A new clinical trial focusing on molecular biomarkers of triple-negative breast cancer (TNBC) is attempting to advance targeted therapy against the deadly disease.
Fifteen to twenty percent of breast cancers are TNBC (i.e., negative for estrogen receptor, progesterone receptor, and human epidermal growth factor type 2 receptor)—among the most difficult breast cancers to treat. Typically, only 50% of patients with TNBC respond to neoadjuvant treatment with standard chemotherapy regimens. Until recently, clinicians have had no method to determine which patients will respond well to chemotherapy.
An innovative clinical trial called ARTEMIS seeks to determine if molecular testing of tumors can improve response to neoadjuvant treatment by guiding patients with chemosensitive tumors to standard chemotherapy (anthracycline followed by a taxane) and those with chemo-insensitive tumors (i.e., tumors with biomarkers that predict a poor response to standard chemotherapy) to clinical trials of agents that target their tumors’ specific molecular drivers. “We want to try to home in on groups of patients for which targeted drugs may have the greatest effects,” said Stacy Moulder, M.D., an associate professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center and the principal investigator of ARTEMIS. “This would be a way to show that targeted drugs can be effective if the correct patient population is identified.”
ARTEMIS is open to patients with previously untreated stage I–III TNBC who have primary tumors at least 1.5 cm in diameter. All patients enrolled in ARTEMIS undergo a biopsy of the primary tumor and molecular testing prior to treatment. To determine if the molecular testing improves outcomes, patients are randomly assigned to one of two study arms; each patient has a 2 in 3 chance of being assigned to arm B, the experimental arm. Patients in arm A do not receive the results of the molecular testing; those in arm B do receive the results.
It takes a few weeks to receive the molecular testing results, so all patients are given neoadjuvant anthracycline-based chemotherapy without delay. After four cycles of standard chemotherapy, patients in both arms work with their oncologists to determine whether the best course of action is to continue standard chemotherapy with a taxane or to enroll in a clinical trial of a targeted agent. However, patients in arm B are given the additional molecular profiling information to guide their treatment decisions.
After the completion of neoadjuvant therapy, patients undergo planned surgical resection. The amount of residual cancer in the surgical specimen is used to determine the efficacy of neoadjuvant therapy for each patient.
The initial molecular profiling of the tumors includes a test for chemosensitivity developed by W. Fraser Symmans, M.D., a professor in the Department of Pathology. To develop the test, Dr. Symmans examined TNBC specimens resected after patients had received neoadjuvant chemotherapy.
The tumors were categorized by chemotherapy response and the presence of specific molecular biomarkers, and Dr. Symmans developed a gene signature profile based on the observed patterns to predict which tumors were chemosensitive and which were chemo-insensitive.
In addition to guiding treatment for patients, the knowledge gained in the ARTEMIS trial will help pharmaceutical companies decide which experimental treatments to pursue in large clinical trials. When particular agents selected on the basis of molecular profiling show promise in ARTEMIS, larger trials of those agents can be conducted in other patients who have chemo-insensitive TNBC with similar profiles.
Enthusiasm from patients has been impressive, according to Dr. Moulder. “About 80% of patients who are approached about this trial ultimately participate—much higher than any other neoadjuvant therapy trial we’ve run. We feel like that is because the trial gives patients the option of a backup plan. The ARTEMIS trial does not mandate the treatment for patients; it simply advises treatment based on new information collected,” Dr. Moulder said. “Patients really develop a relationship with their oncologist because they go through chemotherapy together and then sit down with the molecular testing results and together make decisions about the next steps in the treatment. We’ve had really positive comments made by patients in the study.” This response may reflect the fact that ARTEMIS was designed with input from MD Anderson’s breast cancer patient advocates.
Dr. Moulder is optimistic about the impact ARTEMIS could have for patients and clinicians. “I think this will be one of the first clinical trials to show that precision medicine benefits patients and that targeted therapy has an impact on pathological complete response rates for TNBC,” she said.
For more information, contact Dr. Stacy Moulder at 713-792-2817 or Dr. W. Fraser Symmans T713-792-7962.
Hatzis C, Symmans WF, Zhang Y, et al. Relationship between complete pathologic response to neoadjuvant chemo-therapy and survival in triple-negative breast cancer. Clin Cancer Res. 2016;22:26–33.
OncoLog, November-December 2016, Volume 61, Issue 11-12