Best Practices in Immuno-Oncology Biomarker Testing – AUGUST 2018 | Part 1 of a 4-Part Series
Best Practices in Incorporating Biomarker Testing to Deliver Precision Therapy in Cancer
In the past, cancer was a biologic mystery, with combinations of toxic chemotherapies seemingly the only path to a cure.1 Over the past decade, advances in precision medicine in oncology have enabled the use of molecular information, specifically gene expression data, to predict how patients will respond to various drugs.2 The personalized treatment of cancer that is guided by molecular biomarker assessment requires a team approach—a collaborative effort between the pathologist and the treating oncologist—to achieve informed and effective individualized therapy. However, it has been proposed that “a failure to properly understand molecular biomarkers has prevented their widespread adoption in treatment, comparative benefit analyses, and their integration into individualized patient outcome predictions for clinical decision-making.”3 In this regard, experts in the fields of medical oncology and molecular pathology may provide guidance in understanding how to best utilize molecular biomarkers in developing individualized therapy for patients with lung cancer.
An example of best practices in incorporating molecular biomarker testing in delivering precision therapy in lung cancer was provided in a conversation between Geoff Oxnard, MD, a thoracic oncologist at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston, MA, and Lauren Ritterhouse, MD, PhD, a molecular pathologist and Co-Director of the Molecular Diagnostics and Clinical Genomics Laboratories, University of Chicago, IL. These 2 experts shared their perspectives on how oncologists and pathologists can work together as part of the cancer care team to deliver optimal personalized care for their patients. Many of their insights can be applied broadly to both academic- and community-based practices striving to meet the challenge of effectively incorporating biomarker testing into their treatment of patients with lung cancer.
Impact of Biomarker Testing on Cancer Therapy
Dr Oxnard discussed his approach as an oncologist. “I generally tell my patients with lung cancer that we have 3 broad tools: we have oral targeted therapies, we have immunotherapies, and we have chemotherapies. Before I start treatment for you, I am going to determine whether I can find a targetable genotype such as EGFR or ALK. I am going to look to see if your cancer is sensitive or vulnerable to immunotherapy using a marker such as PD-L1. If I do not have compelling evidence that one of those is going to work, I am going to reach towards chemotherapy. At each decision point I say, ‘I need these data quickly to make an informed decision.’”
Dr Ritterhouse offered the pathologist perspective. “As a pathologist, and particularly a molecular pathologist, running a molecular diagnostics laboratory, [I am] constantly thinking about new biomarkers that we need to incorporate into the laboratory, trying to be ahead of the curve. If there is a new biomarker that is released based on a clinical trial, the time for us to bring that new test in house, develop it, find validation samples, and actually launch it clinically is a much longer process than we, our oncologists, and the patients would like.”
This exchange between the medical oncologist and molecular pathologist set the stage for a discussion regarding the impact that molecular biomarkers have had on their clinical practices. One of the greatest challenges in incorporating molecular biomarkers into patient care is that reports on new biomarkers or new applications of existing biomarkers are occurring at a dizzying pace, making it difficult for medical oncologists to utilize the most current information in making treatment decisions for their patients. Similarly, molecular pathologists have the complex task of prioritizing which biomarkers to include in the test panel to be able to answer the treating physicians’ most important questions regarding turnaround time, efficiency, and getting the answers they need to make informed treatment decisions quickly for their patients.
Individual prognostic biomarkers or combinations of prognostic biomarkers predict the likelihood of a disease-related outcome during a specific time period. Although prognostic biomarkers are typically better predictors than risk biomarkers, cancer is a complex disease process, and therefore rarely can a lone biomarker accurately predict a disease outcome.3 Thus, the oncology treatment team often asks the pathologist to offer a broad spectrum of molecular biomarkers in the test panel to make the treatment decision as informed as possible.
“If there is a new biomarker discovered that can affect patient care, we need a plan for this new biomarker.”-Geoff Oxnard, MD
For example, many targetable activating mutations have been found in non–small-cell lung cancer (NSCLC), including mutations in ALK, EGFR, FGFR, HER2, KRAS, MET, RET, and ROS1, that will inform targeted therapies,1,4 as well as PD-1/PD-L1 that will prompt the use of immunotherapy with immune checkpoint inhibitors.5 However, it is critical to prioritize the number of biomarkers requested by the oncologist.
