State of the Art: Toward Improving Outcomes of Lung and Liver Tumor Biopsies in Clinical Trials—A Multidisciplinary Approach

Abstract

PURPOSE

National Cancer Institute (NCI)–sponsored clinical trial network studies frequently require biopsy specimens for pharmacodynamic and molecular biomarker analyses, including paired pre- and post-treatment samples. The purpose of this meeting of NCI-sponsored investigators was to identify local institutional standard procedures found to ensure quantitative and qualitative specimen adequacy.

METHODS

NCI convened a conference on best biopsy practices, focusing on the clinical research community. Topics discussed were (1) criteria for specimen adequacy in the personalized medicine era, (2) team-based approaches to ensure specimen adequacy and quality control, and (3) risk considerations relevant to academic and community practitioners and their patients.

RESULTS AND RECOMMENDATIONS

Key recommendations from the convened consensus panel included (1) establishment of infrastructure for multidisciplinary biopsy teams with a formalized information capture process, (2) maintenance of standard operating procedures with regular team review, (3) optimization of tissue collection and yield methodology, (4) incorporation of needle aspiration and other newer techniques, and (5) commitment of stakeholders to use of guideline documents to increase awareness of best biopsy practices, with the goal of universally improving tumor biopsy practices.

INTRODUCTION

The concept of personalized medicine has raised expectations of improved treatment outcomes in patients with refractory cancer. Vogenberg et al^1(p560) wrote that the “successful practice of personalized medicine requires changes in practice patterns and management strategies for health care practitioners as well as manufacturers in reimbursement, regulatory practices, and knowledge sharing.” Optimization of practice patterns is required for the collection of high-quality tissue specimens for precision-medicine studies. Moreover, reducing the frequency of sampling failure will improve biopsy outcomes and patient experiences.

Quality specimens allow for detailed diagnosis, optimal therapy, and estimation of prognosis. Developing biomarkers for clinical trials, especially protein-based biomarkers, is essential for understanding mechanisms of drug action. An increasing number of agents target specific mutations that must be identified to guide treatment decisions. In lung cancer, testing for EGFR mutations, expression of programmed cell death ligand 1 (PD-L1), or the presence of ALK or ROS gene fusions is commonly used to direct therapy. In the era of personalized medicine, tissue acquisition must be accompanied by an array of molecular tests to allow for the most complete diagnosis.

NCI-MATCH TRIAL

A prominent precision medicine study from which valuable lessons can be drawn is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. NCI-MATCH is a signal-finding trial in which patients are assigned to one of almost 40 treatment subprotocols on the basis of the molecular profile of their tumor. The goals of the trial are to determine if tumors with prospectively identified genetic mutations or immunohistochemical (IHC) markers can be successfully treated with targeted drugs for better outcomes and to identify promising agents that can advance to larger, more definitive trials.

Trial workflow entailed shipping four core biopsies obtained with a 16- to 18-gauge (g) needle to a central laboratory at MD Anderson Cancer Center (MDACC) for processing into formalin-fixed paraffin-embedded (FFPE) blocks, quality-control checks, and extraction and preparation of DNA and RNA. The central laboratory then sent the nucleic acids to one of four accredited CLIA (Clinical Laboratory Improvement Amendments)– sequencing laboratories at MDACC, Yale University, Massachusetts General Hospital, and the Frederick National Laboratory for Cancer Research. In some circumstances, archival FFPE tissue was permitted instead of fresh biopsy—for example, if the tissue had been obtained within 6 months of screening. The sequencing platform used, ThermoFisher AmpliSeq (Waltham, MA), required 10 ng of DNA and 20 ng of RNA to determine specific nucleotide variations and translocations targeted by available drugs. The sequencing laboratories had achieved high concordance on the assay via harmonization and inter- and intrasite validation.² Results from sequencing and IHC were entered into MATCHBox, an NCI informatics engine, which matched abnormalities detected in the tumor to a study treatment according to predefined levels of evidence.

