Triple-negative breast cancer or TNBC is an aggressive and complex type of invasive breast cancer with several subclasses characterized by the lack of expression of estrogen (ER), progesterone (PR), and human epidermal growth factor receptor-2/neu (HER-2) receptors. [1] Because TNBC lacks ER, PR and HER-2, the disease is not sensitive to endocrine therapy or HER-2 treatment, making standard of care chemotherapy and immunotherapy the main systemic treatment options after surgery.[1][2][3]
According to the American Cancer Society, the disease accounts for 15%-25% of all diagnosed breast cancers and displays features that include high invasiveness, high metastatic potential, proneness to relapse, and overall poor prognosis. The disease is also more likely to be diagnosed in a later stage than other types of breast cancer [3]
A new biomarker
Researchers at Baylor College of Medicine and collaborating institutions have discovered new insights into tumor-induced B-cell changes in blood and bone marrow of triple-negative breast cancer (TNBC) patients. Their study show two distinct patterns of B-cell abnormalities that could serve as biomarkers for determining the likelihood of response to standard-of-care chemotherapy (SoC) and immunotherapy.[3]
The findings from the study, supported by the U.S. Department of Defense, National Cancer Institute, Breast Cancer Research Foundation, McNair Medical Institute, National Institutes of Health and Cancer Prevention and Research Institute of Texas, were published on September 12, 2024 in Nature Cell Biology. [3]
“Even with significant advances in immunotherapy, only about 15 to 20% of patients with triple-negative breast cancer will benefit from this treatment,” noted corresponding author Dr. Xiang H.-F. Zhang, director of the Lester and Sue Smith Breast Center and professor of molecular and cellular biology at Baylor.
“My lab is trying to understand why some cancers do not respond to treatment by examining the crosstalk between the tumor and the body. Many systemic changes arise because of how the body responds to the cancer,” Zhang explained.
B-cell
A previous study from Zhang’s lab showed that even before tumor metastasis, breast cancer remotely induces changes to immune cell development in the bone marrow. Building on those findings, Zhang’s team examined changes in myeloid and B-cells from patient peripheral blood and identified three distinct subgroups (TiBA-0, TiBA-1 and TiBA-2).
Two of the subgroups (TiBA-1 and TiBa-2) showed unique patterns of induced B-cell abnormality associated abnormal myelopoiesis in the bone marrow.
The first group, TiBA-0, has no changes to B-cells.
The second group, TiBA-1, has fewer B-cells, likely due to competition with myeloid (pre-) progenitors in the bone marrow microenvironment.
The third group, TiBA-2, has an increased number of immature B-cells, likely due to excessive neutrophils preventing the B-cells from maturing. In this group, immature B-cells lead to an increase in exhausted T-cells.
The study results also demonstrated that myeloid and B-cells from the peripheral blood of patients diagnosed with with triple-negative breast cancer recapitulate the TiBA subtypes. The researchers found that the distinct TiBA profile strongly correlates with pathologic complete responses (pCR) to standard-of-care immunotherapy.
Response to treatment
Researchers found that the B-cell changes in both TiBA-1 and TiBA-2 types lead to an immunosuppressive effect and poorer response to treatment. In a study of 35 patients, 78.6% of TiBA-0 patients had a complete response to treatment with chemotherapy and immunotherapy, while only 33.3% of TiBA-1 and TiBA-2 patients had a complete response.
“These immune cell changes are not just happening locally inside the tumor. We see them systemically across the entire body, which means that we can identify these immune cell biomarkers with a simple blood draw,” said Zhang, William T. Butler, M.D., Endowed Chair for Distinguished Faculty and a McNair Scholar at Baylor. He also is a member of the Dan L Duncan Comprehensive Cancer Center.
“In the future, we may be able to stratify patients based on these biomarkers and determine which patients are less likely to respond to standard therapies and require additional treatment.”
Ongoing studies
Zhang’s team next will work with other researchers and clinicians at the Dan L Duncan Comprehensive Cancer Center to study the blood biomarkers in a larger patient group over multiple time points throughout treatment to learn more about how immune cells may change over time.
Zhang’s lab is also studying ways to reverse tumor-induced changes in bone marrow to restore normal production of immune cells.
Reference
[1] Yadav BS, Chanana P, Jhamb S. Biomarkers in triple negative breast cancer: A review. World J Clin Oncol. 2015 Dec 10;6(6):252-63. doi: 10.5306/wjco.v6.i6.252. PMID: 26677438; PMCID: PMC4675910.
[2] Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020 Jun 9;22(1):61. doi: 10.1186/s13058-020-01296-5. PMID: 32517735; PMCID: PMC7285581.
[3] Triple-Negative Breast cancer. American Cancer Society. Online. Last accesses on September 12, 2024.
[4] Hao X, Shen Y, Liu J, Alexander A, Wu L, Xu Z, Yu L, Gao Y, Liu F, Chan HL, Li CH, Ding Y, Zhang W, Edwards DG, Chen N, Nasrazadani A, Ueno NT, Lim B, Zhang XH. Solid tumour-induced systemic immunosuppression involves dichotomous myeloid-B cell interactions. Nat Cell Biol. 2024 Sep 12. doi: 10.1038/s41556-024-01508-6. Epub ahead of print. PMID: 39266726.
Featured image: A daughter is encouraging her mother who is diagnosed with breast cancer. Photo courtesy: © 2018-2024 Fotolia/Adobe. Used with permission.
DOI:10.14229/onco.2024.09.13.021
