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Carcinoma of unknown primary (CUP) is a difficult‐to‐manage malignancy. Multi‐omic profiles and treatment outcome vs. degree of precision matching were assessed. Tumours underwent next‐generation sequencing (NGS) [tissue and/or blood‐derived cell‐free DNA (cfDNA)]. Selected patients had transcriptome‐based immune profiling and/or programmed cell death 1 ligand 1 (PD‐L1) immunohistochemistry analysis. Patients could be reviewed by a Molecular Tumor Board, but physicians chose the therapy. Of 6497 patients in the precision database, 97 had CUP. The median number of pathogenic tissue genomic alterations was 4 (range, 0–25), and for cfDNA, was 2 (range, 0–9). Each patient had a distinct molecular landscape. Food and Drug Administration (FDA)‐approved biomarkers included the following: PD‐L1+ ≥ 1%, 30.9% of CUPs tested; microsatellite instability, 3.6%; tumour mutational burden ≥ 10 mutations·Mb−1, 23%; and neurotrophic receptor tyrosine kinase (NTRK) fusions, 0%. RNA‐based immunograms showed theoretically druggable targets: lymphocyte activation gene 3 protein (LAG‐3), macrophage colony‐stimulating factor 1 receptor (CSF1R), adenosine receptor A2 (ADORA2) and indoleamine 2,3‐dioxygenase 1 (IDO1). Overall, 56% of patients had ≥ 1 actionable biomarker (OncoKB database). To quantify the degree of matching (tumours to drugs), a Matching Score (MS; roughly equivalent to number of alterations targeted/total number of deleterious alterations) was calculated post hoc. Comparing evaluable treated patients [MS high, > 50% (N = 15) vs. low ≤ 50% (N = 47)], median progression‐free survival was 10.4 vs. 2.8 months (95% CI 0.11–0.64; HR 0.27; P = 0.002); survival, 15.8 vs. 6.9 months (95% CI 0.17–1.16; HR 0.45; P = 0.09); and clinical benefit rate (stable disease ≥ 6 months/partial/complete response), 71% vs. 24% (P = 0.003). Higher MS was the only factor that predicted improvement in outcome variables after multivariate analysis. In conclusion, CUPs are molecularly complex. Treatments with high degrees of matching to molecular alterations (generally achieved by individualized combinations) correlated with improved outcomes.

Summary: Treatment of rare/ultra-rare tumors is an unmet need due to a lack of standardized therapies and clinical trials. We developed the Molecular Tumor Board (MTB), a multidisciplinary team that integrates molecular profiling to generate personalized, N-of-One treatments for advanced cancers. This study evaluates 112 patients with rare/ultra-rare tumors who presented to the MTB and were evaluable for clinical therapeutic outcome. Overall, 46/112 patients (41%) received a treatment regimen with a high degree of matching between tumor molecular alterations and drugs given (reflected by a high Matching Score (≥50%)). Patients with a high versus low Matching Score experienced significantly longer progression-free survival (p = 0.005) and overall survival (p = 0.047), and higher rates of clinical benefit (stable disease ≥6 months, partial response, or complete response) (54% vs. 32% p = 0.027). The MTB facilitated personalized N-of-One matching of drugs to tumor molecular alterations, which was associated with improved clinical outcomes in patients with rare/ultra-rare cancers.

Abstract Osteoprotegerin (OPG) is a secreted cytokine that functions as a decoy receptor for receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL). Anti-RANKL treatment for bone metastasis has been widely accepted for solid tumors. However, the mechanism of OPG-RANKL-RANK signaling in systemic colorectal cancer (CRC) metastasis remains unclear. In this study, we investigated the relevance and function of OPG expression in CRC liver metastasis. First, we performed in silico analysis using The Cancer Genome Atlas public database and found that lower OPG expression in CRC was associated with poor overall survival. Immunohistochemistry analyses using resected specimen from patients with CRC in our institute confirmed the result. Patient-matched primary CRC and liver metastases showed a significant downregulation of OPG expression in metastatic lesions. In CRC cell lines, OPG expression did not suppress cell proliferation and migration. However, OPG expression inhibited macrophage migration by suppressing the RANKL-RANK pathway. Moreover, in vivo mouse liver metastasis models showed that OPG expression in CRC cells suppressed liver metastases. In addition, treatment with an anti-RANKL neutralizing antibody also suppressed liver metastases. These results showed that downregulation of OPG expression in CRC cells promotes liver metastasis by activating tumor-associated macrophage, which can become a candidate for targeted therapy with anti-RANKL neutralizing antibody for CRC liver metastasis.

