Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards

ASCO University
Mar 15, 2017 9:47 AM

Participant 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).

This month’s topic is led by Drs. Sanja Dacic (Surgical Pathologist from the University of Pittsburgh) and Balazs Halmos (Medical Oncologist from Montefiore Medical Center).

This discussion is inspired on a hypothetical, non-small cell lung cancer (NSCLC) patient case that was suggested by a Molecular Oncology Tumor Board participant. Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

Participants 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.

When posting, please abide by the terms and conditions of this website.

Please click below for supplemental resources related to the case.

JCO Podcast: A New Oncogene Target in Lung Cancer: Exon 14 Alterations in the MET Gene 

Reference List

Clinical Trials

Comments

14296

ASCO University
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 15, 2017 9:49 AM

Patient Case #1

Age/Sex: 67-year-old female

Ethnicity: Chinese origin

Presentation at diagnosis: 67-year-old woman with a moderate smoking history of ½ ppd for 15 years presented with episodes of cough, low-grade fever and a few lb. weight loss in May 2014.

Past medical history: Included well-controlled HTN, PPD positivity and a congenital hearing deficit.

Diagnostic Imaging/Pathology: Evaluation including a CT chest and PET/CT revealed a 4 cm mass with some bronchial obstruction and associated atelectasis of the lingular portion of the left upper lobe. Pathology showed a NSCLC with squamous differentiation. There were no concerns for nodal or more distant metastases. VATS lobectomy was performed and pathology demonstrated a 4.3 cm tumor, T2N0Mx with mixed adeno and squamous differentiation. EGFR/ALK testing was negative.

Adjuvant treatment: 4 cycles of adjuvant Carboplatin/Gemcitabine chemotherapy was delivered which was well tolerated. Carboplatin was substituted for Cisplatin given hearing deficit.

Follow up: Surveillance with every 6 monthly scans was initiated. The findings were found to be negative until May 2016.

Image May 2016

2016 Record

Presenting: In September 2016, patient presented with new left shoulder pain and progressive cough.

Images/Scans/Pathology: PET/CT revealed multiple new bony and lung lesions consistent with metastatic disease and a bone biopsy demonstrated findings compatible with recurrent NSCLC, squamous histology. PD-L1 testing demonstrated PD-L1 TPS of 1%. Several lung lesions appeared to show cavitation and an infectious etiology was raised. Further evaluation showed an elevated quantiferon assay and patient was initiated on anti-TB therapy. Expanded molecular testing was then pursued from the prior surgical pathology specimen and a MET exon 14 alteration was identified along with MDM2 and FRS2 amplification. As patient was deemed a poor candidate for chemotherapy given prior chemotherapy, exposure and ongoing infectious concerns a trial of crizotinib was offered.

Sept 2016 Image 1

Sept 2016 Image 2

14301

ASCO University
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 15, 2017 9:50 AM

Discussion Questions

1. Who should get routine molecular testing at the time of diagnosis of NSCLC and what genes should be included in the molecular panel?
2. What is the proper timing of testing and sequencing of available therapies?
3. What treatment options are available for the management of a patient with an identified MET exon 14 skipping alteration?

14311

Balazs Halmos, MD
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 17, 2017 9:33 AM

Course Faculty Response

The proper incorporation of appropriate molecular and immune biomarker testing is a key issue in the optimal management of patients with advanced non-small cell lung cancer and has resulted in major improvements in patient outcomes (Sharma, 2017). Close collaboration with members of the lung cancer management team – such as pulmonologists, interventional radiologists and pathologists-- is key for facilitating the acquisition, processing, prioritization and reflex testing of retrieved tissue to minimize timelines and maximize utility. As to molecular testing, availability of different testing platforms in-house versus collaboration with commercial entities will yield different protocols but ultimately each protocol will need to achieve the completion of proper testing for the largest possible majority of patients.

