Amy Paturel, M.S., M.P.H.

When Jennifer Fink was a little girl, she was surrounded by cancer. Her grandmother and aunt both developed the disease twice — once in each breast — before she graduated high school. Now a nurse and writer in southeastern Wisconsin, Fink viewed cancer almost like wallpaper. It was always there in the background.

“I don’t remember a time when I didn’t know about my family history of breast cancer,” Fink says. “My grandmother died when I was 5 and my aunt was diagnosed at 39 years old when I was in my teens. Then, when I was in my 20s, my mom was diagnosed with breast cancer, then ovarian cancer 10 years later.”

According to the American Cancer Society, breast cancer will strike more than 350,000 American women in 2023. About 5% of patients with breast cancer carry a genetic mutation that predisposes them to the disease. Although the most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 genes, advances in next-generation sequencing coupled with studies of cancer-prone families have uncovered several milder mutations, including ATM and CHEK2, that are also linked to the disease. 

“Many, but not all, familial breast cancers are due to inherited mutations,” says Dr. Wendy Chung, chief of clinical genetics at Columbia University in New York City. “But cancers may also run in families without any known genetic mutation.” 

No matter which category a patient may fall into, identifying and personalizing the risk of developing breast cancer is crucial. Being proactive about the best way of sidestepping the disease is important. That is where genetic testing comes in.

Genetic Mutations Linked to Breast Cancer

Everyone is born with two copies of genes in every cell of the body — one copy from each parent. Cells typically contain genes that can suppress tumor growth, but when these genes are mutated, tumors can form and grow. 

“Any cell at any time, either as a direct result of something exposure related or just by random chance, can acquire mutations,” says Lisa Madlensky, a genetic counselor and program director of the Family Cancer Genetics Program at Moores Cancer Center at UC San Diego Health in California. “There are billions of pieces of information in trillions of cells, and each time cells grow and divide, it’s like copying volumes and volumes of encyclopedias. That’s not a perfect process.” 

The more you copy those encyclopedias, the more opportunity there is for error. So naturally, most cancers are related to age; however, people who carry certain genetic mutations are more susceptible to developing cancer, earlier in life.

Consider BRCA1 and BRCA2, for example: In normal cells, these function as important tumor suppressor genes that help repair damaged DNA. However, Madlensky says, “If you are born with a mutation in one of those inherited genes, you only have one working gene left in each cell to act as a buffer against the kick-starting of a cancer. It’s almost like you’re going up to bat, but you’ve already got one strike against you.

”Studies show that the risk of breast cancer before age 70 among BRCA1 and BRCA2 female carriers ranges from 38% to 87%. Fink falls into that high-risk category. She inherited the BRCA2 mutation from her mother, Pat Wondra, whose initial breast cancer almost went undetected. Wondra did not feel a lump, but her lower breast felt hard to the touch whereas the middle felt bouncy, like a blood vessel. A clinical examination did not sound any alarm bells. But because Wondra’s mom died of breast cancer, her doctor suggested she see a specialist. 

“The fact that he remembered my mother had breast cancer was lifesaving,” says Wondra, emphasizing that her diagnosis predated the discovery of the BRCA genes in the 1990s. “The tissue they took out during a biopsy looked healthy, but when they put it under the microscope, there was cancer everywhere. It just never coalesced into a lump.” Pat had a double mastectomy, followed by radiation. Ten years later, she was diagnosed ovarian cancer, which had mysteriously metastasized throughout her abdomen. 

“There were thousands of cancerous warts all over my uterus,” Wondra says. “The doctors didn’t expect me to recover.” Nevertheless, they treated her with chemotherapy and she recovered. But 18 months later, doctors discovered a small tumor on her intestines. After surgery to remove the tumor, Wondra received another chemotherapy regimen, first through the vein and then directly into the gut through a port in Wondra’s belly.

Although Wondra, now 85, has had a few scares, she has been free of cancer ever since. Still, she feels tremendous guilt for passing the “cancer gene” to her eldest child, Fink. 

“Finding out that she carried the gene broke my heart — that was harder to hear than my own diagnosis,” Wondra says. But inheriting a genetic mutation does not guarantee cancer will happen, especially if a patient carries a gene with a milder risk profile including ATM or CHEK2 “Inherited mutations are only one part of the equation, and with non-BRCA mutations, they may not be that impactful,” says Dr. Steven Narod, a Tier I Canada Research Chair in Breast Cancer, professor in the Dalla Lana School of Public Health and the Department of Medicine at the University of Toronto, and a senior scientist at Women’s College Research Institute. 

“With BRCA1 and BRCA2 mutations, the risk of developing breast cancer is about the same, regardless of family history. But with CHEK2, for example, your risk of breast cancer is largely dependent on your family history.” According to the American Cancer Society, having a firstdegree relative (mother, father, sister, or daughter) with breast cancer nearly doubles the risk for women, whereas having two firstdegree relatives with the disease Although Wondra, now 85, has had a few scares, she has been free of cancer ever since. Still, she feels tremendous guilt for passing the “cancer gene” to her eldest child, Fink. “Finding out that she carried the gene broke my heart — that was harder to hear than my own diagnosis,” Wondra says. But inheriting a genetic mutation does not guarantee cancer will happen, especially if a patient carries a gene with a milder risk profile including ATM or CHEK2 “Inherited mutations are only one part of the equation, and with non-BRCA mutations, they may not be that impactful,” says Dr. Steven Narod, a Tier I Canada Research Chair in Breast Cancer, professor in the Dalla Lana School of Public Health and the Department of Medicine at the University of Toronto, and a senior scientist at Women’s College Research Institute. “With BRCA1 and BRCA2 mutations, the risk of developing breast cancer is about the same, regardless of family history. But with CHEK2, for example, your risk of breast cancer is largely dependent on your family history.” According to the American Cancer Society, having a firstdegree relative (mother, father, sister, or daughter) with breast cancer nearly doubles the risk for women, whereas having two firstd-egree relatives with the disease increases the risk threefold. 

Fink was newly married and in her 20s when she felt a lump in her breast. She visited her doctor to get it checked out. Despite explaining that she has a strong family history of breast cancer, he dismissed her. 

“I don’t remember whether I pushed for a mammogram or an ultrasound, but I do remember the frustration I felt,” Fink says. “I had this sense of ‘What more do I need to say for you to take this seriously?’ ” A few years after her mom received her ovarian cancer diagnosis, Fink pushed for genetic testing. “I wanted it documented irrefutably in my chart,” says Fink. “I spent my entire life assuming I would eventually get breast cancer, and I’m almost more afraid of the treatment than the diagnosis because I saw what it did to my family members.”

