Dara Chadwick

Patients with non-secretory myeloma, a disease affecting a relatively small number of individuals, can face obstacles including difficulties in receiving a diagnosis, a scarcity of available clinical trials and a lack of connection with fellow patients.

About 98% of people with multiple myeloma have proteins in their blood that can be measured and followed over time, according to Dr. Sascha A. Tuchman, a hematologist and medical oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill.

When doctors do blood tests for multiple myeloma, because the myeloma cells stay in the bone marrow, the tests can’t typically show the actual myeloma cells, Tuchman notes.

“However, in most cases, multiple myeloma conve­niently makes those immunoglobulin proteins that circulate in the blood,” he says. “We can measure those proteins and that enables us to track the disease. As levels go up or down, that typically tells us the myeloma in the person is growing or shrinking.”

However, that’s not the case for everyone with multiple myeloma, as 1% to 2% of patients with myeloma don’t secrete any proteins that can be measured in blood or urine.

“Non-secretory myeloma is not necessarily a separate disease,” explains Dr. Nisha Joseph, a hema­tologist and medical oncologist at the Winship Cancer Institute at Emory University in Atlanta, Georgia. “It presents differently in that when we are evaluating these patients either at diagnosis or relapse, we notice that they don’t secrete this abnormal paraprotein or monoclonal protein in either their blood or urine, which is an important part of our diagnostic workups.” (Paraprotein and monoclonal protein are other terms for immunoglobulin secreted by myeloma.)

According to Joseph, the definition of non-secretory myeloma is that the patient has a negative serum immunofixation (a test for specific proteins in the blood), negative urine immunofixation (a test for abnormal proteins in urine) and normal serum free light chain assay (a blood test for proteins made by plasma cells).

“These are three of the tests we use to detect the abnormal protein that myeloma cells secrete,” she says. “It is essentially a surrogate marker for how much myeloma there is in the body and, usually, the bone marrow.”

It’s been nearly 20 years since Vicki Jones was diagnosed with multiple myeloma, a cancer of the plasma cells. Much of her past two decades have revolved around monthly blood tests to monitor levels of a protein — in her case, immunoglobulin A lambda (IgA) — secreted into her blood by myeloma cells.

Non-secretory myeloma is rare and may become a lonely journey, but Vicki Jones found comfort in a support group for patients like her.

“For 17 years, IgA was a completely reliable marker,” Jones says. “We tested it every month and knew exactly whether chemo­therapy was working. I had a stem cell transplant in 2007 and was on many different chemotherapy types after that. I was never in a complete remission.”

Then, something changed. Jones, 71, of Spokane, Washington, says she was taking a three-drug combination to control the myeloma. She took Darzalex (dara­tumumab), a monoclonal antibody that blocks proteins fueling myeloma cell growth, as well as a corticosteroid drug called Revlimid (lenalidomide) and an immunosuppressant called dexamethasone.

Jones says her IgA levels had been consistent for several years. With her doctor’s blessing, she stopped her medication to get a COVID-19 vaccine. About a month later, her blood test showed her IgA levels had dropped. In fact, her numbers had improved so much that her doctor told her she could take a break from the drugs.

The next month’s regular blood test showed her IgA numbers had dropped again, this time to a level that was better than they ever had been, Jones says.

“That’s when I said, ‘That’s not the way things go for me,’” she says. “‘Miracles do happen, but I don’t think this is one. Something is wrong.’”

A bone marrow biopsy confirmed her instinct. “I had relapsed big time,” she says. “I had 80% myeloma cells in my bone marrow, which is huge. That number had always been about 15% at the most through the years.”

To continue monitoring, Vicki Jones undergoes bone marrow biopsies every four months since she received her diagnosis of non-secretory multiple myeloma.

Her myeloma had become non-secretory myeloma, a rare condition in which myeloma cells don’t secrete or produce proteins. “I felt like I had been diagnosed all over again,” Jones adds. “On the outside, I was totally calm. But on the inside, I was scared to death.”

Plasma cells located in the bone marrow under normal circumstances help a person’s immune system by making proteins called immunoglobulins (antibodies) that bind germs and viruses and kill them. But when plasma cells become cancerous, they grow too much, invade spaces they’re not supposed to be in and secrete abnormally high levels of one clone of antibody protein but at the expense of the normal diversity of antibodies made by the collective immune system. That’s multiple myeloma.

Myeloma can cause a shortage of different blood cell types and brittle bones that break easily. Myeloma can also cause problems with the kidneys, such as kidney failure, when the kidneys stop working entirely due to the toxic effects of the high clonal antibody load.

Typically, myeloma cells live in the bone marrow and don’t circulate in the blood, but myeloma secretes immunoglobulin proteins into blood, after which the proteins are cleared through the kidneys and excreted into urine. Hematologist oncologists rely on these proteins as markers of myeloma activity to determine if myeloma is stable, improving or worsening.

Non-secretors present a diagnostic challenge, according to Tuchman. He notes that hematologist oncologists may suspect myeloma if a person has low blood counts or high blood calcium levels. Doctors may also detect holes in the bones (bone lesions) when someone has an X-ray or other imaging test.

“Those findings often prompt bone marrow biopsy, which leads to a diag­nosis,” he says.

