Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options: the PRECODE study protocol

doi:10.21203/rs.3.rs-4710881/v1

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Study protocol

Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options: the PRECODE study protocol

https://doi.org/10.21203/rs.3.rs-4710881/v1

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Background:

Genomic profiling of advanced solid cancer in patients with no further evidence based standard treatment options is a novel approach to identify potential experimental treatment options based on specific genomic alterations. Due to the expected short survival of these patients timely assessment of potential druggable targets is critical to minimize the risk of deterioration during the analysis.

The primary objective of this prospective study is to evaluate the turnaround time for genomic profiling and the feasibility of clinical investigational procedures. The secondary objectives are to investigate how often genomic alterations in tumor tissue gives rise to a matched treatment offer and evaluate the clinical outcome.

Methods:

The PRECODE study is a prospective, non-randomized, single-center cohort study conducted at Departments of Oncology and Pathology, Odense University Hospital, Denmark. Enrollment between March 1, 2019 and December 31, 2024. Eligibility criteria are age > 18 years, written informed consent, advanced solid tumors, exhausted treatment options, ECOG performance status 0-2, adequate organ function and life expectancy >3 months. A core needle biopsy is analyzed by next generation sequencing using a pan-cancer comprehensive panel. Results are discussed weekly at institutional/local and national multidisciplinary tumor boards.

Discussion:

Strategies and methods for genomic profiling of advanced solid cancers differ. Rapid analysis and interpretation of sequencing data are key to avoiding delays in initiation potential experimental treatments, as these late-stage patients may quickly deteriorate.

A highly optimized setup with fast-track clinical evaluation and genomic profiling has been established. Local and national multidisciplinary teams have been established to optimize individualized treatment decisions

Trial registration: ClinicalTrials.gov Identifier: NCT05385081 (retrospectively registered)

Tumor agnostic therapy

genomic profiling

next generation sequencing

solid cancers

In recent years, treatment of solid cancers has been optimized and in addition to the more traditional use of drugs approved for a specific cancer diagnosis, tumor-agnostic therapy is becoming more common (1). For the latter approach, patients are treated based on genomic alterations of their tumor, which requires genomic profiling to identify these alterations for a matched targeted treatment. Genomic profiling may be performed at early diagnosis of the cancer or, more commonly, when standard evidence-based treatment options have been exhausted.

Genomic profiling of solid tumors frequently identifies multiple genetic alterations and clinicians need to determine which alterations, if any, are druggable and thus relevant for treatment decisions. The frequency of genomic alterations varies between patients and their tumor types. In precision medicine trials, 30–87% of advanced solid tumors harbored actionable genomic alterations (1–5). The actionability of identified somatic variants differs, but is expected to increase in line with the development of new targeted drugs, their testing in clinical trials and cumulative evidence for the benefits of off-label treatment targeting specific genomic alterations. Thus, the frequency of patients receiving a treatment based on a drug-variant match following genomic analysis is also increasing.

When solid tumor patients who have exhausted all treatment options are offered genomic profiling in search of a drug match, the treatment decision may rely on tier III evidence (clinical benefit previously demonstrated in other tumor types or for similar molecular targets) (2). If treating a cancer using drugs approved for a different cancer, the strategy is termed off-label treatment. However, off-label treatment depends on access to the relevant drugs through clinical trials or drug approval by European Medicines Agency (EMA) or Food and Drug Administration (FDA) either as a tumor agnostic or to diagnose specific targeted treatment (3). It is essential that access to these specific targeted drugs is ensured when there is a drug-variant match without which genomic analysis has limited value.

In Denmark, all university hospitals are performing genomic analyses, but the setups differ significantly. Through national cooperation, all genomic profiling sites are now participating in a weekly online meeting of The Danish National Molecular Tumor Board (DNMTB). The purpose of DNMTB is to establish a forum for discussion of specific patient cases, exchanging knowledge, providing advice on targeted treatment and facilitating referrals to clinical trials based on the molecular profile of the tumors. This collaboration helps to equalize the otherwise geographical inequality for patients, providing equal opportunity for all Danes, along with transparency of site-specific trials.

Selection of patients to clinical trials using molecular profiling has been investigated in several recent studies (4–7). Considering the pros/cons of the different profiling methods and the critical state of these patients, the overall priority of this study was a comprehensive yet, fast track process providing high quality focused data within the shortest possible turn-around-time (TAT). Diverse next generation sequencing (NGS) strategies can be used from panel sequencing, whole exome sequencing to whole genome sequencing, and is frequently combined with RNA sequencing. Several large commercial pan-cancer-focused panels are available that provide the possibility to develop focused genomic profiling with short TATs.

