Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

Abstract

Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno‐ and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin‐fixed, paraffin‐embedded tissues. For library preparation, mostly multiplex PCR‐based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event‐free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data.

Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary

“…However, the lack of universal availability of molecular profiling for CUP and validation of these biomarkers, limits current inclusion in a clinic ready nomogram. (37,40) Additionally, due to low prevalence of these biomarkers and limited access to testing and therapy in CUP, we believe that the nomogram will play a critical role in management of a substantial subset of patients with CUP. Ongoing efforts will be needed to study continued performance and refinement as understanding of molecular biology improves and as more therapies become available for CUP patients.…”

Successful treatment using immunotherapy in combination with chemotherapy for metastatic squamous cell carcinoma of unknown primary origin with bulky abdominal mass

“…[ 10 ] The latest research also found that inferior prognosis was associated with KRAS activation by point mutation and gene amplification, and TP53 mutations were associated with an adverse prognosis in the SCC subgroup and in females. [ 11 ]…”

Prognostic impact of copy number alterations and tumor mutational burden in carcinoma of unknown primary

“…NGS panel sequencing is routinely performed at our center to identify molecular targets 10 . Library preparation for the capture‐based TruSight Oncology 500 panel (Illumina) was performed as previously described 25 .…”

“…Several next‐generation panel sequencing‐based studies have elucidated the mutational landscape in CUP. These studies have consistently demonstrated that the mutational spectrum in CUP is diverse, with TP53 , KRAS , CDKN2A/B , MYC , PIK3CA , ARID1A , ERBB2 , and NOTCH1 genes most frequently harboring alterations 4–10 . With respect to prognosis CDKN2A/B deletion and KRAS activation have been identified as adverse prognostic markers 10 …”

“…These studies have consistently demonstrated that the mutational spectrum in CUP is diverse, with TP53, KRAS, CDKN2A/B, MYC, PIK3CA, ARID1A, ERBB2, and NOTCH1 genes most frequently harboring alterations. [4][5][6][7][8][9][10] With respect to prognosis CDKN2A/B deletion and KRAS activation have been identified as adverse prognostic markers. 10 In contrast, the pattern of chromosomal aberrations in CUP has only been assessed in small studies.…”