As to molecular testing, it is helpful to consider the level of evidence supporting of the testing for each biomarker. First tier markers are oncogenic alterations where sufficient evidence exists to recommend first line therapy with a targeted agent versus chemotherapy- currently EGFR/ALK/ROS fall into this category. Testing for this tier is critical to be done in a timeframe that minimizes delays in initiation of first-line therapy.

Second-tier markers are alterations where there is sufficient evidence of activity to recommend a trial of an agent on /off study during the course of the patient’s illness; however, experience is limited to justify routine front-line use. B-Raf, Met exon 14, RET, NTRK etc. alterations fall into this group and are listed accordingly by NCCN guidelines. While biomarker testing for this group of markers is not currently mandated to be done in front-line and could be done separately, in many institutions bundled testing for the whole set will be the most sensible approach, especially when NGS testing platforms are utilized.

Third-tier markers include any other genomic markers where there is at least some experimental/biochemical evidence of actionability; however, clinical evidence currently is lacking and experimental trial referral if available might be an option.

Data is rapidly emerging on the utility of ctDNA testing in a multitude of clinical settings, however currently validated use is for EGFR mutation testing in the frontline setting and EGFR T790M testing in the acquired resistance setting and further information is expected to assist with optimal incorporation for other markers.

MET exon 14 skipping has been defined over the last two years as a key and highly actionable oncogenic alteration present overall in 2-4% of NSCLCs with a higher frequency in the highly aggressive sarcomatoid subtype. It occurs both in smokers and non-smokers without any particular gender predilection (Schrock, 2016). The biological mechanism whereby MET exon 14 skipping leads to increased proliferation/invasive and metastatic properties is by impaired degradation and thereby increased expression/constitutive activation of the MET kinase (Drilon, 2017).

Although the experience is limited to case reports, case series and an expansion phase I cohort from the PROFILE 001 study as to treatment responsiveness of patients with MET exon 14 skipping positive tumors (Drilon, 2016). However, most of the reported cases had significant – at times dramatic --responses justifying overall recommendations (including NCCN guideline) to offer MET inhibitors, such as crizotinib, cabozantinib or other available agents as part of clinical study participation.

14316

Sanja Dacic
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 17, 2017 9:37 AM

Course Faculty Response

The CAP/IASLC/AMP Guidelines published in 2013 (Lindeman, 2013) and endorsed by ASCO in 2014 (Leighl, 2014) recommend routine testing for EGFR mutations and ALK gene rearrangements in patients with advanced  adenocarcinoma, or mixed carcinoma with adenocarcinoma component including adenosquamous carcinoma. Importantly, clinical characteristics such as age, gender, race, and smoking history are not recommended as a selection criterion for molecular testing.  Exceptions to these rules are limited lung cancer specimens (biopsy, cytology) where an adenocarcinoma component cannot be excluded, and cases of squamous or small cell carcinomas occurring in patients with unusual clinical characteristics such as young age or lack of smoking history. There is a strong argument that more comprehensive testing that would include genes for emerging targeted agents should be considered.

The updated draft of the CAP/IASLC/AMP Guideline that was posted for public comments in 2016 recommended (in addition to ALK and EGFR) ROS1, RET, HER2, BRAF and MET to be included in a broad testing panel. We are currently awaiting the final guideline for these additional biomarkers to be published. Testing for genes other than ALK and EGFR is not recommended to be performed as stand-alone tests, but rather as a part of a multigene panel.  ROS1 and RET are translocations that can be detected by FISH, RT-PCR, IHC or NGS. HER2 mutations most frequently occur as insertions in exon 20 and can be detected by mutation detection techniques. They do not correlate with the gene amplification or protein expression and therefore HER2 FISH or IHC should not be performed on the lung cancer specimens. MET gene is more complex and variety of mechanisms of dysregulation of the MET pathway in lung cancer have been reported. Two most important partially overlapping mechanisms include MET exon 14 alterations and MET gene amplification.  Although individual assays (i.e. mutation assays for MET exon 14 mutations or FISH/CISH for MET amplification) can be used, NGS approach seems to be more time and cost-effective.
 
The NGS approach is more efficient than stand-alone sequential assays, particularly in a patient who is known to be negative for some of the more common alterations. Furthermore, some NGS platforms can simultaneously detect mutations, copy number changes and rearrangements. Detection of MET exon 14 alterations can be very challenging for diagnostic testing, because of their diversity (Cui, 2014) (Frampton, 2015). Currently, DNA based broad, hybrid capture NGS is the most frequently used approach. It is worth mentioning   that MET exon 14 variants may not be included in the every NGS platform used in the clinical laboratories.

Therefore, communication between oncologist and pathologists about testing platforms is essential. Although lung cancers with MET exon 14 alterations tend to show high expression of MET by IHC, there are some cases that will be IHC negative despite the presence of mutations (Awad, 2016). More studies are needed to confirm correlation between MET exon 14 alterations and protein overexpression before MET IHC can be used as a screening tool. MET exon 14 alterations are mutually exclusive with other lung cancer driver mutations such as EGFR or KRAS, and have not been associated with acquired resistance to EGFR TKI (Frampton, 2015). In contrast, MET exon 14 mutations can co-exist with MET and MDM2 amplifications. From morphological standpoint, MET exon 14 alterations occur in 3-4% of lung adenocarcinoma, and in 20-30% of sarcomatoid carcinomas (Tong, 2016) (Liu, 2016).

14321

ASCO University
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 17, 2017 9:41 AM

Patient Case #2

Age/Sex: 58-year-old female

Ethnicity: Hispanic

Medical history: Lifelong non-smoker with a history of hyperlipidemia.

June 2016 Record

Prior Treatment History/Response:  Presented in June 2016 with cough and dysphagia, work-up revealed a large right upper lobe mass and bulky right paratracheal adenopathy.

Images/Scans/Pathology:  Bronchoscopy and EBUS demonstrated N2 involvement with a NSCLC, TTF1/napsin positivity confirmed adenocarcinoma histology. EGFR/ALK testing was negative for any alterations. Further work-up including PET/CT and brain MR did not show any further involvement

June 2016 Image

Treatment: She received concurrent chemoradiation with weekly Carboplatin/Taxol followed by consolidation chemotherapy with the same agents for 2 cycles. Treatment was complicated by some esophagitis, anemia and fatigue.

September 2016 Record

Images/Scans/Pathology: Initial post-treatment CT scans in September of 2016 showed a significant response in primary mass and nodes.

September 2016 Image

November 2016 Record

Presenting: Early November she presented with progressive left hip discomfort and evaluation, including a PET/CT and hip MR demonstrated extensive metastatic disease including a large destructive right femoral head mass.

Treatment: Orthopedic surgery pursued internal fixation of femur followed by postop XRT

Images/Scans/Pathology:  While further immune biomarker testing showed PD-L1 TPS score of 0%, expanded molecular testing did reveal a high-level MET amplification in addition to multiple other non-actionable alterations and an intermediate tumor mutation burden. ctDNA testing was also performed confirming presence of MET amplification.

November 2016 Image 1

November 2016 Image 2

Recommendation: Given tumor’s apparent chemo-refractory nature, participation in a study of a novel MET inhibitor was offered

14326

ASCO University
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 17, 2017 9:41 AM

Discussion Questions

1. In what settings is MET amplification emerging as an actionable alteration?
2. What clinical assays are available for the assessment of MET status in lung cancer?

14341

Balazs Halmos, MD
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 24, 2017 11:01 AM

Course Faculty Response

MET has been viewed as a promising treatment target in a multitude of  different cancer settings for many years (Ma, 2005); however, initial studies with several agents (e.g. METMab, tivantinib) did not demonstrate broad activity in patients with advanced NSCLC selected with the use of MET expression as determined by assays, such as IHC (Smyth, 2014).

Recently, more clarity has emerged through the identification of MET exon 14 skipping as a clearly molecularly definable and actionable subset of lung cancers (Ma, 2015) (Borczuk, 2016).

