A novel genetic test may predict how patients with triple-negative early-stage breast cancer will respond to immunotherapy, according to new findings presented by Wolf et al at the 2024 European Breast Cancer Conference (EBCC) (Abstract 2LBA). The research may help patients who are unlikely to respond to immunotherapy avoid unnecessary adverse side effects.
Background
In triple-negative breast cancer, cancer cells are not fueled by either estrogen, progesterone, or the HER2 protein.
The I-SPY2 trial was established in 2010 to establish methods to screen new anticancer drugs and match them to specific biological markers in patients with breast cancer at high risk of early recurrence. Researchers developed the immune classifier ImPrint, which was composed of 53 genes and could predict the likelihood of a patient responding to immunotherapy by analyzing their tumor biology. ImPrint classifies tissue from patient biopsies into two groups: likely responder or likely nonresponder to immunotherapy.
“Previously, we showed that gene expression signatures representing the active components of the immune system can predict the response to pembrolizumab. Both patients with triple-negative disease and also patients with hormone receptor–positive breast cancer, who had not yet received treatment and whose tumors had this active immune biology, showed a significant, up to three times higher, pathologic complete response rate when treated with pembrolizumab,” explained senior study author Laura van ‘t Veer, PhD, Professor of Laboratory Medicine, Co-Leader of the Breast Oncology Program, and Director of Applied Genomics at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. “This classifier had a good performance across triple-negative and hormone receptor–positive breast cancers combined and had very high positive predictive value for hormone receptor–positive breast cancers, meaning that it identified those cancers that would likely respond to … immunotherapy. However, we noticed that the performance of ImPrint for triple-negative breast cancers, where immune oncology drugs are now standard of care, was not yet good enough to identify patients in whom a ‘likely response’ to immunotherapy was so low that harm from serious side effects would be higher than the benefit,” she continued.
Study Methods and Results
In the phase II I-SPY2 trial, the researchers examined the efficacy of an updated version of the immune classifier, ImPrintTN, which was refined to provide more accurate predictions in patients with triple-negative breast cancer.
“This new work now presents an update of the ImPrint classifier specifically for triple-negative breast cancers, ImPrintTN. We found that it can predict patients who are unlikely to respond to immunotherapy, [where] the harms from the treatment are greater than the benefit. This means it would be acceptable for them to forgo an immunotherapy drug in order to avoid the risk of these sometimes life-long irreversible adverse effects,” Dr. van ‘t Veer revealed.
Among 150 patients who received immunotherapy in four arms of the trial and 128 patients in the control arm who received taxane and anthracycline chemotherapy, ImPrintTN identified 66% patients with triple-negative breast cancer who were likely to respond to immunotherapy.
Patients in the immunotherapy arms of the trial were divided equally into two sets: a training set and a test set—both of which were balanced to include an equal number of responders and nonresponders to immunotherapy.
In the independent test set, the pathologic complete response rates were 71% compared with 22% in patients identified as unlikely to respond to immunotherapy. When all five arms were combined, the pathologic complete response rates were 74% in patients that ImPrintTN identified as likely to respond and 16% in those classified as unlikely to respond—representing an improvement over the previous version of ImPrint in which pathologic complete response rates were 38% among patients identified as unlikely to respond.
In the control arm of the trial involving patients who had been treated with standard of care chemotherapy only, pathologic complete response rates were 30% among those identified by ImPrint as responders and 15% among those classified as nonresponders.
“The likelihood of an immunotherapy drug response for triple-negative [breast] cancers that are ImPrint-positive remains very high at 74%, [whereas] among patients that ImPrintTN identified as likely nonresponders, the [pathologic complete response] rates for immunotherapy are now very low at 16%—low enough for the harm from immunotherapy drugs to outbalance the benefit in these patients. This is a clinically important improvement and suggests that ImPrintTN may help to inform prioritization of immunotherapies [compared with] other treatments for patients with triple-negative breast cancer in order to best balance likely benefit vs the risk of serious and irreversible adverse effects. There is a subgroup of patients where the harm of these drugs outweighs the therapeutic benefit,” stressed Dr. van ‘t Veer.
Conclusions
The researchers suggested that as a result of their new findings, the standard of care in patients with triple-negative breast cancer should be reconsidered.
“Immunotherapy drugs can have very severe, irreversible adverse side effects, as observed in the I-SPY2 trial. The findings … should provoke a discussion about whether giving immunotherapy drugs to all patients with triple-negative disease—which has recently become the standard of care in most countries—is the right strategy. Our research shows that it should be adapted so as to select only those patients who are very likely to benefit from this treatment. Patients who are unlikely to respond could then receive alternative therapies,” emphasized Dr. van ‘t Veer. “Once ImPrintTN has been validated further, immunotherapy drugs should only be given to patients with triple-negative or [hormone receptor]–positive disease who have a high likelihood of benefitting,” she underscored.
“It is increasingly appreciated that the one-size-fits-all approach is not optimal for the systemic treatment of patients with early triple-negative breast cancer. The identification of biomarkers to identify patients that do not need neoadjuvant immunotherapy is an unmet medical need. These results … show that ImPrintTN is a promising such biomarker that, if further validated, can spare many [patients] the short- and long-term toxicity of these drugs,” concluded Michail Ignatiadis, MD, PhD, of the Institut Jules Bordet in Brussels and Chair of the 2024 EBCC, who was not involved in the research.
Disclosure: The research in this trial was sponsored by the Quantum Leap Healthcare Collaborative.
