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The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review.

ABSTRACT: Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.

SUBMITTER: Lombardo R

PROVIDER: S-EPMC7225282 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review.

Lombardo Roberta R Tosi Federica F Nocerino Annunziata A Bencardino Katia K Gambi Valentina V Ricotta Riccardo R Spina Francesco F Siena Salvatore S Sartore-Bianchi Andrea A

Frontiers in oncology 20200508

<b>Background:</b> Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. <b>Methods:</b> A ...[more]

PMID: 32457826

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Project description:Cancer of unknown primary (CUP) designates an enigmatic cancer entity with histologic confirmation of malignancy from a metastasis but no identifiable primary tumor in spite of a thorough diagnostic work-up. In this review, we discuss the validity of CUP as a distinct cancer entity as well as diagnostic pitfalls. As arguments against a distinct entity, the diagnosis of CUP is erroneous in some cases. Diagnostic pitfalls include incomplete diagnostics, uncertainty in classifying a lesion as either primary or metastasis and mistaking a relapse of an antecedent malignancy as CUP due to histologic and immunohistologic disparities. Given the high frequency of prior malignancies in CUP patients, relapse of an antecedent cancer should always be carefully excluded. Gene expression profiling-based classifier assays aim at aligning the molecular profile of CUP patients with established primary cancer patterns for highest congruency in order to identify the putative primary and treat accordingly. However, the spectrum of predicted putative primaries by molecular techniques is somewhat at odds with the primaries identified in autopsy series. Also, a first randomized clinical trial did not show superiority of primary-tailored therapy over unspecific platinum-based chemotherapy. CUP cases share an aggressive clinical course, atypical metastasis pattern, rapid progression of metastases, a generally poor response to chemotherapy and dismal outcome as distinct clinical features. Metastatic spread appears to take place in the early stages of tumor evolution, with CUP metastases subsequently undergoing genetic evolution toward a chromosomally highly complex and instable karyotype independent from the primary tumor. In clinical practice, the diagnosis of CUP is valid when no primary tumor is detectable. Treatment should ideally offer broad spectrum coverage across numerous malignancies and be well-established in CUP as is the case for carboplatin/paclitaxel and cisplatin / gemcitabine in particular, but it should also cover the most likely putative primary. The diligent diagnosis of CUP is warranted for clinical trials, making the eligibility process particularly laborious. In conclusion, we deem CUP a distinct cancer entity and the diagnosis accurate in most patient cases.

Dataset Information

The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review.

Publications

The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review.

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