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Understanding Genetics May Predict Treatment Response in Triple-Negative Breast Cancer

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Key Takeaways

  • Keytruda plus chemotherapy improved pathologic complete response and event-free survival in high-risk, early-stage triple-negative breast cancer.
  • Tumor mutational burden and T-cell inflamed 18-gene expression profile were associated with better outcomes in the Keytruda arm.
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Several biomarkers may predict improved treatment responses and outcomes in patients with triple-negative breast cancer.

Illustration of DNA structure.

Several biomarkers were linked to improved outcomes in patients with high-risk, early-stage triple-negative breast cancer, with Keytruda plus chemotherapy.

Several biomarkers, including the T-cell inflamed 18-gene expression profile, were associated with improved pathologic complete response and event-free survival, both with and without Keytruda (pembrolizumab) therapy.

Results from an exploratory analysis of the KEYNOTE-522 study in high-risk, early triple-negative breast cancer were presented at 2024 San Antonio Breast Cancer Symposium.

Tumor mutational burden also correlated with improved event-free survival in the Keytruda plus chemotherapy arm, but not in the placebo plus chemotherapy arm. There were few patients with high tumor mutational burden in this patient population of those with triple-negative breast cancer.

Further, the Keytruda/chemotherapy regimen offered an efficacy advantage compared with chemotherapy alone, regardless of subgroups defined by several biomarkers such as tumor mutational burden, T-cell inflamed 18-gene expression profile and more.

Glossary:

T-cell inflamed 18-gene expression profile: a panel of 18 genes used to predict the response to immunotherapy in patients with cancer.

Pathologic complete response: the lack of all signs of cancer in tissue samples after treatment.

Event-free survival: the time after primary treatment when a patient is free from complications or events that treatment was meant to delay or prevent.

Tumor mutational burden: the total number of mutations in the DNA of cancer cells, which is information that may help with treatment plans. Patients with a high number of mutations may be more likely to respond to certain types of immunotherapy.

Neoadjuvant: the first treatment given to shrink a tumor before the main treatment like surgery.

Adjuvant: additional treatment for cancer given after the primary treatment to reduce the risk for cancer recurrence.

Overall survival: the time from diagnosis or treatment initiation when a patient with cancer is still alive.

Whole-exome sequencing: a laboratory method to learn how the building blocks of a person’s DNA are organized, and can be used to find mutations in genes that may preclude a patient to disease.

RNA sequencing: a laboratory method to learn the exact order in which RNA molecules are situated in a cell, which helps care teams determine which genes are expressed in different types of cells.

PTEN loss signature: a gene that regulates cell growth and survival, and, when lost, can lead to uncontrolled cell growth and potentially tumor formation.

Proliferation: the process of cell division and growth.

Glycolysis: when glucose, or sugar, is broken down in cells via reactions that do not require oxygen, which is a way that cells produce energy.

About the KEYNOTE-522 Exploratory Analysis

The phase 3 KEYNOTE-522 study sought to evaluate the combination of neoadjuvant Keytruda with chemotherapy and adjuvant Keytruda in patients with newly diagnosed, previously untreated, high-risk, early-stage triple-negative breast cancer. Previously reported findings have shown that neoadjuvant Keytruda with chemotherapy followed by adjuvant Keytruda significantly improved pathologic complete response, event-free survival and overall survival versus neoadjuvant placebo plus chemotherapy with adjuvant placebo in patients with high-risk, early triple-negative breast cancer.

In this exploratory biomarker analysis, the end points included evaluating the association of tumor mutational burden, T-cell inflamed 18-gene expression profile and a set of non-T-cell inflamed 18-gene expression profile consensus signatures with pathologic complete response and event-free survival. Secondary end points included evaluating RNA sequence-based molecular subtypes, BRCA/HRD status, HER2 gene expression/signature, and PTEN loss signature associations with pathologic complete response and event-free survival.

Patients with newly diagnosed, previously untreated, high-risk, early triple-negative breast cancer and evaluable pretreatment tumor samples were enrolled in the study. A total of 1,172 patients were randomly assigned and treated, including 783 in the Keytruda plus chemotherapy arm and 389 in the placebo and chemotherapy arm. There were 946 patients who had whole-exome sequencing data, with 641 who received Keytruda/chemotherapy and 305 given placebo/chemotherapy, and 904 had RNAseq data, consisting of 618 and 286 across the study arms.

Tumor mutational burden was assessed through whole-exome sequencing, while T-cell–inflamed 18-gene expression profile and non–T-cell-inflamed 18-gene expression profile consensus signatures were evaluated using RNA sequencing.

Additional Findings

Among the non–T-cell-inflamed 18-gene expression profile consensus signatures, proliferation and glycolysis were positively associated with pathologic complete response in both arms but did not correlate with event-free survival.

For the secondary end points of the study, positive associations of PTEN loss signature and BRCA/HRD status with pathologic complete response were observed in both treatment arms. HER2 gene expression was linked with the T–cell-inflamed 18-gene expression profile; however, it did not show significant associations with pathologic complete response or event-free survival in the Keytruda/chemotherapy arm after adjustment for the T-cell–inflamed 18-gene expression profile.

Subgroup analyses of secondary biomarkers using prespecified cutoffs consistently confirmed the benefit of the Keytruda and chemotherapy combination over the chemotherapy and placebo combination.

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