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Managing TNBC

CE / CME

Cases and Challenges in the Optimal Treatment of Triple-Negative BC

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Nurse Practitioners: 1.00 Nursing contact hours, includes 1.00 hour of pharmacotherapy credit

Released: May 08, 2023

Expiration: May 07, 2024

Jeremy M. Force
Jeremy M. Force, DO
CME/CE Information

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Course Completed

Introduction

Among women with breast cancer, between 10% and 15% will have TNBC, a subtype defined by what it lacks: expression of both estrogen and progesterone receptors and HER2.1,2 TNBC is associated with poorer outcomes than other breast cancer subtypes, partly due to its lack of targetable receptors, but also because triple-negative disease has a more aggressive clinical course in both early and metastatic disease and tends to be of higher grade when diagnosed.2 Approximately 34% of patients with TNBC will have distant recurrence (compared with 22% of patients with other subtypes) and shorter times to both local (2.8 vs 4.2 years) and distant (2.6 vs 5 years) recurrence. Further, TNBC primary tumors are more likely to metastasize to the lungs and brain than other breast cancers.3,4 Although TNBC is more responsive to chemotherapy than other subtypes, it still is associated with earlier and more frequent distant recurrence and poor 5-year overall survival (OS) of 77% in early-stage disease—and only 12% in metastatic disease.1,2,4  For comparison, patients with hormone receptor (HR) and HER2-positive disease have 5-year OS of 91% and 46% with metastatic disease.1

Epidemiologic patterns are evident in TNBC, most importantly that the disease is more prevalent in Black women than women of other ethnicities.4,5 Studies have shown that Black women are more likely than other ethnicities to carry TP53 mutations and have a high Ki67 proliferation index, both of which are associated with TNBC.6 Further, even when mortality rates are adjusted for other factors, TNBC contributes to excess breast cancer–related mortality among Black women.5,6 

TNBC also has a disproportionate effect on younger and premenopausal women, and patients with BRCA1/2 mutations.2,5,7 An estimated 17% of patients with TNBC have germline BRCA1/2 mutations.2 TNBC makes up approximately 70% of breast cancer diagnosed in BRCA mutation-positive premenopausal women.5

Subtypes of TNBC
TNBC is a heterogeneous disease, with distinct genomic subtypes that have been identified. TNBC overlaps with basal-like breast cancer, but the 2 are not synonymous. Approximately 75% of TNBCs are highly proliferative basal-like based on gene expression analysis, and basal TNBC subtypes are more often seen in younger women. About 20% of TNBC tumors are highly enriched in tumor infiltrating lymphocytes and immune checkpoints CTLA4, PD-1, and PD-L1.1,2,4,5,8 TNBC also expresses higher levels of EGFR than other breast cancer types, but also the related PTEN mutations that are associated with resistance to EGFR-targeted treatment. Current consensus defines 4 basic subtypes of TNBC: basal-like 1 (BL1), basal-like 2 (BL2), luminal androgen receptor (LAR), and mesenchymal (M). The largest proportion (35%) are BL1 tumors, which are enriched in cell cycle and DNA damage-response genes and associated with good response to neoadjuvant chemotherapy (41% pathologic complete response [pCR]) and the longest survival. In contrast, BL2 (22%) has the worst prognosis and is enriched in growth factor signaling genes, while the LAR subtype is least common (16%) and has high androgen receptor expression and poor prognosis (29% pCR). The M subtype is found in about 25% of patients and enriched in growth factor pathways.5,8

Risk Factors for TNBC
Modifiable risk factors for TNBC include obesity in premenopausal women, regular moderate or high alcohol consumption, sedentary lifestyle, exogenous hormone use, and younger age at first pregnancy. Any of these, especially in combination, in patients with nonmodifiable risk factors—in addition to ethnicity/race and BRCA1 mutation, early menarche (<12 years) and/or late menopause and family history—increases risk for TNBC.5,6,9

Which of these biomarkers should be tested at recurrence or metastasis of TNBC?

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