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Clinical and immune profiling for cancer of unknown primary site.

ABSTRACT: BACKGROUND:Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS:A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS:The median overall survival of all CUP patients was 29.3?months (95% confidence interval [CI], 15.7-not reached) and 7.1?months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P?=?0.002-0.067; CUP versus non-PD, P?=?0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P?=?0.008, false discovery rate?=?0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS:The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.

SUBMITTER: Haratani K

PROVIDER: S-EPMC6743146 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Clinical and immune profiling for cancer of unknown primary site.

Haratani Koji K Hayashi Hidetoshi H Takahama Takayuki T Nakamura Yasushi Y Tomida Shuta S Yoshida Takeshi T Chiba Yasutaka Y Sawada Takahiro T Sakai Kazuko K Fujita Yoshihiko Y Togashi Yosuke Y Tanizaki Junko J Kawakami Hisato H Ito Akihiko A Nishio Kazuto K Nakagawa Kazuhiko K

Journal for immunotherapy of cancer 20190913 1

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy.<h4>Methods</h4>A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They inc ...[more]

PMID: 31519206

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Project description:ImportanceAlthough profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.ObjectiveTo assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.Design, setting, and participantsThis phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.InterventionsRNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.Main outcomes and measuresThe primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.ResultsOf 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.Conclusions and relevanceThis study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.Trial registrationUMIN Identifier: UMIN000016794.

Project description:BackgroundLiver metastases from cancer of unknown primary (CUPL) constitute a rare disease, particularly among individuals younger than 50 years old. This paper aims to investigate the clinical characteristics of patients with CUPL and analyze prognostic differences across distinct age groups.MethodsData pertaining to patients with CUPL were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was employed to adjust for clinical variables. Cox regression analysis identified risk factors influencing overall survival (OS), while competing-risk analyses were conducted to determine prognostic factors for cancer-specific survival (CSS). Survival differences were compared using the Kaplan-Meier method and cumulative incidence function (CIF).ResultsThe study encompassed 4,691 patients, with 319 (6.8%) in the age <50 years group and 4,372 (93.2%) in the age ≥50 years group. Individuals with unexplained liver metastases exhibited a 1-year OS rate of 14.7% and a 1-year CSS rate of 23%. Following matching, age, histology, brain metastases, and chemotherapy were identified as independent prognostic factors affecting OS. Additionally, race, grade, histology, brain metastases, and chemotherapy were recognized as independent prognostic factors influencing CSS. Notably, the age <50 years group demonstrated superior OS and CSS compared to the age ≥50 years group before and after PSM. Among patients undergoing chemotherapy, the age <50 years group exhibited enhanced OS and CSS compared to their age ≥50 years counterparts. Furthermore, in individuals subjected to radiotherapy, the age <50 years group demonstrated superior OS, although no significant difference in CSS was observed.ConclusionsThe survival prognosis of patients with CUPL was found to be poor. However, both OS and CSS were more favorable in the age <50 years group compared to the age ≥50 years group. Additionally, radiotherapy and chemotherapy were associated with an OS benefit for patients in the age <50 years group.

Project description:BackgroundCancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs.MethodsPatients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed.ResultsA total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease.ConclusionsA significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

Project description:BackgroundCancer of unknown primary (CUP) describes patients with metastatic disease without an identified primary tumor site. Successful diagnosis and treatment of these patients remains difficult. Published guidelines on CUP have highlighted "favorable" subtype groups. We investigated a series of CUP patients to review adherence to guidelines, and identification of primary cancers or "favorable" subtypes.MethodsPatients with histologically confirmed CUP at an academic institution from 2012 to 2018 were identified. Patient demographics, tumor presentation, diagnostic work-up and treatment information were retrospectively collected from electronic data records for descriptive analysis and compared to published clinical guidelines. The primary endpoint was the proportion of patients where the primary site was identified. Multivariable logistic regression models were used to identify factors associated with primary site identification. Kaplan-Meier survival curves were used to determine factors associated with poorer OS.ResultsThree hundred and five patients were included with a median follow-up time of 4.3 months. Primary tumor sites were identified in 109 patients (37.5%), which was most commonly lung cancer (33%). Statistical analyses did not identify any demographic or initial presentation factors associated with identifying the primary or not. More diagnostic tests did not increase the likelihood of primary site identification (P=0.44). Patients with an identified primary did not have longer OS than other patients (median 5.2 months vs. 4.7 months, P=0.47). 57 patients (18.7%) who had a defined "favorable" subtype experienced superior OS (36.6 months vs. 3.8 months; P<0.0001). Further, patients with good prognostic status who followed published treatment guidelines had longer OS (17.6 months vs. 13.2 months; P=0.04).ConclusionsCUP remains a difficult cancer to diagnose and treat. These results suggest identifying the primary has less impact than anticipated, but particular efforts to identify patients with "favorable" subtypes of CUP is important prognostically.

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Clinical and immune profiling for cancer of unknown primary site.

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Clinical and immune profiling for cancer of unknown primary site.

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