Implementation of critical changes improved the trial’s assay success rate from 87% (n = 645) to 93% (n = 5,000).³ Changes included the addition of detailed instructions for the radiologist and research coordinator to the specimen collection kit to optimize sample acquisition and preparation and the requirement of fine needle aspiration (FNA) in addition to core needle biopsy (CNB). FNA cytology samples were able to rescue specimens otherwise unevaluable via the CNB samples. FNA, which pulls epithelial cells from the tumor stroma, can enrich a specimen and enable identification of intact tumor cells when the CNB specimen contains only necrotic debris. FNA, compared with concurrently acquired CNBs, frequently provides better cellularity, higher tumor fraction, and superior sequencing metrics.⁴ Microdissection also helped render a subset of otherwise unevaluable NCI-MATCH specimens evaluable for molecular screening, particularly tumor specimens consisting mainly of stroma and those with heavy inflammation that lowered the tumor cell percentage.

Other important lessons learned from NCI-MATCH include (1) collaboration between interventional radiologists and pathologists is critical for successful specimen collection and processing; (2) assays with minimal specimen requirements, including only a small amount of analyte, are preferred; and (3) NCI support was essential to the successful execution of the complex workflow of the trial. Of note, to support completion of accrual to treatment arms after screening almost 6,000 patients, the trial has expanded its laboratory network to include multiple designated academic and commercial laboratories. These laboratories may refer patients who are identified as potentially eligible for the trial on the basis of standard gene testing ordered by their personal physicians.

TEAM-BASED APPROACH AND THE MD ANDERSON EXPERIENCE

Collaboration among oncologists, interventional radiologists (IRs), pathologists, and research coordinators can clarify workflows to improve biopsy outcomes. Such collaboration includes providing feedback on biopsy quality to the IR and clinical team from multidisciplinary case reviews and early interaction between the trial principal investigator and the IR.

At MDACC, oncologists specify the need for molecular biomarker testing at the time of the request to the IR, allowing the IR to inform the biopsy risk assessment. Principal investigators (PIs) of clinical trials are encouraged to involve an IR during protocol development to provide research biopsy guidelines before institutional review board review. IRs traditionally advise on the type, number, and possible size of samples for specific target lesion sizes for individual patients.

MDACC IRs developed and used a lesion scoring system (Table 1) to estimate the likelihood of adequate yield and utility of a biopsy for molecular diagnostics. This scoring system evaluates the presence of viable tumor, ability to sample aggressively, and risk of major complication. In the NCI-MATCH trial, which incorporated the system, this risk was required to be < 2% for the patient to be eligible for the biopsy.⁵ Scoring requires careful assessment of lesion imaging and serves as an important comparator for quality assurance reviews of biopsy outcomes.

TABLE 1.

MD Anderson Cancer Center Scoring System for Likelihood of Biopsy Yield

In addition, a biopsy checklist accompanies patients enrolled in trials. This checklist provides the protocol number, PI name, IR collaborator, purpose of the biopsy, type of sample, sample disposition, contact information for tissue collection, number and type of encounters required, specific biopsy collection requirements, disposition instructions for each encounter, billing, and physician signoff.

Use of standardized biopsy requisition forms can aid biopsy teams by specifying specimen procurement needs up front. Centralizing biopsy requests, for both clinical and research needs, into one system can help reduce discrepancies among the various sources requesting tissue. Information technology can further aid multidisciplinary biopsy teams by providing tools that integrate clinical, pathologic, radiologic, and molecular data for radiology-pathology correlation.

Sampling error and lesion selection were identified as obstacles to obtaining metastatic lung biopsies in the MDACC BATTLE trial.⁶ As a result, functional imaging correlation was recommended to optimize target lesion selection (fluorodeoxyglucose [FDG]-avid sites) by IRs during prebiopsy image review, which helped reduce sampling error. To address samples with unknown causes of error (ie, lesion and puncture site seemed adequate), on-site FNA cytology assessment was incorporated into subsequent studies, including the BATTLE-2 trial. The number of cores obtained was also increased in BATTLE-2. With these improvements, diagnostic yield increased from 83% to 89% of samples being adequate for molecular profiling.⁷

SPECIMEN ADEQUACY AND GENOMIC ADEQUACY

Whereas success of a CNB is specific to intended use—that is, the material is fit for assay purpose—genomic adequacy refers to acquisition of sufficient material to provide a precise genomic characterization.⁸ Several variables, such as percent tumor nuclei, DNA quantification (ng/μL), mean depth of coverage, and number of loci read at a certain depth of coverage—can complicate the interpretation of genomic results. Additional aspects that complicate sampling success are informatic reporting, clinician’s knowledge, and tumor board consensus, all of which must be optimized. Therefore, specimen adequacy is a conglomerate that must be optimized and quality controlled at each step.

