Prognostic Factor For Progression-free Survival Research Articles

Prognostic factors influencing progression-free survival in HER2 positive metastatic breast cancer patients who treated with lapatinib and capecitabine combination.

e13031 Background: Her2 positivity is detected in about 20% of breast cancer patients. After trastuzumab-based therapy, lapatinib and capecitabine combination is a treatment option in HER2-positive metastatic patients. The study aimed to evaluate the prognostic factors in HER2 positive metastatic breast cancer patients treated lapatinib and capecitabine combination. Methods: We evaluated data of the HER2 positive metastatic breast cancer patients who were treated with lapatinib and capecitabine retrospectively. The patients' clinical, pathological, and treatment features were recorded from the hospital database. Kaplan Meier and Cox regression analysis were used for survival analysis. Results: 102 patients were included in the study. The median age was 47 (range, 24-87), and 99 (97.1%) patients were female. The number of de-novo metastatic patients was 44 (43.1%). The most common metastatic sites were bone (62.4%), brain (58.6%), liver (35.6%), and lung (34.7%), respectively. All patients were previously treated with trastuzumab-based chemotherapy. 44 (44.1%) patients received hormonotherapy (tamoxifen or aromatase inhibitor), and 23 (22.5%) patients palliative radiotherapy. Complete response was 8.2%, partial response 32%, and stable disease 25.8% with lapatinib and capecitabine combinations. At a median follow of 11.6 months, progression-free survival was 8 (95% CI, 5.1-10.8) months. In multivariate analysis, age (p = 0.020), de-novo metastatic disease (p = 0.028), and endocrine therapy (p = 0.020) were statistically significant prognostic factors for progression-free survival. However, history of breast surgery (p = 0.060), number of chemotherapy used with trastuzumab (p = 0.338), number of metastatic sites (p = 0.257), and palliative radiotherapy (p = 0.394) were not significant. Conclusions: We showed real-life outcomes of the lapatinib and capecitabine combination in metastatic HER2-positive breast cancer patients. Also, we detect that being under age 50 years, de-novo metastatic disease, and hormone-negative tumor were poor prognostic factors of progression-free survival.

The association between BIM deletion polymorphism and treatment efficacy of PD-1/PD-L1 inhibitors in advanced NSCLC.

e21055 Background: PD-L1 is a recommended biomarker for immunotherapy, but Some patients with high pD-L1 expression had poor clinical response. Considering the inconsistent correlation between PD- L1 expression and ICI efficacy, A more sensitive biomarker is needed to predict immunotherapy efficacy. B-cell lymphoma-2 (BCL2L11/BIM) belongs to the Bcl-2 family and is a key factor promoting apoptosis. BIM deletion polymorphism (BIM- del) may lead to BH3 deletion and thus hinder cell apoptosis. Loss and decreased expression of BIM may lead to resistance to tumor therapy. A study on patients with metastatic melanoma found that the high level of BIM in CD8+ T cells suggests a stronger PD-1 and PD-L1 interaction, which predicts clinical benefit in patients with metastatic melanoma receiving anti-PD-1 therapy.This study aims to evaluate the relationship between BIM deletion and PD-1/PD-L1 inhibitors efficacy in advanced NSCLC patients. Methods: Patients diagnosed with advanced stage NSCLC that treated with Immune checkpoint inhibitors (ICIs) at Shandong Cancer Hospital between March 2019 and January 2021 were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. Results: A total of 61 patients with advanced NSCLC who received immunotherapy were enrolled, only 18.0% (11/61) patients were detected with BIM-del. Most of the patients were male (73.8%, 45/61), younger than 65 years (72.1%, 44/61), non- smokers (50.8%, 31/61), previous treatment lines 0-1 (90.2%, 55/61),had Eastern Tumor Cooperative group (ECOG) performance status (PS) 0-1 (98.4%, 60/61). There were no associations between the BIM-del and clinical characteristics. There was no difference in the objective response rate between patients with and without BIM-del (27.3% vs 30 %, p = 1.000).BIM-del is associated with shorter progression-free survival (PFS) (5.7 months vs12.0 months, p = 0.001). The median OS had not been reached. Multivariate analysis suggested that BIM-del was an negative independent prognostic factor for PFS in immunotherapy patients with non-small cell lung cancer, but not for OS. Conclusions: BIM-del may be a negative prognostic biomarker for patients with advanced NSCLC treated with immunosuppressive therapy. It is very important to find effective and accurate biomarkers to predict the PD-1/PD-L1 inhibitors Treatment efficacy, and further exploration is needed in the future.

