Trop-2 expression and the tumor immune microenvironment in cervical cancer.

OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.

Lymphocyte-to-monocyte ratio as a prognostic and potential tumor microenvironment indicator in advanced soft tissue sarcoma treated with first-line doxorubicin therapy.

Prognostic value of hematologic indices and their association with the tumor microenvironment (TME) remain unclear in advanced soft tissue sarcoma (STS). We aimed to evaluate their prognostic value and correlation with the TME status in advanced STS treated with first-line doxorubicin (DXR) therapy. Clinical data and three hematological indices, including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were collected from 149 patients with advanced STS. The TME status was pathologically examined by CD3, CD68, and CD20 staining of resected tumor slides. In a multivariate Cox analysis, low LMR and absence of primary tumor resection were independently associated with worse overall survival (OS) (HR 3.93, p = 0.001; HR 1.71, p = 0.03). A prognostic model using these variables predicted OS with greater area under curves than those obtained using Systemic Inflammatory Score and Glasgow Prognostic Score. The LMR significantly correlated with the tumoral CD3/CD68-positive cell ratio in surgical specimens (R = 0.959, p = 0.04). In conclusion, LMR was a prognostic factor in advanced STS treated with first-line DXR therapy. LMR could partially reflect anti-tumor immunity in the TME and have the prognostic value. The potential role of LMR as an indicator of TME status warrants further investigation.

Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study.

Intimal sarcoma is an extremely rare, life-threatening malignant neoplasm. Murine double minute 2 (MDM2) amplification is observed in >70% of intimal sarcomas. Milademetan, an MDM2 inhibitor, may provide clinical benefit in this patient population. We conducted a phase Ib/II study in patients with MDM2-amplified, wild-type TP53 intimal sarcoma as a substudy of a large nationwide registry for rare cancers in Japan. Milademetan (260 mg) was administered orally once daily for 3 days every 14 days, twice in a 28-day cycle. Of 11 patients enrolled, 10 were included in the efficacy analysis. Two patients (20%) showed durable responses for >15 months. Antitumor activity correlated with TWIST1 amplification (P = 0.028) and negatively with CDKN2A loss (P = 0.071). Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma. SIGNIFICANCE: Strategies to optimize outcomes could include the use of new biomarkers (TWIST1 amplification and CDKN2A loss) to select patients with MDM2-amplified intimal sarcoma who might benefit from milademetan and combination with other targeted treatments. Sequential liquid biopsy of TP53 can be used to evaluate disease status during treatment with milademetan. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.

Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is negative for hormone receptors and human epidermal growth factor receptor 2 (HER2). In stage I TNBC, adjuvant therapy or follow-up are performed according to risk factors, but clinical trial data is scarce. In recent years, it has been reported that HER2-low cases (1+/2+ and in situ hybridization negative) have different prognoses than HER2-0 cases. However, the risk of recurrence and risk factors in this HER2-low population for stage I TNBC have not yet been investigated. Methods: Herein, out of 174 patients with TNBC who underwent surgery from June 2004 to December 2009 at the National Cancer Center Hospital (Tokyo), we retrospectively examined 42 cases diagnosed as T1N0M0 TNBC after excluding those treated with preoperative chemotherapy. Results: All patients were female, the median age was 60.5 years, and 11 cases were HER2-low and 31 cases were HER2-0. The median follow-up period was 121 months. Postoperative adjuvant therapy was administered in 30 patients and recurrence occurred in 8 patients. HER2-low cases showed a significantly shorter disease-free survival (HR: 7.0; 95% CI: 1.2- 40.2; P=0.0016) and a trend towards shorter overall survival (hazard ratio [HR]: 4.2, 95% confidence interval [CI]: 0.58-31.4) compared with that of HER2-0 cases. HER2 was also identified as a factor for poor prognosis from the point- estimated values in univariate and multivariate analyses after confirming that there was no correlation between the other factors. Conclusion: For patients with stage I TNBC, the HER2-low population had a significantly worse prognosis than the HER2-0 population.

A new era of the Asian clinical research network: a report from the ATLAS international symposium.

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia.

Molecular pathology quality control in Southeast Asia: Results of a multiregional quality assurance study from MASTER KEY Asia.