Genomic analysis, performed on tumoral tissue DNA and on circulating tumor DNA (ctDNA) from blood, is the cornerstone of precision cancer medicine. Herein, we characterized the clinical prognostic implications of the concordance of alterations in major cancer genes between tissue‐ and blood‐derived DNA in a pan‐cancer cohort. The molecular profiles of both liquid (Guardant Health) and tissue (Foundation Medicine) biopsies from 433 patients were analyzed. Mutations and amplifications of cancer genes scored by these two tests were assessed. In 184 (42.5%) patients, there was at least one mutual gene alteration. The mean number of mutual gene‐level alterations in the samples was 0.67 per patient (range: 0–5). A higher mutual gene‐level alteration number correlated with shorter overall survival (OS). As confirmed in multivariable analysis, patients with ≥2 mutual gene‐level alterations in blood and tissue had a hazard ratio (HR) of death of 1.49 (95% confidence interval [CI]=1–2.2; P=0.047), whereas patients with ≥3 mutual gene‐level alterations had an HR of death 2.38 (95% CI=1.47–3.87; P=0.0005). Together, our results show that gene‐level concordance between tissue DNA and ctDNA analysis is prevalent and is an independent factor predicting significantly shorter patient survival.

Abstract Background The treatment strategy for locally advanced rectal cancer (LARC) has recently expanded from total mesorectal excision to additional neoadjuvant chemoradiotherapy (nCRT) and/or systemic chemotherapy (NAC). Data on disease recurrence after each treatment strategy are limited. Methods Clinical stage II to III rectal cancer patients who underwent curative surgery between July 2005 and February 2021 were analyzed. The cumulative incidence and site of first recurrence were assessed. The median follow-up duration was 4.6 years. Results Among the 332 patients, we performed nCRT and NAC in 15.4% (N=51) and 14.8% (N=49), respectively. The overall recurrence rate was 23.5% (N=78). Although several differences in tumor stage or location were observed, there was no significant difference in the rate among the surgery alone (N=54, 23.3%), nCRT (N=11, 21.6%), and NAC (N=13, 26.5%) groups. In this cohort, the local recurrence rate (18.4%) was higher than the rate of distant metastasis in the NAC group (14.3%). All patients with recurrence in the nCRT group had distant metastases (N=11: one patient had distant and local recurrences simultaneously). For pathological stage 0-I, the recurrence rate was higher in the nCRT and NAC groups than in the surgery-alone group (nCRT, 10.0%; NAC, 15.4%; and surgery-alone, 2.0%). Curative-intent resection of distant-only recurrences significantly improved patients’ overall survival (hazard ratio [95% confidence interval], 0.34 [0.14–0.84]), which was consistent even when stratified according to neoadjuvant treatment. Regardless of neoadjuvant treatment, >80% of recurrences occurred in the first 2.2 years, and 98.7% within 5 years after surgery. Conclusion Regardless of neoadjuvant treatment, detecting distant metastases with intensive surveillance, particularly in the first 2 years after surgery, is important. Also, even if neoadjuvant treatment can downstage LARC to pathological stage 0-I, careful follow-up is needed.