Jones estimates that she has had at least 20 bone marrow biopsies since being diagnosed with multiple myeloma — four of which have been since she became a non-secretor. “It’s been pretty much every four months,” she says, noting that she also has regular PET scans.

Doctors don’t treat patients with non-secretory myeloma any differ­ently than they treat those who have myeloma that secretes proteins.

“Everything is exactly the same,” says Dr. Shaji Kumar, a hematolo­gist and internist at Mayo Clinic in Rochester, Minnesota. “Other than the difference in biology in terms of the secretion of the protein itself, we don’t really think the disease behaves differently when comparing the non-secretory type versus the secretory type.”

Most patients with multiple myeloma receive a combination of chemotherapy or targeted therapy drugs, along with a steroid. Some patients also have a bone marrow or stem cell transplant. However, multiple myeloma isn’t curable. That’s why monitoring the disease and its response to treatment is so critical. Patients with myeloma often relapse after some time in remission.

“Once the disease comes back, we try to use different combinations of drugs and mix and match them to make sure we have drugs that patients haven’t seen before,” Kumar notes. “We also look at side effects they have had with previous therapy, the logistics of administration and whether somebody can come to the clinic once or twice a week to get infusions or (whether) they prefer oral therapies. All those considerations go into making that decision.”

Monitoring patients for relapse is systematic for most individuals with myeloma, as they have intermittent blood and urine tests — but that’s not possible for non-secretors.

“We cannot monitor their blood tests month after month,” Joseph says. “There (are) no set guidelines on frequency, but we rely on serial bone marrow biopsies and PET scans, MRIs or some kind of definitive imaging.

Some patients with myeloma participate in clinical trials of multiple myeloma drugs, giving them access to new therapies. But that’s not typically an option for those with non-secretory myeloma, as the condition is so uncommon.

“There’s just not a lot of data on this, because non-secretory myeloma is a relatively rare phenomenon,” Tuchman says. “Most studies exclude non-secretory myeloma.”

That’s because, according to Tuchman, the standard systems for assessments of response on clinical studies, such as published response criteria by groups such as the International Myeloma Working Group (IMWG), are based on tracking the immuno­globulin protein patterns. Patients start a new treatment, myeloma cells die and make less protein, blood and urine immunoglobulin levels hopefully drop, and that tells clinical researchers, physicians and patients that the treatment is working.

In people with non-secretory myeloma, “it’s impossible to measure response by the standard, protein-based systems, and use those patients’ experience to learn what you’re trying to learn from the study,” he says.

Tuchman notes that large multi-institutional registry studies include databases that can be analyzed to provide some insight into the experiences of individuals with non-secretory myeloma. There’s also much to be learned from the patients themselves.

The HealthTree Foundation, which works to help patients with blood cancers learn about their disease, has started a support community specifically for individuals with non-secretory myeloma. Jones, who serves as a coach for HealthTree and co-leader of its non-secretory myeloma group, has been involved with the group since it began.

“It lets us compare notes and talk to one another and see [whether] things are consistent,” she notes. “Once I found other [patients] who were also non-secretors, it was just so comforting.

“We’ve had doctors come and talk to our group, and we’ve been encouraging them to use us. We’re telling them, ‘Hey, we are something you’ve never seen before; we are a very large group of non-secretors. I think that should be pretty useful to researchers. Here's your study right here — just ask us.”

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There is no difference in treatment for non-secretory multiple myeloma and multiple myeloma, an expert told CURE®.

Tracking a Mystery in Non-Secretory Myeloma 

After 14 months on a regimen of intravenous chemotherapy for metastatic breast cancer, Dr. Kelly Shanahan switched to an oral treatment with an aromatase inhibitor.

Photo credit: Danielle Hankinson of Kindred Soul Photography

Cancer is an intelligent disease. Tumor cells often find ways to outsmart therapies that once kept disease from progressing. Some genes develop changes, or mutations, that allow cancer to grow unchecked.

Such is the case with the ESR1 mutation, a genetic change that occurs in approximately 20% to 40% of people who have hormone receptor (HR)-positive breast cancer and are treated with certain hormone (endocrine) therapies.

“The majority of breast cancers — about two- thirds — have this protein called estrogen receptor,” says Suzanne Fuqua, a professor at the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston. “That receptor becomes the driver for the majority of breast cancers in women. If your tumor has the estrogen receptor present, it fuels the cells to grow and proliferate.”

Oncologists use a variety of endocrine therapies to treat patients with HR-positive cancers before and after surgery. When making treatment decisions, they evaluate a patient’s breast cancer type, whether they are pre- or postmenopausal and which treatments they have already received. They may treat Or patients may be treated with drugs that reduce the amount of estrogen in their body, known as aromatase inhibitors (AI), that are only effective in patients who are postmenopausal because the source of estrogen in this case is from the conversion of androgens to estrogens mediated by the enzyme aromatase. AIs include Femara (letrozole), Arimidex (anastrozole) and Aromasin (exemestane).

Fuqua says that during the past two decades, emerging science has led to increased use of AIs, adding that these agents seem to delay cancer recurrence “a little bit better” than SERMs.

