Abstract P4-05-14: Molecular and immunohistochemical profile of invasive micropapillary breast carcinoma
Authors: Thomas A , Askeland RW , Guseva NV , Sompallae R , Ma D 
Published: August 2014

Background: Invasive micropapillary carcinoma (IMPC) of the breast is an uncommon disease subtype that is generally considered aggressive. A variety of carcinomas can exhibit micropapillary histology including lung, bladder, and ovary. Immunohistochemical (IHC) and genomic studies at these other organ sites have identified potential therapeutic targets including BRAF mutations. The purpose of this study was to characterize the IHC and molecular profile of a cohort of IMPC that could suggest potentially useful targeted therapies.

Design: Eight tumor blocks (from seven patients) of IMPC were identified from the archives at the University of Iowa Hospitals and Clinics from 1997-2012. IHC stains for ER, PR, HER2, PTEN (Dako; clone 6H2.1, 1:100) and NM23H1 (Santa Cruz Biotechnology, clone: Nm301, 1:50) were performed. ER, PR, and HER2 were score according to ASCO/CAP guidelines. PTEN and NM23H1 were scored using a 4-tier system: P: strong homogenous; H: heterogeneous (positive with negative foci); R: reduced in more than 50%; and L: lost in all or majority. Genomic DNA was isolated from the formalin fixed paraffin embedded tumor samples used for IHC. BRAF V600 mutational analysis was analyzed using a laboratory-developed primer extension assay. Massive parallel sequencing (next generation sequencing, NGS) was performed using the Ion AmpliSeq™ Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, CA).

Results: The patients were 50-83 years of age. Six had Elston-Ellis Grade II tumors and one was Elston-Ellis grade I. Four patients had axillary lymph node metastases. All cases examined showed strong and diffuse estrogen and progesterone receptor expression with no over-expression of HER2. Complete PTEN loss was observed in 4 cases including 3 with lymph node positive disease, three of these four cases had concurrent reduced expression of NM23H1. No mutations in exon 15 of the BRAF gene were detected. By NGS, one sample showed a KITc.A1621C (pM541) polymorphism, three had no mutations, and sequencing from the other three was unsatisfactory.

Molecular and IHC Profile of Seven Patients with IMPC of the BreastHistologic GradeAxillary Lymph Node MetastasisER/PRHER2PTENNM23H1NGS2NoPositive/PositiveNegativePPUnsatisfactory1NoPositive/PositiveNegativeLRNegative2NoPositive/PositiveNegativeHPIntronic2YesPositive/PositiveNegativeHPUnsatisfactory2YesPositive/PositiveNegativeLRKIT c.A1621C (pM541)2YesPositive/PositiveNegativeLPNegative2YesPositive/PositiveNegativeLRUnsatisfactory

Conclusions: Loss of PTEN expression was observed in 57% of cases (4/7) and was often associated with lymph node metastasis. A direct correlation between PTEN and NM23H1 expression was observed in six cases. No BRAF or other mutations were detected. PTEN was included in the NGS panel. Reduced expression observed in our study is most likely due to posttranscriptional modifications. Concurrent reduced expression of the metastatic suppressor NM23H1 may play a role in the clinical behavior of IMPC. The high frequency of PTEN loss may have implications for targeted therapy towards the PI3K pathway in this subgroup of patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-14.