A Brighter Outlook for Metastatic Breast Cancer

Sally Palles had just undergone a mammogram in 2015 when the radiologist entered her room and delivered upsetting news: She most likely had breast cancer. “I felt both devastated and foolish because I hadn’t scheduled a mammogram in four years, even though I’m a nurse,” says Palles, who was working at what was then called Carolinas Hospital in Florence, South Carolina.

Palles later learned that she had hormone receptor-positive (HR-positive), HER2-negative breast cancer: The disease was fueled by the hormone estrogen and expressed little or no HER2 protein, which can contribute to the growth of some breast cancers. She had a left breast mastectomy and took an anti-estrogen (also termed hormonal) medication to prevent the cancer from recurring, but eventually stopped these treatments because of severe nausea — and the fact that the disease was not progressing. “I thought the cancer was all gone and not coming back,” says Palles, now 68.

Then, in 2017, she visited an orthopedic physician after hurting her right shoulder. An X-ray revealed that the injury was caused by cancer, which had spread to bones in her arm, back and upper chest. Historically, patients with newly diagnosed metastatic HR-positive cancer have been treated with hormone therapy followed by chemotherapy once anti-estrogen medications stop working. Now these patients have an option that is successfully delaying the transition to chemotherapy: a new biological therapy known as CDK4/6 inhibitors in combination with hormone therapy.

“These targeted medications have transformed the care of HR-positive positive breast cancer,” says Dr. Payal Shah, an assistant professor at the Abramson Cancer Center at the University of Pennsylvania. “They not only improve progression-free survival (meaning they delay the time until disease worsens), but they are also well-tolerated and allow many patients to maintain a higher quality of life than they would on chemotherapy.” Furthermore, recent research is showing that these drugs can also prolong survival.

Three CDK4/6 inhibitors — Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib) — have been approved by the Food and Drug Administration (FDA) in the past five years to treat HR-positive, HER2-negative meta- static breast cancer in both women and men. For metastatic disease, the drugs are combined with hormonal therapies as initial or subsequent (called second-line) treatments, so pre-menopausal women must first be treated with ovarian suppression medications to induce menopause, says Dr. Michelina Cairo, a breast oncologist with Texas Oncology- Houston Memorial City.

Other types of targeted drugs also have made an appearance. Piqray (alpelisib) targets the PI3K protein, which is expressed in breast tumors that harbor a PIK3CA gene mutation, one of the more common mutations in breast cancer. The drug was approved in May in combination with Faslodex (fulvestrant), a medica- tion that blocks the action of estrogen in cancer cells. The drug duo is used to treat postmenopausal women or men with HR-positive, HER2-negative cancer that has a PIK3CA mutation and has progressed on or after initial hormonal therapy. Trial results show that it lengthens the amount of time before disease progresses. New targeted treatments are also benefiting patients with other forms of metastatic breast cancer, including those with triple-negative disease or BRCA gene mutations. Lynparza (olaparib) and Talzenna (talazoparib) were both recently approved to treat BRCA gene-mutated, HER2-negative breast cancer.

In June 2017, Palles started taking Kisqali along with Arimidex (anastrozole), a hormone therapy; this time, nausea was not a problem, because she discovered that the side effect could be mitigated by stopping her antidepressant medication. Though she felt fatigued from the treatment, the cancer was in remission for one year. Then, in spring 2018, it started growing in her cervical spine. Her tumor tested positive for the PIK3CA mutation and she recently started taking Piqray. “My hope is that I can stay on this for a long period of time, and by then something new will be available for me to try,” Palles says.

IMPROVING OVERALL SURVIVAL

Ibrance, initially approved by the FDA in 2015 for certain patients with metastatic breast cancer, was the first CDK4/6 inhibitor to add language to its label broadening the group of patients eligible to use it: In 2017, it was approved as an initial treatment for HR-positive, HER2- negative metastatic breast cancer. Targeted treatments in this class interrupt the cancer cell cycle. “The cell cycle includes various steps, and one of those steps is a checkpoint in which the cell basically evaluates whether it has everything needed to successfully divide,” Shah says. “CDK4/6 inhibitors switch off the CDK protein and ultimately decrease the growth and division of cancer cells.”

