Lung Cancer (October 2016): Molecular Oncology Tumor Boards

ASCO University
Oct 12, 2016 9:33 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This month’s topic is led by Drs. Josephine Feliciano (Medical Oncologist from the University of Maryland) and Lynette Sholl (Surgical and Molecular Genetics Pathologist from Brigham and Women’s Hospital).

Users are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Comments

13496

ASCO University
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 12, 2016 9:34 AM

Patient Case

Patient History: 70-year-old female with rheumatoid arthritis and no smoking history initially presented with cough, shortness of breath and a 15 lb. weight loss over 3 months. Her family physician orders a chest x-ray which revealed a large right sided pleural effusion and right upper lobe lung mass. Follow up CT scan confirmed a 3 cm. right hilar lung mass and large pleural effusion and pleural based tumors.

The patient was admitted for therapeutic thoracentesis and diagnostic procedure. She underwent thoracentesis with over 2 liters of serosanguinous drainage, and pleural mass biopsy was performed. Her shortness of breath was significantly improved after the thoracentesis but re-accumulated with symptoms in three days.

Type of Tumor: A pleural biopsy showed morphologic features of adenocarcinoma. Her tumor was TTF-1+ and p40- by immunohistochemistry, confirming a diagnosis of lung adenocarcinoma.

Relevant markers: Testing for EGFR mutation and ALK rearrangement were performed. No EGFR or ALK alterations were identified.

Prior Treatment History/Response: None

Co-morbidities:  Rheumatoid arthritis previously treated with methotrexate, but currently on no medications for her rheumatoid arthritis.

Images/Scans/Pathology: CT scan as above. PET/CT was done showing no evidence of contralateral parenchymal disease and no evidence of extra-thoracic metastases. MRI of the brain shows no evidence of intracranial metastases.

13501

ASCO University
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 12, 2016 9:35 AM

Discussion Questions

1.    Who should get routine molecular testing at diagnosis for NSCLC and what tests should be performed?
2.    What is the most appropriate initial treatment for this patient?

13506

Anis Toumeh, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 12, 2016 10:27 AM

For patients with newly diagnosed metastatic adenocarcinoma/adenosquamous carcinoma as well as squamous cell carcinoma (in young non smokers) of the lung, initial testing should include, at minimum, EGFR sensitizing mutations, ALK and ROS1 alterations. NGS could be helpful, when feasible, to detect alterations that might make the patient eligible for clinical trials testing other targeted agents as well as  to detect alterations not captured by PCR or FISH. 

As initial treatment, the patient could be enrolled in a clinical trial if available. I believe testing for ROS1 should be performed on this tumor (or NGS). If no alterations detected and no clinical trial available, I would start this patient on platinum based systemic chemotherapy utilizing pemetrexed. 

13511

Thomas B. Tucker, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 12, 2016 3:47 PM

Would test all non-small cell lung cancers by molecular profiling, and now also for PDL-1 expression.  Moswt appropirate inital treatment would depend on those results.  If there are no driver mutations or PDL-1 expression, I would treat with carboplatinum and pemetrexed as first line therapy.

13521

Josephine Louella Feliciano, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 13, 2016 4:07 PM

Thank you Dr. Tucker for your timely response. As recently as this week, Pembrolizumab was reported as superior to platinum based chemotherapy in patients with PD-L1 expressing tumors.(Reck, M. et. Al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small Cell Lung Cancer. NEJM 2016). These impressive results were reported from a phase III trial of 305 patients in the first-line setting whose tumors expressed PD-L1 in at least 50% of tumor cells based on the PD-L1 Immunhistochemistry 22C3 pharmDx assay (Dako North America). The patients who were randomized to pembrolizumab experienced a superior progression free survival, 6-month overall survival rate, and response rate, as well as fewer treatment related adverse events, all of which were statistically significant.  Patients with sensitizing EGFR mutations or ALK translocations were excluded from this trial and so molecular profiling is still crucial, in addition to testing for PD-L1 in the front-line setting to guide initial therapy.