Tissue specimen quality assurance is a major issue of precision medicine for rare cancers. However, the laboratory standards and quality of pathological specimens prepared in Asian hospitals remain unknown. To understand the methods in Southeast Asian oncology hospitals and to clarify how pre-analytics affect the quality of formalin-fixed paraffin-embedded (FFPE) specimens, a questionnaire surveying pre-analytical procedures (Part I) was administered, quality assessment of immunohistochemistry (IHC) staining and DNA/RNA extracted from the representative FFPE specimens from each hospital (Part II) was conducted, and the quality of DNA/RNA extracted from FFPE of rare-cancer patients for genomic sequencing (Part III) was examined. Quality measurements for DNA/RNA included ΔΔCt, DV200, and cDNA yield. Six major cancer hospitals from Malaysia, Philippines, and Vietnam participated. One hospital showed unacceptable quality for the DNA/RNA assessment, but improved by revising laboratory procedures. Only 57% (n = 73) of the 128 rare-cancer patients' specimens met both DNA and RNA quality criteria for next-generation sequencing. Median DV200 was 80.7% and 64.3% for qualified and failed RNA, respectively. Median ΔΔCt was 1.25 for qualified and 4.89 for failed DNA. Longer storage period was significantly associated with poor DNA (fail to qualify ratio = 1579:321 days, p < 0.001) and RNA (fail to qualify ratio = 1070:280 days, p < 0.001). After improvement of pre-analytical factors, the qualification rate increased for hospitals A and E from 41.5% to 70.5% and 62.5% to 86%, respectively. This is the first report to elucidate the pre-analytical laboratory procedures of main Southeast Asian oncology hospitals. An external quality assessment program may improve factors associated with tumor FFPE specimen quality.

High mesothelin expression is correlated with non-squamous cell histology and poor survival in cervical cancer: a retrospective study.

BACKGROUND: Mesothelin (MSLN) is a cell-surface glycoprotein found in various solid tumours. Cancer therapies targeting MSLN have been developed in recent years; however, the available information on MSLN expression in cervical cancer is limited. This study aimed to evaluate MSLN expression in various histological types of cervical cancer and examine its relationship with prognosis. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between January 2000 and December 2020 at our institution. MSLN expression was evaluated by immunohistochemistry using clone SP74 and defined as positive if MSLN was expressed at any intensity. High MSLN expression was defined as an intensity of ≥ 2 + in ≥ 30% of tumour cells. The association between MSLN expression and clinicopathological factors was evaluated. RESULTS: Overall, 123 patients were identified, and 140 tumour samples, including 17 paired primary and metastatic samples, were evaluated. Concerning histological type, 67 patients had squamous cell carcinoma (SCC), whereas 56 had non-SCC. MSLN expression was observed in 98.4% (121/123) of primary tumours. High MSLN expression was observed in 63.4% of samples (78/123), but it differed between the histological types (49.2% for SCC vs. 80.4% for non-SCC, p < 0.001). There was a significant correlation between MSLN expression in primary and metastatic lesions (Rs = 0.557, p = 0.015). In patients with common histological types, overall survival (OS) was shorter in the high MSLN expression group than in the low MSLN expression group (hazard ratio, 3.53; 95% confidence interval, 1.16-15.3, p = 0.03). CONCLUSIONS: MSLN was highly expressed in patients with cervical cancer, especially in those with non-SCC. High MSLN expression in the primary lesion was significantly associated with poor OS, and its expression was maintained in metastatic lesions. Our findings indicate that MSLN may be an attractive therapeutic target for cervical cancer. TRIAL REGISTRATION: Retrospectively registered. 2014-393. 1 June 2015.

High expression of folate receptor alpha is associated with poor prognosis in patients with cervical cancer.

OBJECTIVE: Folate receptor α (FRα) is a membrane protein expressed in various solid tumors but has limited expression in normal cells. Therefore, FRα is an attractive target for cancer treatment. This study aimed to investigate the relationship between FRα expression and the clinicopathological characteristics and survivals of cervical cancer. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between 2000 and 2020 at our institution. Immunohistochemical staining of FRα was performed using an anti-folate-binding protein/FBP antibody. FRα-positive staining was defined as ≥5% of tumor staining and FRα-high as ≥50% tumor staining with ≥2+ intensity. The association between FRα expression and survival was assessed using multivariate Cox regression analysis, adjusting for established prognostic factors. RESULTS: Overall, 123 patients were identified, and 140 tumor samples, including 17 paired primary and metastatic samples, were evaluated. As histological types, 67 patients had squamous cell carcinoma (SCC), and 56 patients had non-SCC. All primary tumors were FRα-positive. High FRα expression was observed in 25% of the cases and differed according to histology (SCC vs. non-SCC, 14.9% vs. 37.5%, p=0.004). FRα expression was significantly higher in metastatic tumors than in primary (170 [IQR, 140-205] vs. 125 [IQR, 110-150], p=0.0006). High FRα expression was significantly associated with worse overall survival (hazard ratio, 6.73; 95% confidence interval, 2.21-20.53; p=0.001). CONCLUSION: In cervical cancer, FRα expression was elevated in metastatic tumors and high expression was associated with a worse prognosis. Our study supports the development of FRα-targeted therapy for advanced cervical cancer.

Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers.