Data from a recent phase 3 trial showed that more than 70% of previously untreated pre- and peri- menopausal patients with metastatic HR-positive, HER2-negative disease who received a combination of Kisqali and anti-estrogen therapy were alive after 42 months versus 46% of patients who received anti- estrogen therapy alone.

At a recent oncology conference, Kisqali’s manufacturer announced that, in a separate trial, the combination of Kisqali and Faslodex significantly improved overall survival as a first- and second-line treatment (used initially upon diagnosis or after the disease has progressed on another treatment) in postmenopausal women with HR-positive and HER2-negative breast cancer. Faslodex plus Verzenio has also shown improvement in overall survival based on recent trial results.

“The fact that we are seeing an improvement in overall survival is encouraging,” says Dr. Tufia Haddad, a breast oncologist at Mayo Clinic in Rochester, Minnesota. “Ultimately, what we’d like to see is a trend toward moving these drugs into the early-stage breast cancer setting.”

Researchers are studying the potential benefits of treating patients with the combination of CDK4/6 inhibitors and anti-estrogens before the disease has spread.

Physicians who regularly prescribe CDK4/6 inhibitors have also been encouraged by the minimal side effects. All three drugs, for example, can lower white blood cell counts, but this rarely leads to infections, Shah says. “These drugs are generally effective even when doses are reduced to help with side effects.”

Verzenio is more likely to cause diarrhea, which can be severe but manageable. One patient told CURE® that taking the medication halfway through her meal, rather than afterwards, made a big difference in easing diarrhea.

DISCOVERING NEW TARGETED THERAPIES

Though CDK4/6 inhibitors have revolutionized care for patients with metastatic HR-positive breast cancer, the disease ultimately develops resistance to these medications, says Dr. Dejan Juric, a breast oncologist and director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital. “Our main goal is to develop a better understanding of the mechanisms of resistance and develop treatments to achieve longer disease control,” he says.

Juric recently was the senior author on the study that led to the approval of Piqray, the first precision oncology agent to target the PIK3CA mutation in breast cancer. About 40% of patients with HR-positive, HER2-negative breast cancer have these mutations, which usually develop early in the course of the disease, Juric says. The mutation can be detected in the tumor, but also with a blood test (known as a liquid biopsy), and the study showed that the combination of Piqray and Faslodex increased progression-free survival by more than five months in patients who had the mutation compared with the control group.

About one-third of the study participants experienced hyperglycemia (high blood sugar). “The medication targets an important pathway in normal cells that is involved in glucose metabolism, which is why patients can experience elevated levels of glucose in the blood,” says Dr. Francisco Esteva, a professor at NYU School of Medicine and director of the breast oncology program at Perlmutter Cancer Center at NYU Langone Health. He regularly tests blood sugar levels of patients on Piqray and, if needed, prescribes diabetes medications or temporarily stops the cancer treatment.

TACKLING OTHER FORMS OF ADVANCED BREAST CANCER

Targeted therapies known as AKT inhibitors are attracting attention as a possible treatment for patients with both hormone receptor-positive as well as triple-negative breast cancer, a form of the disease that does not respond to hormonal therapies or drugs that target the HER2 protein. A phase 2 study showed a median overall survival of more than 23 months when the experimental AKT inhibitor ipatasertib was added to Taxol (paclitaxel), a chemotherapy treatment, compared with 18 months for Taxol alone.

Triple-negative breast cancer also recently became the first form of the disease that could be officially treated with immunotherapy. In March, the FDA approved Tecentriq (atezolizumab), which can help the immune system recognize and attack cancer cells, in combination with the chemotherapy drug Abraxane (nab-paclitaxel) for patients with triple-negative disease whose tumors are infiltrated by immune cells expressing the protein PD-L1.

