168,000 women in the U.S. live with advanced disease

Metastatic breast cancer starts in the breast but then spreads to other parts of the body. For example, it could spread to the bones or the lungs. It's also referred to as stage 4 or advanced breast cancer. It is the most severe form of the disease.

Although rates of recovery from metastatic breast cancer are lower than for other forms of cancer, the number of U.S. women living with the disease is growing. New treatments can lessen symptoms and keep the cancer from spreading further, helping women live longer.

A recent study from the National Cancer Institute found:

• In 2020, an estimated 168,000 women in the U.S. are living with metastatic breast cancer.
• The five-year survival rate of women diagnosed with metastatic breast cancer is increasing, especially among women aged 15 to 39.
• About one-third of women diagnosed with metastatic breast cancer have lived with it for five or more years.
• Some women may live 10 or more years after being diagnosed.

More research is needed to address the health care needs of women who live with this condition, according to the study.

Health Fast Facts

13%

From 1990 to 2017, the breast cancer death rate fell 13% in the U.S.

Treatment options for metastatic breast cancer (cancer that has spread to distant parts of the body) may include the following:

Hormone therapy

In postmenopausal women who have just been diagnosed with metastatic breast cancer that is hormone receptor positive or if the hormone receptor status is not known, treatment may include:

• Tamoxifen therapy.
• Aromatase inhibitor therapy (anastrozole, letrozole, or exemestane). Sometimes cyclin-dependent kinase inhibitor therapy (palbociclib, ribociclib, abemaciclib, or alpelisib) is also given.

In premenopausal women who have just been diagnosed with metastatic breast cancer that is hormone receptor positive, treatment may include:

• Tamoxifen, an LHRH agonist, or both.
• Cyclin-dependent kinase inhibitor therapy (ribociclib).

In women whose tumors are hormone receptor positive or hormone receptor unknown, with spread to the bone or soft tissue only, and who have been treated with tamoxifen, treatment may include:

• Aromatase inhibitor therapy.
• Other hormone therapy such as megestrol acetate, estrogen or androgen therapy, or anti-estrogen therapy such as fulvestrant.

Targeted therapy

In women with metastatic breast cancer that is hormone receptor positive and has not responded to other treatments, options may include targeted therapy such as:

• Trastuzumab, lapatinib, pertuzumab, or mTOR inhibitors.
• Antibody-drug conjugate therapy with ado-trastuzumab emtansine.
• Cyclin-dependent kinase inhibitor therapy (palbociclib, ribociclib, or abemaciclib) which may be combined with hormone therapy.

In women with metastatic breast cancer that is HER2/neu positive, treatment may include:

• Targeted therapy such as trastuzumab, trastuzumab deruxtecan, pertuzumab, ado-trastuzumab emtansine, or lapatinib.
• Targeted therapy with tucatinib, a tyrosine kinase inhibitor used with trastuzumab and capecitabine

In women with metastatic breast cancer that is HER2 negative, with mutations in the BRCA1 or BRCA2 genes, and who have been treated with chemotherapy, treatment may include:

• Targeted therapy with a PARP inhibitor (olaparib or talazoparib).

Chemotherapy

In women with metastatic breast cancer that is hormone receptor negative, has not responded to hormone therapy, has spread to other organs or has caused symptoms, treatment may include:

• Chemotherapy with one or more drugs.

Chemotherapy and immunotherapy

In women with metastatic breast cancer that is hormone receptor negative and HER2 negative, treatment may include:

• Chemotherapy and immunotherapy (atezolizumab).

Surgery

• Total mastectomy for women with open or painful breast lesions. Radiation therapy may be given after surgery.
• Surgery to remove cancer that has spread to the brain or spine. Radiation therapy may be given after surgery.
• Surgery to remove cancer that has spread to the lung.
• Surgery to repair or help support weak or broken bones. Radiation therapy may be given after surgery.
• Surgery to remove fluid that has collected around the lungs or heart.

Radiation therapy

• Radiation therapy to the bones, brain, spinal cord, breast, or chest wall to relieve symptoms and improve quality of life.
• Strontium-89 (a radionuclide) to relieve pain from cancer that has spread to bones throughout the body.

