MD Anderson Researchers Characterize Triple-Negative Breast Cancer Microenvironment and Develop Predictive Gene Panel

A 13-gene panel and machine learning model can predict chemotherapy response in early-stage triple-negative breast cancer, according to a new study from MD Anderson.

Researchers at The University of Texas MD Anderson Cancer Center have conducted a comprehensive analysis of the tumor microenvironment (TME) in early-stage triple-negative breast cancer (TNBC), identifying specific cellular features associated with chemotherapy response. The study resulted in the development of a 13-gene panel and a machine learning model designed to predict patient response to neoadjuvant chemotherapy.

The findings were published in Nature and led by Nicholas Navin, Ph.D., and Clinton Yam, M.D.

Study Methodology and Key Findings

The research involved single-cell analysis of over 427,000 cells from 101 patients, combined with spatial transcriptomic analysis of tumors from 44 patients. Key results include:

• Tumor Archetypes: TNBC tumors were categorized into four patient-level "archetypes" based on gene expression patterns within cancer cells.
• Gene Signature: A coordinated set of 13 highly expressed cancer-specific genes (transcriptional signature) was identified.
• Immune Cell Mapping: The study characterized 49 immune cell states that form eight types of cell neighborhoods within the tumor microenvironment.
• Macrophage Subtypes: Specific macrophage subtypes were associated with chemotherapy response.

Predictive Model

The research team developed a machine learning model utilizing the 13-gene panel to predict which patients are more likely to respond to neoadjuvant chemotherapy.

"The study identified programs and macrophage subtypes associated with positive responses to this treatment," said Dr. Navin.

Dr. Yam added that the insights provide a foundation for understanding differential chemotherapy responses and may guide more individualized care. Further prospective studies are required before the model can be applied clinically.

Context: Spatial Profiling Technologies

The study is part of a broader advancement in spatial profiling technologies used to understand immune responses within tumors. These techniques include spatial proteomics and spatial transcriptomics, which allow researchers to map the location of specific proteins and RNA within tissue samples. This provides a more detailed view of cell types, their functions, and their interactions within the tumor microenvironment compared to traditional methods such as hematoxylin and eosin (H&E) staining or bulk sequencing.

Related Research on Triple-Negative Breast Cancer

A separate, related study led by Shiaw-Yih Lin, Ph.D., at MD Anderson found that blocking the RNase H2 enzyme in TNBC cells damages cancer cell DNA and activates the innate immune system, potentially improving treatment outcomes.

Additional Research Reported by MD Anderson

A Phase 1/2 trial of the RAS inhibitor daraxonrasib in 38 patients with RAS-mutant pancreatic cancer showed a 29% response rate and median overall survival of 15.6 months. David Hong, M.D., deputy chair of Investigational Cancer Therapeutics, stated that the trial suggests the therapy may extend overall survival.

A Phase II study evaluated the combination of tucatinib, trastuzumab, and capecitabine in 17 female patients with newly diagnosed leptomeningeal metastasis (LM) from HER2+ breast cancer. The median overall survival increased from a historical average of 4.4 months to 10 months. At 18 months, 41% of patients were alive. The combination therapy resulted in a median of seven months before central nervous system progression, and seven of 12 evaluable patients experienced improved neurologic deficits.

• Researchers led by Carl Gay, M.D., Ph.D., found that YAP1 protein expression in cancer cells after chemotherapy is linked to treatment resistance and relapse in small cell lung cancer. Targeting YAP1-expressing cells may be a strategy to overcome resistance.
• A separate study identified a strategy to enhance the immune response in glioblastoma (GBM) tumors by simultaneously blocking two "don't eat me signals" present in cancer cells.
• Kai Wucherpfennig and David Reardon's teams at Dana-Farber Cancer Institute applied spatial profiling to analyze glioblastoma samples from patients in clinical trials, both before and after treatment with immunotherapy, with or without radiation. Observations included an increase in T cell numbers and deeper penetration into tumor tissue following treatment.

Savitri Krishnamurthy, M.D., and team identified blood-based genomic biomarkers using TGIRT sequencing to distinguish inflammatory breast cancer from other subtypes. The method may enable monitoring via liquid biopsy.

John Paul Shen, M.D., and team reported that preoperative and postoperative levels of CEA, CA19-9, and CA125 predict outcomes after cytoreductive surgery with or without HIPEC. Elevated markers post-surgery were associated with poorer survival.

A Phase 2 trial tested cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax. Of older or medically fragile patients, 84% achieved remission, with 75% having no detectable leukemia cells. Tapan Kadia, M.D., noted the regimen is safer and effective.

• Jianping Zhao, M.D., Ph.D., and team identified FOXA1 protein as a diagnostic marker for small cell carcinoma of the prostate, which may aid diagnosis for aggressive subtypes.
• A separate study suggests that prostate cancer patients with low testosterone levels may face an increased risk of their cancer progressing to a more aggressive form while under active surveillance.