But not everyone with a strong family history of breast cancer — or inherited mutations — wants to know. Emma Jarrett, a poet, writer and coach in British Columbia Canada, had little knowledge of her family’s history of breast cancer. She knew her grandmother received a diagnosis in her 80s and that her mom’s cousin had breast cancer, but she did not think much about a genetic link. 

“My family are buttoned-up Brits, so any health issues were all shrouded in mystery,” Jarrett says. In fact, when her mom received a diagnosis of breast cancer in 1997, Jarrett learned the news in a letter after she’d already been treated. “She wrote that she’d had a ‘little diagnosis’ and that it was nothing to worry about,” she says. But when Jarrett was 50, she felt little lumps under her armpit.

“They would come and go, and they were never consistent in size, so I figured they were swollen lymph nodes,” she says. “And plenty of ‘Dr. Google’ searches seemed to confirm my theory.” The lumps grew larger, and then painful. “They were no longer ignorable,” Jarrett adds. In July 2016, a mammogram and ultrasound uncovered several suspicious lesions. Jarrett had breast cancer, but decided against genetic testing. At the time of diagnosis, she was convinced her cancer was not driven by a genetic mutation, “and I just didn’t want to know,” she says. Fink’s and Wondra’s siblings seem to feel the same way — none did genetic testing. 

“Deciding whether or not to test when you have a family history isn’t always clear-cut,” Madlensky says. “People may have the sense that their family is riddled with cancer. But when you dig deeper into their family history, you discover their father had prostate cancer in his 80s and their mother had breast cancer when she was in her 70s. So that person may not have an elevated inherited risk, but rather cancer struck their family members due to age-related changes.” 

Five years after her initial diagnosis, Jarrett still does not have a definitive answer about whether her cancer was driven by an inherited mutation. “But I’m absolutely convinced that if I do have a BRCA mutation, there are lifestyle changes I can make to override it, so that’s where I place my focus,” Jarrett says. Jarrett’s decision “not to know” could get flipped on its head if her 19-year-old daughter does her own testing to uncover whether she has an inherited risk of developing breast cancer. Most genetic counselors recommend against cancer genetic testing in children. With advances in technology occurring rapidly, the findings may not be relevant when the results become important for screening guidelines. But if Jarrett’s daughter chooses to test, and no mutation is identified, she may decide to implement screening guidelines based on family history alone. 

“For patients with a strong family history but no known genetic mutation, the general rule is to begin screening 10 years younger than the age when the earliest cancer diagnosis occurred,” Chung says. “If you’re the type of person who seeks information and knowledge, you will self-select for testing. But if you’re not that type of person, no one is going to force you to get tested.”

No parent wants to pass a genetic mutation to their child. But once people know they have an increased risk of developing cancer, they can take proactive steps to ensure the best outcome. 

“We use genetic testing not only to identify whether there’s a breast cancer-associated genetic mutation, but also to understand how high the risk is and at what age it begins,” Chung says. In Fink’s case, genetic testing — and proactive treatments — have allowed her to reduce her risk of developing the disease. But she has been confronted with difficult decisions, ranging from genetic testing to prophylactic mastectomy and/or salpingo-oophorectomy (removal of the ovaries and tubes). Because BRCA-2 and CHEK2-driven cancers are usually estrogen and progesterone positive, removing the ovaries can help protect against a future cancer by reducing circulating estrogen. 

“The people who choose to have prophylactic surgeries tend to be the ones who are suffering from the most anxiety,” Narod says. Although these procedures may reduce the risk of developing breast cancer, they are also big decisions that can dramatically affect quality of life — and they may not be appropriate for women with mild-tomoderate-risk genes. 

“A lot of women hear that they have a genetic mutation linked to breast cancer and they jump right to prophylactic surgery,” Chung says. “But moderate-risk genes — like ATM and CHEK2 — don’t carry the same risks as the BRCA mutations. And if your lifetime risk of developing breast cancer is 25%, that’s very different than if it’s 75%.” 

Even with BRCA1 and BRCA2mutations, pre-emptive surgery is a tough call. In lieu of removing her breasts and ovaries, Fink chose to take tamoxifen for five years beginning at age 43 — a decision that would be expected to reduce her risk of developing breast cancer by 40% or more. At the very least, people with a strong family history or documented genetic mutation may choose to screen for breast cancer more frequently and with more sensitive methods, such as MRI. For people who have received breast cancer diagnoses, inherited mutations are not only relevant to assessing the risk of developing breast cancer, but they can also help guide treatment decisions. Studies show that cancers driven by an inherited BRCA1 or BRCA2 mutation, for example, tend to be more responsive to chemotherapy. BRCA carriers also seem to be highly sensitive to a new class of medications called poly (ADP-ribose) polymerase, or PARP, inhibitors. 

“These drugs are specifically for patients with BRCA1 and BRCA2 carriers,” Chung says.

The goal of genetic testing in the cancer space is to give people information about their personal risk of developing the disease. But genetic testing is not perfect, and the results may not always provide clear, actionable answers. To complicate matters, genetic tests that are available to the public, without medical oversight, may only look for a small number of mutations associated with a specific gene. 

For example, the Food and Drug Administration has approved a commercial test for BRCA mutations, but it only applies to people of Ashkenazi Jewish ancestry. About 1 in 40 such individuals carry a BRCA mutation compared with 1 in 500 people in the general population. However, there are more than 2,900 variants of BRCA1 and more than 3,400 variants of BRCA2 that scientists have identified as pathogenic, many of which would not be detected by this test. 

“People with a negative test result from certain companies might assume they don’t have to be concerned about their risk, when in fact they might still have a different BRCA mutation,” Madlensky says. Accurately determining your genetic risk depends on which specific genes were tested, the laboratory methods used to test those genes, and how long ago the testing was done since there are always improvements in testing technology. To help personalize patients’ risk, scientists are working hard to develop a polygenic risk score. 

“This score will put together 100 or more different genetic variants, each of which might represent teeny tiny risks, or even decreased risks,” Chung says. “The idea is to mathematically pair all of those variants with the major players, such as BRCA1 and BRCA2, to provide patients with a more accurate risk score.” 

In the meantime, patients often have to make decisions based on incomplete information. But when people learn they have a genetic mutation that increases their risk of cancer, they can arm themselves with information, proactive screening measures and prophylactic procedures to mitigate the risk of getting the disease. 