As Dr Oxnard suggested, “Pathologists only have so much bandwidth. They can only do so many tests efficiently and cost effectively. If the oncologist signs up for too many, the laboratory gets stretched thin and results come slowly. There is some balance you need to have. The pathologists say to me, ‘OK, you can have this or you can have this. Which one is it?’”
Best Practices in Communication Within the Oncologist-Pathologist Team
To minimize the aforementioned issues, it is critical for the oncology treatment team to engage in active communication with the pathologist. Dr Oxnard and Dr Ritterhouse agreed that clear and frequent communication between surgical and medical oncologists and pathologists is crucial for optimal molecular biomarker testing in patients with lung cancer. In the large academic centers where they work, the surgical or medical oncologist places the order for molecular biomarker testing, and, in some cases, the process of immunohistochemistry (IHC) and molecular analysis is initiated as soon as a pathologic diagnosis of NSCLC is made, sometimes even before the medical oncologist has seen the patient.
Most pathology laboratories have standard IHC and molecular tests they include in their panels. However, communication between the treating physician and the pathologist is most important in cases where the oncologist wants information on molecular biomarkers not routinely included in the panel. This communication occurs either at a tumor board meeting or through personal conversation or e-mail. In some cancer centers, a special weekly biomarker meeting is convened; this meeting includes surgical, medical, and radiation oncologists and pathologists. These professionals do not meet to discuss individual patients, but to evaluate the menu of biomarkers that need to be included in the pathology laboratory’s armamentarium as a result of the latest clinical data presented at cancer meetings or published in seminal journals, as well as to evaluate resource allocation for the pathology department.
For example, a number of presentations at the 2018 annual meeting of the American Society of Clinical Oncology addressed the efficacy and safety of RET inhibitors for NSCLC, and strategies for RET-directed targeted therapy are now being considered before single-agent immunotherapy.6 Will this trigger oncologists to request that this biomarker be included in every testing panel for patients with NSCLC? How will this affect the workflow of the pathology laboratory?
Dr Oxnard outlined the issue succinctly: “If there is a new biomarker discovered that can affect patient care, we need a plan for this new biomarker. Let us all come together and make that plan. That happens every so often as everyone sees that things are changing, a challenge is accumulating; we need to now put our heads together to make a plan communally. It requires the oncologist who wants the answer, the surgical pathologist who handles the specimen, and the pathologist who will produce the eventual test—those are the key people. Surgeons are often involved as well, and interventional radiologists are also important players to be consulted about tissue handling and tissue stewarding.”
Dr Ritterhouse added, “Another thing that we have done that has been really nice in working on specimen adequacy in these multidisciplinary teams is to work closely with our interventional radiologists. Close to 80% of our lung cancer testing is of site-of-smear specimens from endobronchial ultrasound bronchoscopy procedures. That was a big multidisciplinary group effort to streamline the testing of patients with lung cancer that has been really successful. It required a lot of different people coming to the table.”
The electronic medical record (EMR) can also be used to communicate among the cancer care team and the pathology laboratory, and to increasingly structure the oncologist’s communications with interventional radiology and pathology. For example, the oncologist can specify in the EMR that multiple cores are needed for genomics, that a fine needle aspiration biopsy is needed, etc. Formalized requests through EMRs are yet another way for treating physicians, surgeons, interventional radiologists, and pathologists to communicate so that suitable samples are collected and the appropriate tests are ordered.
PD-1/PD-L1 testing is a good case in point. Quantifying PD-L1 provides the oncologist with valuable information, since the higher the PD-L1 staining percentage, the more likely the chance of benefit from single-agent immunotherapy. In the patient who presents with newly diagnosed advanced NSCLC, whether squamous cell or nonsquamous cell, if the PD-L1 staining percentage is greater than 50%, single-agent immunotherapy is appropriate and there is a better chance of response with less toxicity.5 If the PD-L1 staining percentage is less than 50%, chemotherapy or chemotherapy plus immunotherapy is the choice, but with the potential for greater toxicity.5 In the recurrent disease setting or as second-line therapy, if the patient is anti–PD-1 naive, immunotherapy can be used.