Other treatment options

Other treatment options for metastatic breast cancer include:

• Drug therapy with bisphosphonates or denosumab to reduce bone disease and pain when cancer has spread to the bone. (See the PDQ summary on Cancer Pain for more information about bisphosphonates.)
• Antibody-drug conjugate therapy with sacituzumab govitecan for certain patients with metastatic triple-negative breast cancer.
• A clinical trial of high-dose chemotherapy with stem cell transplant.
• Clinical trials testing new anticancer drugs, new drug combinations, and new ways of giving treatment.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment options for metastatic breast cancer (cancer that has spread to distant parts of the body) may include the following:

Hormone therapy

In men who have just been diagnosed with metastatic breast cancer that is hormone receptor positive or if the hormone receptor status is not known, treatment may include:

• Tamoxifen therapy.
• Aromatase inhibitor therapy (anastrozole, letrozole, or exemestane) with or without an LHRH agonist. Sometimes cyclin-dependent kinase inhibitor therapy (palbociclib) is also given.

In men whose tumors are hormone receptor positive or hormone receptor unknown, with spread to the bone or soft tissue only, and who have been treated with tamoxifen, treatment may include:

• Aromatase inhibitor therapy with or without LHRH agonist.
• Other hormone therapy such as megestrol acetate, estrogen or androgen therapy, or anti-estrogen therapy such as fulvestrant.

Targeted therapy

In men with metastatic breast cancer that is hormone receptor positive and has not responded to other treatments, options may include targeted therapy such as:

• Trastuzumab, lapatinib, pertuzumab, or mTOR inhibitors.
• Antibody-drug conjugate therapy with ado-trastuzumab emtansine.
• Cyclin-dependent kinase inhibitor therapy (palbociclib) combined with letrozole.

In men with metastatic breast cancer that is HER2/neu positive, treatment may include:

• Targeted therapy such as trastuzumab, pertuzumab, ado-trastuzumab emtansine, or lapatinib.

Chemotherapy

In men with metastatic breast cancer that is hormone receptor negative, has not responded to hormone therapy, has spread to other organs or has caused symptoms, treatment may include:

• Chemotherapy with one or more drugs.

Surgery

• Total mastectomy for men with open or painful breast lesions. Radiation therapy may be given after surgery.
• Surgery to remove cancer that has spread to the brain or spine. Radiation therapy may be given after surgery.
• Surgery to remove cancer that has spread to the lung.
• Surgery to repair or help support weak or broken bones. Radiation therapy may be given after surgery.
• Surgery to remove fluid that has collected around the lungs or heart.

Radiation therapy

• Radiation therapy to the bones, brain, spinal cord, breast, or chest wall to relieve symptoms and improve quality of life.
• Strontium-89 (a radionuclide) to relieve pain from cancer that has spread to bones throughout the body.

Other treatment options

Other treatment options for metastatic breast cancer include:

• Drug therapy with bisphosphonates or denosumab to reduce bone disease and pain when cancer has spread to the bone.
• Clinical trials testing new anticancer drugs, new drug combinations, and new ways of giving treatment.

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer:

Adjuvant therapy for early-stage breast cancer: Tamoxifen is FDA approved for adjuvant hormone treatment of premenopausal and postmenopausal women (and men) with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole, letrozole, and exemestane are approved for this use in postmenopausal women.

Research has shown that women who receive at least 5 years of adjuvant therapy with tamoxifen after having surgery for early-stage ER-positive breast cancer have reduced risks of breast cancer recurrence, including a new breast cancer in the other breast, and reduced risk of death at 15 years.

Until recently, most women who received adjuvant hormone therapy to reduce the chance of a breast cancer recurrence took tamoxifen every day for 5 years. However, with the introduction of newer hormone therapies (i.e., the aromatase inhibitors), some of which have been compared with tamoxifen in clinical trials, additional approaches to hormone therapy have become common.

