First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors for Identification of Targeted Therapy Opportunities.

IMPORTANCE: Precision oncology using comprehensive genomic profiling (CGP) by next-generation sequencing is aimed at companion diagnosis and genomic profiling. The clinical utility of CGP before the standard of care (SOC) is still not resolved, and more evidence is needed. OBJECTIVE: To investigate the clinical utility of next-generation CGP (FoundationOne CDx [F1CDx]) in patients with previously untreated metastatic or recurrent solid tumors. DESIGN, Setting, and Participants: This multicenter, prospective, observational cohort study enrolled patients with previously untreated advanced solid tumors between May 18, 2021, and February 16, 2022, with follow-up through August 16, 2022. The study was conducted at 6 hospitals in Japan. Eligible patients were aged 20 years or older and had Eastern Cooperative Oncology Group performance status of 0 to 1 with previously untreated metastatic or recurrent cancers in the gastrointestinal or biliary tract; pancreas, lung, breast, uterus, or ovary; and malignant melanoma. EXPOSURE: Comprehensive genomic profiling testing before SOC for advanced solid tumors. MAIN OUTCOMES AND MEASURES: Proportion of patients with actionable or druggable genomic alterations and molecular-based recommended therapy (MBRT). RESULTS: A total of 183 patients met the inclusion criteria and 180 patients (92 men [51.1%]) with a median age of 64 years (range, 23-88 years) subsequently underwent CGP (lung [n = 28], colon/small intestine [n = 27], pancreas [n = 27], breast [n = 25], biliary tract [n = 20], gastric [n = 19], uterus [n = 12], esophagus [n = 10], ovary [n = 6], and skin melanoma [n = 6]). Data from 172 patients were available for end point analyses. Actionable alterations were found in 172 patients (100.0%; 95% CI, 97.9%-100.0%) and druggable alternations were identified in 109 patients (63.4%; 95% CI, 55.7%-70.6%). The molecular tumor board identified MBRT for 105 patients (61.0%; 95% CI, 53.3%-68.4%). Genomic alterations included in the companion diagnostics list of the CGP test were found in 49 patients (28.5%; 95% CI, 21.9%-35.9%) in a tumor-agnostic setting. After a median follow-up of 7.9 months (range, 0.5-13.2 months), 34 patients (19.8%; 95% CI, 14.1%-26.5%) received MBRT. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that CGP testing before SOC for patients with advanced solid tumors may be clinically beneficial to guide the subsequent anticancer therapies, including molecularly matched treatments.

Multicenter phase II study of trifluridine/tipiracil for esophageal squamous carcinoma refractory/intolerant to 5-fluorouracil, platinum compounds, and taxanes: the ECTAS study.

BACKGROUND: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. METHODS: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity. RESULTS: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis. CONCLUSIONS: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma.

[From the Standpoint of a Core Center Hospital for Cancer Genome Medicine-Establishment of a Provision System for Wide-Area Precision Oncology].

In Japan, 2 comprehensive genome profiling(CGP)tests for cancer was covered by national health insurance in June 2019, and cancer genome medicine was introduced at a total of 225 hospitals designated by the Ministry of Health, Labor and Welfare as"core center hospitals for cancer genome medicine(12 hospitals)"," core hospitals for cancer genome medicine (33 hospitals)", and"collaborative hospitals for cancer genome medicine(180 hospitals)". On the other hand, the interpretation of the results of the cancer CGP test must be discussed by an expert panel conducted at the core center hospitals for cancer genome medicine or the core hospitals for cancer genome medicine, and the results must be explained to patients in order to be covered by insurance. In other words, these hospitals are required to review not only their own cases but also those of collaborating hospitals. In addition, core center hospitals for cancer genome medicine are required to share information and develop human resources with core hospitals and collaborative hospitals for cancer genome medicine. We herein describes the system for providing cancer genome medicine in our hospital as a core center hospital for cancer genome medicine.

[Precision Medicine Provided by National Health Insurance].

From June 2019, 2 different comprehensive genomic profiling(CGP)test panels were covered by National Health Insurance System in Japan. However, the indication of CGP was solid cancer patients refractory to standard chemotherapy or those without standard of care, while other countries indicate CGP to chemotherapy naIve advanced cancer patients. To be covered by National Health Insurance System, certified core hospital for genomic medicine should hold expert panel with affiliated hospitals. We develop a unique system for expert panel collaborated with SYSMEX Corporation to streamline medical staffs' effort. To provide precision medicine to cancer patients, we have to maximize the merit of CGP and solve several issues.

A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head.

PURPOSE: We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH). METHODS: Patients with ONFH (precollapse stage ≤2) received a single local administration of 800 µg of rhFGF-2-impregnated gelatin hydrogel and were followed up for one year. The surgery was performed using a minimally invasive technique involving a 1-cm skin incision, and walking was allowed from day one postoperatively. The primary outcomes included occurrence of adverse events and complications. The secondary outcomes included changes in the Harris hip scores, visual analog scale for pain scores, University of California, Los Angeles (UCLA) activity scores, and radiological images. RESULTS: We included ten patients, of which five experienced 14 adverse events, including one complication from spinal anesthesia. However, patients completely recovered from all adverse events. The mean clinical scores significantly improved by one year postoperatively compared with the pre-operative scores (before vs. after: visual analog score for pain, 21.2 vs. 5.3 mm; UCLA activity score, 5.5 vs. 6.6; Harris hip score, 81.0 vs. 96.9 points). There was only one case of femoral head collapse; however, this occurred in a hip with extensive necrosis. Stage progression and collapse did not occur in the other nine cases. Computed tomography confirmed bone regeneration in the femoral heads. CONCLUSIONS: Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse ONFH was feasible and safe.