Summary Background Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus ...tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting. Methods In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1:1) to receive goserelin 3·6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov , number NCT00605267. Findings Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (anastrozole 70·4% 69 of 98 patients vs tamoxifen 50·5% 50 of 99 patients; estimated difference between groups 19·9%, 95% CI 6·5–33·3; p=0·004). Two patients in the anastrozole group had treatment-related grade 3 adverse events (arthralgia and syncope) and so did one patient in the tamoxifen group (depression). One serious adverse event was reported in the anastrozole group (benign neoplasm, not related to treatment), compared with none in the tamoxifen group. Interpretation Given its favourable risk–benefit profile, the combination of anastrozole plus goserelin could represent an alternative neoadjuvant treatment option for premenopausal women with early-stage breast cancer. Funding AstraZeneca.
Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We ...hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation.
Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold.
Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B.
Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced.
jRCT (Japan registry of clinical trials).
jRCTs031190154.
•We examined whether probiotic Bifidobacterium and TM would decrease AID frequency.•Probiotic Bifidobacterium and TM did not decrease the incidence of grade 2 or greater diarrhea.•The median duration of grade 2 diarrhea was 2 and 2.5 days in arms A and B; only one patient required dose reduction.
The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated.
...Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate.
A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025).
The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer.
Clinical Trial Registration: UMIN-CTR as UMIN000007074.
Background
The one-step nucleic acid amplification (OSNA) method can assess the expression level of cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer. We compared the time required for ...diagnosis and concordance of results between the OSNA method and conventional intraoperative pathological examination. We then examined the relationship between the frequency of non-sentinel lymph node metastasis and (1) the expression level of CK19 mRNA in the sentinel lymph nodes and (2) clinico-pathological features of the primary tumor.
Methods
In the comparison study, pairs of sentinel lymph node sections from 53 consecutive patients were examined: one section by hematoxylin-eosin staining and the other by OSNA assay. The latter involved reverse-transcription loop-mediated isothermal amplification of cytokeratin 19 mRNA, assessed quantitatively. In the second phase, 306 sentinel lymph nodes were removed from 248 consecutive patients, and whole sentinel lymph nodes were examined by OSNA assay alone.
Results
OSNA assay was a little more time-consuming than conventional pathological diagnosis (34–45 vs. 22–25 min,
p
< 0.0001). Concordance between the two methods was 93%. The frequency of non-sentinel lymph node metastasis (
p
< 0.0001) and the total number of lymph node metastases (
p
< 0.0001) increased with the amount of cytokeratin 19 mRNA on OSNA assay. We found no significant relationship between the amount of cytokeratin 19 mRNA in sentinel lymph nodes and breast cancer immunohistochemical subtype.
Conclusions
The OSNA method is suitable to detect sentinel lymph node metastasis and to predict the possibility of non-sentinel metastasis. This semi-automated quantitative analysis system reduces the burden on pathologists.
Purpose
Chemotherapy is the only current effective systemic treatment for triple-negative breast cancer (TNBC) patients. Therefore, the identification of active biological pathways that could become ...therapeutic targets is crucial. In this study, considering the well-reported biological roles of glucocorticoid and androgen receptors (GR, AR) in TNBC, we attempted to explore the effects of glucocorticoids (GCs) on cell kinetics as well as the potential interaction between GR and AR in TNBC.
Methods
We first explored the association between the status of GR, AR, and/or GCs-metabolizing enzymes such as 11β-hydroxysteroid dehydrogenase (11βHSD) 1 and 2 and the clinicopathological variables of the TNBC patients. Thereafter, we also studied the effects of dexamethasone (DEX) with/without dihydrotestosterone (DHT) on TNBC cell lines by assessing the cell proliferation, migration and GC response genes at the transcriptional level.
