Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation

IntroductionThe impact of selective surgical resection for patients with esophageal cancer treated with definitive chemoradiation has not been clearly evaluated long-term.MethodsNRG (National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, Gynecologic Oncology Group) Oncology Radiation Therapy Oncology Group 0246 was a multi-institutional, single-arm, open-label, nonrandomized phase II study that enrolled 43 patients from September 2003 to March 2008 with clinical stage T1–4N0–1M0 squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction from 19 sites. Patients received induction chemotherapy with fluorouracil (650 mg/m²/d), cisplatin (15 mg/m²/d), and paclitaxel (200 mg/m²/d) for two cycles followed by concurrent chemoradiation consisting of 50.4 Gy of radiation (1.8 Gy per fraction) and daily fluorouracil (300 mg/m²/d) with cisplatin (15 mg/m²/d) over the first 5 days. After definitive chemoradiation, patients were evaluated for residual disease. Selective esophagectomy was considered only for patients with residual disease after chemoradiation (clinical incomplete response) or recurrent disease on surveillance.ResultsThis report looks at the long-term outcome of this selective surgical strategy. With a median follow-up of 8.1 years (minimum to maximum for 12 alive patients 7.2–9.8 years), the estimated 5- and 7-year survival rates are 36.6% (95% confidence interval [CI]: 22.3–51.0) and 31.7% (95% CI: 18.3–46.0). Clinical complete response was achieved in 15 patients (37%), with 5- and 7-yearr survival rates of 53.3% (95% CI: 26.3–74.4) and 46.7% (95% CI: 21.2–68.7). Esophageal resection was not required in 20 of 41 patients (49%) on this trial.ConclusionsThe long-term results of NRG Oncology Radiation Therapy Oncology Group 0246 demonstrate promising efficacy of a selective surgical resection strategy and suggest the need for larger randomized studies to further evaluate this organ-preserving approach.     

Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity

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c‐Src inhibitor selectively inhibits triple‐negative breast cancer overexpressed Vimentin in vitro and in vivo

Oncogene c‐Src has been found to be a potential target for the treatment of triple‐negative breast cancer (TNBC). However, the therapeutic effects of the c‐Src inhibitor on TNBC patients are controversial compared to those on cell lines. The molecular mechanisms of the inhibitory effects of the c‐Src inhibitor on TNBC remain unclear. Herein, we showed that a specific c‐Src inhibitor, PP2, was effective in inhibiting phosphorylation of c‐Src in 4 cell lines: T‐47D, SK‐BR‐3, SUM1315MO2, and MDA‐MB‐231, regardless of hormone receptors and human epidermal growth factor receptor 2 (HER2) expression levels. Giving PP2 preferentially reduced the S phase of cell cycles and inhibited colony formation in SUM1315MO2 and MDA‐MB‐231, but not in SK‐BR‐3 and T‐47D cells. Furthermore, PP2 effectively blocked cell migration/invasion and epithelial‐mesenchymal transition (EMT) in TNBC cell lines, SUM1315MO2 and MDA‐MB‐231. An EMT biomarker, vimentin, was highly expressed in 2 TNBC cell lines when they were compared with SK‐BR‐3 and T‐47D cells. Further depletion of vimentin by shRNA remarkably attenuated the inhibitory effects of the c‐Src inhibitor on TNBC cells in vitro and in vivo, indicating a crucial action of vimentin to affect the function of c‐Src in TNBC. This study provides an important rationale for the clinic to precisely select TNBC patients who would benefit from c‐Src inhibitor treatment. This finding suggests that traditional markers for TNBC are not sufficient to precisely define this aggressive type of cancer. Vimentin is identified as an important biomarker to enable categorization of TNBC.     

