Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification

Abstract

BackgroundHER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases.ResultsWe separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers.ConclusionsOur results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0657-6) contains supplementary material, which is available to authorized users.

Translating neoadjuvant therapy into survival benefits: one size does not fit all

“…Using laser-capture microdissection and in situ single-cell analysis, investigators have demonstrated that HER2 amplification and PIK3CA mutations are distributed heterogeneously in breast tumours 96,103 . This spatiotemporal intratumour heterogeneity could interfere with responses to neoadjuvant and adjuvant treatments.…”

Molecular genetic markers of breast cancer

“…Амплификация рецептора HER2 является прогностическим маркером, а также молеку-лярной мишенью для таргетной терапии трастузума-бом, пертузумабом и лапатинибом. Соматические мутации в гене HER2 выявляются с частотой 1,68 % и находятся преимущественно среди HER-2 -подти-пов РМЖ, что вызывает устойчивость к таргетной те-рапии трастузумабом и лапатинибом [39].…”

Tumour Heterogeneity of Breast Cancer: From Morphology to Personalised Medicine

“…HER2 heterogeneity is known to feature either 2 clearly distinct tumour clones or scattered HER2-positive cells within a substantially negative tumour cell population [99]. Recently, the mutational landscape of HER2 heterogeneous carcinomas with 2 separate clones was analysed, and distinct driver genetic alterations in the different components were demonstrated, suggesting that HER2-negative clones are likely driven by genetic alterations not present in the HER2-positive clones, including the BRF2 and DSN1 amplification and the HER2 I767M somatic mutations [98]. Accordingly, biological marker heterogeneity suggests that multiple cores should be obtained for using TMA procedure in the routine and research settings to represent all the possible variability of expression [100].…”

“…By definition, HER2 positivity is heterogeneous, since a 10% cut-off is considered to assign samples to distinct score categories using IHC [97]; scores of 0 and 3+ are more homogeneous in staining and 2+ carcinomas show higher variability [98]. HER2 heterogeneity is known to feature either 2 clearly distinct tumour clones or scattered HER2-positive cells within a substantially negative tumour cell population [99].…”