Less is more? Focused genetic testing recommended for breast and ovarian cancers

 

This article first appeared at the Stanford Medicine News Center in February, 2021 and was written by Krista Conger.

Homing in on about 20 key genes known to be associated with breast or ovarian cancer is likely to provide patients and their doctors with news they can use, according to a new study from Stanford Medicine and the University of Michigan.

In contrast, widening the search to include more and more genes increases the number of uncertain results, particularly for racial and ethnic minorities.

Unfortunately, only about one third of ovarian cancer patients undergo genetic screening to identify mutations that could guide the course of treatment. (Such testing is recommended for all people with ovarian cancer; recommendations for those with breast cancer vary according to age at diagnosis and family history of cancer, among other parameters.)

The finding builds on previous research by Allison Kurian, MD, MSc, a Stanford breast and gynecologic cancer specialist, and Steven Katz, MD, MPH, a University of Michigan professor of medicine and of health management and policy.

The research appears in the Journal of Clinical Oncology.

Too few ovarian cancer patients tested

That research investigated the prevalence of genetic testing in people diagnosed with breast or ovarian cancer in California and Georgia from 2013 to 2014; the new study included people diagnosed through 2017. Unfortunately, little improvement was seen over the longer timespan.

The researchers found that about one-quarter of the nearly 200,000 people with breast cancer and one-third of 14,689 patients with ovarian cancer underwent genetic testing. Overall, testing prevalence increased by about 2% each year during the study period.

"It is striking and concerning that there has been no significant improvement in testing ovarian cancer patients from 2013-2019; still only around one-third are tested, yet all of them should be," Kurian said. "While we don't know all the reasons for this under-testing, our prior work suggested that access disparities associated with insurance status and race and ethnicity might play a role."

Increasing access to testing and genetic counseling might be accomplished by at-home saliva testing or the use of telehealth platforms, the researchers speculate.

Additional genes linked to uncertain results

Genetic testing is critical to identify known cancer-associated mutations that can guide treatment decisions or give hints about a person's prognosis.

But sometimes the testing pinpoints spots in a patient's genes that differ from the expected sequence but have no known clinical impact. These variants of uncertain clinical significance, or VUS, become more prevalent as the number of genes examined increases -- particularly for racial and ethnic minorities.

Kurian and Katz found that the average number of genes analyzed by multi-gene panels meant to detect cancer-associated mutations increased by about 28% each year during the study period. Correspondingly, the prevalence of VUS also increased significantly -- doubling from about 11% in people diagnosed in 2013 to about 27% in 2017. In particular, nearly half of all findings for Black or Asian patients were classified as VUS as compared to about one-quarter of non-Hispanic white people.

"Many fewer minority patients than non-Hispanic whites have undergone genetic testing, and thus we know much less about the normal spectrum of genetic variation in minority populations," Kurian said. "Accordingly, genetic testing of minorities more often reveals variants that have not been well-characterized, and thus are classified as uncertain."

Finding balance

It might seem counterintuitive to examine fewer genes in order to deliver greater benefit. But uncertain results can be disconcerting for patients and their doctors. And, in Kurian and Katz's study, adding ever more genes to the gene panels didn't deliver any additional clinical benefit for most patients.

"We need to find the right balance between 'signal' -- a meaningful pathogenic variant result that can guide clinical decisions -- and 'noise' -- a variant of uncertain significance, which is not useful clinically and may cause patients anxiety or be misinterpreted as an indication for a change in care," Kurian said.

The team found that testing for about 20 cancer-related genes is currently the optimal amount.

Kurian and Katz emphasize that it's important to focus research efforts on understanding whether and how uncertain variants impact the clinical care or outcome in non-white patients.

"Improving the clinical value of genetic testing is crucial not only for patients but also for their family members who may be at risk for hereditary cancers that could be prevented or detected early to save lives," Katz said.

But until then, they argue, less is more.

"Our first priority should be to do what we know is clinically valuable, but too often missed: testing patients with ovarian cancer for a core set of genes associated with their diagnosis," Kurian said.

New Test Predicts Tumors Most Likely to Respond to Radiation, Chemotherapy

 

This article first appeared on the UCSF website and was written by Jeffrey Norris.

Many cancer patients might respond better to treatments with the help of a new prognostic indicator based on a distinctive pattern of gene activity within tumor cells, according to a new study of human cancer data and experiments on human cancer cell lines grown in the lab. 

The new research, led by scientists from UC San Francisco and the Catalan Institute of Oncology, in Barcelona, Spain, shows that the newly identified pattern of gene activity is present in many cases of the most common cancers and could be used to predict who is most likely to benefit from “genotoxic” therapies, which include common treatments such as radiation therapy and long-standard chemotherapies. 

DigiTEAL Learning Series

The National Ovarian Cancer Coalition is offering a series of summer workshops:

June 23 - Summer Foods to Help You Feel Better

June 30 - Calming Stars - Art Therapy for Self-Care and Stress Management

July 14 - Improved Sleep for Healing

July 21 - Communication Between Survivors and Caregivers

July 28 - Caregiver Self-Care (for caregivers only)

Click here to learn more or to register.

