Publications by authors named "Junji Tsurutani"

119 Publications

Antibiotic Usage Reduced Overall Survival by over 70% in Non-small Cell Lung Cancer Patients on Anti-PD-1 Immunotherapy.

Anticancer Res 2021 Oct;41(10):4985-4993

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background/aim: There is an increasing use of immunotherapy for non-small cell lung cancer (NSCLC) patients. The present study analysed the effect of antibiotic use on the outcome of NSCLC patients undergoing treatment with anti-programmed cell death-1 (anti-PD-1) immunotherapy.

Patients And Methods: This was a retrospective study of 69 NSCLC patients. Eighteen out of 69 patients received antibiotics within 21 days before or within 21 days after start of anti-PD-1 therapy.

Results: Patients treated with anti-PD-1 antibodies receiving antibiotics had greatly decreased objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) compared to those who did not use antibiotics. Multivariate analysis showed that antibiotic treatment of patients on anti-PD-1 antibody therapy was an independent negative predictive factor of PFS; however, it was not a significant independent predictive factor of OS.

Conclusion: Use of antibiotics within 21 days before and after anti-PD-1 treatment initiation in patients with NSCLC strongly reduced OS and PFS, suggesting the two treatments should not be combined.
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http://dx.doi.org/10.21873/anticanres.15312DOI Listing
October 2021

Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka-shi 541-8567, Osaka, Japan.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab-paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m/day on days 1-21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab-paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0-11.8} months) than in group E (4.3 {3.6-6.0} months) (hazard ratio, 0.53; < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.
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http://dx.doi.org/10.3390/cancers13174399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430728PMC
August 2021

Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

Breast Cancer 2021 Sep 7. Epub 2021 Sep 7.

Breast Oncology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: To report our findings on quality of life (QoL) in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with metastatic breast cancer (MBC).

Methods: Patients with HER2-negative MBC were randomly assigned to three different doses of q3w nab-PTX (SD 260 mg/m vs. MD: 220 mg/m vs. LD 180 mg/m). QoL was assessed at baseline and during the second, fourth and sixth courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were performed with mixed-model repeated measures (MMRM).

Results: A total of 141 patients were enrolled in the parent study, and 136 (96%) (44, 45 and 47 in the SD, MD, and LD groups) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD vs. SD P < 0.001, LD vs. SD P < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (P = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD vs. SD P = 0.011, LD vs. SD P < 0.001).

Conclusion: QoL of patients treated with 220 or 180 mg/m of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m.

Trial Registration: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN000015516), on 01/11/2014. Details are available at the following address: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017916.
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http://dx.doi.org/10.1007/s12282-021-01290-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421464PMC
September 2021

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

Medicine (Baltimore) 2021 Jun;100(23):e25774

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine.

Introduction: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.

Patients Concerns: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.

Diagnosis: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.

Interventions: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.

Outcomes: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.

Conclusion: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
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http://dx.doi.org/10.1097/MD.0000000000025774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202549PMC
June 2021

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

In Vivo 2021 May-Jun;35(3):1865-1875

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background/aim: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing.

Patients And Methods: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared.

Results: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio.

Conclusion: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.
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http://dx.doi.org/10.21873/invivo.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193338PMC
June 2021

A Correlation Analysis Between Metabolism-related Genes and Treatment Response to S-1 as First-line Chemotherapy for Metastatic Breast Cancer: The SELECT BC-EURECA Study.

Clin Breast Cancer 2021 Oct 1;21(5):450-457. Epub 2021 Feb 1.

National Cancer Center Hospital East, Kashiwa, Japan.

Introduction: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure.

Conclusion: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.
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http://dx.doi.org/10.1016/j.clbc.2021.01.018DOI Listing
October 2021

Indices of peripheral leukocytes predict longer overall survival in breast cancer patients on eribulin in Japan.

Breast Cancer 2021 Jul 7;28(4):945-955. Epub 2021 Mar 7.

Advanced Cancer Translational Research Institute, Showa University, Shinagawa-ku, Tokyo, Japan.