Dr Oxnard added, “[PD-L1 staining] incorporates each decision point and gives me a sense of their chance of benefiting. That helps me think about how to use that therapy for the patients. However, even with high PD-L1, immunotherapy is not perfect. We need to do better. We are working on better and more ambitious combination immunotherapies and improved biomarkers that can be incorporated into clinical decisions. PD-L1 does not stand on its own. I use PD-L1 staining plus the clinical features, smoking history, the patient’s genomic features, presence of a genotype like EGFR and/or ALK, and presence of high tumor mutational burden [TMB]. I pull these things together to get a feel for whether this patient is more likely to benefit or less likely to benefit. It is increasingly a personalized decision.”
This requires close communication between the oncologist and the pathologist on how to report PD-L1 staining, particularly the PD-L1 staining percentage increments being reported.
The Process of Biomarker Testing: Operational Issues
Dr Oxnard pointed out that at the Dana-Farber Cancer Institute, “PD-L1 is now run routinely on NSCLC [specimens]. Then when I see the patient in clinic, I am thinking to myself, are there other questions I want answered? I want to know if they have an EGFR, ALK, ROS, RET, BREF, or HER2 mutation. Thus, I am now routinely ordering next-generation sequencing [NGS] on advanced nonsquamous NSCLC or on light/never smokers. I do not tend to order it on squamous NSCLC because that is not rich with targetable mutations. When I order NGS, I get a great deal of information. I find novel targets where I can sometimes refer the patient for clinical trials. I get a measure of TMB. I can also see some genomic signatures such as UV damage or microsatellite instability [MSI]. All of these things can be seen within an NGS panel.”
Dr Ritterhouse outlined the process at the Molecular Diagnostics and Clinical Genomics Laboratories: “At our institution, for all NSCLC, it is the pathologist who originally puts in the request for the large, targeted NGS panel. We are also in favor of using 1 large NGS panel to look at all biomarkers that are available and get additional information, such as TMB and MSI. This can all be done with 1 test. However, the only limitation is that most of the larger panels require a longer turnaround time, which is not quite what the oncologists want. Our turnaround time for NGS is approximately 10 to 14 business days. We have come up with an agreement with the oncologists that we will also run a smaller targeted panel just to get EGFR information sooner. Then we are also doing ALK fluorescence in situ hybridization in addition to the large panel, even though information from both of those tests will eventually be included on the larger panel, but the oncologists want the EGFR and ALK information sooner. Turnaround times also influence what tests we order and what people are looking for. We have changed how many times we are running tests now to also accommodate this turnaround time issue.”
“At our institution, for all NSCLC, it is the pathologist who originally puts in the request for the large, targeted NGS panel.” -Lauren Ritterhouse, MD, PhD
Table 1 shows the various considerations in molecular testing.7 Biomarker testing can complicate diagnostic algorithms and delay treatment decisions. Because molecular-targeted therapies and immunotherapy often yield better outcomes than chemotherapy with less toxicity, when biomarker results are not yet available at the time of initial oncology consultation, opportunities for patient benefit can be missed.8 Although reflex testing (ie, testing for EGFR mutations and ALK rearrangement) is now commonplace in managing patients with advanced NSCLC, many cancer centers in the United States and abroad continue to be challenged when it comes to timely molecular testing with rapid turnaround time.8 Indeed, in a recently reported study, only 21% of 126 patients with nonsquamous NSCLC who had undergone biomarker testing had test results available at the time of initial consultation with their oncologist.8 In this study, patients with biomarker test results available at the time of initial oncologist assessment had a median time of 0 days from consultation to treatment decision and 16 days to treatment initiation, whereas patients without available biomarker results had a median time of 22 days from consultation to treatment decision and 29 days to treatment initiation.8
Several factors may contribute to the wide variations seen in turnaround time for molecular testing, including the time and distance involved in transporting specimens from outside hospitals to the testing laboratory, necessity of repeating biopsies after failure of the initial test, and various reasons for delays in initiating the testing process. Reflex molecular testing on all diagnostic nonsquamous NSCLC samples initiated by the pathologist may alleviate some of these factors.8 Sometimes insufficient tissue has been collected from diagnostic specimens to enable effective molecular testing. In the aforementioned study, repeat biopsy was performed on 13% of nonsquamous patients tested for biomarkers, resulting in additional delays in treatment.8 In some cases, patients with advanced lung cancer would deteriorate if they waited for biomarker results and personalized treatment. For example, a large number of patients in the study underwent first-line chemotherapy without initiating molecular testing or repeat biopsy to obtain biomarker information, probably because waiting for results would have led to an inferior outcome.8 Patients who did not undergo biomarker testing started treatment a median of 15 days after initial oncologist assessment, similar to those whose biomarker test results were available at the time of initial consultation.8
