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It has been almost 25 years since the approval of Herceptin (trastuzumab), a groundbreaking therapy that targeted the human epidermal growth factor receptor 2 (HER2) oncogene and ushered in a new phase of targeted therapy that has saved thousands of lives. 

Ongoing research in the biology of the HER2 signaling pathway led to many newer lines of investigation that continue to generate novel successful treatments, further improving the life expectancy of patients with HER2-positive breast cancer.

®, a big leap forward has been taken just this summer with the r

. This trial was a first because it addressed a group of patients with tumors that were technically HER2 negative — in that they expressed low levels of HER2 that fall below the threshold for which any response or benefit from Herceptin would be expected. 

The story began when the antibody-drug conjugate, 

Enhertu (fam-trastuzumab deruxtecan- nxki)

, which had recently been approved by the Food and Drug Administration as a later line of therapy for advanced HER2- positive breast cancer, had been shown in a pilot study to break the barrier in activity with patients who had HER2-negative tumors that showed a small amount of HER2 in the cell membrane using standard HER2 antibody staining techniques.

We are still trying to understand this newly coined class of “HER2 low” tumors.

It is not clear that these are biologically different from HER2-negative tumors. However, because Enhertu is an antibody-drug conjugate designed to bind to HER2-expressing cells regardless of their biology, HER2-low cells could be vulnerable due to the way antibody-drug conjugates work. 

The HER2 antibody part of the antibody- drug conjugate binds to the HER2 receptor on the cell surface, and together with the linked toxic drug, is drawn into the cell. 

Like a Trojan horse, the “soldiers” — a drug called deruxtecan that inhibits cell growth by interfering with DNA division — are released into the cell. The design of this antibody-drug conjugate is different than that of earlier versions like Kadcyla (T-DM1, or ado-trastuzumab emtansine), which only kills HER2positive but not HER2-low cells.

The DESTINY-Breast04 trial compared Enhertu to standard chemotherapy for patients with HER2-low breast cancer and showed such a notable improvement in the time to tumor progression and overall survival that it drew a standing ovation when presented at the American Society of Clinical Oncology meeting in June 2022. 

Given the fact that more than half of all breast cancers are HER2 low, this significantly expands options when hormonal or chemotherapeutic drugs are no longer effective. 

Moreover, it lays the foundation for a whole new generation of antibody-drug conjugates made of antibodies that can be customized to bind to proteins expressed by certain tumors and linked to drugs that have not been used as prior therapy, maximizing chances for success.

Professor of Medicine
Chair, Department of Breast Medical Oncology 

The University of Texas MD AndersonCancer Center

Articles

Editor's Page

Enhertu's FDA approval marked a major milestone in the breast cancer space, as it was the first drug to be approved for patients with HER2-low disease.

HER2-Low Classification Is a 'Big Leap Forward' for Breast Cancer Treatment

Advocating for oneself is a critical component throughout the cancer journey. 

Treating cancer while keeping the patient in mind is a fine balance that all cancer teams must strive for. But what if the tables are turned — and it’s the researchers who need to advocate for something they feel strongly about? 

For example, what if a specific measurement has the capacity to predict the response to cancer treatment for a patient, but the time-consuming process of deciphering its results has created “tension between accuracy and efficiency for reading this test”?

®, we see a prime example of this in an article on 

, a protein that’s expressed when tumor cells divide. Researchers have found that measuring a patient’s Ki-67 score — with a higher score indicating aggressive tumor growth — can help cancer teams decide which treatment may be best for a patient with breast cancer. 

Renewed focus on Ki-67 scoring stems from a recent Food and Drug Administration approval of a drug that showed benefit in patients with higher Ki-67 scores.

In the article, we speak with a patient who said her Ki-67 score changed the trajectory of her care plan and created a sense of urgency around treatment. She said that if this test hadn’t been performed, the tumor could have continued to grow and potentially spread. This situation also taught her the importance of self-advocacy because she demanded the biopsy that determined her Ki-67 score.

Another article in this issue examines how patients can navigate a 

 months or years after completing treatment for primary breast cancer. We learn how radiation, a treatment with many benefits, may be the cause of some secondary cancers. 

Although the risk of a secondary cancer is low, it’s important for patients to be diligent no matter where they are in their cancer journey.

Also in this issue, a clinical psychologist pens her advice for patients who experience 

chest numbness after undergoing a mastectomy

. She highlights advancements that potentially alleviate numbness and the value in patients discussing this common side effect with loved ones and their cancer team.

“There are physical and emotional ways to move forward after a mastectomy, but they are only possible by bringing the sadness, embarrassment and pain of sensation loss into the light,” she wrote.