For example, some women may take an aromatase inhibitor, instead of tamoxifen, every day for 5 years. Other women may receive additional treatment with an aromatase inhibitor after 5 years of tamoxifen. Finally, some women may switch to an aromatase inhibitor after 2 or 3 years of tamoxifen, for a total of 5 or more years of hormone therapy. Research has shown that for postmenopausal women who have been treated for early-stage breast cancer, adjuvant therapy with an aromatase inhibitor reduces the risk of recurrence and improves overall survival, compared with adjuvant tamoxifen.

Some premenopausal women with early-stage ER-positive breast cancer may have ovarian suppression plus an aromatase inhibitor, which was found to have higher rates of freedom from recurrence than ovarian suppression plus tamoxifen or tamoxifen alone.

Men with early-stage ER-positive breast cancer who receive adjuvant therapy are usually treated first with tamoxifen. Those treated with an aromatase inhibitor usually also take a GnRH agonist.

Decisions about the type and duration of adjuvant hormone therapy are complicated and must be made on an individual basis in consultation with an oncologist.

Treatment of advanced or metastatic breast cancer: Several types of hormone therapy are approved to treat metastatic or recurrent hormone-sensitive breast cancer. Hormone therapy is also a treatment option for ER-positive breast cancer that has come back in the breast, chest wall, or nearby lymph nodes after treatment (also called a locoregional recurrence).

Two SERMs, tamoxifen and toremifene, are approved to treat metastatic breast cancer. The antiestrogen fulvestrant is approved for postmenopausal women with metastatic ER-positive breast cancer that has spread after treatment with other antiestrogens. Fulvestrant is also approved for postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer who have not previously been treated with hormone therapy. In addition, it may be used in premenopausal women who have had ovarian ablation.

The aromatase inhibitors anastrozole and letrozole are approved to be given to postmenopausal women as initial therapy for metastatic or locally advanced hormone-sensitive breast cancer. Both of these drugs and the aromatase inhibitor exemestane are also approved to treat postmenopausal women with advanced breast cancer whose disease has worsened after treatment with tamoxifen. Men with advanced breast cancer who are treated with an aromatase inhibitor also receive a GnRH agonist.

Some women with advanced breast cancer are treated with a combination of hormone therapy and one of several targeted therapies:

• Palbociclib (Ibrance), is approved for use in combination with letrozole as initial therapy for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women. Palbociclib inhibits two cyclin-dependent kinases (CDK4 and CDK6) that appear to promote the growth of hormone receptor–positive breast cancer cells.
  
  Palbociclib is also approved to be used in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer whose cancer has gotten worse after treatment with another hormone therapy.
• Abemaciclib (Verzenio), another CDK4 and CDK6 inhibitor, is approved to be used in combination with fulvestrant for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease has progressed after treatment with hormone therapy.
  
  Abemaciclib is also approved to be used alone for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease got worse after treatment with hormone therapy and previous chemotherapy given for metastatic disease.
  
  Abemaciclib is also approved to be used with an aromatase inhibitor as first-line hormone therapy in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.
• Ribociclib (Kisqali), another CDK4/6 inhibitor, is approved to be used in combination with an aromatase inhibitor in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer that has not been treated with hormone therapy.
  
  Ribociclib is also approved to be used in combination with fulvestrant in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer who have not been treated with hormone therapy or whose disease got worse during treatment with hormone therapy.
• Lapatinib (Tykerb) is approved to be used in combination with letrozole to treat hormone receptor–positive, HER2-positive metastatic breast cancer in postmenopausal women for whom hormone therapy is indicated. It is a small-molecule inhibitor of the HER2 and EGFR tyrosine kinases.
• Alpelisib (Piqray) is approved to treat breast cancer that is HR positive and HER2 negative and has a mutation in the PIK3CA gene. It is used with fulvestrant to treat postmenopausal women, and men, whose breast cancer is advanced or metastatic and has gotten worse during or after treatment with hormone therapy.
• Some women with advanced breast cancer that is HER2 and HR positive may receive hormone therapy plus trastuzumab with or without pertuzumab.

