Gene profiling of tumor tissue in the diagnosis of patients with carcinoma of unknown primary site (CUP): Evaluation of the Veridex 10-gene molecular assay

21109 Background: Standard treatment for most patients with CUP involves empiric chemotherapy. Since specific treatment now exists for most types of advanced carcinoma, precise identification of the primary site could lead to improved therapy. Veridex developed an optimized set of 10 gene markers, for a qRTPCR assay to identify tissue of origin of metastatic carcinoma in formalin-fixed, paraffin-embedded (FFPE) tissue samples (J Mol Diagn 8:320, 2006). The assay includes markers for 6 primary sites: lung, pancreas, colon, breast, ovary, and prostate. In this retrospective study, we evaluated the Veridex assay in patients with CUP. Methods: We obtained FFPE tissue from diagnostic biopsies on 69 CUP patients previously enrolled in empiric chemotherapy studies. The Veridex assay was performed as previously described. Assay results were correlated with clinical features, pathologic features, and response to treatment. Results: The Veridex assay yielded provisional diagnoses in 42 of 69 patients (61%): lung (15), pancreas (11), colon (12 ), ovary (4), breast (0), and prostate, (0 ). Most patients with diagnoses of lung and pancreas cancer had clinical and pathologic features compatible with these diagnoses; response rates to empiric chemotherapy (usually taxane/platinum-based) in patients with these diagnoses were 29% and 9%, respectively. The 12 patients with colon cancer diagnoses had predominantly intra-abdominal metastases (liver, peritoneum); response rate to therapy (usually taxane/platinum- based) was low (8%). The 4 patients with ovarian cancer had atypical clinical and pathologic features, and only 1 of 4 had PR to first-line taxane/platinum therapy. Conclusions: In this retrospective study, the Veridex 10-gene molecular assay was feasible and provided provisional diagnoses in a majority of patients with CUP. The diagnoses made using this assay (except ovarian cancer) were compatible with clinicopathologic features. The efficacy of cancer-specific treatment in patients diagnosed by this assay will be evaluated in prospective studies. No significant financial relationships to disclose.

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Confirmation of non-small cell lung cancer (NSCLC) diagnosis using ALK testing and genetic profiling in patients presenting with carcinoma of unknown primary site (CUP).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19062 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19062-e19062

Author(s):

William Charles Penley ◽

David R. Spigel ◽

F Anthony Greco ◽

John D. Hainsworth

Keyword(s):

Treatment Options ◽

Specific Treatment ◽

Primary Site ◽

Gene Profiling ◽

Unknown Primary ◽

Rt Pcr ◽

Genetic Profiling ◽

Pathologic Evaluation ◽

Alk Positive ◽

Support Methods

e19062 Background: Emerging data suggest real-time reverse transcriptase-polymerase chain reaction (RT-PCR) tumor profiling can predict the primary site in CUP. We report on CUP patients (pts) predicted to have NSCLC by RT-PCR, in whom detection of ALK rearrangements provided further diagnostic support. Methods: 4 pts were diagnosed with CUP based on standard clinical, radiographic, pathologic evaluation with immunohistochemistry (IHC), and bronchoscopy/endoscopy where indicated. All pts had a RT-PCR assay (CancerTYPE ID, bioTheranostics, Inc.) performed on tumor specimens for the purpose of predicting a primary site. Tissue was also tested for ALK by FISH using a break-apart probe. Results: Pt characteristics are shown (Table). RT-PCR results prompted ALK testing in Pts 2 and 3. ALK testing and RT-PCR testing were performed concurrently in Pts 1 and 4. Each specimen was diagnosed as lung adenocarcinoma (AC) by RT-PCR gene profiling, and also tested positive for an EML4-ALKrearrangement. All pts are being followed for clinical outcome. Conclusions: Gene expression profiling in CUP diagnosed lung AC in 4 pts who also had ALK rearrangements supporting the diagnosis. Identifying ALK-positive NSCLC among pts who present with CUP improves the site-specific treatment options. [Table: see text]

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Molecular Profiling of Carcinoma of Unknown Primary and Correlation With Clinical Evaluation

Journal of Clinical Oncology ◽

10.1200/jco.2007.14.4378 ◽

2008 ◽

Vol 26 (27) ◽

pp. 4442-4448 ◽

Cited By ~ 168

Author(s):

Gauri R. Varadhachary ◽

Dmitri Talantov ◽

Martin N. Raber ◽

Christina Meng ◽

Kenneth R. Hess ◽

...

Keyword(s):

Colon Cancer ◽

Poor Response ◽

Response To Therapy ◽

Response To Treatment ◽

Unknown Primary ◽

Cancer Center ◽

Carcinoma Of Unknown Primary ◽

University Of Texas ◽

Pathologic Features ◽

Tissue Of Origin

Purpose To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site. Patients and Methods Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy. Results The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer–specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement. Conclusion This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

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Prognostic impact of presumed breast or ovarian cancer among patients with unfavorable-subset cancer of unknown primary site

BMC Cancer ◽

10.1186/s12885-018-4092-4 ◽

2018 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Makoto Kodaira ◽

Kan Yonemori ◽

Tatsunori Shimoi ◽

Akihiko Yoshida ◽

Masayuki Yoshida ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Of Unknown Primary ◽

Primary Site ◽

Unknown Primary ◽

Prognostic Impact ◽

Unknown Primary Site

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Evaluating the hidden biology of cancer of unknown primary (CUP) in comparison to known metastatic disease.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e12549 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e12549-e12549

Author(s):

Malek Bassam Hannouf ◽

Salah Mahmud ◽

Eric Winquist ◽

Muriel Brackstone ◽

Gregory S Zaric

Keyword(s):