Response to Cancer Immunotherapy May Be Affected by Genes We Carry from Birth

 

This article first appeared in UCSF and was published on Feb. 11, 2021. It was written by Laura Kurtzman.

For all their importance as a breakthrough treatment, the cancer immunotherapies known as checkpoint inhibitors still only benefit a small minority of patients, perhaps 15 percent across different types of cancer. Moreover, doctors cannot accurately predict which of their patients will respond.  

A new study finds that inherited genetic variation plays a role in who is likely to benefit from checkpoint inhibitors, which release the immune system’s brakes so it can attack cancer. The study also points to potential new targets that could help even more patients unleash their immune system’s natural power to fight off malignant cells. 

 

OCRA Inspire Online Community

From Ovarian Cancer Research Coalition: Those who have faced an ovarian or gynecologic cancer diagnosis have so much to offer to others going through a similar experience – be it support, tips or friendship. Inspired Advice is a blog series that tackles specific topics – from managing feelings of isolation to navigating a new diagnosis – and shares advice and reflections from our OCRA Inspire Online Community. They are, in many ways, the experts.*

*OCRA Note:Sharing ideas and experiences can be extremely helpful but, as always, we advise speaking with your physician before making any dietary changes or adding herbs, teas, vitamins or supplements to your routine.

Smart Cell Therapies for Solid Cancers Ready to Move Toward Clinical Trials

This article first appeared in UCSF and was written by Lindzi Wessel.

Immunotherapies that fight cancer have been a life-saving advancement for many patients, but the approach only works on a few types of malignancies, leaving few treatment options for most cancer patients with solid tumors.

Now, in two related papers published April 28, 2021, in Science Translational Medicine, researchers at UCSF have demonstrated how to engineer smart immune cells that are effective against solid tumors, opening the door to treating a variety of cancers that have long been untouchable with immunotherapies.

By “programming” basic computational abilities into immune cells that are designed to attack cancer, the researchers have overcome a number of major hurdles that have kept these strategies out of the clinic up to now. The two new papers show that the resulting “smart” therapies are more precise, flexible and thorough than previous approaches, and the researchers say that their approach may be ready for clinical trials in the near future.

In one paper, research teams led by Wendell Lim, PhD, chair and Byers Distinguished Professor of cellular and molecular pharmacology, and Hideho Okada, MD, PhD, the Kathleen M. Plant Distinguished Professor of neurological surgery, tested the system in glioblastoma, the most aggressive form of brain cancer that affects adults and children, and which physicians have yet to successfully treat with immunotherapies due to the complexity of the tumors. The team showed the new system, which uses a two-step process to hunt down cancer cells, could completely clear human patient-derived tumors from the brains of mice without the dangerous side effects or high risk of recurrence currently associated with immunotherapy treatment in solid tumors.

In the second paper, Kole Roybal, PhD, assistant professor of microbiology and immunology, and Bin Liu, PhD, professor of anesthesia at UCSF, led a study showing how components of this system can be switched out like the heads of an interchangeable screwdriver to target other difficult-to-treat cancers in other parts of the body. The team also identified a particularly important set of “screwdriver heads” that could make powerful tools against cancers of the ovaries, lungs and other organs, which together kill tens of thousands every year.

In addition, both papers address the issue of so-called “T-cell exhaustion,” a long-standing challenge in which traditional CAR-T cells — the re-programmed intruder-hunting immune cells behind some of the most promising cancer immunotherapies — tire out when engaged in prolonged battles against the cancer. The new smart cells stay consistently strong through the entire fight, conserving their energy by switching to a standby mode when not directly engaged with the cancer.

“These findings address all critical challenges that have been in the way of developing immunotherapies for patients who suffer from these cancers,” said Okada, who also serves as director of the Brain Tumor Immunotherapy Center at UCSF. “This science is ready to move towards clinical trials.”

Expanding Immunotherapies to Deadly Brain Cancers
Glioblastomas are a particularly tragic case in which patients so far haven’t been able to benefit from CAR-T cells. Every year, over 20,000 adults in the United States are diagnosed with glioblastoma or other types of malignant brain cancer, and with current treatments, the prognosis is grim.
“It’s like a death sentence,” says Okada, noting that brain tumors are also the leading cause of cancer-related mortality and morbidity in children. “The outcome for malignant brain tumors in kids remains dismal.” Okada, who is an expert in brain cancers, partnered with Lim, who was developing novel cell engineering technologies, in the hopes of changing this.

Previous work had identified a molecule that is frequently found on glioblastoma cells, giving researchers hope that CAR-T cells could target this molecule and do away with the deadly cancer. Though this strategy was effective in killing some glioblastoma cells, not all glioblastoma cells display this molecule. This allowed some cancer cells to evade the CAR-T therapy and eventually resulted in the cancer’s return.

Targeting other molecules came with the opposite, but equally perilous problem. Though some molecules are found on glioblastoma cells, they’re also found on healthy, non-brain tissues such as the liver, kidney, esophagus and genital organs. Targeting cells that display these molecules with CAR-T could damage healthy tissue and put patients in danger. This catch-22 leaves clinicians without an ideal molecular target, a pervasive problem that has thwarted CAR-T’s use in most solid tumors.