Abstract Background Liver injury associated with oxaliplatin (L‐OHP)‐based chemotherapy can significantly impact the treatment outcomes of patients with colorectal cancer liver metastases, especially when combined with surgery. To date, no definitive biomarker that can predict the risk of liver injury has been identified. This study aimed to investigate whether organoids can be used as tools to predict the risk of liver injury. Methods We examined the relationship between the clinical signs of L‐OHP‐induced liver injury and the responses of patient‐derived liver organoids in vitro. Organoids were established from noncancerous liver tissues obtained from 10 patients who underwent L‐OHP‐based chemotherapy and hepatectomy for colorectal cancer. Results Organoids cultured in a galactose differentiation medium, which can activate the mitochondria of organoids, showed sensitivity to L‐OHP cytotoxicity, which was significantly related to clinical liver toxicity induced by L‐OHP treatment. Organoids from patients who presented with a high‐grade liver injury to the L‐OHP regimen showed an obvious increase in mitochondrial superoxide levels and a significant decrease in mitochondrial membrane potential with L‐OHP exposure. L‐OHP‐induced mitochondrial oxidative stress was not observed in the organoids from patients with low‐grade liver injury. Conclusions These results suggested that L‐OHP‐induced liver injury may be caused by mitochondrial oxidative damage. Furthermore, patient‐derived liver organoids may be used to assess susceptibility to L‐OHP‐induced liver injury in individual patients.

Introduction: Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion. Methods: This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status. Results: The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months; p = 0.006) and overall survival (18.1 vs 8.0 months; p = 0.04) after treatment with ICB. TIL-PD-1–positive patients had an objective response rate (ORR) of 41% (95% CI, 24–61; N = 12/29) compared with 17% (95% CI, 4–43; N = 3/17) for TIL-PD-1–negative patients (p = 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson r = 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (p < 0.0001). TIL-PD-1–positive status is also associated with enrichment of pathologic variants within several genes, most notably TP53 (adjusted p < 0.05). Conclusion: TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB. ClinicalTrials.gov ID: NCT02478931

Abstract Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.

Treatment for advanced colorectal cancer is often limited by complex molecular profiles, which promote resistance to systemic agents and targeted monotherapies. Recent studies suggest that a personalized, combinatorial approach of matching drugs to tumor alterations may be more effective. We implemented a precision medicine strategy by forming a Molecular Tumor Board (MTB), a multidisciplinary team of clinicians, scientists, bioinformaticians and geneticists. The MTB integrated molecular profiling information and patient characteristics to develop N‐of‐One treatments for 51 patients with advanced colorectal cancer. All patients had metastatic disease and 63% had received ≥ 3 prior therapy lines. Overall, 34/51 patients (67%) were matched to ≥ 1 drug recommended by the MTB based on individual tumor characteristics, whereas 17/51 (33%) patients received unmatched therapies. Patients who received matched therapy demonstrated significantly longer progression‐free survival (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21–0.81; P = 0.01) and a trend towards higher clinical benefit rates (41% vs. 18%, P = 0.058) (all multivariate) compared to patients receiving unmatched therapy. The MTB facilitated personalized matching of drugs to tumor characteristics, which was associated with improved progression‐free survival in patients with advanced colorectal cancer.

Abstract Though advanced cancers generally display complex molecular portfolios, there is a subset of patients whose malignancies possess only one genomic alteration or alterations in one oncogenic pathway. We assess how N-of-One therapeutic strategies impact outcomes in these patients. From 12/2012 to 9/2018, 429 therapy-evaluable patients with diverse treatment-refractory cancers were presented at Molecular Tumor Boards at Moores Cancer Center at UC San Diego. The clinical benefit rate, defined by RECIST1.1, was assessed for patients with solid tumors who underwent next-generation sequencing (NGS) profiling revealing one genomic or pathway alteration, subsequently managed with N-of-One therapies. Nine of 429 patients (2.1%) met evaluation criteria. Using matched therapy indicated by NGS, the clinical benefit rate (stable disease ≥ 6 months/partial/complete response) was 66.7%. Median progression-free survival was 11.3 months (95% CI: 3.4–not evaluable). Thus, a small subset of diverse cancers has single pathway alterations on NGS testing. These patients may benefit from customized therapeutic matching.