In the present study PRECODE (PREcision medicine in Cancer in Odense, DEnmark), we evaluate the feasibility of genomic profiling by panel sequencing of solid cancers in a multidisciplinary university hospital setting using a newly established and highly optimized setup with both fast-track clinical evaluation and genomic profiling. Our investigational procedures ensured a minimal time delay from patient consent to clinical decision making based on DNMTB guidance. The primary objective of this prospective study is to evaluate the turnaround time for genomic profiling and the feasibility of clinical investigational procedures. The secondary objectives are to investigate how often genomic alterations in tumor tissue give rise to a matched treatment offer and evaluate the clinical outcome.

This prospective, non-randomized, single-center cohort study was initiated in March 2019 at the Departments of Oncology and Pathology at Odense University Hospital (Odense, Denmark). The study is still recruiting using the following criteria:

A fresh tumor biopsy, if feasible, is obtained for all patients included in the study. Feasibility of the investigational procedures including biopsy and genomic profiling is evaluated with regard to timelines. The procedure for biopsy is evaluated in terms of feasibility at different locations and the number of patients in whom no biopsy is possible or re-biopsy is required. If biopsy is not possible, failed or canceled for another reason due to patient-related issues (refusal of biopsy or deteriorated health) the patient is designated a screen failure (SF). If fresh tumor biopsy is not possible or failed (no tumor cells or inconclusive) and a formalin-fixed, paraffin-embedded (FFPE) archival sample available for DNA and RNA extraction, we use the archived tissue for analysis.

Only patients who have provided written and oral consent are evaluated.

Patient selection

Consecutive cancer patients are still currently being referred from the treating oncologists in the Department of Oncology or from other Centers of Oncology in Denmark (enrollment period 3/1/19 − 12/31/24). Eligibility criteria are age ≥ 18 years, written informed consent, advanced solid tumors, evidence based treatment options exhausted, ECOG performance status (PS) 0–2, adequate organ function assessed by blood tests and life expectancy of at least 3 months.

Clinical information regarding patient medical histories are obtained from the hospital digital medical file system using patient Danish Civil Registration numbers (CPR), allowing follow-up with accurate censoring at emigration or death. The registered data are abstracted from medical files by local investigators and collected and managed using REDCap electronic data capture tools hosted at OPEN, Open Patient data Explorative Network, Odense University Hospital, Region of Southern Denmark.

Patient interviews, obtained informed consent, coordination of assessments and participation in local and national tumor board takes place in the Clinic of Precision Medicine, Department of Oncology, Odense University Hospital, Denmark.

Planned procedures

Blood samples will be taken and participants referred for contrast-enhanced PET/CT scans to evaluate disease status and select lesions for core needle biopsies. When NGS analysis is complete, the results will be discussed at local Tumor Board (OUH-TB) with possible further referral to DNMTB depending on the results of the genomic test (Fig. 1).

If the genomic profiling results in a targeted treatment offer, the Growth Modulation Index (GMI) (8) will be calculated based on the progression free survival (PFS) on recent and current treatment. Treatment administered without an actionable genomic target (i.e PD1/PD-L1 inhibitors or chemotherapy) will likewise be evaluated for efficacy using the PFS and GMI, however these patients will not be included in the cohort of patients with a genomic target. Patients with no further systemic treatment offers will be evaluated by time to progression (TTP) and death (overall survival (OS)) after providing consent.

Timelines in the course of investigation will be calculated using date of informed consent, PET/CT scan, biopsy, OUH-TB, DNMTB, and dates of start of next treatment, progression and death. The calculated timelines will be compared to expected timelines.

The planned timelines for investigation in our trial is a fast track from patient consent to biopsy, genomic profiling, presentation at DNMTB and finally a clinical decision. The NGS procedure runs continuously to ensure as short a response time as possible, potentially no more than two weeks from biopsy to genomic profile and an overview of the possible treatment options.

Since the schedule for OUH-TB and DNMTB are Mondays and Thursdays respectively, and TAT for NGS analysis is 5–8 days, the day of the week for biopsy will be decisive for the final investigation time from biopsy to conclusion.

Blood samples

Blood is drawn to evaluate organ function (hematology, kidney and liver tests) and coagulation parameters. For future biomarker analysis blood samples are processed for storage in a biobank (-80^o C). Samples of 4 x 10 ml EDTA glasses, refrigerated centrifuge at 4 °c, 3000 G for 15 minutes. Plasma is distributed in 8 pieces of 3.6 ml tubes (Nunc). Buffycoat is transferred to 4 pieces of 3.6 ml tubes (Nunc).

Imaging-based selection of site of biopsy

A combined positron emission tomography (PET) scan with fluorine-18-fluordeoxyglucose (¹⁸F-FDG) and contrast enhanced (CE) computed tomography (CT) (¹⁸F-FDG CE PET/CT) (8) is performed to identify the disease burden and to choose lesions available for full thickness biopsy. If a suitable imaging (combined PET/CT scan no older than 4 weeks) is already available, this is used to determine the biopsy site. Patients with bone only disease or predominantly bone metastases are referred for whole body magnetic resonance imaging (MRI) as an alternative or supplement to the combined PET/CT scan.

The majority of patients will undergo an ¹⁸F-FDG CE PET/CT (9) from the skull to mid-thigh. The Department of Nuclear Medicine can choose an alternative tracer if this better serves the purpose for the patient, such as ⁶⁸Ga-DOTATOC, a somatostatin receptor–targeted ligand, for neuroendocrine tumors (NET’s), sodium fluoride (NaF) to assess bone metastases or prostate-specific membrane antigen (PSMA)–targeted PET imaging (¹⁸F-PSMA) for prostate cancer patients.

All PET/CT scans are performed on GE Discovery MI systems (GE medical Systems, Milwaukee, USA) according to European guidelines (9). PET-scans are reconstructed with both OSEM (4 iterations, 17 subsets) and Q.Clear (β = 500) including time-of-flight reconstruction. Prior to the PET-scan a low-dose CT-scan is performed for attenuation correction, the contrast-enhanced diagnostic CT (CE-CT) scan is obtained after the PET-scan with the following parameters: 120 kV and 100–540 mA, Smart mA; Auto mA; rotation time 0.5 s; pitch 0.984:1; Noise Index 25

The PET and the CE-CT’s are reported simultaneously by a trained specialist in Nuclear Medicine and Radiology with assessment of the best site(s) for sampling.

In cases with bone-only metastases or where progression is only found in bone/bone marrow an attempt will be made to sample hypercellular lesions based on apparent diffusion coefficient (ADC) values and DIXON-FatFraction (10) in MR studies according to MET-RADS (11).

In the more common cases of metastases in solid organs or lymph nodes, the biopsy-site is chosen by this prioritized algorithm:

1. Recently progressing lesion by comparison to prior CT or PET/CT scans that can be safely reached under imaging guidance, usually liver, lymph node or lung metastasis.
2. Highly FDG-avid lesions that can be safely reached under imaging guidance, if no obvious size increase is found.

Ultrasound guided biopsies under local anesthesia are preferred for patient comfort and easier logistics, but in retroperitoneal locations or skeletal lesions CT-guided procedures are usually necessary. Biopsies from lesions with increased risk of complications or procedures requiring general anesthesia (GA) are generally avoided. When no other options are available some patients undergo resection of e.g. peripheral lymph nodes in GA.

Patients with tumor burden in the thorax and without other obvious lesions accessible for biopsy are referred to the Department of Pulmonary Medicine for biopsy. The lesions potentially available for core needle biopsy includes central and peripheral intrathoracic tumors, lesions involving the thoracic wall, including the pleura and lymph nodes which can be sampled histologically (12–14). Mediastinal lymph nodes are excluded from sampling as only cytological samples can be obtained with bronchoscopy with endobronchial ultrasound (EBUS / EUS-B) (15). For the same reason pleural fluid is not included as a viable sampling modality. Patients who have peripheral lesions that are only possible to sample by surgery (Video Assisted Thoracoscopic Surgery (VATS)) are not included.

Once the decision to sample a lesion is made, a modality has to be chosen. For patients with lesions in whom nonsurgical biopsies are indicated, the choice of sampling locale depends on lesion size, location, presence of emphysema and local expertise. Options includes CT or ultrasound guided transthoracic needle biopsy (TTNB) (14, 16) or bronchoscopic biopsy including conventional and image-guided bronchoscopy techniques such as the use of fluoroscopy, Radial probe EBUS or Electromagnetic Navigation bronchoscopy (ENB). CT or ultrasound-guided biopsy is preferred for lesions in proximity to the chest wall or for deeper lesions if fissures are not needed to be traversed and there is no surrounding emphysema (which increases the risk of pneumothorax). The preference is based upon studies showing higher diagnostic yields using TTNB compared with those reported for image-guided bronchoscopy techniques.

The image-guided bronchoscopy techniques, which includes ENB, radial EBUS, fluoroscopy or combinations thereof are chosen as appropriate alternatives to TTNB, particularly in patients at high risk of pneumothorax or bleeding complications because endoscopic procedures are generally well-tolerated with fewer reported complications than TTNB. The procedures are performed with conscious sedation as same day procedures. Histological samples are obtained with a forceps. Brush biopsies, needle aspiration and bronchial washing were not optional due to the recovering of only cytological samples. For central lesions in the airways, conventional bronchoscopy with mucosal biopsies is sufficient.

In case of brain metastasis as only lesion available or primary CNS tumors in progression or suspected CNS relapse the patient is only included if a surgical procedure is already planned for diagnostic or therapeutic reasons. In that case we accept inclusion independent of further (late line) treatment options.

Handling of bioptic material

Core needle biopsies (16–18 gauge needle) or biopsies by surgical resection are obtained and immediately transported unfixed, in a humidity chamber, to the Department of Pathology where it is processed within an hour of biopsy retrieval. Half the material is processed for DNA and RNA extraction for genomic profiling, while the other half is formalin-fixed and paraffin-embedded (FFPE) for histopathological analysis to estimate the percentage of tumor cells (%), to confirm the suitability of the material and determine whether there is agreement with the known histopathological diagnosis. Immune histochemical analysis, IHC, is performed depending on tumor type and assessed by an experienced pathologist.

Genomic profiling

The samples for molecular analysis are homogenized before DNA and RNA are extracted. Fresh tissue is handled as follows: DNA is extracted with QIAamp DNA Mini Kit (Qiagen) and RNA with RNeasy® Plus Mini Kit (Qiagen) according to manufacturer’s instructions. FFPE archived material is handled as follows: QIAamp DNA FFPE Advanced Kit (Qiagen) for DNA, and RNeasy FFPE kit (Qiagen) according to manufacturer’s instructions. Initially, NGS analysis was performed using the Oncomine Comprehensive Assay v3 (OCA v3) (ThermoFisher Scientific) investigating 161 genes. In selected patients, determination of tumor mutational burden (TMB) using an NGS gene panel (Oncomine TML Assay, ThermoFisher) was also conducted. In August 2023, the panel was replaced with the Oncomine Comprehensive Plus (OCP-plus) panel comprising 517 genes, which was an upgrade of the v3 panel, to also include biomarkers as molecular computed tumor cell content, microsatellite instability (MSI) and TMB. All NGS were run on the Ion Torrent S5 prime platform (ThermoFisher Scientific). Both panels enables analysis of different variants, including single/multiple nucleotid variants (SNVs/MNVs), indels, copy number variants (CNVs) and gene fusions, relevant in the identification of genomic actionable targets

Variant interpretation

Variants are classified based on the ACMG guidelines (17), with a somatic angle, as essentially described in Horak et al (2022) (18). Variant classification has evolved during the course of this study from completely manual curation (OCA v3) to a more software-assisted process (OCA v3/OCP Plus). The variants were initially assessed by Varsome (freeware version) (19), and in May 2022 we switched to QCII (Qiagen). After the initial software assisted classification, a manual curation of each variant is conducted using various databases: dbSNP (NIH) (20) (including data from ExAC, GnomAD), The Clinical Knowledge Base (CKB)/Jackson (20), OncoKB (21), ClinVar (NIH) (22), COSMIC (23) and literature (primary search engine: Mastermind Pro (24)). Furthermore, gene-specific databases can be used if necessary, such as BRCA Exchange (25). Variants are classified as benign/ likely benign, variant of unknown significance (VUS), likely pathogenic (LP) or pathogenic (P). First, all auto-classified variants, by QCII are manually curated as likely pathogenic/pathogenic. Second, the remaining VUS variants are bioinformatically filtered using an in silico list (Table 1) and manually curated. For OCA v3, all VUS, LP and P variants were included in the genomic report. For OCP-plus LP, P and VUS present on the in silico list are included in the genomic report.

Data from the comprehensive profiling is included in an integrated genomic report that combines the results of genomic profiling with the clinical history of the patient and the result of histopathological analysis of the biopsy.

Table 1

In silico list applied for auto-classified (QCII) VUS variants identified by the NGS panel OCP Plus.
ACD	FGF10	MAP2K2	RAD51D
AKT1	FGF11	MAX	RAD54L
AKT2	FGF12	MDH2	RB1
ALK	FGF13	MDM2	RET
APC	FGF14	MEN1	REV3L
ARAF	FGF16	MERTK	RNASEH2A
ATM	FGF17	MET	RNASEH2B
ATR	FGF18	MLH1	RNF43
ATRIP	FGF19	MLH3	SDHA
ATRX	FGF2	MRE11	SDHAF2
AXIN2	FGF20	MSH2	SDHB
AXL	FGF21	MSH3	SDHC
BAP1	FGF22	MSH6	SDHD
BARD1	FGF3	MTOR	SETD2
BMPR1A	FGF4	MUTYH	SMAD4
BRAF	FGF5	NBN	SMARCB1
BRCA1	FGF6	NF1	SMO
BRCA2	FGF7	NF2	STK11
BRIP1	FGF8	NOTCH1	TERF2IP
CDH1	FGF9	NOTCH2	TERT
CDK12	FGFR1	NOTCH3	TMEM127
CDK4	FGFR2	NRAS	TP53
CDKN2A	FGFR3	NTHL1	TRIM37
CDKN2B	FGFR4	NTRK1	TSC1
CHEK1	FH	NTRK2	TSC2
CHEK2	FLCN	NTRK3	VHL
CHTF8	FLT1	PALB2	WT1
DICER1	FLT3	PDGFRA
EGFR	FLT4	PDGFRB
EGLN1	FZR1	PIK3CA
EGLN2	GNAQ	PMS2
ELOC	GNAS	POLD1
EPAS1	GREM1	POLE
EPCAM	HRAS	POT1
ERBB2	IDH1	PTCH1
ERBB3	IDH2	PTEN
ESR1	KDR	RAD17
FANCA	KIT	RAD50
FANCL	KRAS	RAD51B
FGF1	MAP2K1	RAD51C

Tumor Board

OUH-TB is a weekly multidisciplinary team conference (MDT) consisting of Study Coordinators and experts in clinical oncology, molecular biology, pathology and clinical genetics. Individual integrated genomic reports are reviewed at OUH-TB, and if potential genomic targets are discovered, the genomic profile is further discussed at the weekly DNMTB virtual meeting. Cases where no genomic variants are found (silent profile) or the patient´s condition has deteriorated are not referred to DNMTB. The final decision about a patient´s treatment is made locally but can be supported by advice from the DNMTB. Neither OUH-TB nor DNMTB prioritize between standard treatments. If more than one drug-match is found and the drugs are available, the agent with the highest level of evidence is selected. The outcome of DNMTB may include referral to a clinical trial based on the genomic profile, referral to all-comer trials that include specific cancer diagnoses or solid tumors independent of genomic profile, if no druggable target was identified. If no clinical trial is available, but clinical data e.g FDA or EMA approval justifies treatment with a certain drug based on genomic profile, the DNMTB can recommend the targeted therapy despite not yet being approved by the Danish healthcare system. The treatment offer might be off-label treatment if the drug is prescribed for a different purpose than the FDA/EMA-approved indication. Some patients are offered treatment in managed access program (MAP) or similar programs.

Statistical considerations

The sample size of at least 1300 patients was selected to enable subgroup analyses for e.g., specific tumor entities with a predefined minimum number of patients. For example, given the distribution of patients for specific tumor entities at our department, we expect 100 patients or more in each of the following cancer entities: gastrointestinal, lung, breast, head and neck and genitourinary.

All patients fulfilling the eligibility criteria will be included in the full analysis set. All variables will be analyzed in a descriptive manner. Categorical variables will be presented as absolute and relative frequencies and continuous variables as number of observations, median and range.

Study status

More than 1,100 patients has been included as of 6/1/24. A highly optimized and effective genomic profiling program for solid cancers in adults has been established in a multidisciplinary university hospital setting. The study is still recruiting.

The time between initiating genomic profiling to determing whether a genomic-based (experimental) treatment can be offered is crucial in these severely ill patients, as they are at increased risk of deterioration before a conclusion using previous approaches is reached. A tightly controlled collaboration on bioptic procedure and our choice of a commercial pan-cancer NGS panel as the tool for genomic profiling, ensures a rapid patient flow with the ability to detect well-known actionable mutations.

The landscape of actionable genomic alterations is constantly changing since more drugs against novel targets are being developed. A target that is defined as not druggable at the time of the tumor board might be druggable at a later time due to new evidence or approaches.

The increasing number of clinical trials in precision medicine and the increasing number of available targeted drugs approved for clinical use creates a continuing need for re-biopsy and genomic examination in solid tumors. Even if no actionable genomic alterations are found, the result will provide clarification for the patient as knowledge that all possibilities have been explored. Moreover some patients will be directed to a treatment offer independent of the genomic profile such as a clinical trial including solid tumors. Using panel sequencing, we aim to conduct faster genomic profiling while still expecting identification of actionable genomic alterations, potentially triggering a drug match. During the study the initial panel was upgraded with a larger panel, and this expansion of genes, including biomarkers (TMB, MSI), may increase the possibility of detecting a druggable variant.

For rare molecular targets, it is difficult to conduct traditional clinical phase 3 trials where PFS and OS are generally evaluated. The GMI (26), the ratio of PFS on the current therapy to TTP on the most recent prior line of therapy can be used in this setting and incorporate patients as their own control (8). A GMI ≥ 1.33 (33% improvement of PFS) has been used as a threshold of clinical meaningful activity, as well as to determine whether a growth-modulating agent is having a clinical effect before a randomized Phase III trial is launched.

