Browsing by Author "Yoon, Harry H."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group
    (BMC, 2011-05-17) Yoon, Harry H.; Catalano, Paul J.; Murphy, Kathleen M.; Skaar, Todd C.; Philips, Santosh; Powell, Mark; Montgomery, Elizabeth A.; Hafez, Michael J.; Offer, Steven M.; Liu, Geoffrey; Meltzer, Stephen J.; Wu, Xifeng; Forastiere, Arlene A.; Benson, Al B.; Kleinberg, Lawrence R.; Gibson, Michael K.
    Background Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA. Methods Eighty-one eligible treatment-naïve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP. Results The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs. Conclusions Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus.
  • Thumbnail Image
    Item
    Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study
    (Springer Nature, 2019-07) Bang, Yung-Jue; Kang, Yoon-Koo; Catenacci, Daniel V.; Muro, Kei; Fuchs, Charles S.; Geva, Ravit; Hara, Hiroki; Golan, Talia; Garrido, Marcelo; Jalal, Shadia I.; Borg, Christophe; Doi, Toshihiko; Yoon, Harry H.; Savage, Mary J.; Wang, Jiangdian; Dalal, Rita P.; Shah, Sukrut; Wainberg, Zev A.; Chung, Hyun Cheol; Medicine, School of Medicine
    BACKGROUND: The multicohort, phase II, nonrandomized KEYNOTE-059 study evaluated pembrolizumab ± chemotherapy in advanced gastric/gastroesophageal junction cancer. Results from cohorts 2 and 3, evaluating first-line therapy, are presented. METHODS: Patients ≥ 18 years old had previously untreated recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma. Cohort 3 (monotherapy) had programmed death receptor 1 combined positive score ≥ 1. Cohort 2 (combination therapy) received pembrolizumab 200 mg on day 1, cisplatin 80 mg/m2 on day 1 (up to 6 cycles), and 5-fluorouracil 800 mg/m2 on days 1-5 of each 3-week cycle (or capecitabine 1000 mg/m2 twice daily in Japan). Primary end points were safety (combination therapy) and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by central review, and safety (monotherapy). RESULTS: In the combination therapy and monotherapy cohorts, 25 and 31 patients were enrolled; median follow-up was 13.8 months (range 1.8-24.1) and 17.5 months (range 1.7-20.7), respectively. In the combination therapy cohort, grade 3/4 treatment-related adverse events occurred in 19 patients (76.0%); none were fatal. In the monotherapy cohort, grade 3-5 treatment-related adverse events occurred in seven patients (22.6%); one death was attributed to a treatment-related adverse event (pneumonitis). The objective response rate was 60.0% [95% confidence interval (CI), 38.7-78.9] (combination therapy) and 25.8% (95% CI 11.9-44.6) (monotherapy). CONCLUSIONS: Pembrolizumab demonstrated antitumor activity and was well tolerated as monotherapy and in combination with chemotherapy in patients with previously untreated advanced gastric/gastroesophageal junction adenocarcinoma.