The role of galectin-1 in in vitro and in vivo photodynamic therapy with a galactodendritic porphyrin

Conventional photodynamic agents used in clinic are porphyrin-based photosensitizers. However, they have low tumour selectivity, which may induce unwanted side-effects and damage to healthy tissues. In this study, we used a porphyrin with dendritic units of galactose (PorGal₈) developed by us, which can target the galactose-binding protein, galectin-1, known to be overexpressed in many tumour tissues. In vitro and in vivo studies had been conducted for the validation of PorGal₈ effectiveness. We showed a specific uptake of PorGal₈ and induction of apoptotic cell death by generating oxidative stress and alterations in the cytoskeleton of bladder cancer cells overexpressing galectin-1. We further validated the photodynamic efficiency of PorGal₈ in athymic nude mice (Balb/c nu/nu) bearing subcutaneously implanted luciferase-positive bladder cancer xenografts, overexpressing galectin-1 protein. PorGal₈ (5 μmol/kg, intraperitoneal), injected 24 h before light delivery (50.4 J/cm²), inhibited tumour growth. We conclude that the use of PorGal₈ enables selective target and cytotoxicity by photodynamic therapy in cancer cells overexpressing galectin-1, preventing undesired phototoxicity in the surrounding healthy tissues.     

Hypocrellin B‐loaded,folate‐conjugated polymeric micelle for intraperitoneal targeting of ovarian cancer in vitro and in vivo

Photodynamic therapy (PDT) is considered an innovative and attractive modality to treat ovarian cancer. In the present study, a biodegradable polymer poly (ethylene glycol) (PEG)‐poly (lactic acid)(PLA)‐folate (FA‐PEG‐PLA) was prepared in order to synthesize an active‐targeting, water‐soluble and pharmacomodulated photosensitizer nanocarrier. Drug‐loading content, encapsulation efficiency, in vitro and in vivo release were characterized, in which hypocrellin B (HB)/FA‐PEG‐PLA micelles had a high encapsulation efficiency and much slower control release for drugs compared to free drugs (P < .05). To evaluate the targeting ability of the HB/FA‐PEG‐PLA micelles, a cellular uptake study in vitro was carried out, which showed significantly enhanced uptake of HB/FA‐PEG‐PLA micelles in SKOV3 (FR+) compared to A2780 cancer cells (FR?). The enhanced uptake of HB/FA‐PEG‐PLA micelles to cancer cells resulted in a more effective post‐PDT killing of SKOV3 cells compared to plain micelles and free drugs. Binding and uptake of HB/FA‐PEG‐PLA micelles by SKOV3 cells were also observed in vivo after ip injection of folate‐targeted micelles in tumor‐bearing ascitic ovarian cancer animals. Drug levels in ascitic tumor tissues were increased 20‐fold (P < .001), which underscored the effect of a regional therapy approach with folate targeting. Furthermore, the HB‐loaded micelles were mainly distributed in kidney and liver (the main clearance organs) in biodistribution. These results showed that our newly developed PDT photosensitizer HB/FA‐PEG‐PLA micelles have a high drug‐loading capacity, good biocompatibility, controlled drug release, and enhanced targeting and antitumor effect, which is a potential approach to future targeting ovarian cancer therapy.     

Adenovirus vector-mediated upregulation of spermidine /spermine N1-acetyltransferase impairs human gastric cancer growth in vitro and in vivo

Spermidine/spermine N ¹-acetyltransferase (SSAT) is the rate-limiting step in polyamine catabolism. In a previous study, we constructed a recombinant adenovirus, Ad-SSAT, which can express human SSAT. In the present study, we investigated the effect of upregulated and downregulated SSAT on gastric cancer cells. We found that upregulated SSAT could inhibit the growth of MGC803 and SGC7901 cells, whereas adverse results were found with downregulated SSAT. We further analyzed cell cycle profiles and the expression levels of the major cell cycle regulatory proteins of S phase. The results showed that the growth inhibition was caused by S phase arrest. Ad-SSAT suppressed the expression of cyclin A and nuclear factor E2F1 in MGC803 and SGC7901 cells. We observed the E2F promoter activity caused by Ad-SSAT using a reporter gene assay. We also investigated the antitumorigenicity of upregulated SSAT by Ad-SSAT using a SGC7901 xenograft model in nude mice. Our results suggest that the upregulation of SSAT by Ad-SSAT infection inhibited the growth of gastric cancer in   vitro and in vivo . Ad-SSAT arrested gastric cancer cells in S phase, which was mediated through downregulation of the cyclin A-E2F signaling pathway. ( Cancer Sci 2009); 000: 000–000     

