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Lung Cancer NOS Diagnoses
Clinical Dilemma: A Patient With a Diagnosis of Stage IV NSCLC-NOS Is Referred to You for a Second Opinion

Released: November 21, 2016

Expiration: November 20, 2017

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Recently, I’ve thought about a scenario in which a patient has a new diagnosis of stage IV non-small-cell lung cancer (NSCLC)–not otherwise specified (NOS) and gets tested for PD-L1 since this test does not depend on knowing tumor histology. In this scenario, if the PD-L1 test is not at least 50% PD-L1 positive, first-line checkpoint inhibition is not an option and you still don’t know which chemotherapy to choose, nor do you know if you should do molecular testing. So clearly, even with our new treatment paradigm, we need to avoid a diagnosis of NOS.

Importance of Histology
Knowing tumor histology is important for choosing an optimal chemotherapy regimen and potentially for molecular testing. Agents like bevacizumab and pemetrexed that are effective in nonsquamous NSCLC are contraindicated in squamous cell histology. Moreover, although some institutions allow molecular testing on all tumor histologies, others restrict molecular testing to patients with adenocarcinoma. Therefore, at an institution where molecular testing is restricted, a diagnoses of NSCLC-NOS could impede the ability to make optimal treatment decisions for a patient in whom it is unknown whether he or she has squamous or nonsquamous NSCLC. To assure optimal care for our patients with NSCLC, it is of critical importance to avoid a diagnosis of NSCLC-NOS, which we can accomplish by asking our radiologists and pulmonologists to get good, ample tissue samples when our patients with lung cancer go in for biopsy and by completing appropriate histological evaluation and molecular testing.

Current Biopsy Recommendations
For a patient who presents with or is suspected to have stage IV NSCLC, the general recommendation to prove metastatic disease is to biopsy the most distant disease site. For example, if a patient has both lung and liver metastases, ideally you would biopsy the liver to document metastatic disease. However, following this recommendation in patients with lung and bone metastases can sometimes be more of a challenge. Although histology definitely can be classified based on a bone biopsy, if the biopsy is decalcified, it is no longer adequate for molecular testing. Because you don’t want to put a patient through an additional biopsy, it is important to notify the pathologist ahead of time that the bone biopsy is for both histology and potential molecular testing so that the specimen can be preserved in such a way that also allows for molecular testing.

In the diagnosis of lung cancer, a core biopsy is preferred over fine needle aspirates (FNA). Although an FNA might provide enough information to sort out tumor histology, there is a chance for distortion, which can make determination of histology challenging. Furthermore, although an FNA can be spun down into a cell block to allow for molecular testing, it is unknown if an accurate PD-L1 assessment can be made from an FNA. With the first-line approval of pembrolizumab in patients with PD-L1 in at least 50% of tumor cells and negative for EGFR and ALK genetic aberrations, PD-L1 testing has become a requirement in the diagnosis of advanced NSCLC, and up to now, PD-L1 testing by IHC in patients enrolled on clinical trials has always been done from core biopsy samples. Furthermore, a core biopsy will maximize the amount of tissue you have for testing, including for PD-L1 by IHC.

Because of the importance of biomarker testing, biopsy specimens should be used wisely. For current best practice, one or two slides from a formalin-fixed, paraffin-embedded core tissue biopsy should be enough to determine histology by IHC, with TTF-1 and napsin A positivity indicating adenocarcinoma and p40 positivity indicating squamous cell NSCLC. The remainder can be used for molecular and PD-L1 testing. Staining slides from the block exhaustively for other histology markers is unnecessary and uses up valuable tissue, potentially requiring the patient to undergo a second biopsy to do essential molecular testing and PD-L1 assessment. That being said, in the age of targeted therapies and chemotherapies that are chosen based on histology and molecular testing, if you take time to carefully explain what a big impact molecular testing has on treatment decisions, many patients are willing to undergo an additional biopsy.