The scientists devised a solution to this problem by employing a system called synNotch, a customizable molecular detector that Lim’s lab has been perfecting for several years. The synNotch system lets scientists program CAR-T cells to detect specific molecules found on the surface of cancer cells, ensuring that CAR-Ts attack only when they encounter the molecules they’re programmed to target.

To kill glioblastomas, the team took a novel, two-step approach. The first step uses synNotch to give CAR-Ts the ability to carefully judge if they are in a tumor versus other parts of the body, while a second set of synNotch sensors ensures a strong and comprehensive tumor killing response. Once the CAR-T cells confirm that they are in the tumor, the second set of sensors are activated, allowing the CAR-Ts to detect and kill glioblastoma cells based on multiple brain-tumor molecules. This two-step process leads to more complete tumor killing and prevents tumor cells from accumulating simple mutations that would allow them to evade CAR-Ts.

Experiments described in the paper show that this strategy is effective. In mice with human patient-derived glioblastomas, synNotch CAR-Ts wiped out tumors that weren’t cleared by normal T-cells or traditional CAR-Ts, with no signs of dangerous side effects.

“We’ve been saying for a while that we should think of these cells like computers — smart enough to integrate multiple data points and make complex choices,” said Lim, who also directs the Cell Design Institute at UCSF. “Now we’re seeing this working in a real-world model of a very deadly cancer for both adults and children.”

SynNotch Is a Flexible, Powerful System for Building Smarter Immunotherapies
The second paper further demonstrated the efficacy of this approach by identifying additional molecular targets for the synNotch system. The researchers searched public cancer databases for molecules found in tumor cells that could be useful in CAR-T therapies against now-intractable diseases. They found a molecule called ALPPL2 that’s common to many forms of cancer, including the asbestos-driven mesothelioma as well as ovarian, pancreatic and testicular malignancies. Importantly, the molecule is rarely found in healthy tissue.

In tests of synNotch circuits that were engineered to detect ALPPL2, CAR-T cells were able to recognize and kill mesothelioma and ovarian cancer cells with precision. “We can build cells that recognize ALPPL2 and then upregulate other sensors against more general tumor antigens,” said Roybal, also a founding member of the Cell Design Institute. “This is a completely viable, clinical grade antigen we can use to build cell therapies for use in people.”

A striking finding from both studies is that synNotch CAR-Ts maintained stable levels of activity throughout the cancer killing process, eliminating the challenge of T-cell exhaustion, which hinders traditional CAR-T therapies. Researchers believe exhaustion occurs because traditional CAR-Ts are designed to continuously express a kill switch, meaning they are always on and eventually deplete their resources, leading to a “cell that isn’t doing much of anything,” Roybal said.

“Amazingly this wasn’t the case in our synNotch systems,” he said. The researchers found that synNotch CAR-T cells remain in standby mode until they identify the cancer, conserving their energy. “These papers show that there are a variety of reasons these synNotch T-cells could be better than the current state-of-the-art CAR-T cell technology.”

 

2021 Retreat Registration Forms Are Here!

 

It's that time of year! If you are interested in applying for a spot at the retreat, please fill out the three forms you will find by clicking the link below.

You can either email the forms to mastrangelom@comcast.net or you can print, fill out and then mail the PDF forms to: 

Margaret Mastrangelo

4 East Commons Dr.

Hadley, MA 01035

The three forms are available by clicking on the following link:

2021 TTT Registration Forms

There you will find the instructions for the application, as well as three documents that will need to be completed and returned in order for your application to be accepted for review. 

To complete these forms online and return via email:

• Once you click on the above link, right click "TTT 2021 Registration Forms" at the top of the page. 

• Click "Download"

• Complete the forms through your PDF viewer OR print the forms and fill out by hand to send.
• If you complete your forms on your computer, email them to: mastrangelom@comcast.net
• If you complete your forms by hand, you can:
• mail to:

Margaret Mastrangelo

Hadley, MA 01035

4 East Commons Dr.

• Scan and email your documents to: 

mastrangelom@comcast.net

Survivor Relief Fund

 The National Ovarian Cancer Coalition offers the following. See NOCC website for further details.

NOCC Survivor Relief Fund

The Reality: Here & Now
Times have changed, ovarian cancer has not.

"Although the world around us looks a little different these days, one thing that will never change is our commitment to you, our NOCC community. You will remain at the heart of everything that we do - it is just that simple"
Melissa Aucoin, Chief Executive Officer

Our community needs our support now more than ever. Women and their families are facing significant hurdles beyond their ovarian cancer diagnosis and treatment - they are confronting additional concerns that are weighing heavily on their minds during this health crisis. After speaking with our community, we learned that there are two areas where we can provide support assistance and relieve added stress caused by COVID-19.

The Future: We are Here for You Now & Always
We are pleased to announce the launch of the National Ovarian Cancer Coalition Survivor Relief Fund to deliver support services to our Survivors and Caregivers through two additional programs that assist with financial burden and hardship during these difficult times. 