The combination was approved based on the results of a phase 3 trial that tested Abraxane with or without Tecentriq, with 451 patients assigned to each regimen. The median progression-free survival was 7.2 months versus 5.5 months among those who took the combination versus Abraxane alone, respectively. In patients whose tumors expressed the protein PD-L1, progression-free survival was 7.5 months with the combination versus 5.0 months with Abraxane alone. At an interim analysis, median overall survival was 21.3 months with the combination compared with 17.6 months with Abraxane alone. For patients whose tumors expressed PD-L1, overall survival was 25 months with the combination versus 15.5 months with Abraxane alone. Most side effects were due to chemotherapy, but there was a bit more nausea and coughing in patients who took the combination regimen. Hypothyroidism occurred in 17.3% of patients taking the combination versus 4.3% receiving chemotherapy alone.

“New studies are also exploring whether using immunotherapy earlier may be more effective,” says Dr. William Gradishar, chief of the hematology/oncology division at Northwestern University Feinberg School of Medicine and director of the Maggie Daley Center for Women’s Cancer Care in Chicago. A recent phase 3 clinical trial known as KEYNOTE- 522 showed promising results when patients with triple- negative breast cancer received the immunotherapy Keytruda (pembrolizumab) and chemotherapy before having surgery.

Researchers are also exploring how to use antibody-drug conjugates, which employ antibodies to deliver chemotherapy to cancer cells, as a potential treatment for triple-negative breast cancer. Sacituzumab govitecan (IMMU-132) is one such drug that may have potential as a future treatment for triple-negative breast cancer. “The preliminary data has shown proof of principle,” Gradishar says.

Oncologists are also seeing the benefits of targeted treatments known as PARP inhibitors for patients who have inherited BRCA1 or BRCA2 gene mutations, which includes about 5% of those with breast cancer. These mutations make it difficult for damaged DNA to repair itself, which increases the risk of developing breast cancer. PARP inhibitors interfere with an enzyme known as poly ADP-ribose polymerase (PARP), which cancer cells depend on to repair DNA. This further interferes with DNA repair and can lead to cancer cell death.

In January 2018, the FDA approved a first PARP inhibitor to treat breast cancer, Lynparza (olaparib), based on a trial that showed longer remission times and higher response rates compared with chemotherapy. The drug is used for patients with HER2-negative metastatic breast cancer in the presence of a germline (inherited) BRCA mutation. Later that year a similar drug, Talzenna (talazoparib), was approved for patients with HER2-negative disease that also tested positive for BRCA mutations. Now researchers are exploring the benefits of combining PARP inhibitors with immunotherapy, says Dr. Vandana Abramson, an assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “These are exciting combinations because we may be able to use one drug to unleash the potential of another drug,” she says. “DNA damage caused by PARP inhibitors may create an environment that is conducive for immunotherapy to work.”

BECOMING A CHRONIC DISEASE

Although there is still no cure for metastatic breast cancer, oncologists like Abramson are optimistic as they see patients living longer. “We are able to offer less toxic treatments that are more effective,” she says. “Breast cancer is increasingly becoming a chronic disease because patients have effective treatment options once they develop resistance to one drug.”

Helen Black, 54, who learned in 2017 that she has metastatic breast cancer, is hopeful that she can enjoy a high quality of life for years. She was surprised by her diagnosis because the initial symptom was a tickle in the back of her throat. Black was first treated with antibiotics because an X-ray suggested pneumonia, but, in fact, breast cancer had spread to her left lung. She started chemotherapy to stabilize her lung and sought a second opinion from an oncologist at The University of Texas MD Anderson Cancer Center in Houston. Black was premenopausal, so her oncologist suggested that she have a hysterectomy before starting Ibrance combined with hormone therapy.

Black, a mother of nine, has no evidence of disease in her body now and continues working as a professional advocate for people with developmental disabilities. She took time off briefly when she was recovering from her hysterectomy and exercises regularly by biking, practicing yoga and walking. When she’s tempted to fear the future, Black remembers the woman in her breast cancer support group who has been taking Ibrance for seven years.

“When I asked my doctor what happens after Ibrance, he explained that his answer would have been very different five years ago because there were fewer treatment options,” says Black, who lives in Spokane, Washington. “He said my job is to live, and when this one stops working, we will have others to try.”