“Even with unexpected genetic test results, studies show that most people have the initial shock, but then they feel empowered,” says Madlensky. “That’s partly because the focus of genetic testing for cancer risk is always on prevention and early detection.” Fink is 50 now, just six years younger than her mom was diagnosed with breast cancer. “When you reach this age, more and more people around you get diagnosed with breast cancer,” she says. “So there’s this voice in my head reminding me that my best-laid plans for the next year, or five years, could change at any point in time. I like to believe that helps me lead my best life.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Family history of breast and other cancers can mean some people are more likely to develop the disease at a younger age. But advances in testing may improve prevention and survival rates. 

Inheriting a Cancer Risk

After spending a warm spring day in 2022 pulling weeds and planting perennials, Renata Muller, 66, tucked herself into bed and noticed that she was short of breath. When she woke up the next morning, she felt pressure in her chest. 

“I figured I overdid it with the garden work,” she says. But her symptoms didn’t subside. They got worse. 

As the day went on, she felt overwhelmingly tired, was unable to go up the stairs without becoming winded and began struggling to breathe. Concerned, her husband, Ralph, took her to the emergency room that evening.

“After 11 hours of waiting and tests, the doctor told me I had a buildup of fluid in the space around my heart and I needed immediate surgery,” Muller recalls. 

Four days later, she learned she had stage 4 lung cancer.

After experiencing shortness of breath, Renata Muller's husband, Ralph, took her to the hospital. Eventually, she was diagnosed with lung cancer.

Lung cancer is the leading cause of cancer death worldwide, and non-small cell lung cancer (NSCLC) accounts for 85% of those deaths. 

In recent years, immunotherapy drugs have dramatically extended the lives of patients with advanced lung cancer, so Muller’s oncologist was optimistic. 

He ordered comprehensive genetic testing called next-generation sequencing (NGS). With this kind of sequencing, doctors can detect 4 million variants, some of which can be targeted with treatment.

“My doctor wanted to put me on an immunotherapy drug called Keytruda (pembrolizumab) right away, even before the (next-generation sequencing) results came back, followed by several cycles of two chemotherapy drugs,” she says.

But when Muller realized that starting the treatment regimen would prevent her from participating in a clinical trial, she transferred her care to Stanford. By then, she had the NGS results, which indicated that her cancer was driven by a rare mutation called epidermal growth factor receptor (EGFR) exon 20 insertion, which is often described as an “undruggable” target in the lung cancer world. 

For the 1% to 2% of patients with NSCLC who have these mutations, immunotherapy agents offer limited benefit and can even cause additional harm.

Muller’s decision to transfer care opened the door for her to participate in a clinical trial investigating an agent that specifically targets EGFR exon 20 insertion mutations: Exkivity (mobocertinib), a small-molecule kinase inhibitor approved by the Food and Drug Administration (FDA) in November 2021. Six months earlier, the agency had approved another drug targeting the same mutations, a bispecific antibody called Rybrevant (amivantamab).

“For the first time, we have options that target these rare genetic mutations, and that’s a game changer for patients,” says Dr. Estelamari Rodriguez, a thoracic oncologist and clinical research lead of the Thoracic Site Disease Group at Sylvester Comprehensive Cancer Center at the University of Miami. 

“In the past, after patients failed chemotherapy, we didn’t have much to offer. ... Now we have these new targeted therapies that are currently used for what doctors call ‘salvage therapy,’ after patients don’t respond to chemotherapy.”

The drugs are the first FDA-approved treatments to specifically target EGFR exon 20 insertion mutations, but several more are in the pipeline, and they may buy patients more time so that science can effectively catch up to them.

EGFR is a protein in cells known as a growth factor receptor, which helps them grow. Some mutations in the EGFR gene can activate the receptor and lead to uncontrolled cell growth, thus leading to or accelerating cancer. 

With NGS, doctors can uncover the changes in the DNA that might be fueling (driving) cancer. In NSCLC, EGFR mutations are one of those oncogenic drivers.

Think of DNA as an instruction manual. If there’s a typo in the manual, cells receive incomplete or incorrect instructions and may become cancerous. Doctors look for those typos to determine whether a patient is a candidate for therapies that target them specifically. 

Besides misspelled words (point mutations), there may be other mistakes, like missing words (deletions) and added words (insertions). EGFR mutations include all three.

Mutations in exon 19 and exon 21, which are often referred to as “classical” EGFR mutations, account for about 85% of EGFR mutations in NSCLC. 

Doctors treat them with drugs called tyrosine kinase inhibitors, which block the action of enzymes that preferentially signal cancer cells to divide and grow. 

Up to 80% of patients with classical EGFR mutations respond to tyrosine kinase inhibitors, which can keep the cancer at bay for an average of 19 months — and much longer for a subset of patients.

“Unfortunately, the treatments we use for classical EGFR mutations aren’t effective in patients with EGFR exon 20 insertions,” says Dr. John V. Heymach, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston. 

The additional insertions in these mutations cause defects in the drug-binding pocket, reducing sensitivity to tyrosine kinase inhibitors.

That’s why it’s important for patients with lung cancer to characterize their disease before beginning treatment. For NGS, doctors place tumor tissue in a machine that can rapidly sequence the tumor’s DNA and identify a large number of biomarkers all at once. 

If patients can’t undergo a traditional biopsy for NGS, doctors may use a liquid biopsy to search for the biomarkers by analyzing tumor DNA in the bloodstream.

“PCR (polymerase chain reaction) testing is not sufficient to pick up certain mutations, including EGFR exon 20 insertion mutations,” Rodriguez says. “So it’s extremely important for patients to get NGS or a liquid biopsy upfront, so they can take advantage of new treatments that can extend their lives.”

Experts say that NGS should be standard of care following a diagnosis for all patients with lung cancer because treatments vary depending on the mutations they have. According to some estimates, however, only half of patients know this critical information when they begin treatment.

Many patients with EGFR exon 20 insertion mutations have never smoked, so they’re not flagged for lung cancer screening. By the time they develop symptoms, they have advanced disease and surgery is no longer an option. And radiation won’t work because the cancer has spread throughout the body and there are too many targets to treat. 

That leaves two options: cutting off the fuel that is driving the cancer and/or killing the cancer cells.

Doctors typically start with traditional platinum-based chemotherapy, but in patients with EGFR exon 20 insertion mutations, chemotherapy shrinks tumors by only 20% to 25%, which may provide patients six months on average, according to Heymach. 

Now, however, doctors have two additional treatments.

Delivered by infusion every two weeks, Rybrevant targets both
EGFR and an oncogene called MET. Instead of disabling the ATP-binding kinase activity of EGFR, as tyrosine kinase inhibitors do, the antibodies in Rybrevant go after the EGFR protein on the cell surface to disable the receptor and allow the body’s natural killer cells to attack the cancer. 

Studies show a response rate of up to 40% with Rybrevant, and a median progression-free survival (the length of time during and after treatment when a patient with cancer lives without disease worsening) of seven months.