• Teal Comfort for the Soul
  No women should have to worry about making sure they have a warm meal on the table when dealing with ovarian cancer. With this program, we will ensure quality prepared food will be delivered weekly. Teal Comfort for the Soul will allow our community with compromised immune systems to stay home and receive healthy meals at their doorstep. 
• Teal Comfort for the Mind
  We understand the stress of a new diagnosis, the anxiety of a recurrence, or the pressures that come from being a Caregiver can be emotionally overwhelming. We have partnered with BetterHelp to provide emotional support to anyone impacted by ovarian cancer. This opportunity includes a subscription with access to one-on-one licensed counselor sessions. Survivors and loved ones can connect with their counselor through a variety of ways; phone, video, live chat, or text in the comfort of their own home.  

TTT Registration Opens June 15 - NOT JULY 15

Please note that there was an error in the TTT brochures that were mailed out a while ago which stated that registration begins on July 15.

Please note that the retreat registration will open on June 15th and women will be notified by 'phone or email of their acceptance by July 23rd. We will continue to accept applications however, honoring those who followed the dates on our TTT brochure so that NO ONE will be penalized!

We cannot express enough our deep dismay that this error got past a number of proof readers.

Ovarian Cancer: Treating This As a Chronic Disease

 

This article was originally posted CURE Today on April 1, 2019. Written by Deborah Abrams Kaplan

Women with this disease are living longer, despite common recurrence.

 When Luci Berardi received a stage 4 ovarian cancer diagnosis in October 2010, she did not want to know her chances of survival. The physician told her family she'd be lucky to make it through Christmas, but no one passed that on to her. "I knew I had cancer and needed chemotherapy. It was bad enough (that) I knew it was stage 4," Berardi says. She focused on her treatment and healing and revamped her diet, while still teaching yoga and working part time doing administrative work for a dental practice.

About 85 to 90 percent of ovarian cancers are epithelial cancer. For those with stage 4 disease, "the statistics may say that 17 to 20 percent will survive five years, but it's not zero," Berardi says. "People survive." Survival rates are higher for other ovarian cancers — for all types, the five-year relative survival is 47 percent. If the disease is found early and has not spread outside the ovary, that rate jumps to 92 percent.

Like Berardi, women are living longer with ovarian cancer, and it's increasingly seen as a chronic disease. Front-line, or initial, treatment hasn't changed much in the past decade. But in recent years, new treatments have been added to the mix. These include oral therapies instead of IV; combination, immuno- and anti-angiogenic therapies; and PARP inhibitors. Most of these are for recur­rent disease and may be based on genetic testing results. For the estimated 22,530 women a year who receive an ovarian cancer diagnosis in the United States, this is good news. Testing for genetic mutations may look at inherited mutations, which a person is born with, and show a higher likelihood of cancer risk. Genetic testing can also be done on the tumor tissue, showing genetic changes that were acquired later, and results may indicate whether specific treatments are more likely to help.

Luci Berardi says she views her disease no different than someone who has high blood pressure or diabetes.

THE STANDARD APPROACH

About 75 percent of women with ovarian cancer receive their diagnosis when the disease is stage 3 or 4. "The majority of them can be treated with curative intent," says Pam Khosla, M.D., section chief of hematology and oncology at Sinai Health System in Chicago. That includes debulking surgery, in which surgeons remove as much as they can of the visible tumors and cancerous tissue. Microscopic cancer cells and cancerous tissue that can't be surgically removed are then treated with chemotherapy — typically, carboplatin and Taxol (paclitaxel).

Some doctors recommend surgery before the standard six cycles of chemotherapy, whereas others recommend three cycles, surgery and then three more cycles. Surgery may be the first step if the tumor is causing pain or physical issues, such as a bowel obstruction, or the physician is unsure whether cancer is causing the problems.

That was the case for Erica Roberts. In December 2015, she had abdominal cramping so severe, she thought her appendix was bursting. A trip to the emergency room and radiology imaging led the physician to believe she had an ovarian cyst. Only during the operation several weeks later did he realize she had stage 3A high-grade serous carci­noma, and he removed her ovaries and affected organs.

Not all patients are candidates for surgery — maybe the cancer is too extensive or the surgeon doesn't think enough diseased tissue can be removed. The patient would typically receive chemotherapy every three weeks — two weeks on, one week off — or weekly, depending on the oncologist. After three cycles (or nine weeks) of treat­ment, imaging is repeated and cancer antigen (CA) 125 — a protein found in the blood — is measured. A CA 125 blood test can indicate a rise in ovarian cancer growth and determine how well the patient is responding to chemo­therapy. If chemotherapy is working, patients who have not yet had surgery may be scheduled.

In June 2018, the Food and Drug Administration (FDA) approved Avastin (bevacizumab), a targeted therapy that belongs to a class of drugs called angiogenesis inhibitors, to use with chemotherapy and then alone for about a year, for women with stage 3 or 4 ovarian epithelial cancer that has been surgically removed. It was shown to increase the average amount of time before a recurrence. "To date, it hasn't led to improvement of overall survival, but it keeps the cancer in remission four months longer than not using it," says Ursula Matulonis, M.D., director of gynecologic oncology at the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston.

