Quadruple Negative Breast Cancers (QNBC) Demonstrate Subtype Consistency among Primary and Recurrent or Metastatic Breast Cancer

Abstract

PURPOSE: Despite the availability of current standards of care treatments for triple negative breast cancer (TNBC), many patients still die from this disease. Quadruple negative tumors, which are TNBC tumors that lack androgen receptor (AR), represent a more aggressive subtype of TNBC; however, the molecular features are not well understood. METHODS: Immunohistochemistry of estrogen receptor (ER), progesterone receptor (PR), HER2, and AR was determined in 244 primary and 630 recurrent/metastatic site biopsies. Expression was correlated with a panel of 25 cancer-related genes and proteins by IHC and in situ hybridization (ISH). RESULTS: We observed that 80.2% (65 of 81) of primary TNBC tumors and 75.7% (159 of 210) of recurrent/metastatic TNBC tumors are QNBC. Bivariate fit analysis demonstrated that QNBC (n = 224) significantly (P < .03) correlated with younger aged patients at initial biopsy compared to AR positive TNBC patients (n = 51). In paired primary tissue samples and primary to recurrent/metastatic samples, at least 70% Luminal, HER2 enriched, and QNBC subtype did not change molecular profile. But, TNBC seems to be the “unstable” subtype. Within the total cohort, discordance in molecular profiles was identified in both synchronous (20%) and asynchronous (21%) intra-individual analyses. Irrespective of sample type, (Synchronous or Asynchronous), QNBC demonstrated higher concordant than TNBC. IHC and ISH results of the cancer related genes, demonstrated that gene/protein expression differ by molecular profile: TNBC (HR-/HER2-, AR+) and QNBC (HR-/HER2-, AR-). IHC in metastatic tumors, showed that the percentage of tumors positive of EGFR were higher, while PTEN and TLE3 were lower in QNBC compared to TNBC. CONCLUSION: Standard treatment of Breast Cancer (BC) relies on reliable assessment by IHC analysis of ER, PR, and HER2. Our analyses suggest that the heterogeneity of TNBC is at least partially associated with the presence or absence of AR expression, suggesting that QNBC should be considered as a clinically relevant BC subtype. IHC analysis of AR appears to be a practical assay to determine the most aggressive TNBC subtypes and identifies tumors that could benefit from available targeted therapies.

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

“…Age at diagnosis was greater among the LAR subtype [ 3 ] and AR-positive TNBC [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ] in comparison to other subtypes and AR-negative TNBC, respectively. This phenomenon could be attributed to the use of hormonal replacement therapy in postmenopausal patients, or to the more indolent profile of AR-positive tumors, therefore appearing in older patients [ 26 ].…”

“…A high discordance rate is present in biomarker expression between primary and metastatic lesions [ 14 , 24 ], as well as between primary tumor and recurrent lesion [ 66 ]. Likewise, a significant degree of discordance in biomarkers among all breast cancer subtypes has been studied, with the highest discordance rate among TNBC [ 23 ]. When AR was negative, TNBC discordance rate between primary, metastatic, and recurrent tumor decreased.…”

Quadruple-Negative Breast Cancer: An Uneven Playing Field

“…Yet another consideration is a switch in hormone receptor status that often follows cancer recurrence, especially so in TNBC, which exhibits elevated metastatic potential. Angajala et al 34 observed an increase in QNBC subtype at second profile status of TNBC that had progressed to a recurrent/metastatic stage. So although AR-positive TNBC exhibited a heterogeneous profile with a greater frequency of being diagnosed as AR negative at an advanced stage, QNBC displayed a more stable phenotype.…”

“…So although AR-positive TNBC exhibited a heterogeneous profile with a greater frequency of being diagnosed as AR negative at an advanced stage, QNBC displayed a more stable phenotype. 34 In view of the complex role of AR in BC and the distinctive characterization its presence and absence effects in the TNBC landscape, it is imperative to include AR analysis in routine clinical practice (together with the assessment of ER, PR, and HER2 expression). Because there is little consensus on AR positivity cut-off as determined by immunohistochemistry, a more reliable means of assessment, such as an androgen-driven gene signature, should be depended on instead.…”

Comparative assessment of proteins between cell lines and tissues representing carcinomas of the breast using 2-dimensional gel electrophoresis

“…Lack of facilities for early detection, the advent of quadruple negative breast cancer types, and poor access to various treatment methods are the major contributors to increased mortality rates in developing countries (Angajala et al, 2019). Although existing therapies are ef icient, a number of drawbacks and side effects were reported.…”