
==== Front
JCO Precis Oncol
JCO Precis Oncol
po
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JCO Precision Oncology
2473-4284
Wolters Kluwer Health

39231374
PO.24.00191
10.1200/PO.24.00191
00205
Original Reports
Diagnostics
Personalized Therapy Selection by Integration of Molecular Cancer Classification by the 92-Gene Assay and Tumor Profiling in Patients With Cancer of Unknown Primary
https://orcid.org/0000-0002-7837-8359
Fuentes Bayne Harry E. MD 1
https://orcid.org/0000-0002-5169-7085
Kasi Pashtoon M. MD 2
Ma Li PhD 3
Hart Lowell L. MD 4
Wong Jenna MS 3
https://orcid.org/0000-0003-3215-9465
Spigel David R. MD 5
Schnabel Catherine A. PhD 3
Reeves James A. MD 4
https://orcid.org/0000-0001-8460-1257
Halfdanarson Thorvardur R. MD 1
https://orcid.org/0009-0006-3443-3578
Treuner Kai PhD 3
https://orcid.org/0000-0003-2802-3741
Greco F. Anthony MD 5
1 Mayo Clinic, Rochester, MN
2 Weill Cornell Medicine, New York, NY
3 Biotheranostics, a Hologic Company, San Diego, CA
4 Florida Cancer Specialist, Fort Myers, FL
5 Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN
F. Anthony Greco, MD; e-mail: fgreco@tnonc.com.
2024
4 9 2024
4 9 2024
8 e240019121 3 2024
18 7 2024
7 8 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/

PURPOSE

Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression–based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF, in patients with CUP in the MOSAIC database to highlight potential treatment options.

METHODS

MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF.

RESULTS

CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS, IDH1/2, BRCA, and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)–approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients.

CONCLUSION

This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials.

Enabling Precision Site-Specific Therapies in CUP Patients with CancerTYPE ID

OPEN-ACCESSTRUE
==== Body
pmcINTRODUCTION

Cancer of unknown primary (CUP) is a syndrome characterized by metastatic cancers with an unidentifiable primary site after a thorough diagnostic workup.1-3 Despite advances in diagnostic techniques, CUP remains a significant clinical challenge due to its poor prognosis. It accounts for 2%-5% of metastatic cancers and ranks as the fourth leading cause of cancer-related deaths globally.1-3 The heterogeneity of CUP arises from concealed primary sites, which create diagnostic and therapeutic challenges due to inconclusive pathological evaluations.4,5 Although site-specific therapy improves outcomes in 15%-20% of cases, 80%-85% of patients with CUP face uncertain tumor origins, leading to empiric chemotherapy and a median survival of just 3-10 months.2,3,6 Identifying the tissue of origin is crucial for optimal therapy selection.1,7 CancerTYPE ID, a molecular classifier, helps identify CUP origins by matching gene expression results with a comprehensive reference database.1 The MOSAIC database includes thousands of CUP cases that underwent CancerTYPE ID testing and tumor type–guided biomarker analysis to identify the tissue of origin and actionable biomarkers.

CONTEXT

Key Objective

To assess whether molecular cancer classification combined with tumor profiling identifies additional treatment options for patients with cancer of unknown primary (CUP) or unclear diagnoses.

Knowledge Generated

The 92-gene assay (CancerTYPE ID) identified a tumor type in 92.5% (2,929 of 3,168) of CUP cases. Aberrations in KRAS, IDH1/2, BRCA, and BRAF genes were detected in about 20% of all patients, and a cancer-specific US Food and Drug Administration–approved or investigational targeted therapy was potentially available for 24.6% of these patients with a molecularly diagnosed cancer type.

Relevance

Obtaining a molecular diagnosis along with molecular profiling may allow more patients with CUP or uncertain diagnosis to benefit from site-specific targeted therapies.

The advent of precision medicine has introduced several new cancer therapies targeting specific gene alterations. For example, KRAS G12C inhibitors are approved for lung cancer, IDH1 inhibitors for cholangiocarcinoma, BRAF inhibitors for BRAF V600E-mutated tumors, and combinations of BRAF and MEK inhibitors for BRAF V600E/V600K-mutated melanoma.8-12 Additionally, therapies targeting BRCA1/2 mutations are approved for metastatic castration-resistant prostate cancer and BRCA1/2-mutant ovarian cancers.13,14 Building on these advancements, this study presents an analysis of actionable mutations in the MOSAIC database for KRAS, IDH1/2, BRCA1/2, and BRAF, highlighting potential targeted treatment options for patients with CUP or unclear diagnoses.

METHODS

Molecular Profiling

Clinicians and pathologists ordered the 92-gene assay (CancerTYPE ID) on biopsy specimens for patients with CUP or unclear histological diagnoses. The tumor of origin was identified by the CancerTYPE ID assay from formalin-fixed paraffin-embedded tissue. Gene expression analyses were performed and queried against a reference database containing over 2,000 samples with known tumor types.15-17 Tumor samples not identified by CancerType ID were reported as indeterminate. Multimodal biomarker testing was performed using NeoTYPE tumor profiles, which combines next-generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization assays.18

MOSAIC Database

This research involved a retrospective analysis of patient data in the MOSAIC database, an Institutional Review Board (IRB)–approved, dedentified database of CUP and diagnostically ambiguous cases submitted for CancerTYPE ID testing with multimodal biomarker testing (NeoGenomics, Fort Myers, FL). The current analysis is based on data from 3,168 patients tested between 2018 and 2021 with both CancerTYPE ID and NeoTYPE tumor profiling. The study was conducted in compliance with the guidelines of the Declaration of Helsinki and was approved by the Western-Copernicus Group, IRB adhering to US Food and Drug Administration (FDA) regulations, US Department of Health and Human Services regulations, and the International Conference on Harmonisation guidelines. The study uses a deidentified database and meets exemption criteria under 45 CFR §46.101(b)(4) and was waived for informed consent under 45 CFR 164.512 by the IRB.