Background: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin.

Methods: This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan-Meier method, with the cut-off value of 1500/μL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3.

Results: The median OS was longer in patients with an ALC of ≥ 1500/μL than in those with an ALC of < 1500/μL (19.4 vs. 14.3 months; hazard ratio [HR]: 0.628; 95% confidence interval [CI]: 0.492, 0.801). Patients with an NLR of ≥ 3 showed shorter OS than those with an NLR of < 3 (13.2 vs. 18.8 months; HR: 1.552; 95% CI 1.254, 1.921), and NLR also separated OS in patients with an ALC of < 1500/μL.

Conclusions: Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.
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http://dx.doi.org/10.1007/s12282-021-01232-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213560PMC
July 2021

The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer.

Pancreas 2021 02;50(2):167-175

Division of Medical Oncology, Department of Medicine, School of Medicine.

Objectives: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection.

Methods: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves.

Results: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes.

Conclusions: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.
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http://dx.doi.org/10.1097/MPA.0000000000001731DOI Listing
February 2021

Novel Anti-FOLR1 Antibody-Drug Conjugate MORAb-202 in Breast Cancer and Non-Small Cell Lung Cancer Cells.

Antibodies (Basel) 2021 Feb 1;10(1). Epub 2021 Feb 1.

Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.

Antibody-drug conjugates (ADCs), which are currently being developed, may become promising cancer therapeutics. Folate receptor α (FOLR1), a glycosylphosphatidylinositol-anchored membrane protein, is an attractive target of ADCs, as it is largely absent from normal tissues but is overexpressed in malignant tumors of epithelial origin, including ovarian, lung, and breast cancer. In this study, we tested the effects of novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 in breast cancer and non-small cell lung cancer (NSCLC) cell lines. FOLR1 expression, cell proliferation, bystander killing effects, and apoptosis were evaluated in seven breast cancer and nine NSCLC cell lines treated with MORAb-202. Tumor growth and FOLR1 expression were assessed in T47D and MCF7 orthotopic xenograft mouse models after a single intravenous administration of MORAb-202 (5 mg/kg). MORAb-202 was associated with inhibited cell proliferation, with specific selectivity toward FOLR1-expressing breast cancer cell lines. Eribulin, the payload of MORAb-202, was unleashed in HCC1954 cells, diffused into intercellular spaces, and then killed the non-FOLR1-expressing MCF7 cells in co-culture systems. In orthotopic xenograft mouse models, FOLR1-expressing T47D tumors and non-FOLR1-expressing MCF7 tumors were suppressed upon MORAb-202 administration. The novel anti-FOLR1 antibody-eribulin conjugate MORAb-202 has potential antitumor effects in breast cancer.
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http://dx.doi.org/10.3390/antib10010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930947PMC
February 2021

Characteristics of interstitial lung disease in patients from post-marketing data on metastatic breast cancer patients who received abemaciclib in Japan.

Breast Cancer 2021 May 16;28(3):710-719. Epub 2021 Jan 16.

Kobe City Medical Center General Hospital, Kobe, Japan.

Background: This study evaluated characteristics of patients treated with abemaciclib and diagnosed with interstitial lung disease (ILD), using 12-month post-marketing data from the real-world setting in Japan.

Methods: Spontaneous reports of adverse events in patients receiving abemaciclib were collected regularly from healthcare providers (HCPs) from November 30, 2018, to November 29, 2019. Detailed follow-up was requested on suspected ILD cases via questionnaires and/or interviews. Radiological images (when available) were reviewed by an ILD adjudication committee of specialists. The age distribution of patients prescribed abemaciclib in Japan was estimated based on insurance claims data.

