Medium levels of transcription and replication related chromosomal instability are associated with poor clinical outcome.

Genomic instability (GI) influences treatment efficacy and resistance, and an accurate measure of it is lacking. Current measures of GI are based on counts of specific structural variation (SV) and mutational signatures. Here, we present a holistic approach to measuring GI based on the quantification of the steady-state equilibrium between DNA damage and repair as assessed by the residual breakpoints (BP) remaining after repair, irrespective of SV type. We use the notion of Hscore, a BP "hotspotness" magnitude scale, to measure the propensity of genomic structural or functional DNA elements to break more than expected by chance. We then derived new measures of transcription- and replication-associated GI that we call iTRAC (transcription-associated chromosomal instability index) and iRACIN (replication-associated chromosomal instability index). We show that iTRAC and iRACIN are predictive of metastatic relapse in Leiomyosarcoma (LMS) and that they may be combined to form a new classifier called MAGIC (mixed transcription- and replication-associated genomic instability classifier). MAGIC outperforms the gold standards FNCLCC and CINSARC in stratifying metastatic risk in LMS. Furthermore, iTRAC stratifies chemotherapeutic response in LMS. We finally show that this approach is applicable to other cancers.

Patterns of care, prognosis, and survival in patients with metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-line sunitinib.

BACKGROUND: Data regarding the management and outcome of patients with metastatic gastrointestinal stromal tumors (GIST) refractory to 1st-line imatinib and 2nd-line sunitinib are limited. METHODS: Medical records of 223 imatinib-resistant and sunitinib-resistant GIST who were treated in 11 major referral centers were reviewed. RESULTS: The three most frequent drugs used in the 3rd-line setting were: nilotinib n = 67 (29.5%), sorafenib n = 55 (24.5%), and imatinib n = 40 (17.5%). There were 18 patients (8%) who received best supportive care (BSC) only. The median progression-free survival (PFS) and overall survival (OS) on 3rd-line treatment were 3.6 months [95% confidence interval (95% CI), 3.1-4.1] and 9.2 months (95% CI, 7.5-10.9), respectively. Multivariate analysis showed that, in the 3rd-line setting, albumin level and KIT/PDGFRA mutational status were significantly associated with PFS, whereas performance status and albumin level were associated with OS. After adjustment for prognostic factors, nilotinib and sorafenib provided the best PFS and OS. Rechallenge with imatinib was also associated with improved OS in comparison with BSC. CONCLUSION: In the 3rd-line setting, rechallenge with imatinib provided limited clinical benefit but was superior to BSC. Sorafenib and nilotinib have significant clinical activity in imatinib-resistant and sunitinib-resistant GIST and may represent an alternative for rechallenge with imatinib.

[Gastrointestinal stromal tumors: molecular aspects and therapeutic implications]. / Aspects moléculaires et stratégies thérapeutiques des tumeurs stromales gastro-intestinales.

Approximately 90 % of gastrointestinal tumors (GISTs) harbor an activating mutation in KIT or PDGFR alpha oncogene known to confer imatinib sensitivity. Imatinib is a tyrosine kinase inhibitor of KIT and PDGFRs that yields a 6-months progression-free survival (PFS) rate of 80 % in patients with advanced GISTs. Several studies have shown that response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFR alpha. Moreover, most if not all patients treated with imatinib for advanced GIST will secondarily develop progressive disease under treatment. In the majority of cases, such progressions are the result of acquired resistance due to occurrence of secondary C-KIT mutations; especially for GIST with primary exon 11 mutations. Sunitinib is another approved drug and an inhibitor of multiple tyrosine kinases including KIT, PDGFR alpha as well as PDGFR beta and VEGFRs which are associated with angiogenesis. Sunitinib, in phase II and III trials was associated with durable clinical benefit in nearly 25 % of patients with advanced GIST resistant/intolerant to imatinib. Clearly, a better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors may allow in the near future new individualized therapeutic strategies for GISTs patients.