Some people with advanced breast cancer may one day be able to begin treatment without traditional chemotherapy.
Researchers at the Icahn School of Medicine at Mount Sinai tested a combination of four targeted medicines and found encouraging results in a small clinical trial. The approach is designed for a specific type of breast cancer that is driven by both hormones and a protein called HER2.
Breast cancer is not one single disease. Tumors can have different biological features that determine how quickly they grow and which medicines are most likely to work. Doctors routinely test breast cancers for hormone receptors and HER2 because these results help guide treatment.
Hormone receptor-positive breast cancer uses hormones such as estrogen to help it grow. HER2-positive breast cancer has unusually high activity of a protein called HER2, which sends growth signals to cancer cells. Around 10% of breast cancers are both hormone receptor-positive and HER2-positive, according to the researchers.
When breast cancer becomes metastatic, it has spread beyond the breast and nearby lymph nodes to other parts of the body. Common sites include the bones, liver, lungs and brain. Metastatic breast cancer is generally treated as a long-term illness, with therapies aimed at controlling the disease, easing symptoms and helping patients live longer.
Current first treatments for HER2-positive metastatic disease often include medicines that target HER2 together with chemotherapy. These treatments can be highly effective, but chemotherapy can also damage healthy rapidly dividing cells. This may cause fatigue, nausea, hair loss, infection risk and other short- or long-term problems.
The Mount Sinai researchers wanted to see whether they could attack the cancer through several targeted pathways without initially using chemotherapy. Their treatment combined anastrozole, palbociclib, trastuzumab and pertuzumab. Each medicine has a different job.
Anastrozole is a hormone treatment that reduces the amount of estrogen available to stimulate cancer growth. Palbociclib blocks proteins that cancer cells use to move through the cell division cycle. Trastuzumab and pertuzumab both target HER2, but they interfere with the protein in different ways.
By combining these treatments, the researchers hoped to block both major growth systems used by this cancer subtype. The approach was studied in the multicenter phase 1/2 ASPIRE clinical trial. The findings were published in the Journal of the National Cancer Institute.
The trial involved patients whose HR-positive, HER2-positive metastatic breast cancer had not previously been treated in the metastatic setting.
Participants were enrolled at five clinical sites connected with Mount Sinai, NYU Langone Health and Columbia University. Researchers first worked out an appropriate dose of palbociclib and then evaluated the complete four-drug regimen in 29 patients.
The early results were promising. During the first six months, 97% of participants experienced what researchers called clinical benefit, meaning their cancer responded to treatment or remained controlled. This suggests that the regimen was able to keep the disease from worsening in most patients during that early period.
The median time before the cancer progressed was nearly 25 months. A median means that half the patients experienced progression before that point and half remained without progression longer. Some responses lasted considerably longer, including one patient who had remained on the treatment for more than six years.
After a median follow-up of about 39 months, nearly 93% of the participants were still alive. The researchers had not yet reached the median overall survival, meaning more than half of the patients were still living at the time of the analysis. Longer follow-up will be needed to understand the full survival picture.
A chemotherapy-free regimen does not mean a side-effect-free regimen. Palbociclib can reduce blood cell counts, while HER2-targeted drugs and hormone treatments have their own risks. The most common problems in this trial included low levels of neutrophils, low overall white blood cell counts, diarrhea and anemia.
Neutrophils are white blood cells that help the body fight infection. When their numbers become too low, patients may become more vulnerable to infections and need closer monitoring, dose changes or temporary treatment breaks. Even so, only one participant stopped the study treatment because of side effects, and there were no treatment-related deaths.
Senior author Dr. Amy Tiersten said the findings suggest that a chemotherapy-free strategy can produce lasting responses with a manageable safety profile for some patients.
First author Dr. Rima Patel noted that avoiding chemotherapy may be especially attractive for older adults and people with other health conditions. A regimen based largely on targeted treatments could also reduce some of the practical burden associated with chemotherapy.
Convenience can matter greatly in metastatic cancer because treatment may continue for months or years. Some of the medicines in the experimental regimen can be taken by mouth, while HER2-targeted treatment can be delivered in forms that may reduce the time spent receiving treatment. Less disruptive treatment could potentially improve quality of life if effectiveness is maintained.
However, the study is far too small to establish a new standard of care. Only 29 patients received the full four-drug combination, and there was no randomized comparison group receiving the current standard first-line treatment. Without such a comparison, researchers cannot know whether the experimental approach is better, equally effective or less effective than existing therapy.
The strong survival figures also need careful interpretation. Participants in small early-stage trials can differ from the broader population of people with metastatic breast cancer. Results from a selected group at major academic medical centers may not be reproduced exactly in larger and more diverse patient populations.
Still, the study has an important strength: it tested a biologically logical way of attacking both hormone-driven and HER2-driven cancer at the same time.
The long responses seen in some patients show that the idea deserves further testing. Avoiding or delaying chemotherapy could be meaningful if larger trials show that cancer control is not sacrificed.
The next step is a randomized trial that directly compares this approach with standard treatment. Such research should examine not only how long patients live without disease progression, but also overall survival, side effects, quality of life and treatment convenience.
Until those results are available, the four-drug regimen should be viewed as a promising experimental strategy rather than a replacement for standard chemotherapy-based care.
Source: Icahn School of Medicine at Mount Sinai.