Investigators at Duke University define success for tissue intended for Sanger sequencing as at least a 2-mm² area in the top slide of the tissue block containing at least 15% tumor nuclei. Pathologists circle this area, and pinpoint microdissection is performed before a molecular assay is run. If < 15% tumor nuclei are present, the pathologist will write “LIM” on the slide for “limited sample,” in which case negative results from next-generation sequencing (NGS) are difficult to interpret. If no tumor nuclei are found, the process stops as unable to result (UTR). For NGS, the success cutoff has not been established, but the same process of indicating percent tumor nuclei on the slide is performed. For every nucleic acid extraction, the A260/A280 ratio is obtained to determine quality.

Duke investigators studied how sample type and tumor content can affect adequacy by examining UTR rates in 722 solid-tumor FNA, core biopsy, and surgical resection specimens tested using an NGS panel (Ion Torrent 50-gene hotspot, Life Technologies; McCall, unpublished data). Among colon cancer specimens, UTR rates were highest in the FNA specimens (27% in FNA v 8% across FNA, core, and resection specimens combined). In the other solid tumor specimens, results were similar: a 27% UTR rate in FNA versus 12% across all three specimen types, with a 5% UTR rate in core biopsy and a 7% rate UTR in surgical resection. The UTR rate decreased substantially if the pathologist could circle a 2-mm² area of ≥ 10% tumor nuclei: for FNA specimens, the UTR rate decreased from 35.7% (< 10% tumor nuclei) to 12.5% (≥ 10% tumor nuclei). Across all specimen types (n = 92), the UTR rate decreased from 21.3% (< 10% tumor nuclei) to only 2.2% (≥ 10% tumor nuclei).

Among FNA, core biopsy, and resection specimens, DNA quality was highest from FNA biopsies, with a A260/280 ratio of 1.74, close to the 1.8 ratio of “pure” DNA. This may be due to the minimal ischemic time, rapid fixation, and lack of exposure to formalin. However, FNA had reduced DNA quantity and a higher UTR rate. It is possible that an optimized FNA protocol could yield increased DNA quantity in the future.

The study identified a trend in which mean depth of coverage increased with increased pathologist-designated percent tumor: specimens with areas of 60%-80% tumor nuclei yielded good read depths. As mean depth of coverage decreases, the number of genes on an assay with at least one locus that cannot be read at a sufficient depth increases. At very low mean depth of coverage, the number of underrepresented genes increases considerably, and care must be taken to describe the limited results and avoid false negatives.

Needle gauge can also affect yield. A prospective study of surgical specimens and lung biopsies found a greater than 4.5-times (P < .001) higher nucleic acid yield with use of an 18g needle compared with multiple passes with a 20g needle.⁸ The lowest nucleic acid yields for both DNA and RNA resulted from a single pass with a 20g needle. Yield increased with two passes using a 20g needle but was still less than yield from a single pass using an 18g needle. In samples with an RNA integrity number > 7, the trend favored gauge size over number of passes. No difference in DNA and RNA yield and RNA integrity number was found between surgical and biopsy cohorts.⁸

Success rate may be increased by using cytopathologic real-time assessment via telepathology, which offers economy of scale, resulting in cost savings. Retrospective analysis of 40 clinical research biopsies obtained at Duke found a success rate of 86% if real-time immediate cytopathologic assessment was performed (McCall, unpublished data). If no such immediate assessment was performed, the success rate decreased to 65%.

Taking multiple cores from a lesion increases the likelihood of obtaining an evaluable core. Splitting each core into two specimens, one for diagnosis and one for special studies, and embedding each core separately into a block can result in multiple blocks, conserving tissue for molecular testing.⁹

The concepts of genomic adequacy and intra- and intertumoral heterogeneity pose challenges to tumor sampling and to the design of precision medicine–based approaches. The degree to which molecular drivers are heterogeneous across the tumor is a topic of some debate. Whereas Gerlinger et al¹⁰ and Zhai et al¹¹ found evidence for such heterogeneity, others found evidence of consistency of molecular drivers across the tumor.^12-14 Another group showed that tumor drivers were not consistent over time, perhaps as a result of targeted therapies inducing changes in the molecular profile of a tumor—particularly as patients undergo first-, second-, and third-line targeted therapies.¹⁵

