Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.
Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval CI, 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).
Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).
DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity ...during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS.
This review summarizes how DNA replication stress is induced and determines the cell destiny in the process of tumor development. This review also explains how cancer therapeutic drugs exploit the stress in malignant tumors.
Topochemical synthesis of gold nanoparticles (AuNPs) was achieved on crystalline cellulose single nanofibers (CSNFs), which were tailored from native cellulose. Exposed AuNPs@CSNFs composite ...exhibited an excellent catalytic efficiency: the turnover frequency of the AuNPs@CSNFs was up to 840 times that of conventional polymer-supported AuNPs, for a model aqueous reduction reaction. Our novel strategy provides a promising solution to realize efficient use of limited noble metals using natural bioresources.
Single-walled carbon nanotubes (SWNTs), especially their semiconducting type, are promising thermoelectric (TE) materials due to their high Seebeck coefficient. In this study, the in-plane Seebeck ...coefficient (S), electrical conductivity (σ), and thermal conductivity (κ) of sorted semiconducting SWNT (s-SWNT) free-standing sheets with different s-SWNT purities are measured to determine the figure of merit ZT. We find that the ZT value of the sheets increases with increasing s-SWNT purity, mainly due to an increase in Seebeck coefficient while the thermal conductivity remaining constant, which experimentally proved the superiority of the high purity s-SWNT as TE materials for the first time. In addition, from the comparison between sorted and unsorted SWNT sheets, it is recognized that the difference of ZT between unsorted SWNT and high-purity s-SWNT sheet is not remarkable, which suggests the control of carrier density is necessary to further clarify the superiority of SWNT sorting for TE applications.
This study aimed to develop a questionnaire on the quality of working life among female medical and healthcare professionals and examine its validity and reliability. The questionnaire was developed ...from an item pool drawing on the literature. The four trait scales included 40 items, covering female-specific stress in continuing a career, stress of lifestyle in maintaining personal values, job satisfaction and social support network. The questionnaire’s validity and reliability were assessed using data from 1,784 female doctors, dentists, and nurses. Validity was examined using exploratory factor analysis on each trait for construct validity, and multitrait scaling analysis for convergent and discriminant validity. Reliability was tested using Cronbach’s alpha for trait subscales and scales. Exploratory factor analysis on each trait was convergent. One trait derived three subscales, and another two. The remaining two traits were convergent for one factor. Multitrait scaling analysis showed that all scales and subscales were independent. The questionnaire was therefore internally consistent and had construct validity. Cronbach’s alpha was 0.85 for the total and between 0.72 and 0.83 for the subscales. These results validate the four-trait combination questionnaire and suggest that it would be suitable for use in future research, perhaps in combination with other existing scales.
Purpose
Addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) has improved pathological complete response (pCR) rates in previous studies. We ...present long-term survival outcomes (disease-free survival DFS, pre-planned secondary endpoint; overall survival OS, post hoc exploratory endpoint) of our randomized study of the addition of CBDCA to NAC for HER2-negative breast cancer.
Methods
Patients with stage II/III, HER2-negative breast cancer (
N
= 179) were randomly assigned to receive CP–CEF (four 3-week cycles of CBDCA area under the curve, 5 mg/mL/min, day 1 and weekly paclitaxel wPTX, 80 mg/m
2
, day 1, 8, 15 followed by four 3-week cycles of cyclophosphamide, epirubicin, and 5-fluorouracil CEF, 500/100/500 mg/m
2
) or P–CEF (four cycles of wPTX followed by four cycles of CEF) as NAC. DFS and OS were analyzed at each population of pCR status and assigned treatment arm.
Results
Of 179 patients, 154 were available for long-term follow-up. At a median follow-up of 6.6 years (range, 0.7–8.0 years), patients who achieved pCR
n
= 42, 23.5% (CP–CEF:
n
= 28, P–CEF:
n
= 16) had longer DFS and OS than non-pCR patients DFS; HR 0.15 (0.04–0.61),
P
= 0.008, OS; log-rank
P
= 0.003. Addition of carboplatin to NAC significantly improved DFS and OS in the subset of patients with TNBC DFS: HR, 0.22 (0.06–0.82),
P
= 0.015; OS: HR, 0.12 (0.01–0.96),
P
= 0.046, but not in the subset of patients with hormone receptor-positive disease or among all patients.
Conclusions
Addition of carboplatin to neoadjuvant chemotherapy significantly improved DFS and OS in patients with TNBC but not in those with hormone receptor-positive, HER2-negative breast cancer.
Breast cancer is a heterogeneous disease. Approximately 70% of breast cancers are estrogen receptor (ER) positive. Endocrine therapy has dramatically improved the prognosis of ER‐positive breast ...cancer; however, many tumors exhibit de novo or acquired resistance to endocrine therapy. A thorough understanding of the molecular mechanisms regulating hormone sensitivity or resistance is important to improve the efficacy of and overcome the resistance to endocrine therapy. The growth factor receptor signaling pathways, particularly the phosphatidylinositol 3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway can mediate resistance to all forms of endocrine therapy. In contrast, FOXA1 transcription factor is a key determinant of ER function and endocrine response. Intriguingly, a link between hormone resistance induced by the PI3K/Akt/mTOR pathway and the function of FOXA1 has been suggested. In this review, we focus on the PI3K/Akt/mTOR pathway and functions of FOXA1 in terms of the molecular mechanisms regulating the hormone sensitivity of breast cancer.