The prognostic significance of pretreatment squamous cell carcinoma antigen levels in cervical cancer patients treated by concurrent chemoradiation therapy and a comparison of dosimetric outcomes and clinical toxicities between tomotherapy and volumetric modulated arc therapy

BackgroundTo analyze the prognostic factors associated with stage IB-IVA cervical cancer in patients who underwent concurrent chemoradiation therapy (CCRT) and to compare the clinical toxicities and dosimetric parameters of organs at risk between the different radiotherapy techniques.MethodsThis retrospective study enrolled 93 patients with stage IB-IVA cervical cancer who underwent definitive CCRT between April 2009 and December 2017. Nine patients (9.7%) received 3DCRT, 43 patients (46.2%) underwent VMAT, and 41 patients (44.1%) received tomotherapy, and all of them followed by brachytherapy using a 2D planning technique. The treatment outcomes and related prognostic factors were analyzed. We also compared the clinical toxicities and dosimetric parameters between the different techniques used for the last 30 patients.ResultsWith a median follow-up of 52.0 months, the 5-year overall survival (OS), progression-free survival (PFS), locoregional recurrence–free survival (LRRFS), and distant metastases–free survival (DMFS) were analyzed. In a Cox proportional hazards regression model, pretreatment SCC Ag > 10 ng/mL was a significant prognostic factor for PFS (hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.03–4.70; P = 0.041), LRRFS (HR, 3.48; 95% CI 1.07–11.26; P = 0.038), and DMFS (HR 2.80; 95% CI 1.02–7.67; P = 0.045). Increasing the rectal volume receiving a radiation dose exceeding 30 Gy (V30 of rectum; odds ratio [OR] 1.15; 95% CI 1.10–1.30; P = 0.03) was associated with a higher possibility of ≥ Grade 2 acute radiation therapy (RT)-related diarrhea. The median rectal V30 values were 56.4%, 97.5%, and 86.5% for tomotherapy, 3-dimensional conformal radiation therapy (3DCRT), and volumetric modulated arc therapy (VMAT), respectively (P < 0.001). In addition, the chance of experiencing ≥ Grade 2 acute diarrhea were 10.0%, 66.7%, and 54.5% for tomotherapy, 3DCRT, and VMAT, respectively (P = 0.029).ConclusionsPatients with pretreatment SCC Ag ≤ 10 ng/mL have better PFS, LRRFS, and DMFS than those with pretreatment SCC Ag > 10 ng/mL. The rectal V30 is a significant predictor of severe acute diarrhea. Tomotherapy significantly decreased the rectal V30, reducing the severity of acute RT-related diarrhea during external beam RT.Trial registration This study was approved by the institutional review board at Kaohsiung Medical University Hospital. The registration number is KMUHIRB-E(I)-20190054 and retrospectively registered on 2019/3.

MP27-07 COMPARISON OF CLINICAL OUTCOMES BETWEEN ANDROGEN DEPRIVATION THERAPY WITH UP-FRONT ABIRATERONE AND BICALUTAMIDE FOR JAPANESE PATIENTS WITH LATITUDE HIGH-RISK PROSTATE CANCER IN A REAL-WORLD MULTICENTER ANALYSIS

