Finding New Hope in Triple-Negative Breast Cancer Treatments

CURE, 2021 Breast Cancer Special Issue ,

Three therapeutic breakthroughs are revolutionizing care for triple-negative breast cancer and saving women’s lives.

Sarah Hosea was terrified. In February 2019, the 27-year-old had just received a diagnosis of breast cancer, and she didn’t like the information that a Google search turned up.

“I didn’t really know anything about triple-negative breast cancer (TNBC),” says Hosea, now 30, who lives in Missouri City, Texas. “No one in my family had ever had breast cancer. I didn’t even know there were different types. But when you Google it, it’s not a pretty picture. It’s pretty scary.”

Doctors at her local hospital were frank. The diagnosis was a difficult one, with a significant chance that she would not survive. They wanted her to begin a rigorous course of chemotherapy later that week. But Hosea hesitated. She knew time was of the essence, but she decided to seek a second opinion at The University of Texas MD Anderson Cancer Center in Houston.

TNBC is defined more by what it isn’t than what it is. TNBC cells lack receptors for the hormones estrogen and progesterone and do not overproduce the HER2 protein. That means that targeted drugs against hormone or HER2 receptors are not effective for this cancer type, so chemotherapy is generally required. But that’s not to say that all TNBCs are the same.

“Triple-negative breast cancer refers to a very heterogeneous group of breast cancers,” says Dr. Rita Nanda, an associate professor of medicine and director of the breast oncology program at UChicago Medicine in Illinois. “All these triple-negative cancers get lumped together because of lack of expression. But there are differences.”

There is some nuance among TNBCs, but generally there are variations that make the cancer more likely to respond to one treatment over another. A prime example is a mutation in the BRCA1 or BRCA2 genes, which is what Hosea had. It responds to poly (ADP ribose) poly- merase inhibitors, commonly known as PARP inhibitors, which work by blocking an enzyme that cancer cells produce to repair their DNA, ultimately killing the cells since BRCA mutations also affect DNA repair, giving the cells a “double whammy.”

TNBCs are widely thought of as aggressive because they tend to be diagnosed at higher grades, often appear in younger people and grow faster than some other breast cancers. Furthermore, when these cancers do not respond to chemotherapy at early stages, they have a high tendency to spread to other parts of the body. The American Cancer Society reports that the five-year relative survival rate for people with TNBC is 77% for all stages, 65% with regional metastases and 12% with distant metastases. Even when the disease is caught early, by some estimates, approximately one-third of patients will experience a relapse of TNBC after standard therapy with chemotherapy and surgery.

“For patients with pretreated metastatic TNBC, standard chemotherapy is associated with low response rate and poor progression-free survival,” explains Dr. Aditya Bardia, director of the breast cancer research program and an associate professor of medicine at Harvard Medical School in Boston. “TNBC traditionally has been tough to treat because it lacks actionable receptors and is associated with significant genomic heterogeneity and aggressive tumor biology.”

He estimates that with standard-of-care chemotherapy for patients with pre-treated metastatic TNBC, the response rate is as low as 5% to 10%. Further, patients with metastatic TNBC who receive standard chemotherapy often see their disease progress within two or three months.

However, as researchers learn more about the variations in TNBC and develop more targeted therapies, a diagnosis that used to seem hopeless now comes with new rays of hope, largely thanks to major advances in treatment that have taken place over the past two or three years. “I would say we’ve made a ton of advancement recently,” Nanda says. “Within the past couple of years we’ve had a lot of drugs approved for triple-negative disease.”

Bardia adds that the difficulty of treating TNBC is precisely what has spurred these recent developments. “Triple-negative breast cancer represents a major unmet need in the field of breast oncology and consequently there has been considerable interest in developing novel therapies for patients,” he explains.

Recent advances in TNBC can be sorted into three categories: immunotherapy drugs, antibody-drug conjugates and PARP inhibitors.