Study Design and MOSAIC Workflow

Tumor samples of patients with CUP or unclear diagnoses were sent to Biotheranostics for CancerTYPE ID testing. Biopsy specimens were further analyzed with NeoTYPE tumor profiles on the basis of CancerTYPE ID results (Appendix Table A1). Patients were identified for potential cancer-specific targeted therapies by comparison of FDA-approved therapies and corresponding biomarkers (Appendix Fig A1). Descriptive statistics were used to summarize the distribution of CancerTYPE ID predicted tumor types and genomic alterations across the tumor types. Any difference between the total number of cases diagnosed and cases tested for a particular oncogene is due to providers opting for a large discovery panel (336 biomarkers), a precision panel (83 biomarkers), a tumor-specific panel, or other solid tumor panel (ranging from 5 to 103 biomarkers). In addition, cases may not have been reported due to insufficient or lack of tumor tissue, reported as quantity not sufficient (QNS) or test not performed (TNP), as well as the evolving content of the NeoTYPE tumor profile panels.

RESULTS

Frequency of Cancer Types and Mutations in MOSAIC

A specific molecularly diagnosed tumor type was determined in 2,929 (92.5%) of 3,168 cases, comprising 27 different cancer types, illustrating the heterogeneity of the cancers in CUP (Fig 1). The most common tumor type identified was pancreaticobiliary with 789 cases (24.9% of cases), including cholangiocarcinoma, pancreatic adenocarcinoma, and gallbladder adenocarcinoma. Adenocarcinomas represented the most frequent histology (75.8% of all tumors) followed by squamous cell carcinomas (13.8%), neuroendocrine tumors (5.6%), and sarcomas (4.8%; Fig 1). Among the 403 samples diagnosed with squamous cell carcinoma, 165 were lung, 175 were head and neck/skin, and 63 were cervix. A list of the 15 most frequently mutated genes for each of the top 10 molecularly diagnosed cancer types revealed several genes with available targeted therapy options (Appendix Table A2). These include BRCA1 mutations, actionable in ovarian and prostate cancers with PARP inhibitors; IDH1 mutations in pancreaticobiliary/cholangiocarcinoma with IDH1 inhibitors; and KRAS G12C and BRAF V600E mutations in lung, pancreatic, and colorectal carcinoma (CRC) with recently FDA-approved targeted therapies. Several other mutated genes have ongoing clinical trials but no current FDA-approved therapy.

FIG 1. CUP and uncertain diagnoses: distribution of cancer type molecular diagnoses by CancerTYPE ID. CUP, cancer of unknown primary; GIST, GI stromal tumor; QNS, quantity not sufficient.

Prevalence of KRAS G12C Mutation in MOSAIC

Given the FDA approval of KRAS G12C inhibitors, we sought to identify KRAS mutations within the MOSAIC database. Among 369 patients with any KRAS mutation, 50 patients harbored a G12C mutation across six cancer types/subtypes (Table 1). Of the 178 molecularly diagnosed non–small-cell lung cancer (NSCLC) cases, 24 (13.5%) would be potentially eligible for FDA-approved KRAS inhibitor treatment, whereas another 26 (5.3%) of 493 cases may be eligible for investigational KRAS inhibitor trials in pancreaticobiliary, colorectal, and gastroesophageal adenocarcinomas.

TABLE 1. CUP and Uncertain Diagnoses: Prevalence of KRAS G12C Mutation Across Molecularly Diagnosed Cancer Types

Main Type/Subtype	Total Cases in MOSAIC	Cases Reported for KRAS	KRAS Mutation Frequency, %	KRAS G12C Mutation Frequency, %	
Pancreaticobiliary (gallbladder adenocarcinoma)	461	237	50.2	8.0a	
Intestine (colorectal adenocarcinoma)	123	57	49.1	3.5a	
NSCLC (lung adenocarcinoma)	220	110	47.3	19.1b	
Gastroesophageal adenocarcinoma	186	91	38.5	4.4a	
NSCLC (squamous cell carcinoma lung)	165	68	14.7	4.4b	
Pancreaticobiliary (cholangiocarcinoma)	312	108	11.1	0.9a	
Pancreaticobiliary (pancreatic adenocarcinoma)	16	7	85.7	Mutation not detected	
Thymus	4	2	50.0	
Urinary bladder	121	45	46.7	
Germ cell	39	18	38.9	
Intestine (small intestine adenocarcinoma)	81	42	38.1	
Endometrial adenocarcinoma	19	8	25.0	
Ovary	110	52	23.1	
Cervix adenocarcinoma	50	22	22.7	
Squamous cell carcinoma (cervix)	63	32	18.8	
Sarcoma	142	67	17.9	
Neuroendocrine	165	69	15.9	
Squamous cell carcinoma (head and neck/skin)	175	73	15.1	
Prostate adenocarcinoma	22	7	14.3	
Breast adenocarcinoma	83	43	9.3	
Kidney	86	26	7.7	
Head and neck salivary gland carcinoma	81	31	3.2	
Liver hepatocellular carcinoma	103	35	2.9	
Abbreviations: CUP, cancer of unknown primary; FDA, US Food and Drug Administration; NSCLC, non–small-cell lung cancer.

a KRAS G12C inhibitor eligibility: investigational.

b KRAS G12C inhibitor eligibility: FDA-approved.