Facilitating the uptake and timeliness of biomarker testing will require streamlining the NSCLC diagnostic pathway—for example, making reflex biomarker testing at the level of the pathologist a standard procedure and further educating specialists who obtain diagnostic cancer specimens—particularly as new targeted therapies, along with their corresponding predictive biomarkers, are introduced.8
Are liquid biopsies the answer to reducing the length of time that it takes to perform and report the results of molecular biomarker testing? Peripheral blood from patients with cancer has been shown to contain viable tumor-derived cells, which are most likely responsible for the development of intractable metastatic disease.1 Although circulating tumor cells (CTCs) are extremely rare, their use in detecting, characterizing, and monitoring nonhematologic cancers may be preferable to invasive biopsies as a source of tumor tissue for testing.1,9-11 The technology needed to obtain CTCs from peripheral blood is an evolving field of research and is challenged by the ability to isolate these cells in a condition that can be utilized for molecular analysis and propagation into CTC-derived xenografts.1 In resectable NSCLC, analysis of whole blood using the CELLSEARCH System has detected CTCs in 19% to 39% of patients, whereas using the ISET (isolation by size of epithelial tumor cells) method has detected CTCs in 36% to 50% of patients.12,13 CTC counts are generally higher in metastatic NSCLC, and studies have shown 32% to 78% positivity with the CELLSEARCH System and as high as 80% with the ISET method.13-15
Dr Oxnard had quite a bit to say about liquid biopsies. “I’ve done a lot of work developing liquid biopsies or testing of the plasma cell-free DNA [cfDNA] because tumor biopsies are inconvenient for the patient, because they are risky, they cause delays, and they are frustrating. They are inconvenient for the pathologist at times, because the specimen is too small and it does not work out. There is an urgency to get answers back faster when possible and more efficiently. We did a study at Dana-Farber where we showed, in patients who had a liquid biopsy as well as a tumor biopsy, results from the blood test took an average of 3 days, whereas the biopsy results took an average of 28 days to get back. This is dramatically different for a patient with advanced lung cancer. We are increasingly using liquid biopsies as an early screening test to look for a key mutation. If it is present, you can act on it. If it is not present, you cannot trust the negative result—you must go to tissue biopsy. The sensitivity of liquid biopsies is not that great—perhaps in the range of 70% for advanced lung cancer. We send it at a moment when I am trying to make a decision—I am looking for an EGFR mutation, I want to start a targeted therapy—so I send the blood test. The results often come back within a week, which is great. It is certainly faster than ordering a tissue biopsy, but if it is negative, then I proceed with a tissue biopsy. It does require some nimbleness for doctors to figure out how to build these diagnostics into patient care, but it really fits a need because of the frustrations in obtaining tumor biopsies and the delays involved in getting tumor NGS results in some situations. However, it is a shortcut, a convenient insight into the tumor biology, so you need to take it with a grain of salt because it really is not tumor genotyping. It is not cfDNA analysis. There is not tumor DNA; it is a potpourri of mixed DNA you are looking at, hoping to see what the tumor is like by testing this plasma DNA.”
Dr Ritterhouse agreed. “There are many instances in which liquid biopsy could be very helpful. The specimen inadequacy is something that we deal with. It is very, very common, especially in lung cancer biopsies, which can be very scant. The patient may have been to several institutions, multiple people have ordered IHC, so there is very little tissue left, and perhaps the patient is too ill to get another biopsy. That situation is a really excellent opportunity for liquid biopsy to make a big impact in patient care, and in a rapid turnaround time as well. At our institution, liquid biopsies are mostly used for looking for resistance mutations. Occasionally, if there is no other material available or all the material is gone or has been used, then liquid biopsy can be used in the first line setting.”
“At our institution, liquid biopsies are mostly used for looking for resistance mutations.” -Lauren Ritterhouse, MD, PhD
Another way to streamline the biomarker testing process and reduce turnaround time is for the clinician placing the order for testing to communicate clearly to the pathologist what he or she is looking for (ie, details about the patient and the specific molecular targets of interest). Again, communication is key—the medical oncologist may order the biopsy and include a wealth of information in the order, but the surgical oncologist or interventional radiologist may actually write the pathology requisition. Thus, care must be taken to transmit all the information from the entire cancer care team to the pathologist to ensure that the correct testing is carried out.
