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
Background:
Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor ...2 negative (HR+/HER2−) advanced breast cancer. New Adjuvant Trial with Ribociclib LEE011 (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2− early nonmetastatic breast cancer (EBC).
Methods/design:
NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2− EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day investigator’s discretion plus goserelin men or premenopausal women) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival.
Discussion:
The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2− EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment.
Trial registration:
ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334)
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. ...However, whether tumor‐draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up‐regulation of oncogenic Il‐17rb in cancer cells derived from TDLNs contributes to their malignancy. TGF‐β1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up‐regulation of Il‐17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF‐β1 neutralization or depletion of Tregs. Consistently, clinical data showed that the up‐regulation of IL‐17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL‐17RB expression could therefore be a potential approach to curb the process.
Synopsis
Treg‐secreted TGF‐β1 in the tumor‐draining LN (TDLN) microenvironment up‐regulates IL‐17RB expression in breast cancer cells, thereby enhancing their metastatic potential.
Breast cancer cells isolated from TDLN displayed aggressive phenotypes; removal of TDLN reduced distant organ metastasis.
Tregs in TDLN was the major cell type contributing to the enhanced malignancy of breast cancer cells.
TGF‐β1 secreted from Tregs in TDLN up‐regulated IL‐17RB expression in breast cancer cells.
Up‐regulation of IL‐17RB by TGF‐β1 occurred through Smad2/3/4 signal pathway.
Treg‐secreted TGF‐β1 in the tumor‐draining LN (TDLN) microenvironment up‐regulates IL‐17RB expression in breast cancer cells, thereby enhancing their metastatic potential.
Objectives
Breast cancer is the most common cancer among women in Taiwan, and treatment and coping with the disease become prominent features in a survivor’s life. Here, we examined Taiwanese ...survivors’ perceived causes of breast cancer, the influence of support networks on their perceptions, and the behavioral changes they made to prevent recurrences.
Methods
In this qualitative study, we used an explanatory approach involving semi-structured in-depth interviews based on grounded theory. We recruited (via physician referrals) 29 survivors aged ≥20 who had received their initial diagnosis at least 6 months earlier.
Results
Although the participants had made behavioral changes in many areas of their lives after diagnosis, most still believed that “stress and emotions” were the most crucial factor in causing cancer. They strongly emphasized reducing stress levels to prevent recurrences. However, when maintaining healthy behaviors became stressful, they chose to level off healthy lifestyles for the sake of their emotional well-being. They made career changes to improve their quality of life yet continued to experience a deep fear of recurrence. Adopting behavioral changes leading to healthy lifestyles and following regular follow-ups helped to reduce their anxiety concerning recurrence.
Conclusion
The participants’ behavioral changes were strongly associated with the perceived causes of cancer. Health-promotion programs aimed at breast cancer prevention should focus on participants’ subjective perception of the cause of cancer.
Purpose
In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor ...(HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative early stage breast cancer.
Methods
Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 #3 and shMAP3K1 #5). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0–3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort.
Results
In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%,
p
= 0.003) and overall survival (OS) (81.9% vs. 96.3%,
p
= 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK (
p
< 0.001) and phospho-JNK (
p
< 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS.
Conclusion
Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.
Purpose
Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with
BRCA
...mutations.
Methods
A total of 128 breast cancer patients with germline
BRCA
mutations and 4,754 control breast cancer patients were enrolled. Data on clinical–pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan–Meier method.
Results
The mean age of onset in
BRCA
mutation carriers was significantly younger than control patients (
BRCA
vs. Non-
BRCA
: 43.9 vs. 53.2 years old).
BRCA
mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%,
p
< 0.001). The risk of CBC was significantly higher in
BRCA
mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71–5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00–7.82) for
BRCA1
and 3.13 (1.78–5.49) for
BRCA2
carriers, respectively. Moreover,
BRCA1
mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29–9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients.
Conclusion
Our study suggest that
BRCA
patients had a significantly higher risk of developing CBC, particularly for
BRCA1
mutation carriers with TNBC as the first breast cancer.
Background.
A rapid surge of young‐female breast cancer (YFBC) has been observed in Taiwan and other East Asian countries. We recently reported that these cases of YFBC, in contrast to their Western ...counterparts, are predominantly luminal A subtype. YFBC in Asia may have distinct clinicopathological features and outcomes.
Methods.
Data collected prospectively by participating hospitals were retrieved from the Taiwan Cancer Database. A total of 15,881 women with newly diagnosed stage I–III breast cancer in 2002–2006 were included. The age at diagnosis was categorized into nine 5‐year groups (from <30 years to ≥65 years). Clinicopathological variables and patient disease‐free survival (DFS) were compared by age group.
Results.