Approximately 65% of patients have an infusion reaction, which may include becoming flushed, feverish and short of breath, so the first infusion is often delivered very slowly, says Dr. Jyoti D. Patel, medical director of thoracic oncology and assistant director for clinical research at the Lurie Cancer Center of Northwestern University in Chicago. 

Most patients have a reaction only to the first or second infusion. Other side effects include rash (86%), paronychia, an infection of the nail bed (45%), and diarrhea (12%).

Exkivity is active against both EGFR and human epidermal growth
factor receptor 2 (HER2). A capsule taken orally, Exkivity is specially designed to accommodate the narrow binding pocket of the EGFR exon 20 insertion mutation.

“It attaches to the internal part of the EGFR receptor, interrupting signaling from the receptor downstream,” says Dr. Lyudmila A. Bazhenova, a medical oncologist at Moores Cancer Center, University of California, San Diego.

The response rate with Exkivity hovers around 28%, and the median progression-free survival is seven months. 

Its side effects are similar to Rybrevant’s but more pervasive, with up to 82% of patients experiencing diarrhea, 46% rash and 39% nausea and vomiting.

There hasn’t been a head-to-head study comparing the safety and efficacy of these drugs, so doctors aren’t sure which works best. 

But they know that both eventually stop working.

“Patients can develop secondary mutations that prevent the medications from binding appropriately, or the cancer becomes more resistant and learns to bypass EGFR,” Heymach says.

Without a clear advantage, patients typically decide whether they want to start with an oral medication or an infusion. Because they have different mechanisms of action, doctors usually sequence the drugs, starting with one and then turning to the other when the disease progresses.

“Unfortunately, neither of these drugs show(s) significant activity in the brain or spinal cord, and most patients with EGFR mutations suffer from metastases to the brain,” says Patel. “So there’s a huge need for new drugs that can penetrate the central nervous system, and some of the drugs under development are being designed specifically for that purpose.”

In the meantime, patients like Muller whose have brain metastases are affected turn to Gamma Knife radiation treatments that deliver multiple radiation beams simultaneously to kill cancer cells while sparing healthy tissue.

“To ensure the rays are focused on the tumors, they stretch a mask over your head and face, making you look like a superhero,” says Muller, who has had two Gamma Knife procedures, each in under an hour.

Once her brain lesions were addressed, she started on Exkivity and has been taking the drug ever since. “As long as I’m able to tolerate the medication, and it’s keeping the cancer at bay, I’ll stay on it,” she says.

On Feb. 15, 2021, Jeff Battles, 53, felt odd chest pains. They became so intense that he went to the emergency room at 2 a.m., during a blizzard.

A computed tomography scan revealed large tumors in his chest and throughout his rib cage. Battles had stage 4 lung cancer.

Jeff Battles' lung cancer was responding to targeted treatments for seven months until it started to progress, which is a common occurrence in patients with this genetic mutation.

A local oncologist ordered NGS genetic testing on his tumor, and while Battles awaited the results, he did two cycles of chemotherapy. 

“A few weeks later, when testing showed I had the EGFR exon 20 insertion mutation, we started looking into clinical trials,” says Battles, who owns a medical device manufacturing company in Meadville, Pennsylvania.

The trial, ZENITH20, at Cleveland Clinic was designed to assess the efficacy and safety of poziotinib.

“I took an 8-milligram pill daily, and it stalled disease progression for about seven months,” says Battles. “But when the cancer began growing and spreading again, my doctors put me on (Rybrevant) infusions.”

As he had with poziotinib, Battles experienced a noticeable reduction in tumor size during the first month, but after seven months on Rybrevant, the effects leveled off. When his disease began progressing again, Battles did two more rounds of chemotherapy.

“We’ve used most of the tools in the toolbox at Cleveland Clinic, so now we’re investigating other trials and treatments,” he says.

Unfortunately, Battles’ experience is common among patients with EGFR exon 20 insertion mutations. 

Targeted treatments like Rybrevant and Exkivity can control the cancer for months or even years, depending on the patient and the drug, but they will not cure it.

The hallmark of cancers driven by EGFR exon 20 insertion mutations is “acquired resistance,” meaning that they learn to outsmart treatments. 

When resistance is acquired, doctors often repeat biopsies and order biomarker testing to identify new mutations they can target with different therapies — and for the first time, patients with these rare mutations have options.

“This is the beginning of the story,” Rodriguez says. “It’s our first attempt at getting at this mutation for patients who had previously been bundled into the EGFR category. But since we’re getting a response from targeted treatment after patients (progress on) chemotherapy, we know these are effective agents.”

Now that scientists have established EGFR exon 20 insertion mutations as a targetable mutation, the next step is learning how to improve response rates with currently approved drugs. That starts with understanding the different drug responses within EGFR exon 20 insertion mutations. For instance, emerging research suggests that the insertion location within EGFR mutations affects how patients respond to treatment. 

The more scientists learn about these responses, the better equipped they’ll be to target them.

The good news is that the pace of research is rapid. Several drugs that target EGFR exon 20 insertion mutations are under development, and a few are already available. And, unlike other drugs, these treatments can work quickly, with patients responding systemically within six weeks in some cases.

Previously, overall survival of only two to three years was probable. But patients on Exkivity and Rybrevant are living much longer.

“And there’s a host of other new drugs coming down the pipeline,” Heymach says. “The exciting thing is, it’s very likely there’s going to be multiple options for these patients in the future.”

In the meantime, the goal for these patients is to stay one step ahead of the cancer by using Rybrevant and Exkivity as a bridge to the next best therapy.

“When I was diagnosed ... I didn’t anticipate I’d be doing this well several months later,” Renata says. “My blond hair is more gray these days, and I don’t have the high energy I used to, but I’m able to do most of my usual activities, including gardening.” Next up: a trip to Indonesia with her husband. “I’d like to go scuba diving,” she says.

To learn more about Jeff Battles' experience with lung cancer, 

New treatments may stall lung cancer progression in patients with EGFR exon 20 insertion mutations.

Targeting the 'Typos' for Lung Cancer Harboring Rare Genetic Mutations

Kris Munday was 10 years old when she smoked her first cigarette. Her friend’s mom had packs stashed in her purse and the girls smuggled them. By age 12, Munday was smoking regularly, and in her 20s, she was up to a pack and a half a day. When she moved to Sutherlin, Oregon, with her fiance and retired at age 35, her daily cigarette count doubled to fill the time.

