Chie Watanabe

Significant Effect of Polymorphisms in CYP2D6 on Response to Tamoxifen Therapy for Breast Cancer; a Prospective Multicenter Study.

Purpose: CYP2D6 is the key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen.” There are still controversial reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of CYP2D6 genotype on tamoxifen therapy. Experimental Design: We enrolled 279 patients with hormone receptor–positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker for response to tamoxifen. We prospectively investigated the effects of allelic variants of CYP2D6 on Ki-67 response, pathological response, and hot flushes. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (P = 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor–positive cells in breast cancer tissues were significantly associated with Ki-67 response (P = 0.0076 and 0.0023, respectively). Although CYP2D6 variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (P = 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele). Conclusions: This is the first prospective study evaluating the relationship between CYP2D6 variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in CYP2D6 is a key predictor for the response to tamoxifen in patients with breast cancer. Clin Cancer Res; 23(8); 2019–26. ©2016 AACR.

Incisional Intercostal Hernia With Prolapse of the Colon After Right Partial Nephrectomy

A 75-year-old woman with a history of myocardial infarction, gallstones, and right renal cancer was referred to our department because of right flank pain. She had a surgical scar on the right abdomen between the 10th and 11th ribs; computed tomography demonstrated intercostal herniation of the colon. Recognizing the possibility of adhesions of the hernia and colon, we used a median skin incision and patched a polyester mesh coated with absorbent collagen. The patient had an uneventful postoperative course, with no pain for 6 months postoperatively. Transdiaphragmatic intercostal hernias with abdominal contents commonly develop after trauma or thoracic surgery. Incisional intercostal hernias seldom develop after nephrectomy; the present case is only the fourth report. We conjecture that a costochondral incision can induce subluxation of the costotransverse joint, intercostal nerve injury, and atrophy of the intercostal and abdominal oblique muscles. Surgeons must therefore recognize the potential, albeit rare, for intercostal hernia after nephrectomy.

Hepatectomy for hepatocellular carcinoma in patients with severe thrombocytopenia.

BACKGROUND/AIMS Hepatic resection for hepatocellular carcinoma (HCC) is risky for cirrhotic patients with severe thrombocytopenia. METHODOLOGY Among 23 patients with histologically proven cirrhosis who underwent hepatic resection for HCC at our hospital since 2006, 7 had severe thrombocytopenia (platelet count <5×104/mm3). The clinical background and surgical outcomes of these 7 patients were retrospectively evaluated and compared to those of the 16 cirrhotic patients without severe thrombocytopenia. RESULTS All 7 patients had hepatitis C virus-related liver cirrhosis. The median preoperative platelet count was 4.3×104/mm3 (range, 3.9-4.9×104/mm3) and the median operative time and intraoperative bleeding were 77min and 193cc, respectively. Postoperative complications were observed in 4 patients (57%) and all were managed conservatively. Four patients received an intraoperative platelet-rich transfusion, but this had no beneficial effect on intraoperative bleeding or postoperative changes in platelet counts. The cirrhotic patients with severe thrombocytopenia were significantly younger and had a significantly shorter operative time compared to those without severe thrombocytopenia. There were no other differences between the groups. CONCLUSIONS Our results suggest that the indication for hepatectomy in cirrhotic patients should not be based on platelet counts alone. However, we note that the younger age and shorter operative time for the patients with severe thrombocytopenia might have contributed to the safety of hepatectomy.

A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study

Purpose Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen. Experimental design We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days. We used Ki-67 response in breast cancer tissues after preoperative short-term tamoxifen therapy as a surrogate marker for response to tamoxifen. We performed GWAS and genotype imputation using 275 patients, and an independent set of 72 patients was used for replication study. Results The combined result of GWAS and the replication study, and subsequent imputation analysis indicated possible association of three loci with Ki-67 response after tamoxifen therapy (rs17198973 on chromosome 4q34.3, rs4577773 on 6q12, and rs7087428 on 10p13, Pcombined = 5.69 x 10−6, 1.64 x 10−5, and 9.77 x 10−6, respectively). When patients were classified into three groups by the scoring system based on the genotypes of the three SNPs, patients with higher scores showed significantly higher after/before ratio of Ki-67 compared to those with lower scores (P = 1.8 x 10−12), suggesting the cumulative effect of the three SNPs. Conclusion We identified three novel loci, which could be associated with clinical response to tamoxifen. These findings provide new insights into personalized hormonal therapy for the patients with breast cancer.

Abstract 2031: Association between CYP2D6 genotype and response to tamoxifen in a prospective multicenter study in Japan

