Crizotinib is a standard treatment for advanced
ALK
‐positive non‐small‐cell lung cancer (
NSCLC
). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and ...pharmacogenomic factors that may increase the risk of adverse events (
AE
s). We defined clinically significant
AE
s as grade 4 hematological toxicity, grade ≥3 non‐hematological toxicity, and any grade of interstitial lung disease. Eight subjects with
ALK
‐positive
NSCLC
scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4–61.0 kg). All patients developed
AE
s, five developing six clinically significant
AE
s. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration–time curve from 0–12 h (
AUC
0–12
) on day 15 was significantly increased in patients with clinically significant
AE
s (
n =
5) compared with those without (
n =
3) (
P
= 0.04). Genetic polymorphisms of
ABCB
1
were analyzed. One patient with the
ABCB
1
1236
TT
‐2677
TT
‐3435
TT
genotype was an outlier, with an
AUC
0–12
and peak concentrations on day 15 of 2.84× and 2.61× the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese
NSCLC
patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and ...other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48–22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99–14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies.
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Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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