PAM50 and Risk of Recurrence Scores for Interval Breast Cancers

Abstract

Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared to screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically-screened women diagnosed with primary invasive breast cancer from 1993-2013 (n=370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0-24 months before diagnosis, cancers were classified as screen-detected (N=165) or interval-detected (N=205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors (> 2 cm) (OR=2.3; 95% C.I.: 1.5, 3.7), positive nodal status (OR=1.8; 95% C.I.: 1.1, 2.8), and triple negative subtype (OR=2.5; 95% C.I.: 1.1, 5.5). Interval cancers were more likely to have non-Luminal A subtype (OR=2.9; 95% C.I.: 1.5, 5.7), while screen-detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates.

Comparison of Mortality Among Participants of Women’s Health Initiative Trials With Screening-Detected Breast Cancers vs Interval Breast Cancers

“…[25][26][27][28][29] Our study corroborates previous research showing that IBC tumors are larger and more likely to be advanced, with more lymph node involvement and a higher proportions of lobular histologic characteristics, than breast cancers detected by screening. [5][6][7]11 However, previous studies did not compare IBCs by screening interval. The unique findings from our study are that IBCs that emerge within 1 year after negative mammogram results might have distinct tumor characteristics that identify them as at a particularly high risk for metastasis.…”

“…44,45 Also, the combination of germline genomic testing with mammography may help distinguish indolent breast cancers from aggressive breast cancers detected by screening. 7 This study adds to a growing body of literature [46][47][48][49] that argues for the development of novel approaches to detect life-threatening cancers currently missed by mammographic screening.…”

“…4 Most of these missed cancers are interval breast cancers (IBCs), defined as cancers that emerge after nonsuspicious mammogram results but before the patient's next scheduled screening. Interval breast cancer tumors are often diagnosed at a later stage than cancers detected by screening, [5][6][7][8] and they are associated with a 2-fold to 3-fold increased risk of breast cancer-specific mortality compared with cancers detected by screening, even after adjustment for clinically relevant variables. 5,7,9,10 Other studies report mortality rates among women with IBC that are comparable to those among women who did not undergo screening, 1,11 emphasizing the need for additional study.…”

Interval breast cancer is associated with interferon immune response

“…That is not surprising given the ability of the PAM50 classification to capture intrinsic biological features and to predict clinical outcomes [10,11]. Others have also reported that interval cancers are associated with both more aggressive non-luminal molecular subtypes and with the PAM50 risk of recurrence score, independently of mammographic density [12]. Because the PAM50 subtypes are mainly a marker for tumour growth rate, it comes easy that tumours that grow within two screening intervals (i.e.…”

Acute Leukemia Classification Using Transcriptional Profiles From Low-Cost Nanopore mRNA Sequencing

“…[15][16][17][18][19] Gene expression profiling (GEP) is a powerful tool for discovery and can provide clinically actionable information in many subtypes of malignancies. 15,17,[20][21][22][23][24] Comprehensive classification of acute leukemia using single-platform short-read RNA sequencing is established in research settings, allowing determination of leukemia lineage, genomic subtypes, small mutations, and aneuploidy. 18,25 The base-pair accuracy of short-read sequencing by synthesis makes it the reference standard in cancer research and clinical care in high-income countries.…”