Additional topics include recent study results on metastatic breast cancer and the fear of recurrence.

As always, we hope you find our stories inspirational and informative. Thank you for reading.

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

It is essential that patients with breast cancer speak up to their health care providers, be it advocating for genetic testing or discussing symptoms. 

Self-Advocacy Is Critical in Cancer Care

Just as a loss of hearing or sight can fundamentally shape a patient’s identity, so too can a loss of sensation, especially in an area of the body as essential to one’s identity as the breasts.

For many women, the breasts and chest are not only part of their sexuality, but also part of their identity. That’s why a lack of sensation can feel like walking through the world with a piece of you missing.

Chest numbness is a common side effect of mastectomy. This may be acknowledged as a possible side effect in the preoperative paperwork, but a patient may not be prepared for the actual effects it will have on their quality of life as a cancer survivor or previvor. The chest area accounts for nearly 10% of a body’s surface, and it’s the heart space that a person presents to the world.

It can be difficult to grasp the full effect of a lack of sensation, especially in the whirlwind of being diagnosed with breast cancer or the BRCA1 or BRCA2 gene. A hug no longer has that enveloping power. A woman may not be able to feel her child’s head against her chest as she rocks them to sleep. How she interacts with her romantic partner may shift. She may move through the world silently feeling “different” from other women.

The good news is that patients don’t have to cope with this side effect on their own — and it may not be something they have to live with. Thanks to recent advances in treatment, there is hope to restore sensation during breast reconstruction or some revision surgeries.

A patient who underwent a mastectomy may be hesitant to talk about chest numbness. Perhaps she feels an overwhelming sense of “I should just be grateful to be alive” and worries that others will think it’s trivial. In truth, a person can feel deeply grateful to be alive and also desire to live without a loss of chest sensation.

It’s natural to want to have sensation in all parts of one’s body — especially the intimate area of one’s chest.

In my practice as a clinical psychologist, my first course of action when a client mentions chest numbness is to suggest they talk with their physician to determine if any medical interventions are available. It’s wise, however, to be proactive whenever possible, meaning that a woman doesn’t have to wait until after mastectomy to address the potential for numbness with her oncology care team.

Surgical intervention could potentially restore sensation. During a mastectomy, nerves are severed when cancerous breast tissue is removed. If the nerves aren’t surgically repaired, the connection is lost between the skin on one’s chest and their brain — hence, a lack of sensation.

Even women who had a mastectomy years ago may have options. With breast neurotization (breast nerve repair), a specially trained plastic reconstructive surgeon may be able to reconnect nerves cut during the mastectomy using a nerve graft at the time of breast reconstruction or during some revision procedures.

Nerves regenerate over time, which can lead to regaining sensation in the chest and breasts. Many plastic surgeons who perform breast neurotization report that women typically start to regain sensation several months after surgery and that the feelings can continue to develop for up to two years.

Patients who lose sensation in their chest area following a mastectomy don’t have to settle for going through life as though a piece of them is missing. A skilled mental health professional can help them prepare for sensation loss prior to surgery and develop the tools to cope as they go forward in their cancer journey.

Although everyone has experienced temporary numbness before — whether it’s a foot that’s fallen asleep from sitting too long or numbness following a dental procedure — it can be hard to imagine what that numbness would be like over a large part of the body. I can’t fully prepare my clients for what it may feel like to lose sensation in their chest area, but I can guide them through visualizations and demonstrations.

For instance, I may have a client hug their partner with a piece of cardboard between them to prepare for what having a sensation barrier might feel like. I may also support the client in learning how to talk about the numbness in an age-appropriate way with a child or other loved one.

Self-care is also vital as a woman heals and moves toward embodying herself fully. With a lack of sensation, the breasts may feel like a “hands off” area, but my advice is to show that area self-care in ways that bring joy, such as doing self-massages and using essential oils.

One’s chest may not have sensation yet, but it can still be a loved part of their being.

The most powerful thing that can be done is to talk about it with loved ones, the cancer care team and other survivors. There are physical and emotional ways to move forward after a mastectomy, but they are only possible by bringing the sadness, embarrassment and pain of sensation loss into the light.

This article was written and submitted by Carla Marie Manly, PhD. Manly is a clinical psychologist based in Sonoma County, California.

Chest numbness following a mastectomy can be truly daunting, but patients with breast cancer don’t have to suffer in silence — and it may not be something they have to live with.

How Breast Cancer Survivors, Patients Can Cope With Sensation Loss and Numbness After a Mastectomy 

The speed at which cancer cells grow can be an important factor in determining cancer treatment. Among the best-known biomarkers for the rate of cancer growth is a protein known as Ki-67, which is expressed when tumor cells divide.