Other best practices in streamlining/expediting molecular biomarker testing and reporting are evolving. As Dr Oxnard pointed out, “The tricks that I’m learning as an oncologist are, if there is urgency, make sure the proceduralist knows that—make sure that the surgeon or the radiologist knows, ‘I need that done quickly.’ Sometimes even the patient will not realize the urgency. They will be scheduled for a biopsy in 2 weeks, and you will say, ‘No, I need to see you tomorrow.’ Communicating to the pathologist is also critical: the oncologist orders the biopsy, and at the same time, he sends a note to the thoracic pathologist, saying, ‘I am getting this biopsy, I am getting it for resistance testing. Please, as soon as you get the specimen, cut the slides, and send it to the molecular pathologist. Please, move us into molecular testing, because that is what is so important. Do not spend too much time on IHCs and diagnosis. You can do this. It takes a little extra time.’ The final piece you can do is to recommend a fine needle aspirate and a cytology specimen with each core biopsy, because that can be an extra specimen that can be tested very quickly without needing to wait for the block to be made, the cutting, and the extra handling of the specimen.”
Dr Ritterhouse added, “The cytology specimens also have the benefit of when the actual biopsy is taken, there is a cytopathologist in the operating room suite that looks at the slide and says, ‘Yes, this will be OK for molecular testing.’ The adequacy of the specimen is determined immediately, instead of if the core biopsy gets embedded, histology is cut, and 3 days later a pathologist looks at it and says, ‘Oh, there are only 10 tumor cells. We cannot do anything with this.’ Then, when you get to the end and you do not have enough DNA or you do not have material, you have to start all over; that is even more of a devastating setback as far as getting the results for the patient. Every time you cut into a paraffin block you lose some sample, so cutting the slides that you need for molecular testing upfront, at the same time you cut the original slides, has been shown to dramatically increase the adequacy of specimens and really improve on outcomes from all the small biopsies we get. Working at each step of the way to work on efficiencies is critical. Cytosmears work great—we get amazing amounts of DNA from them. They are our best specimens that we test. Lastly, interpretation reporting, that takes a lot of time if it is a very large NGS panel. At each step of the way, it is important to sit and think, ‘How can we improve this, increase the efficiency, and try to decrease the turnaround time as much as possible.’”
Cost and Value in Biomarker Testing
Before 2018, the Centers for Medicare & Medicaid Services (CMS) “14-day rule” did not allow reference and independent laboratories to bill Medicare directly for molecular pathology tests if they were ordered less than 14 days from an outpatient’s hospital discharge date.16,17 Rather, the laboratory would be reimbursed by the hospital, which would bill Medicare. If molecular tests were ordered within 14 days of a patient’s discharge, CMS treated them as if they were bundled into hospital payment packages by the Hospital Outpatient Prospective Payment System (OPPS) fee schedule, which they were not. The problematic issue here is the CMS date of service (DOS) policy, which specifies that the DOS for clinical diagnostic laboratory services be the date the specimen is collected, not the date the test is done. Per Medicare, this may affect payment for a test, particularly if specimen collection occurs during the patient’s hospital stay but testing is done after the patient is discharged. Not only does this represent an administrative challenge for the laboratory and the hospital, but it also may result in delays in patient testing, access to test results, and decisions regarding treatment plans.
To remedy the situation, the 2018 CMS OPPS final rule created an exception to the 14-day rule, modifying its DOS policy for hospital outpatients who undergo molecular biomarker tier 1 and tier 2 tests and advanced diagnostic laboratory tests.16,17 Beginning January 1, 2018, in the case of the aforementioned tests, the DOS must be the date the test was performed instead of the date the specimen was obtained, only if the following conditions are met17:
- The test is performed following a hospital outpatient’s discharge from the hospital outpatient department
- The specimen was collected from a hospital outpatient during an encounter (as both are defined in 42 CFR 410.2)
- It was medically appropriate to have collected the sample from the hospital outpatient during the hospital outpatient encounter
- The results of the test do not guide treatment provided during the hospital outpatient encounter
- The test was reasonable and medically necessary for the treatment of an illness.