Neoadjuvant treatment of breast cancer: The use of hormone therapy to treat breast cancer to reduce tumor size before surgery (neoadjuvant therapy) has been studied in clinical trials. These trials have shown that neoadjuvant hormone therapy—in particular, with aromatase inhibitors—can be effective in reducing the size of breast tumors in postmenopausal women, but it is not yet clear how effective it is in premenopausal women.

Hormone therapy is sometimes used for the neoadjuvant treatment of HR-positive breast cancer in postmenopausal women who cannot tolerate chemotherapy or when surgery needs to be delayed.

Rarely are the terms “cure” and “metastatic cancer” used together. That’s because cancer that has spread from where it originated in the body to other organs is responsible for most deaths from the disease.

But in 1995, two cancer researchers put forth a controversial concept: There is a state of cancer metastasis that isn’t necessarily fatal. They called it oligometastatic cancer, describing it as existing between a cancer that is contained to where it originated (e.g., the breast or colon) and one that has spread extensively throughout the body.

In oligometastatic cancer, the patient has only a few, usually small metastases (“oligo” means few). For some patients, this form of metastatic cancer “should be amenable to a curative therapeutic strategy,” Ralph Weichselbaum, M.D., and Samuel Hellman, M.D., both from the University of Chicago, wrote some 25 years ago.

At the time, and still today, most people with metastatic cancer are treated only with therapies meant to kill cancer cells anywhere they may be in the body, known as systemic treatment. The assumption being that any evidence of metastatic cancer, Dr. Weichselbaum said, “means that metastases are everywhere, and that’s not necessarily true.” 

That assumption, however, has also translated into the belief that direct, or “localized,” treatment of individual metastatic tumors is pointless and only subjects patients to unnecessary treatment. But that may not be the case for oligometastatic cancer, Drs. Weichselbaum and Hellman argued. Since the cancer does not appear to be widespread, perhaps treatments that directly remove the metastatic tumors, such as surgery or targeted radiation, are worthwhile.

It’s taken time, but over the last 5 years or so, the duo’s hypothesis has been put to the test, primarily in small clinical trials.

The key question is whether direct treatment of these oligometastatic tumors “can either prolong or improve the quality of life for patients?” said Bhadrasain Vikram, M.D., associate deputy director of NCI’s Radiation Research Program. “The data for that are pretty skimpy at the moment.”

The trials done to date have suggested that this approach may improve how long patients live. But Dr. Vikram and others have cited shortcomings in the studies that they say weaken their findings.

More definitive tests—in the form of larger clinical trials—are already ongoing or are in the works. What those studies find will help to shape how this concept influences patient treatment moving forward, said Joseph Salama, M.D., professor of radiation oncology at the Duke University School of Medicine.

The notion of oligometastatic cancer “is still relatively new,” Dr. Salama said. “It looks like something that could be promising for patients,” he continued, but how best to apply it “is something we’re still trying to figure out.”

Treating Everywhere… and A Few Other Places

Aggressive, systemic treatment of metastatic cancer has evolved over time. For decades, it primarily involved chemotherapy, as well as hormone treatments for cancers like breast and prostate, but now includes a growing number of targeted therapies and immunotherapy.

This reliance on systemic therapies is linked in part to the way in which metastatic tumors are identified—namely, imaging technologies such as PET and CT scans.

“We’re limited by the ability to accurately image metastases,” Dr. Vikram said. “Each year, [the technology] seems to get better,” he continued. But even the most cutting-edge approaches still have limitations and can’t necessarily rule out the presence of tiny deposits of tumor cells, called micrometastases, hiding in the lungs, brain, or bones.

As a consequence, treating individual metastases has not been a common part of cancer care, aside from doing so to control pain.

One situation where directly treating metastases is not uncommon is in patients with colorectal cancer that has spread to a limited number of spots on their liver. In fact, several observational studies, including one conducted in the United States and one in Europe, have reported that approximately 20% of patients initially treated with surgery to remove only their primary tumors and metastatic tumors on their liver survived for at least 10 years. 

Neither study was a prospective clinical trial, however, or comprehensively documented other treatments these patients may have received.