MAINTENANCE AND SUBSEQUENT TREATMENTS

About 70 percent of women with ovarian cancer will face a recurrence, according to the Ovarian Cancer Research Alliance. However, recurrence also varies by stage of disease. Maintenance therapy can help prevent the cancer from returning after the completion of chemotherapy. Up until a few months ago, Lynparza (olaparib), a PARP inhibitor, was approved only for patients who had a recurrence. But in December 2018, the FDA approved the oral medication as a first-line maintenance treatment for women with BRCA inherited (familial) genetic mutations — BRCA1 and BRCA2 raise a person's risk of developing certain cancers, such as ovarian, breast and prostate — and advanced-stage disease. The drug targets an enzyme inside cancer cells to make it less likely that the cancer cell will repair itself, resulting in cell death. "It's shown impressive results," Matulonis says, with an increase of three years in progression-free survival compared with placebo.

Regardless of BRCA mutation status, PARP inhibitors were already approved as a maintenance strategy, says Maurie Markman, M.D., president of medicine and science and a medical oncologist with Cancer Treatment Centers of America in Philadelphia. The PARP inhibitor Rubraca (rucaparib) is approved for women with BRCA-positive advanced ovarian cancer who received multiple lines of chemotherapy treatment, and Zejula (niraparib) was approved after subsequent chemo­therapy, no matter the BRCA status.

Although chemotherapy is the standard initial treatment, it doesn't work for everyone. Diane Davis learned of her stage 2C ovarian cancer diagnosis in January 2017. After having 18 inches of her sigmoid colon removed because of tumor involvement, she began chemotherapy. Three cycles in, she felt just as bad as she had before surgery. Radiology studies showed that the cancer had grown back, spreading into her lymph nodes. "I was dumbfounded," she says. "No one ever says people don't make it through chemo."

Genetic testing revealed that her tumor was microsatellite instability high (MSI-H) — cancer cells that have a greater than normal number of genetic markers and respond well to immunotherapy. Although immunotherapy has not been highly successful with ovarian cancer, Keytruda (pembrolizumab) was approved in 2017 for adult and pediatric patients with unresectable or metastatic solid tumors identified as MSI-H, just at the time she needed it. Davis started the two-year treatment that June, and in August, a CT scan showed that the new tumor was gone and the lymph node tumors shrunk. "We all cried," Davis says. "My doctor said he'd never seen anything like it."


IMPORTANCE OF GENETIC TESTING

Genetic testing should be done on all patients at the start of treatment, Matulonis says. This often involves blood tests that look at hereditary mutations. "Right now, there are at least 11 implicated genes for high-risk transmis­sion," she says. She recommends including as many genes as possible in the testing panel, not just the BRCA mutations. A genetic panel also covers Lynch syndrome, an inherited condition that increases a person's risk of developing cancers such as colon, endometrial and ovarian and is linked to several gene alterations. Davis is living with Lynch syndrome. In addition to those that are inherited, mutations can also be acquired in the tumor.

Tumor assays can be used that may point to experimental therapies that attack the cancer's vulnerabilities.

Although genetic testing is now highly recommended, not all patients think to ask for it. "A lot of people in my local support group hadn't heard of it," Davis says. "It's important — not only knowing that you might have a genetic mutation that could give you other types of cancer but (also) to know (about) other treatments avail­able. If my doctor hadn't done testing on my tumor, I couldn't get immunotherapy, and I'd not be talking to you today."

Berardi also found genetic testing helpful. When she had a recurrence in 2014, her doctor recommended chemotherapy because she did well on it previously. She heard about genetic testing and sent a tissue sample from the baseball-size tumor the surgeon found during surgery. The genetic profile showed that the standard chemo­therapy would not work well for the tumor. Instead, her doctor gave her etoposide, a chemotherapy less commonly used in ovarian cancer. It put her in remission, with no evidence of disease.

UNDERSTANDING PALLIATIVE CARE

Living with a chronic disease may affect a person physi­cally and mentally. For instance, chemotherapy-related fatigue and nausea are common. Women with ovarian cancer also face sexual health concerns, such as painful sex, libido loss, early menopause and infertility. All these symptoms can lead to mental health issues such as depression and anxiety.

Through palliative care, health care providers can help patients through these concerns and improve their quality of life. "Palliative care doesn't mean hospice," Markman says. "'Palliate' means 'to improve, to make better.'" He prefers the term "supportive care." The goal of palliative care is to prevent or treat the symptoms of the disease as early as possible, according to the National Cancer Institute.

Patients within Sinai Health System meet with a multidisciplinary team, including a pharmacist, supportive oncology coordinator, nurse navigator and behavioral therapist, to schedule care, answer questions and address any issues, Khosla explains. Using this team approach has both improved patient satisfaction and quality of life and reduced hospital visits. Some hospitals reserve the palliative care specialists for those whose lives are heavily affected by treatment, though nurses and oncologists are trained to help with symptoms. "If you're feeling side effects, chances are they have something to help you get better," Roberts says of her oncology nurses. "You don't get a gold medal for going through chemo without taking pain pills."

Receiving palliative care can improve more than how a person feels, according to a study published in Annals of Behavioral Medicine, which showed that it can keep patients alive longer. Researchers analyzed studies that compared patients with advanced cancer who received palliative care with those who didn't. They found that the palliative care group lived 4.5 months longer.