If all of the requirements are met, the DOS of the test must be the date the test was performed, which effectively separates the laboratory test from the hospital outpatient encounter. As a result, the laboratory performing the test must bill Medicare directly for the test, instead of seeking payment from the hospital outpatient department.17 It is important to note the following exceptions to this laboratory DOS change16:
- This exception does not apply to specimens obtained from hospital inpatients
- Gene sequencing procedures, proprietary laboratory analysis tests, and protein-based molecular multianalyte assays with algorithmic analyses are not included in the CMS 2018 exception; therefore, hospitals must continue to bill Medicare if these tests are ordered within 14 days of an outpatient’s discharge date.
Dr Ritterhouse was very vocal about this issue. “The reimbursement landscape for molecular testing is something that causes a great deal of anxiety for molecular pathology laboratory directors. For the most part, we are well reimbursed for our patients with lung cancer—that is one of the solid tumors that has been at the forefront of getting precision medicine and targeted therapies, so that is better understood and reimbursed by insurance companies. For other tumor types, it can be kind of hit or miss as to whether they get reimbursed or not. Recently, with CMS’s National Coverage Determination, the final version of that was a bit better than the initial one, which said that Medicare was only going to reimburse FDA-approved tests. In the United States, there is a single laboratory that does FDA-approved tests, so none of the laboratory-developed tests and none of the academic hospitals would have been reimbursed, resulting in a panic for a couple of months. The final coverage determinations allowed for local Medicare Administrative Contractors [MACs] to continue their coverage of laboratory-developed tests if they so wanted. We are breathing a little bit better now, as far as reimbursement. How the private payers are going to react and follow how the local MACs may change their coverage is still up in the air, so we are a little bit nervous about that. Also, more recently there is the requirement by certain insurance companies for preauthorization of all molecular tests—some of them say all molecular tests, including molecular tests that have been done for over a decade that are supercheap. For a molecular test, the DOS, depending on what it falls under, if it meets the new 14-day rule or not, can be when the specimen is obtained. You are supposed to have preauthorization done before the specimen is obtained, which is insane in the molecular pathology setting. It is not physically possible. As far as I know, the 14-day rule has not significantly affected our reimbursements from CMS.”
“The payers’ idea is that you should not need this more than once for lung cancer. That is not a reality.” -Geoff Oxnard, MD
Dr Oxnard added, “We’ve definitely had to have a sit-down with our local payers to come up with some guidelines and consensus. We have some systems where we can acknowledge each time we ordered an NGS that it conforms to certain specifications. If it is an advanced lung cancer and they have not had an NGS in the past 6 months, we can facilitate the approval. The payers’ idea is that you should not need this more than once for lung cancer. That is not a reality. The fact is that patients develop resistance or develop multiple primary lung cancers, and in those cases, NGS is much more useful than a one-time test. There are some centers that are more constrained by the 14-day rule. It is a source of incredible frustration and incredible delay. It seems to be a ridiculous rule. We have the good fortune that at Dana-Farber, we are not that constrained by it, but I need to acknowledge that it is a problem that many sites are struggling with. I do know it can put pressure on community hospitals or smaller laboratories more so than a large academic setting.”
Payers support biomarker testing in oncology because it usually means they will be paying for drugs a patient is likely to respond to rather than paying for treatment that may have little therapeutic effect.18,19 However, payers differ in their approach to payment for different technologies, with most paying for molecular tests independent of the associated therapy.18,20 A recent survey of commercial and government managed care health plans covering more than 150 million lives showed that health plans may be reluctant to reimburse biomarker tests without evidence of clinical utility, because they may prove ineffective in improving patient outcomes, and, therefore, are financially wasteful.20 This survey indicated that 62% of payers felt that, for oncology diagnostic tests to gain acceptance, they must be accompanied by a demonstration of cost-effectiveness.20 When asked to rank the primary benefit of using genetic testing in oncology, the ability of the test to predict efficacy of therapy and help select appropriate treatment both ranked #1 (Table 2).20 Moreover, almost 80% of the payers felt that data showing proof of greater specificity and sensitivity were required from genetic tests in oncology for acceptance (Figure).20 Indeed, it has been suggested that payment for a new oncology drug may actually be easier to obtain than payment for a biomarker test.18,21
Payers often must determine the necessity of biomarker testing before they will cover new molecular therapies.18,21 Once that necessity has been established, payers may not agree to pay for associated molecular-based therapy until they are presented with clear evidence of a tumor’s biomarker positivity.18,21 Now, in addition to efficacy, payers are also requesting evidence that the test is cost-effective, not merely inexpensive. Even if expensive, tests such as molecular biomarker testing can be considered a good value if they provide a substantial clinical benefit to the patient versus the available alternative (ie, standard therapy that has not been individualized to the characteristics of the patient and the tumor).18,22
Conclusions: Applying Best Practices in Biomarker Testing
When the experts were asked what they considered to be the greatest challenges to biomarker testing today and how their practice or hospital overcame these challenges, Dr Oxnard suggested that “the greatest challenge for biomarker testing remains tissue stewardship—using it well, using it right—and the increasing complexity with more and more biomarkers to be tested for doctors to keep track of, and the increasing complexity of the results coming back to us: getting overwhelmed with data and figuring out how to handle it right for our patients. For each of these elements, doctors need to invest in infrastructure to do it well, and we need to help them simplify, focus, and make a way to help the patient as effectively as possible.”