Prevalence of IDH1/2 Mutations in MOSAIC

IDH1 and IDH2 mutations, common in gliomas and acute myeloid leukemia, are also found in prostate cancer, breast adenocarcinoma, cholangiocarcinoma, and thyroid cancer and have an available targeted therapy option.19,20 IDH1/2 mutations were identified in 14 different tumor types within the MOSAIC database (Table 2). An IDH1 mutation was identified in 28 (33.7%) of 83 cholangiocarcinomas and five (2.9%) of 173 gallbladder adenocarcinomas, whereas IDH2 was mutated in 13 (15.5%) of 84 cholangiocarcinomas.

TABLE 2. CUP and Uncertain Diagnoses: Prevalence of IDH1/2 Mutation and IDH Inhibitor Eligibility Across Molecularly Diagnosed Tumor Types

Main Type/Subtype	Total Cases in MOSAIC	Cases Reported for IDH1	IDH1 Mutation Frequency, %	Cases Reported for IDH2	IDH2 Mutation Frequency, %	
Pancreaticobiliary (cholangiocarcinoma)	312	83	33.7a	84	15.5b	
Pancreaticobiliary (gallbladder adenocarcinoma)	461	173	2.9b	173	Mutation not detected	
Sarcoma (PNET)	16	4	50.0	2	
Prostate adenocarcinoma	22	5	20.0	5	
Neuroendocrine (Merkel cell carcinoma)	21	5	20.0	4	
Intestine (colorectal adenocarcinoma)	123	17	5.9	16	
Urinary bladder	121	35	5.7	35	2.9	
Squamous cell carcinoma (head and neck/skin)	175	61	4.9	61	1.6	
Liver hepatocellular carcinoma	103	30	3.3	30	3.3	
Neuroendocrine (small/large cell lung carcinoma)	100	46	2.2	46	6.5	
Intestine (small intestine adenocarcinoma)	81	32	Mutation not detected	31	3.2	
Squamous cell carcinoma (lung)	165	19	18	5.6	
Kidney (clear cell renal cell carcinoma)	44	4	5	20.0	
Ovary (clear cell adenocarcinoma)	11	1	2	50.0	
Abbreviations: CUP, cancer of unknown primary; FDA, US Food and Drug Administration; PNET, primitive neuroectodermal.

a IDH inhibitor eligibility: FDA-approved.

b IDH inhibitor eligibility: investigational.

Prevalence of BRCA1/2 Mutations in MOSAIC

To assess the potential role of PARP inhibitors, we determined the frequency of BRCA1/2 mutations across tumor types. A total of 85 ovarian, 83 breast, 16 pancreaticobiliary (pancreatic adenocarcinoma), and 1,737 cases across 15 other molecular diagnosed cancers were evaluated for the presence of BRCA1/2 mutations (Table 3). Of the 30 serous adenocarcinomas, seven (23.3%) were identified with a BRCA1 mutation and five (16.7%) with a BRCA2 mutation. BRCA1 and BRCA2 mutations were also identified in one (10%) of 10 and one (9.1%) of 11 ovarian endometrioid adenocarcinomas, respectively. Among 40 identified breast cancers, four (10.0%) carried a BRCA1 mutation and one (2.5%) carried a BRCA2 mutation. Additionally, 14 cases with BRCA1 mutation and 25 cases with BRCA2 mutation were identified across 15 other cancer types. BRCA1/2 frequencies in prostate and pancreatic cancer could not be assessed due to limited testing.

TABLE 3. CUP and Uncertain Diagnoses: Prevalence of BRCA1/2 Mutation and PARP Inhibitor Eligibility Across Molecularly Diagnosed Tumor Types

Main Type/Subtype	Total Cases in MOSAIC	Cases Reported for BRCA1	BRCA1 Mutation Frequency, %	Cases Reported for BRCA2	BRCA2 Mutation Frequency, %	
Ovarian (serous adenocarcinoma)	63	30	23.3a	30	16.7a	
Ovarian (endometrioid adenocarcinoma)	22	10	10.0a	11	9.1a	
Breast adenocarcinoma	83	40	10.0a	40	2.5a	
Pancreaticobiliary (pancreatic adenocarcinoma)	16	1	0a	1	0a	
Prostate	22	0	0a	0	0a	
Germ cell (nonseminoma)	32	3	33.3	2	0	
Sarcoma (undifferentiated sarcoma [MFH])	74	11	18.2	11	18.2	
Melanoma	31	6	16.7	5	20	
Squamous cell carcinoma (lung)	165	20	15.0	18	5.6	
Intestine (colorectal adenocarcinoma)	123	18	11.1	16	12.5	
Squamous cell carcinoma (head and neck/skin)	175	17	11.8	16	18.8	
Intestine (small intestine adenocarcinoma)	81	9	11.1	8	0	
Urinary bladder	121	12	8.3	12	0	
Cervix adenocarcinoma	50	12	8.3	12	8.3	
Lung adenocarcinoma	220	21	Mutation not detected	23	21.7	
Neuroendocrine (Merkel cell carcinoma)	21	4	5	20.0	
Skin basal cell carcinoma	20	5	5	20.0	
Squamous cell carcinoma (cervix)	63	7	7	14.3	
Pancreaticobiliary (gallbladder adenocarcinoma)	461	49	51	11.8	
Neuroendocrine (small/large cell lung carcinoma)	100	12	12	8.3	
Cancer types with no footnote potentially eligible for investigational PARP inhibitors.

Abbreviations: CUP, cancer of unknown primary; FDA, US Food and Drug Administration; MFH, malignant fibrous histiocytoma.

a PARP inhibitor eligibility: FDA-approved.

Prevalence of BRAF Mutations in MOSAIC

Following recent FDA approvals for drugs targeting BRAF V600E mutations in colorectal and lung carcinomas, we explored the prevalence within the database. BRAF mutations were identified in 89 (3.4%) of 2,606 cases across 19 tumor types and subtypes. Of these 89 cases, 27 (30.3%) had BRAF V600E mutations in a tumor type eligible for FDA-approved BRAF inhibitor treatment, including melanoma, non–small-cell lung carcinoma, colorectal adenocarcinoma, thyroid cancer, and other tumor types. Another 26 (29.9%) BRAF-mutated cases were detected in a tumor type with ongoing BRAF inhibitor clinical trials, including lymphoma, pancreaticobiliary, and ovarian cancer (Table 4).

TABLE 4. CUP and Uncertain Diagnoses: Prevalence of BRAF Mutation and BRAF Inhibitor Eligibility in Different Molecularly Diagnosed Tumor Types

Main Type/Subtype	Total Cases in MOSAIC	Cases Reported for BRAF	BRAF Mutation Frequency, %	BRAF V600E Mutation Frequency, %	
Thyroid	10	4	25.0	0	
Melanoma	31	17	23.5	5.9	
Lymphoma	8	5	20.0	20.0	
Intestine (small intestine adenocarcinoma)	81	39	12.8	7.7	
Indeterminate	236	109	11.9	4.6	
Gastroesophageal adenocarcinoma	186	87	11.5	4.6	
Liver hepatocellular carcinoma	103	35	11.4	2.9	
Squamous cell carcinoma (head and neck/skin)	175	72	11.1	5.6	
Mesothelioma	25	9	11.1	0	
Urinary bladder	121	36	11.1	0	
NSCLC (lung adenocarcinoma)	220	102	9.8	4.9	
NSCLC (squamous cell carcinoma lung)	165	65	7.7	1.5	
Pancreaticobiliary	789	317	6.9	1.6	
Ovarian	110	50	6	2.0	
Germ cell	39	17	5.9	5.9	
Sarcoma	142	68	5.9	Mutation not detected	
Cervix adenocarcinoma	50	21	4.8	
Intestine (colorectal adenocarcinoma)	123	47	4.3	
Squamous cell carcinoma (Cervix)	63	28	3.6	
Neuroendocrine	165	67	3	
Abbreviations: CUP, cancer of unknown primary; NSCLC, non–small-cell lung cancer.

DISCUSSION

Molecular tumor profiling has become an important tool in clinical practice to personalize therapy selection for advanced cancers. Clinical trials targeting specific molecular aberrations are increasingly focused on obtaining tumor-agnostic approvals, making molecular profiling essential to identify eligible patients. Currently, most biomarker-directed FDA-approved indications are for specific cancers. Therefore, identifying the tissue of origin in CUP, followed by comprehensive biomarker analysis, yields a reasonable probability of determining biomarker-directed targeted therapy. Patients with CUP treated with site-specific therapies on the basis of a molecular diagnosis have outcomes superior to empirical chemotherapy and similar to those with known anatomical primaries treated with site-specific therapies.21-28

Therapy selection in CUP often relies on a diagnostic panel of IHC stains and/or a validated molecular classifier assay like CancerTYPE ID, followed by NGS and other biomarker testing.1,3,29,30 The results reported here show that CancerTYPE ID identified a tissue of origin in 92.5% of patients with CUP or diagnostic ambiguity. The distribution of histological subtypes in the identified tissues of origin is comparable with previous reports in CUP using light microscopy.3,31

The prevalence of specific gene mutations, including IDH 1/2 and BRCA 1/2, in CUP with molecularly diagnosed cholangiocarcinoma and breast/ovarian carcinomas is similar to the reported prevalence of these mutations in known cholangiocarcinoma and breast/ovarian carcinomas, supporting the accuracy of the CancerTYPE ID molecular diagnoses. This largely CUP cohort shows additional nuances, such as under-represented BRAF mutations in CRC and over-represented KRAS mutations compared with other studies.32-35

This study aimed to determine the frequency of actionable mutations in key oncogenes with FDA-approved targeted drugs, including KRAS, IDH1/2, BRCA1/2, and BRAF, within the MOSAIC database. Aberrations in these six oncogenes were identified in 8.4% of all CUP cases following molecular diagnosis. The genetic alterations generally mirror those observed in specifically identified cancers.

KRAS G12C mutations, occurring in approximately 12%-14% of NSCLC cases, were found in 13.5% (24/178) of the molecularly identified NSCLC cohort of CUP and uncertain diagnoses.36 Although not FDA-approved, KRAS G12C inhibitors have shown activity in pancreatic and colorectal adenocarcinoma and have been guideline-directed.37-39 Within the 50 cases identified with a KRAS G12C mutation, 24 (48%) could be currently treated with an FDA-approved KRAS inhibitor, whereas the remaining cases involve cancer types under clinical investigation (Table 1). Both single-agent and combinatorial therapy with EGFR inhibitors provide options for these patients.40 Several other investigational drugs are targeting KRAS, not just G12C.