You have accessJournal of UrologyCME1 May 2022MP27-07 COMPARISON OF CLINICAL OUTCOMES BETWEEN ANDROGEN DEPRIVATION THERAPY WITH UP-FRONT ABIRATERONE AND BICALUTAMIDE FOR JAPANESE PATIENTS WITH LATITUDE HIGH-RISK PROSTATE CANCER IN A REAL-WORLD MULTICENTER ANALYSIS Taku Naiki, Kiyoshi Takahara, Toshiki Ito, Keita Nakane, Yosuke Sugiyama, Takuya Koie, Ryoichi Shiroki, Hideaki Miyake, and Takahiro Yasui Taku NaikiTaku Naiki More articles by this author , Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Toshiki ItoToshiki Ito More articles by this author , Keita NakaneKeita Nakane More articles by this author , Yosuke SugiyamaYosuke Sugiyama More articles by this author , Takuya KoieTakuya Koie More articles by this author , Ryoichi ShirokiRyoichi Shiroki More articles by this author , Hideaki MiyakeHideaki Miyake More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002570.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Combining abiraterone (Abi) with androgen deprivation therapy (ADT) improves overall survival, compared to ADT only, in patients with metastatic castration-sensitive prostate cancer (mCSPC). In Japan, bicalutamide (Bica) and ADT (combined androgen blockade: CAB) is frequently provided for mCSPC. Because these two treatments have not been compared, mCSPC patients who received either treatment were retrospectively analyzed. METHODS: Of 178 patients with LATITUDE high-risk mCSPC, 103 had received ADT plus upfront Abi (Abi group) and 75 had received ADT plus Bica (Bica group) in multiple institutions of the Tokai Urologic Oncology Research Seminar. Kaplan–Meir curves were used to retrospectively analyze survival and cancer recurrence. Univariate and multivariate Cox regression analyses identified potential prognostic factors for progression-free survival (PFS). In addition, the propensity score matched analysis was also estimated. RESULTS: Significant differences in major clinicopathological characteristics between the two groups were not observed. The rate of CRPC development was higher in the Bica compared to Abi group (50.6% vs. 25.2%, p<0.001). The median PFS in the Bica group was 13.6 months (95% CI: 9.2–22.2); however, in the Abi group, PFS did not reach the median (p<0.001). Time to second progression for the Abi group was superior (p=0.07). Univariate and multivariate analyses revealed Gleason pattern 5, high alkaline phosphatase levels, and conventional CAB using Bica as significant prognostic factors for short PFS. In addition, by propensity matched analysis, similar to findings for the total cohort, the development of CRPC was found to be significantly higher in the Bica compared to Abi group (49.3% for Bica group vs. 23.9% for Abi group, p<0.01). The median PFS in the Bica group was 13.6 months (95% CI: 9.1–24.0); however, in the Abi group, the median was not reached (95% CI: 15.6–NA, p<0.05). CONCLUSIONS: In patients with LATITUDE high-risk mCSPC, upfront use of Abi combined with ADT resulted in favorable prognostic outcomes compared with conventional ADT with Bica. Source of Funding: none © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e452 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Taku Naiki More articles by this author Kiyoshi Takahara More articles by this author Toshiki Ito More articles by this author Keita Nakane More articles by this author Yosuke Sugiyama More articles by this author Takuya Koie More articles by this author Ryoichi Shiroki More articles by this author Hideaki Miyake More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement PDF DownloadLoading ...

Verification of HPV16 as a good prognostic factor for cervical adeno-adenosquamous carcinoma via an international collaborative study

ObjectiveThis study (Asian Gynecologic Oncology Group [AGOG]13-001/Taiwanese Gynecologic Oncology Group [TGOG]1006) was to validate human papillomavirus (HPV)16 as an independent good prognostic factor and investigate the impact of treatment modalities to cervical adenocarcinoma and adenosquamous carcinoma (AD/ASC). Materials and methodsPatients receiving primary treatment at AGOG and TGOG member hospitals for cervical AD/ASC were retrospectively (1993–2014) and prospectively (since 2014) enrolled. DNA extraction from paraffin-embedded tissue (FFPE) specimens was used for HPV genotyping. Those with suspected endometrial origin were excluded for analysis. ResultsA total of 354 patients with valid HPV results were enrolled, 287 (81.1%) of which had HPV-positive tumors. The top-3 types were HPV 18 (50.8%), HPV16 (22.9%) and HPV45 (4.0%). The HPV16-negativity rates varied widely across hospitals. 322 patients were eligible for prognostic analyses. By multivariate analysis, advanced stage (HR5.8, 95% confidence interval [CI] 2.1–15.8; HR5.8, 95% CI 1.6–20.5), lymph node metastasis (HR4.6, 95% CI 2.7–7.9; HR7.3, 95% CI 3.8–14.0), and HPV16-positivity (HR0.3, 95% CI 0.1–0.6; HR0.3, 95% CI 0.1–0.9) were independent prognostic factors for progression-free survival (PFS) and overall survival (OS). Stage I patients with primary surgery had better 5-year PFS (82.8% vs 50.0% p = 0.020) and OS (89.3% vs 57.1%, p = 0.017) than those with non-primary surgery, while the propensity scores distribution were similar among the treatment groups. ConclusionThis study confirmed that HPV16-positivity was a good prognostic factor for PFS and OS in AD/ASC, and patients seemed to have better outcome with primary surgery than non-primary surgery.

