Copy Number Imbalances between Screen- and Symptom-Detected Breast Cancers and Impact on Disease-Free Survival

Abstract

Background Screening mammography results in the increased detection of indolent tumors. We hypothesized that screen and symptom-detected tumors would show genotypic differences as copy number imbalances (CNIs) that in part explain differences in the clinical behavior between screen and symptom-detected breast tumors. Methods We evaluated 850 women aged ≥ 40 diagnosed with stage I–II breast cancer at the MD Anderson Cancer Center between 1985 to 2000 with information available on method of tumor detection (screen versus symptoms). CNIs in screen and symptom-detected tumors were identified using high-density molecular inversion probe arrays. Cox proportional modeling was used to estimate the effect of method of tumor detection on disease-free survival after adjusting for age, stage and the CNIs. Results The majority of tumors were symptom-detected (n=603) compared to screen-detected (n=247). Copy number gains in chromosomes 2p, 3q, 8q, 11p and 20q were associated with method of breast cancer detection (p<0.00001). We estimated that 32% and 63% of the survival advantage of screen-detection was accounted for by age, stage, nuclear grade and Ki67 in women aged 50–70 and aged 40–87, respectively. In each age category, an additional 20% of the survival advantage was accounted for by CNIs associated with method of detection. Conclusion Specific CNIs differ between screen and symptom-detected tumors and explain part of the survival advantage associated with screen-detected tumors. Measurement of tumor genotype has the potential to improve discrimination between indolent and aggressive screen-detected tumors and aid patient and physician decision making about use of surgical and adjuvant treatments.

Low-grade fibromatosis-like spindle cell carcinomas of the breast are molecularly exiguous

“…CNAs are frequently identified in breast tumours (>90%)29 30 with particular types of aberrations associated with specific subtypes of breast cancers 30–32. For example, Letessier et al 32 reported frequent amplification of chromosomal regions 8p12, 8q24, 11q13, 17q12 and 20q13 in breast cancers, and in particular, 12p13 amplification was associated with basal molecular type.…”

A Novel, Patient-Specific Mathematical Pathology Approach for Assessment of Surgical Volume: Application to Ductal Carcinomain situof The Breast

“…We would expect these tumors to become large enough to be self-palpated prior to being detected on screening mammography. This expectation is reflected in the finding that symptom-detected breast cancers have more copy number imbalances, which is associated with more aggressive behavior [59]. Thus, the screening process is biased to detect less aggressive tumors that do not progress to an invasive state.…”

Copy number analysis of ductal carcinoma in situ with and without recurrence

“…High copy number gains were 41.2 and homozygous deletions o − 1.2. Segmented copy number data were also obtained from published studies [17][18][19] and imported into Nexus. Copy number thresholds of ± 0.2 were used for the invasive cohorts to take into account the higher level of normal cell contamination.…”

“…(a) Frequency plots of copy number gain (blue) and loss (red) in pure DCIS, DCIS synchronous with invasive breast cancer and invasive breast cancer. 17 Below are difference plots comparing pure DCIS with invasive breast cancer and pure DCIS with DCIS synchronous to invasive breast cancer. Blue line is the difference in gain frequency; red is the difference in loss frequency.…”