INTRATUMORAL AMPLIFICATION HETEROGENEITY IN HER2/neu-POSITIVE BREAST CANCER MOLECULAR-GENETIC SUBTYPES
Larisa Nikolaevna VASHCHENKO1, Larisa Eduardovna ZAVALISHINA2, Irina Arkadyevna PAVLENKO3, Patritsiya Edmundovna POVILAITITE3
1Rostov Research Institute of Oncology of Minzdrav of Russia
2Russian Medical Academy of Continuous Professional Education of Minzdrav of Russia
3Rostov Regional Bureau of Pathology
Keywords: рак молочной железы, внутриопухолевая гетерогенность, амплификация гена HER2, флуоресцентная гибридизация in situ, таргетная терапия, breast cancer, intratumoral heterogeneity, HER2 gene amplification, fluorescence in situ hybridization (FISH), targeted therapy
Abstract
The defining feature of
HER2/neu-positive Luminal B and HER2/neu-positive (non-luminal) subtype
breast cancer is HER2/neu gene amplification and protein overexpression
on cancer cell membrane. The HER2-targeted therapy is nowadays available
for patients with HER2-positive breast cancer However, a significant
fraction of HER2+ tumors acquire or possess intrinsic mechanisms of
resistance, based on multiple factors, and genetic heterogeneity among
them. The aim of our study was to quantify the heterogeneity of HER2/neu
amplification in HER2/neu-positive Luminal B and HER2/neu-positive
(non-luminal) subtypes of breast cancer. Material and methods. A
retrospective analysis of 210 cases referred for dual probe fluorescence
in situ hybridization (FISH) confirmation of an immunohistochemical
equivocal 2+ result was performed. Results. Our results demonstrated a
heterogeneous amplification pattern of HER2/neu gene, whose expression
is a substantial cause of HER2/neu-positive Luminal B and
HER2/neu-positive (non-luminal) subtypes of breast cancer, in 31 % of
invasive breast cancer cases. As heterogeneous, we interpreted tumors
containing cells with HER2/CEP17 ratio < 2 and gene copies 4 ≤
HER2/neu < 6, that is, those without HER2/neu amplification. The
amount of heterogeneous tumors between HER2/neu-positive Luminal B and
HER2/neu-positive (non-luminal) subtypes was not statistically
significant. ROC analyses identified optimal cutoff point for HER2/CEP17
ratio as 2.6 for distinguishing heterogeneous tumors. Conclusion. The
heterogeneity of HER2/neu amplification is determined by FISH in 31 % of
cases and is independent of molecular breast cancer subtype. If a
HER2/neu-positive breast cancer has HER2/CEP17 ratio ≤ 2,6, it contains
minor subclones without HER2/neu amplification with a probability of 95
%. Our results demonstrated that HER2/neu amplification heterogeneity
may be important for prognosis of survival and treatment decisions.
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