LIVING IN REMISSION

As many as 20 percent of patients with advanced stage disease have no recurrence after front-line therapy. Still, life after treatment doesn't necessarily bring a sense of relief, especially when it's time for periodic CA 125 testing.

Roberts finished her front-line treatment in 2016, including surgery and IV and intraperitoneal chemo­therapy. She's been in remission since. "The closer I get to the three-month checkup, the drumbeat gets louder," and she thinks about the cancer constantly, she says. In addition to taking medications to handle her anxiety, she sees a counselor and goes to a Gilda's Club support group. "The physical scars are just about healed. The emotional footprints are left," she says.

Although difficult, the treatment process can still make women feel tended to. Once chemotherapy finished, Carol Hyman felt a cloud hanging over her — she felt alone and concerned about recurrence. "Even though the chemo is terrible, you're being taken care of; you're checked on continuously," she says. Hyman received a stage 3B diagnosis when she was 65. Physicians found three large tumors and removed about a dozen lymph nodes.

In addition to finding her own support network, Berardi changed her diet. She sees a naturopath to get high-dose vitamin C infusions and supplements to reduce inflammation. She eliminated processed sugar and dairy and decreased her intake of carbohydrates. She takes a small amount of naltrexone and metformin, prescribed by her naturopath, in hopes of preventing recurrence. Patients sometimes use naltrexone at low doses to inhibit cancer growth and balance the immune system. Metformin targets stromal inflam­mation, which may provide resistance to cancer growth. Neither is approved by the FDA for ovarian cancer treatment because of lack of clear proof from controlled clinical trials, but anecdotal evidence suggests that some patients may benefit from these medications. "I'm trying to create an internal environment that is not conducive for the cancer to survive," Berardi says.

Although she has had two recurrences, she says, the experience was in a way a blessing. "It took some of the anxiety away," Berardi says. "My mindset now is that it's a chronic disease, nothing different than high blood pressure or diabetes. You have to monitor it." She also wrote a book, "Chasing Rainbows: My Triumph Over Ovarian Cancer," because she was unable to find that sort of resource when she first received her diagnosis.

Hyman also finds support groups comforting. At her first meeting, she realized that every woman there had had at least one recurrence. Even though that talk can be scary, Hyman says, it gave her hope. One woman's comment left a lasting impact: "I'm not dying from ovarian cancer — I'm living with ovarian cancer."

OCRA "Staying Connected" Weekly Support Discussions

 

Gynecologic cancer patients and survivors are invited to join weekly virtual support discussions facilitated OCRA's Oncology Licensed Clinical Social Worker. This online gathering is a great way to meet others, share experiences and connect while social distancing. Registration is required. Please click here for group descriptions and to register.

Utility of HRD Testing in Ovarian Cancer Expands, but Standardization Remains Elusive

 

This article first appeared in OncLive and was written by Hayley Virgil. 

Thomas C. Krivak, MD, discusses the significance of HRD in ovarian cancer, approved and prospective HRD tests, and considerations for genomic testing in this population.

Two tests for homologous recombination deficiency (HRD) have been FDA approved for patients with ovarian cancer: myChoice CDx and FoundationOne CDx. Their results provide important information that can be used to guide treatment decisions, according to Thomas C. Krivak, MD, but differences between these next-generation sequencing assays can make standardization of their use difficult.

myChoice CDx, developed by Myriad Genetics, was approved by the FDA in May 2020 as a companion diagnostic for niraparib (Zejula) monotherapy and olaparib (Lynparza) plus bevacizumab (Avastin) in patients with advanced ovarian cancer, respectively, and FoundationOne CDx, developed by Foundation Medicine, was approved in November 2017 to identify molecular abnormalities in several solid tumors, including ovarian cancer.1-3 Although both tests are useful, the clinical data to support myChoice CDx may be more compelling, according to Krivak.

Two tests for homologous recombination deficiency (HRD) have been FDA approved for patients with ovarian cancer: myChoice CDx and FoundationOne CDx. Their results provide important information that can be used to guide treatment decisions, according to Thomas C. Krivak, MD, but differences between these next-generation sequencing assays can make standardization of their use difficult.

myChoice CDx, developed by Myriad Genetics, was approved by the FDA in May 2020 as a companion diagnostic for niraparib (Zejula) monotherapy and olaparib (Lynparza) plus bevacizumab (Avastin) in patients with advanced ovarian cancer, respectively, and FoundationOne CDx, developed by Foundation Medicine, was approved in November 2017 to identify molecular abnormalities in several solid tumors, including ovarian cancer.1-3 Although both tests are useful, the clinical data to support myChoice CDx may be more compelling, according to Krivak.

Importantly, each test defines HRD in a different way. myChoice CDx identifies HRD based on deleterious or suspected deleterious mutations in BRCA1/2 and/or a positive Genomic Instability Score.4 In comparison, FoundationOne CDx defines HRD based on tumor tissue with BRCA positivity and/or a high loss of heterozygosity.5 Because approved and prospective tests have different definitions of HRD, standardization may not be possible, according to Krivak.

