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.

Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer.

PURPOSE: This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide. RESULTS: Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C max and AUC (0-t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t last) increased 2.5-fold after both doses under fed conditions. CONCLUSIONS: Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients.

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.

Can we improve breast cancer mortality in Okinawa? Consensus of the 7th Okinawa Breast Oncology Meeting.

The rate of breast cancer mortality in Okinawa has gradually been increasing up to 2010. Now Okinawa has the second worst mortality rate in Japan, in part due to the enormous dietary changes resulting from the post-World War II US military occupation, high incidence of obesity, high non-optimal treatment rate, and low breast-cancer screening rate. To reduce breast cancer mortality in Okinawa, we established the Okinawa Breast Oncology Meeting (OBOM) in 2012. At the 7th OBOM held on January 10th, 2014, we discussed the breast cancer mortality in Okinawa focusing on lifestyle, breast cancer screening and optimal treatments. The Okinawan women who were overweight and/or obese during premenopausal and postmenopausal ages had a statistically significant higher risk of breast cancer development compared to those with non-overweight and/or obese women. The traditional diet of Okinawa consists of foods low in calories but rich in nutritional value. Therefore, we recommend Okinawan people not to forget the Okinawan traditional lifestyle, and to reduce their bodyweight to prevent breast cancer. One of the main goals of the OBOM is to raise breast cancer screening attendance rates to 50% (29.2% in 2010). We should standardize the quality control for breast cancer screening in Okinawa. It is important to continue enlightening the Okinawan population to receive optimal treatment. In addition, we are striving to establish systematic medical cooperation between the hospitals specializing in breast cancer treatment with rural hospitals. The OBOM group endeavors to contribute to the improvement of breast cancer mortality in Okinawa.

A new scarless oncoplastic breast-conserving surgery: modified round block technique.

Round block technique (RBT) is often utilized in breast-conserving surgery, but has problems of late-onset scar widening and changes in the shape or the position of the areola. We have modified RBT (MRBT) to resolve those problems. A circumferential incision was made without excision of the periareolar skin, and subcutaneous dissection was extended to the entire breast. The wound could be widened and moved onto the distant tumor by application of a wound retractor. Partial mastectomy was then performed under direct vision. The wound was easily closed without tension. Forty breast cancer patients were treated with MRBT. The median distance between the nipple and the tumor was 5.2 cm, and the median areolar size was 2.8 cm. Cosmetic results were satisfactory with minimal scar formation. There were neither subsequent changes in the shape nor the position of the areola. MRBT is a useful oncoplastic technique in patients with small areolae, and/or when the tumor location is distant from the nipple.

The challenge to reduce breast cancer mortality in Okinawa: consensus of the first Okinawa breast oncology meeting.

Breast cancer mortality is gradually increasing in Okinawa. The 1st Okinawa Breast Oncology Meeting was held on 6 July 2012 and discussions on how to curb the rising trend were focused on breast cancer screening, adjuvant treatment, socioeconomic and geographic issues, and the problem of complementary and alternative medicine. The consensus of the 1st Okinawa Breast Oncology Meeting was that ultrasonography screening is an acceptable screening system for Okinawan women because of the geographic disadvantage of having many small islands and rural areas. Educational and economic support is needed for women in rural areas to get correct information, for access to urban areas and to be treated by evidence-based optimal therapy for breast cancer. In addition, new approaches are needed for Okinawan people to successfully educate patients to correctly interpret evidence-based information.

Breast conserving surgery using the round block technique combined with partial reconstruction using the latissimus dorsi flap.

The round block technique (RBT) is one of the frequently used volume displacement procedures in oncoplastic breast surgery. We report a useful technique which combines RBT with immediate partial breast reconstruction using the latissimus dorsi flap (LD flap) for breast-conserving surgery (BCS). A wide oval periareolar wound allows both resection of a large amount of a breast tissue and reconstructive procedures using the LD flap, which ultimately results in a minimal periareolar scar and a good cosmetic result. This combined technique may provide BCS with increasing indications and better cosmesis.

Free omental flap for partial breast reconstruction after breast-conserving surgery.

UNLABELLED: Recent advances in endoscopic surgery have allowed laparoscopic harvesting of the omental flap with reduced donor-site morbidity and deformity. Between August of 2004 and May of 2010, the authors performed immediate breast reconstruction with the free omental flap in 10 breast cancer patients, employing it either as a pedicle flap or as a free flap for volume replacement. Only one complication occurred during the follow-up. Cosmetic results were mostly satisfactory. The free omental flap is a safe procedure with minimal donor-site morbidity and deformity and can be an additional option for immediate partial breast reconstruction after breast-conserving surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Pyogenic vertebral osteomyelitis in a breast cancer patient: report of a case.

We herein report a rare case of pyogenic vertebral osteomyelitis (PVO) coexisting with breast carcinoma. A 71-year-old female presented with neck pain without fever. Magnetic resonance imaging (MRI) showed suspected metastatic lesions in her neck (C7 and Th1). Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) showed increased FDG uptake in the neck spines and in the left breast. A core needle biopsy of the left breast revealed the presence of invasive ductal carcinoma. Our first tentative diagnosis of the patient was left breast carcinoma with bone metastases, and first-line endocrine therapy was started. However, surgical intervention for the spines had to be considered, because her neurological symptoms progressed. A repeated MRI scan showed a narrowing of the disc space and fluid accumulation around the vertebrae. This suggested the presence of PVO rather than metastases. Surgery confirmed the presence of PVO in C7 and Th1, and a culture of the abscess yielded Escherichia coli. The patient's neurological symptoms dramatically improved after surgery. Breast conserving surgery was performed 3 months after the surgery for PVO. The patient is well and has no clinical evidence of disease 18 months after the breast conserving surgery. PVO is rare, but should be included in the differential diagnosis in patients presenting with early breast carcinoma.