median PFS for the TMB-high group was 2.1 months (95% CI, 2.1-3.7), and was also 2.1 months (95% CI, 2.1-2.3) in the TMB-low cohort. The 12-month PFS rates were 24.3% versus 14.0%, respectively.
The median OS was 11.1 months (95% CI, 8.1-16.1) in the TMB-high group, compared with 13.3 months (95% CI, 11.5-14.8) in the TMB-low group. The 12-months OS rates were 48.0% versus 52.9%, respectively.
There were no new safety signals compared with earlier published research with pembrolizumab.
Data from the KEYNOTE-158 trial previously supported pembrolizumab’s initial tumor-agnostic approval. In May 2017, pembrolizumab was approved for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.
The approval was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials, one of which was KEYNOTE-158. Ninety patients had colorectal cancer (CRC) and the remaining 59 patients had 1 of 14 other tumor types.
The ORR with pembrolizumab was 39.6% (95% CI, 31.7-47.9), including 11 (7.4%) complete responses and 48 (32.2%) partial responses. The ORR was 36% in patients with CRC and 46% in patients with other tumor types. The median duration of response was not yet reached (range, 1.6+ months to 22.7+ months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.
The combination use of niraparib plus bevacizumab significantly improved clinical outcomes, compared with niraparib alone, in patients with recurrent ovarian cancer.
The combination use of niraparib (Zejula) plus bevacizumab (Avastin) significantly improved clinical outcomes, compared with niraparib alone, in patients with recurrent ovarian cancer, according to updated survival data from the phase 2 portion of the AVANOVA trial (NSGO-AVANOVA2/ENGOT-OV24; NCT02354131) that were made available as part of the 2020 ASCO Virtual Scientific Program.1
The updated results continued to support earlier findings, with an observed 66% reduction in the risk of disease progression or death (HR, 0.34; 95% CI, 0.21-0.54). The median progression-free survival (PFS) in the bevacizumab arm was 12.5 months versus 5.5 months with niraparib alone.
Statistically significant improvements in time to second progression or death, or PFS2, was demonstrated in the bevacizumab/niraparib combination arm versus the niraparib control, with corresponding medians of 20.5 versus 15.7 months (HR, 0.56; 95% CI, 0.35-0.89; P = .015).
Other end points were also assessed, with a median follow-up of 24.7 months. Median time to first subsequent therapy was longer with the addition of bevacizumab at 14.3 months versus 7.2 months with niraparib alone (HR, 0.45; 95% CI, 0.29-0.70; P = .004). Similarly, time to second subsequent therapy was better with bevacizumab plus niraparib compared with the single-agent PARP inhibitor (21.8 vs17.3 months; HR, 0.56; 95% CI, 0.36-0.89; P = .014).
Although the study was not powered to detect differences in overall survival, there was a trend toward improvement with the niraparib plus bevacizumab combination versus niraparib alone, with medians of 29.4 months versus 27.8 months, respectively (HR, 0.75; 95% CI, 0.44-1.28).
The study authors who were led by Mansoor Raza Mirza, MD, chief oncologist in the Department of Oncology at Rigshopitalet–Copenhagen University Hospital in Denmark and medical director of the Nordic Society of Gynaecological Oncology, concluded that these results support the rationale behind a randomized phase 3 trial that is poised to change the current standard-of-care in this patient population.
In addition, patient-reported outcomes based on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, or EORTC QLQ-C30, showed that the combination did not result in detrimental effects on patient’s quality of life.
The investigators identified hypertension and proteinuria as adverse effects (AEs) with a significantly increased occurrence in the bevacizumab arm compared with the niraparib-alone arm. Previously reported results indicated that the most common all-grade AEs in both groups were anemia, fatigue, and gastrointestinal effects. Treatment-related AEs led to discontinuation of bevacizumab in 19% and niraparib in 13% of patients in the combination group; 10% in the niraparib group alone stopped receiving PARP inhibitor therapy.2
Patients treated on the trial were those with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer and high-grade serous or endometrioid histology. Patients with any number of prior therapies were allowed to enroll and prior experience with bevacizumab was allowed. Stratification factors included homologous recombination deficiency status (positive vs negative) and chemotherapy-free interval (6-12 vs >12 months).
All patients received niraparib 300 mg daily and those in the combination arm were treated with bevacizumab at 15 mg/kg every 3 weeks until disease progression or toxicity.
Results of the open-label, randomized trial were originally reported in Lancet Oncology in 2019, and showed that the trial met its primary end point of PFS superiority at a median follow-up of 16.9 months (HR, 0.35; 95% CI, 0.21-0.57; P <.0001).2 The trial randomized 97 patients 1:1 to either the combination arm (n = 48) or the single agent arm (n = 49).
Pembrolizumab monotherapy continues to show modest antitumor activity in patients with recurrent advanced ovarian cancer, according to updated results of the KEYNOTE-100 study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting (May 29-31, 2020).
In the interim analysis of KEYNOTE-100, patients with recurrent advanced ovarian cancer showed modest clinical activity after treatment with pembrolizumab and a median follow-up of 16.9 months.
Ursula A Matulonis, MD, chief of the division of gynecologic oncology, Dana-Farber Cancer Institute (Boston, MA), and colleagues presented the results of the protocol-specific final analysis of KEYNOTE-100 based on a data cutoff of September 18, 2019. Among the eligibility criteria for patients were epithelial ovarian, fallopian tube, or primary peritoneal cancer; confirmed recurrence following front-line platinum-based therapy; ECOG performance status of 0-1; and provision of a tumor sample for biomarker analysis. Patients were divided into two cohorts – those in Cohort A (n = 285) received two or less lines of prior chemotherapy for recurrent advanced ovarian cancer and had a platinum-free or treatment-free interval of at least 3 to 12 months, and patients in Cohort B (n = 91) received three to five lines of prior chemotherapy and had a platinum-free or treatment-free interval of at least 3 months.
Tumor imaging was performed every 9 weeks for 12 months and every 12 weeks thereafter, researchers noted. The primary endpoint of the study was ORR per RECIST v1.1 by independent central review in both cohorts and by tumor PD-L1 expression using the combined positive score.
Dr Matulonis and colleagues found that in Cohorts A and B, ORR was 8.1% and 9.9%, respectively, in the total population; 6.9% and 10.2%, respectively, in patients with a combined positive score of at least 1; and 11.6% and 18.2%, respectively, in patients with a combined positive score of at least 10. Median duration of response was 8.3 months and 23.6 months, respectively, they added.
Additionally, researchers reported that median progression-free survival was 2.1 months in both cohorts. Median overall survival was 18.7 months and 17.6 months, respectively, in the total population; 20.6 months and 20.7 months, respectively, in patients with a combined positive score of at least 1; and 21.9 months and 24.0 months, respectively, in patients with a combined positive score of at least 10.
“Pembrolizumab monotherapy was associated with modest antitumor activity in patients with recurrent advanced ovarian cancer,” authors of the study concluded. “There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts.”
No new safety signals were identified in the final analysis, they added.—Zachary Bessette
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