Cyclohexanone curcumin analogs inhibit the progression of castration‐resistant prostate cancer in vitro and in vivo

Many prostate cancer patients develop resistance to treatment called castration‐resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti‐metastasis properties and found that 2,6‐bis‐(4‐hydroxy‐3‐methoxy‐benzylidene)‐cyclohexanone (2A) and 2,6‐bis‐(3,4‐dihydroxy‐benzylidene)‐cyclohexanone (2F) showed higher anti‐invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP‐2 and MMP‐9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10‐bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo.     

Antitumor effect of focal adhesion kinase inhibitor PF562271 against human osteosarcoma in vitro and in vivo

Focal adhesion kinase (FAK) overexpression is related to invasive and metastatic properties in different kinds of cancers. Target therapy by inhibiting FAK has achieved promising effect in some cancer treatments, but its effect in human osteosarcoma has not been well studied. In the present study, we analyzed the antitumor efficacy of PF562271, an FAK inhibitor, against osteosarcoma in vitro and in vivo. Phosphorylated FAK (Y397) was highly expressed in primary human osteosarcoma tumor samples and was associated with osteosarcoma prognosis and lung metastasis. PF562271 greatly suppressed proliferation and colony formation in human osteosarcoma cell lines. In addition, treatment of osteosarcoma cell lines with PF562271 induced apoptosis and downregulated the activity of the protein kinase B/mammalian target of rapamycin pathway. PF562271 also impaired the tube formation ability of endothelial cells in vitro. Finally, oral treatment with PF562271 in mice dramatically reduced tumor volume, weight, and angiogenesis of osteosarcoma xenografts in vivo. These results indicate that FAK inhibitor PF562271 can potentially be effectively used for the treatment of osteosarcoma.     

Impact of Response to Prior Chemotherapy in Patients With Advanced Urothelial Carcinoma Receiving Second-Line Therapy: Implications for Trial Design

BackgroundThe prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown.MethodsSix phase II trials evaluating second-line therapy (n = 504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if Hb, LM, PS, and TFPC were available. Response by Response Evaluation Criteria in Solid Tumors 1.0 to first-line therapy was recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan–Meier method.ResultsA total of 275 patients were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo, or vinflunine (2 trials). Those with prior response (n = 111) had a median OS of 8.0 months (95% confidence interval [CI], 6.8-9.4), compared with 5.9 months (95% CI, 5.0-6.6) for those without prior response (n = 164). Those with prior response had a median PFS of 3.0 months (95% CI, 2.6-4.0) compared with 2.6 months (95% CI, 2.0-2.8) in patients without response. Multivariable analysis did not reveal a significant independent impact of prior response on PFS and OS.ConclusionsBest prior response in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Given that the setting of prior chemotherapy (metastatic or perioperative) has not appeared significant in a prior study, patients who received prior chemotherapy in perioperative or metastatic settings may be enrolled in the same second-line trial stratified for PS, Hb, LM, and TFPC.     

Histidine‐rich calcium binding protein promotes growth of hepatocellular carcinoma in vitro and in vivo

We have recently shown that the histidine‐rich calcium binding protein (HRC) promotes the invasion and metastasis of hepatocellular carcinoma (HCC). In the current study, we evaluated whether HRC may also affect the growth of HCC. We found that ectopic expression of HRC obviously enhanced proliferation and colony formation, while suppression of HRC exhibited inhibitory effects. Furthermore, we demonstrated that HRC promoted tumor growth in nude mice. These effects may result from the ability of HRC to upregulate cyclinD1 and cyclin‐dependent kinase 2 (CDK2) expressions and promote G1/S transition. Further study showed that MEK/ERK signaling pathway was involved in HRC‐induced cell proliferation. Interestingly, overexpression or depletion of HRC revealed its regulation on endoplasmic reticulum stress (ERS) and apoptosis, which was partially dependent on PERK/ATF4/CHOP signaling pathway. In addition, blocking ERS using 4‐phenylbutyric acid (4‐PBA) not only downregulated the expression of PERK, ATF4 and CHOP, but also significantly decreased apoptosis induced by HRC silence, whereas ERS inducer thapsigargin (TG) exerted the opposite effects. Our study thus demonstrates a role of HRC in promoting HCC growth, besides its role in inducing HCC metastasis, and highlights HRC as a promising intervention target for HCC.     

