21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair.

BACKGROUND: We aimed to investigate clinicopathologic factors leading to different clinical outcomes in patients with deficient mismatch repair protein (d-MMR) gastric cancer (GC) treated with nivolumab plus chemotherapy (nivolumab chemotherapy). METHODS: This retrospective study included 28 patients with d-MMR advanced GC treated with first-line nivolumab chemotherapy. As a control group, 68 treated with first-line chemotherapy alone were included. Clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and PD-L1 combined positive score (CPS), were analyzed with regards to the efficacy outcomes. RESULTS: Progression-free survival (PFS) was longer (median PFS; not reached [NR] vs. 5.2 months, hazard ratio [HR] 0.28, P < 0.001), and overall survival (OS) tended to be longer (median OS; NR vs. 17.9 months, HR 0.43, P = 0.057) in patients treated with nivolumab chemotherapy than those treated with chemotherapy. The PFS benefit of nivolumab chemotherapy over chemotherapy was pronounced in the subgroup with a lower NLR (< 3.80 [median NLR]) (HR 0.10), whereas it was less prominent in patients with a high NLR (≥ 3.80) (HR 0.58). Among patients treated with nivolumab chemotherapy, PFS was worse in patients with a higher NLR (≥ 3.80) than in those with a lower NLR (< 3.80), and survival outcomes were similar between those with PD-L1 CPS ≥ 5 and < 5. CONCLUSION: Nivolumab chemotherapy was associated with better efficacy outcomes than chemotherapy alone among patients with d-MMR GC, but survival outcomes were poor even with nivolumab chemotherapy for those with a high NLR. Survival outcomes were not different according to PD-L1 CPS among d-MMR patients treated with nivolumab chemotherapy.

DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.

BACKGROUND: The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. METHODS: Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. RESULTS: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58 years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). CONCLUSION: Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.

Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

BACKGROUND: We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. METHODS: This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. RESULTS: The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). CONCLUSION: PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 study for clinical and biomarker analysis.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS: This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS: Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS: Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.

Thiotepa, busulfan, and cyclophosphamide or busulfan, cyclophosphamide, and etoposide high-dose chemotherapy followed by autologous stem cell transplantation for consolidation of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma for which standard treatment has yet to be established. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a suitable consolidation strategy for patients who respond to induction chemotherapy. The purpose of this study was to compare the outcome and toxicity profile of the combination of busulfan, cyclophosphamide, and etoposide (BuCyE) with that of the combination of thiotepa, busulfan, and cyclophosphamide (TBC) as conditioning regimens of upfront ASCT for consolidation therapy in PCNSL. The PCNSL registry data set, prospectively collected from March 1993 to May 2017 at Asan Medical Center, was reviewed retrospectively. Patients with objective response to induction chemotherapy who received BuCyE or TBC as conditioning regimen for ASCT were included in the analysis. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Among 241 patients with a diagnosis of PCNSL, 53 received ASCT as upfront consolidation therapy with TBC (28 patients) or BuCyE (25 patients) as conditioning regimen. No median OS or PFS was reached in the TBC group, while the BuCyE group reached a median OS of 4.9 years (p = 0.02) and median PFS of 1.1 years (p = 0.007). The incidence of oral mucositis, nausea, and vomiting was higher with TBC than BuCyE. The median admission duration and days to engraftment were similar between the two groups. Despite the greater incidence of adverse events, TBC showed better outcomes than BuCyE in terms of survival.

Efficacy of fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer after failure of gemcitabine plus cisplatin: retrospective analysis of 321 patients.