Abstract Background Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. Methods A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). Results Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R 2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. Conclusions Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. Trial registration I-PREDICT ( NCT02534675 ) was registered on August 25, 2015.

Molecular characterization of cancers is important in dictating prognostic factors and directing therapy. Next‐generation sequencing of plasma circulating tumor DNA (ctDNA) offers less invasive, more convenient collection, and a more real‐time representation of a tumor and its molecular heterogeneity than tissue. However, little is known about the clinical implications of ctDNA assessment in gynecologic cancer. We describe the molecular landscape identified on ctDNA, ctDNA concordance with tissue‐based analysis, and factors associated with overall survival (OS) in gynecologic cancer patients with ctDNA analysis. We reviewed clinicopathologic and genomic information for 105 consecutive gynecologic cancer patients with ctDNA analysis, including 78 with tissue‐based sequencing, enrolled in the Profile‐Related Evidence Determining Individualized Cancer Therapy (NCT02478931) trial at the University of California San Diego Moores Cancer Center starting July 2014. Tumors included ovarian (47.6%), uterine (35.2%), cervical (12.4%), vulvovaginal (2.9%), and unknown gynecologic primary (1.9%). Most ovarian and uterine cancers (86%) were high grade. 34% (N = 17) of ovarian cancers had BRCA alterations, and 22% (N = 11) were platinum sensitive. Patients received median 2 (range 0–13) lines of therapy prior to ctDNA collection. Most (75.2%) had at least one characterized alteration on ctDNA analysis, and the majority had unique genomic profiles on ctDNA. Most common alterations were TP53 (N = 59, 56.2% of patients), PIK3CA (N = 26, 24.8%), KRAS (N = 14, 13.3%), BRAF (N = 10, 9.5%), ERBB2 (N = 8, 7.6%), and MYC (N = 8, 7.6%). Higher ctDNA maximum mutation allele frequency was associated with worse OS [hazard ratio (HR): 1.91, P = 0.03], while therapy matched to ctDNA alterations (N = 33 patients) was independently associated with improved OS (HR: 0.34, P = 0.007) compared to unmatched therapy (N = 28 patients) in multivariate analysis. Tissue and ctDNA genomic results showed high concordance unaffected by temporal or spatial factors. This study provides evidence for the utility of ctDNA in determining outcome and individualizing cancer therapy in patients with gynecologic cancer.

A molecular tumor board (MTB) is often used as a platform that integrates clinical and molecular parameters for clinical decision making. Here, the authors review the outcome of 715 cancer patients presented at their institution’s MTB, and demonstrate that patients who received a MTB-recommended regimen received therapy that was better matched to their alterations and achieved better clinical outcomes.

We examined the impact of spatial, temporal, histologic, and quantitative factors on concordance between TP53 alterations in tissue DNA vs in circulating tumor DNA (ctDNA). Four hundred and thirty‐three patients underwent next‐generation sequencing (NGS) in which both tissue and blood samples were evaluated. TP53 was detected in 258 of 433 patients (59.6%); 215 had tissue TP53 alterations (49.7%); 159, ctDNA (36.7%); and 116, both tissue and ctDNA (27.8%). Overall concordance rate between ctDNA and tissue biopsies for TP53 alterations was 67.2%; positive concordance was 45.0%. Overall concordance for TP53 did not vary among patients with ≤ 2 months vs > 6 months between test samples; however, positive concordance trended higher when time intervals between test samples were shorter, suggesting that the lack of difference in overall concordance may be due to the large number of negative/negative tests. There was a trend toward higher overall concordance based on biopsy site (metastatic vs primary) (P = 0.07) and significantly higher positive concordance if the tissue biopsy site was a metastatic lesion (P = 0.03). Positive concordance significantly decreased in noncolorectal cancer patients vs colorectal cancer patients (P = 0.02). Finally, higher %ctDNA was associated with higher concordance rates between blood and tissue (P

Abstract Background Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient’s major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB. Methods Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient’s MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient. Results The median progression-free survival (PFS) for PHBR score 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients. Conclusions Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.