Comparison of Segmentectomy and Lobectomy in Stage IA Adenocarcinomas

IntroductionRecent studies have suggested that segmentectomy may be an acceptable alternative treatment to lobectomy for surgical management of smaller lung adenocarcinomas. The objective of this study was to compare survival after lobectomy and segmentectomy among patients with pathological stage IA adenocarcinoma categorized as stage T1b (>0 to ≤20 mm) according to the new eighth edition of the TNM system.MethodsIn total, 7989 patients were identified from the Surveillance, Epidemiology, and End Results registry. Propensity scores generated from logistic regression on preoperative characteristics were used to balance the selection bias of undergoing segmentectomy. Overall and lung cancer–specific survival rates of patients undergoing segmentectomy and lobectomy were compared in propensity score–matched groups.ResultsOverall, 564 patients (7.1%) underwent segmentectomy. Lobectomy led to better overall and lung cancer–specific survival than segmentectomy for the entire cohort (log-rank p < 0.01). After 1:2 propensity score matching, segmentectomy (n = 552) was no longer associated with significantly worse overall survival (5-year survival = 74.45% versus 76.67%, hazard ratio = 1.09, 95% confidence interval: 0.90–1.33) or lung cancer–specific survival (5-year survival = 83.89% versus 86.11%, hazard ratio = 1.12, 95% confidence interval: 0.86–1.46) compared with lobectomy (n = 1085) after adjustment for age, sex, lymph node quantity, and histological subtype. Similar negative findings were identified when patients were stratified according to sex, age, histological subtype, and number of evaluated lymph nodes.ConclusionsPatients who underwent segmentectomy may have survival outcomes no different than those of some patients who received lobectomy for pathological stage IA adenocarcinomas at least 10 but no larger than 20 mm in size. These results should be further confirmed through prospective randomized trials.     

Efficacy and Safety of Anti–PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF,HER2, or MET Mutations or RET Translocation: GFPC 01-2018

IntroductionImmune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting.MethodsIn this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).ResultsThere were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were never-smokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6–not reached [NR]) months, 4.7 (95% CI: 2.3–7.4) months, and 16.2 (95% CI: 12.0–24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF–non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2–NR) and 4.3 (95% CI: 2.1–8.5) months, respectively, and OS was 11.7 (95% CI: 4.1–NR) and 35.8 (95% CI: 9.0–35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three.ConclusionsIn this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.     

Erratum zu: „Translationale Forschung – eine nationale Herausforderung“

best practice onkologie - Ein Erratum zu dieser Publikation wurde veröffentlicht: https://doi.org/10.1007/s11654-020-00250-3     

Selective NTPDase2 expression modulates in vivo rat glioma growth

The ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) are a family of ectoenzymes that hydrolyze extracellular nucleotides, thereby modulating purinergic signaling. Gliomas have low expression of all E-NTPDases, particularly NTPDase2, when compared to astrocytes in culture. Nucleotides induce glioma proliferation and ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of glioma cultures. We have previously shown that the co-injection of apyrase with gliomas decreases glioma progression. Here, we tested whether selective re-establishment of NTPDase2 expression would affect glioma growth. NTPDase2 overexpression in C6 glioma cells had no effect on in vitro proliferation but dramatically increased tumor growth and malignant characteristics in vivo . Additionally, a sizable platelet sequestration in the tumor area and an increase in CD31 or platelet/endothelial cell adhesion molecule-1 (PECAM-1), vascular endothelial growth factor and OX-42 immunostaining were observed in C6-Enhanced Yellow Fluorescent Protein (EYFP)/NTPDase2-derived gliomas when compared to controls. Treatment with clopidogrel, a P2Y₁₂ antagonist with anti-platelet properties, decreased these parameters to control levels. These data suggest that the ADP derived from NTPDase2 activity stimulates platelet migration to the tumor area and that NTPDase2, by regulating angiogenesis and inflammation, seems to play an important role in tumor progression. In conclusion, our results point to the involvement of purinergic signaling in glioma progression. ( Cancer Sci 2009)     