13526

Lynette M. Sholl, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 17, 2016 9:46 AM

Course Faculty Response

This patient, who is a non-smoker, was found to have a non-small cell lung cancer (NSCLC), adenocarcinoma type by histology and immunohistochemistry. Given the recent advances in treatment of NSCLC including the discovery of the Epidermal Growth Factor Receptor (EGFR) mutations, Anaplastic Lymphoma Kinase (ALK) and ROS1 rearrangements, and other molecular variants under investigation, it is now standard of care to perform molecular testing on patients with a new diagnosis of advanced NSCLC, particularly in non-squamous histology. Multiple organizations including National Comprehensive Cancer Network (NCCN), College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), Association for Molecular Pathology (AMP) and American Society of Clinical Oncology (ASCO) have now developed or endorsed guidelines for molecular testing in advanced NSCLC. Testing for EGFR mutations and ALK rearrangements is recommended for all patients with advanced stage non-squamous NSCLC or for squamous cell cancers in patients with a light or never smoking history (Levy, 2015) (Leighl, 2014) (Lindeman, 2013).  Furthermore, crizotinib has recently been approved for patients with advanced, ROS1-rearranged NSCLC patients based on a phase I study of 50 patients with ROS1 rearrangements where investigators observed complete responses in 6% and partial responses in 66% of participants (Shaw, 2014). Thus, it is also reasonable to request ROS1 testing in patients with a new diagnosis of advanced, nonsquamous NSCLC.

13531

Josephine Louella Feliciano, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 17, 2016 9:49 AM

Course Faculty Response

There was no EGFR or ALK mutation at initial presentation for this patient and therefore she was not a candidate for oral tyrosine kinase therapy in the first line setting. However, she would be a candidate for first line platinum based chemotherapy. Chemotherapy with a platinum doublet, such as carboplatin and pemetrexed is effective, particularly in adenocarcinoma histology, and one could also consider a regimen such as carboplatin, paclitaxel, and bevacizumab if she has no contraindications for bevacizumab (Ciuleanu, 2009) (Sandler, 2006). Given this patient’s concern about various toxicities, she was treated with carboplatin and pemetrexed and had an excellent response and tolerated it very well. She continued with maintenance pemetrexed until progression (Ciuleanu, 2009).

In addition, if her mutational status was unknown, or unobtainable at presentation, it would also be reasonable to recommend first line chemotherapy. Cytotoxic chemotherapy is active in patients with EGFR or ALK alterations. Although most studies comparing tyrosine kinase inhibitor to chemotherapy in patients with either an EGFR or ALK alteration demonstrate superior progression free survival with a tyrosine kinase inhibitor, most data, including meta-analyses, suggest similar overall survivals with either form of therapy, likely due to eventual cross-over (Des Guetz, 2016) (Gao, 2012).  Cytotoxic chemotherapy can be given while additional attempts to perform molecular testing are made.

13536

ASCO University
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 17, 2016 9:50 AM

Patient Case Update

The patient received an initial therapy with carboplatin and pemetrexed for 6 cycles, followed by maintenance pemetrexed. She had a complete response of her disease which persisted for 28 months. Incidentally, her rheumatoid arthritis also improved while on chemotherapy. However, at 28 months, she was found to have progression on routine follow up scans in her hilar and mediastinal lymph nodes and no longer responded to single agent pemetrexed. She was asymptomatic.

She undergoes an endoscopic ultrasound guided biopsy of the hilar and supraclavicular lymph nodes. Her specimen is sent for genomic sequencing and she is found to have the following mutations:

BRAF c.1799T>A (p.V600E)
CDKN2B c.156+2delTAGC (splice site)
TP53 c.560-1G>C (splice site)

13541

ASCO University
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 17, 2016 9:51 AM

Discussion Questions

1.    What would be your next step in the management of this patient?
2.    Would she be a candidate for second line immunotherapy?
3.    What are potential targeted therapies for which she may be eligible?

13546

Claire Lenee Hiles, MD, BA
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 20, 2016 9:38 PM

1. Would  strongly favor nivolumab if PDL1 statud unknown and pembrolizumab over atezolizumab if PD-L1 expression was >50% in tumor cells. Would review options for at least a phase II, prefenetially a phase III clinical trial for targeted therapy while patient remained asymptomatic. Eg. NCT02672358 phase II trial for Dabrafenib and Trametinib Combination Therapy in Japanese Patients With BRAF V600E Stage IV NSCLC. 

2. She appears to be a candidate for nivolumab and pending PD-L1 testing possibley also pembrolizumab over atezolizumab. Her controlled RA is not a contraindication to immunotherapy but careful attention should be made to monitor for signs of RA flare on immunotherapy.

3. As above, there is an pending recruitment phase II trial for combination BRAF + MEK inhibitors. Limited search on clinicaltrials.gov did not reveal a CDKN2B or TP53 open trial. May consider a basket trial for solid tumors with targetable mutations but again would consider this moreso in the third/latter-line setting after trial of immunotherapy.