ENDOBRONCHIAL ULTRASOUND–GUIDED BRONCHOSCOPY WITH TRANSBRONCHIAL NEEDLE ASPIRATION

Another form of tissue sampling considered at the conference was endobronchial ultrasound–guided bronchoscopy with transbronchial needle aspiration (EBUS-TBNA), typically recommended for lung cancer staging before surgical resection.¹⁶ EBUS-TBNA is different from previously available anatomy-guided (commonly known as “blind”) TBNA, for which no guidance or aid to localize lesions was available. Currently, there are two types of EBUS systems available in the United States: a radial probe and a linear probe ultrasound. The linear probe EBUS bronchoscope consists of a built-in small ultrasound probe at the tip of the instrument, which allows identification of lymph node, mediastinal, or parenchymal masses located beyond the airway. After a target lesion is identified on ultrasound, repeated needle passes can be obtained through the dedicated working channel of the bronchoscope under real-time ultrasound guidance. This allows precise sampling of tissue from the lesion and even avoids necrotic areas, if present.

Conversely, a radial probe EBUS is used primarily to locate peripheral lung lesions or masses during bronchoscopy. This does not allow real-time imaging that requires additional skills and training. In addition, the sensitivity of the EBUS decreases with sampling of more distal peripheral lung lesions.¹⁷ Approximately 71% of respiratory cytology specimens currently are provided by pulmonologists.¹⁸

In EBUS-TBNA, pulmonologists use 19-22g needles to obtain a cytology sample. In certain cases, a TBNA blood clot core also may be obtained, which can increase diagnostic yield by 10% when the cytology specimen is insufficient.¹⁹ Cryobiopsy, obtained during bronchoscopy, likewise has increased diagnostic yield in randomized trials, yielding a larger amount of tissue than that obtained by forceps biopsy.²⁰ When available, rapid on-site evaluation is used during bronchoscopy to determine tissue adequacy in real time. At least three passes should be obtained from each lymph node station, with additional passes performed as needed. These are placed in RPMI media or cytolyte solution for further analysis. Two randomized trials have recently documented that availability of rapid on-site evaluation has no impact on diagnostic yield of EBUS-TBNA while it may reduce the number of passes needed.^21,22

Recent guidelines on molecular testing suggest that any cytology specimen with adequate cellularity and preservation can be used instead of the previously recommended cell block.²³ Multiple studies have shown that EBUS-TBNA not only can support diagnosis but also provides adequate tissue for NGS, IHC, and various molecular testing in lung cancer.^24-27 Moreover, RNA yield from EBUS-TBNA has been shown to be significantly higher than RNA yield from transbronchial or endobronchial biopsy specimens and computed tomography (CT)–guided core biopsies.²⁸ Tumor cell count is substantially higher in EBUS-TBNA specimens compared with transbronchial biopsy specimens.²⁹

EBUS-TBNA is minimally invasive, can be performed under moderate sedation, and carries a lower risk of pneumothorax compared with percutaneous lung biopsy. Bronchoscopic examination during EBUS-TBNA also permits identification and sampling of any radiologically occult, subtle endobronchial lesions. Last, transbronchial or endobronchial biopsy in addition to EBUS-TBNA can be used to provide additional tissue, if feasible.

EBUS-TBNA has some limitations. A tissue core usually is not obtained with EBUS-TBNA, limiting a detailed morphologic examination. This is particularly important in hematologic malignancies, such as lymphoma. In suspected lymphoma, flow cytometry should be performed. Although feasible in chronic obstructive pulmonary disease (COPD), and when risk of pneumothorax is minimal, EBUS-TBNA should be used cautiously in patients with severe COPD. Performing EBUS-TBNA requires additional skills. Although the majority of the pulmonary fellowship programs in the United States currently provide training in EBUS, there is still a paucity of skilled operators, limiting widespread availability of this technique in the community. A good team of pulmonologists and IRs can complement each other in obtaining adequate lung tissue samples.

RISK CONSIDERATIONS

In lung biopsy, significant resistance to 18g percutaneous core biopsies exists among community practitioners. Unfortunately, prospective comparative studies to compare complication rates for different-sized needle devices require large patient cohorts and considerable expense. Although an 18g needle yields more tissue, 20g needles have lower complication rates, and multiple passes (eg, 4-5) with a 20g needle can still yield sufficient substrate for tests, which require increasingly lower amounts of analyte. For patients with COPD, complications can be reduced by avoiding emphysematous lung tissue.

