Molecular Differences between Screen-Detected and Interval Breast Cancers Are Largely Explained by PAM50 Subtypes

Abstract

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. 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 and 2012 in the Stockholm/Gotland regions. A subset of 307 breast tumors was successfully sequenced, of which 113 were screen-detected and 60 were 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. In the univariate analyses, , and 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. Molecular differences by interval cancer status were observed, but they were largely explained by PAM50 subtypes. This work offers new insights into the biological differences between the two tumor groups. .

PAM50 and Risk of Recurrence Scores for Interval Breast Cancers

“…The only study that has reported associations between PAM50 results and mode of detection was based within a clinical cancer sequencing study in Sweden with 173 patients. That study had similar findings, showing that interval cancer was associated with basal-like subtype(19). Higher ROR-PT among interval cancers has not been assessed previously.…”

“…Previous studies have shown that interval cancers have a more aggressive profile with respect to clinical factors such as estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor (HER)2-status(8,13), but only one study has reported associations between interval cancer and RNA-based genomic subtype such as the PAM50 intrinsic subtype(19). No study to our knowledge has reported associations for the genomic risk of recurrence (ROR-PT) score based on PAM50.…”

Five-Year Overall Survival of Interval Breast Cancers is Better than Non- Interval Cancers from Korean Breast Cancer Registry

“…first reported that these two types of breast cancer may have unique underlying biology based on a 77 single-nucleotide polymorphism risk score However, a recent, well-designed study indicated molecular differences between less aggressive screening-detected breast cancer and more aggressive ICs. The two diseases are biologically distinct in terms of somatic mutations, copy number aberrations, and gene expression, but most of these differences are no longer significant after adjusting for breast cancer subtypes and mammography density (Li et al, 2017).…”

Discontinuation of adjuvant hormone therapy among breast cancer patients not previously attending mammography screening

“…However, despite that, interval cancers have been reported to have a similar survival as cancers diagnosed among women not participating in screening [36, 37]. This observation is somewhat contradictory to the common belief that interval cancers have a more aggressive molecular phenotype and a faster growth rate [23, 32, 38]. This also challenges the theory of a strong correlation between growth rate and metastatic potential, and the belief that patients with interval cancers should receive more aggressive treatment [36, 37].…”