Nevertheless, the approach is now regularly used, said Nataliya Uboha, M.D., Ph.D., of the University of Wisconsin Carbone Cancer Center, who specializes in treating gastrointestinal cancers. “We can actually cure a small percentage of patients with metastatic [colorectal cancer] that is isolated to the liver when the primary and liver tumors are completely removed surgically,” Dr. Uboha said.

She cautioned, however, that nearly all these patients would also get 3 to 6 months systemic therapy at some point during their treatment.

Putting Oligometastatic Cancer in Context

Even among cancer researchers, Dr. Weichselbaum noted, the oligometastatic concept is not always well understood. “The most important idea is that metastasis is a spectrum,” he said, both in the number of tumors and the speed at which the disease spreads. 

Part of the confusion is that there’s no precise definition of oligometastatic cancer, he acknowledged. 

In fact, as Dr. Salama noted, there isn’t an agreed upon number of metastases that clearly delineates oligometastatic cancer from more widespread disease. Many studies have drawn the line at five, he explained, but that number was “arbitrarily decided upon.”

But the number of metastatic tumors has to be placed in context for each patient. For example, where are the metastatic tumors located and can they safely be removed? There is also the matter of timing. Was the patient initially diagnosed with oligometastatic cancer, or was she diagnosed with a localized cancer and one or two metastases became apparent on imaging tests several months later, after a few rounds of systemic treatment?

Such distinctions are important, Dr. Uboha said, because they likely reflect the biology of the individual patient’s cancer. She cited the example of a patient initially diagnosed with widely metastatic cancer who responds well to chemotherapy and, after a period, has only one or two remaining tumors.

“Widespread disease that is down-staged with chemo, in my opinion, is still widespread disease,” she said. “Just because we don’t see it on CT scans doesn’t mean it’s completely gone.” That form of oligometastatic cancer, she believes, “represents a very different entity” than other situations in which only a few metastases have been identified.

Number Isn’t Enough

To that point, Dr. Weichselbaum said, the available data suggest that it’s not just the number of small metastatic tumors that matters. “You need to do biological characterization of the tumors,” he said. 

Such information can hopefully help researchers identify specific molecular features, or “biomarkers,” that can offer insights into how aggressive a patient’s cancer is and guide the approach to treatment, he continued.

Biomarkers are desperately needed, Dr. Uboha agreed. “Right now, we look at the CT scan and we count the spots. Is that good enough? No, it’s definitely not.”

Along those lines, Drs. Weichselbaum and Hellman, in collaboration with colleagues at the University of Chicago and elsewhere, have been trying to identify molecular signatures of oligometastatic cancer. 

In some of that work, they have homed in on molecules called microRNAs, whose primary function is to turn off the activity of genes. In their research, they have identified specific microRNAs that appear to influence whether metastatic tumor cells can continue their uncontrolled spread. 

In one study, they identified a small group of specific microRNAs in metastatic tumor samples from people with different cancer types that was directly linked with limited spread of the disease. Further experiments in mouse models of breast cancer showed that these microRNAs blocked cancer cells’ ability to move and invade tissue, disrupting their ability to form metastases.

In more recent work, they have focused on in-depth molecular analyses of liver metastases from people with oligometastatic colorectal cancer. In that research, they discovered specific molecular features of the metastases, and those related to the immune system response, that appeared to predict how long patients survived. Such molecular patterns, the team concluded, could identify patients whose cancer is less aggressive and could thus be good candidates for direct treatment of their metastatic tumors.

While these results are promising, Dr. Weichselbaum cautioned, more research to identify and validate such biomarkers is needed before they can be used to guide everyday patient care. 

Testing the Concept in Clinical Trials

The gold standard for research that typically moves the needle of cancer care is a clinical trial, particularly a large trial that randomly assigns participants to one of two (or more) groups, each of which receive different treatments.

Only a handful of randomized clinical trials have specifically enrolled patients with oligometastatic cancer and tested direct treatment of their metastatic tumors, and most of these have been relatively small. 

One such trial, called SABR-COMET, enrolled approximately 100 patients with any type of solid cancer as long as they had five or fewer metastases. Participants were randomly assigned to the standard treatment for their particular cancer (control group) or the standard treatment and a targeted form of radiation called stereotactic body radiation therapy (SBRT)—also known as SABR—to treat their metastases.