“Everyone around the world pretty much switched their patients to aromatase inhibitors,” she says.

However, as the use of AIs in treating patients with breast cancer increased, clinicians noted a key change in those whose cancer had spread, or metastasized. When endocrine therapies denied estrogen receptor (ER)-positive cancers the hormone they needed to grow, certain genes mutations were favored selectively through the process of tumor evolution.

“The ESR1 gene is the gene that encodes for the estrogen receptor, a key driver of tumor initiation and tumor progression in hormone receptor-positive breast cancers,” says Dr. Rinath Jeselsohn, an assistant professor of medicine at Dana-Farber Cancer Institute in Boston. Estrogen receptors without a mutation need both estrogen and proteins known as coactivators to become activated, she says.

But when the ESR1 gene has a mutation, the estrogen receptor in the cancer cell changes and allows coactivators to bind to it without estrogen. In short, the estrogen receptor no longer needs estrogen to become active and help cancer grow. “This means that drugs such as aromatase inhibitors that block the production of estrogen will not be effective in the presence of an ESR1 mutation,” Jeselsohn says.

ESR1 mutations allow cancer to spread in patients being treated with certain endocrine therapies, according to Jeselsohn. “In patients who have primary hormone receptor-positive breast cancer, these mutations are very rare,” she says. “They really evolve when patients are treated with aromatase inhibitors.

In particular, they evolve during treatment with aromatase inhibitors in metastatic disease.”

For patients with metastatic breast cancer, ESR1 gene mutations require a therapeutic change to stop cancer from worsening.

Dr. Kelly Shanahan, 63, of South Lake Tahoe, California, is one of those people.

In April 2008, Shanahan was 47 and had her own busy obstetrics/ gynecology practice. After a routine mammogram revealed early-stage, HR-positive, HER2-negative breast cancer, she considered her options. As a busy doctor and mom to a then-9-year-old daughter, “I didn’t have time to drive 45 minutes each way, five days a week, for five to seven weeks for radiation therapy,” she says. Instead, Shanahan opted for a bilateral mastectomy.

When a biopsy confirmed cancer in one of her lymph nodes, she began a 16-week course of chemotherapy followed by an AI. But when the drug caused arthritis symptoms that made performing surgery difficult for her, she stopped taking it.

Later, excruciating back pain sent Shanahan for a PET scan and MRI. The results shocked her.

“I had cancer in every bone in my body,” she says.

She spent the next 14 months on a regimen of intravenous chemotherapy. When her treatment ended, Shanahan — by then retired from her medical practice — began taking Aromasin, an oral AI.

For six years, she had no evidence of active disease. But in April 2021, her disease progressed. A blood test known as liquid biopsy confirmed a mutation in the ESR1 gene and a mutation in the PIK3CA gene. Aromasin was no longer working.

“Most people get two years on an AI alone,” Shanahan says. “I got six years out of it.”

ESR1 mutations are not unexpected in people with metastatic breast cancer who have been treated with AIs. The mutation was first identified by Fuqua in the 1990s when she examined laboratory samples of metastatic breast tumors. She hypothesized that mutations in the estrogen receptor were allowing cancer cells to bypass the therapies used at the time and driving the metastatic behavior of cells.

Her research was controversial, she says. She notes that she was using metastatic tumors, whereas other breast cancer research focused on primary tumors. 

“Now the field has changed to where we know that the metastatic tumor is different from the primary tumor,” Fuqua says.

Larger studies done in 2013 and 2014 used next-generation sequencing to study metastatic samples, including research led by Jeselsohn, helped researchers “really start to understand the significance of ER mutations,” Jeselsohn says. “Since then, we’ve been learning more about them in the lab. In the clinic, we’re understanding more about the resistance they cause.”

Today, biopsies of metastatic tumors, liquid biopsies and tumor sequencing allow oncologists to target drug treatments to specific mutations such as ESR1. Previously, clinicians would typically treat people with a cancer recurrence in the same way their primary cancer had been treated.

With a liquid biopsy, Fuqua says, doctors can determine whether mutations are developing during treatment. “What we’ve found is that patients with ESR1 mutations quickly have another recurrence when they’re on an aromatase inhibitor alone,” she says.

There are other treatment options for people who develop resistance to AIs. Many get a monthly injection of Faslodex (fulvestrant). This selective estrogen receptor degrader (SERD) binds to the cell’s estrogen receptor and breaks it down, disrupting the cell’s signaling pathway. Shanahan was taking Faslodex and Ibrance (palbociclib), a CDK 4/6 inhibitor and a type of targeted therapy that blocks the CDK4 and CDK6 enzymes that fuel cell division, until September, due to progression of her disease. She is currently enrolled in an endocrine therapy clinical trial.

“When a patient develops an ESR1 mutation on an aromatase inhibitor in the second-line and beyond setting, we tend to use (Faslodex)-based therapy,” says Dr. Aditya Bardia, director of the breast cancer research program at Massachusetts General Hospital Cancer Center in Boston. “Some physicians would use (Faslodex) alone. Some would use (Faslodex) plus a CDK 4/6 inhibitor, and some would use (Faslodex) plus Piqray (alpelisib), a PI3 kinase inhibitor, if a patient has PIK3CA-mutant breast cancer.”