IDH1 mutations were identified in 33.7% of molecularly diagnosed cholangiocarcinomas, making these patients eligible for treatment with the FDA-approved IDH1 inhibitor ivosidenib.41 A diagnosis of any pancreaticobiliary subtype by CancerTYPE ID followed by an IDH1/2 mutational analysis led to a 1.8-fold increase in patients eligible for IDH1/2 targeted therapy. Similarly, obtaining a diagnosis of cholangiocarcinoma by CancerTYPE ID combined with IDH1/2 mutational analysis resulted in an over 5-fold increase in patients potentially eligible for FDA-approved targeted therapies.

In some cases, a gene mutation was identified without an FDA-approved targeted therapy option. For instance, 26.7% of patients with IDH1 mutations were identified in tumor types with no FDA-approved IDH therapy, whereas 56.5% of IDH2 mutations overlapped with tumor types that have ongoing clinical trials for targeting IDH2. There were 13 (15.5%) of 84 cholangiocarcinomas with potentially actionable IDH1 mutations using FDA-approved ivosidenib or IDH2 mutations identified for potential enrollment in investigational trials.

Germline BRCA1/2 mutations are associated with a significantly higher risk of breast, ovarian, pancreatic, and prostate cancers.42-44 However, no clinical information was available for BRCA1/2 mutation carrier status in MOSAIC. In this cohort, the frequency of BRCA mutations in molecularly diagnosed breast adenocarcinoma was 10% for BRCA1 and 2.5% for BRCA2. Interestingly, BRCA mutations were observed more frequently in serous ovarian adenocarcinomas than in breast carcinomas (23.3% BRCA1 and 16.7% BRCA2). The reported frequency of BRCA1/2 mutations for epithelial ovarian cancer in the overall population is approximately 18%, whereas in this metastatic cohort, the frequency for all molecularly diagnosed ovarian cancers was 20% for BRCA1 and 14.6% for BRCA2, making this cohort of CUP cases more likely to have this mutation, supporting broader clinical assessment of BRCA mutations.45

In 89 patients with BRAF mutations across 19 tumor types, 30.3% had BRAF V600E tumor types eligible for FDA-approved BRAF inhibitors, including melanoma, NSCLC, colorectal, and thyroid carcinomas. An additional 29.9% of BRAF-mutated cases were detected in a tumor type with ongoing BRAF inhibitor clinical trials, including lymphoma, pancreaticobiliary, and ovarian carcinomas (Table 4).

Tumor-agnostic trials following a master protocol study the efficacy of biomarker-directed treatments across various cancer types. Since 2017, the FDA has approved several tumor-agnostic treatments, including the combination of dabrafenib and trametinib (for patients with BRAF V600E mutations) for any previously treated advanced cancer.46 Despite the promise of agnostic therapies, considerable challenges remain. In CUP, <2% of patients have BRAF V600E mutations as an agnostic target. For those who have their tissue of origin determined, the approved agnostic therapy would not be indicated for most as first-line therapy. The FDA-approved therapy would also differ from the agnostic therapy for several specific cancers harboring BRAF V600E mutations (encorafenib with binimetinib for melanoma and lung; encorafenib with cetuximab for colorectal). Even with agnostic approval, efficacy is limited in patients with CRC who respond very poorly to BRAF inhibitors alone but respond favorably when combined with cetuximab, an EGFR inhibitor.47 Therefore, the primary tissue of origin diagnosis in CUP is still essential to identify the most appropriate first-line therapy for most patients. Currently, most biomarker-directed FDA-approved indications are tumor type–specific. Despite the absence of specific data on this point, we believe that identifying the primary tumor type first, followed by comprehensive biomarker analysis, yields the best chance of identifying optimal biomarker-directed targeted therapy for the patient.

This study has several limitations, including the retrospective evaluation and lack of knowledge of patient therapies and outcomes due to deidentified patient data, lack of detailed standardized centralized IHC staining, and unavailability of some clinical features at the time of molecular testing. Limited data on BRCA1/2 mutation are currently available in pancreas and prostate adenocarcinomas despite the FDA approvals associated with these mutations for both tumor types. Additionally, some clinically relevant mutations might not have been included in previous versions of some tumor panels due to the rapidly advancing knowledge, and not all samples yielded results due to QNS and TNP. Regarding the CancerTYPE ID test, it is not 100% accurate (about 87% accurate for cancers in the database), 7.4% of cases in this series were reported as indeterminate, rare cancers are not included in the reference database, and there are possible overlapping diagnoses, particularly in pancreaticobiliary.16

In summary, these findings support molecular type classification in CUP combined with multimodal biomarker profiling to identify site-specific targeted treatment options. The MOSAIC analysis identified metastatic patients with actionable mutations in KRAS, IDH1, BRCA1/2, and BRAF eligible for selected FDA-approved therapies and those who may be clinical trial candidates on the basis of tumor type and mutation status (Appendix Table A3). These identified molecular alterations reflect the various specific cancers in the CUP syndrome. Although only selected mutations with FDA-approved therapies were reported in detail here, the same process of molecular testing is applicable for the identification of many other actionable targets present in many known cancers presenting as CUP (Appendix Table A3).

ACKNOWLEDGMENT

We thank the clinicians and pathologists for submitting cases for CancerTYPE ID testing. We further thank Madhu Rengaraj and Harish Advani from NeoGenomics for providing the NeoTYPE testing results.