Results: Of 4700 patients estimated to be exposed to abemaciclib, 82 cases of ILD were reported (46 serious, 13 fatal). Most (91%) had ≥ 1 symptom at diagnosis, commonly dyspnea/shortness of breath (59%), cough (44%), and/or fever (37%). The majority (68%) received steroid therapy (24 [56%] recovered/recovering; 5 [12%] not recovered; 13 [30%] deaths, 1 [2.3%] unknown). No specific imaging patterns or sites of predilection were identified, but a diffuse alveolar damage (DAD) pattern was observed at outcome in 3 of 4 evaluated fatal cases (16 in total evaluated). Features of fatal cases included advanced age, pre-existing interstitial change, and advanced Eastern Cooperative Oncology Group Performance Status.

Conclusion: Advanced age and a DAD pattern were identified as potential risk factors for cases with poorer outcomes, as previously reported for drug-induced ILD. HCPs should consider the benefit-risk profile when prescribing abemaciclib, informing patients of risks and regularly monitoring treated patients to ensure early detection and treatment of ILD.
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http://dx.doi.org/10.1007/s12282-020-01207-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064939PMC
May 2021

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Int J Oncol 2021 01 12;58(1):57-69. Epub 2020 Nov 12.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance‑related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient‑derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next‑generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug‑treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan‑Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.
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http://dx.doi.org/10.3892/ijo.2020.5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721086PMC
January 2021

Randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer.

Breast 2021 Feb 9;55:63-68. Epub 2020 Dec 9.

National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Background: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin-bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX.

Methods: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m [SD260] vs Medium: 220 mg/m [MD220] vs Low: 180 mg/m [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was <0.75 or >1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded.

Results: One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42-1.28) in MD220 vs SD260, 0.77 (95% CI 0.47-1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56-1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180.

Conclusions: Intravenous administration of low-dose nab-PTX at 180 mg/m q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC.
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http://dx.doi.org/10.1016/j.breast.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753189PMC
February 2021

BRCAness as a prognostic indicator in patients with early breast cancer.

Sci Rep 2020 12 3;10(1):21173. Epub 2020 Dec 3.

The Third Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Huanhu West Road, Hexi District, Tianjin, China.

BRCAness is defined as a phenotypic copy of germline BRCA mutations, which describes presence of homologous recombination defects in sporadic cancers. We detected BRCAness by multiplex ligation-dependent probe amplification (MLPA) and explored whether BRCAness can be used as a predictor of prognosis. BRCAness status was classified for total 121 breast cancer patients. Forty-eight patients (39.7%) were identified as BRCAness positive. Tumors of BRCAness were more likely to be hormone receptors negative (95.8% vs. 50.7%, P < 0.001), nuclear grade III (76.1% vs. 48.4%, P = 0.001) and triple-negative breast cancer subtype (91.6% vs. 42.5%, P < 0.001). Five-year disease free survival (DFS) (54.0% vs. 88.0%, P < 0.001) and overall survival (OS) (76.3% vs. 93.1%, P = 0.002) were significantly lower in BRCAness patients. In neoadjuvant chemotherapy subgroup analysis, clinical response rate for taxane-based regimen was significantly lower in BRCAness patients (58.3% vs. 77.8%, P = 0.041). Cox regression multivariate analysis showed that BRCAness was the independent prognostic factor for DFS (HR 2.962, 95%CI 1.184-7.412, P = 0.020), but not for OS (HR 2.681, 95%CI 0.618-11.630, P = 0.188). BRCAness is associated with specific characteristics and may suggest resistance to taxane-based chemotherapy. BRCAness can be used as a negative prognostic indicator for breast cancer.
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http://dx.doi.org/10.1038/s41598-020-78016-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713365PMC
December 2020

HER2-D16 oncogenic driver mutation confers osimertinib resistance in EGFR mutation-positive non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):2178-2183

Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.21037/tlcr-20-578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653124PMC
October 2020

A high number of PD-L1 CD14 monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Feb 5;70(2):337-348. Epub 2020 Aug 5.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.

Purpose: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies.

Patients And Methods: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3, CD4, CD8, CD45RA and CCR7 T cells; CD20 B cells; CD14 and CD16 monocytes were measured via flow cytometry before treatment. The percentages of PD-L1 cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed.

Results: The percentages of PD-L1 with CD3, CD4 and CD8 T cells including naïve and memory T cell subsets, or CD20 B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1 CD14 monocyte subset was significantly correlated with OS (p = 0.0426).

Conclusion: Increase in pretreatment expression levels of PD-L1 on CD14 monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.
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http://dx.doi.org/10.1007/s00262-020-02686-6DOI Listing
February 2021

Reply to T.J.A. Dekker.

J Clin Oncol 2020 10 13;38(28):3351-3352. Epub 2020 Jul 13.

Shanu Modi, MD, Memorial Sloan Kettering Cancer Center, New York, NY; Haeseong Park, MD, MPH, Washington University School of Medicine, St Louis, MO; Rashmi K. Murthy, MD, MBE, University of Texas MD Anderson Cancer Center, Houston, TX; Hiroji Iwata, PhD, MD, Aichi Cancer Center Hospital, Nagoya, Japan; Kenji Tamura, MD, PhD, National Cancer Center Hospital, Tokyo, Japan; Junji Tsurutani, MD, PhD, Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan and Kindai University Faculty of Medicine, Osaka, Japan; Alvaro Moreno-Aspitia, MD, Mayo Clinic, Jacksonville, FL; Toshihiko Doi, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan; Yasuaki Sagara, MD, Social Medical Corporation Hakuaikai Sagara Hospital, Kagoshima, Japan; Charles Redfern, MD, Sharp HealthCare, San Diego, CA; Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute, Boston, MA; Caleb Lee, MD, PhD, Daiichi Sankyo, Basking Ridge, NJ; Yoshihiko Fujisaki, MS and Masahiro Sugihara, PhD, Daiichi Sankyo, Tokyo, Japan; Lin Zhang, MD, PhD and Javad Shahidi, MD, Daiichi Sankyo, Basking Ridge, NJ; and Shunji Takahashi MD, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1200/JCO.20.01212DOI Listing
October 2020

High expression levels of polymeric immunoglobulin receptor are correlated with chemoresistance and poor prognosis in pancreatic cancer.

Oncol Rep 2020 Jul 11;44(1):252-262. Epub 2020 May 11.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer has extremely poor prognosis, warranting the discovery of novel therapeutic and prognostic markers. The expression of polymeric immunoglobulin receptor (pIgR), a key component of the mucosal immune system, is increased in several cancers. However, its clinical relevance in pancreatic cancer remains unclear. In the present study, the prognostic value of pIgR in pancreatic cancer patients after surgical resection was assessed and it was determined that the expression of pIgR was correlated with poor prognosis. Ten pancreatic cancer patient‑derived xenograft (PDX) lines were established, followed by next‑generation sequencing of tumor tissues from these lines after standard chemotherapy. Immunohistochemical analysis of chemoresistance‑related molecules using 77 pancreatic cancer tissues was also performed. The expression of pIgR mRNA in the PDX group treated with anticancer drugs was higher than in the untreated group. High pIgR expression in tissue specimens from 77 pancreatic cancer patients was significantly associated with poor prognosis and was revealed to be an independent prognostic factor, predicting poor outcomes. High pIgR mRNA and protein levels were independent prognostic factors, indicating that pIgR could be a novel predictor for poor prognosis of pancreatic cancer patients.
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http://dx.doi.org/10.3892/or.2020.7610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251687PMC
July 2020

[Evaluation of the Benefits of Administering Hand Therapy to Patients with Chemotherapy-Induced Peripheral Neuropathy].

Gan To Kagaku Ryoho 2020 May;47(5):783-788

Dept. of Pharmacology, School of Medicine, Showa University.