13551

Lynette M. Sholl, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 21, 2016 9:15 AM

Course Faculty Response

1.Next generation sequencing (NGS)-based testing is increasingly used to simultaneously test multiple genes important in cancer.  Given the large number of oncogenes that are now recognized to each drive a small percentage of lung adenocarcinomas, this approach is more efficient than sequential testing of several gene targets, particularly in a patient who is known to be negative for some of the more common alterations. In addition to mutations, some NGS tests can also detect copy number changes (such as gene amplification) and rearrangements. (Zheng, 2014) (Suh, 2016). This type of test can use small amounts of archival (formalin-fixed) tissues, providing results in a relatively short turnaround time.  A repeat biopsy obtained via a surgical approach (such as cervical mediastinoscopy) or by fine needle aspiration (such as endobronchial ultrasound guided biopsy) can typically provide sufficient material to both confirm the diagnosis and perform molecular studies, however communication between oncologist, operator and pathologist should emphasize the need for molecular studies in order to ensure careful sample handling and streamlined diagnostic workup.  Although cytologic materials are often overlooked as substrates for molecular testing, several studies have shown that cytology preparations are technically equivalent to biopsy materials for use in NGS (Zheng, 2016) (Karnes, 2014).  

3.The most common BRAF mutations occur in two hotspots: in exon 15 around codon 600 and exon 11 around codons 464-469.  In melanoma, a variety of mutations have been described immediately adjacent to codon 600, many of which have been shown to activate the kinase and to confer responsiveness to BRAF targeted inhibition.  In the lung, V600E mutations comprise about half of BRAF mutations in lung cancers, and the remainder typically occur in exon 11.  BRAF exon 15 mutations occurring outside of codon 600 are rare in lung cancers.  Exon 15 hotspot mutations should be distinguished from those occurring in exon 11. Mutations in exon 11 lead to variable activation of the BRAF kinase (Cardarella, 2013) and have not been systematically evaluated for responsiveness to targeted inhibitors. In the pre-targeted therapy setting, BRAF V600E mutations occur in a mutually exclusive fashion with other common oncogenic mutations such as in KRAS or EGFR, whereas exon 11 mutations may be seen as “passenger” mutations occurring in tandem with a variety of other oncogenic alterations. At this time, the NCCN recognizes only BRAF V600E as a biomarker for emerging targeted therapies.  Ongoing studies, however, are currently evaluating several agents (ERK and MEK inhibitors) that may have clinical activity in tumors with some non-V600E BRAF alterations, thus referral for a clinical trial of these targeted agents may be reasonable when these alterations are identified.

CDKN2B and TP53 are both important tumor suppressor genes involved in regulating the cell cycle.  TP53 in particular is commonly mutated in lung cancers.  Although some drugs have theoretically shown activity in tumor cells deficient in these proteins, there is little clinical evidence to support the use of drugs targeting these deficiencies in lung cancer.  However, with the availability of NGS for clinical testing, information about genes that may influence disease behavior or response to targeted therapies is now being generated more routinely.  Some early data suggests that the presence of a TP53 mutation may negatively influence response to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC (Aisner, 2016) (Labbe, 2016).

13556

Josephine Louella Feliciano, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 21, 2016 9:22 AM

Course Faculty Response

1.In this situation, a biopsy at the time of progression, if feasible, would be warranted. Repeat biopsy is encouraged for multiple reasons. Patients with a diagnosis of lung cancer, particularly smokers, are at risk for second primary tumors, which can differ in histology and warrant a change in therapy (Boyle, 2015).  Those who harbor oncogenic driver mutations, such as in EGFR, may develop a resistance mutation such as T790M mutation, that could be identified on re-biopsy and predict response to subsequent therapies (Kuiper, 2014) (Oxnard, 2011).  Transformation to a different histology, such as lung adenocarcinoma to small cell cancer, has also been described (Norkowski, 2013).  Additionally, driver mutations in genes other than EGFR, ALK, or ROS1 have been identified more recently with potential targeted therapeutics under investigation or commercially available.

2.This may be a challenging situation given that this patient had a diagnosis of rheumatoid arthritis. Second line immunotherapy with either nivolumab or pembrolizumab has been approved in patients who have received first line cytotoxic chemotherapy based on randomized trials that have demonstrated superior efficacy compared to docetaxel chemotherapy (Brahmer, 2015) (Herbst, 2016).  However, many of the clinical trials involving immunotherapies for lung cancer have excluded patients with a pre-existing diagnosis of an autoimmune condition, despite a possible prevalence of autoimmune conditions in lung cancer of 13-24% based on population-based estimates (Khan, 2016).  Therefore, there is little safety data regarding its use in a patient with known rheumatoid arthritis. However, there are small series to report the use of another type of type of immune therapy, ipilumumab, in patients with melanoma and pre-existing auto-immune conditions. These small reports suggest that these agents may be active but can induce exacerbations of their pre-existing autoimmune conditions but that they may be managed similarly to other drug related immune events seen with immunotherapies (Johnson, 2016).

3.This patient’s tumor was re-biopsied and sent for next-generation sequencing, and three aberrations were identified: BRAF V600E and splicing mutations in CDKN2B and TP53. However, only BRAF V600E is a potential candidate for targeted inhibition. BRAF mutations are more prevalent in melanoma. The BRAF inhibitors, vemurafenib and dabrafenib, have been investigated and approved for use in metastatic melanoma (Long, 2015) (Larkin, 2014). In contrast, BRAF mutations are found in approximately 2-4% of lung cancers and V600E mutations comprise about half of these mutations (Nguyen-Ngoc, 2015). Early descriptions of the clinical and patient features associated with this mutation suggested they may be more frequent in  current or former smokers, but later descriptions suggest BRAF mutations may not  correlate with smoking status or gender (Marchetti, 2011) (Cardarella, 2013).

The activity of BRAF inhibitors in lung cancers harboring a BRAF V600E mutation have recently been investigated with promising results (Marchetti, 2011). In phase II studies, dabrafenib, with or without a MEK inhibitor, appears active in BRAF V600E mutant NSCLC (Planchard, 2016) (Planchard, 2016). In a phase II study of 84 patients with a BRAF V600E mutation, including some who were heavily pretreated, dabrafenib as a single agent was associated with an overall response rate of 33%, disease control rate of over 50% (Planchard, 2016). Additionally, in a phase II study of previously treated NSCLC patients harboring BRAF V600E mutation, dabrafenib and the MEK inhibitor, trametinib, were associated with an overall response rate of 63% and a disease control rate of 75% (Planchard, 2016). While not yet FDA approved, oral BRAF inhibitors may represent a new class of targeted therapeutics for patients with BRAF mutant lung cancer.

13566

Lynette M. Sholl, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 26, 2016 7:59 AM

Course Faculty Summary

  • It is feasible to perform next generation sequencing from a variety of archival tumor specimens, including formalin fixed specimens and cytology preparations.
  • Next generation sequencing is an efficient approach to detection of less common alterations in lung adenocarcinoma and may also detect tumor suppressor gene alterations with potential implications for response to targeted therapies.
  • A spectrum of BRAF mutations may be found in lung adenocarcinoma, but to date only BRAF V600E has been associated with response to targeted inhibition in clinical trials.

13571

Josephine Louella Feliciano, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 26, 2016 8:01 AM

Course Faculty Summary

  • Through this case-based approach, we addressed the initial indications for molecular testing in a newly diagnosed NSCLC patient. We discussed that current guidelines recommend EGFR and ALK testing, primarily for non-squamous NSCLC, and that ROS-1 may soon be added to those recommendations. We also discussed that molecular testing on repeat biopsy is important in patients who have progressed as new molecular aberrations are identified, and more refined testing techniques are utilized.
  • We discussed that the standard of care in patients without a known EGFR or ALK mutation in the first line setting are appropriately treated with platinum doublet chemotherapy.
  • We discussed the increasing importance of repeating biopsies for various indications such as re-evaluating for molecular testing, or evaluating for a different histology tumor.

13576

ASCO University
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 26, 2016 8:03 AM

Thank you to Drs. Feliciano and Sholl for leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments and participants can claim CME credit and 1 ABIM MOC point through ASCO University.

Please check back in mid-November for a new case in this series related to acute myeloid leukemia. 
   
Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

13586

Sharon Sanborn Wagamon, MD
Re: Lung Cancer (October 2016): Molecular Oncology Tumor Boards
Oct 31, 2016 3:54 PM

I typically try to send NGS on all newly diagnosed advanced adenocarcinoma NSCLC patients and some squamous cell carcinomas.  Carbo/pem followed by pem maintenance would be my typical approach, but with the new data on pembro I am starting to test for PDL1.  For BRAF positive patients, NCCN does note that dabrafenib +/- trametinib or vemurafenib can be considered.  


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