Purpose: Trastuzumab has been administered to HER2-positive breast or gastric cancer patients as an effective treatment, however, the cardiotoxicity is identified as one of the life-threatening side effects. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a genome-wide association study (GWAS).Experimental Design: We carried out a GWAS using 11 cases (with trastuzumab-induced cardiotoxicity) and 257 controls (showing no sign of trastuzumab-induced cardiotoxicity). Top 100 single nucleotide polymorphisms (SNPs) which revealed smallest P value in GWAS (P = 1.61 x 10-7 -1.97 x 10-4) were further examined using replication samples consisted of 14 cases and 199 controls. Results: The combined analysis of the GWAS and replication study indicated possible association of five loci with trastuzumab-induced cardiotoxicity (chromosome 13q14.3, 4q25, 15q26.3, 17q25.3 and another 15q26.3, Pcombined = 6.00 x 10-6, 8.60 x 10-5, 1.01 x 10-4, 1.07 x 10-4, 1.60 x 10-4, respectively). Furthermore, we developed a risk prediction model for trastuzumab-induced cardiotoxicity, using five SNPs which revealed smallest P value at each locus. The incidence of trastuzumab-induced cardiotoxicity in patients with risk score ≥5 was 42.5% (P =8.69 x 10-15) . This scoring system using five candidate loci could be used to predict the risk of the adverse event before administration of trastuzumab.Conclusion: We identified five novel loci, which could be associated with trastuzumab-induced cardiotoxicity. These findings provide new insights into personalized trastuzumab therapy for patients with HER2-positive cancer.Citation Format: Chihiro Udagawa, Mari Hara, Arata Shimo, Yasuyuki Kojima, Reiko Yoshie, Hisamitsu Zaha, Norie Abe, Tokiwa Motonari, Mikiko Unesoko, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Hiroshi Okamura, Taisei Mushiroda, Koichiro Tsugawa, Hitoshi Zembutsu. A genome-wide association study identifies five novel genetic markers for trastuzumab-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2951.
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.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.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.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.
Malignant fungating tumors are neoplastic tumors associated with skin ulcers, which are susceptible to microbial colonization. Bacterial infection and proliferation may lead to malodor causing distress to patients. Metronidazole—an effective agent against anaerobes—may contribute to deodorization and improvement in quality of life (QOL). This study investigated the efficacy and safety of topical metronidazole 0.75 % gel for alleviation of malodor in anaerobically infected fungating neoplastic tumors. This was a multicenter, open-label, non-controlled, phase III study including subjects aged 20 years or older with cutaneous fungating tumors releasing malodor (minimum score of 2 (mildly offensive smell) on a scale from 0 (no smell) to 4 (extremely offensive smell) based on investigator's assessment). Subjects applied metronidazole 0.75 % gel once or twice daily at the investigator's discretion for 14 days. Success was defined as an odor score of 0 or 1 at day 14, as assessed by the investigator. Patient satisfaction was assessed using a satisfaction questionnaire. Adverse events (AEs) that occurred after application of metronidazole 0.75 % gel were also reported. A total of 21 subjects at a median age of 65.0 years were enrolled. The success rate of deodorization at day 14 was 95.2 % (20/21 subjects). The patient satisfaction assessment showed that 71.4 % (15/21) of subjects were markedly or moderately improved. The treatment was well tolerated with only two AE cases of skin neoplasm bleeding (one mild and one moderate). Metronidazole 0.75 % gel is an effective and safe treatment for deodorization of malodorous fungating tumors.
Background: The purpose of this retrospective study was to investigate the predictive ability of the Ki67 labeling index (LI) for relapse-free survival (RFS) of patients with stage I-II invasive breast cancer after breast-conserving therapy.Materials and methods: Between 2012 and 2016, 240 patients with stage I-II invasive breast cancer were treated at our hospital with breast-conserving therapy. Survival outcomes were analyzed using the Kaplan-Meier and cumulative incidence methods. Factors including T stage, N stage, estrogen receptor, HER2, and Ki67 LI were evaluated with regard to RFS using Cox proportional hazard regression.Results: The median duration of follow-up in the surviving patients was 36 months (range, 14–62 months). Rates of 3-year overall survival and RFS were 98.1% and 96.4%, respectively. Three-year cumulative rates of local recurrence, regional recurrence, and distant metastasis were 1.3%, 1.2%, and 2.1%, respectively. Multivariate analysis revealed that a Ki67 LI ≥33.3% was the only prognostic factor for RFS.Conclusion: A Ki67 LI ≥33.3% was a predictor of significantly worse RFS.
Abstract 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.
To elucidate molecular mechanisms of mammary carcinogenesis and discover novel therapeutic targets for breast cancer, we previously carried out a genome‐wide expression profile analysis of 81 breast cancer cases by means of a combination of cDNA microarray and laser microbeam microdissection. Among the upregulated genes, we focused on the functional significance of protein regulator of cytokinesis 1 ( PRC1 ) in the development of breast cancer. Western blot analysis using breast cancer cell lines revealed a significant increase in endogenous PRC1 levels in G 2 /M phase. Treatment of breast cancer cells with small interfering RNA against PRC1 effectively suppressed its expression and inhibited the growth of breast cancer cell lines T47D and HBC5. Furthermore, we found an interaction between PRC1 and kinesin family member 2C/mitotic centromere‐associated kinesin (KIF2C/MCAK) by coimmunoprecipitation and immunoblotting using COS‐7 cells, in which these molecules were introduced exogenously. These findings suggest the involvement of a PRC1–KIF2C/MCAK complex in breast tumorigenesis, and this complex should be a promising target for the development of novel treatments for breast cancer. ( Cancer Sci 2007; 98: 174–181)
Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (Pcombined = 4.92 × 10-5 and 5.50 × 10-5, respectively). These data suggest that rs8032978 and rs7406710 could be predictive markers of trastuzumab-induced cardiotoxicity in Japanese and Singaporean populations, and support their potential use in clinical risk assessment. These findings offer a first step toward the development of clinically available markers for the potential risk of trastuzumab-induced cardiotoxicity as well as an improved understanding of the pathogenesis of this complication.
We investigated factors related to the recurrence and prognosis of patients with triple-negative breast cancer (TNBC)after neoadjuvant chemotherapy(NAC). Of the 545 patients who underwent surgery after NAC between January 2013 and December 2016, 131 patients had TNBC. An analysis of each TNBC case indicated that the presence or absence of clinical lymph node metastasis(cN)before treatment might be a predictive factor of prognosis. There were 57(43.5%)pathological complete response(pCR)(ypT0 or ypTis/N0)cases after NAC. Overall survival(OS)and disease free survival(DFS) were significantly better in pCR cases than in non-pCR cases. However, recurrence was observed in 8 of 57(14%)pCR cases and 29 of 74(39%)non-pCR cases. The factors defining DFS from the univariate analysis of the non-pCR group were cN, ypT, ypN, and vascular invasion. The multivariate analysis of these factors suggested that residual cN and vascular invasion might be independent factors predicting DFS. Residual vascular invasion was found to predict OS, and was considered to be a poor prognostic factor.