“I no longer had to work in an office environment, which meant I had more time to smoke,” says Munday, a dog rescuer and breeder. “It had gotten so bad that I was waking up in the middle of the night to smoke.” To curb midnight cravings, Munday started wearing a nicotine patch overnight. But in 2014, when she was 45, she developed a horrific cough. Despite multiple rounds of antibiotics and half a dozen X-rays, doctors couldn’t get to the bottom of her coughing fits.

Within months, Munday developed debilitating fatigue and her cough became so aggressive her lungs partially collapsed. Doctors ordered two bronchoscopies at separate facilities to determine the cause of her symptoms, which showed that Munday had a pea-sized spot on her lungs. “I was hospitalized for unrelated gallbladder surgery and the pulmonologist came to my room and said, ‘Kristine, you have lung cancer,’” she remembers.

Kris Munday quit smoking after receiving a diagnosis of lung cancer. Before her diagnosis, her smoking habit had increased after she retired at 35 and became a dog rescuer and breeder full time.

Lung cancer will affect an estimated 236,000 Americans this year, and cigarette smoking is the No. 1 risk factor for the disease, according to the Centers for Disease Control and Prevention. In the United States alone, smoking accounts for 80% to 90% of lung cancer deaths, with smokers up to 30 times more likely to die from lung cancer than those who are smoke free. The more years a person smokes and the more cigarettes they puff daily, the higher the odds of negative effects. But cigarettes aren’t the only culprit. Tobacco products, including e-cigarettes and cigars, also increase a person’s risk of lung cancer.

“Tobacco harms every organ and system in the body,” says Judith (Jodi) Prochaska, an addiction specialist with the Stanford Prevention Research Center in California. “It can affect wound healing, post-surgical outcomes and the metabolism of medications, including chemotherapy.” In fact, there’s evidence to suggest that nicotine spurs the growth of new blood vessels that feed cancerous tumors. So patients with lung cancer who continue to smoke after receiving a diagnosis are not only more vulnerable to a second lung cancer, but they’re also at higher risk of developing other cancers, such as head and neck, bladder, cervical, stomach and pancreatic.

To make matters more complex, nicotine is highly addictive. “Even patients who have quit smoking for years may crack under the pressure of a lung cancer diagnosis and return to cigarettes,” Prochaska says. To address these challenges, the National Cancer Institute (NCI) developed the Cancer Center Cessation Initiative in 2017 as part of then-Vice President Joe Biden’s Cancer Moonshot initiative. Since then, more than 50 NCI-designated cancer centers have implemented smoking cessation treatment programs.

Major cancer organizations, including the American Society of Clinical Oncology, the American Association of Cancer Research and the Association for the Study of Lung Cancer, say smoking cessation should be standard of care for patients with cancer — and for good reason. The benefit of quitting on survival rates is on par with emerging therapeutics for lung cancer. Unlike smoking cessation, these therapies could cost thousands of dollars and may not be accessible for the lion’s share of patients. But quitting smoking is possible for every smoker, and many smoking cessation resources are completely free for patients.

Charlie Thurlow was 57 when doctors told him he had stage 3B lung cancer. After months of coughing, weight loss, night sweats and eventually the collapse of his right lung, Thurlow’s doctor ordered a CT scan. “There was an 11-centimeter tumor across the top of my right lung,” says Thurlow, now 70 years old and retired from a publishing career in New York City. “And there was pain there, too. At times, I’d tried to wrap my chest with a knee bandage so I wouldn’t cough so deeply.”

Charlie Thurlow was able to quit smoking, a habit he had maintained for 40 years, after he was diagnosed with stage 3B lung cancer.

Thurlow had been smoking at least a pack of cigarettes a day for 40 years (more during his college and graduate school years). By the time the pulmonologist said, “It’s cancer, and I think it’s curable,” he was struggling to light up. What had once brought him immeasurable pleasure was now producing excruciating pain. “For the last several weeks before the diagnosis, I was stretching one to two cigarettes over the course of a day because that’s all I could stand,” Thurlow remembers. “I’d light up, suck in a drag or two then snuff the thing out. I’d repeat the process with the same cigarette a few hours later. I could extract half a dozen such episodes from one cigarette.”

Fortunately, ditching cigarettes has an immediate impact on the immune system, producing a dramatic drop in the body’s natural inflammatory response after someone stops smoking. “Getting rid of that inflammatory load before surgery has a profound impact on treatment outcomes,” says Dr. Matthew Triplette, medical director of the Lung Cancer Early Detection and Prevention Clinic at Seattle Cancer Care Alliance in Washington state.

Plus, there’s strong evidence that people who quit smoking after a lung cancer diagnosis do better than those who don’t. “They live longer and they’re less likely to have a recurrence of the cancer after treatment,” says Dr. Nancy Rigotti, director of the Tobacco Research and Treatment Center at Massachusetts General Hospital in Boston. “They’re also more likely to tolerate the treatment and have fewer adverse events than those who continue smoking.” They also lower their risk for getting a second cancer associated with smoking such as head and neck or bladder cancer.

Charlie Thurlow has been cancer free ever since he quit smoking and underwent treatment, which included chemotherapy, radiation and surgery.

According to a 2021 study published in the Annals of Internal Medicine, of 517 patients with non-small cell lung cancer, patients who stopped smoking lived almost two years longer without disease recurrence compared with patients who continued smoking (6.6 years versus 4.8 years). Smokers who quit also had higher three- and five-year survival rates than those who kept at it. Other research, including a review of 10 studies consisting of nearly 11,000 patients for the 2020 Surgeon General’s Report, suggests that smoking cessation improves treatment outcomes and increases survival among patients with cancer. The longer a person goes without smoking, the lower their year-to-year risk of getting lung cancer becomes.

For the 40% to 50% of patients who are current smokers when they receive a lung cancer diagnosis, these findings may provide much-needed motivation to quit. “When smokers get a lung cancer diagnosis, they sometimes think that the worst has already happened, so why quit,” Triplette explains.

That was certainly the case for Thurlow, who quit smoking as soon as he found out he had cancer. Unfortunately, doctors weren’t sure they could operate because his tumor was attached to the chest wall, but after eight weeks of low-dose chemotherapy coupled with 15 rounds of radiation, the tumor had shrunk. Thurlow became a candidate for surgery to remove the remaining cancer. He went on a high-powered chemotherapy regimen following surgery to ensure the cancerous cells were gone, and he has been cancer free ever since.

While the perks of quitting are undeniable, walking away from nicotine isn’t easy. Like most addictions, smoking is entangled in a complex web of physiological and psychological factors. Studies show that about 70% of smokers want to quit, and in any given year, 55% of smokers try to do so.