When initial results were published 2 years ago, trial researchers reported that patients in the SBRT group lived more than a year longer than those in the control group. 

The trial has received some criticism, however. Among the critiques is that there were many more patients with prostate cancer in the SBRT group than the control group. Prostate cancer patients with metastases live longer than patients with other metastatic cancers (e.g., lung), Dr. Vikram said, and this “imbalance” could likely have accounted for the better outcomes in that group.

In addition, three patients in the SBRT group had treatment-related deaths. Even tumor-directed treatments like SBRT “are not ‘what-do-you-have-to-lose,’” Dr. Vikram said. “It is not a risk-free enterprise.”

Other trials have only included people with specific cancers, with lung cancer being a particularly intense focus. The results thus far, albeit from small clinical trials, have been positive.

One randomized trial, for example, enrolled 29 patients with non-small cell lung cancer who had only a few metastases that after they received initial chemotherapy. Patients whose oligometastatic tumors were then treated with SBRT and additional chemotherapy lived nearly three times longer without any evidence of their cancer progressing than patients who only got additional chemotherapy. A somewhat larger trial (49 patients) had similar results.

All the trials completed to date have had notable limitations, Dr. Vikram said, such as differences in treatments that participants received. The time has come, he continued, “to move past those to larger trials, to show: Does this [approach] really make a difference?”

And that is happening. For example, a trial similar to but much larger than SABR-COMET, called SABR-COMET-3, is currently underway that is enrolling patients with any solid tumor. There is also the SABR-COMET-10 trial, which is enrolling patients with 4–10 metastases.

And Dr. Uboha is leading an NCI-funded phase 3 clinical trial enrolling people with oligometastatic esophageal and gastric cancer. To participate, patients must have no more than three metastatic tumors. They will be randomly assigned to receive either standard chemotherapy or the standard therapy along with additional radiation to all sites of their disease.

Two other NCI-supported trials of people with cancer and limited metastases include one for patients with non-small cell lung cancer and another for those with triple-negative breast cancer.

Researchers are particularly excited about the prospect of combining direct treatment of oligometastatic tumors with immunotherapy. The idea builds on a concept in cancer called the abscopal effect. Although it is thought to rarely occur in patients, the abscopal effect describes a situation where radiation delivered to a single tumor kick-starts an immune response against the cancer throughout the body.

Dr. Vikram said he is cautiously enthusiastic about studying the combination of localized radiation therapy with immunotherapy treatments like immune checkpoint inhibitors.

Rather than trying to treat “one metastatic tumor at a time, at least the ones we can see,” he said, it’s using the radiation “to help attack metastases all over the body.” As such, he continued, it may also have implications for patients with widespread metastatic cancer.

Several smaller clinical trials have tested this approach in people with NSCLC who have just a few metastases. One of those trials enrolled patients who were initially diagnosed with oligometastatic disease. In all patients, SBRT was used to treat individual metastases, which was then followed by treatment with the checkpoint inhibitor pembrolizumab (Keytruda).

Combining the two therapies did not increase the risk of serious side effects, and the results suggest that the addition of pembrolizumab may increase how long patients live without their cancer getting worse.

Dr. Salama agreed that combining local treatments like SBRT with immunotherapy looks promising. “But these [results] need to be confirmed,” he said.

There are many questions about the concept of oligometastatic cancer that still need to be answered, Dr. Salama added. 

Although he believes it will eventually “help many patients” by improving their treatment, any substantial changes to everyday cancer care should wait until “we see the results of these [larger trials],” he said.

Before TIL therapy, a woman with breast cancer had metastatic lesions in her chest wall (top, left) and liver (bottom, left). After receiving the immunotherapy, her tumors shrank completely, and recent scans (right) show that she remains cancer free more than five years later.National Cancer Institute

An experimental form of immunotherapy that uses an individual’s own tumor-fighting immune cells could potentially be used to treat people with metastatic breast cancer, according to results from an ongoing clinical trial led by researchers at the National Cancer Institute’s (NCI) Center for Cancer Research, part of the National Institutes of Health. Many people with metastatic breast cancer can mount an immune reaction against their tumors, the study found, a prerequisite for this type of immunotherapy, which relies on what are called tumor-infiltrating lymphocytes (TILs).