BACKGROUND: We aimed to assess the efficacy of second-line fluoropyrimidine-based chemotherapy in patients with advanced biliary tract cancer (BTC) after failure of gemcitabine plus cisplatin (GEMCIS). METHODS: We retrospectively examined patients with histologically documented advanced BTC who received first-line GEMCIS between December 2010 and June 2015. Among 748 patients treated with first-line GEMCIS, 321 (43%) subsequently received fluoropyrimidine-based second-line systemic chemotherapy. RESULTS: Fluoropyrimidine monotherapy and fluoropyrimidine-platinum combination were used in 255 and 66 patients, respectively. In patients with measurable disease, the overall response rate (ORR) was 3% and disease control rate was 47%. After a median follow-up of 27.6 months (range, 0.9-70.4 months), the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval (CI), 1.6-2.2) and 6.5 months (95% CI, 5.9-7.0), respectively. The ORR was significantly higher in patients who received fluoropyrimidine-platinum combination compared with those who received fluoropyrimidine alone (8 vs 1%, P=0.009), although the PFS (P=0.43) and OS (P=0.88) did not significantly differ between these groups. CONCLUSIONS: Fluoropyrimidine-based chemotherapy was modestly effective as a second-line chemotherapy for advanced BTC patients after failure of GEMCIS. Fluoropyrimidine-platinum combination therapy was not associated with improved survival outcomes, as compared with fluoropyrimidine monotherapy.

Recent Advances in Systemic Therapy for Advanced Intrahepatic Cholangiocarcinoma.

Background: The incidence of intrahepatic cholangiocarcinoma (IHCCA) is rising around the world. The disease is becoming a major global health issue. Conventionally, most patients with cholangiocarcinoma present with advanced disease and systemic therapy is the mainstay of treatment. This review discusses recent advances in systemic treatments for patients with IHCCA. Summary: The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively. They have provided a treatment option for patients without actionable alterations who progressed to first-line therapy. For patients with actionable genomic alterations, including FGFR2 rearrangement, IDH1 mutation, BRAF mutation, and ERBB2 amplification, targeted agents have shown encouraging efficacy in several phase 2-3 trials, and are recommended as subsequent treatments. Immune checkpoint inhibitors are being investigated for the treatment of previously treated patients, although only a small proportion of patients showed durable responses. Key Messages: Recent advances in systemic treatments have improved clinical outcomes in patients with advanced IHCCA. However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

GASTric Cancer HER2 Re-Assessment Study 2 (GASTHER2): HER2 Re-assessment for Initially HER2-Negative Advanced Gastric Cancer Patients after Progression on First-Line Treatment.

PURPOSE: Heterogeneous human epidermal growth factor receptor 2 (HER2) overexpression in gastric cancer may lead to a misdiagnosis of HER2 status. Accurate assessment of HER2 status is essential for optimal treatment as novel HER2-directed agents are being investigated in various clinical settings. We evaluated the usefulness of HER2 re-assessment following progression on first-line treatment in initially HER2-negative advanced gastric cancer (AGC) patients. MATERIALS AND METHODS: We enrolled 177 patients with baseline HER2-negative AGC and performed HER2 re-assessment after progression on first-line treatment from February 2012 to June 2016 at Asan Medical Center, Seoul, Korea. The re-assessed HER2 status was analyzed with baseline HER2 status and clinical characteristics. RESULTS: The median age was 54 years (range, 24 to 80 years), and 123 patients (69.5%) were men. Seven patients (4.0%) were HER2-positive on the re-assessment. Patients with baseline HER2 negativity confirmed by a single test (n=100) had a higher HER2-positive re-assessment rate compared to those who had repeated baseline testing (n=77) (5.0% vs. 2.6%). Among the patients with single baseline HER2 testing, the rate was higher in patients with baseline HER2 immunohistochemistry (IHC) 1+ compared to those with IHC 0 (13.4% vs. 3.6%). CONCLUSION: Overall, 4.0% of patients with baseline HER2-negative AGC were HER2-positive on re-assessment, and the HER2-positive re-assessment rate was higher among patients who had a single test at baseline. HER2 re assessment may be considered for initially HER2-negative patients to determine their eligibility for HER2-directed therapy, particularly if their HER2 negativity was determined by a single test, especially if they had a single baseline HER2 IHC 1+ test.