Results
GR positivity in carcinoma cells was significantly associated with adverse clinical outcome of the patients and AR positivity was significantly associated with lower histological grade and Ki-67 labeling index of the cases examined. In particular, AR positivity was significantly associated with decreased risks of developing recurrence in GR-positive TNBC patients. The subsequent in vitro studies revealed that DEX-promoted cell migration was inhibited by the co-treatment with DHT in GR/AR double-positive HCC38 cells. In addition, DHT inhibited the DEX-increased serum and glucocorticoid-regulated kinase-1 (SGK1) mRNA expression.
Conclusion
This is the first study to reveal that the interaction of GR and AR did influence the clinical outcome of TNBC patients and GCs induced cell migration in TNBC cells.
Background Radiotherapy (RT) following breast-conserving surgery (BCS) is mainly used to decrease the rate of ipsilateral breast tumor recurrence (IBTR) in women with breast ductal carcinoma in situ ...(DCIS). Recent studies have demonstrated that low-dose tamoxifen significantly reduces IBTR in breast DCIS. Here, we aim to determine whether the administration of low-dose tamoxifen is non-inferior to RT in preventing IBTR in patients with low-risk characteristics of breast DCIS. Methods/design This is a prospective, international, open-label, randomized, non-inferiority trial. Patients with low-risk clinicopathologic features (> 40 years old, low risk of breast cancer susceptibility gene (BRCA) 1 and BRCA2 mutations, mammographically detected unicentric and non-mass lesions, low- or intermediate-grade without comedo or necrosis, measuring < 2.5 cm with margins greater than or equal to 3 mm, and estrogen receptor-positive status) of DCIS who underwent BCS will be randomized at a 1:1 ratio to either receive tamoxifen (5 mg/day) for 5 years or undergo RT with conventional fractions (50 Gy in 25 fractions) or hypofractionations (40.05 Gy in 15 fractions). Randomization will be stratified by the Taiwan Breast Cancer Consortium. As approximately 5% of patients cannot tolerate the side effects of low-dose tamoxifen and will receive RT, we estimate that 405 patients will be randomized to a low-dose tamoxifen arm and 405 patients to the RT arm, according to a non-inferiority margin within 5% of IBTR difference and 90% beta-power noticing non-inferiority. The primary endpoints are breast tumor recurrence, including ipsilateral, regional, contralateral, and distant recurrence of breast DCIS or invasive cancer. The secondary endpoints are overall survival and adverse effects of RT and tamoxifen. Translational studies will also be conducted for this trial. Discussion This is the first non-inferiority trial on breast DCIS. This study will provide an important recommendation for clinical physicians on whether to use low-dose adjuvant tamoxifen for patients with low-risk breast DCIS who do not want to receive adjuvant RT. Trial registration ClinicalTrials.gov, ID: NCT04046159, Registered on April 30, 2019. Keywords: Ductal carcinoma in situ, Breast, Tamoxifen, Radiotherapy, Low-risk
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: The bone is the most frequent site of metastasis from breast cancer. However, evaluation for the response to systemic therapy in bone lesion is troublesome. The bone scan index ...(BSI) is a quantitative tool for improving the interpretability and clinical relevance of bone scans. The utility of the BSI is well studied in prostate cancer. In both hormone-sensitive and castration-resistant prostate cancer, the pre-treatment BSI is significantly correlated with overall survival. Moreover, patients with a lower BSI after endocrine therapy or chemotherapy exhibited better survival than those without a lower BSI. owever its utility for metastatic breast cancer is unknown. The purpose of this study was to investigate whether pretreatment BSI and treatment-related changes in BSI are related with prognosis and adverse events of breast cancer patients with bone metastasis. Patients and Methods: To evaluate the utility of BSI in patients with breast cancer and bone metastasis, we conducted a multi-institutional prospective cohort study. Key inclusion criteria are histologically or cytologically diagnosed breast cancer with bone metastasis, and less than 3 lines of systemic treatments. Primary endpoint is progression free survival (PFS), and the secondary endpoints are overall survaival (OS) and skeletal related events (SREs). Bone scintigraphy was performed at enrollment, 12 and 24 weeks after enrollment. BSI was calculated by determining the percentage of each bone that is involved by the tracer in relationship to the total skeletal mass, as determined from reference man, which is using the BONEVAVI® automated method (FUJIFILM RI Pharma Co., Ltd., Tokyo, Japan). All patients received standard medical treatment according to guidelines and bone modifying agent. A landmarking Cox model was used to predict PFS and OS by baseline and on-treatment BSI changes. Because on-treatment BSI changes could be observed 12 or 24 weeks, the origin of PFS/OS was set to 12 or 24 weeks and analysis set was defined those who are at risk at 12 or 24 weeks, respectively.Results:Between June 2015 and November 2017, a total of 153 patients from 19 centers were enrolled. The median age of was 63 years old interquartile range,(IQR): 54-70. All the patients had bone disease, 17 % (n=26) patients had lung and 5 % (n=7) had liver metastasis. The proportion of each intrinsic subtype was follows; luminal type; 84 % (n=125), luminal HER2 type; 6 % (n=9), HER2 type; 4 % (n=6), TN type; 6 % (n=9) and unknown; n=4. 71% (n=109) of the patients received endocrine therapy, 18% (n=27) received chemotherapy and 11% (n=17) received Anti-HER2 therapy. During the follow-up period (median: 22.5 month, IQR:16.8-29.5), 124 events of disease progression and 51 events of death were observed. The baseline BSI was merely associated with PFS hazard ratio (HR): 1.01, 95% CI: 0.93 to 1.09 and OS (HR: 1.07, 95%CI: 0.95 to 1.21). The change in BSI from baseline to 12 weeks were significantly correlated with PFS (HR, 1.25, 95% CI: 1.13 to 1.40) and OS (HR: 1.26, 95% CI: 1.08 to 1.47). Similarly, the change in BSI from baseline to 24 weeks on treatment prognosticated for PFS (HR: 1.32, 95% CI: 1.06 to 1.65) and OS (HR: 1.47, 95% CI: 1.11 to 1.95). Conclusion: This study is the first to report the clinical significance of evaluating BSI for metastatic breast cancer patients with bone metastasis. Changes in BSI from baseline to 12 weeks and 24 weeks predicts PFS and OS, which could help patients and physicians to guide treatment decision making.
Citation Format: Naoto Kondo, Yoichi Naito, Isao Yokota Yokota, Rikiya Nakamura, Yuichiro Kikawa, Hideki Maeda, Hiromitsu Akabane Akabane, Yasuaki Sagara Sagara, Tomohiko Aihara, Mina Takahashi, Yoko Ohtani, Shoichiro Ohtani, Hirofumi Mukai. Clinical utility of bone scan index (BSI) for breast cancer patients with bone metastasis -Multi-institutional prospective cohort study- abstract. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-03-02.
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
genotype ...and tamoxifen efficacy. Hence, we performed a prospective multicenter study to evaluate the clinical effect of
genotype on tamoxifen therapy.
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
on Ki-67 response, pathological response, and hot flushes.
Ki-67 labeling index in breast cancer tissues significantly decreased after preoperative tamoxifen monotherapy (
= 0.0000000000000013). Moreover, proportion and Allred scores of estrogen receptor-positive cells in breast cancer tissues were significantly associated with Ki-67 response (
= 0.0076 and 0.0023, respectively). Although
variants were not associated with pathologic response nor hot flushes, they showed significant association with Ki-67 response after preoperative tamoxifen therapy (
= 0.018; between two groups, one with at least one wild-type allele and the other without a wild-type allele).
This is the first prospective study evaluating the relationship between
variants and Ki-67 response after tamoxifen therapy. Our results suggest that genetic variation in
is a key predictor for the response to tamoxifen in patients with breast cancer.
.
Background
We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of ...postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS.
Patients and methods
We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records.
Results
We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio OR 1.8; 95% confidence interval CI 1.2–2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2–2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2–2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2–2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm.
Conclusion
We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.
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