“With each puff of a cigarette, the feel-good hormone dopamine floods your system, and that keeps you coming back for more,” Prochaska explains. “Plus, if you’re used to smoking when you’re drinking coffee or chatting on the phone, smoking becomes almost Pavlovian. You hear the bell; where’s the drug?”

Despite the massive tumor lodged in Thurlow’s chest and permanent pulmonary damage, he still reached for a nonexistent pack in response to a variety of triggers, such as a ringing telephone. “I had a nagging sense of a hole that I couldn’t fill, an itch that I couldn’t scratch,” he explains. Today, Thurlow is 12 years out and he still hasn’t entirely freed himself of these vague yearnings, and he still loves the smell of cigarette smoke when a waft comes his way.

“Preoccupation with my disease and mortality provided a distraction from withdrawal,” says Thurlow. “Psychologically, a belligerent attitude is an undervalued ally in the great battle, and defying my addiction went hand-in-hand with defying my disease. I had to satisfy myself (with the fact) that I was doing everything within my power to get well, and smoking would have violated that commitment. Smoking would also have betrayed the trust of everyone embracing the cause of my recovery — particularly my wife, but also my children and other family; my oncologist, radiologist, and surgeon; an army of nurses and social workers; and countless friends. Had I smoked, I’d have felt guilty. Not smoking, I could enjoy a clear conscience.”

Munday took a more methodical approach. A respiratory nurse at the hospital where she had gallbladder surgery coached her on how to quit. “She told me that a nicotine craving lasts only three minutes and that you can tolerate anything for three minutes,” she says. “She also explained that it takes three days for your body to adjust to a new level of nicotine. So if you gradually cut back each week, you can be done with cigarettes inside of a month.”

Armed with that information, Munday set out to be smoke free before her first chemotherapy treatment. Every five days, she took half a pack of cigarettes and set it aside, starting by dropping from three packs a day to two-and-a- half packs, and then from two-and-a-half packs to two. She also began chewing ice to fill the void of smoking cigarettes. “It took me three to four weeks to stop smoking completely,” Munday says.

Munday had tried to quit before. She even paid $900 for hypnosis sessions, but her attempt to quit lasted less than a month, in part because her fiance was also a smoker. This time, however, they kept a smoke-free zone on one side of their home, and she used a nicotine pen to take the edge off. “I used the pen part-way through chemotherapy and radiation and then just titrated down my use the same way I had with the cigarettes,” she says.

According to Triplette, a week or even a day without cigarettes before smoking again isn’t a sign of failure. Instead, it shows that they can break the biochemical addiction and be able to do it again. The threat of a cancer diagnosis may even make the idea of quitting more palatable. “Cancer is a teachable moment. Something profound that happens in your life that you can directly tie to a behavior,” says Triplette. “When you make that link for the patient, it can improve the success of their quit attempt.”

After receiving a lung cancer diagnosis, some people can quit more easily than they imagined because smoking becomes physically difficult. But many others struggle
to quit. Navigating cancer is stressful, and many turn to cigarettes when they’re stressed. Yet according to the 2020 Surgeon General’s Report, less than one-third of people who try to quit smoking use evidence-based smoking cessation treatments.

With smoking, there is a very addictive, habit-forming behavior in addition to a substance — nicotine — that is physiologically addictive. To address both parts of the equation, a growing number of comprehensive cancer centers are offering patients a full buffet of options, including evidence-based counseling approaches, medications to help reduce withdrawal symptoms and curb cravings, and nicotine replacement therapy. Cessation programs that combine counseling with pharmacotherapies show cessation rates up to 57% in the first six months after starting the program, according to some studies. “Each of these approaches can work alone but they work better when they’re combined,” Rigotti says.

To give patients who smoke the best shot, many cancer centers incorporate tobacco treatment into standard patient care unless a patient opts out. At Seattle Cancer Care Alliance, for example, patients who indicate they are current or former smokers are automatically connected with the smoking cessation team. They don’t have to worry about getting a referral for treatments like counseling and medication for tobacco dependence.

“Patients may be hesitant to share that they’re smoking or even that they’re former smokers, so we’ve worked hard to overcome barriers around stigma,” Triplette says.
Social workers can also help connect smokers and former smokers with support groups specific to patients with cancer who are trying to quit. Prochaska’s team even uses breath sample analysis to show former smokers how their CO levels have dropped to zero. “That can be motivating both for the patient and for those who are in the group,” she says.

Other avenues of support include the federal government-sponsored quit line (1-800-QUIT-NOW), where a tobacco counselor guides individuals through a quit process through telephone appointments. “Many free resources, including the quit line, also provide nicotine replacement therapies, such as patches, lozenges and gum, to help people quit smoking,” Rigotti says.

For many smokers, that support is critical, and it’s one reason Thurlow became a volunteer with the Cancer Hope Network, a nonprofit organization that matches patients to survivors by diagnosis and treatment. Although he was able to quit cold turkey, he recognizes that it is often harder for most and always suggests hospital-based cessation programs first. “But the best thing I can tell a match is that despite a dreary prognosis, I’ve been cancer free for 12 years, in no small part because I have had a team of supporters in my corner, including my wife and children.”

While Munday’s loved ones, friends and medical team applauded her efforts to quit smoking and reveled in her success, she didn’t have that same support at home. After four total weeks of chemotherapy and 37 rounds of radiation, Munday realized she couldn’t stay with her fiance. “He refused to stop smoking in our home and our cars,” she explains. “There were other reasons, too, but that was a huge one.” She ended the 18-year relationship and moved into her own place a few months after completing cancer treatment.

“When I went back to the oncologist two months shy of my five-year mark, he said, ‘You’re 100% cancer free,’” she says. That was a welcome turn of events for Munday, who was once told that her odds of surviving the disease were 20% to 30%. Could ditching cigarettes be the reason she survived? No one knows for sure. But there’s no doubt that going smoke free has given Munday a second lease on life.

Studies show that quitting smoking after a lung cancer diagnosis has a huge payoff for patients. Many smoking cessation programs in cancer centers have tools to help patients quit.

Programs May Help Patients Go Smoke-Free After a Lung Cancer Diagnosis

In the fall of 2016, Dr. Mark DeAntonio learned he had a mass on his bladder. Doctors suspected stage 4 bladder cancer, and they confirmed the diagnosis with a biopsy. Over the next year, DeAntonio participated in two rounds of intensive chemotherapy, but the cancer didn’t regress — it spread. That’s when doctors referred him to the University of Southern California to participate in a clinical trial.

It turns out, DeAntonio didn’t have bladder cancer after all. “The tumor developed at the end of the prostate near the bladder, where it busted through the bladder wall,” says DeAntonio, now 67. “It was prostate cancer all along.”