Postmenopausal women and adult men with ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer whose cancer has progressed after at least one line of endocrine therapy also now have access to a new FDA-approved oral estrogen receptor degrader.

In January 2023, the FDA approved Orserdu (elacestrant) for these patients.

“(Orserdu) has shown activity that’s superior to standard endocrine therapy, including (Faslodex) in a randomized phase 3 clinical trial,” Bardia says, referring to the EMERALD trial, in which participants taking the drug showed improved progression-free survival, which is the amount of time a patient lives without their disease progressing. He expects its approval to mark a practice change, as it may be used over agents such as Faslodex. Shanahan says she has looked forward to another treatment option for people with ESR1 mutations. “A lot of my friends are on (Faslodex),” she says. “Some of them have a lot of problems with the injections. They have pain and develop lumps on their (buttocks from the injection). I have zero problems with (Faslodex).” She says hydrating before her injection, exercising the day she’s getting the shot and turning on the seat heaters in her car helped to keep her comfortable.

Bardia notes there’s significant interest in other emerging therapies to treat patients with ESR1 mutations. He mentioned the new SERDs giredestrant and camizestrant as well as the PROTAC ARV471— all of which are being studied in clinical trials — as novel endocrine agents to watch.

Judy Morgan, who has had breast cancer since 1993, says she has done well with the selective estrogen receptor modulator lasofoxifene and CDK 4/6 inhibitor Verzenio (abemaciclib).

Judy Morgan, 66, of Lafayette, Louisiana, has had breast cancer since 1993. Her initial treatment, which she calls “aggressive,” included chemotherapy, radiation and an autologous bone marrow transplant. Seven years later, cancer spread to her sternum. Surgeons removed the tumor, and she began taking Arimidex.

In 2017, Morgan needed a hip replacement. The news wasn’t good: Cancer had spread to her hip, and a subsequent liquid biopsy revealed an ESR1 mutation. She began a regimen of the CKD 4/6 inhibitor Ibrance and monthly Faslodex injections. But by 2021, the cancer had again progressed.

Morgan’s oncologist at The University of Texas MD Anderson Cancer Center in Houston recommended she enroll in the ELAINE 2 study, a clinical trial to evaluate the selective estrogen receptor modulator lasofoxifene in combination with the CDK 4/6 inhibitor Verzenio (abemaciclib).

The trial was open to postmenopausal and premenopausal women on ovarian suppression with locally advanced or metastatic HR-positive, HER2-negative breast cancer with an ESR1 mutation.

Morgan says she’s done well on the combined therapy, with the most notable side effect being diarrhea. “To me, the gain is worth more than any side effects that you may have to deal with,” she says. “I felt better, like there was an improvement in my overall health.”

Bardia encourages people with ESR1 mutations to ask their doctor if a clinical trial is right for them. 

“Any time there is disease progression, we recommend having a discussion with the physician about the standard options and clinical trial options available,” he says. “The advantage of a clinical trial is that it offers access to something that’s otherwise not available. In the metastatic setting, we often use therapy sequentially. The advantage of a trial is it increases the number of potential options.”

He also recommends that patients ask their doctors about getting a liquid biopsy. “It’s less invasive, and you can check it serially over time,” he says.

Fuqua encourages patients to have their tumors sequenced. “The challenge is making patients aware of the potential for targeted therapy,” she says. “We call it precision therapy. That’s the sexy word people like to use, but it’s finding the mutation in the patient’s sample and looking for what drugs we can use. That knowledge is your strength. Knowledge gives you your way forward with targeted therapy.”

Morgan encourages others with metastatic breast cancer and an ESR1 mutation to avoid being passive. “Don’t be afraid to try new things,” she says. “When you’re battling something like breast cancer, you want the latest and greatest.”

For Shanahan, self-advocacy means asking questions and being clear about what you want.

She told her doctor she didn’t want to take a medication targeting the PIK3CA mutation. When her doctor wanted to use Verzenio, the CDK 4/6 inhibitor known to cause diarrhea, before Shanahan’s road trip with her daughter, she declined. 

“Our doctors and care teams should educate us and point us in the right direction, but so much of the time, we have to do it ourselves,” Shanahan says, noting that she now advocates for others with metastatic breast cancer. “I think it’s incumbent upon us to educate ourselves because not everybody is going to have a care team that prioritizes that,” she says.

Her advice is not to be afraid to ask questions or to get a second opinion.

“As a doctor, when a patient told me she wanted to get a second opinion, I’d feel really smart if she came back and that person had agreed with my recommendation. And if they didn’t agree, then I learned something. A good doctor will welcome you getting a second opinion. We (patients) have to put ourselves first,” Shanahan says.

Editor's Note: Judy Morgan died shortly after this feature was posted online on Dec. 20, 2023. Our thoughts go out to her family and friends.

New tools help manage ESR1 mutations in metastatic breast cancer.

When Cancer Evolves

In spring 2021, Kathy Ventre, 56, of Cincinnati, sensed something wasn’t right. She felt what she describes as menstrual cramps. She also felt tenderness near her ovary, as though she were ovulating. Yet, she was five years past menopause.