Clinical Outcomes of Small Cell Carcinoma of the Genitourinary Tract and the Prognostic Significance of the Tumor Immune Microenvironment.

PURPOSE: Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype. MATERIALS AND METHODS: Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population. RESULTS: A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1-expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02). CONCLUSION: Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in patients with recurrent non-small cell lung cancer after definitive concurrent chemoradiation or radiotherapy.

PURPOSE: Whether prior radiotherapy (RT) affects the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitor (TKI) remains elusive. METHODS: Patients with EGFR-mutated NSCLC treated with EGFR TKIs who recurred after curative treatment at Asan Medical Center, Seoul, Korea were included. The progression-free survival (PFS) and overall survival (OS) from the initiation of EGFR TKI in patients who recurred after definitive RT were analyzed and compared to the outcomes of RT-naïve patients with advanced NSCLC treated with EGFR TKIs from previously reported prospective clinical trial results. RESULTS: A total of 60 patients who recurred after definitive RT were included. The median age was 70 years (range, 38-88), with 24 patients (40.0%) being males. Among the 60 patients, 52 patients (86.7%) had exon 19 deletion or L858R mutation, with 49 patients (81.7%) receiving gefitinib as the first-line EGFR TKI. The median PFS and OS from the initiation of EGFR TKI were 10.4 months (95% confidence interval [CI], 7.4-13.2) and 21.3 months (95% CI, 13.4-28.8), respectively. CONCLUSION: The EGFR TKI efficacy in EGFR-mutated patients with NSCLC who recurred after RT was comparable with that in historic controls of RT-naïve patients with advanced NSCLC treated with EGFR TKIs, indicating that RT may not affect EGFR TKI efficacy.

Treatment With Liposomal Irinotecan Plus Fluorouracil and Leucovorin for Patients With Previously Treated Metastatic Biliary Tract Cancer: The Phase 2b NIFTY Randomized Clinical Trial.

Importance: The NIFTY trial demonstrated the benefit of treatment with second-line liposomal irinotecan (nal-IRI) plus fluorouracil (FU) and leucovorin (LV) for patients with advanced biliary tract cancer (BTC). Objective: To report the updated efficacy outcomes from the NIFTY trial with extended follow-up of 1.3 years with reperformed masked independent central review (MICR) with 3 newly invited radiologists. Design, Setting, and Participants: The NIFTY trial was a randomized, multicenter, open-label, phase 2b clinical trial conducted between September 5, 2018, and December 31, 2021, at 5 tertiary referral centers in South Korea. Patients with advanced BTC whose disease progressed while receiving first-line gemcitabine plus cisplatin with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors, version 1.1, were eligible. Data analysis was completed on May 9, 2022. Interventions: Patients were randomized 1:1 to receive LV, 400 mg/m2, bolus and FU, 2400 mg/m2, for a 46-hour infusion intravenously every 2 weeks with or without nal-IRI, 70 mg/m2, before LV intravenously. Patients were treated until disease progression or unacceptable toxic effects. Main Outcomes and Measures: Primary end point was progression-free survival (PFS) as assessed by MICR. Secondary end points were PFS as assessed by the investigator, overall survival, and objective response rate. Results: A total of 178 patients (75 women [42.1%]; median [IQR] age, 64 [38-84] years) were randomly assigned, and 174 patients were included in the full analysis set (88 patients [50.6%] in the nal-IRI plus FU/LV group vs 86 patients [49.4%] in the FU/LV alone group). In this updated analysis, the median MICR-assessed PFS was 4.2 months (95% CI, 2.8-5.3) for the nal-IRI plus FU/LV group and 1.7 months (95% CI, 1.4-2.6) for the FU/LV alone group (hazard ratio, 0.61; 95% CI, 0.44-0.86; P = .004), in contrast to the 7.1 and 1.4 months reported in the previous study, respectively. The discordance rate for tumor progression date between the MICR and investigators was 17.8% (vs 30% in the previous study). Conclusions and Relevance: The NIFTY randomized clinical trial demonstrated significant improvement in PFS with treatment with nal-IRI plus FU/LV compared with FU/LV alone for patients with advanced BTC after progression to gemcitabine plus cisplatin. The combination of nal-IRI plus FU/LV could be considered as a second-line treatment option for patients with previously treated advanced BTC. Trial Registration: clinicaltrials.gov Identifier: NCT03524508.