Prostate cancer is the second most common cancer among men, affecting nearly 250,000 Americans annually. It happens most often when men have reached the height of their careers and are heading toward retirement — and it’s often highly treatable when diagnosed early. But for 10% to 20% of patients like DeAntonio, the disease can spread throughout the body and be remarkably resistant to treatment, especially the most common initial therapy used — androgen deprivation therapy (ADT). Called metastatic castration-resistant prostate cancer (mCRPC), these cancers grow and spread even in the absence of their preferred fuel: testosterone.

Dr. Mark DeAntonio received compassionate-use approval from the FDA for treatment with a particular PSMA-targeted therapy.

Since DeAntonio had already received chemotherapy for what he thought was bladder cancer, doctors prescribed ADT. These testosterone-blocking drugs controlled the cancer for several months, but within a year, DeAntonio’s PSA level began climbing again.

He tried immunotherapy to stimulate his immune system to fight the cancer, followed by radiation to destroy the stubborn cells. Doctors even recommended surgery to remove his prostate and bladder.

DeAntonio resisted. The procedure wouldn’t change his prognosis, but it would severely compromise his quality of life. “The pain and stiffness in my pelvis was debilitating, and moving into noncurative treatments was scary,” DeAntonio says. “I was running out of options.”

A child and adolescent psychiatrist at the University of California in Los Angeles, DeAntonio ultimately received compassionate-use approval from the Food and Drug Administration (FDA) for six treatments with lutetium-Lu-177-PSMA-617 (

Lu-PSMA-617), a targeted treatment for prostate cancer. Used in Germany, Australia, India and parts of South Africa, 

Lu-PSMA-617 is part of a class of radioactive drugs that target a protein on the surface of prostate cancer cells called prostate-specific membrane antigen, or PSMA.

“PSMA is highly overexpressed in prostate cancer cells, whether they’re confined to the prostate or have metastasized to other sites,” says Dr. Jeremie Calais, an assistant professor of nuclear medicine and theranostics at the David Geffen School of Medicine at UCLA. “While some normal tissues express small amounts of PSMA, the PSMA-targeted radioactive agent preferentially attaches to cancerous cells, not the normal tissues.”

PSMA-targeted radionuclides are part of a new class of therapies known as theranostics, which offer both therapy and diagnostic capabilities. Scientists have developed ligands — antibodies and small molecules — that recognize and bind to PSMA. To this ligand, they attach a radionuclide that emits radiation when it decays. Depending on the choice of radionuclide, you get either a smart bomb that delivers molecularly targeted radiation directly to the target or a smart imaging tracer with less radiation that highlights PSMA-avid cells using standard positron emission tomography (PET ) imaging techniques. Add it all together, and a growing body of research both in the United States and abroad suggests that taking a PSMA-targeted approach could be a game changer for advanced prostate cancer.

Dating back to the late 1980s and early 1990s, scientists were laser-focused on identifying tumor-specific targets that could help them distinguish cancerous cells from normal cells.

At the time, Dr. Neil Bander, now director of urological oncology research at Weill Cornell Medicine in New York, suspected that targeting PSMA could serve as a powerful weapon in the battle against prostate cancer — but researchers didn’t yet understand how to harness its potential.

Targeting PSMA diagnostically and therapeutically isn’t new. “The first PSMA imaging agent was approved more than 20 years ago,” says Dr. Scott Tagawa, medical director of the Genitourinary Oncology Research Program at Weill Cornell Medical College. Since then, researchers have been targeting PSMA in myriad ways from chemotherapy and antibody-drug conjugates to radionuclides, an approach that investigators expect to gain FDA approval in the coming months.

What makes PSMA unique? It’s consistently overexpressed in prostate cancer cells. PSMA should not be confused with PSA, a protein produced by cells of the prostate gland that may indicate prostate cancer at elevated levels. Normal prostate cells are also PSMA positive, but cancerous cells boast 100 to 1,000 times more PSMA than healthy tissue. The more stubborn and resistant to treatment the prostate cancer, the more PSMA on the surface of the cells. So if you target PSMA, you’re selectively targeting the cancer.

As luck would have it, one of the first-line treatments for prostate cancer — ADT — increases the load of PSMA on the surface of cancer cells. “PSMA levels are tightly linked to the androgen receptor pathway, and they increase as resistance to hormone therapy develops,” Tagawa says. So, in a sense, taking ADT is like using a homing beacon to detect an elusive target. Add a radioactive payload to the mix, and you have a veritable molecular grenade delivering cancer-obliterating radiation directly to hormone-resistant prostate cancer cells.

“Because of the radioactivity, we can confirm the therapy is reaching its target on imaging,” says Dr. A. Oliver Sartor, medical director of Tulane Cancer Center in New Orleans and a world-renowned prostate cancer researcher. “Radiation does not extend far beyond the cancer cell, so there is little damage to surrounding tissue.”

Because the radioactive isotope seeks out PSMA, just as a dog scours the floor for table scraps, the treatment can even find hidden cancerous cells that are too small to see on traditional imaging. The only hiccup: Not every patient with prostate cancer has easy-to-spot PSMA-expressing tumor cells circulating near tumors. Studies suggest that up to 10% of patients with metastatic, treatment-resistant prostate cancer have tumors that don’t light up on imaging.

The jury is out on whether patients who are PSMA negative or PSMA weak are less likely to respond to treatment. In addition, most patients with prostate cancer in the United States can’t access imaging with a PSMA-targeted agent — at least not yet.

For the past several years, researchers in the United States have been testing PSMA-targeted treatments, specifically 

Lu-PSMA-617, in patients with mCRPC that didn’t respond to prior therapies. They have demonstrated that 95% of prostate cancers are PSMA positive and that PSMA spikes in response to ADT. They even have high-powered imaging that shows the treatment is reaching its target. Yet the FDA has not approved PSMA-targeted agents for the treatment of prostate cancer. And until recently, PSMA imaging was only available at two sites in California (UCLA and UCSF), or as part of a clinical trial.

Dr. Mark DeAntonio avoided serious complications while undergoing treatment.

But that tide is about to change. Earlier this year, the FDA approved another PSMA PET imaging agent that will make PSMA PET imaging available throughout the United States. More importantly, for therapy, the FDA granted breakthrough therapy designation to 

Lu-PSMA-617 after a phase 3 clinical trial showed improvements in survival among patients with mCRPC. For the trial, Sartor and his colleagues enrolled more than 800 patients with mCRPC that had disease progression on other treatments and a positive PSMA PET scan. Trial participants randomized to the 

Lu-PSMA- 617 group were 40% less likely to die and 60% less likely to show disease progression on imaging versus those who received standard of care alone.

