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Background Patients with advanced cancer have been reported to be more likely to receive goal-concordant care if they have accurate prognostic awareness. However, many patients do not have this awareness. This study aimed to examine the prognostic awareness among Japanese patients with advanced cancer. Methods This single-center, follow-up cohort study included Japanese patients with advanced cancer who received chemotherapy at Tohoku University Hospital between January 2015 and January 2016. Patients were surveyed at enrollment and followed up for clinical events for 5 years thereafter. We compared (i) the patients’ prognostic awareness with both actual survival time and physician’s prediction of survival and (ii) physician’s prediction of survival time with actual survival. Factors associated with accurate prognostic awareness were identified by univariate analysis. Results Of the 133 patients eligible for the study, 57 patients were analyzed. Only 10 (17.5%) patients had accurate prognostic awareness. Forty-three patients (75.4%) were optimistic about their prognosis; >80% of patients were more optimistic than their physicians about their prognosis. The physicians’ predictions were accurate in for patients (37.5%). Accurate prognostic awareness was associated with physician’s explanation of the prognosis and patients’ perception of a good death. Conclusions A majority of the patients with advanced cancer in this study had prognostic awareness that was more optimistic in comparison with their actual survival, and most were more optimistic than their physicians about their prognosis. Further research is needed to develop programs to facilitate the discussion of life expectancy with patients in a manner that is consistent with their preferences.

A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions.This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations.The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%).The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

An 18-year-old Japanese man was diagnosed with an undifferentiated sarcoma of the spermatic cord, with multiple distant metastases to the lungs and bones. The patient received doxorubicin-based standard chemotherapy. Although the chemotherapy was effective, it induced severe adverse events, which led to treatment discontinuation. A comprehensive genomic profiling test using resected tumor tissue revealed the BRAF V600E mutation. Based on the result, the patient received combination therapy with dabrafenib and trametinib. The combination therapy achieved a good response with few adverse events. However, 6.5 months later, pleural metastases and meningeal dissemination had emerged. A liquid comprehensive genomic profiling test was performed after the progression to identify the resistance mechanism, which resulted in the detection of no actionable gene alterations other than BRAF V600E. This report shows that the BRAF V600E mutation may be a promising therapeutic target and that resistance to the targeted therapy could also occur in soft tissue sarcoma. The significance of BRAF mutations across different types of cancer should be validated, and it is necessary to apply targeted therapies and develop methods to overcome resistance based on the optimal use of comprehensive genomic profiling tests.

Purpose: Achieving “good death” is one of the important goals of palliative care. Providing goal-concordant care and an environment tailored to the patient's preferences can contribute to “good death.” However, the concordance rate between the preferred and actual places of death among advanced cancer patients in Japan is less explored. This study aimed to identify the concordance between patients’ preferred and actual places of death, and the associated factors among patients with advanced cancer in Japan. Methods: Patients with advanced cancer who underwent chemotherapy between January 2015 and January 2016 were enrolled and followed up for 5 years. The enrolled patients were asked about their preference for their place of death. The response options were: “Own home,” “General ward” and “Palliative care unit (PCU).” We compared the actual place of death with the patient’s preference through a follow-up review of the medical records. Results: A total of 157 patients with advanced cancer were enrolled between January 2015 and January 2016. Of these patients, 22.9% (11/48) died at home according to their preference, 64.0% (16/25) in the general ward, and 37.9% (11/29) in the PCU. Only thirty-seven (37.3%) patients died where they wanted, based on the comparison between patients' preferences and actual places of death. Conclusion: The concordance rate between the preferred and actual places of death is not high in Japan. Improving concordance between patients' preferences and actual places of death has the potential to improve end-of-life care.

