Abstract P2-03-03: Molecular differences between screen-detected and interval breast cancers are largely explained by PAM50 subtypes
Authors: Czene K , Ivansson E , Klevebring D , Tobin NP , Lindström LS , Holm J , Prochazka G , Hilliges C , Palmgren J , Törnberg S , Humphreys K , Hartman J , Frisell J , Rantalainen M , Lindberg J , Hall P , Bergh J , Grönberg H , Li J 
Published: March 2017

Purpose:Interval breast cancer is of clinical interest as it exhibits an aggressive phenotype and evades detection by screening mammography. A comprehensive picture of somatic changes that drive tumors to become symptomatic in the screening interval can improve understanding of the biology underlying these aggressive tumors.

Experimental design:Initiated in April 2013, Clinical Sequencing of Cancer in Sweden (Clinseq) is a scientific and clinical platform for the genomic profiling of cancer. The breast cancer pilot study consisted of women diagnosed with breast cancer between 2001-2012 in the Stockholm/Gotland regions. A subset of 318 breast tumors were sequenced, of which 113 were screen-detected and were 60 interval cancers.We applied targeted deep-sequencing of cancer-related genes, low-pass whole-genome sequencing and RNA-sequencing technology to characterize somatic differences in the genomic and transcriptomic architecture by interval cancer status. Mammographic density and PAM50 molecular subtypes were considered.

Results:In the crude analyses, TP53, PPP1R3A, and KMT2B were significantly more frequently mutated in interval cancers than in screen-detected cancers. Acquired somatic copy number aberrations with a frequency difference of at least 15% between the two groups included gains in 17q23-q25.3 and losses in 16q24.2. Gene expression analysis identified 447 significantly differentially expressed genes, of which 120 were replicated in an independent microarray dataset. After adjusting for PAM50, most differences were no longer significant.

Conclusions: Molecular differences by interval cancer status were observed, but they were largely explained by PAM50 subtypes. This work offer new insights into the biological differences between the two tumor groups.

Translational relevance: Although screen-detected cancers are biologically distinct from interval cancers in terms of somatic mutations, copy number aberrations and gene expression, most of the differences are no longer significant after adjusting for breast cancer intrinsic subtypes (PAM50). We also show that the molecular differences appear to form a spectrum from less aggressive (screen-detected) to more aggressive (interval) manifestations of the disease, which can be characterized by PAM50 subtypes, namely, luminal A, luminal B, HER2-enriched and basal-like, in that order. This work clarifies the picture on what type of breast cancer we are likely to identify through population-based screening, and what type of cancer we are likely to miss. Current knowledge of PAM50 subtype-specific risk factors need to be expanded as our findings might influence how we screen women with a higher risk of basal-like breast cancer for example, beyond known risk groups BRCA1 mutation carriers and women of African-American descent.

Citation Format: Czene K, Ivansson E, Klevebring D, Tobin NP, Lindström LS, Holm J, Prochazka G, Hilliges C, Palmgren J, Törnberg S, Humphreys K, Hartman J, Frisell J, Rantalainen M, Lindberg J, Hall P, Bergh J, Grönberg H, Li J. Molecular differences between screen-detected and interval breast cancers are largely explained by PAM50 subtypes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-03.