PRIOR PRESENTATION

AUTHOR CONTRIBUTIONS

Conception and design: Harry E. Fuentes Bayne, Pashtoon M. Kasi, Li Ma, Catherine A. Schnabel, Thorvardur R. Halfdanarson, Kai Treuner, F. Anthony Greco

Provision of study materials or patients: Lowell L. Hart

Collection and assembly of data: Harry E. Fuentes Bayne, Li Ma, Lowell L. Hart, Jenna Wong, Catherine A. Schnabel

Data analysis and interpretation: Harry E. Fuentes Bayne, Pashtoon M. Kasi, Li Ma, Lowell L. Hart, David R. Spigel, Catherine A. Schnabel, Thorvardur R. Halfdanarson, Kai Treuner, F. Anthony Greco, James A. Reeves

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

APPENDIX

FIG A1. Integration of tumor typing and molecular profiling to enable personalized therapy selection in CUP or other uncertain diagnoses. CUP, cancer of unknown primary.

TABLE A1. Pairing of Classifications with Tumor Profiles

CancerTYPE ID Result	NeoTYPE Profile Reflex	
Brain, meningioma	NeoTYPE Brain Tumor Profile	
Breast adenocarcinoma	NeoTYPE Breast Tumor Profile	
Cervix adenocarcinomal	NeoTYPE Cervical Tumor Profile	
Intestine—colorectal	NeoTYPE Colorectal Tumor Profile	
Endometrial adenocarcinoma	NeoTYPE Endometrial Tumor Profile	
Gastroesophageal adenocarcinoma	NeoTYPE Gastric Tumor Profile	
GIST	NeoTYPE GIST Profile	
Liver hepatocellular carcinoma	NeTYPE Liver/Biliary Tumor Profile	
Lung adenocarcinoma, squamous cell carcinoma—lung	NeoTYPE Lung Tumor Profile	
Lymphoma	NeoTYPE Lymphoma Tumor Profile	
Melanoma	NeoTYPE Melanoma Tumor Profile	
Ovary	NeoTYPE Ovarian Tumor Profile	
Sarcoma	NeoTYPE Soft Tissue Tumor Profile	
Thyroid	NeoTYPE Thyroid Profile	
Adrenal
Germ cell
Head and neck salivary gland carcinoma
Intestine—small intestine adenocarcinoma
Kidney
Mesothelioma
Neuroendocrine
Pancreaticobiliary	Prostate adenocarcinoma
Sex cord stromal tumor
Skin basal cell carcinoma
Squamous cell carcinoma—cervix
Squamous cell carcinoma—head and neck/skin
Thymus
Urinary bladder	NeoTYPE Other Solid Tumor Profile	
Indeterminate		NeoTYPE Precision Profile for Solid Tumors + MSI	
NOTE. When CancerTYPE ID and NeoTYPE Cancer Profiles are ordered together, the NeoTYPE profile performed will be on the basis of the CancerTYPE ID result as follows in this table.

Abbreviations: GIST, GI stromal tumor; MSI, microsatellite instability.

TABLE A2. CUP and Uncertain Diagnoses: Mutational Frequency of the 15 Most Commonly Mutated Genes by Molecularly Diagnosed Tumor Type

Tumor Type	N	Mutational Frequency (%) of the 15 Most Common Mutations by Tumor Type	
Pancreaticobiliarya	789	TP53	KRAS	FGFR2 fusion	ARID1A	LRP1B	BAP1	STK11	KMT2C	CDKN2A	KMT2D	SMARCA4	PBRM1	FAT1	KEAP1	IDH1	
45.3	38.9	33.3	22.0	21.3	20.0	17.7	17.5	17.3	17.1	16.2	13.6	13.3	13.3	12.6	
Squamous cell carcinomab	403	TP53	KMT2D	LRP1B	KMT2C	FAT1	BCORL1	PIK3CA	KEAP1	SMARCA4	NOTCH1	ARID1A	MTOR	NF1	ATM	RB1	
71.98	41.54	34.04	33.33	31.82	27.91	25.77	23.81	23.33	22.29	22.22	22.0	21.5	19.7	19.7	
Lung adenocarcinoma	220	TP53	KRAS	KEAP1	LRP1B	STK11	SMARCA4	KMT2D	BRCA2	KMT2C	ARID1A	ARID2	CDKN2A	DICER1	GLI1	NF1	
69.2	47.3	42.2	28.0	27.6	27.1	26.8	21.74	21.7	19.6	18.2	18.2	17.4	17.4	16.7	
Intestine	204	TP53	KRAS	KEAP1	LRP1B	STK11	SMARCA4	KMT2D	BRCA2	KMT2C	ARID1A	ARID2	CDKN2A	DICER1	GLI1	NF1	
69.17	47.27	42.19	28	27.59	27.12	26.79	21.74	21.74	19.64	18.18	18.18	17.39	17.39	16.7	
Gastroesophageal	186	TP53	KRAS	KMT2C	ARID1A	LRP1B	APC	FAT1	KEAP1	SMARCA4	CDKN2A	PREX2	ATM	ATR	FANCD2	KMT2D	
63.5	38.5	29.2	27.1	24.0	23.1	21.7	20.0	16.7	14.6	14.6	13.0	13.0	13.0	13.0	
Neuroendocrinec	165	TP53	LRP1B	APC	RB1	NBN	KMT2C	SMARCA4	PTEN	PIK3CA	CTNNB1	DICER1	MED12	MTOR	PRDM1	RANBP2	
67.9	30.0	27.8	26.3	25.0	22.2	21.1	19.4	17.46	16.7	16.7	16.7	16.7	16.7	16.7	
Sarcomac	142	TP53	KMT2D	TERT	LRP1B	CDKN2A	FAT1	SPTA1	BAP1	KRAS	ARID2	CARD11	EP300	SMARCA4	NF1	ARID1A	
53.2	38.5	33.3	30.8	24.5	22.7	21.7	20.8	17.9	17.4	17.4	17.4	17.4	16.3	14.6	
Urinary bladder	121	TP53	LRP1B	KRAS	SMARCA4	TERT promoter	PIK3CA	APC	ATR	ROS1	TET2	ARID1A	ATM	RANBP2	SMAD4	ATRX	
73.1	50.0	46.7	38.5	33.3	30.8	25.0	25.0	25.0	25.0	23.1	23.1	23.1	20.0	16.7	
Ovaryc	110	TP53	KRAS	RNF43	RANBP2	ATM	ARID1A	CHEK2	BRCA1	ASXL1	AXL	DOT1L	FLT4	KDM5A	KMT2C	SPEN	
68.7	23.1	21.4	20.0	17.9	16.7	16.67	16.0	15.4	15.4	15.4	15.4	15.4	15.4	15.4	
Liver hepatocellular carcinoma	103	NBN	RAD51B	TP53	KMT2D	BAP1	PBRM1	TSC2	FANCD2	FLT4	GID4	RANBP2	ARID1A	AKT3	BCORL1	CIC	
50.0	50.0	50.0	33.3	23.5	22.2	22.2	20.0	20.0	20.0	20.0	18.8	16.7	16.7	16.7	
NOTE. Targeted therapy availability: FDA approval in current identified tumor type or certain subtypes of the identified tumor type in bold; FDA approval not in current identified tumor type in italic.