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Spatial analysis of tumor-infiltrating lymphocytes in histological sections using deep learning techniques predicts survival in colorectal carcinoma.

This study aimed to explore the prognostic impact of spatial distribution of tumor‐infiltrating lymphocytes (TILs) quantified by deep learning (DL) approaches based on digitalized whole‐slide images stained with hematoxylin and eosin in patients with colorectal cancer (CRC). The prognostic impact of spatial distributions of TILs in patients with CRC was explored in the Yonsei cohort (n = 180) and validated in The Cancer Genome Atlas (TCGA) cohort (n = 268). Two experienced pathologists manually measured TILs at the most invasive margin (IM) as 0–3 by the Klintrup–Mäkinen (KM) grading method and this was compared to DL approaches. Inter‐rater agreement for TILs was measured using Cohen's kappa coefficient. On multivariate analysis of spatial TIL features derived by DL approaches and clinicopathological variables including tumor stage, microsatellite instability, and KRAS mutation, TIL densities within 200 μm of the IM (f_im200) remained the most significant prognostic factor for progression‐free survival (PFS) (hazard ratio [HR] 0.004 [95% confidence interval, CI, 0.0001–0.15], p = 0.0028) in the Yonsei cohort. On multivariate analysis using the TCGA dataset, f_im200 retained prognostic significance for PFS (HR 0.031 [95% CI 0.001–0.645], p = 0.024). Inter‐rater agreement of manual KM grading was insignificant in the Yonsei (κ = 0.109) and the TCGA (κ = 0.121) cohorts. The survival analysis based on KM grading showed statistically significant different PFS in the TCGA cohort, but not the Yonsei cohort. Automatic quantification of TILs at the IM based on DL approaches shows prognostic utility to predict PFS, and could provide robust and reproducible TIL density measurement in patients with CRC.

A Retrospective Study of First-Line Therapy Involving Immune Checkpoint Inhibitors in Patients With Poor Risk Metastatic Renal Cell Carcinoma.

PurposePatients with International Metastatic RCC Database Consortium (IMDC) poor risk metastatic renal cell carcinoma (mRCC) rarely respond to first-line tyrosine kinase inhibitors (TKIs) including sunitinib, and carries a very poor prognosis. In recent years, combination therapy involving immune checkpoint inhibitors (ICIs) have demonstrated superior efficacy to sunitinib in poor risk disease.Materials and MethodsIn a retrospective study using a cancer chemotherapy registry, 206 consecutive patients with mRCC in the first-line setting were identified between Oct 2019 and Dec 2020. Sixty-one patients had a poor risk mRCC, and were treated with TKI monotherapy (n=36), nivolumab plus ipilimumab (n=16), or pembrolizumab plus axitinib (n=9). Endpoints included overall survival (OS), progression-free survival (PFS), response rate (RR), and safety.ResultsPatients’ median age was 61 years and the median number of risk factors was 3 (range, 3-5). During a median 23.0 months of follow-up, the median OS was 24.3 months with ICI-based combinations and 14.8 months with TKI monotherapy, and the median PFS periods were 9.3 months and 3.4 months, respectively. An objective response occurred in 60% of the patients receiving ICI-based combinations and in 19% of those receiving TKI monotherapy (P=0.001). In the multivariate regression model, number of IMDC risk factors and the ICI-based combination therapy were independent prognostic factors for PFS. All-causality grade 3 or 4 adverse events were 44% for ICI-based combinations and 50% for TKI monotherapy.ConclusionsAmong patients with poor risk mRCC, first-line ICI-based therapy showed significantly longer OS and PFS, as well as a higher RR, than TKI monotherapy.

