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FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer
Authors:Sebastian Mondaca  Walid K. Chatila  David Bates  Jaclyn F. Hechtman  Andrea Cercek  Neil H. Segal  Zsofia K. Stadler  Anna M. Varghese  Ritika Kundra  Marinela Capanu  Jinru Shia  Nikolaus Schultz  Leonard Saltz  Rona Yaeger
Affiliation:1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;2. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY;3. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY;4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY;5. Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Abstract:

Background

Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Patients and Methods

We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy – essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin – in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers.

Results

Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations.

Conclusions

FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.
Keywords:Cisplatin  5-Fluorouracil  Human papillomavirus  Massively parallel sequencing  Platinum
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