Abbreviation: FDA, US Food and Drug Administration.

a Pancreas, bile duct, and gall bladder.

b Cervix, head and neck/skin, and lung.

c Multiple subtypes.

TABLE A3. CUP and Unclear Diagnoses: Prevalence of FDA-Approved Biomarkers in the MOSAIC Database

FDA-Approved Biomarkers	Cases Tested	Positive	Positive, %	
ALK	542	8	1.5	
BRAF	1,217	89	7.3	
BRCA1 (also HRR genes)	388	26	6.7	
BRCA2 (also HRR genes)	386	32	8.3	
ATM (also HRR genes)	480	62	12.9	
dMMR or MSI-h	1,145	21	1.8	
EGFR (HER1) exon mutation	206	0	0	
EGFR (HER1) mutation	973	59	6.1	
ERBB2 (HER2) mutation	691	39	5.6	
ERBB2 (HER2) expression	721	38	5.3	
EZH2 mutation	299	2	0.7	
FGFR2 fusion	13	2	15.4	
FGFR3 fusion	1	0	0	
FGFR3 mutation	1,202	47	3.9	
FLT3 (ITD/TDK): FLT3 mutation	304	11	3.6	
HRR genes				
 HRR genes: BARD1	329	10	3.0	
 HRR genes: BRIP1	336	19	5.7	
 HRR genes: CDK12	330	11	3.3	
 HRR genes: CHEK1	328	8	2.4	
 HRR genes: CHEK2	330	20	6.1	
 HRR genes: FANCL	327	10	3.1	
 HRR genes: PALB2	333	16	4.8	
 HRR genes: RAD51B	153	5	3.3	
 HRR genes: RAD51C	149	1	0.7	
 HRR genes: RAD51D	150	3	2.0	
 HRR genes: RAD54L	151	8	5.3	
IDH1	717	45	6.3	
IDH2	714	23	3.2	
KIT	1,130	57	5.0	
KRAS	1,285	375	29.2	
MET	1,597	59	3.7	
NTRK1, NTRK2 and NTRK3	1,537	93	6.1	
PD-L1	2,149	1,719	80.0	
PIK3CA mutation analysis	1,124	162	14.4	
PIK3CA LDT mutation analysis by sequencing	105	0	0	
RET fusions	598	5	0.8	
ROS1 fusions	535	6	1.1	
TMB-H	1,296	254	19.6	
Abbreviations: CUP, cancer of unknown primary; dMMR, deficient DNA mismatch repair; FDA, US Food and Drug Administration; HRR, homologous recombination repair; MSI-h, microsatellite instability- high; TMB-H, tumor mutational burden-high.

Presented in part at ASCO Annual Meeting 2021, virtual, June 4-8, 2021; ASCO Annual Meeting 2022, Chicago, IL, June 3-7, 2022; ASCO GI 2022, San Francisco, CA, January 20-22, 2022; and North America Conference on Lung Cancer (NACLC) 2023, Chicago, IL, December 1-3, 2023.