A high Ki-67 index indicates aggressive tumor growth. 

For example, Kate Laseter of Thornton, Colorado, was diagnosed with stage 2 invasive ductal carcinoma in September 2021 and informed that her Ki-67 score was 65%. Of note, the median Ki-67 score is 15%. 

As a histological technician with Theralink Technologies, Laseter immediately knew what that meant.

“It was very aggressive and growing rapidly and had invaded everything,” she recalls. “I looked at my (results) ... and I had less than 10% normal tissue in my biopsy.”

Because Laseter was just 29 when she noticed a lump in her breast, she was told that it was probably just a fibrous mass and to wait and see. She refused and demanded a biopsy. 

Based on her high Ki-67 score, she was placed on treatment immediately and received a chemotherapy regimen that included carboplatin and docetaxel in combination with the targeted therapies Herceptin (trastuzumab) and Perjeta (pertuzumab). She also underwent a bilateral mastectomy. 

In March 2022, she was declared in remission and cancer-free.

“My Ki-67 score clearly changed how quickly my care team wanted to start treatment on me,” Laseter observes. “If they hadn’t performed that test, my tumor could have just kept growing and possibly metastasized. It’s important for patients to educate and advocate for themselves.”

Ki-67 is used to determine tumor growth in several types of cancer including breast cancer, says Dr. Ruth O’Regan, chair of the department of medicine at the University of Rochester in New York. 

“We use it to determine the type of breast cancer a patient has, which helps us make treatment decisions,” O’Regan notes. “It’s commonly used in cancers that express estrogen receptors, which makes up about two-thirds of the breast cancers that we treat.”

Ki-67 has been used to determine the rate of tumor growth for many years, but there have been issues around the consistency and reproducibility of clinical scoring of Ki-67 levels. However, using more automated technology to read scores and consensus meetings of the experts in the area have led to more widespread acceptance.

The protein was given a boost in October 2021 when the Food and Drug Administration (FDA) approved Verzenio (abemaciclib), a CDK4/6 inhibitor, with endocrine therapy for adjuvant treatment (additional therapy given after primary treatment to lower the risk of the cancer returning) of adults with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)- negative, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score of 20% or greater.

“This was a game changer because it was the first FDA approval of a CDK4/6 inhibitor in the curative setting, notably after this class of drugs had dramatically improved outcomes when added to hormone therapy for metastatic breast cancer,” observes Dr. Heather McArthur, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center in Dallas. 

“It’s hugely impactful to have the addition of a CDK4/6 inhibitor in our arsenal of drugs for early-stage breast cancer.”

The efficacy of Verzenio with endocrine therapy was evaluated in monarchE, a multicenter clinical trial that included women and men with the above-described form of early breast cancer with a high risk of recurrence. 

Patients received either two years of Verzenio plus their physician’s choice of standard endocrine therapy or standard endocrine therapy alone. 

In patients with high risk of recurrence and a Ki-67 score of 20% or greater, the trial showed a statistically significant improvement in invasive-disease-free survival (the time after treaatment that a patient survives without signs of cancer) among the cohort receiving Verzenio.

Ki-67 levels are usually scored at the time of diagnosis. When a tumor is biopsied, a small sample is stained through a process known as immunohistochemistry, which reveals the cells expressing Ki-67. 

In some labs, pathologists examine the slide and estimate the number of cells rather than actually count them, notes Dr. David Rimm, a professor in the department of pathology at Yale University School of Medicine in New Haven, Connecticut. 

“Some would only count a few cells, and some would count more because the more cells you count, the more accurate you are, though it takes more time,” he explains. “So there was a sort of tension between accuracy and efficiency for reading this test.”

For breast cancer, a Ki-67 score of 5% or less is considered low, and greater than 30% is considered high. 

“Those are the cutoff points at which we can have great concordance among pathologists, and the International Ki67 in Breast Cancer Working Group also recommends those cut points,” says Rimm.

The FDA’s approved cutoff point for the use of Verzenio is 20%, which could result in different interpretations among pathologists. 

“The maker of (Verzenio) didn’t take that into account when they designed their cut point,” Rimm says. “There are laboratories that still use a cut point of 12%, 13% or 14%, which is what led to the problems of nonreproducibility in the first place. It’s tough for pathologists to be really reproducible in that range, even counting every cell.”

In response, the American Society of Clinical Oncology and the National Comprehensive Cancer Network issued their own recommendations for consideration of Verzenio in high-risk patients, says McArthur, although their recommendations were agnostic of Ki-67 and did not include a cutoff.

“Those decisions were made based on a variety of reasons, namely the fact that not every cancer center performs Ki-67 testing, that Ki-67 has been a notoriously unreliable biomarker with a lot of interobserver and interlab variability, and uncertainty as to the optimal cutoff for determining high-versus-low scores,” McArthur notes. 