Tumour Size ◽

Primary Tumour ◽

Cancer Of Unknown Primary ◽

Primary Site ◽

Unknown Primary ◽

Primary Cancer ◽

Phenotypic Characteristics ◽

Wilcoxon Rank Sum Test ◽

Pathologic Features ◽

Tumour Characteristics

e12549 Background: No consensus exists yet on whether CUP is a group of metastatic tumours with undetected primary sites or a unique clinicopathological entity with distinct genetic and phenotypic characteristics. We aimed to characterize the clinical and pathologic features of a cohort of CUP patients who had their latent primary site subsequently detected during their life or at autopsy in comparison to a cohort of patient presented with metastatic known primary cancers at initial diagnosis. Methods: We used historical snapshot files available in the Manitoba Cancer Registry (MCR) to identify all patients diagnosed with histologically or cytologically confirmed metastatic tumours in Manitoba during the period from January 1, 2002 to December 31, 2012. We linked all identified patients with their updated tumour-specific files available in the MCR for the purpose of identifying our two study cohorts. The first cohort included all patients who were initially diagnosed with CUP and who had their latent primary cancer identified and confirmed using either histology, cytology or autopsy at least 2 months after their initial CUP diagnosis. The second cohort included all patients initially diagnosed with a metastatic known primary cancer and whose cancer diagnosis did not change during lifetime or at autopsy. Information on patient and tumour characteristics was obtained from the MCR. Results: Out of 16,085 patients diagnosed with metastatic tumours, 2654 (%16.5) patients were initially diagnosed with CUP and 13,431 (84.5%) patients diagnosed with metastases of a known primary cancer. Out of the CUP group, 1033 (39%) patients had their latent primary site subsequently detected. Distribution of primary sites did not differ significantly between CUP patients who had their latent primary detected and patients diagnosed with metastases of a known primary cancer (p=0.44, Wilcoxon rank sum test). With the exception of tumour size, all other patient and tumour characteristics did not differ significantly between the two study cohorts across primary tumour sites. Conclusions: The clinical and pathologic features of CUP patient do not appear to be fundamentally different from those with metastatic known primary cancers.

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The 30 ROC trial: Precision intra-treatment imaging guiding major radiation reduction in human papillomavirus related oropharyngeal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6019 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6019-6019

Author(s):

Nancy Y. Lee ◽

Eric Jeffrey Sherman ◽

Heiko Schöder ◽

Sean Matthew McBride ◽

Yao Yu ◽

...

Keyword(s):

Weight Loss ◽

Human Papillomavirus ◽

Specific Treatment ◽

Concurrent Chemotherapy ◽

Primary Site ◽

Locoregional Control ◽

Patient Specific ◽

Unknown Primary ◽

Oropharyngeal Carcinoma ◽

Nodal Disease

6019 Background: Our previously published proof-of-concept trial using functional imaging to select patient with human papillomavirus (HPV) oropharyngeal carcinoma (OPC) for radiation de-escalation showed promising results. Here we report the outcome of a larger validation trial using the same paradigm where select HPV+ OPC patients received a definitive dose of 30Gy concurrently with chemotherapy and were subsequently observed. Methods: The trial enrolled patients who had p16+, T0-2, N1-N2c, M0 OPC by AJCC 7th TNM. Patients were required to have resection of the primary site (negative margin not required) or core biopsy of lymph node if unknown primary. In addition to standard positron emission tomography (PET), a pre-radiation dynamic 18F-FMISO (fluoromisonidazole) PET was performed to identify hypoxia in gross nodal disease. Patients with evidence of hypoxia ( > 1.2 tumor to muscle standard uptake value on 18F-FMISO) underwent repeat18F-FMISO PET around 2 weeks into radiation. Patients without pre-radiation hypoxia or with resolution of hypoxia on 18F-FMISO PET received 30Gy with 2 cycles of concurrent chemotherapy (cisplatin 100mg/m2 or carboplatin AUC 1.25 x 4 with 5-fluorouracil 2400 mg/m2). Results: From 11/2/17-1/4/21, 158 HPV+ OPC patients consented and were enrolled on trial. Patient characteristics were as follows: male (90%); ages 36-80 years; T-stage T0(26), T1(77), T2(55); N stage N1(19), N2a(15), N2b(95), N2c(29). Of the 114 patients with pre-treatment hypoxia, 24 had persistent hypoxia and received 70Gy. 128 patients were de-escalated to 30Gy and chemotherapy (86% cisplatin). 6 patients withdrew from trial [3 decided to receive standard of care; 3 refused 18F-FMISO PET]. Acute mucositis rates were 11% grade 0, 59% grade 1, and 30% grade 2, respectively. Acute xerostomia rates were 92% grade 1 and 8% grade 2, respectively. Weight loss was infrequent and only 19% complained of grade 1 and 5% complained of grade 2 weight loss. Six patients experienced grade 3 adverse events (diarrhea (2), syncope (2), vasovagal (1), dysphagia (1)). No patients required PEG tubes. With a median follow-up is 12 months (range: 2 months to 40 months), the 1-year locoregional control, distant metastasis-free overall survival rates were 94%, 100%, and 100%, respectively. Among the 30Gy de-escalated patients, none failed in the primary site. 8 patients had recurrent nodal disease underwent successful salvage surgery of which no additional therapy was given to 4 patients. Conclusions: Major de-escalation to 30Gy using patient specific treatment response based on hypoxia resolution resulted in excellent locoregional control with significant toxicity reduction. Updated results along with detailed correlative analysis will be presented. Clinical trial information: NCT03323463.

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