T Cells, TMB, HRD, and PTEN Loss: Turning Points in Triple-Negative Breast Cancer

Predicting Treatment Response

Presented by Dr. Joyce O’Shaughnessy at the San Antonio Breast Cancer Symposium (SABCS) 2024, the phase 3 KEYNOTE-522 trial's new findings reveal, in early-stage triple-negative breast cancer (TNBC), treated with pembrolizumab immunotherapy plus chemotherapy, the biological factors that influence treatment response .

This research highlights the interplay between immune signatures, tumor mutational burden (TMB), molecular subtypes, and treatment outcomes. The findings strongly confirm pembrolizumab's effectiveness across patient subgroups while laying the groundwork for future biomarker-directed treatment strategies.

Pembrolizumab for Early-Stage Triple-Negative Breast Cancer: Previous FDA Approval and Subgroup Analysis

Pembrolizumab, for use with neoadjuvant chemotherapy followed by adjuvant monotherapy in high-risk early-stage TNBC, received FDA approval on July 26, 2021 . The approval was based on the KEYNOTE-522 trial's successful pathological complete response (pCR) and event-free survival results.

KEYNOTE-522: A New Era in TNBC Treatment With Pembrolizumab and Chemotherapy

KEYNOTE-522 showed that adding pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly improved the following outcomes compared with chemotherapy alone in high-risk early-stage TNBC:

• Pathological complete response rate (pCR)

• Event-free survival (EFS, event-free survival)

• Overall survival (OS, overall survival)

The current biomarker analysis discussed in this article aimed to identify the effects of the T-cell-inflamed

• gene expression profile (GEP),
• TMB and
• molecular subtypes on response and survival.

T-cell inflammation or T-cell inflammatory activity refers to the immune system's T lymphocytes (T cells) producing an inflammatory response in a particular area. In cancer research, this term is used especially to describe the activity of immune cells in the tumor microenvironment.

Immune Signatures: T-Cell Inflammation Emerges as a Prognostic Marker

Main Findings:

• The T-cell-inflamed GEP showed a strong positive association with pCR and EFS (P < 0.001).

• Among non-T-cell-inflamed signatures , proliferation and glycolysis signatures were associated with higher pCR rates but had no significant effect on EFS.

These findings appear consistent with the TNBC literature. T-cell inflammation gene signatures have prognostic value in TNBC with both chemotherapy and immunotherapy combinations.

TMB: A Complex Marker With Limited Clinical Use

Association With Treatment Outcomes:

• TMB was significantly associated with pCR in both groups (P < 0.001).

• High TMB was associated with an EFS benefit only in the pembrolizumab plus chemotherapy group (P < 0.001).

• However, the proportion with high TMB being less than 10% limited the reliability of these findings.

These data should therefore be interpreted cautiously because the proportion of patients with high TMB is small and commercial tests report this threshold differently.

Molecular Subtypes: Pembrolizumab-Specific Responses

Luminal Androgen Receptor (LAR) Subtype:

• LAR is a TNBC subtype characterized by high androgen receptor expression.

• With chemotherapy alone, the LAR subtype had the lowest pCR rate .

• However, adding pembrolizumab produced the greatest improvement .

The LAR subtype may be resistant to chemotherapy but benefits substantially from adding immunotherapy with pembrolizumab.

HER2 Gene Expression:

• The HER2 (Human Epidermal Growth Factor Receptor 2) gene is a receptor regulating cell growth and proliferation.

• An inverse correlation was observed between HER2 expression and the T-cell-inflamed GEP (−0.32).

• This indicates that as HER2 levels increase, the tumor immune activity represented by T-cell inflammation decreases.

HER2 positivity may indicate less immune-system infiltration into the tumor in TNBC. Immunotherapy response may therefore be limited when HER2 expression is high.

PTEN Loss and HRD Status: Additional Biomarker Findings

PTEN Loss:

• PTEN (Phosphatase and Tensin Homolog) is a tumor suppressor gene that inhibits cell growth.
• PTEN loss was positively associated, in both the pembrolizumab + chemotherapy and placebo + chemotherapy groups, with pCR rates.
• However, in the pembrolizumab group, an additional benefit for EFS was observed.

HRD Status:

• HRD (Homologous Recombination Deficiency) means a defect in DNA repair and leads to genetic instability in tumors.
• HRD positivity increased, in both the pembrolizumab + chemotherapy and placebo + chemotherapy groups, pCR rates .
• However, HRD status alone should not be a decisive factor in treatment selection .

HRD may predict response to chemotherapy and immunotherapy combinations, but should be assessed alongside other biomarkers when making treatment decisions.

Commentary

The new findings presented at SABCS 2024 from the KEYNOTE-522 trial, which concern early-stage triple-negative breast cancer (TNBC) treatment with pembrolizumab plus chemotherapy, provide a detailed biomarker-based account of effectiveness.

The study highlights the effects of T-cell inflammation, tumor mutational burden (TMB), and molecular subtypes on treatment response, illustrating the potential importance of biomarkers in immunotherapy strategies.

Although immunotherapy has been shown to play an important role in early-stage TNBC treatment, it should be remembered that these treatments may not suit every patient. Strong predictive biomarkers such as T-cell inflammation are particularly important in determining treatment response. However, the low proportion of patients with high TMB and inconsistencies in commercial tests remain major obstacles to clinical biomarker use.

Meanwhile, analyses based on molecular subtypes show, for example, that in the LAR subtype chemotherapy resistance is observed, while adding pembrolizumab significantly improves treatment response. These findings support future personalized treatment strategies guided by biomarkers by laying an important foundation for their development.