Recommended Molecular Testing
Recommended biomarker testing for newly diagnosed metastatic NSCLC includes assessment of PD-L1 by IHC and molecular testing for EGFR sensitizing mutations, ALK translocations, and ROS1 rearrangements as part of broad molecular profiling. It is also recommended that all testing be done at the same time. If testing is done sequentially, it can take too long for all of the information to come back—if you do one test and 14 days later those results come back, and then you do the next test and you wait another 14 days for those results, that patient would be almost 6 weeks out from their original diagnosis before you initiate treatment. PD-L1 testing requires the PD-L1 IHC 22C3 pharmDx companion diagnostic assay that is specifically approved for use with pembrolizumab for newly diagnosed metastatic NSCLC. Although IHC or FISH can be used to detect ALK translocations, the current standard method to detect ROS rearrangements is by FISH. PCR-based or next‑generation sequencing (NGS) multiplex assays are used to detect mutations in multiple genes, including EGFR, ALK, and ROS1 simultaneously. PCR-based testing can be quicker but generally evaluates fewer genes than NGS. Although NGS platforms provide a wealth of interesting information about what genetic abnormalities are present in a tumor sample, this information is not always helpful—there may often be no FDA‑approved therapies or clinical trials available for a patient with a particular genetic abnormality. Furthermore, in light of the suggestion that mutational burden can predict response to checkpoint inhibition, NGS reports are also now including tumor mutational burden. However, this information is often quite confusing to read and is not readily interpretable.

There are also some blood‑based molecular testing platforms, including NGS and PCR-based multiplex assays, that can be used when a patient does not have enough tissue for molecular testing even after a second biopsy. It is important to keep in mind that the sensitivity of these tests is only approximately 80%. What this means is that if a blood-based molecular test comes back positive (eg, a patient is found to have a KRAS mutation based on NGS), you can probably rely on that result. However, if the test comes back negative, it is not safe to assume that a patient has no molecular abnormalities; it just may be that the assay was not sensitive enough to detect the abnormalities or that the level of circulating tumor cells and circulating free DNA was below the detection limit.

Waiting for Results vs Starting Treatment
Guidelines recommend that molecular testing results report within 10-14 days from biopsy, which is an amount of time that most patients can wait before starting treatment. IHC testing for PD-L1 and ALK reports within 3-4 days, much faster than PCR-based or NGS multiplex assays. Even so, waiting on the results of multiplex testing is important. EGFR mutations are much more common than ALK translocations or ROS rearrangements. Although more patients are PD-L1 positive than ALK positive, the percentage of patients whose tumors stain at least 50% PD-L1 positive, and thus are candidates for frontline checkpoint inhibition, is not large at approximately 20% with no apparent difference seen across the different histologies.

If a patient is highly symptomatic and you need to start treatment before the biopsy testing results come back, the NCCN guidelines recommend starting doublet chemotherapy. Then, if the molecular testing results for that patient come back as EGFR positive, ALK positive, or ROS1 positive during the course of the first cycle of treatment, you can have a discussion with the patient about whether to complete platinum-based doublet chemotherapy followed by maintenance therapy with a targeted agent or immediately switch them to a targeted therapy. If the patient is tolerating chemotherapy, it’s not unreasonable to complete the chemotherapy. But if the patient is not tolerating chemotherapy or isn’t experiencing a symptomatic benefit from chemotherapy, it would be reasonable to switch at that time.

Concluding Remarks
Overall, I think it is important for clinicians to remember that, to ensure our patients with advanced lung cancer receive optimal treatment strategies, we must communicate with the radiologists and pulmonologists to get good biopsy samples, submit samples for testing in a timely manner with reflex molecular testing and PD-L1 testing, and avoid diagnoses of NSCLC-NOS for our patients with lung cancer. In my own practice, if I had a patient referral like the one I described above, I would be sure to explain to the patient just how important both biopsy and appropriate testing are to optimize care and outcomes.


Please share your thoughts or questions on biopsy and pathologic testing for patients with advanced lung cancer in the comment box below.

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