Similarly, data is starting to emerge that suggests that MET amplification can also be another potential biomarker to define tumors with responsiveness to MET-targeting agents.

The first data emerged from the setting of EGFR-mutated lung cancers where MET amplification was validated to be a key bypass mechanism for acquired resistance and at least several case reports had been published to suggest that in such cases dual EGFR/MET inhibition might have value (Engelman, 2007) (Bean, 2007) (Yu, 2013) (Gainor, 2016).

This issue is being addressed now by several carefully designed experimental studies where stringent cut-offs for Met amplification are used. Similarly, over the last few years, a small subset of MET amplified NSCLCs had been identified where MET inhibition has significant activity (Ou, 2011).

Defining cut-offs has been a significant challenge for the field. Recent data suggests that with more stringent cut-offs, the more likely that MET amplification is a sole oncogenic driver; in such cases a high response rate has been observed with the use of MET inhibitors, such as crizotinib (Noonan, 2016). Currently, the prudent approach  is referral of such cases for key ongoing studies, such as the MATCH study for better assessment of true action ability.

14346

Sanja Dacic
Re: Non-Small Cell Lung Cancer (March 2017): Molecular Oncology Tumor Boards
Mar 24, 2017 11:24 AM

Course Faculty Response

For METexon 14 alterations testing see case 1.

De novo MET amplification occurs in 1-5% of lung adenocarcinoma and its prevalence depends on the assay and defined cutoff points. Amplification and polysomy are two main mechanisms that can result in copy number changes. Broad, hybrid capture NGS assays has been increasingly used for detection of gene amplifications (Cheng, 2015). It is essential to compare the sequence of targeted regions from the tumor sample to a diploid normal sample to distinguish between polysomy and gene amplification.  It is also important that NGS platforms are validated against tumor samples with known gene amplifications determined by other methods such as HER2 FISH. NGS approach has a main advantage of providing information about other concurrent genomic alterations that may guide treatment decisions and that could be obtained from the same, frequently limited sample.  Cutoff points vary significantly between the laboratories and platforms, and is something that needs to be standardized.  FISH has been traditionally used for detection of gene amplification in clinical practice.

Currently, there is no guideline for cutoff of MET positivity in lung cancer specimens. Several positivity criteria have been reported such as five or more MET signals per cell (Cappuzzo, 2009), a MET/CEP7 ratio =2 (PathVysion kit) and adopted HER2 criteria for breast cancer. Lack of standardized interpretation criteria complicates comparison of reported studies, particularly in respect to outcomes from therapy.

Furthermore, MET amplification can occur synchronously with other oncogenic mutations such as KRAS, EGFR, BRAF etc in 41 to 63% of the lung cancer cases (Noonan, 2016). However, it has been shown that cases with a high level of amplification defined as MET/CEP7 ratio =5 show no overlap with other oncogenic mutations suggesting that MET amplification is probably a true oncogenic driver (Noonan, 2016).

It is also worth mentioning that about 20% of lung adenocarcinomas with METexon14 mutations also have high-level MET amplification (Awad, 2016) (Paik,2015) (Tong, 2016). Therefore, the choice of assay used for MET TKIs remains to be determined. Cases with METexon 14 mutations without MET amplification show response to MET TKI; however, it is uncertain if MET amplification alone can be used as a predictive biomarker. The proposed CAP/IASLC/AMP guideline does not provide recommendation for MET testing in respect to assay. Therefore, based on available studies testing for both METexon14 mutations and MET amplification may be considered for all MET inhibitors.
 
In this case, liquid biopsy sample showed concordant results with the tissue sample. Liquid biopsy is an evolving approach to noninvasive capture of circulating tumor cells (CTCs) and nucleic acids including cell-free RNA, microRNA, and circulating cell-free DNA (cfDNA), of which a subset may represent circulating tumor DNA. In lung cancer so far, the FDA has approved the cobas EGFR mutation test v2, a blood-based companion diagnostic for Tarceva. No other blood tests for other gene targets have been approved mostly because of low sensitivity (Copin, 2016).