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Purpose: Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs. Methods: Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR. Results: Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach ( n = 6), rectum ( n = 3), esophagus ( n = 2), liver ( n = 1) and pancreas ( n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5 %. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6 %) and febrile neutropenia (30.8 %). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively). Conclusions: AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse. [ABSTRACT FROM AUTHOR]

The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS ( KRAS/ NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor ( EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti- EGFR antibody therapy may be ineffective: First, anti- EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/ NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti- EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices. [ABSTRACT FROM AUTHOR]

Bevacizumab is a widely used agent for treatment for colorectal cancer. Though it relates to several adverse events, a few cases have been reported of drug-induced interstitial lung damage in bevacizumab-based chemotherapy for advanced colorectal cancer. In this study, we retrospectively reviewed a consecutive series of 72 patients with advanced colorectal cancer who received bevacizumab-based chemotherapy and identified five cases (6.9 %) who developed interstitial pneumonia (IP). The median age was 68 years, all five were male, and four of five patients were smokers. Three cases were asymptomatic, and they immediately recovered by withdrawal of chemotherapeutic drugs. On the other hand, two severe cases were required high-dose infusion of corticosteroid. It is suggested that early diagnosis of IP contributes to prevent exacerbation of the event and results in better outcomes. IP may have been associated with systemic chemotherapy, suggesting that a caution should be raised for pulmonary damage by bevacizumab-based chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Capecitabine plus cisplatin (XP) is recognized as one of the global standard first-line chemotherapy regimens for patients with metastatic gastric cancer (mGC). Recent multinational phase III trials in mGC have been conducted with XP as the control arm, although no data on XP in Japanese patients with mGC have been published to date. The AVAGAST (XP ± bevacizumab in mGC) and ToGA (XP ± trastuzumab in human epidermal growth factor receptor 2 [HER2]-positive mGC) studies were the first two global studies including Japanese mGC patients. The aim of this analysis was to investigate the efficacy and safety of XP in Japanese mGC patients, using AVAGAST and ToGA subgroup data. Methods: Efficacy and safety analyses were carried out in Japanese patients with mGC receiving XP alone, based on results from the AVAGAST and ToGA studies. There were differences in the target populations between the two studies; for example, the ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately. Results: Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 % in the AVAGAST and 58.5 % in the ToGA study. Adverse events were generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea. Conclusions: XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort. [ABSTRACT FROM AUTHOR]

Purpose: The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer. Methods: This study initially had been planned as a phase I/II study. Eighty mg/m of irinotecan on days 1 and 8, 80 mg/m of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level −1; 7.5 mg/kg) were administered on day 1 every 3 weeks. Results: Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity. Conclusions: This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer. [ABSTRACT FROM AUTHOR]

The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade ≥3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU. [ABSTRACT FROM AUTHOR]

Background: The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients. Methods: We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n = 51; chemotherapy, n = 50). Results: Median overall survival in the Japanese subgroup was 15.9 months (95% confidence interval 12-25) for trastuzumab plus chemotherapy and 17.7 months (95% confidence interval 12-24) for chemotherapy (hazard ratio 1.00; 95% confidence interval 0.59-1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95% confidence interval 0.36-1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios. Conclusions: After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone. [ABSTRACT FROM AUTHOR]

Introduction: Using the recommended doses obtained from our previous phase 1 trial of a modified Saltz chemotherapy regimen for metastatic colorectal cancer (weekly irinotecan and bolus 5-fluorouracil/l-leucovorin for 3 weeks every 28 days), we performed the present phase 2 trial to evaluate efficacy and toxicity.Methods: A total of 29 patients with metastatic colorectal cancer were included. Our modified Saltz regimen was administered. The primary endpoint was overall response rate.Results: Of the 29 patients, 11 had previous chemotherapy. A partial response occurred in 11 patients, stable disease in 16 patients, and progressive disease in two patients. Disease control rate was 93.1%. Response rates with and without previous treatment were 18.2% and 50%, respectively. Median progression-free survival was 17.3 months. The main hematologic toxicities were leukopenia (22.6%) and neutropenia (45.2%). No treatment-related deaths occurred.Conclusion: Our modified Saltz regimen exhibited sufficient efficacy, feasibility, and manageable toxicity as a therapeutic option for selected colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Using the recommended doses obtained from our previous phase 1 trial of a modified Saltz chemotherapy regimen for metastatic colorectal cancer (weekly irinotecan and bolus 5-fluorouracil/ l-leucovorin for 3 weeks every 28 days), we performed the present phase 2 trial to evaluate efficacy and toxicity. Methods: A total of 29 patients with metastatic colorectal cancer were included. Our modified Saltz regimen was administered. The primary endpoint was overall response rate. Results: Of the 29 patients, 11 had previous chemotherapy. A partial response occurred in 11 patients, stable disease in 16 patients, and progressive disease in two patients. Disease control rate was 93.1%. Response rates with and without previous treatment were 18.2% and 50%, respectively. Median progression-free survival was 17.3 months. The main hematologic toxicities were leukopenia (22.6%) and neutropenia (45.2%). No treatment-related deaths occurred. Conclusion: Our modified Saltz regimen exhibited sufficient efficacy, feasibility, and manageable toxicity as a therapeutic option for selected colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced STEAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more STEAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition. [Copyright &y& Elsevier]