The rates of stage I, estrogen receptor‐positive (ER+), and progesterone receptor‐positive breast cancer were higher in the younger patients (<50 years) than in the older patients (≥50 years). Univariate analysis showed that the 40–44 and 45–49 age groups were significantly associated with longer DFS than the other age groups. In the ER+ subgroup, multivariate analysis consistently showed that the 40–44 age group was significantly associated with longer DFS than the other age groups except for the 45–49 age group. In contrast, multivariate analysis of the ER‐negative subgroup revealed no significant difference of DFS between the 40–44 age group and other age groups.
Conclusion.
Emerging YFBC in Taiwan is uniquely associated with favorable pathological features and better outcomes and should not be regarded as the mirror image of its Western counterpart.
摘要
背景. 在台湾地区以及东亚其他地区已发现年轻女性乳腺癌（YFBC）迅速飙升。我们最近报告了与西方国家相比，东亚YFBC病例主要为luminal A亚型。亚洲YFBC可能具有独特的临床病理学特征以及疾病转归。
方法. 在台湾地区癌症数据库中进行检索，参与研究的医院前瞻性收集数据。共入组15 881例2002∼2006年新诊断的I∼III期乳腺癌女性。 确诊时年龄分成9组，每5岁为1个年龄组（<30岁∼ ≥65岁）。比较各年龄组的临床病理学变量与患者无疾病生存期（DFS）。
结果. 年轻患者（< 50岁）中I期、雌激素受体阳性（ER+）、孕激素受体阳性乳腺癌发生率高于年老患者（≥ 50岁）。单变量分析显示，40 ∼ 44岁与45 ∼ 49岁年龄组DFS显著长于其他年龄组。对于ER+亚型，多变量分析一致显示，除外45 ∼ 49岁年龄组，40 ∼ 44岁年龄组DFS显著长于其他年龄组。相反，对ER阴性亚型的多变量分析表明，40 ∼ 44岁年龄组DFS与其他年龄组之间差异无统计学意义。
结论. 台湾地区出现的YFBC病例具有良好的病理学特征以及更好的转归，不应与西方病例等同视之。The Oncologist 2014;19:583–591
A rapid surge of young‐female breast cancer (YFBC) has been observed in Taiwan and other East Asian countries. This study showed that emerging YFBC in Taiwan is uniquely associated with favorable pathological features and better outcomes and should not be regarded as the mirror image of its Western counterpart.
In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of ...HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT.
Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined.
T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab HR, 2.02; 95% confidence interval (CI), 1.32-3.11, but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples.
T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
Although the incidence of invasive breast cancer (BC) among women in Asian is generally lower than that in Western countries, the incidence of BC has been on the rise in the past three decades in ...Asian countries. This hospital-based case-control study aimed to explore the relationship between dietary and metabolic factors and BC risk in pre- and post-menopausal women. We enrolled 285 patients with newly diagnosed BC at the National Taiwan University Hospital and 297 controls from the local community and hospital staff. Before receiving anticancer therapy, all patients with BC and control participants completed a 57-question semi-quantitative Food Frequency Questionnaire. For pre-menopausal women, plant-based factor scores rich in seeds and nuts, soy, fruits, and seaweeds correlated significantly with reduced BC risks, whereas menarche occurring at <12 years of age, reduced physical activity, and high-density lipoprotein <40 mg/dL were associated with increased BC risks. For post-menopausal women, plant-based dietary factor scores were also associated with reduced risks, whereas increased body mass index and energy intake levels correlated with increased BC risks. Diets rich in plant-based dietary patterns are protective against BC risk, regardless of menopausal status. Habitual physical activity is protective against BC risk among pre-menopausal Taiwanese women. Maintaining optimal weight and caloric intake is beneficial for reducing post-menopausal BC risk.
Purpose:
A computer-aided detection (CADe) system based on quantitative tissue clustering algorithm was proposed to identify potential tumors in automated breast ultrasound (ABUS) images.
Methods:
...Our three-dimensional (3D) ABUS images database included 148 biopsy-verified lesions (size 0.4–7.9 cm; mean 1.76 cm). An ABUS volume was comprised of 229–282 slices of two-dimensional (2D) images. For tumor detection, the fast 3D mean shift method was used to remove the speckle noise and the segment tissues with similar properties. The hypoechogenic regions, i.e., the tumor candidates, were extracted using fuzzy c-means clustering. Seven features related to echogenicity and morphology were quantified and used to predict the likelihood of identifying a tumor and filtering out the false-positive (FP) regions.
Results:
The sensitivity of the proposed CADe system achieved 89.19% (132/148) with 2.00 FPs per volume. For the volumes without lesion, the FP rate was 1.27. The sensitivity was 92.50% (74/80) for malignant tumors and 85.29% (58/68) for benign tumors.
Conclusions:
The proposed CADe system provides an automatic and quantitative procedure for tumor detection in ABUS images. Further studies are needed to reduce the FP rate of the CADe algorithm.
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