When conducting trials that depend on a drug match, the agnostic approach to treating solid tumors in a basket trial ensures faster recruitment and allows increase sample size. Several phase 2 trials are evaluating the efficacy and toxicity of drugs outside of their approved indications (off-label treatment) (7, 27–32).

Histopathological examination of the biopsy determines whether there is agreement with the known primary cancer or a second primary cancer is identified (33, 34). If a secondary cancer is diagnosed, the treatment will be adapted to this new knowledge. Alterations in IHC marker expression may also cause changes in the treatment of the primary cancer e.g. altered hormone receptor status, expression of PD-L1 or neuroendocrine markers.

In conclusion, the PRECODE trial is designed to evaluate the feasibility of fast track genomic profiling of solid cancers in a multidisciplinary university hospital setting and to investigate the frequency of genomic alterations in tumor tissue that gives rise to a matched treatment offer based on genomic-informed clinical decision-making.

PRECODE: PREcision medicine in Cancer in Odense, DEnmark

EMA: European Medicines Agency

FDA: Food and Drug Administration

DNMTB: The Danish National Molecular Tumor Board

TAT: turn-around-time

NGS: Next generation sequencing

SF: Screen failure

PS: ECOG performance status

CPR: Danish Civil Registration numbers

OPEN: Open Patient data Explorative Network

OUH-TB: Local Tumor Board

GMI: Growth Modulation Index

PFS: Progression free survival

TTP: Time to progression

OS: Overall survival

PET: Positron emission tomography

CT: Computed tomography

EDTA: Ethylenediaminetetraacetic acid

FDG: Fluordeoxyglucose

CE: Contrast-enhanced

¹⁸F: Fluorine-18

MRI: Magnetic resonans imaging

⁶⁸Ga-DOTATOC: Gallium-68-DOTA-D-Phe1-Try3-Octreotide

NET: Neuroendocrine tumor

NaF: Sodium fluoride

PSMA: Prostate-specific membrane antigen

ADC: Apparent diffusion coefficient

GA: General anesthesia

EBUS: Endobronchial ultrasound

EUS-B: Esophageal ultrasound with ultrasound bronchoscope

VATS: Video Assisted Thoracoscopic Surgery

TTNB: Transthoracic needle biopsy

ENB: Electromagnetic Navigation bronchoscopy

CNS: Central nervous system

DNA: Deoxyribonucleic acid

RNA: Ribonucleic acid

FFPE: formalin-fixed, paraffin-embedded

IHC: Immune histochemical analysis

OCA v3: Oncomine Comprehensive Assay v3

OCP-plus: Oncomine Comprehensive Plus

TMB: Tumor mutational burden

MSI: Microsatellite instability

SNV: Single nucleotid variant

MNV: multiple nucleotid variant

CNV: Copy number variant

BRCA: Breast cancer gene

VUS: variant of unknown significance

LP: Likely pathogenic

P: Pathogenic

MDT: Multidisciplinary team conference

MAP: Managed access programs

Ethics approval and consent to participate:

The study was approved by the Regional Ethics Committee (Danish Ethics Committee, Projekt-ID: S-2018014, date of approval: 27- FEB- 2019) and the Danish Data Protection Agency (Journal no: 18/58329, date of approval: 23-NOV-2018). Protocol amendments and modifications are submitted to the appropriate authorities for approval.

All patients provided signed informed consent. The study is conducted according to the international standards of IHC/Good Clinical Practice and in accordance with the Declaration of Helsinki.

Germline analysis is not carried out as part of the project, but patients are informed about the potential findings and consequences of genomic analysis. Clinical genetics experts participate in our tumor board and evaluates the detected variants from their perspective. If genomic profiling gives rise to suspicion of important potential germline findings, the patient will be informed and referred to the clinical genetics department for further investigation and genetic counseling.

Consent for publicatio

Not applicable.

Availability of data and materials

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare that they have no competing interests.

Funding

Funding for the study was supported by the Region of Southern Denmark. The funders of the study have no role in the study design, data collection, data analysis, or data interpretation. The funding bodies will be informed of any planned publications.

Authors’ contributions

KHH, MBL, ARK, TKK, and HJD developed the study concept and protocol. KHH, MBL, ARK, JTA, AA, HP, LK, SE, TKK, and HJD provided significant input to the further development of the study. KHH drafted the manuscript. KHH, MBL, ARK, JTA, AA, HP, SE, TKK, and HJD revised the manuscript. All authors approved the final manuscript and agreed to its publication.

Acknowledgements

We gratefully acknowledge the support for the PRECODE study by the whole PRECODE team. We acknowledge the important contribution by Marianne Ewertz and Niels Marcussen during the study initiation, and M Kat Occhipinti for the editorial assistance.