“It’s a test that’s been fraught with challenges over the years, and it was interesting that the FDA decided to include the 20% cutoff in their approval.”

Concern over the accuracy of Ki-67 scoring may also result from the inherent heterogeneity of tumors, adds Rimm. 

“Even though we can measure the amount of Ki-67 relatively accurately, we’re only sampling a tiny piece of the tumor,” he explains. “When we make a diagnosis of cancer, we sample less than 1% of the tumor, so if proliferation is heterogeneous (varies by location), it might be inaccurate or only represent part of the tumor.”

As medicine moves into the era of digital pathology, automated approaches to scoring Ki-67 are becoming more commonly accepted, Rimm notes. 

“I led the work by the (International Ki67 in Breast Cancer Working Group), which showed that an automated assessment was as good or even better than the assessment by counting pathologists,” he says. “However, we didn’t want to require automated assessment because there are still sites that don’t have the machinery to do it.” 

UT Southwestern is among the institutions that do not use automated assessment to score Ki-67 in breast tumors, although it does see it more consistently in outside reports, says McArthur. 

“We typically repeat all biomarkers in-house to ensure that our breast cancer-dedicated pathologists agree with outside interpretations, especially when they are automated,” she adds. “We are pretty rigorous in confirming those results within our breast cancer-dedicated pathology service.”

A tumor’s Ki-67 score helps establish the rate of tumor growth, but its influence in developing treatment options often depends on the oncologist in charge, says Dr. Joseph Geradts, a clinical professor in the department of pathology and laboratory medicine at the East Carolina University Brody School of Medicine in Greenville, North Carolina.

“The oncologists at (East Carolina University) usually make treatment decisions in the absence of a Ki-67 index, and that’s true for many oncologists around the country,” he explains. 

“This is because they already have a lot of information that allows them to make treatment decisions, such as the routine pathology report, which includes the tumor grade and mitotic index, both of which are correlated with the Ki-67 index, and other assays such as Oncotype DX. It’s a relatively small group of patients for whom Ki-67 adds a lot to what is already known, though there are oncologists who rely on it more heavily.”

In addition to helping determine the rate of tumor growth at diagnosis, Ki-67 expression can be a useful monitor of tumor response to preoperative endocrine therapy. 

“In many cases, preoperative endocrine or chemotherapy is very effective, but sometimes it is not,” Geradts says. “That’s where Ki-67 comes in because it has been shown that in those tumors where the Ki-67 index goes down after treatment, the patient benefits from that therapy. That’s another area where Ki-67 has proved useful, but admittedly, it’s a relatively small percentage of patients.”

Although Ki-67 may play a minimal role in deciding treatment for some patients, an extremely high Ki-67 score can be quite determining for others.

Megan-Claire Chase of Dunwoody, Georgia, had her treatment influenced by a high Ki-67 score. After months of unusual symptoms followed by the discovery of a hard lump in her left breast, Chase was diagnosed in September 2015 with stage 2 invasive lobular breast cancer. 

Her treatment regimen included 16 rounds of chemotherapy (Adriamycin PFS [doxorubicin hydro- chloride], Cytoxan [cyclophosphamide] and Taxol [paclitaxel]), 33 rounds of radiation, and a lumpectomy, reduction and reconstruction.

“The biopsy of my tumor showed that I was ER (estrogen receptor) positive (95%), PR (progesterone receptor) positive (99%), HER2 negative, and my Ki-67 score was 60%,” says Chase, who is the breast cancer program director at SHARE Cancer Support. 

“With that plus genetic counseling, my family history and the fact that I had an unknown variant, my oncologist felt it was important to give me the motherload of chemotherapy to kill everything.”

As she entered the survivorship phase, Chase chose another oncologist, who shocked her by telling her that he wouldn’t have recommended chemotherapy even with her high Ki-67 score. 

However, Chase did her own research and realized that her Ki-67 score and other factors made her an ideal candidate for the treatment she received. 

"The chemo was supposed to, first, contain my tumor from spreading, and then shrink it as much as possible, and that’s what it has done,” she states.

Unlike Laseter, Chase was unfamiliar with Ki-67 at the time of her diagnosis. 

Intent on understanding as much as possible about her cancer, she questioned the reasoning behind her recommended treatment regimen. 

“I asked, ‘Why are you giving me this? Is this a cookie-cutter treat- ment?’ And I was told no. It was based on several factors, including my Ki-67 score of 60%,” Chase says.

Although the FDA approval of Verzenio with endocrine therapy 

for early breast cancer put a new spotlight on the role and value of Ki-67, most pathologists believe the approval was a one-off that won’t lead to significantly greater use within cancer pathology. 