PURPOSE: Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach. PATIENTS AND METHODS: Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS. RESULTS: Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS. CONCLUSION: Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers. CLINICAL REGISTRATION: [https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

BRCA Gene Mutations and Poly(ADP-Ribose) Polymerase Inhibitors in Triple-Negative Breast Cancer.

Breast cancer is the most common cancer in women worldwide. Treatment is chosen according to its hormone receptor status and human epidermal growth factor receptor 2 (HER2) status. Among the four main clinically set subtypes, hormone receptor-negative/HER2-negative subtype, also called triple-negative subtype (TNBC), is the most aggressive type with limited choices of therapy. However, recent research has provided important new insights into effective treatments for this subtype. One molecular target that has gained attention is the BRCA gene. BRCA proteins are involved in the maintenance of genomic integrity, therefore playing an important role as a "caretaker" DNA repair protein. Approximately 5% of all breast cancer patients are BRCA mutation carriers, and among the patients with BRCA mutations, 57.1% have the clinical TNBC subtype, showing a high association between BRCA mutations and TNBCs. When cells lack either BRCA1 or BRCA2, all types of homology-directed repairs are compromised, and poly(ADP-ribose) (PAR) polymerase (PARP) acts as a backup system to maintain the genome, consequently making the cells highly sensitive to PARP1 inhibitors. PARP inhibitors have shown promising activity in preclinical and early clinical trials, and today, phase III trials are ongoing. In this chapter, we discuss the mechanism and the role of PARP inhibitors in BRCA-mutated breast cancers and further elaborate the clinical potential of PARP inhibitors as well as their barriers.

Comparison of Amrubicin and Weekly Cisplatin/Etoposide/Irinotecan in Patients With Relapsed Small-cell Lung Cancer.

BACKGROUND: Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients. PATIENTS AND METHODS: Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients' characteristics and treatments to explore factors associated with the survival outcomes were reviewed. RESULTS: A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P = .007) and AMR as second-line treatment (vs. PEI) (P = .005) as independent favorable prognostic factors for survival. CONCLUSION: AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted.

Disseminated herpes zoster infection initially presenting with abdominal pain in patients with lymphoma undergoing conventional chemotherapy: A report of three cases.

Visceral disseminated varicella zoster virus (VZV) disease has a high mortality rate, and occurs in immunocompromised hosts, mostly subsequent to allogeneic stem cell transplantation. Only a few cases of this disease that onset during conventional chemotherapy in patients with lymphoma have been reported. The present study reports the cases of 3 patients with disseminated and visceral VZV infection undergoing treatment for follicular lymphoma, diffuse large B-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. All 3 patients presented with initial symptoms of abdominal pain, and 2 patients demonstrated syndrome of inappropriate antidiuretic hormone and hepatitis. All patients developed widespread cutaneous dissemination, and all had a low cluster of differentiation 4 cell count or lymphocyte count at the time of VZV diagnosis and at least 4 month prior. With intravenous systemic acyclovir therapy (Cases 1 and 3, 1500 mg/day; Case 2, 750 mg/day), the patients achieved complete recovery by day 14 of therapy. Visceral disseminated VZV infection is not limited to patients undergoing stem cell transplantation, and may present with abdominal pain with or without skin eruption. Visceral infection may take a poor clinical course, therefore, in patients with prolonged duration of low lymphocyte count and/or long-term use of steroids, the prophylactic use of acyclovir may be considered.

Irinotecan plus cisplatin in patients with extensive-disease poorly differentiated neuroendocrine carcinoma of the esophagus.

BACKGROUND: Poorly-differentiated neuroendocrine carcinoma (NEC) of the esophagus is a rare subtype that has a poor prognosis and is distinguished from well-differentiated neuroendocrine neoplasms in accordance with the 2010 World Health Organization classification. Irinotecan-plus-cisplatin (IP) is used as first-line chemotherapy for extensive-disease (ED) small-cell lung cancer and its use is plausible for first-line chemotherapy in ED esophageal NEC. We retrospectively analyzed the efficacy and toxicity of IP for ED esophageal NEC. PATIENTS AND METHODS: Patients with ED esophageal NEC treated with IP between 2000 and 2013 were retrospectively identified from our database. The end-points were objective response rate, progression-free survival (PFS) and overall survival (OS). Data on adverse events were also collected. RESULTS: An objective response was achieved in 50% (95% confidence interval [CI]: 25% to 75%) of 12 identified patients. Median progression-free survival was 4.0 months (95% CI: 0.9 to 7.6) and overall survival was 12.6 months (95% CI: 4.6 to 28.6). Grade 3/4 hematological toxicities included leukopenia in 50% of patients and neutropenia in 67%. The rate of febrile neutropenia was 25%. No treatment-related deaths were observed. CONCLUSION: IP appears acceptable as first-line chemotherapy for ED esophageal NEC.