Pashtoon M. Kasi

Leadership: Precision Biosensors

Stock and Other Ownership Interests: Elicio Therapeutics

Consulting or Advisory Role: Taiho Pharmaceutical (Inst), Ipsen (Inst), Natera, Foundation Medicine, MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Daiichi Sankyo/AstraZeneca, Eisai, Seagen, SAGA Diagnostics, Illumina, BostonGene, NeoGenomics Laboratories, Elicio Therapeutics, Guardant Health, Regeneron

Research Funding: Advanced Accelerator Applications (Inst), Tersera (Inst), Boston Scientific (Inst)

Travel, Accommodations, Expenses: AstraZeneca

Li Ma

Stock and Other Ownership Interests: Hologic/Biotheranostics

Lowell L. Hart

Honoraria: Novartis, G1 Therapeutics, Circulogene Theranostics

Consulting or Advisory Role: Genentech/Roche, Amgen, G1 Therapeutics, Merck, Seagen

Speakers' Bureau: Novartis, Circulogene Theranostics

Research Funding: Novartis (Inst), Genentech/Roche (Inst), Bristol Myers Squibb (Inst), G1 Therapeutics (Inst), Seagen (Inst)

Jenna Wong

Employment: Hologic

Stock and Other Ownership Interests: Hologic

David R. Spigel

Leadership: ASCO (Inst)

Consulting or Advisory Role: Genentech/Roche (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), GlaxoSmithKline (Inst), Jazz Pharmaceuticals (Inst), Sanofi/Aventis (Inst), Ipsen (Inst), Monte Rosa Therapeutics (Inst), AbbVie (Inst), Lyell Immunopharma (Inst), Novocure (Inst), Amgen (Inst), MedImmune (Inst)

Research Funding: Genentech/Roche (Inst), Novartis (Inst), Celgene (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), AstraZeneca (Inst), University of Texas Southwestern Medical Center - Simmons Cancer Center (Inst), Merck (Inst), G1 Therapeutics (Inst), Neon Therapeutics (Inst), Nektar (Inst), Celldex (Inst), Daiichi Sankyo (Inst), Astellas Pharma (Inst), GRAIL (Inst), Transgene (Inst), Aeglea Biotherapeutics (Inst), Ipsen (Inst), Eisai (Inst), ImClone Systems (Inst), Janssen Oncology (Inst), MedImmune (Inst), Agios (Inst), GlaxoSmithKline (Inst), Tesaro (Inst), Cyteir (Inst), Novocure (Inst), Elevation Oncology (Inst), Calithera Biosciences (Inst), Arcus Biosciences (Inst), Arrys Therapeutics (Inst), Bayer (Inst), BeiGene (Inst), Blueprint Medicines (Inst), Boehringer Ingelheim (Inst), Hutchison MediPharma (Inst), Incyte (Inst), Kronos Bio (Inst), Loxo (Inst), Macrogenics (Inst), PureTech (Inst), Razor Genomics (Inst), Repare Therapeutics (Inst), Rgenix (Inst), Tizona Therapeutics, Inc (Inst), Verastem (Inst), BioNTech (Inst), AbbVie (Inst), Amgen (Inst), Anheart Therapeutics (Inst), Ascendis Pharma (Inst), Endeavor BioMedicines (Inst), Erasca, Inc (Inst), Faeth Therapeutics (Inst), Fujifilm (Inst), Gilead Sciences (Inst), Jazz Pharmaceuticals (Inst), Lyell Immunopharma (Inst), Millennium (Inst), Moderna Therapeutics (Inst), Monte Rosa Therapeutics (Inst), Peloton Therapeutics (Inst), Shenzhen Chipscreen Biosciences (Inst), Stemline Therapeutics (Inst), Synthekine (Inst), Taiho Oncology (Inst), Tango Therapeutics (Inst), Tarveda Therapeutics (Inst), Zai Lab (Inst), Apollomics (Inst), Strata Oncology (Inst), Asher Biotherapeutics (Inst), Denovo Biopharma (Inst), Ellipses Pharma (Inst), EMD Serono (Inst), Evelo Biosciences (Inst), Foundation Bio (Inst), Immunogen (Inst), Janux Therapeutics (Inst), Oncologie (Inst), Pfizer (Inst), Phanes Therapeutics (Inst), PTC Therapeutics (Inst), Seagen (Inst), Takeda (Inst)

Travel, Accommodations, Expenses: AstraZeneca, Genentech, Novartis

Catherine A. Schnabel

Employment: Ionis Pharmaceuticals

Stock and Other Ownership Interests: Ionis Pharmaceuticals, Nucleix

Patents, Royalties, Other Intellectual Property: Biotheranostics/Hologic

Travel, Accommodations, Expenses: Ionis Pharmaceuticals

James A. Reeves

Employment: Florida Cancer Specialists and Research Institute

Consulting or Advisory Role: No relationships to disclose

Research Funding: Sarah Cannon Research Institute (Inst)

Thorvardur R. Halfdanarson

Consulting or Advisory Role: Ipsen (Inst), Advanced Accelerator Applications (Inst), Tersera, Crinetics Pharmaceuticals (Inst), ITM Isotope Technologies Munich (Inst), Viewpoint Molecular Targeting (Inst), Camurus (Inst)

Research Funding: Thermo Fisher Scientific (Inst), Turnstone Bio (Inst), Advanced Accelerator Applications (Inst), Novartis (Inst), ITM Isotope Technologies Munich (Inst), Camurus (Inst), Crinetics Pharmaceuticals (Inst), Perspective Therapeutics (Inst)

Uncompensated Relationships: North American Neuroendocrine Tumor Society

Kai Treuner

Employment: Biotheranostics

Stock and Other Ownership Interests: Biotheranostics

Patents, Royalties, Other Intellectual Property: Related to research conducted at Biotheranostics, Inc

Travel, Accommodations, Expenses: Biotheranostics

F. Anthony Greco

Honoraria: Biotheranostics

Consulting or Advisory Role: Biotheranostics

Speakers' Bureau: Biotheranostics

No other potential conflicts of interest were reported.
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