Prognostic value and biological function of LRRN4 in colorectal cancer

BackgroundSeveral nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear.MethodsWe examined the expression and clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry in a Chinese cohort. Furthermore, colony formation, flow cytometry, wound healing assays and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted coexpression network analysis, DAVID and western blot analysis were used to explore the potential molecular mechanism.ResultsWe provide the first evidence that LRRN4 expression, at both the mRNA and protein levels, was remarkably high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K. LRRN4 knockdown resulted in downregulation of Akt, p-Akt, ERK1/2 and p-ERK1/2, the downstream of the Ras/MAPK signaling pathway, overexpression of LRRN4 leaded to the upregulation of these proteins.ConclusionsOur results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 regulating several malignant phenotypes of neoplastic cells via RAS/MAPK signal pathways.

Surgical treatment of patients with lymph node involvement in recurrent ovarian cancer: immediate and long-term results

Objective: analysis of the immediate and long-term results of surgical treatment of patients with lymph node (Ln) involvement in recurrent ovarian cancer (OC), as well as the search for prognostic factors for progression-free survival (PfS) and overall survival (OS).Materials and methods. The retrospective analysis included patients under the age of 75 who underwent surgery for recurrence of OC with Ln involvement at n.n. Blokhin national medical Research Center of Oncology in the period from 2005 to 2020. All patients had previously received combined treatment due to a primary diagnosis of OC. Exclusion criteria: the presence of concomitant pathology in the decompensation phase, primary multiple malignant tumors and recurrences of non-epithelial ovarian tumors. The analysis of the main operational characteristics, the frequency of postoperative complications according to Clavien–Dindo within 30 days after surgery, PfS, OS, as well as parameters affecting the long-term results of treatment were performed.Results. The study included 123 patients: a cohort of isolated lesions of the Ln (n = 65) and a group of combined recurrence in the Ln and other anatomical locations (n = 58). The frequency of complete cytoreduction was significantly higher in the group of patients with isolated recurrence in the Ln: 86.62 % versus 53.4 % in patients with combined relapse, p &lt;0.0001. The median duration of the operation was also significantly higher in patients with combined recurrence: 245 min versus 180 min in a cohort of patients with isolated recurrence in the Ln, p &lt;0.0001. Postoperative complications of grade III B were more often observed in the group of combined recurrence: 6.8 % versus 1.5 % in the group of isolated recurrence in the Ln, p = 0.148. none of the patients in the group of isolated recurrence in the Ln had postoperative mortality, while in the group of combined recurrence 2 (3.4 %) patients died after surgery from developed complications. In patients with isolated recurrence in the Ln and combined recurrence of OC, the median PfS was significantly higher when complete cytoreduction was achieved: 31.0 months and 18.0 months versus 10.0 months and 9.0 months with incomplete repeated cytoreduction, p &lt;0.0001. In patients with isolated recurrence in the Ln and combined recurrence of OC, the median OS was identically significantly higher when complete repeated cytoreduction was achieved: 97.0 months and 60.0 months versus 34.0 months and 27.0 months with incomplete cytoreduction, p &lt;0.0001.Conclusion. Surgical treatment of recurrence of OC is justified only if it is possible to achieve complete cytoreduction and platinum-sensitive type of recurrence of OC. Low grade tumor, platinum-sensitive type of recurrence, absence of marker recurrence of OC, isolated recurrence in Ln, complete repeated cytoreduction and lymphodissection were identified as predictors of PfS in multivariate analysis. The following factors had an independent favorable effect on OS in multivariate analysis: low tumor grade, platinum-sensitive type of recurrence, satisfactory overall status on the ECOg scale (0–1 points) at the time of detection of relapse, isolated recurrence in the Ln and complete repeated cytoreduction.

The efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer patients with different driver gene mutations