Of greater interest are technologies that make Ki-67 scoring more reliable and less subjective.

“I believe an automated way of measuring Ki-67 will be important because it takes the subjectivity out of the measurements,” says O’Regan. “But honestly, more and more, we’re moving toward looking at genes rather than proteins in terms of what drives cancer. So it may be that how proliferation is measured will be completely different than what we do now.”

Geradts also believes that digital image analysis is the way of the future, noting, “Ki-67 is very much observer dependent, and that can be eliminated by using computer algorithms. As these algorithms become more commonplace and affordable, we’ll likely see an increased number of laboratories that will choose to quantitate Ki-67 because it will be much more reproducible.”

It all makes for a very exciting time to be treating breast cancer, says McArthur.

“We have had in recent years an unprecedented number of FDA approvals that have had a huge clinical impact in terms of decreasing risk of developing metastatic disease for patients with early-stage breast cancer and improving overall survival for patients who do have metastatic breast cancer,” she says. 

“We want to learn more about cell proliferation and other factors so that we can offer more effective treatments to patients who need it and optimize treatment recommendations for those who can achieve those same great outcomes — but with less toxicity in the form of fewer drugs.”

To learn more about Kate Laseter's journey with stage 2 invasive ductal carcinoma and using her experience as an employee at a breast cancer research facility to push back against doctors who minimized her ultrasound findings,

 listen to this "Cancer Horizons" podcast episode

Feature

An FDA approval put Ki-67 scoring — which may predict tumor growth — in the spotlight, but what that means long term to patients depends on who you ask. 

Will There Be a Resurgence of Ki-67 Scoring in Breast Cancer?

Throughout 15 years as a medical oncologist primarily caring for patients with breast cancer, I have found that fear of recurrence — the fear that cancer will return or advance — is nearly universal among patients with cancer undergoing curative treatment.

My conversations with patients experiencing this fear and associated feelings are among the most challenging and complex.

Much of the survivorship literature has described this fear along a spectrum, ranging from mild to severe symptoms involving feelings of worry, distress or concern that a cancer may recur or persist despite curative treatment. At the mild end, patients may experience occasional thoughts about cancer. But with moderate to severe symptoms, patients may suffer from the inability to control more frequent thoughts of recurrence, causing intrusive distress to daily life and feelings of hopelessness and despair.

Studies have revealed that close to 70% of patients with breast cancer are vulnerable to this type of fear, driven by a range of factors including the predicted risk of recurrence, young age and psychosocial adjustment following treatment completion.

Women initially diagnosed with breast cancer before age 35 may carry significant fear about life expectancy as well as perceived risk of developing recurrent breast cancer throughout their lifetime. Furthermore, a patient’s underlying stress, anxiety and depression at diagnosis can lead to 

To bring this younger patient population to life, let me share a story about my patient, Sally*, a 34-year-old mother of three young children, a practicing attorney and an avid athlete who was diagnosed with locally advanced triple-negative breast cancer. During our first meeting, she described feelings of stress related to caring for her young children and older mother through treatment, coupled with uncertainty about family finances, completing treatment, achieving health and ultimately survival.

She also had trouble processing certain information we discussed due to losing a friend to cancer.

To help Sally manage her fear, we openly and thoroughly discussed her treatment, possible side effects and chances of recurrence. We also screened her level of distress through a validated questionnaire. Our care team provided close psychological monitoring via face-to-face interactions and telephone discussions to help alleviate anxiety and distress and to provide 

coping strategies aimed at maintaining lower levels of stress

Upon completing treatment, Sally reported her fear was low. At her first survivorship visit, she expressed distress over development of chemotherapy-induced neuropathy in her feet that required long-term physical therapy with strength and balance rehabilitation. She returned to work but needed acclimation to walking slower and shifting her weight properly when going downstairs to prevent falls.

I reminded Sally that her fear was normal and experienced by many survivors. In fact, upon completion of curative treatment, more than 95% of women with early-stage breast cancer will achieve remission and join the more than 3.9 million survivors (as of 2019) who begin their journey anticipating that life will settle back into normalcy.

Yet, for countless patients, side effects from cancer or its treatment create a new norm with significant challenges — challenges that require developing coping mechanisms to help them achieve greater balance and overcome physical, emotional and psychosocial challenges. Like Sally, numerous patients experience anxiety-inducing side effects driven by reduced quality of life, inability to assimilate back to daily routines and a perpetual fear of cancer recurrence.

I believe in partnering with my patients throughout their cancer journeys. With Sally, that meant creating a lineup of empowering strategies and actions in her survivorship. It also meant listening to her questions and ideas.