BACKGROUND Immune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODS A database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTS Nine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSION A small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATION ClinicalTrials.gov, NCT02478931.FUNDING Joan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

Abstract Background Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. Methods ctDNA was analyzed in 112 patients with PDAC (54–73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. Results The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0–6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85–10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months. Conclusions Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

Objective: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score. Methods: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves. Results: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models. Conclusions: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected.

BACKGROUND Although CDK4/6 inhibitors are an established treatment for hormone receptor–positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODS We investigated factors associated with clinical outcomes from CDK4/6 inhibitor–based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTS Overall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182–465 genes) and therapy outcome of (non–breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0–24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor–based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs.

Background Several cancer types harbor alterations in the gene encoding AT-Rich Interactive Domain-containing protein 1A (ARID1A), but there are no approved therapies to address these alterations. Recent studies have shown that ARID1A deficiency compromises mismatch repair proteins. Herein, we analyzed 3403 patients who had tumor tissue next-generation sequencing.Findings Among nine cancer subtypes with >5% prevalence of ARID1A alterations, microsatellite instability-high as well as high tumor mutational burden was significantly more frequent in ARID1A-altered versus ARID1A wild-type tumors (20% vs 0.9%, p

Although immunotherapies have achieved remarkable salutary effects among subgroups of advanced cancers, most patients do not respond. We comprehensively evaluated biomarkers associated with the “cancer-immunity cycle” in the pan-cancer setting in order to understand the immune landscape of metastatic malignancies as well as anti-PD-1/PD-L1 inhibitor resistance mechanisms. Interrogation of 51 markers of the cancer-immunity cycle was performed in 101 patients with diverse malignancies using a clinical-grade RNA sequencing assay. Overall, the immune phenotypes demonstrated overexpression of multiple checkpoints including VISTA (15.8% of 101 patients), PD-L2 (10.9%), TIM3 (9.9%), LAG3 (8.9%), PD-L1 (6.9%) and CTLA4 (3.0%). Additionally, aberrant expression of macrophage-associated markers (e.g. CD68 and CSF1R; 11-23%), metabolic immune escape markers (e.g. ADORA2A and IDO1; 9-16%) and T-cell priming markers (e.g. CD40, GITR, ICOS and OX40; 4-31%) were observed. Most tumors (87.1%, 88/101) expressed distinct immune portfolios, with a median of six theoretically actionable biomarkers (pharmacologically tractable by Food and Drug Administration approved agents [on- or off-label] or with agents in clinical development). Overexpression of TIM-3, VISTA and CD68 were significantly associated with shorter progression-free survival (PFS) after anti-PD-1/PD-L1-based therapies (among 39 treated patients) (all P

Background Esophageal diverticulum is commonly associated with esophageal motility disorders, which can be diagnosed using high-resolution manometry (HRM) according to the Chicago classification. Although midesophageal diverticulum (M-ED) is associated with inflammatory processes, esophageal motility disorders have been recently identified as an etiology of M-ED. Case presentation We present the case of a patient with M-ED and elevated intrabolus pressure (IBP), which did not meet the criteria for esophageal motility disorders according to the Chicago classification. A 71-year-old man presented with gradually worsening dysphagia for two years and was diagnosed as having an 8-cm-long M-ED and multiple small diverticula in lower esophagus. HRM revealed a median integrated relaxation pressure of 14.6 mmHg, a distal latency of 6.4 s, and an average maximum IBP of 35.7 mmHg. He underwent thoracoscopic resection of the M-ED and myotomy, which successfully alleviated the symptoms and reduced the intrabolus pressure to normal levels. Conclusions It is important to recognize the esophageal diverticulum pathology with HRM findings even in cases where the results may not meet the Chicago classification and to include myotomy based on the results. [ABSTRACT FROM AUTHOR]