Objective: To explore the efficacy and prognostic factors of immunotherapy in advanced non-small cell lung cancer (NSCLC) patients with different driver gene mutations. Methods: Medical records of advanced NSCLC patients who harbored driver gene mutations (EGFR, KRAS, ALK and etc.) and received PD-1 inhibitors in Henan Cancer Hospital from April 2016 to May 2021 were collected. Treatment patterns, progression free survival (PFS), overall survival (OS) and prognostic factors of patients with driver gene mutations were estimated. Results: A total of 120 patients were included. There were 70 males and 50 females, with a median age [M(Q1,Q3)] of 57 (50, 65) years. Of these, 52 patients harbored KRAS mutations, 42 patients harbored EGFR mutations, 16 patients harbored ERBB2 mutations, 5 patients harbored MET mutations or amplifications, 5 patients harbored ROS-1 mutations, 2 patients harbored BRAF mutations, and the last 2 patients harbored ALK and RET mutations, respectively. The PFS and OS [M (95%CI)] were 6.4 (5.1-7.8) and 31.2 (22.0-40.3) months in 120 participated patients. Patients with KRAS mutations showed the greatest survival benefit from Immune checkpoint inhibitors (ICIs) with the PFS of 9.7 (4.8-14.6) months and OS of 31.2 (19.4-50.6) months. They mostly received the first-line (34.6%, 18/52) and second-line (38.5%, 20/52) ICIs. The PFS and OS of EGFR mutant patients were 3.9 (1.8-6.1) months and 18.0 (12.1-23.8) months, respectively. They tended to receive ICIs after resistance to EGFR-tyrosine kinase inhibitors (TKIs), and the proportion of second-, third-, fourth or further-line drugs was 38.1% (16/42), 11.9% (5/42), and 47.6% (20/42), respectively. PD-L1 expression level (negative vs ≥50% positive: HR=3.710, 95%CI: 1.372-10.031, P=0.010; 1%-49% positive vs ≥50% positive: HR=2.738, 95%CI: 0.841-8.912, P=0.094), age (every additional year: HR=0.957, 95%CI: 0.933-0.982, P=0.001) and different driver mutations status (EGFR vs KRAS: HR=2.676, 95%CI: 1.317-5.436, P=0.006; ERBB2 vs KRAS: HR=3.411, 95%CI: 1.493-7.792, P=0.004; other mutations vs KRAS: HR=0.727, 95%CI: 0.322-1.643, P=0.444) were prognostic factors for PFS. While PD-L1 expression level (negative vs ≥50% positive: HR=2.305, 95%CI: 0.748-7.103, P=0.146; 1%-49% positive vs ≥50% positive: HR=1.286, 95%CI: 0.337-4.913, P=0.713), and treatment lines of ICIs (first-line vs ≥ third-line: HR=0.322, 95%CI: 0.114-0.914, P=0.033; second-line vs ≥ third-line: HR=0.375, 95%CI: 0.178-0.789, P=0.010) were prognostic factors for OS. Conclusions: KRAS mutant NSCLC patients mostly receive ICIs at the front line, and have best survival benefits from immunotherapy. While EGFR mutant NSCLC patients tend to receive ICIs at the back line, and obtain reasonable survival benefits. PD-L1 expression level, age, and different driver mutations status are prognostic factors for PFS, and PD-L1 expression level and treatment lines of ICIs are prognostic factors for OS.

Clinicopathological features and programmed death-ligand 1 immunohistochemical expression in a multicenter cohort of uterine and ovarian melanomas: a retrospective study in Japan (KCOG-G1701s).

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients with HER2-positive metastatic breast cancer: a phase II, multicenter, single-arm study (SYSUCC-005)

BackgroundDespite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer.MethodsPatients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1–14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS).ResultsBetween January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151–2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%).ConclusionThe switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer.Trial registrationThis trial was registered on ClinicalTrials.gov (NCT02362958) on 13/02/2015.

Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma.

Increased expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14) is associated with the development of many cancers. MT1-MMP may promote the entry of yes-associated protein1 (YAP1) into the nucleus by regulating the regulation of β1-integrin. The purpose of this study was to investigate the effects of MT1-MMP, β1-integrin and YAP1 on the prognosis of gliomas. The expression of proteins was detected by bioinformatics and immunohistochemistry. The relationship between three proteins and clinicopathological parameters was analyzed by the χ 2 test. Survival analysis was used to investigate the effects of three proteins on prognosis. The results showed that high expressions of MT1-MMP, β1-integrin and YAP1 were found in glioblastoma (GBM) compared with lower-grade glioma (LGG). There was a significantly positive correlation between MT1-MMP and β1-integrin (r = 0.387), MT1-MMP and YAP1 (r = 0.443), β1-integrin and YAP1 (r = 0.348). Survival analysis showed that patients with overexpression of MT1-MMP, β1-integrin and YAP1 had a worse prognosis. YAP1 expression was the independent prognostic factor for progression-free survival (PFS). There was a statistical correlation between the expression of MT1-MMP and YAP1 and isocitrate dehydrogenase 1 (IDHl) mutation. Thus, this study suggested that MT1-MMP, β1-integrin and YAP1, as tumor suppressors, are expected to be promising prognostic biomarkers and therapeutic targets for glioma patients.

Real-world experience of pembrolizumab and lenvatinib in recurrent endometrial cancer: A multicenter study in Korea

ObjectiveTo investigate the effectiveness and safety of pembrolizumab and lenvatinib (PEMBRO+LEN) for recurrent endometrial cancer (EC) in a real-world setting. MethodsThis multicenter retrospective cohort study included patients with recurrent EC who received PEMBRO+LEN between March 2020 and May 2021 at three tertiary hospitals in Korea. We summarized patient characteristics and evaluated the response rates, survival outcomes, and treatment-related adverse events (AEs). ResultsIn total, 48 patients were included in the study. The median age of the patients was 62.5 (range, 42–78) years. The most common histologic subtype was endometrioid adenocarcinoma (43.8%), followed by serous adenocarcinoma (25.0%). Most patients (91.7%) had mismatch repair-proficient tumors. Patients received PEMBRO+LEN for a median of 4.5 cycles, during which the best objective response rate and disease control rate were 23.8% (95% CI, 11.9–38.1) and 76.2% (95% CI, 61.9–88.1), respectively. Overall, 56.2% of patients experienced LEN dose reduction once or more and 16.7% experienced LEN interruption. The most common treatment-related AEs were fatigue (18.8%), hypertension (16.7%), and hypothyroidism (14.6%). Total of 8 patients (16.7%) discontinued LEN during the treatment because of treatment-related AEs. Serum CA-125 level was the only prognostic factor for progression-free survival (adjusted hazard ratio, 4.41; 95% confidence interval, 1.19–16.36; p = 0.03). ConclusionsIn our real-world study, Korean patients with recurrent EC who received PEMBRO+LEN showed lower treatment response rate and similar treatment discontinuation rate, compared to clinical trials.

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials

BackgroundThe prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS).Patients and methodsThis retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020.ResultsOverall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%.ConclusionsEarly phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit.

The Use of 18F-FDG PET/CT Metabolic Parameters in Predicting Overall Survival in Patients Undergoing Restaging for Malignant Melanoma

Malignant melanoma is one of the more aggressive cancers in the skin, with an increasing incidence every year. Melanoma has a better prognosis if diagnosed early and survival tends to decrease once the disease has metastasized. Positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) has been used extensively over the past two decades in staging and assessing responses to therapy in patients with melanoma. Metabolic PET parameters have been demonstrated to be independent prognostic factors for progression-free survival (PFS) and overall survival (OS) in different malignancies, melanoma included. In our study, we evaluated the metabolic parameters of 18F-FDG PET/CT (flourodeoxyglucose positron emission tomography/computed tomography) in predicting the overall survival in patients with malignant melanoma who presented for restaging. Metabolic PET parameters (maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG)) of the primary tumor, as well as whole-body MTV and TLG of the metastatic disease, were measured. Survival curves for OS were constructed and mortality rates were determined using the different PET variables. Forty-nine patients who presented for a PET/CT restaging in melanoma were included in this study. We found that non-survivors had significantly higher median MTV (11.86 cm3 vs. 5.68 cm3; p-value = 0.022), TLG (3125 vs. 14; p-value = 0.0357), whole-body MTV (53.9 cm3 vs. 14.4 cm3; p-value = 0.0076) and whole-body TLG (963.4 vs. 114.6; p-value = 0.0056). This demonstrated that high MTV and TLG values of the primary tumor and whole-body TLG as quantified by 18F-FDG PET/CT were prognostic factors for overall survival. The findings may potentially guide clinicians in decision making and identifying patients with a poorer prognosis.

High AKAP8L expression predicts poor prognosis in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC.MethodsThe mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson’s chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan–Meier survival curve was used for survival analysis.ResultsWe found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan–Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001).ConclusionsIn conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.

Potential efficacy of weekly low-dose administration of bevacizumab as a combination therapy for platinum-resistant ovarian carcinoma: a retrospective analysis

BackgroundBevacizumab (Bev) plays the central role of the adjuvant therapy for patients with ovarian carcinoma. The aim of our study was to examine whether differences in the administration of Bev influence the prognosis of patients.MethodsPatients with ovarian carcinoma who received treatment at two hospitals between 1999 and 2020 were identified. Patients treated with weekly low-dose administration of Bev (100 mg Bev on days 1 and 8 and 200 mg Bev on day 15, monthly) at one hospital (group A) and those with monthly high-dose administration of Bev (15 mg/kg of Bev on day 1, monthly) at another hospital (group B) were retrospectively compared.ResultsAmong the total patients, 44 were assigned to group A and 33 were assigned to group B. More patients in group A had advanced disease (p = 0.03) and a lower dose of Bev at the first time during the first cycle administration (p < 0.01) than in group B. Progression-free survival (PFS) was better in group A than in group B (p < 0.01). Multivariate analysis revealed that group A was a better prognostic factor for PFS (hazard ratio 0.53, p = 0.03). Stable duration was longer in group A than in group B (p < 0.01). The incidences of adverse effects, including hematological toxicities such as neutropenia (p = 0.01) and nonhematological toxicities such as hypertension (p < 0.01), intestinal obstruction (p < 0.01), and thromboembolic events (p < 0.01), were lower in group A than in group B.ConclusionsWeekly low-dose administration of Bev might improve prognosis and decrease the frequency of adverse effects associated with this drug although the prospective study was needed to get corroboration.

Association of early alpha-fetoprotein response with survival in patients with HBV-related hepatocellular carcinoma receiving lenvatinib.

448 Background: Lenvatinib is a standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). We assessed the value of early alpha-fetoprotein (AFP) response for predicting clinical outcomes to lenvatinib treatment in patients with HBV-related uHCC and elevated AFP levels. Methods: This was a retrospective analysis of the medical records of consecutive patients with HBV-related uHCC and baseline AFP levels ≥20 ng/ml who received lenvatinib for &gt; 1 month at The First Hospital of Jilin University between November 2018 and May 2021. Early AFP response was defined as a &gt; 20% decrease in AFP serum level from baseline after 4 weeks of lenvatinib treatment. We evaluated radiological response using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as well as progression-free survival (PFS), and overall survival (OS) in AFP responders and non-responders. Potential prognostic factors for PFS and OS were assessed using univariate and multivariate Cox proportional hazards models. Intergroup differences were compared using a Mann–Whitney U test for continuous variables, a Fisher’s exact test for categorical variables and a log–rank test for survival data. Results: Medical records from 79 patients were screened and a total of 46 patients were included in the analysis; 84.4% had received lenvatinib in first-line, 63% were Child-Pugh class A, 56.4% had extrahepatic metastases, 35.6% had portal vein thrombosis and 10.3% and 87.2% had BCLC stage B and C disease, respectively. Of the 46 patients, 65.2% (n = 30) were early AFP responders and 34.8% (n = 16) were AFP non-responders. Baseline characteristics were balanced between early AFP responders and non-responders, except for age (≥60 years: 43.3% vs. 12.5%; p = 0.0366) and presence of portal vein thrombosis (46.7% vs. 13.3%; p = 0.0277). The median follow-up time was 18.0 (IQR, 3-29) months. Early AFP responders versus non-responders had a significantly higher objective response rate (34.5% vs 6.3%, p = 0.0349), disease control rate (82.8% vs 50.0%; p = 0.0203) and a longer median PFS (13.0 vs 7.0 months; HR, 0.464; 95% CI, 0.222-0.967; p = 0.028). Multivariate analysis confirmed that early AFP response (HR, 0.366; 95% CI, 0.169-0.795; p = 0.0110), ECOG PS of 0 (HR, 0.497; 95% CI, 0.323-0.877; p = 0.0326) and ALBI grade 1 (HR, 0.411; 95% CI, 0.277-0.863; p = 0.0283) were independent prognostic factors for longer PFS. Conclusions: AFP is an important prognostic factor and a predictive biomarker of survival benefit for patients with HBV-related uHCC receiving treatment with lenvatinib.