Taxanes, which are used to treat breast cancer, damage the microtubules of normal nerve cells, causing numbness of the fingers related to chemotherapy-induced peripheral neuropathy(CIPN); therefore, effective methods for reducing numbness are needed. In 2017, it was reported that physical stimuli related to massage improved finger blood flow volumes, contributing to the regeneration of damaged nerves. We developed a method of hand therapy for breast cancer patients complaining of numbness related to anticancer drug administration, and examined its effects on numbness. Hand therapy was performed by a single therapist who received lectures at the Sophia Phytotherapy College, which is accredited by the Japan Handcare Association. The fingertips to wrist, ankle, metacarpal bones, palm, and elbow were massaged using the bilateral arms/fingers for 15minutes. We investigated the influences of daily living status(Support Team Assessment Sched- ule-Japan: STAS-J), age, body mass index(BMI), severity/site of numbness, type of numbness, type of drug, duration of breast cancer, duration of numbness, and presence or absence of lymph node dissection, and evaluated the severity of numbness using a 10-cm Visual Analog Scale(VAS). The study included 51 breast cancer patients complaining of numbness of the fingers, with a mean age of 59 years. In patients with relatively mild numbness(STAS-J 1), the VAS scores before and after hand therapy were 4.7±1.8 and 1.9±1.3, respectively, showing a marked decrease. In STAS-J 2 patients, the values were 4.9 ±1.4 and 2.1±1.3, respectively, also showing a marked decrease. Thus, this hand therapy reduced numbness in mild- and moderate-status patients. Statistical comparisons were performed between the STAS-J 1/2(mild/moderate numbness)and STAS-J 3/4(severe numbness)groups. Although the severity of numbness was not correlated with age, BMI, type of drug, lymph node dissection, or duration of breast cancer, the proportion of patients with a B1-year history of numbness was significantly larger in the STAS-J 1/2 group. The most frequent site of numbness was from the proximal interphalangeal joints to the fingertips. Concerning the severity of numbness, many patients complained of severe numbness, as represented by that after sitting straight. These results suggest that this hand therapy is effective for reducing numbness in patients receiving taxanes and complaining of mild to moderate numbness.
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May 2020

Trastuzumab, pertuzumab, and eribulin mesylate versus trastuzumab, pertuzumab, and a taxane as a first-line or second-line treatment for HER2-positive, locally advanced or metastatic breast cancer: study protocol for a randomized controlled, non-inferiority, phase III trial in Japan (JBCRG-M06/EMERALD).

Trials 2020 May 7;21(1):391. Epub 2020 May 7.

Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake Koto-ku, Tokyo, 135-8550, Japan.

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade.

Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m on days 1 and 8) or taxane (docetaxel 75 mg/m on day 1 or paclitaxel 80 mg/m on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested.

Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 mBC in Japan.

Trial Registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.
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http://dx.doi.org/10.1186/s13063-020-04341-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206765PMC
May 2020

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Breast Cancer 2020 May 2;27(3):322-331. Epub 2020 Apr 2.

Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.

Purpose: We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Methods: The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting.

Results: The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ.

Conclusion: The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.
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http://dx.doi.org/10.1007/s12282-020-01085-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062371PMC
May 2020

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.

Cancer Discov 2020 05 25;10(5):688-701. Epub 2020 Mar 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or -mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In -mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and -mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or -mutant solid tumors, especially -mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292921PMC
May 2020

HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers.

Cancer Discov 2020 05 25;10(5):674-687. Epub 2020 Mar 25.

mProbe Inc., Rockville, Maryland.

Amplification of and oncogenic mutations in , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196485PMC
May 2020

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study.

J Clin Oncol 2020 06 14;38(17):1887-1896. Epub 2020 Feb 14.

The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Purpose: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported.

Patients And Methods: Eligible patients had advanced/metastatic HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed.

Results: Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd-induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee.

Conclusion: The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.
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http://dx.doi.org/10.1200/JCO.19.02318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280051PMC
June 2020

Effectiveness and safety of eribulin in Japanese patients with HER2-negative, advanced breast cancer: a 2-year post-marketing observational study in a real-world setting.

Invest New Drugs 2020 10 16;38(5):1540-1549. Epub 2020 Jan 16.

Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.