USING THE IMMUNE SYSTEM

Immunotherapy options for patients dealing with cancer are not new. But on July 26, the Food and Drug Administration (FDA) announced it had approved the immunotherapy drug Keytruda (pembrolizumab) for the treatment of high-risk, early-stage TNBC. Immunotherapy drugs work by activating the body’s immune system to attack cancer cells. Keytruda is approved both in combination with typical chemotherapy as a neoadjuvant, or pre-surgery, treatment and for use alone and as an adjuvant therapy.

Kristen Perello, who received a diagnosis of stage 2 TNBC in August 2017, participated in the phase 3 clinical trial, called KEYNOTE-522, examining the efficacy of Keytruda that led to the drug’s approval. “It was definitely a total shock,” she remembers. “I didn’t know people could survive from this type of diagnosis.”

One week after Perello’s initial appointment, her surgeon introduced her to Dr. Joyce O’Shaughnessy at Texas Oncology, Baylor Sammons Cancer Center, who was running the trial, and with a treatment plan in place, Perello felt a sense of relief.

Perello joined the trial, in which 1,174 patients with newly diagnosed, untreated, early-stage, high-risk TNBC were randomly assigned to receive placebo plus chemotherapy before surgery followed up by placebo after surgery or Keytruda plus chemotherapy before surgery followed by Keytruda monotherapy after surgery.

Because of the design of the study, Perello does not know for sure whether she received Keytruda or a placebo as part of her treatment plan, but she took her prescribed medications and went through 16 rounds of chemotherapy followed by a double mastectomy and completed 16 rounds of chemotherapy, with a complete response after just three rounds. Through it all, she dressed up for her treatments and maintained high spirits. Chemotherapy is often a difficult experience characterized by fatigue and side effects such as hair loss and nausea, but Perello’s course of treatment was fairly uneventful. “Honestly, I felt great the whole time,” she says.

Although she avoided many side effects, Perello did find herself fatigued during so-called red devil treatments, which consist of an infusion of a bright-red chemotherapy drug called doxorubicin and are notoriously grueling for patients. But she was able to keep going to the gym and working full-time throughout her chemotherapy. Through cold capping, a practice in which patients wear devices on their heads to cool the scalp during chemotherapy, she was able to minimize hair loss.

“I would say I was positive during treatments. I would also say that with the positives come dark moments, too, that only other survivors are going to understand,” she says.

In the trial, Keytruda combined with chemotherapy produced a complete pathological response in 63% of patients, meaning nearly two-thirds of patients had no evidence of cancer after treatment, compared with 56% among those who were assigned to receive chemotherapy alone. Overall, the drug reduced the risk for disease progression, recurrence or death by 37%.

Although Perello experienced differently, side effects in the study’s participants were common. The most frequently reported were fatigue (70%), nausea (67%), hair loss (61%), rash (52%), constipation (42%) and diarrhea and peripheral neuropathy (both 41%).

ATTACKING CANCER AT THE SOURCE

Another major breakthrough for TNBC treatment is with antibody-drug conjugates, which are medications that combine monoclonal antibodies — artificially made proteins that target proteins on cancer cells — with highly toxic, tumor-killing chemicals. The result is a drug that delivers extremely potent anticancer medications directly to the tumors without harming the rest of the body, sometimes referred to as a “Trojan horse” effect.

Bardia is particularly interested in the antibody-drug conjugate Trodelvy (sacituzumab govitecan-hziy) and led a large randomized phase 3 trial, called ASCENT, on the therapy. In April 2020, the drug received accelerated FDA approval for metastatic TNBC that did not respond to other treatments based on an earlier phase 2 trial showing remarkable activity in heavily pre-treated patients, and a year later it received the FDA’s regular approval for the same indications when the randomized trial showed a doubling of survival compared with standard chemotherapy options.

In the data recently published from the trial, Bardia and his team reported that patients with metastatic TNBC who received Trodelvy went a median of 5.6 months before their disease progressed, compared with less than two months in patients who received typical chemotherapy. Not only did patients live longer before their disease progressed, but they also lived longer overall: Median overall survival was 12.1 months in patients assigned to Trodelvy, compared with just 6.7 months in those who received standard chemotherapy. Trodelvy’s most common severe side effects were neutropenia (low white blood cell count), which occurred in 51% of the Trodelvy group compared with 33% of the chemotherapy group, diarrhea (11% versus less than 1%, respectively), anemia (8% versus 5%) and febrile neutropenia (5% versus 2%).