Moreover, there is a feeling that the pathologists’ reports are too complex and sometimes difficult to interpret. As Dr Oxnard noted, “Some results present information about a reliable, targetable driver and the drugs that are available to target that driver, but occasionally, they go on to say there is this fascinating other mutation, and you can think about enrolling the patient in this clinical trial. The doctor says, ‘Well, that is interesting. Should I do the trial or use the reliable FDA-approved drug?’ In most cases, the provider should pick the FDA-approved drug; the additional information was there to make the report seem more interesting. That other stuff, tone that down a little bit and focus on on-label therapy. Focus on the highlights and avoid the risk of confusing the patient, the doctor, and confusing the care.”
Dr Ritterhouse agreed. “I think that it is really helpful feedback to have, especially when you have molecular pathologists and genetic counselors reviewing things; they may go into the minutiae of this 1 in vitro study done 10 years ago that showed that this variant may have this effect. I think sometimes the reports are generated and the pathologist does not know how it is read or interpreted. I think these conversations are helpful between the pathologist and the individual reading the reports, whether it’s community oncologists or oncologists at an academic setting. What do they want out of the report? What are they getting or not getting? We have even had conversations about trying to move the reports into EMRs so that, for example, if you are following EGFR mutations or resistance mutations, there should be a molecular tab for you to consult. I think there are many ways that everyone can work better about simplifying the reports and making sure that the oncologists are getting the data that is important, and the patients are getting therapy directed appropriately.”
The experts were also asked to share best practices and key success factors in their institutions that other cancer centers or private practices may adopt to optimize molecular biomarker testing.
Dr Oxnard ventured, “As an oncologist who treats lung cancer, I want them to be genotyped, I want them to be characterized and tested. In my first line, I keep track of whether they are EGFR mutant or KRAS mutant. A patient who gets ill without testing and who dies without testing has missed out on potentially significant opportunities. We need to make sure that every patient gets an opportunity for molecular testing to find the drugs that will work best. If that requires starting therapy while at the same time pursuing biomarker testing, I think it is really important. We need to make sure we have backup plans for our patients, and molecular testing is what allows us to do that. That is the movement towards precision oncology that all of us need to adopt day-to-day.”
Dr Ritterhouse added, “Best practice for surgical pathologists and molecular pathologists is to remember that you are not working in isolation and to form very close working relationships with our clinical colleagues and the oncologists, and to have open dialogues and frequent dialogues about the best way to take care of our patients. Moreover, we need to discuss the challenges that oncologists are facing with either getting the specimens or getting the report, digesting the report in an efficient manner, and really working together to improve little things. Many of the best changes that we have had at our institution have come from these multidisciplinary efforts of increasing specimen adequacy and reducing turnaround time. It is really important to reach out to all of your colleagues in different departments and figure out a way to move things forward and make things better. There have been attempts, which have been not so successful, to have an institution-wide molecular tumor board. With several different tumor types and different care teams, everyone already has their own tumor board. At my institution, there are two primarily molecular pathologists, and we cannot be at every single tumor board every week. But we can have discussions about molecular biomarkers a couple of times a year, and we try to make sure we get everyone together to address certain issues. Then, we convene as needed with smaller groups as needed. It is not a formalized meeting that we have every month; we just try to find the big issues that need to be addressed and try to get everyone in the same room at least once or twice a year.”
- Mamdani H, Ahmed S, Armstrong S, et al. Blood-based tumor biomarkers in lung cancer for detection and treatment. Transl Lung Cancer Res. 2017;6:648-660.
- Suphavilai C, Bertrand D, Nagarajan N. Predicting cancer drug response using a recommender system. Bioinformatics. 2018 June. doi:10.1093/bioinformatics/bty452. Epub ahead of print.
- Burke HB. Predicting clinical outcomes using molecular biomarkers. Biomark Cancer. 2016;8:89-99.
- Cheng L, Alexander RE, MacLennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Mod Pathol. 2012;25:347-369.
- Tsiara A, Liontos M, Kaparelou M, et al. Implementation of immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). Ann Transl Med. 2018;6:144.
- Sabari JK, Offin MD, Wu SL, et al. RET-rearranged lung cancers: immunophenotype and response to immunotherapy. Presented at: 2018 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2018; Chicago, IL. Abstract 9034.
- Schwartzberg L, Kim ES, Liu D, et al. Precision oncology: who, what, when, and when not? Am Soc Clin Oncol Educ Book. 2017;37:160-169. https://meetinglibrary.asco.org/record/137923/edbook#fulltext. Accessed June 14, 2018.
- Lim C, Tsao MS, Le LW, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann Oncol. 2015;26:1415-1421.
- Nagrath S, Sequist LV, Maheswaran S, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235-1239.
- Mocellin S, Hoon D, Ambrosi A, et al. The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis. Clin Cancer Res. 2006;12:4605-4613.
- Pantel K, Alix-Panabières C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16:398-406.
- Tanaka F, Yoneda K, Kondo N, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res. 2009;15:6980-6986.
- Wong MP. Circulating tumor cells as lung cancer biomarkers. J Thorac Dis. 2012;4:631-634.
- Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non–small-cell lung cancer. J Clin Oncol. 2011;29:1556-1563.
- Hofman V, Ilie MI, Long E, et al. Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: comparison of the efficacy of the CellSearch Assay™ and the isolation by size of epithelial tumor cell method. Int J Cancer. 2011;129:1651-1660.
- The new year rings-in change to CMS’ “14-Day Rule” for its laboratory date of service policy [white paper]. www.apsmedbill.com/whitepapers/new-year-rings-change-cms%E2%80%99-%E2%80%9C14-day-rule%E2%80%9D-its-laboratory-date-service-policy. APS Medical Billing. Published January 16, 2018. Accessed June 20, 2018.
- Centers for Medicare & Medicaid Services. Laboratory date of service policy. CMS.gov website. www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/Clinical-Lab-DOS-Policy.html. Updated February 27, 2018. Accessed June 14, 2018.
- Allen TC. Payment for cancer biomarker testing. Arch Pathol Lab Med. 2015;139:300-304.
- Shelley S. Biomarkers create opportunities, complicate drug dispensing. Pharm Commerce. 2012;7:21. https://pharmaceuticalcommerce.com/brand-marketing-communications/biomarkers-create-opportunities-complicate-drug-dispensing/. Published July 16, 2012. Accessed June 14, 2018.
- Trogan G. What do payers want in oncology diagnostics?: insights from a national survey of top commercial and Medicare health plans. Am Drug Health Benefits. August 2011;4(special issue). www.ahdbonline.com/issues/2011/august-2011-vol-4-no-4-special-issue/790-article-790. Accessed June 14, 2018.
- Dupere B. Companion biomarkers and cancer treatment: lessons learned for oncology new product planning. Oncol Bus Rev. September 2008:24-29.
- Thariani R, Veenstra DL, Carlson JJ, et al. Paying for personalized care: cancer biomarkers and comparative effectiveness. Mol Oncol. 2012;6:260-266.
On December 12, 2019, the FDA issued draft guidance to implement amendments to the Federal Food, Drug, and Cosmetic (FD&C) Act that will facilitate early assessment of studies of molecularly targeted oncology drugs that may be effective in the treatment of pediatric cancers.
Best Practices in Biomarker-Assisted Targeted Therapy in Lung Cancer: Lessons Learned From the Yale Cancer Center
Introduction The last decade has witnessed significant advances in the development of biomarkers in oncology that play a critical role in the understanding of molecular and cellular mechanisms that drive tumor initiation, maintenance, and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as investigators begin to [ Read More ]