A recent study found that the rate of pneumothorax requiring a chest tube is similar for navigation bronchoscopy compared with a percutaneous approach.³⁰ In EBUS-TBNA, centrally located lesions, such as mediastinal or hilar lymph nodes, can be sampled using a 22g, 21g, or 19g needle with minimal risk of pneumothorax.

In a rebiopsy population at the University of California, Los Angeles, in the KEYNOTE-001 trial, a clinical trial of pembrolizumab, an anti–programmed cell death-1 therapy for non–small-cell lung cancer, incidence of significant complications was similar to that observed in a diagnostic biopsy population. In a rebiopsy population of 101 patients undergoing 110 biopsies, pneumothorax, the most common complication, was observed in 25 biopsies (22.7% of all biopsies performed). Four of the biopsies complicated by pneumothorax required chest tube placement (4.0%). Overall, the mean number of CNB samples obtained was 7.9.³¹

For liver biopsies, standard practice at Mt Sinai Medical Center is to use a 20g needle and collect 4-5 cores to ensure adequate tumor cellularity, which is seen in > 50% of cores. Some institutions have transitioned to 18g core biopsies in general. The addition of 18g cores for all biopsy sites except lung and the addition of FNA has increased success rates from 61% to 88% at MDACC. Clinicians may be willing to perform an 18g biopsy despite the perceived increased risk if the patient’s therapeutic options are very limited or when biopsy is required for trial participation.

Our overall understanding of risk involved in biopsy of liver neoplasia or metastasis is incomplete. Potential risks of liver tumor biopsy are bleeding and needle track seeding. Although a large number of studies published between 1970 and 2008 for metabolic (not neoplastic) liver disease report low complication rates associated with needle biopsy,^32,33 few literature references address the safety of needle biopsy in liver cancer, particularly with regard to needle gauge, number of passes, and optimal results.³² In a meta-analysis, risk of tumor seeding after liver biopsy was reported to be 2.7%, with a median time interval between biopsy and seeding of 17 months.^34,35 The most frequently reported complications from ultrasound-guided biopsies were pain and ephemeral fevers, and these were unlikely contributors to prolonged hospital stay or substantial patient injury.

CURRENT CHALLENGES FOR IMAGING

Preprocedural imaging has a limited ability to guide biopsy target selection for optimal yield. Targeting optimal metastatic lesions generally is guided by an enhancement pattern after administration of vascular contrast material or radiopharmaceutical uptake to distinguish viable tumor. Many factors, including tumor heterogeneity; stromal fibrosis; and, particularly in colorectal liver metastases, the presence of mucin, may contribute to poor metastatic tumor tissue sampling.

Scurr et al³⁶ demonstrated the potential for improved image guidance to select optimal targets in mucinous tumors. Diffusion-weighted magnetic resonance imaging (MRI) was used to identify metabolically active viable tumor portions and avoid the undesirable mucinous areas that often contain few tumor cells. The study also observed that a high-intensity rim, an indication of central necrosis, was a common characteristic of the colorectal liver metastases studied.

Cross-sectional imaging can characterize the precise sampling location in three-dimensional space and allow geometric correlation of tumor cellularity, stroma, and expression. Such biopsy site documentation is important in failure-mode analysis and planning for repeat sampling.

Several new and emerging technologies promise to improve sampling via image guidance. Although they currently may be used in specialized settings, they demonstrate the possibilities for enhancing biopsy yield through advanced technology.

Radiogenomic mapping seeks to address tumor heterogeneity by correlating imaging phenotypes with genomic signatures present within the tumor. A study of 155 patients with hepatocellular carcinoma across three centers assessed the diagnostic accuracy of radiogenomic venous invasion in predicting microvascular invasion and underscored the importance of sampling bias and tumor heterogeneity.³⁷ In a subset of 22 patients who underwent preoperative biopsy, the diagnostic accuracy, sensitivity, and specificity of identifying microvascular invasion through biopsy were lower than for the radiogenomic approach.

