Researchers have found that measuring the activation of immune system B cells may be more effective than measuring the activation of either T cells or tumor-infiltrating lymphocytes (TILs) in predicting whether patients with HER2-positive breast cancer will respond to treatment. These findings were published by Fernandez-Martinez et al in JAMA Oncology.
Understanding why cancers respond—or don’t respond—to therapy is crucial to effective and personalized treatment. In HER2-positive breast cancer, the immune system is key to the effectiveness of response to anti-HER2 drugs. Important cells in the body’s immune system include B cells, which create antibodies that neutralize cancer cells and infections, as well as T cells, which directly fight cancers and infections.
Measuring Immune System Activation
In the current study, investigators combined the results of two large clinical trials—CALGB 40601 and PAMELA—to look at different measures of immune system activation. Six signatures of immune cell gene activation from B cells were better than measuring immune cell numbers on a microscope slide at predicting whether the drugs would completely clear the tumor. These results may allow doctors to be more precise in choosing which drugs, and how many drugs, to use in treating patients with HER2-positive breast cancer.
Lisa A. Carey, MD, ScM, FASCO
“When there are active immune cells circulating around a tumor, the cancer tends to be easier to treat and cure,” said Lisa A. Carey, MD, ScM, FASCO, Deputy Director of Clinical Science and the L. Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at UNC Lineberger Comprehensive Cancer Center and corresponding author of the study. “This is important because determining immune cell activity may allow us to identify which women with HER2-positive breast cancer will do well with standard, or even minimized, therapy.”
The 305 patients enrolled in CALGB 40601 received paclitaxel and trastuzumab as well as lapatinib, or a combination of the two, for 16 weeks. The 151 patients in PAMELA received trastuzumab and lapatinib for 18 weeks. In both trials, the patients then proceeded to surgery to remove their tumors.
B-Cell Signatures Associated With Better Survival
While TILs were associated with the elimination of breast cancers in the trials, six of seven B-cell immune signatures were most strongly associated with higher elimination rates. The six B-cell signatures were also associated with better survival, while the TILs did not predict survival outcomes effectively. This finding may have applicability beyond HER2-positive breast cancers.
Charles M. Perou, PhD
“We know that breast cancers have molecularly distinct features with differing biological bases and outcomes. In that regard, we need biomarker tools to guide treatment escalation and de-escalation for many types of breast cancer, in particular, HER2-positive and triple-negative breast cancers, which can be difficult to treat,” said Charles M. Perou, PhD, the May Goldman Shaw Distinguished Professor of Molecular Oncology, co-leader of the UNC Lineberger Breast Cancer Research Program, and a co-author of this study. “Some of our previous studies have already shown the prognostic and predictive ability of B cell–related signatures in triple-negative breast cancers. It would not surprise us if a similar analysis in triple-negative breast cancer found the same results as those in this current study of HER2-positive cancers.”
Aranzazu Fernandez-Martinez, MD, PhD, the paper’s first author and a research associate in Dr. Perou’s lab, said the researchers have created a large and integrated database combining gene expression and clinical data, including response to therapy and survival outcomes from over 1,000 women who are participating in clinical trials. “The analysis of these data will provide essential information for biomarker development and precision medicine in HER2-positive breast cancer, and the insights will inform clinicians when someone may need more (or less) chemotherapy, and more (or less) anti-HER2 drugs,” she said.
Disclosure: The research was supported by National Institutes of Health, the Breast Cancer Research Foundation, Susan G. Komen, Fundación SEOM, Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2018, and Fundación Científica Asociación Española Contra el Cáncer: Ayudas Investigador AECC 2021- INVES21943BRAS. For full disclosures of the study authors, visit jamanetwork.com.
