Relationship of Extreme Chromosomal Instability with Long-term Survival in a Retrospective Analysis of Primary Breast Cancer

Abstract

Background Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumours, however, evidence from pre-clinical and mouse tumour models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumour CIN status, efficiently delineate outcome in ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes. Methods Direct assessment of CIN requires single cell analysis methods such as centromeric fluorescence in situ hybridisation (FISH) aimed at determining the variation around the modal number of two or more chromosomes within individual tumour nuclei. Here we document the frequency of tumour CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome. Results There was increased CIN and clonal heterogeneity in ER-negative compared to ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN. Conclusions The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumour CIN status, fail to predict outcome in this subgroup. Impact Assessment of tumour CIN status may support risk stratification in ER negative breast cancer and requires prospective validation.

Role of chromosomal instability in cancer progression

“…Analysis of chromosomal instability levels in patients echoed this work from model systems, demonstrating that patients with tumours exhibiting 'extreme' CIN showed better prognosis . This was supported by subsequent studies in breast cancer (Roylance et al 2011, Jamal-Hanjani et al 2015, and also more recently in a pan-cancer analysis (Andor et al 2016).…”

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

“…On the other hand, tumors would be vulnerable to either a decrease or an increase of CIN rates outside of the optimal range that supports clonal evolution. This is indeed supported by a number of clinical observations and experimental evidence (Bakhoum et al 2011;Birkbak et al 2011;Roylance et al 2011;Jamal-Hanjani et al 2015;Andor et al 2016). Among colorectal cancer-derived cell lines, chromosomally unstable cells are more resistant to targeted kinase inhibition as compared with their chromosomally stable counterparts (Lee et al 2011).…”

Chromosomal instability and cancer: a complex relationship with therapeutic potential

“…In tumors in which CIN is associated with poor prognosis, such as DLBCL (48), suppressing chromosome missegregation could reduce the frequency of metastasis and drug resistance. Yet, given that extremely elevated rates of CIN also appear to decrease tumor fitness in some cancers (67,74,83), further increasing chromosome missegregation rates could be beneficial. Therefore, determining chromosome missegregation frequencies of a given tumor and comparing these to the optimal level of CIN that allows for tumor adaptation might be a prerequisite to any therapeutic approach targeting CIN.…”