Ventre wondered why she felt like she was going to menstruate. “I even had acne all over my face,” she says. “It was strange.”

She saw a gynecologist. “He did an exam and didn’t feel anything,” Ventre says. “But he said, ‘You took the time to come in, so let’s do an ultrasound.’ ”

Kathy Ventre experienced a feeling similar to menstrual cramps five years postmenopause, a symptom which led to a diagnosis of stage 3 high-grade epithelial ovarian cancer. 

She underwent both an abdominal and a transvaginal ultrasound. She also had a blood test to check for CA-125, a protein sometimes elevated in people with ovarian cancer. Above 35 units per milliliter is considered high — Ventre’s level was 300. A CT scan confirmed a tennis ball-sized mass on her left ovary.

“Ovarian cancer symptoms are vague,” says Dr. Amy Bregar, a gynecologic oncologist and surgeon at Massachusetts General Hospital in Boston. “Things like bloating, weight gain, feeling full after eating — all of us experience those symptoms at one point or another.”

In May 2021, Ventre had a complete hysterectomy. The diagnosis was stage 3 high-grade epithelial ovarian cancer. Twenty days later, she began chemotherapy, with six rounds of carboplatin and Taxol (paclitaxel).

Surgery followed by chemotherapy is the first-line treatment for many patients with ovarian cancer. But ovarian cancer recurs in approximately 70% of patients, according to the Ovarian Cancer Research Alliance. Still, there’s reason for optimism with the potential of new developments in ovarian cancer treatments.

What’s transpired in ovarian cancer research in the past few years has been revolutionary, says Dr. Anil K. Sood, a gynecologic oncologist at The University of Texas MD Anderson Cancer Center in Houston.

“There are many biologically targeted drugs, such as (the tumor blood vessel formation inhibitor) drug Avastin (bevacizumab), PARP [Poly (ADP-ribose)] inhibitors and antibody-drug conjugates such as Elahere (mirvetuximab soravtansine). There are also immunotherapies that are being developed and tested,” he says. “We want people to understand they have a lot more options now for treatment than we did 15 years ago. And that portfolio of options continues to expand rapidly.”

Elahere made history in 2022 as the first antibody-drug conjugate approved by the Food and Drug Administration (FDA) for treatment of patients with platinum-resistant ovarian cancer, and the first approval since 2014 for this patient population.

PARP inhibitors — drugs that block enzymes that repair damaged cell DNA, preventing cancer cells from making repairs, leading to their destruction — were primarily used starting in 2014 to treat patients with recurrent BRCA-mutated ovarian cancer and as maintenance for those with newly diagnosed and recurrent platinum- sensitive disease.

In 2022, three PARP inhibitors that had been approved by the FDA were voluntarily removed by their companies for efficacy issues, specifically Lynparza (olaparib), Rubraca (rucaparib) and Zejula (niraparib), Dr. Ursula A. Matulonis, chief of the division of gynecologic oncology and the Brock Wilson Family Chair at Dana-Farber Cancer Institute in Boston, says. Matulonis was co-principal investigator of the SORAYA trial, the findings of which were the basis of the FDA’s approval of Elahere.

Ovarian cancer treatments were traditionally were based on observation, surgery and chemotherapy. But antibody-drug conjugates — which, as explained by the National Cancer Institute, target proteins found on cancer cells, then latch onto the cells and deliver cancer-fighting drugs — are a more targeted approach.

Elahere’s approval by the FDA, Matulonis says, “is definitely a step forward for our patients.”

Epithelial carcinoma is the most common type of ovarian cancer. Tumors grow in the tissue that lines the fallopian tube or covers the ovary (epithelium). Pathologists assign a grade — low or high — based on how the tumor looks under a microscope. Epithelial carcinoma may also be serous subtype (beginning in the serous membrane) or nonserous.

There are also rare types of ovarian cancer, including mucinous carcinoma and ovarian clear cell carcinoma.

“Ovarian cancer is not one disease,” says Sood. “Getting the right diagnosis and making sure the right subtype is diagnosed are critically important.”

Information about a patient’s specific genetic mutations and a tumor’s molecular makeup helps oncologists recommend personalized targeted therapies such as PARP inhibitors.

“I had genetic testing and learned I had a mutation in the BRCA1 gene,” says Ventre. “That made me a good candidate for a PARP inhibitor.”

PARP inhibitors show promise in treating women with BRCA gene mutations. They also help people who have homologous recombination deficiency, a defect in the specific pathway cells use to repair themselves.

“PARP inhibitors are an important part of treating patients with ovarian cancer,” Sood says. “We also know there are many patients who, despite receiving a PARP inhibitor, either don’t derive benefit from it or it works for a period of time and then their cancer starts to grow.”

Sood and his colleagues recently studied ovarian cancer cell lines that were either homologous recombination (HR) deficient or HR proficient. Their goal was to “see if there are drugs that could amplify or improve the effectiveness of PARP inhibitors,” Sood says.

 After testing cell lines with 335 different drugs, researchers found four drugs that combined well with Lynparza. They then evaluated clinical data on the toxicity of these drugs.

“Taking all that into account, we focused on a drug called CT-7439,
a specific inhibitor of cyclin- dependent kinase (CDK),” Sood says, noting initial validation studies indicate it combines well with Lynparza. “We’re excited about this.”