During subsequent follow-ups, I emphasized addressing versus suppressing feelings of distress and anxiety by connecting with family, friends and her psychologist. We also identified possible fear- and anxiety-invoking triggers such as follow-up visits, imaging scans and the anniversary of her diagnosis.

Through her reading and research, Sally shared with me antioxidants and herbal medicines that may protect her from cancer recurrence. I recognized her diligence and further explained that although supplements such as minerals, vitamins and antioxidants are vital components to our diet, no long-term studies have shown consistent or long-term benefit with any particular supplement.

We discussed what a healthy lifestyle for people who have had breast cancer looks like:

Stay on top of cancer screening, which enables greater control in detecting early recurrence.

Maintain a healthy, balanced diet, which includes dietary fiber and plant-based foods, and reduce processed meats and refined sugars to help lower cancer risk.

Limit alcohol intake to one to two drinks daily.

Engage in stress-reducing activities like hobbies and exercise (if possible, a minimum of 150 minutes of exercise per week may help reduce risk of recurrence, reinforced by multiple studies demonstrating beneficial results in breast cancer survivors).

With the support of our follow-ups, conversations and interventions, Sally has been coping well and maintaining a better balance in her quality of life and daily activities.

The fear of recurrence is real. It’s natural. There are ways to manage this fear, so it doesn’t become overwhelming or debilitating. Physicians like me and a network of resources are here to help.

This article was written and submitted by Dr. Ajaz M. Khan. Khan is a medical oncologist and chair of the department of medical oncology at Cancer Treatment Centers of America in Chicago.

There are ways to manage the fear of cancer recurrence, so it doesn’t become overwhelming or debilitating. Physicians like me and a network of resources are here to help.

The Fear of Cancer Recurrence is Real, Natural and Nearly Universal

In February 2014, Tiffany O’Donnell, then 33, felt an odd pain in her right breast.

The discovery was enough to send her to a doctor, who referred her for a mammogram. The mammogram led to a biopsy, at which point she received life-changing news.

“I had the biopsy done on a Friday,” says O’Donnell. “That Monday, I got a phone call to come into the office because it was breast cancer.”

Although the mass in her right breast was benign, she had stage 2B cancer in her left breast.

“I went into a little bit of shock,” O’Donnell remembers. “I think it took a while for it to really sink in.”

O’Donnell recalls those early days after her diagnosis as “a whirlwind.”

She remembers meeting doctors and scheduling an operation, but in general, she says, the period was a blur. Along with her husband, O’Donnell brought her father with her to medical appointments. He helped keep track of what her care team told her about her illness and treatment and was able to ask questions that O’Donnell, overwhelmed by an avalanche of information, might not have thought to mention on her own.

After she underwent a double mastectomy with reconstructive surgery and chemotherapy, it looked as though O’Donnell’s condition was stable. But in 2019, after speaking to doctors about back pain that wouldn’t go away, she learned that the cancer had metastasized to her bones. In the years that followed, she also developed metastases on her liver and brain.

The HER2 status (or receptor status) of the cancer was different now as well. The initial disease had been classified as human epidermal growth factor receptor 2 (HER2) negative, meaning the cancer did not express abnormal levels of HER2, a protein involved in cell growth that is sometimes found to be overexpressed in breast cancer. This time, however, the disease fell into a category called HER2 low.

The designation of HER2-low status is rapidly reshaping how researchers and care providers think about breast cancer. As many as four out of five instances are considered HER2 negative, according to the National Cancer Institute, meaning the cells in the tumor do not express overly high levels of the HER2 protein. But in truth, many cancers that have been called HER2 negative might be more accurately characterized as HER2 low, meaning they produce only small amounts of this protein.

Although having marginal levels of HER2 expression is common in breast cancers (the National Cancer Institute estimates that anywhere from 50% to 60% of breast cancers can be considered HER2 low), it wasn’t until very recently that doctors were able to exploit this trait to treat the disease.

Understanding why HER2-low status represents a breakthrough requires a quick lesson in breast cancer subtypes. Historically, doctors have used three major markers to distinguish between breast cancers: two to describe those expressing receptors for the hormones estrogen and progesterone and another to describe those expressing unusually high levels of the protein HER2.

“If the tumor expresses hormone receptors, we call that breast cancer ‘hormone-receptor positive’ breast cancer. If HER2 is overexpressed on the tumor, we call the cancer ‘HER2-positive breast cancer.’ If none of these three (estrogen receptors, progesterone receptors or HER2) are expressed, then we call those breast cancers ‘triple-negative breast cancer,’” explains Dr. Heather Han, director of research in the department of breast oncology at Moffitt Cancer Center in Tampa, Florida.