Purpose: This single-arm, phase II clinical study evaluated the efficacy and safety of sequential treatment with S-1 followed by cisplatin in patients with advanced or recurrent gastric cancer. Methods: Fifty patients with histologically confirmed advanced or recurrent gastric cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who had measurable and/or assessable lesions and gave written informed consent were enrolled. S-1 (40 mg/m, bid) was administered on days 1-21, and cisplatin (70 mg/m) was given as an intravenous infusion on day 22 of a 35-day cycle. Treatment was continued until disease progression or intolerable adverse events. Cisplatin was administered for 6 cycles. Adverse events were assessed according to Common Terminology Criteria of Adverse Events version 3.0, and efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.0 for patients with measurable lesions and by the criteria of the Japanese Research Society for Gastric Cancer for all patients. Results: Efficacy could be evaluated in 49 of the 50 enrolled patients. The median age was 62 years. Lesions were measurable in 38 patients and assessable in 11. The response rate was 44.7% in patients with measurable lesions and 40.8% overall. The progression-free survival and overall survival were, respectively, 233 days (7.8 months) and 574 days (19.0 months) in patients with measurable lesions and 192 days (6.4 months) and 402 days (13.4 months) overall. Serious adverse events (grade 3 or higher) included neutropenia (24.5%), anemia (20.4%), and anorexia (20.4%) and were safely managed. Conclusion: The safety and effectiveness of sequential treatment with S-1 followed by cisplatin every 35 days is equivalent to that reported for conventional chemotherapeutic regimens in patients with advanced or recurrent gastric cancer. [ABSTRACT FROM AUTHOR]

The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan is expected to be a promising regimen for advanced colorectal cancer. This study was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with S-1 in a 3-week cycle regimen and to observe the safety and efficacy for patients with previously untreated advanced colorectal cancer. Eighty milligrams per m of S-1 was given orally for 14 consecutive days and escalated doses of irinotecan were administered on days 1 and 8 every 3 weeks in the phase I trial. Forty patients were treated at the RD during the phase II trial. Forty-three patients were enrolled between February 2005 and March 2007. The dose-limiting toxicity was diarrhea and abdominal pain. The MTD of irinotecan was 100 mg/m and the RD was determined to be 80 mg/m of irinotecan combined with 80 mg/m of S-1. The phase II trial showed that 22 of 40 patients achieved a complete or partial response and eight had stable disease. The overall response rate was 55.0%. The median progression-free survival time and median survival time were 6.7 and 21 months, respectively. There were no treatment-related deaths. The main toxicities were leukopenia, neutropenia, anorexia and diarrhea. This study suggests the combination of irinotecan and S-1 repeated every 3 weeks is tolerable and effective for patients with previously untreated advanced colorectal cancer. ( Cancer Sci 2010; 101: 2591-2595) [ABSTRACT FROM AUTHOR]

Oxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities. In order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies. One hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17%) were found to have developed allergic reactions. Sixteen patients (13%) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4%) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2–15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients’ background characteristics such as sex, history of allergy, and profile of other adverse events. Allergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions. [ABSTRACT FROM AUTHOR]