MR susceptibility imaging for detection of tumor-associated macrophages in glioblastoma

Journal of Neuro-Oncology - Tumor-associated macrophages (TAMs) are a key component of glioblastoma (GBM) microenvironment. Considering the differential role of different TAM phenotypes in iron...     

Rethinking end-points for bone-targeted therapy in advanced cancer

The principal objective for any medical therapy is to improve either the duration of life and/or its quality. Metastases in bone can lead to clinically defined events termed skeletal-related events (SREs) which are a quantifiable measure of skeletal morbidity. Avoidance and/or delay of SREs have become the principal objective in trials exploring the efficacy of bone-targeted therapy in patients with skeletal metastases. Despite reductions in the frequency or rate of SRE occurrence, trials of bone-targeted therapy have failed to show any effect on either progression-free or overall survival when compared with placebo or other bone-targeting agents. Similarly, trials of bone-targeted therapy have not shown consistent effects on quality of life. The validity of SRE-based primary outcome measures in cancer clinical trials is therefore, questionable. More novel end-point selection for trials of bone-targeted therapy seems warranted. Composite measures comprising occurrence of symptomatic skeletal events and patient reported outcomes may be an effective solution and warrants further investigation.     

Tumor Cells Modulate Macrophage Phenotype in a Novel In Vitro Co-Culture Model of the NSCLC Tumor Microenvironment

IntroductionMacrophage phenotype in the tumor microenvironment correlates with prognosis in NSCLC. Immunosuppressive macrophages promote tumor progression, whereas proinflammatory macrophages may drive an antitumor immune response. How individual NSCLCs affect macrophage phenotype is a major knowledge gap.MethodsTo systematically study the impact of lung cancer cells on macrophage phenotypes, we developed an in vitro co-culture model that consisted of molecularly and clinically annotated patient-derived NSCLC lines, human cancer-associated fibroblasts, and murine macrophages. Induced macrophage phenotype was studied through quantitative real-time polymerase chain reaction and validated in vivo using NSCLC xenografts through quantitative immunohistochemistry and clinically with The Cancer Genome Atlas (TCGA)–“matched” patient tumors.ResultsA total of 72 NSCLC cell lines were studied. The most frequent highly induced macrophage-related gene was Arginase-1, reflecting an immunosuppressive M2-like phenotype. This was independent of multiple clinicopathologic factors, which also did not affect M2:M1 ratios in matched TCGA samples. In vivo, xenograft tumors established from high Arginase-1–inducing lines (Arg^hi) had a significantly elevated density of Arg1+ macrophages. Matched TCGA clinical samples to Arg^hi NSCLC lines had a significantly higher ratio of M2:M1 macrophages (p = 0.0361).ConclusionsIn our in vitro co-culture model, a large panel of patient-derived NSCLC lines most frequently induced high-expression Arginase-1 in co-cultured mouse macrophages, independent of major clinicopathologic and oncogenotype-related factors. Arg^hi cluster-matched TCGA tumors contained a higher ratio of M2:M1 macrophages. Thus, this in vitro model reproducibly characterizes how individual NSCLC modulates macrophage phenotype, correlates with macrophage polarization in clinical samples, and can serve as an accessible platform for further investigation of macrophage-specific therapeutic strategies.     

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort

AimAdjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.MethodsA population combining patients from Protocol for Herceptin^® as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan–Meier method, and comparisons between groups were based on the log rank test.ResultsThe SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86–1.19) and similar DFS (HR = 1.08; 95% CI: 0.96–1.21).ConclusionThese results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.