Two novel biomarkers have been found to correlate with improved outcomes with immunotherapy in metastatic breast cancer and may help to identify the patients most likely to benefit from this treatment, according to exploratory studies reported at the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Meeting 2020. The biomarkers studied were an increase in the number of PDL1 (also known as CD274) genes measured by copy number alteration, and the programmed cell death ligand 1 (PD-L1) combined positive score (CPS), which assesses PD-L1 expression on both tumor and immune cells.
“Metastatic breast cancer remains incurable, with many unmet needs and challenges. Triple-negative breast cancer has the poorest prognosis among breast cancer subtypes and limited treatment options, mainly involving chemotherapy,” commented Sherene Loi, MD, PhD, a medical oncologist and Head of Translational Breast Cancer Genomics and Therapeutics at the Peter MacCallum Cancer Centre, Melbourne, in an ESMO press release. “Immunotherapy has resulted in long durations of disease control and even cures with improved quality of life compared with chemotherapy in other cancers. We are hoping this might also be applicable for some [patients with] breast cancer.”
“Previous studies show that not all patients with metastatic breast cancer benefit from immunotherapy. Preexisting immunity, which can be detected by PD-L1 expression, is required for response to immunotherapy agents that target [programmed cell death protein 1] (PD-1) or PD-L1. The key question is whether we can identify further patients with metastatic breast cancer that respond to immunotherapy using biomarkers other than just PD-L1 expression,” she continued.
PDLI/CD274 Gain or Amplification as a Predictive Marker for Durvalumab Treatment
To explore new potential biomarkers for immunotherapy in advanced breast cancer, researchers assessed the predictive value of copy number alteration for the PDL1 gene, which measures whether the gene number has decreased, remained the same, or increased. Researchers measured copy number alteration values in tumor tissue collected from 126 patients with metastatic breast cancer taking part in the SAFIR-IMMUNO study, the first randomized trial comparing immunotherapy with durvalumab to maintenance chemotherapy in this setting (Abstract 128O).
“The main predictive markers of immunotherapy efficacy in metastatic breast cancer to date are the absence of hormone receptors and PD-L1 positivity on immune cells,” said lead author study Thomas Bachelot, MD, PhD, Director of the Breast Cancer Unit, Leon Berard Centre, Lyon, France. He added, however, that “immunohistochemistry analysis of PD-L1 expression is not standardized, and a more robust predictor of response to immunotherapy is needed.”
Results showed that nearly one in four (23.8%) of the patients had copy gain (3 or 4 copies) or amplification (> 4 copies) of the PDL1 gene. Improvement of overall survival with durvalumab was limited to this group, with a median overall survival of 9 months (95% confidence interval [CI] = 4–18) in the chemotherapy arm and not reached in the durvalumab arm (hazard ratio [HR] = 0.17, 95% CI = 0.05–0.55).
“This exploratory translational analysis suggested a higher efficacy of durvalumab as maintenance treatment for patients with PDL1 copy gain or amplification,” said Dr. Bachelot. He suggested, “PDL1 copy number alteration could be an important predictive marker for PD-L1 inhibitor efficacy. If confirmed in larger series, this could have important implications for the development of immunotherapy in patients with metastatic breast cancer, enabling us to better identify patients who are sensitive to PD-L1 inhibitors than current testing for PD-L1 positivity on immune cells.”
“At the moment, patients with estrogen–receptor positive breast cancer are not treated with immunotherapy because results of trials were poor…. But maybe, if we can select the subpopulation that will benefit—the 10% of patients with [copy number alteration] abnormalities—and show immunotherapy is beneficial for them, too, then this would be important,” he explained.
Commenting on the potential relevance of the data, Dr. Loi said, “The study suggests that PDL1 amplification may be a predictor for benefit to durvalumab monotherapy, interestingly, in all subtypes as well as in triple-negative breast cancer.”
She added, “It was an unplanned, retrospective analysis so requires further validation in larger studies. There was no analysis presented of whether PDL1 amplification was associated with overexpression at the protein level, which would be important to understand the underlying biologic mechanism of this observation.”
Pembrolizumab vs Chemotherapy in Metastatic Triple-Negative Breast Cancer: Health-Related Quality of Life
A second study by Schmid et al looked at health-related quality of life in patients with metastatic triple-negative breast cancer randomly assigned to receive either the PD-L1 inhibitor pembrolizumab or chemotherapy in the KEYNOTE-119 trial (Abstract 141P). Previously reported efficacy results for the trial showed no significant difference in overall survival between the two treatments, but this analysis described patient-reported outcomes for patients by their PD-L1 combined positive score. CPS is a novel biomarker that assesses PD-L1 expression on both tumor cells and immune cells, in contrast to PD-L1 tumor proportion score (TPS), which has been used as a biomarker for immunotherapy in other cancers but does not account for immune cell PD-L1 expression.
“The benefit of pembrolizumab vs chemotherapy was observed in nearly all prespecified patient-reported outcome endpoints,” said lead author Peter Schmid, MD, PhD, Lead of the Centre for Experimental Medicine at Barts Cancer Institute, Queen Mary University of London. “Importantly, time to deterioration score for global health status/quality-of-life scale was longer for patients treated with pembrolizumab compared to those treated with chemotherapy.”
The median time to deterioration was 4.3 months for pembrolizumab vs 1.7 months with chemotherapy (HR = 0.70, 95% CI = 0.46–1.05). Scores for symptom scales for fatigue, nausea and vomiting, pain, dyspnea, and loss of appetite all increased with chemotherapy but remained stable or improved slightly with immunotherapy.
“In this CPS-enriched population of patients with metastatic triple-negative breast cancer receiving second- and third-line treatments, health-related quality of life was better for patients receiving pembrolizumab than those receiving chemotherapy,” said Dr. Schmid.
He added, “We are still learning a lot about immunotherapy in metastatic breast cancer. Trials for single-agent immunotherapy in the first-line setting have not been positive. But these results clearly show there is a group of patients who do at least as well with single-agent immunotherapy as chemotherapy in terms of survival and probably better in terms of quality of life.”
Dr. Loi commented, “Patients who expressed high levels of PD-L1 protein according to their CPS score had better overall survival with pembrolizumab compared with chemotherapy, and pembrolizumab was far better tolerated than chemotherapy according to health-related quality-of-life measures. This underscores the importance of PD-L1 testing in the advanced setting as well as identifying other biomarkers that can help identify those who do best with pembrolizumab monotherapy, given its favorable health-related quality-of-life impact.”
Disclosure: For full disclosures of the study authors, visit cslide.ctimeetingtech.com.