The patients in that trial all had advanced disease that did not respond to other treatments, and Bardia hopes to see this therapy turned into a first choice for patients with earlier-stage disease.

Dr. Tiffany Traina, who is section head of the TNBC research program at Memorial Sloan Kettering Cancer Center in New York, was a researcher on the ASCENT trial and is enthusiastic about the expanding range of options for patients with TNBC.

“Immunotherapy is curing more women of triple-negative breast cancer,” she says. “And some of the novel agents (such as Trodelvy) are really moving the needle in how long women are living with their breast cancer, even with advanced disease,” she says. “We’ve seen greater hope for women with triple-negative breast cancer in a meaningful way. ... This drug showed incredible activity.”

Generally speaking, new cancer treatments make their debut as alternative strategies in late-stage cases, then make their way to being used as a frontline, or first-choice, therapy.

“Moving forward, the drug needs to be evaluated in earlier lines, including first-line therapy for metastatic TNBC,” Bardia adds. “In the ASCENT trial, patients who had received prior immunotherapy also had benefit with (Trodelvy) suggesting there is no cross-resistance between (Trodelvy) and immunotherapy, and potentially combining (the drug) with immunotherapy would be an attractive therapeutic option for patients with PD-L1-positive metastatic TNBC.”

CUTTING OFF CANCER’S DEFENSE

When Hosea went to MD Anderson for a second opinion, she was asked whether she wanted to participate in a clinical trial as part of her treatment for early stage TNBC. “Let’s do it!” she remembers telling her care team. “Give me a plan.”

She enrolled in an open-label phase 2 study, which means all of the 61 patients enrolled received Talzenna (talazoparib), a PARP inhibitor.

Hosea was one of a few dozen women with BRCA- mutated TNBC who took a PARP inhibitor as part of the study.

Dr. Jennifer Litton, vice president of clinical research and professor of breast medical oncology at MD Anderson, reported at the 2021 American Society of Clinical Oncology (ASCO) meeting that 49.2% of patients experienced a complete pathological response to Talzenna, meaning there was no evidence of cancer left in the affected breast after treatment and surgery.

“It was six months of a daily pill,” Hosea says. “It would eventually make the cancer die.” Depending on her progress with Talzenna, she could stay in the trial or drop out and proceed to the standard of care, which was chemotherapy. “I always had the choice to leave,” Hosea says, which helped her make the decision to participate.

Throughout the drug trial, her hemoglobin levels dropped to levels so low that it looked as though she might need to drop out of the trial. “We had to reduce
my dosage multiple times, but even with that I had a complete response,” she says. This would remain an issue throughout her chemotherapy, as well.

Although she had no significant side effects with Talzenna, during chemotherapy she dealt with neutropenia and contracted pneumonia.

After the trial, Hosea had surgery, and no cancer was found — demonstrating that she had a complete pathologic response to Talzenna. She completed 30 rounds
of radiation therapy after her double mastectomy, and received chemotherapy for six months.

“PARP inhibitors are really exciting as a proof of concept of using the DNA damage repair pathways,” Litton says. “An oral drug really improves quality of life for patients with metastatic cancer and a germline BRCA mutation, and I’m looking forward to the next generation of DNA damage repair agents that can potentially have similar or longer-lasting effects with less toxicity.”

Hosea initially hoped that her life would go back to normal after cancer, but like Perello, she found that some part of her had permanently changed.

In some ways, the change was bad, leaving a physical and emotional scar from a difficult diagnosis and intensive treatment. “The hardest part was that it happened at all,” Perello says.

But in one major way, the change was a good thing. “I’ve always been a worrier,” Hosea recounts. “And just worried a lot about every little thing. And I don’t anymore. I always tell people I’m so thankful for this perspective.”

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