Pairing a PARP inhibitor with a CDK inhibitor could make PARP inhibitors more effective.

Sood hopes to test in animal models next to learn whether the combined drugs may provide more benefit than PARP inhibitors alone in some patients. He adds that researchers also hope to improve the effectiveness of PARP inhibitors and prevent adaptive resistance.

These findings are good news for women like Ventre, who experienced cancer recurrence after 18 months on Lynparza. A scan showed four small cancerous spots in her abdomen, so she’s now on a chemotherapy regimen of carboplatin and Gemzar (gemcitabine).

She says she’ll soon begin treatment with drug Avastin.

“My doctor is reluctant to do a PARP inhibitor again so fast because the cancer figured out a way to work around it,” she says.

The goal is to achieve stability and use Avastin as a maintenance therapy, according to Ventre, who is now a volunteer for the Ovarian Cancer Alliance of Greater Cincinnati and the Woman to Woman support and mentorship program from the Ovarian Cancer Research Alliance.

Improving surgery for ovarian cancer is another area of study. An abstract presented at the 2023 American Society of Clinical Oncology Annual Meeting found that in patients with ovarian clear cell carcinoma, surgical removal of lymph nodes (lymphadenectomy) was associated with improved disease-free survival. But more research is needed to determine whether lymphadenectomy is beneficial in some people.

Debulking surgery, in which surgeons remove as much of a tumor as they can, is the first step for most women with ovarian cancer.

“The standard of care remains open surgery,” Bregar says. “But there’s ongoing research investigating whether minimally invasive surgery can be used for ovarian cancer.”

Also being studied is when to perform surgery.

“For high-grade serous ovarian cancer, we know it probably doesn’t matter whether you have chemotherapy or surgery first,” she says. “But while it’s probably equivalent in terms of overall survival, there may be less risk and less toxicity to have chemotherapy first.”

Sood says operating first isn’t always effective — some patients have so much cancer that complete surgical removal isn’t possible.

“We’ve gone to more personalized approaches,” he says. “We do laparoscopic assessment upfront for those patients who are surgical candidates. Those who are most likely to benefit from surgery go to upfront surgery. Our complete resection rates are high in that group. Patients whose cancer is such that it cannot be removed upfront receive neoadjuvant chemotherapy and then have surgery after three to four cycles.”

Elle Simone Scott, 46, of Salem, Massachusetts, was diagnosed with stage 1C3 ovarian cancer in 2016. She had surgery to remove her right ovary and fallopian tube, followed by chemotherapy treatment.

Elle Simone Scott diagnosed with ovarian cancer in 2016, has enrolled in multiple clinical trials and is a proponent of participating in research. 

When cancer recurred in 2020, it had spread into her bladder and bowel. She was treated with three rounds of Doxil (liposomal doxorubicin) and cisplatin before having a complete hysterectomy and resection of her bladder and bowel.

Surgery was followed by three more rounds of chemotherapy.

“After that, my doctor told me it was in my best interest to go on maintenance therapy,” Scott says. “He didn’t know if he could ever cure me, but he told me I could live with ovarian cancer chronically and still have a good quality of life.”

After surgery, Scott took Lynparza for a year. But she developed a “terrible face rash” and says the drug wasn’t effective. She then joined a clinical trial where participants received the immunotherapy drug Opdivo (nivolumab), Avastin and the PARP inhibitor Rubraca (rucaparib). She ended her participation after experiencing severe gastrointestinal side effects.

Scott, who has enrolled in a new clinical trial of the antibody-drug conjugate Enhertu and Lynparza in treating patients with HER2-expressing cancers, remains a proponent of participating in ovarian cancer research.

“If it weren’t for people who are willing to go through clinical trials, we wouldn’t have the groundbreaking medicine we have today,” she says, adding that if you’re in a clinical trial, it’s important to pay attention to your body. “When something doesn’t feel right, communicate with your medical team. Ask them to give you what you need to be successful.”

Research studies have led to deeper understanding of how best to treat patients with different ovarian cancer types. Bregar notes that chemotherapy doesn’t work as well in low-grade serous cancers (about 10% of ovarian cancers). 

“Low-grade cancer tends not to be as sensitive to chemotherapy when compared with high-grade cancers,” she says. “These cancers may be more hormonally driven. This is why we think hormone maintenance is so important.”

Bregar and her colleagues recently published a retrospective study on the benefit of oral hormone therapy for a subset of patients with low- grade ovarian cancer after treatment with surgery and chemotherapy. Patients in this subset who received surgery and chemotherapy followed by hormone maintenance had a 60-month survival rate of 71% compared with 61% among patients who did not initiate maintenance hormonal therapy — an increase in life expectancy of about 3.6 months.

Using results from a randomized controlled trial showing benefits of hormone maintenance, Bregar and her colleagues looked back at previously treated patients. “What we found confirmed that patients with low-grade serous cancers benefit from hormone maintenance,” she says.

“For low-grade ovarian cancers, we know hormones work in the maintenance setting.”

