Relationship between usefulness of irinotecan and pegylated liposomal doxorubicin therapy and the UGT1A1 genotype in patients with recurrent ovarian cancer (TGCU 104 study)

Objective: The authors investigated the relationship between the usefulness of CPT-11 + PLD combination therapy and the UGT1A1 genotype. Materials and Methods: Forty-one patients who provided informed consent were divided into the following two groups according to UGT1A1 genotypes: wild type and non-wild type. Adverse events, antitumor effect, and outcomes were compared between these two groups. Results: Twenty-three patients were wild type and 18 were non-wild type for UGT1A1. A total of 94 and 73 treatment cycles were prescribed to the wild-type and non-wild-type groups, respectively. No significant differences in the incidence of any grade 3 or higher adverse events were observed between the two groups. However, the next treatment cycle was postponed in 9.6% of the wildtype group and 12.3% of the non-wild-type group (p = 0.891). The antitumor effects as assessed by response rate were 26.1% in the wildtype group and 55.6% in the non-wild-type group (p = 0.054). The median observation period was 13 months. The median progression-free survival was three months in the wild-type group vs. five months in non-wild-type group (p = 0.913), while the median overall survival was 24 vs. 22 months (p = 0.535). Conclusions: This study did not demonstrate a statistically significant difference in the usefulness of CPT-11 + PLD combination therapy for recurrent ovarian cancer between the two groups of UGT1A1 genotypes. This study was considered to have significance as the first study conducted in Japan to prospectively evaluate the relationship between the usefulness of CPT-11-based chemotherapy and the UGT1A1 genotype for recurrent ovarian cancer.

[1] Ando Y., Saka H., Ando M., Sugiura S., Shimokata K., Kamataki T.: “Polymorphisms of UDP glucuronosyltransferase gene and irinote-can toxicity: A pharmacogenetic analysis”. Cancer Res., 2000, 60, 6921.

[2] Iyer L., Das S., Janisch L., Wen M., Ramírez J., Karrison T., et al.: “UGT1A1*28 polymorphism as a determinant of irinotecan dispo- sition and toxicity”. Pharmacogenomics J., 2002, 2, 43.

[3] Innocenti F., Undevia S.D., Iyer L., Chen P.X., Das S., Kochergin- sky M., et al.: “Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan”. J. Clin. Oncol., 2004, 22, 1382.

[4] Marcuello E., Altés A., Menoyo A., Del Rio E., Gómez-Pardo M., Baiget M.: “UGT1A1 gene variations and irinotecan tratment in pa- tients with metastatic colorectal cancer”. Br. J. Cancer, 2004, 91, 678.

[5] Rouits E., Boisdron-Celle M., Dumont A., Guérin O., Morel A., Gamelin E.: “Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 pa- tients”. Clin. Cancer Res., 2004, 10, 5151.

[6] Minami H., Sai K., Saeki M., Saito Y., Ozawa S., Suzuki K., et al.: “Irinotecan pharmacokinetics / pharmacodynamics and UGT1A genetic polymorphisms in Janpanese: roles of UGT1A1*6 and *28”. Pharmacogenet Genomics, 2007, 17, 497.

[7] Takatori E., Shoji T., Miura Y., Takeuchi S., Yoshizaki A., Sugiyama T.: “Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 pre- senting with serious adverse events during irinotecan hydrochlo- ride/nedaplatin therapy”. J. Obstet. Gynaecol. Res., 2013, 39, 1354.

[8] Shoji T., Takatori E., Omi H., Kumagai S., Yoshizaki A., Yokoyama Y., et al.: “Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study)”. Int. J. Gynecol. Cancer, 2011, 21, 44.

[9] Shoji T., Takatori E., Kaido Y., Omi H., Yokoyama Y., Mizunuma H., et al.: “A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Can- cer Unit 104 study)”. Cancer Chemother. Pharmacol., 2014, 73, 895.

[10] Matsumoto K., Katsumata N., Yamanaka Y., Yonemori K., Kohno T., Shimizu C., et al.: “The safety and efficacy of the weekly dosing of irinotecan for platinum-and taxanes-resistant epithelial ovarian cancer”. Gynecol. Oncol., 2006, 100, 412.

[11] Takano M., Kato M., Yoshikawa T., Sasaki N., Hirata J., Furuya K., et al.: “Clinical significance of UDP-glucuronosyltransferase 1A1*6 for toxicities of combination chemotherapy with irinote- can and cisplatin in gynecologic cancers: A prospective multi- institutional study”. Oncology, 2009, 76, 315.

[12] Chen Y.J., Hu F., Li C.Y., Fang J.M., Chu L., Zhang X., et al.: “The association of UGT1A1*6 and UGT1A1*28 with irinotecan- induced neutropenia in Asians: a meta-analysis”. Biomarkers, 2014, 19, 56.

[13] Takano M., Yamamoto K., Tabata T., Minegishi Y., Yokoyama T., Hirata E., et al.: “Impact of UGT1A1 genotype upon toxicities of combination with low-dose irinotecan plus platinum”. Asia. Pac. J. Clin. Oncol., 2016, 12, 115.

[14] Yoshino K., Kamiura S., Yokoi T., Nakae R., Fujita M., Takemura M., et al.: “Combination chemotherapy with irinotecan and gemc- itabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)”. Cancer Chemother. Pharmacol., 2017, 80, 1239.