BRCA1 functions as a tumor suppressor in DNA repair and centrosome regulation. Previously, Obg-like ATPase 1 (OLA1) was shown to interact with BARD1, a heterodimer partner of BRCA1. OLA1 binds to BRCA1, BARD1, and γ-tubulin and functions in centrosome regulation. This study determined that overexpression of wild-type OLA1 (OLA1-WT) caused centrosome amplification due to centriole overduplication in mammary tissue–derived cells. Centrosome amplification induced by overexpression of the cancer-derived OLA1 mutant, which is deficient at regulating centrosome number, occurred in significantly fewer cells than in that induced by overexpression of OLA1-WT. Thus, it was hypothesized that overexpression of OLA1 with normal function efficiently induces centrosome amplification, but not that of OLA1 mutants, which are deficient at regulating centrosome number. We analyzed whether overexpression of OLA1 missense mutants of nine candidate phosphorylation residues, three residues modified with acetylation, and two ATP-binding residues caused centrosome amplification and identified five missense mutants that are deficient in the regulation of centrosome number. Three of them did not bind to BARD1. Two phosphomimetic mutations restored the binding to BARD1 and the efficient centrosome amplification by their overexpression. Knockdown and overexpression of BARD1 also caused centrosome amplification. BARD1 mutant reported in cancer failed to bind to OLA1 and rescue the BARD1 knockdown-induced centrosome amplification and reduced its centrosomal localization. Combined, these data reveal that the OLA1–BARD1 interaction is important for the regulation of centrosome number.Implications: Regulation of centrosome number by BRCA1/BARD1 together with OLA1 is important for the genome integrity to prevent tumor development. Mol Cancer Res; 16(10); 1499–511. ©2018 AACR.

Supplementary Figure 4. BARD1 expression in Hs578T cells transfected with BARD1 siRNA and expression vector.

OLA1 residues responsible for the biological functions.

Supplementary Figure 3. Kinetics of surface marker expression by IL-4 producing cells from tumor draining LNs and surface marker in tumor infiltrated CD4 T cells.

Summary of biological functions of OLA1 mutants.

Immune cells constitute a large fraction of the tumor microenvironment and modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL4 in particular is upregulated. Here, we demonstrate that T follicular helper (Tfh) cells arise in tumor-draining lymph nodes where they produce an abundance of IL4. Deletion of IL4-expressing Tfh cells improves antitumor immunity, delays tumor growth, and reduces the generation of immunosuppressive myeloid cells in the lymph nodes. These findings suggest that IL4 from Tfh cells affects antitumor immunity and constitutes an attractive therapeutic target to reduce immunosuppression in the tumor microenvironment, and thus enhance the efficacy of cancer immunotherapy. Cancer Immunol Res; 5(1); 61–71. ©2016 AACR.

Knockdown of OLA1 did not cause centrosome amplification in non-mammary tissue-derived cell lines.

Supplementary Figure 1. Increased IL-4 and IL-21 expression in tumor draining LNs.

Centrosome amplification induced by overexpression of BRCA1.

Direct binding of OLA1 mutants with �-tubulin and the N-terminal region of BRCA1.

Supplementary Figure 2. GATA3 or FoxP3 expression in IL-4-produced cells.

Supplementary Figure Legends

Supplementary Figure 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

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Supplementary Figure and Table Legends from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of β-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers. [Mol Cancer Ther 2006;5(10):2563–71]

Supplementary Figure 4 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Purpose: Analyses of the pattern of p53 mutations have been essential for epidemiologic studies linking carcinogen exposure and cancer. We were concerned by the inclusion of dubious reports in the p53 databases that could lead to controversial analysis prejudicial to the scientific community.Experimental Design: We used the universal mutation database p53 database (21,717 mutations) combined with a new p53 mutant activity database (2,300 mutants) to perform functional analysis of 1,992 publications reporting p53 alterations. This analysis was done using a statistical approach similar to that of clinical meta-analyses.Results: This analysis reveals that some reports of infrequent mutations are associated with almost normal activities of p53 proteins. These particular mutations are frequently found in studies reporting multiple mutations in one tumor, silent mutations, or lacking mutation hotspots. These reports are often associated with particular methodologies, such as nested PCR, for which key controls are not satisfactory.Conclusions: We show the importance of accurate functional analysis before inferring any genetic variation. The quality of the p53 databases is essential in order to prevent erroneous analysis and/or conclusions. The availability of functional data from our new p53 web site (http://p53.free.fr and http://www.umd.be:2072/) will allow functional prescreening to identify potential artifactual data.