Purpose: Although gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been demonstrated to exhibit its antitumor activity by the blockade of EGF receptor, the role of signaling pathways downstream of EGFR in gefitinib sensitivity remains unknown. In this study, we investigated the mechanistic role of Src and Ras, major oncogene products implicated in the pathogenesis of many human cancers in gefitinib sensitivity. Methods: Using parental and v- src- or c-H- ras-transfected HAG-1 human gallbladder adenocarcinoma cell lines, effects of gefitinib on cytotoxicity, cell cycle purtubation and apoptosis, and tyrosine phosphorylation of EGFR, Akt, and Erk were determined by WST-1 assay, flow cytometry, and Western blots, respectively. Results: Activated Ras and Src conferred a strong resistance to gefitinib by nearly 30-fold and 200-fold, respectively. Gefitinib induced accumulation of cells in the G0/G1 phase of the cell cycle at 24-h, with progressive expansion of apoptotic cell population in parental HAG-1 cells, but these effects were completely abolished in v- src- or c-H- ras-transfected cell line. Upon gefitinib treatment, EGFR activation and subsequent downstream activation through Erk and Akt were significantly inhibited in HAG-1 cells. By contrast, gefinitib failed to inhibit the activation of both Akt and Erk in v-src-transfected cells and Erk, but not Akt in c-H-ras-transfected cells, despite the blockade of EGFR activation in these respective cell lines. Treatment of v-src-transfected cells with herbimycin A, a Src tyrosine kinase inhibitor, partially reversed the gefitinib resistance, with concomitant inhibition of Akt and Erk. Conclusion: Our results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways, thus providing a strategic rationale for assessment of these specific signaling molecules downstream of EGFR to customize treatment. [ABSTRACT FROM AUTHOR]

This study focused on the question of how monocyte-derived dendritic cells (Mo-DCs) that capture dead tumor cells (Mo-DCs-Tum) secrete interleukin 12 (IL-12) and tumor necrosis factor a (TNF-a). Mo-DCs-Tum showed higher secretions of IL-12 and TNF-a than were shown by Mo-DCs. Enhanced nuclear factor-kappa B (NF-?B) activation was also induced in Mo-DCs-Tum within 6 h. The NF-?B inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed both IL-12 and TNF-a secretions from Mo-DCs-Tum. Administration of recombinant TNF-a or IL-12 enhanced IL-12 or TNF-a secretion respectively in Mo-DCs-Tum. Addition of anti-TNF-a or anti-IL-12 neutralizing antibody decreased NF-?B activation and IL-12 or TNF-a secretion in Mo-DCs-Tum. These results suggest that TNF-a or IL-12 secretion induces NF-?B activation, and it stimulates further TNF-a and IL-12 secretions, i.e., an IL-12/TNF-a/NF-?B autocrine loop, in Mo-DCs-Tum. Thus, Mo-DCs-Tum secrete a large amount of IL-12 and TNF-a through accelerated NF-?B activation induced by the IL-12/TNF-a/NF-?B autocrine loop. [ABSTRACT FROM AUTHOR]

Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration. [ABSTRACT FROM AUTHOR]

Background: FOLFOXIRI plus bevacizumab is a standard first-line chemotherapy for patients with metastatic colorectal cancer (mCRC). However, due to the severe toxicities, this regimen is not widely used. There is limited data on the real-world efficacy and safety. Methods: We conducted a retrospective analysis of clinical data from mCRC patients who received FOLFOXIRI plus bevacizumab as first-line chemotherapy at 31 institutions. The initial dose was standardized according to the TRIBE regimen. Induction therapy was defined as a combination of oxaliplatin, irinotecan, and fluorouracil. Results: Out of 104 patients who met the criteria, the median age was 58 years (range, 16–72). 81% of patients had an eastern cooperative oncology group performance status (PS) of 0. An initial dose reduction was observed in 63% of patients. The median number of preplanned induction therapy cycles was 12 (range, 4–12). The completion of scheduled induction therapy cycles was observed in 45% of patients, with treatment-related toxicities being the main reason for discontinuation (63%). The median progression-free survival and overall survival were 12.8 months (95% CI, 10.6–15.0) and 27.9 months (95% CI 21.6–34.2), respectively. The objective response rate and disease control rate were 63.7% and 98.9%, respectively. The R0 resection rate was 21.2%. The main grade 3 or higher toxicities were neutropenia (51%), febrile neutropenia (10%), and nausea/vomiting (5%). No treatment-related deaths were observed. Conclusion: In a real-world clinical setting, FOLFOXIRI plus bevacizumab demonstrated efficacy and safety comparable to previous clinical trials. [ABSTRACT FROM AUTHOR]

PURPOSE: The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. METHODS: We conducted a retrospective study using real-world clinical data and next-generation sequencing–based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. RESULTS: In 114 patients with human epidermal growth factor receptor-2 (HER2)–positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P =.044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1 / ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2 -nonamplified tumors; P <.0001). ERBB2 -activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2 -mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P =.046). CONCLUSION: CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2 -activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer. [ABSTRACT FROM AUTHOR]