“We have these groups because we target these markers to tailor specific treatments for patients,” Han continues. “So far, we were able to identify effective treatments targeting hormone receptors and HER2-targeted therapy for HER2-positive breast cancer. Once HER2 was identified as a marker many decades ago, we knew some tumors had some expression of HER2, but not at high enough levels for us to call it overexpressed. HER2-targeted therapy worked the best for only HER2 overexpressed tumors.”

The first and still commonly used anti-HER2 antibody, Herceptin (trastuzumab), only is effective for truly HER2-positive but not HER2-low tumors. This was proven in a large clinical trial.

The problem with these HER2-low cancers was that even though oncologists knew about them, there was no way to use the biomarker to inform treatment for this subset of patients with cancer. This was the case for Janie Branscomb, a patient of Han’s from Myakka City, Florida. Unlike O’Donnell, Branscomb had metastatic disease when she was first diagnosed.

“The doctor came in and she said, ‘There’s nothing we can do. You’re stage 4,’” Branscomb says.

The doctor estimated that she had three to five years to live.

“That’s when I was like, I’m not good with that. We’ve got to figure something else out,’” Branscomb says.

When she found out she had HER2-low cancer, there wasn’t much anyone could do with the information. Her breast biopsy was HER2 negative, but her metastases were HER2 low.

“I was diagnosed in 2017, so they really weren’t saying too much about HER2 low,” Branscomb recalls. “It was either negative or positive. There wasn’t really much of the in between.”

Historically, clinicians had to use chemotherapy on HER2-low breast cancer, which produced only limited success. But in the past few months, a new drug has offered a possible solution.

the Food and Drug Administration (FDA) approved Enhertu

 (fam-trastuzumab deruxtecan-nxki) for treating patients with metastatic HER2-low breast cancer. Laboratory studies suggested that HER2-low tumor growth could also be blocked with Enhertu, and it was subsequently confirmed in a small study of patients with HER2-low tumors. This led to a larger trial that led to the new approval and dramatically expanded the number of patients eligible to be treated with the medication.

The FDA based its approval on the DESTINY-Breast04 study, a randomized clinical trial that included more than 500 adults with HER2-low breast cancer that had either metastasized to other parts of their bodies or couldn’t be removed with surgery. Researchers randomly assigned the patients to two groups: one that was treated with a doctor’s choice of existing chemotherapies and another group, twice as large as the first, that was treated with Enhertu.

The results were dramatic enough that an article about the trial published by the American Society of Clinical Oncology called Enhertu “a new standard of care” for people with metastatic HER2-low breast cancer. Not only that, but the study’s principal investigator, Dr. Shanu Modi of Memorial Sloan Kettering Cancer Center in New York, received a standing ovation after she gave a presentation of her team’s findings — an uncommon occurrence at these meetings.

Risk of dying or disease progression was cut in half

 for patients in the study assigned to intravenous infusions of Enhertu. Overall, patients assigned to Enhertu were 36% less likely to die than those assigned to conventional chemotherapy. Patients assigned to Enhertu lived for a median of 9.9 months before cancer progression compared with 5.1 months for the chemotherapy group, the researchers reported. In terms of overall survival, patients given Enhertu lived for a median of 23.4 months compared with 16.8 months for those given conventional chemotherapy.

Traditionally, most cancer treatments start out as an option only for patients with advanced disease. Once researchers can see the therapy in action, further studies will explore expanding the number of patients who can be treated with Enhertu.

“The ultimate goal is for the medicine to be studied in patients with high-risk early-stage (disease), so potentially we can cure more patients,” says Han.

Enhertu is an antibody-drug conjugate, which means it belongs to a group of therapies that use the proteins expressed by cancer cells to deliver cancer-killing drugs right to the source. In the case of Enhertu, the medicine uses HER2 proteins as an actual target to attach to and enter cancer cells and kill them.

“It’s a chemotherapy drug that is attached to a HER2-targeted agent,” says Dr. Jane Lowe Meisel, an associate professor of hematology and medical oncology at Emory University School of Medicine in Atlanta. “It gets driven to the HER2-overexpressing cells by the targeting agent, and then the chemotherapy gets deployed into that cancer cell and can kill it off more selectively (than standard chemotherapy).”

An antibody is a protein made by the immune system that attacks foreign bodies, like viruses or bacteria.

HER2 proteins may not be necessarily driving the growth of these breast cancers, but they are a door through which medicine can infiltrate and destroy tumor cells. Dr. V.K. Gadi, a researcher and medical oncologist in the department of hematology and oncology at the University of Illinois Cancer Center in Chicago, describes the antibody-drug conjugate as a sort of guided missile.