Offin M, Liu D, Drilon A. Tumor-Agnostic Drug Development. Am Soc Clin Oncol Educ Book [Internet]. 2018 May [cited 2024 Mar 14];(38):184–7. Available from: https://ascopubs.org/doi/10.1200/EDBK_200831
Mateo J, Chakravarty D, Dienstmann R, Jezdic S, Gonzalez-Perez A, Lopez-Bigas N, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol [Internet]. 2018 Sep [cited 2024 Jan 23];29(9):1895–902. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0923753419341791
Mosele F, Remon J, Mateo J, Westphalen CB, Barlesi F, Lolkema MP, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol [Internet]. 2020 Nov [cited 2024 Jan 23];31(11):1491–505. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0923753420399713
Tuxen IV, Rohrberg KS, Oestrup O, Ahlborn LB, Schmidt AY, Spanggaard I, et al. Copenhagen Prospective Personalized Oncology (CoPPO)—Clinical Utility of Using Molecular Profiling to Select Patients to Phase I Trials. Clin Cancer Res [Internet]. 2019 Feb 15 [cited 2024 Jan 23];25(4):1239–47. Available from: https://aacrjournals.org/clincancerres/article/25/4/1239/9939/Copenhagen-Prospective-Personalized-Oncology-CoPPO
Ladekarl M, Nøhr AK, Sønderkær M, Dahl SC, Sunde L, Vesteghem C, et al. Feasibility and early clinical impact of precision medicine for late-stage cancer patients in a regional public academic hospital. Acta Oncol [Internet]. 2023 Mar 4 [cited 2024 Jan 23];62(3):261–71. Available from: https://www.tandfonline.com/doi/full/10.1080/0284186X.2023.2185542
Aoyagi Y, Kano Y, Tohyama K, Matsudera S, Kumaki Y, Takahashi K, et al. Clinical utility of comprehensive genomic profiling in Japan: Result of PROFILE-F study. Kang H, editor. PLOS ONE [Internet]. 2022 Mar 31 [cited 2024 Jan 23];17(3):e0266112. Available from: https://dx.plos.org/10.1371/journal.pone.0266112
Mangat PK, Halabi S, Bruinooge SS, Garrett-Mayer E, Alva A, Janeway KA, et al. Rationale and Design of the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. 2018;
Radovich M, Kiel PJ, Nance SM, Niland EE, Parsley ME, Ferguson ME, et al. Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers. Oncotarget [Internet]. 2016 Aug 30 [cited 2024 Mar 1];7(35):56491–500. Available from: https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.10606
Boellaard R, Delgado-Bolton R, Oyen WJG, Giammarile F, Tatsch K, Eschner W, et al. FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur J Nucl Med Mol Imaging. 2015 Feb;42(2):328–54.
Bray TJ, Chouhan MD, Punwani S, Bainbridge A, Hall-Craggs MA. Fat fraction mapping using magnetic resonance imaging: insight into pathophysiology. Br J Radiol. 2018 Sep;91(1089):20170344.
Padhani AR, Tunariu N. Metastasis Reporting and Data System for Prostate Cancer in Practice. Magn Reson Imaging Clin N Am. 2018 Nov;26(4):527–42.
Fontaine-Delaruelle C, Souquet PJ, Gamondes D, Pradat E, De Leusse A, Ferretti GR, et al. Negative Predictive Value of Transthoracic Core-Needle Biopsy: A Multicenter Study. Chest. 2015 Aug;148(2):472–80.
Lee SM, Park CM, Lee KH, Bahn YE, Kim JI, Goo JM. C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of lung nodules: clinical experience in 1108 patients. Radiology. 2014 Apr;271(1):291–300.
Takeshita J, Masago K, Kato R, Hata A, Kaji R, Fujita S, et al. CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan. AJR Am J Roentgenol. 2015 Jan;204(1):29–34.
Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013 May;143(5 Suppl):e142S-e165S.
Choi SH, Chae EJ, Kim JE, Kim EY, Oh SY, Hwang HJ, et al. Percutaneous CT-guided aspiration and core biopsy of pulmonary nodules smaller than 1 cm: analysis of outcomes of 305 procedures from a tertiary referral center. AJR Am J Roentgenol. 2013 Nov;201(5):964–70.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med Off J Am Coll Med Genet. 2015 May;17(5):405–24.
Horak P, Griffith M, Danos AM, Pitel BA, Madhavan S, Liu X, et al. Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC). Genet Med Off J Am Coll Med Genet. 2022 May;24(5):986–98.
Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Wren J, editor. Bioinformatics [Internet]. 2019 Jun 1 [cited 2024 Jul 5];35(11):1978–80. Available from: https://academic.oup.com/bioinformatics/article/35/11/1978/5146783
Patterson SE, Liu R, Statz CM, Durkin D, Lakshminarayana A, Mockus SM. The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies. Hum Genomics [Internet]. 2016 Dec [cited 2024 Jul 5];10(1):4. Available from: http://www.humgenomics.com/content/10/1/4
Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017 Jul;2017:PO.17.00011.
ClinVar [Internet]. [cited 2024 Jul 5]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
Sondka Z, Dhir NB, Carvalho-Silva D, Jupe S, Madhumita, McLaren K, et al. COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res [Internet]. 2024 Jan 5 [cited 2024 Jul 5];52(D1):D1210–7. Available from: https://academic.oup.com/nar/article/52/D1/D1210/7335750
Chunn LM, Nefcy DC, Scouten RW, Tarpey RP, Chauhan G, Lim MS, et al. Mastermind: A Comprehensive Genomic Association Search Engine for Empirical Evidence Curation and Genetic Variant Interpretation. Front Genet [Internet]. 2020 Nov 13 [cited 2024 Jul 5];11:577152. Available from: https://www.frontiersin.org/articles/10.3389/fgene.2020.577152/full
BRCA Exchange [Internet]. [cited 2024 Jul 5]. Available from: https://brcaexchange.org/
Von Hoff DD. There are no bad anticancer agents, only bad clinical trial designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res Off J Am Assoc Cancer Res. 1998 May;4(5):1079–86.
Puco K, Fagereng GL, Brabrand S, Niehusmann P, Støre Blix E, Samdal Steinskog ES, et al. IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results. Acta Oncol [Internet]. 2024 May 23 [cited 2024 Jul 4];63(1):379–84. Available from: https://medicaljournalssweden.se/actaoncologica/article/view/28322
Verlingue L, Desevre M, Polito M, Garin G, Rodriguez C, Qing W, et al. The French multicentric molecular analysis platforms and personalized medicine trials MOST, MOST Plus and MEGAMOST. Acta Oncol [Internet]. 2024 May 28 [cited 2024 Jul 4];63(1):411–7. Available from: https://medicaljournalssweden.se/actaoncologica/article/view/32745
Jalkanen KJ, Alanne E, Iivanainen S, Kääriäinen OS, Tanner M, Auranen A, et al. A national precision cancer medicine implementation initiative for Finland. Acta Oncol [Internet]. 2024 May 23 [cited 2024 Jul 4];63(1):395–7. Available from: https://medicaljournalssweden.se/actaoncologica/article/view/32661
Kringelbach T, Højgaard M, Rohrberg K, Spanggaard I, Laursen BE, Ladekarl M, et al. ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling – a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial. BMC Cancer [Internet]. 2023 Feb 22 [cited 2024 Feb 27];23(1):182. Available from: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-10632-9
Hoes LR, Van Berge Henegouwen JM, Van Der Wijngaart H, Zeverijn LJ, Van Der Velden DL, Van De Haar J, et al. Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment. Clin Cancer Res [Internet]. 2022 Apr 1 [cited 2024 Feb 27];28(7):1402–11. Available from: https://aacrjournals.org/clincancerres/article/28/7/1402/682217/Patients-with-Rare-Cancers-in-the-Drug-Rediscovery
Haj Mohammad SF, Timmer HJL, Zeverijn LJ, Geurts BS, Spiekman IAC, Verkerk K, et al. The evolution of precision oncology: The ongoing impact of the Drug Rediscovery Protocol (DRUP). Acta Oncol [Internet]. 2024 May 23 [cited 2024 Jul 4];63(1):368–72. Available from: https://medicaljournalssweden.se/actaoncologica/article/view/34885
Geng F, Liu M, Chen J, Ge Y, Wei S, Li F, et al. Clinical characteristics of second primary malignancies among first primary malignancy survivors: A single-center study, 2005-2020. Oncol Lett. 2023 Jan;25(1):24.
Zheng X, Li X, Wang M, Shen J, Sisti G, He Z, et al. Second primary malignancies among cancer patients. Ann Transl Med. 2020 May;8(10):638.

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Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options: the PRECODE study protocol

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Abstract

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Background

Methods/Design

Patient selection

Planned procedures

Blood samples

Imaging-based selection of site of biopsy

Handling of bioptic material

Genomic profiling

Variant interpretation

Tumor Board

Statistical considerations

Study status

Discussion

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Competing interests

Funding

Funding for the study was supported by the Region of Southern Denmark. The funders of the study have no role in the study design, data collection, data analysis, or data interpretation. The funding bodies will be informed of any planned publications.

Authors’ contributions

Acknowledgements

References

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