“I do not believe there is going to be standardization,” Krivak said. “I would have to say HRD is this concept that each company is going to define, and then it is going to be up to the individual clinician, whether that is a pathologist or someone who specializes in genetics and cancer, who will say, ‘We think this is the best test for these reasons, and this is what we are going to do in our practice.’ I do not think a perfect test is out there.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on ovarian cancer, Krivak discussed the significance of HRD in ovarian cancer, approved and prospective HRD tests, and considerations for genomic testing in this population. He is director of the Ovarian Cancer Center for Excellence and cochair of the Society of Gynecologic Oncology Research Institute at Allegheny Health Network.

OncLive®: What are some of your key treatment considerations for patients with ovarian cancer?

Krivak: For patients with advanced ovarian cancer, you have to always think about germline testing. We do not want to have everyone focused on tumor testing. First, think about a good surgery, chemotherapy for the majority of patients, and then the germline genetic testing component. That is important [to] help us to determine who may qualify for medications after chemotherapy.

Also, an ounce of prevention is better than a pound of cure. [If] we can identify patients who have germline mutations that place their family members at a higher risk for ovarian cancer, then we can intervene in those patients with risk-reducing surgery. With technology, if you have a patient who has a daughter aged 21 [years and] tested positive, we are going to make interventions at that point for her. However, even [in terms of] reproductive capabilities, there are [institutions] in the country where you can do prenatal genetic testing before you implant the embryos.

Also, we really have to do some type of molecular interrogation to classify and select our medications. We have numerous medications that we can use to treat these patients; now we have to figure out what the optimal timing is to initiate these medications, as well as what sequence [they should be given in]. Hopefully, some of this molecular information will help.

How does HRD testing fit into the molecular testing landscape?

Someone who has HRD and is known to be BRCA [wild-type] is going to triage to some type of maintenance strategy. If patients have a germline mutation, testing them for HRD up front probably is not a great use of resources because you are going to use an oral medication. If that patient recurs, you may want to test them later on or you may want to actually use a different test; you may not want to use an HRD test. You may say, “I want to get more molecular information, such as tumor mutation burden and DNA mismatch repair [MMR] status.” This other type of information may be gained through molecular interrogation.

[We should] test up front. If someone is going to receive chemotherapy followed by maintenance in the recurrent setting, if they have not received a PARP [inhibitor and] have not been tested, especially the platinum-sensitive [patients, testing] may help triage [what] to use: oral medications or potentially intravenous medications. Or [the choice may be to not use any if the patient is] HRD proficient.

What we are really testing is the tumor. To me, that can be looked at as unfavorable if you do not have any tumor [tissue] available and maybe the patient did not undergo debulking. If I’m going to test a patient, I want to test the most recent biopsy because chemotherapy may potentially induce some changes within the tumor itself. Most of us would say, if someone has recurred [for] the third or fourth [time], and you are going to do some molecular interrogation at that time, you would want to biopsy that patient and use the most recent tumor [specimen] that you can get. If you cannot get that, then you go back to the initial specimen.

As to why [we] want to test, [it is] so we can get more information on how to best treat patients. Certain medications may be indicated for only 3% to 5% of patients. Microsatellite instability or MMR deficiency may be present in only 3% to 5% of patients with ovarian cancer, but those patients now qualify for checkpoint inhibition. That may open up that strategy for that patient who may not otherwise be [considered for it].

We do not have all the answers and we do not know how to sequence chemotherapy appropriately. This is another piece of information that will help guide us through how we are going to sequence treatments. How we [choose to] treat our patients will be based upon curability and noncurability, prior treatment-related adverse effects, and possibly cost and distance to [the institution]. If we look at the molecular profile of the tumor, that may [present] us [with] other ideas for someone who may have not experienced any response in the past.

Do you have a preference among available HRD tests?

Each company is developing a test [and is defining what] HRD is. We, as clinicians, need to be able to say, “This patient is homologous recombination deficient [according to] this test,” whether it is the Caris Life Sciences test or the Tempus test. The 2 tests that are FDA approved are by Myriad and Foundation Medicine. All those companies I mentioned are very solid companies with good research, but, no doubt, Myriad has really done a tremendous amount of research to develop their test. Foundation Medicine [has, as well,] in very different ways. However, when someone calls me and says, “Hey, listen, I have this patient who has this, this, and this, and they are HRD positive,” my immediate reflex is to answer, “Wait a second, how do you define that? Is that by Myriad or Foundation Medicine?”

Do you believe HRD testing will ever become standardized?

I wish we could say, “HRD is defined as this.” If you had spoken to me 3 years ago, I would have said that I define HRD as any molecular alteration within that homologous recombination pathway…I do not want to say that I have no data, [but we] have very limited data. It is mostly intuition. The way I defined [HRD back then is not how I define it now]. We are probably never going to have a standard definition for [HRD]; it probably just boils down to economics. All companies want to say that their test is [best].

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NOCC's Annual "Together in Teal - No Boundaries"

On Saturday, September 25 NOCC will unite across the country for Together in TEAL® - No Boundaries ! We’ll use our voices and actions during the weeks leading up to event day to turn our country TEAL from coast-to-coast by showcasing our activism! On September 26, kick off the day with an activity YOU CHOOSE. Run, walk, ride, skip, jump -- whatever gets you moving safely. Then come together with family, friends, and supporters and watch our online National Broadcast Celebration featuring stories and celebrating the accomplishments of our TEAL community. 