Background Data on eribulin as the first- or second-line treatment in a clinical setting, especially the overall survival (OS) of patients, are scarce. Therefore, we assessed the effectiveness and safety of eribulin as the first-, second-, and third- or later-line treatments in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in Japan. Methods This multicenter, prospective, post-marketing, observational study enrolled patients from September 2014 to February 2016 in Japan and followed them for 2 years. Patients were categorized by eribulin use into the first-, second-, and third- or later-line treatment groups. Results Of 651 registered patients, 637 patients were included in the safety and effectiveness analysis. In all, first-, second-, and third or later-line treatment groups, median OS (95% confidence interval) were 15.6 (13.8-17.6), 22.8 (17.3-31.0), 16.3 (12.4-19.9), and 12.6 (11.2-15.1) months and time to treatment failure (TTF) (95% confidence interval) were 4.2 (3.7-4.4), 5.2 (3.7-5.9), 4.2 (3.7-5.1), and 3.8 (3.5-4.2) months, respectively. Prolonged TTF was associated with complications of diabetes and the development of peripheral neuropathy after eribulin treatment, according to multivariate Cox regression analysis. Grade ≥ 3 adverse drug reactions (ADRs) were reported in 61.7% of the patients. Neutropenia (49.5%) was the most common grade ≥ 3 ADR in all groups. Conclusions The effectiveness and safety results of eribulin as the first- or second-line treatment were favorable. Thus, these suggest eribulin may be a first-line treatment candidate for patients with HER2-negative advanced breast cancer in Japan.
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http://dx.doi.org/10.1007/s10637-019-00890-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497681PMC
October 2020

High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer.

PLoS One 2020 10;15(1):e0226707. Epub 2020 Jan 10.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology & Therapeutics, Showa University, Tokyo, Japan.

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor predicting poor outcomes. Overall, our study revealed that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor in pancreatic cancer. OLFM4 may be a candidate therapeutic target in pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953839PMC
April 2020

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.

N Engl J Med 2020 02 11;382(7):610-621. Epub 2019 Dec 11.

From Memorial Sloan Kettering Cancer Center, New York (S.M.); Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (C.S., J.C.), and IOB Institute of Oncology, Quiron Group, Barcelona and Madrid (J.C.); Kanagawa Cancer Center, Yokohama (T.Y.), National Cancer Center Hospital (K.T.), the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (Y.I.), and the Advanced Cancer Translational Research Institute, Showa University (J.T.), Tokyo, Aichi Cancer Center Hospital, Nagoya (H.I.), Kindai University Faculty of Medicine, Osaka (J.T.), Shikoku Cancer Center, Matsuyama (K.A.), and the National Hospital Organization Kyushu Cancer Center, Fukuoka (E.T.) - all in Japan; Samsung Medical Center (Y.H.P.), Asan Medical Center, University of Ulsan College of Medicine (S.-B.K.), Yonsei Cancer Center, Yonsei University Health System (J. Sohn), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (S.-A.I.), Seoul, and the National Cancer Center, Gyeonggi (K.S.L.) - all in South Korea; Institut Gustave Roussy, Université Paris-Sud, Villejuif (F.A.), and Centre Eugène Marquis, Rennes (C.P.) - both in France; the US Oncology Network, Virginia Cancer Specialists, Arlington (N.D.); the University of California, Los Angeles-Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H.); Daiichi Sankyo, Basking Ridge, NJ (C.L., S.C., L.Z., J. Shahidi, A.Y.); and the Dana-Farber Cancer Institute, Boston (I.K.).

Background: 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.

Methods: 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.

Results: 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%).

Conclusions: 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.).
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http://dx.doi.org/10.1056/NEJMoa1914510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458671PMC
February 2020

Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study.

J Clin Oncol 2020 02 10;38(6):558-566. Epub 2019 Dec 10.

Keio University School of Medicine, Tokyo, Japan.

Purpose: In patients taking tamoxifen, the genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome.

Methods: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes.

Results: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM 51.1 nM; < .0001) and were also higher compared with wt/wt patients (72.0 nM; = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months ( = .43).

Conclusion: In patients with -variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The genotype solely cannot explain individual variability in the efficacy of tamoxifen.
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http://dx.doi.org/10.1200/JCO.19.01412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030889PMC
February 2020
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