“Many of these patients were on their fourth-, fifth- and sixth-line treatments,” says Sartor. “The more treatments a patient receives, the more resistant they are to the next line of therapy, so if we can show activity in patients who have already been treated with multiple lines of therapy, we anticipate the response will be even better in patients who are treatment naive.”

While these targeted treatments await approval, patients like 66-year-old Steve G.* are getting creative. Steve had a prostatectomy in 2015, but because he hadn’t received chemotherapy, he wasn’t eligible for PSMA-targeted trials in the United States. A computer scientist, Steve made it his mission to learn everything he could about prostate cancer — and he wasn’t opposed to hopping around the globe to get the best care. “It’s in my DNA,” Steve jokes.

In the early ’80s, the surgeon who pioneered nerve-sparing prostatectomies, Dr. Patrick Walsh, operated on Steve’s father at Johns Hopkins Medicine. “That set the precedent for me,” says Steve, who ventured to New York to see the top surgeons and oncologists in the country, then to UCLA to get a PSMA PET scan and finally to Germany — five times — so doctors could inject him with 

“The ‘compassionate use’ program in Germany allows for the use of untested therapies in patients who have exhausted all approved treatment options,” Sartor says. But German investigators only treat patients whose PSMA PET scans light up like a neon sign that reads “targetable cancer cells HERE!” With this carefully curated population, they’re able to achieve striking response rates.

So if patients are willing to take the risk — and can afford multiple trips to Germany — they can access promising, but unproven, treatments outside a formal clinical trial. In fact, the growing number of American patients who make that trek are adding to the repository of data showing that targeted radionuclides could provide hope, and even durable remissions, in patients with mCRPC.

Lu-PSMA-617 in Germany is both similar and different than in the United States. Staff ensure that they have paid upfront. Then they give patients the traditional hospital wristband before directing them to the nuclear medicine ward. “The facility in Munich is like a labyrinth of old buildings connected by walkways,” Steve says. “You travel the hallways walking on solid ground and then shift to walking on wood. It’s quite quaint.”

Against a backdrop of gray walls and dim lighting, staff insert an IV to draw blood for testing and then flood the patient’s system with fluids. The additional fluid coaxes their body to excrete any radiation that isn’t attached to the cancer. Steve had an IV dripping for more than an hour before the five-minute infusion.

Lu-PSMA-617), the technician turns on the pump and practically runs out the door,” Steve says. “You have to quarantine for a minimum of three days before they release you back into the world in order to comply with strict emission standards in Germany.”

Lu-PSMA-617 has a half-life of around a week, so patients emit measurable amounts of radiation for weeks after the treatment.

After Steve received five treatments, two of which took place at the height of the COVID-19 pandemic, his PSA level had become undetectable by various assays — and it has remained undetectable ever since. His last PSMA PET scan at UCLA revealed that his cancer has almost disappeared, although a few slightly PSMA-positive lymph nodes remain.

Radioisotopes are unstable chemical elements that release radioactive particles. They destroy cancer by damaging its DNA. Different elements release different types of particles, such as alpha or beta, and each behaves in distinct ways.

Isotopes such as actinium 225 and radium 223 emit alpha particles when they decay. These high-energy particles have a very short range and obliterate everything in their path. Beta particles, such as those emitted by 

Lu-PSMA-617, have 2,000 to 4,000 times less energy, depending on the alpha, but travel farther, setting up crossfire in a PSMA-avid tumor. The isotope lutetium 177 has the bonus of emitting a small percentage of gamma rays when it decays, which makes it detectable for imaging. So if alpha-emitting particles are like precisely delivered atomic bombs, lutetium 177 is a radioactive hand grenade with GPS tracking.

In a case study published in Acta Radiologica Open, one patient who had significant disease progression on multiple lines of treatment had experienced dramatic results with a PSMA molecule carrying actinium 225. The “before and after” images revealed that the widespread metastatic cancer had completely disappeared. And the patient’s PSA levels plummeted from the hundreds and thousands to undetectable.

Unfortunately, it’s tough to produce spectacular results like that without some collateral damage. “An alpha particle in the right spot is so powerful it will destroy the target on contact,” Tagawa says. “The problem is an alpha in the wrong spot can produce permanent damage.”

Historically, scientists have shied away from small molecules because they can readily target normal tissues that express low levels of PSMA, such as the salivary and lacrimal glands. That can lead to dry mouth and dry eye. “Beta particles emitted by (

Lu-PSMA-617) trigger only mild toxicities that are usually reversible. But alpha particles can permanently destroy the salivary glands, and that’s not a small problem,” says Calais, explaining that without salivary glands, patients cannot taste or eat, and, over time, teeth fall out.

And because the radioisotope is excreted through the kidneys and bladder, there’s a risk of kidney toxicity, particularly with the alpha-emitting isotopes. Decreased blood counts may also occur because of effects on the bone marrow. Such serious and often irreversible toxicities with alpha-emitting particles are one reason why beta particles are leading the charge in the United States. Tagawa knows of only four prospective studies using PSMA-targeted alpha particles, and three of the four use antibodies, not small molecules (antibodies are too large to reach those unintended targets).

Fortunately, DeAntonio and Steve both sidestepped serious complications. But even with only 

Lu-PSMA-617, Steve developed dry mouth after his fourth treatment and DeAntonio had a horrible inflammatory reaction after his first injection. “It felt like I had a bad flu along with tremendous pelvic pain. The reaction went away after five days, but two weeks before my second treatment, the pain came back,” DeAntonio says.

There isn’t enough experience with this treatment to know whether the inflammatory response is a good sign.

DeAntonio’s PSA level was also higher after treatment. “If you base my response on lab studies, there has been no improvement in my disease state, but clinically, I’m better,” says DeAntonio, who is just about to meet his first grandchild.

For DeAntonio and many other patients with mCRPC, the focus is on the horizon. A whole new class of drugs is emerging for prostate cancer. The idea is to keep the cancer at bay and extend patients’ lives long enough to take advantage of new treatment options.

“I’m not expecting a cure,” says DeAntonio, “but I have no interest in dying.”

Emerging data suggest that combining both alpha- and beta-emitting particles may improve outcomes for patients with advanced castrate-resistant prostate cancer (CRPC) and minimize toxicity. Investigators expect radionuclides that target prostate-specific membrane antigen to become standard of care for CRPC in the not-so-distant future. Over time, and perhaps with more refinements, it may even become an earlier-line therapy for patients who recently received a diagnosis.

After decades of research, scientists inch closer to FDA approval for PSMA-targeted treatments that show promise for patients with an advanced form of prostate cancer.

Amy Paturel, M.S., M.P.H.

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