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Pursing PARP Beyond HRD+ Ovarian Cancer

 

Single-agent olaparib (Lynparza) and niraparib (Zejula) have shown a significant extension in progression-free survival (PFS) as frontline maintenance therapy in patients with homologous recombination deficient (HRD)–positive ovarian cancer, explained Hye Sook Chon, MD, who added that although the addition of bevacizumab (Avastin) to niraparib demonstrated a numerical improvement in PFS in homologous recombination proficient tumors, the combination may not be the optimal treatment strategy in this patient population.

This article appears in OncLive  and was written by Caroline Seymour.

Hye Sook Chon, MD, teases out some of the differences between the data with PARP inhibitors in the frontline maintenance setting and shed light on ongoing research with combinations that could broaden their utility in patients with advanced ovarian cancer.

Single-agent olaparib (Lynparza) and niraparib (Zejula) have shown a significant extension in progression-free survival (PFS) as frontline maintenance therapy in patients with homologous recombination deficient (HRD)–positive ovarian cancer, explained Hye Sook Chon, MD, who added that although the addition of bevacizumab (Avastin) to niraparib demonstrated a numerical improvement in PFS in homologous recombination proficient tumors, the combination may not be the optimal treatment strategy in this patient population.

“[Patients with] homologous recombination proficient [tumors] need to have more study. For those patients, ongoing clinical trials are looking at immunotherapy or immunotherapy with a PARP inhibitor with or without bevacizumab. We’d like to see whether we can [make some progress for] those patients with unmet need. We may be able to use biomarkers as a starting point for more biomarker-driven treatment options in this patient population,” said Chon.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on ovarian cancer, Chon, a gynecologic oncologist at Moffitt Cancer Center, teased out some of the differences between the data with PARP inhibitors in the frontline maintenance setting and shed light on ongoing research with combinations that could broaden their utility in patients with advanced ovarian cancer.

OncLive®: How has the use of bevacizumab changed since the FDA approved it for use in combination with a PARP inhibitor as frontline maintenance treatment?

Chon: The indication for bevacizumab as a maintenance treatment has been a roller coaster until it got approval back in 2017, even though the first publication came in many years prior to that FDA approval. Even though there is a benefit in PFS with bevacizumab maintenance that is clearly more beneficial in a certain patient population who has suboptimal debulking or patients with stage IV ovarian cancer.

I usually use bevacizumab as a maintenance treatment in not all my patients with ovarian cancer, but rather those with the high-risk features I just described. Using bevacizumab in the era of PARP inhibitors as maintenance treatment is based on the PAOLA-1 study. [The study showed that] using bevacizumab in combination with a PARP inhibitor in the HRD-positive [population is associated with] a benefit in PFS. I use bevacizumab with a PARP inhibitor in those patients.

Have PARP inhibitors shown benefit in all patients, irrespective of HRD status?

It is an exciting time for us as gynecologic oncologists that treat patients with ovarian cancer because of the benefit we’ve observed from multiple phase 3 randomized trials with maintenance treatment. However, we are aware that not everybody will benefit from bevacizumab or a PARP inhibitor in the maintenance setting.

The PRIMA trial, even though the benefit [was seen in] all-comers, regardless of BRCA mutation or HRD [status], the true gain from the maintenance treatment compared with the [PAOLA-1 trial], albeit a different patient population and eligibility criteria, was not as robust.

I’m so grateful that we identified those patients who can benefit [from frontline PARP maintenance].

What role could checkpoint inhibitors play in frontline maintenance therapy? Could they be combined with PARP inhibitors?

Immunotherapy does not appear to be as [effective in ovarian cancer as in] other solid tumors such as lung cancer and melanoma based on the data that have been presented so far. There are multiple clinical trials, especially in lung cancer, using combination treatment with chemotherapy [and immunotherapy]. In ovarian cancer, combination approaches rather than single-agent approaches may be more beneficial. We also are aware that there can be more of a synergistic effect between bevacizumab, PARP inhibitors, and checkpoint inhibitors. We will continue to work on defining patient populations who can benefit [from these approaches].

However, we thought that there would be a synergistic effect between bevacizumab and a PARP inhibitor, but the PAOLA-1 study showed modest activity with a more additive benefit rather than a synergistic benefit. We are hoping for more treatment options in that patient population, but caution needs to be taken based on what we learned from the PAOLA-1 study.

What is the importance of not generalizing these study results for application in practice?

We are very excited to have multiple, large, randomized clinical trials in the setting of frontline maintenance treatment. However, we need to be cautious when we interpret or bring these data into clinical practice that we cannot compare [these studies] head-to-head. We need to understand the patient population of each study, and also the primary objective from that study.

When you dig into each study, you will see different patient populations between SOLO-1, PAOLA-1, PRIMA, and GOG-218. You can’t generalize PFS when you apply these data in your clinical practice. Moreover, the patient population you’re dealing with may be different from other colleagues. It is our job as gynecologic oncologists and clinicians sitting across the table with patients to know your patients more than anyone else. From those phase 3 clinical trials, it is your job to interpret those data and apply them to your patient population.