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection.

PURPOSE: There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). MATERIALS AND METHODS: Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. RESULTS: Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. CONCLUSION: Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

Current status and future perspective of neoadjuvant therapy in locally advanced and borderline resectable pancreatic adenocarcinoma: a narrative review.

BACKGROUND AND OBJECTIVE: The concept of neoadjuvant approach for patients with locally advanced pancreatic cancer (LAPC) has been evolving with the advancement in therapeutic modalities. In this narrative review, we aimed to discuss the updates and future perspectives on the treatment of LAPC. METHODS: We discussed the recent literature and up-to-date evidence along with the future perspectives for the treatment of LAPC using the neoadjuvant approach. Reviewed literatures were searched by systematic search of PubMed and Google Scholar, including articles published in English between January 1st, 2013, and October 31st, 2021. KEY CONTENT AND FINDINGS: We aimed to review the efficacy outcomes of modern-era chemotherapy regimens and chemoradiation therapy for LAPC based on the results of up-to-date clinical trials and pivotal observational studies. Moreover, we aimed to discuss the role of conversion surgery and studies on the prediction of resectability after neoadjuvant therapy along with the necessity of adjuvant therapy for patients who have received neoadjuvant systemic treatments. Finally, we have addressed several unanswered questions regarding the optimal management of patients with LAPC and determined the future directions by introducing some ongoing trials. CONCLUSIONS: Current chemotherapy and chemoradiation therapy has improved clinical outcomes and the conversion surgery rate in patients with LAPC. Future randomized clinical trials and biomarker studies are needed to provide better evidence that can aid in the selection of optimal treatment modalities for individual patients.

Histopathologic and Molecular Biomarkers of PD-1/PD-L1 Inhibitor Treatment Response among Patients with Microsatellite Instability‒High Colon Cancer.

PURPOSE: Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC. MATERIALS AND METHODS: MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning-based classification model was built to predict treatment response among MSI-H CRCs patients. RESULTS: A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response. CONCLUSION: We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

Clinical Benefit of Maintenance Therapy for Advanced Biliary Tract Cancer Patients Showing No Progression after First-Line Gemcitabine Plus Cisplatin.

PURPOSE: Gemcitabine plus cisplatin (GemCis) is the standard first-line chemotherapy for patients with advanced biliary tract cancer (BTC). In ABC-02 study, the BTC patients received up to 6-8 cycles of 3-weekly GemCis; however, those without progression often receive more than 6-8 cycles. The clinical benefit of maintenance treatment in patients without progression is uncertain. MATERIALS AND METHODS: Advanced BTC patients treated with GemCis between April 2010 and February 2015 at Asan Medical Center, Seoul, Korea, were retrospectively analysed. The patients without progression after 6-8 cycles were stratified according to further treatment i.e., with or without further cycles of GemCis (maintenance vs. observation groups). The primary endpoint was overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 740 BTC patients in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group, 120 in the maintenance group). The median OS from the GemCis initiation was 20.5 months (95% confidence interval [CI], 15.4 to 25.6) and 22.4 months (95% CI, 17.0 to 27.8) in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months (95% CI, 7.0 to 13.8) and 13.2 months (95% CI, 11.3 to 15.2), respectively (p=0.320). CONCLUSIONS: GemCis maintenance is not associated with an improved survival outcome.

Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients.

PURPOSE: Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment. METHODS: Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea. RESULTS: In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2-30.5), the median PFS and OS were 5.2 months (95% CI 4.7-5.6) and 10.4 months (95% CI 9.6-11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0-1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05). CONCLUSIONS: Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC.