Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer.

BACKGROUND: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863). METHODS: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise. FINDINGS: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months). INTERPRETATION: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

A phase II study of osimertinib in patients with NSCLC harboring EGFR exon 20 insertion: A multicenter trial of the Korean Cancer Study Group (LU17-19).

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions account for up to 10% of all EGFR mutations. Clinical outcomes in patients receiving approved EGFR exon 20 insertion-specific inhibitors have been variable. Although osimertinib has demonstrated antitumor activity in clinical trials, its clinical efficacy and translational potential remain to be determined in non-small cell lung carcinoma (NSCLC) with EGFR exon 20 insertion. METHODS: In this multicenter phase II study, patients with advanced NSCLC harboring EGFR exon 20 insertions for whom the standard chemotherapy failed received 80 mg osimertinib once daily. The primary endpoint was the investigator-assessed objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety profile. RESULTS: Among 15 patients enrolled at stage 1, the best response was most commonly disease stabilization (73.3 %), which did not meet the stage 1 threshold (objective response ≥ 2/15). As of data cutoff, two patients remained on the treatment. The median PFS and OS were 3.8 (95 % confidence interval [CI] = 1.7-5.5) months and 6.5 (95 % CI = 3.9-not reached) months, respectively. Adverse events (≥grade 3) were anemia, hypercalcemia, and pneumonia (13.3 % each), and asthenia, femur fracture, increased alkaline phosphate, hyperkalemia, bone pain, and azotemia (6.7 % each). Pre-existing EGFR C797S mutation detected in plasma limited the efficacy of osimertinib. CONCLUSION: Osimertinib at 80 mg once daily had limited efficacy and mostly showed disease stabilization with an acceptable safety profile in advanced NSCLC harboring EGFR exon 20 insertions. CLINICALTRIALS: govIdentifier: NCT03414814.

Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Current status of advance care planning, palliative care consultation, and end-of-life care in patients with glioblastoma in South Korea.

BACKGROUND: Given the typical trajectory of glioblastoma, many patients lose decision-making capacity over time, which can lead to inadequate advance care planning (ACP) and end-of-life (EOL) care. We aimed to evaluate patients' current ACP and EOL care status. PATIENTS AND METHODS: We conducted a cohort study on 205 patients referred to oncologists at a Korean tertiary hospital between 2017 and 2022. We collected information on sociodemographic factors, cancer treatment, palliative care consultation, ACP, legal documents on life-sustaining treatment (LST) decisions, and aggressiveness of EOL care. RESULTS: With a median follow-up time of 18.3 months: 159 patients died; median overall survival: 20.3 months. Of the 159 patients, 11 (6.9%) and 63 (39.6%) had advance directive (AD) and LST plans, respectively, whereas 85 (53.5%) had neither. Among the 63 with LST plans, 10 (15.9%) and 53 (84.1%) completed their forms through self-determination and family determination, respectively. Of the 159 patients who died, 102 (64.2%) received palliative care consultation (median time: 44 days from the first consultation to death) and 78 (49.1%) received aggressive EOL care. Those receiving palliative care consultations were less likely to receive aggressive EOL care (83.3% vs 32.4%, P < .001), and more likely to use more than 3 days of hospice care at EOL (19.6% vs 68.0%, P < .001). CONCLUSIONS: The right to self-determination remains poorly protected among patients with glioblastoma, with nearly 90% not self-completing AD or LST plan. As palliative care consultation is associated with less aggressive EOL care and longer use of hospice care, physicians should promptly introduce patients to ACP conversations and palliative care consultations.

Alteration of HER2 Status During Breast Cancer Progression: A Clinicopathological Analysis Focusing on HER2-Low Status.

Recent studies have shown that novel antibody-drug conjugates (ADCs) can improve clinical outcomes in patients with HER2-low breast cancers. This study aimed to investigate alteration of HER2 status during breast cancer progression with an emphasis on HER2-low status. Using 386 paired samples of primary and recurrent breast cancers, HER2 discordance rate between primary and matched recurrent samples, the relationships between HER2 discordance and clinicopathological characteristics and clinical outcomes of the patients were analyzed. HER2 discordance rate between primary breast cancer and first recurrence was 25.9% (κ = 0.586) with mostly zero-to-low (10.6%) or low-to-zero (9.3%) conversion. There was no significant difference in the discordant rates according to type or location of the recurrence. Of 70 cases with a second recurrence, HER2 discordance rate between the primary tumor and the second recurrence was 27.1% (κ = 0.554). HER2 discordance was associated with lower HER2 level, lymphovascular invasion, and progesterone receptor positivity of the primary tumor. In further analyses, HER2-zero-to-low conversion was associated with lymph node metastasis and hormone receptor (HR) positivity, whereas HER2-low-to-zero conversion was associated with HR negativity and triple-negative subtype. In survival analyses, HER2 discordance was associated with decreased overall survival of patients in the HR-positive group but not in the HR-negative group. Furthermore, patients with HER2-low-to-zero converted tumors showed worse overall survival compared with those with HER2-low concordant tumors. In conclusion, HER2 status changes during breast cancer progression in significant proportions, mostly between zero and low status. As HER2 instability increases during progression and affects clinical outcome, HER2 status needs to be reevaluated in recurrent settings.

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Alteration of PD-L1 (SP142) status after neoadjuvant chemotherapy and its clinical significance in triple-negative breast cancer.

PURPOSE: The tumor immune microenvironment can change after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC). We aimed to investigate the effects of NAC on PD-L1 (SP142) status and its clinical significance in TNBC. METHODS: Paired samples of biopsy and resection specimens were collected from 182 patients with TNBC before and after NAC. PD-L1 (SP142) expression in immune cells in pre- and post-NAC breast cancer samples and the changes between them were analyzed, along with their relationships with the clinicopathological features and clinical outcomes of the patients. RESULTS: Of the 182 patients, 61 (33.5%) achieved pathologic complete response (pCR) after NAC. PD-L1 (SP142) positivity, defined as immune cell staining in ≥ 1% of tumor area, was a predictor for pCR. PD-L1-positive immune cells significantly increased after NAC (2.8% to 5.2% on average) in 109 patients with measurable residual disease. Alteration of PD-L1 status was observed in 24 (22.0%) of the 109 patients with measurable residual tumors after NAC, and all PD-L1 status-converted patients, except one, revealed negative-to-positive conversion. Regarding chemotherapeutic agents, the use of platinum agents was associated with a significant increase in PD-L1-positive immune cells after NAC. In survival analyses, a positive PD-L1 status after NAC and increase of PD-L1-positive immune cells after NAC were associated with better recurrence-free survival of the patients. CONCLUSION: PD-L1 (SP142) status changes after NAC, mostly as a positive conversion. As PD-L1 (SP142) status can convey prognostic and predictive information, it needs to be tested before and after NAC.

Impact of concurrent medications on clinical outcomes of cancer patients treated with immune checkpoint inhibitors: analysis of Health Insurance Review and Assessment data.

PURPOSE: Medications regulating immune homeostasis and gut microbiota could affect the efficacy of immune checkpoint inhibitors (ICIs). This study aimed to investigate the impact of concurrent medications on the clinical outcomes of patients with cancer receiving ICI therapy in South Korea. METHODS: We identified patients newly treated with ICI for non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), and malignant melanoma (MM) between August 2017 and June 2020 from a nationwide database in Korea. The effect of concurrent antibiotics (ATBs), corticosteroids (CSs), proton-pump inhibitors (PPIs), and opioids prescribed within 30 days before ICI initiation on the treatment duration and survival was assessed. RESULTS: In all, 8870 patients were included in the ICI cohort (NSCLC, 7,128; UC, 960; MM, 782). The patients were prescribed ATBs (33.8%), CSs (47.8%), PPIs (28.5%), and opioids (53.1%) at the baseline. The median overall survival durations were 11.1, 12.2, and 22.1 months in NSCLC, UC, and MM subgroups, respectively, since starting the ICI mostly as second-line (NSCLC and UC) and first-line (MM) therapy. Early progression was observed in 34.2% of the patients. Opioids and CS were strongly associated with poor survival across all cancer types. A high number of concurrent medications was associated with early progression and short survival. Opioid and CS use was associated with poor prognosis in all patients treated with ICIs. However, ATBs and PPIs had a cancer-specific effect on survival. CONCLUSION: A high number of concurrent medications was associated with poor clinical outcomes.

Impact of Patient Sex on Adverse Events and Unscheduled Utilization of Medical Services in Cancer Patients Undergoing Adjuvant Chemotherapy: A Multicenter Retrospective Cohort Study.

PURPOSE: The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex. MATERIALS AND METHODS: This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea. RESULTS: A total of 1,170 patients with colorectal, gastric, or non-small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits. CONCLUSION: Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.

PD-L1 (SP142) Expression in Primary and Recurrent/Metastatic Triple-Negative Breast Cancers and Its Clinicopathological Significance.

PURPOSE: The programmed death-ligand 1 (PD-L1) SP142 assay identifies patients with triple-negative breast cancer (TNBC) who are most likely to respond to the anti-PD-L1 agent atezolizumab. We aimed to compare PD-L1 (SP142) expression between primary and recurrent/metastatic TNBCs and elucidate the clinicopathological features associated with its expression. MATERIALS AND METHODS: Primary and recurrent/metastatic TNBCs tested with PD-L1 (SP142) were collected, and clinicopathological information of these cases was obtained through a review of slides and medical records. RESULTS: PD-L1 (SP142) positivity was observed in 50.9% (144/283) of primary tumors and 37.8% (31/82) of recurrent/metastatic TNBCs with a significant difference. Recurrent or metastatic sites were associated with PD-L1 positivity, with high PD-L1 positivity in the lung, breast, and soft tissues, and low positivity in the bone, skin, liver, and brain. When comparing PD-L1 expression between primary and matched recurrent/metastatic TNBCs using 55 paired samples, 20 cases (36.4%) showed discordance; 10 cases revealed positive conversion, and another 10 cases revealed negative conversion during metastatic progression. In primary TNBCs, PD-L1 expression was associated with a higher histologic grade, lower T category, pushing border, and higher tumor-infiltrating lymphocyte infiltration. In survival analyses, PD-L1 positivity, especially high positivity, was found to be associated with favorable prognosis of patients. CONCLUSION: PD-L1 (SP142) expression was lower in recurrent/metastatic TNBCs, and substantial cases showed discordance in its expression between primary and recurrent/metastatic sites, suggesting that multiple sites may need to be tested for PD-L1 (SP142) when considering atezolizumab therapy. PD-L1 (SP142)-positive TNBCs seems to be associated with favorable clinical outcomes.

The Hospitalist-Oncologist co-ManagemEnt (HOME) system improves hospitalization outcomes of patients with cancer.

BACKGROUND: The hospitalist system has been introduced to improve the quality and safety of inpatient care. As its effectiveness has been confirmed in previous studies, the hospitalist system is spreading in various fields. However, few studies have investigated the feasibility and value of hospitalist-led care of patients with cancer in terms of quality and safety measures. This study aimed to evaluate the efficacy of the Hospitalist-Oncologist co-ManagemEnt (HOME) system. METHODS: Between January 1, 2019, and January 31, 2021, we analyzed 591 admissions before and 1068 admissions after the introduction of HOME system on January 1, 2020. We compared the length of stay and the types and frequencies of safety events between the conventional system and the HOME system, retrospectively. We also investigate rapid response system activation, cardiopulmonary resuscitation, unplanned intensive care unit transfer, all-cause in-hospital mortality, and 30-day re-admission or emergency department visits. RESULTS: The average length of stay (15.9 days vs. 12.9 days, P < 0.001), frequency of safety events (5.6% vs. 2.8%, P = 0.006), rapid response system activation (7.3% vs. 2.2%, P < 0.001) were significantly reduced after the HOME system introduction. However, there was no statistical difference in frequencies of cardiopulomonary resuscitation and intensive care unit transfer, all-cause in-hospital morality, 30-day unplanned re-admission or emergency department visits. CONCLUSIONS: The study suggests that the HOME system provides higher quality of care and safer environment compared to conventional oncologist-led team-based care, and the efficiency of the medical delivery system could be increased by reducing the hospitalization period without increase in 30-day unplanned re-admission.

Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer.

Genomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, it remains unclear whether this approach can be applied to cell-free DNA (cfDNA) and whether it can address the issue of low tumor purity encountered in tissue-based methylation profiling. In this study, we developed an assay named iMethyl, designed to estimate the genomic hypomethylation status from cfDNA. This was achieved through deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n = 167; tissue n = 137; cfDNA early during treatment n = 40), breast cancer (cfDNA n = 91; tissue n = 50; PBMC n = 50; cfDNA at progression n = 44), and ovarian cancer (tissue n = 74). iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. In conclusion, our iMethyl-liquid method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.

Primary Intracranial Ewing Sarcoma With EWSR1-FLI1 Gene Translocation Mimicking a Meningioma and a Multidisciplinary Therapeutic Approach: A Case Report and Systematic Review of Literatures.

Ewing sarcoma and peripheral primitive neuroectodermal tumor (ES/pPNET) is an undifferentiated malignant tumor that is most prevalent in children and young adults and often radiologically mimics a meningioma. A 38-year-old female patient visited our hospital with complaints of right-sided tinnitus, right hemiparesis, and imbalance. She underwent preoperative imaging and was subsequently diagnosed as having a meningioma on the petrous ridge. After partial resection, EWSR1-FLI1 gene fusion was confirmed, and she was diagnosed with ES/pPNET. The tumor was successfully treated using a multidisciplinary approach of adjuvant chemo- and radiotherapy. This case is noteworthy because it is an extremely rare case of an intracranial ES/pPNET, and it is worth sharing our clinical experience that the tumor was successfully treated through a multidisciplinary therapeutic approach even though complete resection was not achieved.

Clinical activity of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer: A phase IB/II study (KCSG BR18-16).

AIM: We evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. METHODS: In this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. RESULTS: Forty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31-71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3-7.4) and 3.0 (95% CI: 2.1-5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. CONCLUSION: Nivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. TRIAL REGISTRATION: NCT04061863.

Clinical validity of oncogenic driver genes detected from circulating tumor DNA in the blood of lung cancer patients.

Background: This study aimed to evaluate the concordance of oncogenic driver mutations between tumor tissues and circulating tumor DNA (ctDNA) in patients with lung cancer. In addition, this study attempted to reveal the clinical utility of ctDNA in lung cancer treatment. Methods: Recurrent or metastatic non-small cell lung cancer (NSCLC) patients were prospectively enrolled in this study. Tumor tissue and serial blood samples were obtained from newly diagnosed patients (Cohort A) or patients treated with targeted therapy (Cohort B) and targeted gene panel sequencing was conducted to identify tumor mutational profiles. Results: At the time of diagnosis, patients in Cohort A with a high cell-free DNA (cfDNA) concentration had poorer overall survival than those with a low cfDNA concentration. The sensitivity and precision of ctDNA analysis in pre-treatment patients compared with those of tissue sequencing were 58.4% and 61.5%, respectively. Known lung cancer-associated variants of oncogenic driver genes, including EGFR and KRAS, and tumor suppressor genes, including TP53 and APC, were frequently detected in the ctDNA of the patients (76.9%). An association between smoking and TP53 mutation status was observed in both tissues and ctDNA (P=0.005 and 0.037, respectively). In addition, the EGFR T790M resistance mutation was detected solely from the ctDNA of two patients after treatment with an EGFR tyrosine kinase inhibitor. Conclusions: ctDNA may be a reliable prognostic biomarker with an additional role in treating patients with lung cancer. Further analyses are necessary to understand the properties of ctDNA and widen its clinical use.

Development and External Validation of a Machine Learning Model to Predict Pathological Complete Response After Neoadjuvant Chemotherapy in Breast Cancer.

PURPOSE: Several predictive models have been developed to predict the pathological complete response (pCR) after neoadjuvant chemotherapy (NAC); however, few are broadly applicable owing to radiologic complexity and institution-specific clinical variables, and none have been externally validated. This study aimed to develop and externally validate a machine learning model that predicts pCR after NAC in patients with breast cancer using routinely collected clinical and demographic variables. METHODS: The electronic medical records of patients with advanced breast cancer who underwent NAC before surgical resection between January 2017 and December 2020 were reviewed. Patient data from Seoul National University Bundang Hospital were divided into training and internal validation cohorts. Five machine learning techniques, including gradient boosting machine (GBM), support vector machine, random forest, decision tree, and neural network, were used to build predictive models, and the area under the receiver operating characteristic curve (AUC) was compared to select the best model. Finally, the model was validated using an independent cohort from Seoul National University Hospital. RESULTS: A total of 1,003 patients were included in the study: 287, 71, and 645 in the training, internal validation, and external validation cohorts, respectively. Overall, 36.3% of the patients achieved pCR. Among the five machine learning models, the GBM showed the highest AUC for pCR prediction (AUC, 0.903; 95% confidence interval [CI], 0.833-0.972). External validation confirmed an AUC of 0.833 (95% CI, 0.800-0.865). CONCLUSION: Commonly available clinical and demographic variables were used to develop a machine learning model for predicting pCR following NAC. External validation of the model demonstrated good discrimination power, indicating that routinely collected variables were sufficient to build a good prediction model.

AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20).

BACKGROUND: Loss of PTEN function leads to increased PI3Kß signaling. AZD8186, a selective PI3Kß/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss. METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

Mid-upper Arm Circumference as an Indicator of Quality of Life of Patients with Advanced Cancer.

Objective: Mid-upper arm circumference (MUAC) has been used to assess malnutrition and health status across various disease groups. However, it is unclear whether MUAC is associated with quality of life (QOL) of patients with advanced cancer. Our goal was to investigate the relationship between MUAC and QOL in ambulatory out-patients with advanced cancer. Method: This was a cross-sectional study conducted in a tertiary cancer center in South Korea. A total of 200 patients with advanced cancer at oncology clinics of Seoul National University Bundang Hospital from March 2016 to January 2019 were enrolled. Out-patients with advanced cancer whose survival was expected to be less than one year by their oncologists were enrolled. QOL of patients was evaluated using the European Organization for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30). Associations of QOL with MUAC and nutritional parameters were examined with generalized linear models. Results: The most common cancer sites were the lung, colon or rectum, and genitourinary tract. In univariate analyses, significant factors associated with higher summary score of EORTC QLQ-C30 were higher MUAC (≥ 26.5 cm, p < 0.001), higher body mass index (BMI) (≥ 22 kg/m2, p < 0.001), higher serum albumin (≥ 3.7 g/dL, p < 0.01), higher creatinine (≥ 0.8 mg/dL, p = 0.023), and higher uric acid (≥ 5 mg/dL, p < 0.01). In multivariate analysis, higher serum albumin (≥ 3.7 g/dL, p < 0.01) and higher MUAC (≥ 26.5 cm, p = 0.03) were independently associated with better summary score of EORTC QLQ-C-30. Conclusion: MUAC was highly associated with QOL in terms of summary score and overall health status. Thus, MUAC, with its simplicity, can be a useful tool to reflect QOL in patients with advanced cancer.

The effect of metformin or dipeptidyl peptidase 4 inhibitors on clinical outcomes in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

BACKGROUND: Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. METHODS: Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression-free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune-related adverse events (irAEs). RESULTS: Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second-line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all-grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). CONCLUSIONS: Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.