Supplementary Figure 2 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Table 1 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 3 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 5 from Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

Supplementary Figure 3 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Table 1 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Tumor suppressor p53-dependent apoptosis is thought to be one of the most important tumor-suppressive functions in human tumorigenesis. However, whether the major mechanism underlying the p53-dependent apoptosis is transactivation dependent or independent remains unclear. Using 179 mutant p53s with diverse transcriptional activities for distinct p53-binding sequences in yeast, we evaluated both their sequence-specific transcriptional activities on six p53 target genes and their ability to induce apoptosis in Saos-2 cells. These mutant p53s also represented diversity in their ability to both transactivate target genes and induce apoptosis. We identified 17 mutant p53s with superior ability to induce apoptosis than wild-type p53 that tend to cluster at residues 121 or 290 to 292. There was no significant correlation between the two functional properties on any single target gene examined. Furthermore, the 17 mutant p53s were not classified in a specific cluster by hierarchical cluster analysis on their diverse transcriptional activities, indicating that these mutant p53s were not similar in the transcriptional activity of downstream genes. These results suggested that transactivation-dependent apoptosis does not always play a major role in p53-dependent apoptosis, indirectly supporting the importance role of the transactivation-independent mechanism.

Supplementary Information from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Figure 1 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Figure Legends from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Figure 4 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Figure 2 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Figure 5 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Table 2 from Lack of Correlation between p53-Dependent Transcriptional Activity and the Ability to Induce Apoptosis among 179 Mutant p53s

Supplementary Table 1 from Identification of Breast Tumor Mutations in BRCA1 That Abolish Its Function in Homologous DNA Recombination

Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.

Background TP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status. Methods We developed a multiplex reverse transcription–polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed. Results The diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer. Conclusion This simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer.

About 4 and a half years have passed since"Cancer Genome Medicine"was first mentioned in the Third Phase of the Basic Plan to Promote Cancer Control Programs that started in October 2017. Currently, cancer genomic medicine is being carried out by the cancer gene panel test, which is covered by public insurance, mainly at the 12 Cancer Genome Medicine Core Center Hospital designated nationwide by the Ministry of Health, Labor, and Welfare in Japan. Cancer genomic medicine has come to be positioned as a standard medical treatment. However, there are various challenges in operating an expert panel that professionally examines the results of the gene panel tests and reports treatment recommendations and secondary findings that suggest hereditary tumors. In addition, there is an urgent need to disseminate and educate healthcare professionals and patients about cancer genomic medicine. In this panel discussion on January 14, 2022, 10 panelists discussed how to solve these issues and the prospects for the future.

Breast cancer gene 1 (BRCA1) plays roles in DNA repair and centrosome regulation and is involved in DNA damage-induced centrosome amplification (DDICA). Here, the centrosomal localization of BRCA1 and the kinases involved in centrosome duplication were analyzed in each cell cycle phase after treatment with DNA crosslinker cisplatin (CDDP). CDDP treatment increased the centrosomal localization of BRCA1 in early S-G2 phase. BRCA1 contributed to the increased centrosomal localization of Aurora A in S phase and that of phosphorylated Polo-like kinase 1 (PLK1) in late S phase after CDDP treatment, resulting in centriole disengagement and overduplication. The increased centrosomal localization of BRCA1 and Aurora A induced by CDDP treatment involved the nuclear export of BRCA1 and BRCA1 phosphorylation by ataxia telangiectasia mutated (ATM). Patient-derived variants and mutations at phosphorylated residues of BRCA1 suppressed the interaction between BRCA1 and Aurora A, as well as the CDDP-induced increase in the centrosomal localization of BRCA1 and Aurora A. These results suggest that CDDP induces the phosphorylation of BRCA1 by ATM in the nucleus and its transport to the cytoplasm, thereby promoting the centrosomal localization Aurora A, which phosphorylates PLK1. The function of BRCA1 in the translocation of the DNA damage signal from the nucleus to the centrosome to induce centrosome amplification after CDDP treatment might support its role as a tumor suppressor.