Two emerging multiparametric imaging navigation tools with potential to improve sampling yields are (1) cone beam CT (CBCT) with or without multiple detector CT (MDCT) registration and (2) electromagnetic or optical tracking + CBCT/MDCT/MRI fusion. Other technologies to augment needle placement accuracy include robotics, laser guidance/angle selection devices (to optimize puncture angle), and camera-based line-of-sight registration of an ultrasound image with CT image coordinates.

Image-guided tissue sampling may evolve into a two-step process: co-localization of multiparametric imaging features of a target lesion on a single screen and navigation of the instrument to the desired point on the fused image. Diagnostic modalities (eg, positron emission tomography [PET]–CT or MRI) can guide sampling point determination according to a specified rationale, and sampling modalities (eg, ultrasound, MDCT, or CBCT) provide visualization of needle entry into the sampling target.

Fusing FDG-based PET with CBCT permits targeting of FDG-avid site(s) and enhances biopsy yield.^38,39 In addition to FDG-PET, tumor perfusion, elasticity, and diffusion coefficient values have been used as discriminatory markers for tumor viability. Diffusion-weighted MRI and diffusion coefficients also may provide insight into the degree of stroma formation within lesions.

Fusing MRI with transrectal ultrasound has improved prostate biopsy yields.⁴⁰ This fusion technology diagnosed 30% more high-grade cancers than standard ultrasound-guided biopsy, although it identified 17% fewer low-risk cancers. In addition, MRI transrectal ultrasound fusion allows the location to be mapped for active surveillance or focal ablation; however, the technology is expensive, and availability is limited.

Ultrasound often is preferred for liver biopsy guidance. However, ultrasound images do not provide a reproducible tomographic characterization of the needle sampling site. Line-of-sight fusion of real-time ultrasound and diagnostic CT potentially addresses this shortcoming. Ultrasound-guided sampling can be performed even when the target lesion is invisible, at ultrasound after fusion with CT, especially if the patient cannot cooperate with respiratory instructions. This approach provides a way to document needle tip location on the registered CT image for pathologic correlation purposes.

Newer tools have the potential to characterize specimen adequacy at the time of biopsy before tissue processing. Use of optical imaging with spectroscopy for characterizing target tissue holds great promise. Multiple types of spectroscopy have been developed: diffuse reflectance spectroscopy, autofluorescence spectroscopy, elastic scattering spectroscopy, and Raman spectroscopy. The spectroscopic imaging device can be made to fit as small as a 28g needle lumen.

For liver tumor biopsies, adding spectroscopy to needle biopsy results in a smart probe that can guide the needle to the tumor on the basis of spectroscopic values for bile content, because bile is less prevalent in liver tumors than in normal liver tissue. As the needle is driven toward the liver lesion, spectroscopy data are generated to indicate bile content; low content is indicative that the needle is in the tumor. Using direct spectroscopy, Spliethoff et al⁴¹ achieved a high (91%) rate of recovery of hepatic metastatic tumor tissue identified on the basis of derived values for bile content. Spectroscopy also improves lung tumor biopsy yields: optical imaging with spectroscopy identified tumor-containing specimens, whereas conventional CT-guided biopsy yielded nondiagnostic specimens.⁴²

Optical molecular imaging with fluorochromes is possible based on the observed concentration within tumor tissue. The fluorochrome indocyanine green localizes in hepatocellular carcinoma and metastatic colorectal cancer. Fluorescence from the fluorochrome becomes evident even in small lesions when the optical imaging probe is placed within the tumor. Real-time quantitative information from spectroscopy can be displayed on a screen during needle positioning to confirm adequacy of a potential tumor sampling site.

Novel specimen preservation methods include a device currently under development that uses in situ freezing to immediately preserve a specimen. This approach potentially improves sampling yields for labile biomarkers, such as proteins interrogated in phosphoproteomics.

CONSENSUS RECOMMENDATIONS

• Clinical trial infrastructure should support multidisciplinary biopsy teams. Collaboration is key—that is, good communication is necessary among pathologists (including use of telepathology), oncologists, pulmonologists, radiologists, surgeons, research scientists, coordinators, and information technology.

  • The role of interventional radiologists (IRs)/pathology/research coordinators is vital.

  • Feedback on biopsy quality should be relayed back to the IR and the clinical team after regular team review of biopsy procedures.

  • Clinical, pathologic, radiographic, and molecular data should be captured centrally and integrated via a formalized information capture process.

