Abstract P1-08-24: High tumor RNA disruption is associated with increased survival in patients with locally advanced breast cancer

Abstract

Abstract Background: We recently reported that epirubicin/docetaxel treatment of locally advanced breast cancer patients in the MA.22 clinical trial reduced tumor RNA integrity and that low mid-treatment tumor RNA integrity was associated with a pathologic complete response (pCR) post-treatment [Breast Cancer Res. Treat. 119:347-356]. A novel method for detection of chemotherapy-dependent loss of RNA integrity, the RNA disruption assay (RDA), has since been developed, which stratifies RNA disruption into 3 zones. Zone 1 represents drug effect inadequate to obtain a pCR [RNA disruption index (RDI) ≤ 10, NPV>0.99]. Zone 2, an intermediate zone (RDI >10 and ≤35) had 1 pCR in our study, while Zone 3 (RDI >35) had the most pCRs (n = 7). Methods: We have now evaluated the relationship between tumor RNA disruption and both treatment response and patient survival in all evaluable MA.22 patients (n = 85). RNA was isolated from 2-3 tumor biopsies/patient prior to and after 3 (Schedule A) or 4 (Schedule B) cycles of chemotherapy at 3- or 2-weekly intervals, respectively. RNA quality was assessed on an Agilent 2100 Bioanalyzer and RNA disruption quantified using RDA. Results: Chemotherapy exposure reduced maximum tumor RNA content from 197 ± 24 ng/μl (mean ± standard error) pre-treatment to 94.0 ± 12.8 ng/μl mid-treatment, with maximum tumor RDI values increasing from 26.0 ± 5.8 to 88.1 ± 19.1 (p<0.01 for both observations by Sign test). At the time of assessment, there were similar numbers of deceased patients across tumor RDA zones 1, 2, and 3 mid-treatment (7, 8, and 9 patients, respectively). In contrast, there were 2.9-fold more living patients with tumors in RDA zone 3 (29) than in zone 1 (10). Disease-free survival (DFS) was significantly greater (by 23.6 months) for zone 3 patients (56.9 ± 5.6 months) compared to zone 1 patients (33.3 ± 6.8 months) (p = 0.0096 by Mann Whitney Wilcoxon Test for this and all subsequent statistical tests). Living patients with tumor RDA values in zone 3 exhibited 24.5 months greater DFS than living patients with tumors in zone 1 (68.2 ± 5.5 months versus 43.7 ± 9.5 months, respectively; p = 0.015). Given their high frequency within the patient population, we were also able to conclude that greater DFS (an additional 28.6 months) could be seen for patients with estrogen receptor positive (ER+) tumors in zone 3 (59.2 ± 7.2 months) compared to patients with similar tumors in zone 1 (30.6 ± 6.3 months; p = 0.0088). Living patients with ER+ tumors in zone 3 had even greater DFS (+42.5 months) compared to living patients with ER+ tumors in zone 1 (71.8 ± 5.8 months versus 29.3 ± 8.7 months, respectively; p = 0.0012). There were also 2.5-fold more living patients with ER+ tumor RDA values in zone 3 (15) than in zone 1 (6). None of the above significant differences were observed when pre-treatment tumor RDI values or pre-treatment patient characteristics were assessed. Irrespective of breast tumor receptor subtype, chemotherapy-dependent RNA disruption mid-treatment was typically higher in patients that achieved a pCR post-treatment than for patients that did not. Conclusions: Our findings suggest that tumor RNA disruption measurements during treatment will be highly useful to predict response and survival for locally advanced breast cancer patients. Our data demonstrate that non-responding patients (zone 1 by RDA) have considerably reduced DFS with very little chance of achieving a pCR. Such patients can be spared the toxicities associated with continuing an ineffective regimen and can be considered quickly for alternate treatments, including surgery, radiation therapy, or other anti-cancer drugs. The impact of treatment schedule and dose on RDA's ability to predict patient response and survival is currently being assessed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-24.