1413P - ATRX-associated alternative lengthening of telomere (ALT) may be correlated with chemotherapy response in leiomyosarcoma (LMS)

Abstract

Response to systemic chemotherapy in LMS varies and no predictive biomarker exists. ALT, a common mechanism to maintain telomere in sarcoma, is associated with altered DNA repair mechanism. Loss of a chromatin modifier &agr;-thalassemia/mental retardation syndrome X-linked (ATRX) has been implicated as one of the factors leading to ALT. We aimed to determine the relationship between ALT, ATRX and chemotherapy response in patients with advanced LMS. Histology-proven advanced LMS patients (pts) treated with systemic chemotherapy in National Taiwan University Hospital from January 1995 to December 2014 were selected. Patient demographic data and clinical outcomes including tumor response, progression-free survival and overall survival were recorded. We used formalin-fixed paraffin-embed tumor samples for ALT and ATRX status assessment by telomere-specific fluorescence in situ hybridization and immunohistochemistry, respectively. 30 pts with advanced LMS treated with systemic chemotherapy were identified. Table 1 summarizes the clinicopathological information. 21 pts received anthracycline-based first line chemotherapy. 20 pts (67%) were ALT-positive (ALT+). 10 pts (33%) were ATRX-negative (ATRX-), among which all but 1 were also ALT+. ALT positivity was not correlated with chemotherapy response (odds ratio = 1.25, p = 0.7844). In the 9 ALT + /ATRX- patients, a lower odds, albeit non-significant, of response to chemotherapy was noted compared to non ALT + /ATRX- patients (11.3% vs 42.9%, odds ratio = 0.17, 95% CI = 0.01-1.58, p = 0.11). PFS was significantly shorter in ALT + / ATRX- patients (median 2.0 mos vs 7.7 mos, p < 0.001, hazard ratio 6.5, 95% CI 2.4-17.7). No significant difference in OS was noted (median 11.7 mos vs 23.9 mon, p = 0.314) between ALT + /ATRX- and non-ALT + /ATRX- pts.Tabled 1Patient demographics and clinicopathological featuresn = 30 (%)Age, median (range)51 (28-67)Sex- Male2 (7)- Female28 (93)Tumor Origin- Uterus22 (73)- Retroperitoneum/intra-abdomen3 (10)- Others5 (17)Metastatic site- Lung25 (83)- Liver14 (47)- Bone7 (23)- Intra-abdomen (excluding liver)7 (23)Cell Morphology- Spindle19 (63)- Epithelioid/pleomorphic11 (37)FNCLCC Grade- Grade 1/212 (40)- Grade 318 (60)ALT FISH- Positive20 (67)- Negative10 (33)ATRX Expression- Present20 (67)- Loss10 (33)1st-line Chemotherapy- Anthracycline-based21 (70)- Nonanthracycline-based9 (30) Open table in a new tab ALT+ with ATRX- may predict poorer response to chemotherapy in advanced LMS.