• IRs, pathologists, and pulmonologists who will acquire biopsy specimen should be engaged early in the development of a clinical trial protocol. Tissue requirements for clinical trials should be communicated up front with the diagnostic team.

• Taking multiple cores from a lesion and adding fine needle aspiration (FNA) to core biopsy can increase yield.

• Tissue acquisition in clinical trials in lung and mediastinal cancer should include endobronchial ultrasound–guided bronchoscopy with transbronchial needle aspiration or bronchoscopy, because adequate tissue sample can be obtained from FNA to minimize the need for needle core samples.

• Use of validated scoring systems can aid selection of target lesions.

• Needle gauge versus number of passes should be considered according to the potential risk to the individual patient.

• Standard operating procedures (SOPs) that improve biopsy yields, such as rapid assessment of specimen quality during biopsy, should be implemented and updated. Joint Commission and College of American Pathologists recommendations should be considered in the development of SOPs.

• Guideline documents should be developed to increase awareness of best tumor biopsy practices, with the goal of universally improving tumor biopsy practices.

• Biopsy-related effort should be reimbursed commensurately, for example through re-evaluation of relative value units.

• Clinical trials should allow easy introduction of new technologies, such as multiparametric image fusion, that can offer improved guidance of the sampling needle.

• The clinical impact of intra- and intertumoral genomic and phenotypic heterogeneity should be further elucidated.

AUTHOR CONTRIBUTIONS

Conception and design: Elliot B. Levy, Maria I. Fiel, Peter Schirmacher, Robert D. Suh, Alda L. Tam, Katherine Ferry-Galow, Hala R. Makhlouf

Collection and assembly of data: Stanley R. Hamilton, David E. Kleiner, Shannon J. McCall, Peter Schirmacher, William Travis, Michael D. Kuo, Robert D. Suh, Alda L. Tam, Shaheen U. Islam, Katherine Ferry-Galow, Rebecca A. Enos, Hala R. Makhlouf

Data analysis and interpretation: David E. Kleiner, Peter Schirmacher, William Travis, Michael D. Kuo, Robert D. Suh, Katherine Ferry-Galow, James H. Doroshow, Hala R. Makhlouf

Provision of study material or patients: Maria I. Fiel, Stanley R. Hamilton, Hala R. Makhlouf

Administrative support: Rebecca A. Enos, James H. Doroshow, Hala R. Makhlouf

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

State of the Art: Toward Improving Outcomes of Lung and Liver Tumor Biopsies in Clinical Trials—A Multidisciplinary Approach

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/journal/jco/site/ifc.

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

Elliot B. Levy

Stock and Other Ownership Interests: Halyard Health

Maria I. Fiel

Consulting or Advisory Role: Alexion Pharmaceuticals, Progenity

Stanley R. Hamilton

Stock and Other Ownership Interests: The Johns Hopkins University School of Medicine

Consulting or Advisory Role: HalioDx, ThermoFisher Scientific, Bristol-Myers Squibb, Loxo, Merck, Guardant Health, Cell Medica

Peter Schirmacher

Honoraria: Roche, AstraZeneca

Consulting or Advisory Role: Bristol-Myers Squibb, MSD, Novartis, ROche

Research Funding: Novartis (Inst), Roche (Inst), Bristol-Myers Squibb (Inst)

William Travis

Consulting or Advisory Role: Genentech

Speakers' Bureau: Genentech

Michael D. Kuo

Employment: Ensemble Group

Stock and Other Ownership Interests: Ensemble Group

Research Funding: Ensemble Group

Patents, Royalties, Other Intellectual Property: Inventor, diagnostic and treatment methods

Robert D. Suh

Honoraria: NeuWave Medical, Boehringer Ingelheim, BTG

Alda L. Tam

Honoraria: Merit Medical Systems, Galil Medical, Endocare

Consulting or Advisory Role: AbbVie, Jounce Therapeutics, Siemens, Boston Scientific

Research Funding: AngioDynamics, Guerbet, BTG

Travel, Accommodations, Expenses: Guerbet

Shaheen U. Islam

Honoraria: Pinnacle Biologics

Patents, Royalties, Other Intellectual Property: Royalty for writing chapters on bronchoscopy from UpToDate

Travel, Accommodations, Expenses: Intuitive, Pulmonx

Katherine Ferry-Galow

Stock and Other Ownership Interests: Johnson & Johnson

No other potential conflicts of interest were reported.