Bregar also notes that a lack of screening for ovarian cancer often leads to later diagnosis. “Ovarian cancer is rare,” she says. “Lifetime risk is only 1.4%. Because symptoms are so vague and there’s no way to screen, it’s like finding a needle in a haystack.”

She says more research is needed on how to detect ovarian cancer sooner.

“Something I’m looking at is whether we can find a way to diagnose ovarian cancer early by doing what we call a uterine lavage, or washing of the uterus,” she says.

What Role Do Integrative Therapies Play? 

It also is critical to treat the whole person, not just their cancer. 

“We know the psychological aspects or stress aspects of cancer are so important,” Sood says. Whole-person care is a critical focus for Dr. Tara Berman, a medical oncologist specializing in gynecology at the Inova Schar Cancer Institute in Fairfax, Virginia, and an expert in integrative oncology services. Earlier this year, Berman and her colleagues published a review of clinical research supporting the effectiveness of integrative modalities in ovarian cancer care.

According to Berman, these services include three components: mind and body practices, natural products and lifestyle modification.

“They’re not meant to supplant conventional cancer treatments,” she says. “Integrative oncology is about using other modalities in conjunction with standard of care to help improve quality of life and ideally, efficacy outcomes.”

Integrative oncology services, which include nutrition, exercise, massage, acupuncture and emotional support, help improve quality of life, she says. They also help patients tolerate and better adhere to treatment, Berman notes.

They can also help manage side effects. “Massage increases circulation and blood flow,” she says. “And acupuncture is helpful in the setting of chemotherapy-induced neuropathy.”

Berman says data are beginning to “scratch the surface” of integrative oncology’s potential — for example, the role of fat cells in certain cancers.

“Estrogen can be a driver for promoting the growth of cancer cells,” she says. “In some ovarian cancers, tumors have estrogen receptors. Even though we block estrogen by taking out the ovaries and giving certain hormonal medications, estrogen is also produced by fat cells. So, through diet and exercise, by reducing body mass index and the amount of fat in the body, we can effectively reduce estrogen levels.”

Recent developments in PARP inhibitor combinations and antibody-drug-conjugates are changing the landscape of ovarian cancer treatment. 

Optimism Abounds in Ovarian Cancer Research

Byron Warner, 82, remembers when he knew the experimental immunotherapy drug combination he had been taking to combat non-small cell lung cancer (NSCLC) was working. 

“I go for walks every day and for a long time, breathing was just agony,” he says. “I’d walk to the end of my block and back and it felt like wind sprints in football. But one morning, I went out to walk and I could breathe. It was the most encouraging thing I’ve felt all along.”

The Nashville, Tennessee, resident says he is once again jogging up a hill he struggled to climb before treatment. “I’m really happy,” Warner says.

This is the hope that new immunotherapy drugs targeting an immune checkpoint inhibitor known as TIGIT are bringing to people with lung cancer. TIGIT, short for T cell immunoreceptor with immunoglobulin and ITIM domain, is a new target for immunotherapy drugs that treat cancer that is hoped to build further on the successes seen with standard immunotherapy.

Byron Warner had his wife, Cindy , by his side while being treated with a new therapy in lung cancer. 

Therapies that improve quality of life and survival for patients — and that are well tolerated — are the “holy grail,” according to Dr. Jeffrey Clarke, a medical oncologist at Duke Cancer Institute in Durham, North Carolina. “That’s always what we’re looking for and striving for to grow our armamentarium,” he says.

Anti-TIGIT therapies may offer that promise for people with lung cancer
in that their mechanisms of action are distinct from that of approved “check- point inhibitor” treatments. Although no anti-TIGIT immunotherapy drug has been approved by the Food and Drug Administration (FDA) at this time, clinicians are encouraged by early data from clinical trials.

“It could be even better in some ways than some of the drugs we have,” Clarke says.


Immunotherapies are drugs that work to help the immune system destroy cancer. Each day, immune cells (T cells) sweep the body to search for and mitigate bacteria, viruses and cells that should not be there. To protect, the immune system includes built-in stop signs that keep T cells from going too far and destroying healthy cells.

The body creates these stop signs when T cells recognize and bind with certain proteins designed to halt their work. These stop signs are called immune checkpoints. But cancer cells are wily in the way they evolve. They take advantage of these checkpoints to escape notice. When cancer cells can get around immune checkpoints, tumors grow unchecked.

Immunotherapy drugs work by shutting off immune checkpoints to make it easier for T cells to identify cancer. Each of these drugs — known as immune checkpoint inhibitors — works on a specific type of immune checkpoint (sometimes called a pathway).

Immune checkpoints that have FDA-approved therapies for treating lung cancer include CTLA-4, PD-1 and a protein related to PD-1 (PD-L1). Approved immune checkpoint inhibitors include the PD-1 inhibitors 

 for some people with NSCLC, as well as the PD-L1 inhibitor 

 is also used to treat some lung cancers.

Byron Warner didn’t want to die and leave his wife, so he had no hesitations starting an anti- TIGIT therapy.

Like targeted therapies (drugs targeting cancer cells that have a specific gene mutation), immunotherapies are known as personalized medicine. Dr. Wallace Akerley, a lung cancer oncologist at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, has been studying lung cancer for
30 years and says personalized medicine has changed how clinicians treat lung cancers.