Purpose: CYP2D6 is key enzyme responsible for the generation of the potent active metabolite of tamoxifen, “endoxifen”. We previously reported that reduced- or null-function alleles of CYP2D6 were significantly associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are still discrepant reports questioning the association between CYP2D6 genotype and tamoxifen efficacy. Hence, we carried out prospective multicenter studies to evaluate the value of CYP2D6 genotyping in tamoxifen therapy. Patients and Methods: We studied 279 patients with hormone receptor-positive and Her-2 negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 - 28 days. Ki-67 response in breast cancer tissues after tamoxifen therapy was used as a surrogate marker of response to tamoxifen. We investigated the effects of allelic variants of CYP2D6 on Ki-67 change in breast cancer tissues, histological response, breast conservative operation and hot flash. Results: Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy for 14-28 days (P = 0.00000000024). Moreover, proportion of estrogen receptor positive cells in breast cancer tissues were significantly associated with Ki-67 change after tamoxifen therapy (P = 0.0099). CYP2D6 variants were not significantly associated with histological response, breast conservative operation and hot flash (P = 0.25, P = 0.28 and P = 0.34, respectively). However, CYP2D6 variants were significantly associated with Ki-67 decrease after the preoperative tamoxifen therapy (P = 0.000014; in patients with two variant alleles v patients carrying one or two wild-type alleles). Conclusion: Our result suggest that genetic variation in CYP2D6 is a key predictor for the prognosis of patients with breast cancer treated with tamoxifen. Citation Format: Hitoshi Zembutsu, Seigo Nakamura, Sadako Akashi-Tanaka, Takashi Kuwayama, Chie Watanabe, Tomoko Takamaru, Hiroyuki Takei, Kana Miyahara, Hiroshi Matsumoto, Yoshie Hasegawa, Goro Kutomi, Hiroaki Shima, Fukino Satomi, Hideki Maeda, Minoru Okazaki, Hisamitsu Zaha, Mai Onomura, Ayami Matsukata, Yasuaki Sagara, Shinichi Baba, Akimitsu Yamada, Kazuhiro Shimada, Daisuke Shimizu, Koichiro Tsugawa, Arata Shimo, Tan Ern Yu, Mikael Hartman, Chan Ching Wang, Soo Chin Lee, Yusuke Nakamura. Association between CYP2D6 genotype and response to tamoxifen in a prospective multicenter study in Japan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2031.

Evaluation of the BRCA1 and BRCA2 mutation prediction models in Japanese patients with breast cancer.

46 Background: The breast cancer genetic risk models for predicting BRCA1/2 mutation are widely used before genetic testing. BRCAPRO and Myriad II are common in Europe and America, and KOHBRA BRCA risk calculator (KOHCal) is utilized in the Asian model. However, it is unknown whether these mutation prediction models are useful in Japanese. In this study, we evaluated the accuracy of BRCAPRO, Myriad II and KOHCal in Japanese patients with breast cancer. METHODS We compared sensitivity and specificity with the 10% cut off value in 131 patients with breast cancer who underwent comprehensive BRCA1/2 genetic testing at Showa University Hospital between 2011 to 2014. All patients met the genetic testing criteria of NCCN Guidelines (Genetic/Familial High-Risk Assessment: Breast and Ovarian ver.1 2014) and were received counseling before genetic testing. We assessed validity of each model by constructing receiver operating characteristic (ROC) curves, and evaluating the area under each ROC curve (AUC). The carrier probabilities of BRCA1/2 with Myriad II were calculated using BRCA risk calculator from the Myriad company1), with BRCAPRO using the CancerGene software program (version 6.0) from the University of Texas South-western Medical Cernter2), and with KOHCal using KOHBRA BRCA risk calculator from the KOHBRA Study website (www.kohbra.kr)3). RESULTS DNA analysis identified 31 deleterious mutations (23.7%) and 10 unclassified variants (7.6%). The sensitivity of KOHcal (87.1%) was higher than BRCAPRO 67.7%) and Myriad II (72.2%) . BRCAPRO (AUC=0.882) had higher diagnostic accuracy than KOHCal (AUC=0.810) and Myriad II (AUC=0.763). KOHCal might be most suitable model to pick up patients for further genetic testing because its sensitivity was higher than Myriad II and BRCAPRO, although it had lower specificity than the other. CONCLUSION Our results suggest that BRCAPRO and KOHCal are useful in Japanese patients with breast cancer for decision making for further genetic testing for BRCA1/2 mutations.

A nomogram to predict nonsentinel lymph node involvement in breast cancer patients with sentinel lymph node metastases.

14 Background: Several nomograms have been described as predictors of non-sentinel axially lymph node (non-SN) metastases in breast cancer with positive sentinel nodes (SN). However, all these predicting models were based on data from western countries. The purpose of this study was to examine predictive factors of non-SN status among SN metastatic patients, in order to develop a nomogram based on Japanese large data set. METHODS This research was analyzed by using a clinical database of 11,228 Japanese breast cancer patients who registerd to cohort study as SN biopsy between March 2008 and Octover 2009 in Japan. We reviewed data retrospectively to extract patients with SN metastases who underwent complementary axillary lymph node dissection. In this cohort, we examined predictive factors of non-SN metastases. All clinical and pathologic features were analyzed to predict the non-SN status, by using univariate and multivariate logistic regression model. A receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated. RESULTS Among the database, SN metastases were found in 1,029 patients, and 345 (33.5%) were non-SN positive. Univariate analysis showed a significant association between non-SN involvement and primary tumor size (p<0.001), histologic grade (p=0.011), lymphatic invasion (p<0.001), venous invasion (p=0.005) and the number of involved SNs among all identified SNs (p<0.001). Tumor size (p<0.001), lymphatic invasion (p<0.001), and the size of SN metastasis (p<0.001) were associated with non-SN metastasis in multivariate analysis. Based on the multivariate analysis, we developed a scoring system to predict the likelihood of non-SN metastases in breast cancer patients with SN involvement. The discriminatory ability of our nomogram, as measured by the AUC, was 0.752. CONCLUSIONS In patients with invasive breast cancer and a positive SN, primary tumor size, lymphatic invasion, and the size of SN metastases among all identified SNs were independently predictive of non-SN involvement, and used for a nomogram. Validation study will be performed in the future investigation.