Endocrine therapy has dramatically improved the prognosis of ER‐positive breast cancer, however, many tumors exhibit de novo or acquired resistance to endocrine therapy. A thorough understanding of the molecular mechanisms regulating hormone sensitivity or resistance is important to improve the efficacy of and overcome the resistance to endocrine therapy. In this review, we focus on the PI3K/Akt/mTOR pathway and functions of FOXA1 in terms of the molecular mechanisms regulating the hormone sensitivity of breast cancer.
Purpose
The aim of this study was to investigate whether young age at onset of breast cancer is an independent prognostic factor in patients from the Japanese Breast Cancer Registry, after adjustment ...of known clinicopathological prognostic factors.
Methods
Of the 53,670 patients registered between 2004 and 2006 and surveyed after a 5-year follow-up prognosis, 25,898 breast cancer patients (48.3 %), who were obtained prognostic data, were examined. Clinicopathological factors were compared between young adult (YA; <35 years), middle-aged adult (MA; 35–50 years), and older adult (OA; >50 years) patients. Five-year disease-
free
survival (DFS) and overall survival (OS) rates were studied.
Results
YA patients were associated with an advanced TNM stage and aggressive characteristics (e.g. human epidermal growth factor receptor 2 (HER2)-positive or oestrogen receptor (ER)-negative breast cancers) compared to MA and OA patients (
P
< 0.001). The 5-year DFS and OS rates were 79.4 % and 90.8, 88.5 and 95.0 %, and 87.8 % and 91.6 % for YA, MA, and OA patients, respectively. From the multivariable regression analysis, young age at onset was confirmed as an independent prognostic factor for both DFS (hazard ratio 1.73, 95 % confidence interval 1.42–2.10;
P
< 0.001) and OS (hazard ratio 1.58, 95 % confidence interval 1.16–2.15;
P
= 0.004).
Conclusions
Young age at onset is an independent negative prognostic factor in breast cancer. Further studies are required to develop new therapeutic strategies for YA breast cancer patients.
Abstract Background The association between Axl and vimentin protein expression has been observed in several cell lines. However, the clinical importance of Axl and vimentin expression in breast ...cancer have not been fully determined. Patients and Methods The expressions of Axl and vimentin were evaluated by immunohistochemistry in a total of 343 patients with invasive ductal carcinoma. The relationships between expression of Axl and vimentin and clinicopathological characteristics and prognosis were analyzed. Results Axl expression was classified into high (n = 170) and low (n = 173) expression groups. Axl expression alone was not associated with any clinicopathological factor or prognosis. Coexistence of vimentin-positive and Axl-high expression was observed in 10.5 % (n = 36). Vimentin-positive and Axl-high tumors were associated with triple-negative breast cancers ( P = .0396), and poor prognosis in terms of both recurrence-free survival (RFS, P = .0126) and overall survival (OS, P = .0005) when compared with the other group including vimentin-positive and Axl-low tumors, vimentin-negative and Axl-high tumors, and vimentin-negative and Axl-low tumors. Multivariate analysis showed that coexistence of vimentin-positive and Axl-high expression was an independent poor prognostic factor for RFS (hazard ratio (HR) 2.78, 95% CI 1.23–5.68, P = .0158) and OS (HR 3.72, 95% CI 1.51–8.47, P = .0059). Conclusion Coexistence of vimentin-positive and Axl-high expression is a poor prognostic factor for primary breast cancer. Vimentin and Axl expression might contribute to the aggressive phenotype in breast cancer.
Young breast cancer survivors have specific needs related to age. Clarifying the relationships between unmet information needs and quality of life (QOL) in young breast cancer survivors can ...contribute to constructing a support system to enhance QOL in patients.
This study aimed to identify the unmet information needs and examine the relationships between unmet information needs and QOL in young breast cancer survivors in Japan.
Participants completed an information needs questionnaire containing 26 items, the World Health Organization Quality of Life Instrument-Short Form (WHOQOL-BREF), and a demographic and medical information questionnaire.
Fifty participants (30.7%) were unsatisfied with "overall communication with medical professionals." The mean scores on all subscales of the WHOQOL-BREF of the participants who were satisfied with "overall communication with medical professionals" were significantly higher than those of the unsatisfied group. "follow-up tests," "treatment for recurrence of breast cancer," "strategies about communication with medical staff," and "nutrition" were significantly related with all subscales in the WHOQOL-BREF. "Secondary menopause caused by hormonal therapy" was significantly related with physical and psychological health.
Japanese young breast cancer survivors have unmet information needs, including age-specific issues. These unmet information needs are related to QOL. In particular, "overall communication with medical professionals," which is the most unmet information need, is related to QOL.
Oncology nurses should teach patients communication skills, provide adequate information, and provide education and emotional support to medical professionals to improve QOL in young breast cancer survivors.
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