“Now, when we see a patient, we do a panel of biomarkers to define what the cancer’s weaknesses might be,” he says, adding that his clinic looks for gene mutations that can be treated with eight different gene-specific drugs (targeted therapies). 

The clinic also does an immune panel that looks for PD-L1 expression. The findings, Akerley notes, determine which of three therapies individually or in combination — chemotherapy, targeted therapy or immunotherapy — will be used to treat a patient’s specific lung cancer.

Those with genetic mutations start on targeted therapy, whereas patients with high PD-1 or PD-L1 expression get immunotherapy. 

“If you have neither of those, you would be getting a chemoimmunotherapy or even dual immunotherapy,“ he says, adding that immune therapies work so well with chemotherapy that most people no longer have chemotherapy alone.

TIGIT: A New Pathway in Lung Cancer Immunotherapy

TIGIT is a more recently identified immune checkpoint that is now being targeted with various therapies in clinical trials. Researchers have been studying patient response to anti-TIGIT therapy as a monotherapy (the only treatment given) and in combination with other immunotherapy drugs.

“The TIGIT drug has been looked at individually and there’s been some activity seen,” Akerley explains. “It’s also been used in conjunction with PD-1 inhibition so two checkpoint blockades. There is preliminary data that this is much more effective.”

Warner took part in a clinical trial of an anti-TIGIT drug in combination with another immunotherapy. After being diagnosed with NSCLC — specifically, a 7-centimeter inoperable tumor in his upper left lung — he had six weeks of radiation (five treatments per week) combined with weekly chemotherapy. 

When he finished this grueling course of treatment, his oncologist, Dr. Melissa Johnson, director of the Lung Cancer Research program at Sarah Cannon Research Institute in Nashville and a medical oncologist with Tennessee Oncology, recommended that Warner enter a study assessing the anti-TIGIT immunotherapy tiragolumab in combination with Tecentriq.

Of note, the drug combination was granted a breakthrough therapy designation by the FDA in early 2021 based on data from the 

Warner was enrolled in the phase 3 SKYSCRAPER-03 which is investigating the safety and efficacy of tiragolumab in combination with the FDA-approved PD-L1 inhibitor Tecentriq against Imfinzi (durvalumab) — an anti-PD-L1 therapy — in people with inoperable stage 3 NSCLC who had been previously treated with a combination of chemotherapy and radiation.

For just over a year, Warner had a monthly infusion of the combined immunotherapies. The results of the trial are not available to the public yet.

There are several anti-TIGIT therapies being studied in clinical trials. Among the drugs being studied in lung cancer treatment are tiragolumab, ociperlimab, vibostolimab and a TIGIT inhibitor known as BMS-986207.

“Treatment of lung cancer has transformed with the introduction of immunotherapy, with significant improvements in survival,” adds Dr. Jessica Bauman, a thoracic oncologist and chief of the Division of Head and Neck Medical Oncology at Fox Chase Cancer Center in Philadelphia. 

“TIGIT is an intriguing type of novel immunotherapy. When it is blocked, it may enhance the immune system and improve the responses to current immunotherapies. From the early clinical studies, it does look to be most effective in combination with PD-1 or PD-L1 blockade as well.”

Clarke says the data he has seen from anti-TIGIT drug clinical trials in patients with high expression of PD-L1 are the most exciting. 

“Patients who have the highest expression of PD-L1 seem to have the most benefit,” he explains. “This could help guide us decide who should get this type of treatment versus another type of treatment. I think we need to have more data to tell us for sure who’s going to benefit from this treatment versus who wouldn’t.”

For many people with lung cancer, questions about potential side effects from cancer treatment loom large. Immunotherapy side effects include inflammation, which could involve any organ in the body, according to Clarke. 

“Rash is very common, as is colitis causing diarrhea,” he says.

In treating cancers with immunotherapy, clinicians want the immune system to be activated to find the cancer and kill it but do not want the immune system to be activated against healthy tissue, Bauman says. That creates a need for a delicate balance when using these drugs.

“We see the immune system causing pneumonitis, hepatitis, colitis, myocarditis, thyroiditis, as well as others,” she says. “Those immune-related toxicities are often treatable with high-dose steroids and patients do well. One of the concerns about using multiple avenues to activate the immune system is that you increase the risk of immune toxicities.”

But early data from studies of immunotherapy combinations that include anti-TIGIT drugs are not showing a significant increase in toxicities, according to Bauman. 

“Immune toxicities look similar to what is already known from the PD-1 therapies, which have a lower rate of toxicities than some of the other checkpoints that have been studied in trials,” she adds.

Warner notes that treatment is strenuous for people with cancer. “Radiation and chemo together just really sap your strength and your mental energy as well,” he says. “When I went to immunotherapy, I noticed that I was feeling down and a little bit listless for three or four days afterward, but then I came back stronger.”

Anti-TIGIT immunotherapy drugs may improve quality of life and survival, while being well tolerated by patients.

Dara Chadwick

Tracking a Mystery in Non-Secretory Myeloma

When Cancer Evolves

Optimism Abounds in Ovarian Cancer Research

A New Path Emerges in Lung Cancer Treatment

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