In a clinical trial of 42 women with metastatic breast cancer, 28 (or 67%) generated an immune reaction against their cancer. The approach was used to treat six women, half of whom experienced measurable tumor shrinkage. Results from the trial appeared Feb. 1, 2022, in the Journal of Clinical Oncology).

“It’s popular dogma that hormone receptor–positive breast cancers are not capable of provoking an immune response and are not susceptible to immunotherapy,” said study leader Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research. “The findings suggest that this form of immunotherapy can be used to treat some people with metastatic breast cancer who have exhausted all other treatment options.”

Immunotherapy is a treatment that helps a person’s own immune system fight cancer. However, most available immunotherapies, such as immune checkpoint inhibitors, have shown limited effectiveness against hormone receptor–positive breast cancers, which are the majority of breast cancers.

The immunotherapy approach used in the trial was pioneered in the late 1980s by Dr. Rosenberg and his colleagues at NCI. It relies on TILs, T cells that are found in and around the tumor.

TILs can target tumor cells that have specific proteins on their surface, called neoantigens, that the immune cells recognize. Neoantigens are produced when mutations occur in tumor DNA. Other forms of immunotherapy have been found to be effective in treating cancers, such as melanoma, that have many mutations, and therefore many neoantigens. Its effectiveness in cancers that have fewer neoantigens, such as breast cancer, however, has been less clear.

The results of the new study come from an ongoing phase 2 clinical trial being carried out by Dr. Rosenberg and his colleagues. This trial was designed to see if the immunotherapy approach could lead to tumor regressions in people with metastatic epithelial cancers, including breast cancer. In 2018, the researchers showed that one woman with metastatic breast cancer who was treated in this trial had complete tumor shrinkage, known as a complete response.

In the trial, the researchers used whole-genome sequencing to identify mutations in tumor samples from 42 women with metastatic breast cancer whose cancers had progressed despite all other treatments. The researchers then isolated TILs from the tumor samples and, in lab tests, tested their reactivity against neoantigens produced by the different mutations in the tumor.

Twenty-eight women had TILs that recognized at least one neoantigen. Nearly all the neoantigens identified were unique to each patient.

“It’s fascinating that the Achilles’ heel of these cancers can potentially be the very gene mutations that caused the cancer,” said Dr. Rosenberg. “Since that 2018 study, we now have information on 42 patients, showing that the majority give rise to immune reactions.”

For the six women treated, the researchers took the reactive TILs and grew them to large numbers in the lab. They then returned the immune cells to each patient via intravenous infusion. All the patients were also given four doses of the immune checkpoint inhibitor pembrolizumab (Keytruda) before the infusion to prevent the newly introduced T cells from becoming inactivated.

After the treatment, tumors shrank in three of the six women. One is the original woman reported in the 2018 study, who remains cancer free to this day. The other two women had tumor shrinkage of 52% and 69% after six months and 10 months, respectively. However, some disease returned and was surgically removed. Those women now have no evidence of cancer approximately five years and 3.5 years, respectively, after their TIL treatment.

The researchers acknowledged that the use of pembrolizumab, which has been approved for some early-stage breast cancers, may raise uncertainties about its influence on the outcome of TIL therapy. However, they said, treatment with such checkpoint inhibitors alone has not led to sustained tumor shrinkage in people with hormone receptor–positive metastatic breast cancer.

Dr. Rosenberg said that with the anticipated opening early this year of NCI’s new building devoted to cell-based therapies, he and his colleagues can begin treating more individuals with metastatic breast cancer as part of the ongoing clinical trial. He noted that this new immunotherapy approach could potentially be used for people with other types of cancer as well.

“We’re using a patient’s own lymphocytes as a drug to treat the cancer by targeting the unique mutations in that cancer,” he said. “This is a highly personalized treatment.”