Immune cells can recognize tumor antigens and elicit an adaptive immune response, potentially resulting in tumor regression. Drug-induced dead tumor cells have been reported to enhance anti-tumor immunity, but results are conflicting, possibly due to the immunosuppressive effects of the cytotoxic drugs. To investigate whether apoptotic tumor cells trigger anti-tumor immunity independent of anti-cancer treatment, local immune responses were evaluated after direct induction of tumor cell apoptosis using a herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) system. The inflammatory cytokines IFNγ and IL-12β and anti-inflammatory factor PD-1 and TGFβ1 were upregulated at the tumor site after apoptosis induction. HSV-tk/GCV-induced tumor cell apoptosis resulted in suppression of tumor growth in vivo and promoted the infiltration of CD8 and CD4 T lymphocytes in tumor. To explore the role of T cells after induction of tumor cell death, GCV was administered together with anti-CD8 or anti-CD4 depleting antibodies to syngeneic HSV-tk transfected tumor-bearing mice. CD8 T cell depletion abrogated the anti-tumor efficacy of GCV, indicating that tumor regression was mainly dependent on CD8 T cells. This anti-tumor immunity was enhanced by anti-PD-1 antibody injection. On the contrary, CD4 T cell depletion further inhibited tumor growth than GCV alone, suggesting the potential role of CD4 T cells in suppressive tumor immunity. To elucidate this immunological mechanism, tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion. Foxp3, a regulatory T cell marker, was decreased after CD4 T cell depletion. In addition, Arg1, a marker of immunosuppressive myeloid cells, was significantly downregulated, which was expressed on tumor-associated macrophages (TAMs) and monocytic myeloid-derived suppressor cells (mMDSCs). Collectively, these findings indicate that tumor cell apoptosis accelerates CD8 T cell-dependent anti-tumor immunity and CD4 T cell-mediated Arg1 production from TAMs and mMDSCs. Citation Format: Sho Umegaki, Hidekazu Shirota, Tomoyuki Iwasaki, Yuki Kasahara, Chikashi Ishioka. Differential role of CD8 cells and CD4 cells in anti-tumor immunity triggered by tumor cell apoptosis using HSVtk/GCV system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6389.

Purpose:This study aimed to identify factors associated with specialized palliative care (SPC) use and aggressive care at the end of life (EOL) among Japanese patients with advanced cancer. Methods:This single-center, follow-up cohort study involved patients with advanced cancer who received chemotherapy at Tohoku University Hospital. Patients were surveyed at enrollment, and we followed clinical events for 5 years from enrollment in the study. We performed multivariate logistic regression analysis to identify independent factors related to SPC use and chemotherapy in the last month before death.Results:We analyzed a total of 135 patients enrolled between January 2015 and January 2016. No patients were admitted to the intensive care unit, and few received resuscitation or ventilation. We identified no factors significantly associated with SPC use. Meanwhile, younger age (20–59 years, odds ratio [OR] 4.10; 95% confidence interval [CI] 1.30–12.91; p=0.02) and no receipt of SPC (OR 4.32; 95% CI 1.07–17.37; p=0.04) were associated with chemotherapy in the last month before death.Conclusion:Younger age and a lack of SPC were associated with chemotherapy at the EOL in patients with advanced cancer in Japan. These findings suggest that Japanese patients with advanced cancer may benefit from access to SPC.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors.We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS).In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS.Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

179 Background: TP53 tumor suppressor gene is frequently inactivated by loss-of-function mutations. Some of the mutations gain additional oncogenic functions and are known as gain-of-function (GOF) mutations. This study analyzed the association among primary tumor site (PS), genome-wide DNA methylation status (GWMS), and TP53 mutation subtypes about prognosis in metastatic colorectal cancer (mCRC). Methods: Tumor tissues of mCRC patients registered in the TRICOLORE Study (clinical trial number) were analyzed for GWMS and TP53 mutation as translational research and were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) for GWMS, and wild-type , GOF mutation and non-GOF mutation for TP53 mutation. Overall survival (OS) was compared between single or combined subgroups, and Cox regression analysis was performed to identify factors contributing to OS. Results: A total of 209 patients were analyzed, HMCC and LMCC were 60 (28.7%) and 149 (71.3%), respectively. TP53 wild-type , GOF mutation and non-GOF mutation were 35 (16.7%), 79 (37.8%) and 95 (45.5%), respectively. HMCC showed a significantly worse prognosis than LMCC (median OS 25.3 vs. 40.3 months, P < 0.01, hazard ratio 1.87). Combining GWMS and TP53 mutation subtypes about prognosis, the HMCC/GOF (n = 26) group had a significantly poorer prognosis than the other three groups including HMCC/non-GOF (n = 22), LMCC/GOF (n = 53), and LMCC/non-GOF groups (n = 73) (median OS 17.7, 35.3, 40.3, 41.2 months, p = 0.007, p < 0.001, p < 0.001, respectively). The HMCC/GOF group had a poorer prognosis than the other 3 groups regardless of the PS. In the multivariate analysis in the GOF mutation subgroup, HMCC (p < 0.01) was the only poor prognostic factor, while right-sided colon cancer (p = 0.03) and RAS mutations (p = 0.01) were significant poor prognostic factors in the multivariate analysis in the non-GOF mutation subgroup. Conclusions: TP53 gain of function mutations are independent poor prognostic factors in high-methylated metastatic colorectal cancer.