“Unlike normal antibodies that your body generates because it’s seeing a virus or bacteria, trastuzumab was engineered in a laboratory,” Gadi explains, noting that this is a simplified explanation. “And instead of caring about bacteria or a virus, it was engineered to attack HER2. And once it found HER2, it invited an immune response to that area.”

But trastuzumab had only limited success when there were smaller amounts of the HER2 protein on the surface of the cell, Gadi adds. The same was true of many conventional chemotherapies: The substances designed to enter and destroy cancer cells didn’t work particularly well in the presence of low HER2 levels.

“(The researchers who created Enhertu) took that molecule trastuzumab, and now they’ve glued on a super-toxic chemotherapy to it,” says Gadi. “By putting the chemotherapy on that antibody, which works like a little guided missile, now that chemotherapy’s being delivered straight to the cancer cell.”

The chemotherapy, deruxtecan, is especially effective because it is chemically different from many chemotherapies used in breast cancer, says Gadi. Patients with advanced disease have already been heavily treated with conventional chemotherapy, so the disease is often resistant to many types of chemotherapy. Deruxtecan, on the other hand, is not as closely related to these therapies, which means the tumor is less likely to resist treatment.

Furthermore, experts say, Enhertu has what’s known as a “bystander effect,” in which the drug kills cancer cells neighboring those that were initially targeted.

“Not only did the missile kill the target, it killed the neighborhood around it as well,” Gadi says. “If you have enough of those things happening, you can impact the whole tumor.”

The result is a medicine that works for patients with both high and low levels of HER2 expression.

“We used to define patients as either HER2 positive or negative,” Meisel says. “The HER2-low category was really created by the investigators who came up with the idea for this study. This trial really brought that term to life.”

New Disease Classification Expands Patient Options

The study and subsequent FDA approval has prompted care providers, including Meisel, to review the disease characteristics of some of their patients.

“As I’ve had patients in my own clinic who’ve progressed, before making a choice about what to offer them next, I’ve actually gone back and said, ‘Were they really HER2 negative? Or were they HER2 low?,’” Meisel says. “And then I’d classify them in our clinic notes and be able to explain to them this new way that we are defining their cancer, and the options this might open up for them going forward.”

In some cases, the new classification has resulted in Meisel recommending Enhertu to her patients.

“That’s been an exciting thing to be able to offer,” she says.

The sheer number of patients who stand to benefit is also noteworthy.

“It could impact as many as half the patients living with stage 4 breast cancer,” says Meisel, adding that some studies are already examining the possibility of using Enhertu in earlier stages of breast cancer and that it could become common in treating high-risk, early-stage disease in the next several years. She describes the rise of antibody-drug conjugates in breast cancer as “a new paradigm.”

O’Donnell began Enhertu after doctors found new lesions on her liver in July 2022.

In O’Donnell’s case, it wasn’t the changing terminology that led to her newfound HER2-low status, but rather an actual change in the biomarkers of the tumors: Cancers can change their HER2 status during the course of treatment.

She’d discussed the possibility of trying Enhertu with her oncologist already, and because of her job as an administrator at the Penn State Health Breast Center in Hershey, Pennsylvania, O’Donnell was more informed about new breakthroughs in the field than other people might have been. She has already been through several lines of therapy, including multiple chemotherapies, and with two Enhertu treatments under her belt so far, she says the side effects are much less severe than with some conventional chemotherapy drugs she’s taken.

But it’s too soon to tell whether the drug has begun to work for her.

The designation of HER2-low status is rapidly reshaping how researchers and care providers not only think about, but also treat, breast cancer.

CURE^® Breast Cancer 2022 Special Issue

HER2-Low Classification Is a 'Big Leap Forward' for Breast Cancer Treatment

Self-Advocacy Is Critical in Cancer Care

How Breast Cancer Survivors, Patients Can Cope With Sensation Loss and Numbness After a Mastectomy

Will There Be a Resurgence of Ki-67 Scoring in Breast Cancer?

The Fear of Cancer Recurrence is Real, Natural and Nearly Universal

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Latest News

CURE® Breast Cancer 2022 Special Issue

HER2-Low Classification Is a 'Big Leap Forward' for Breast Cancer Treatment

Self-Advocacy Is Critical in Cancer Care

How Breast Cancer Survivors, Patients Can Cope With Sensation Loss and Numbness After a Mastectomy

Will There Be a Resurgence of Ki-67 Scoring in Breast Cancer?

The Fear of Cancer Recurrence is Real, Natural and Nearly Universal

New Way To Define Breast Cancer Opens Doors to Treat Previously-Missed Subtype of Patients

Latest News

CURE^® Breast Cancer 2022 Special Issue