Lung Cancer (April 2018): Molecular Oncology Tumor Boards

ASCO University
Apr 11, 2018 9:13 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).

A new case will be presented every other month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Lynette Sholl (Pathologist from Brigham and Women’s Hospital) and Apar Ganti (Medical Oncologist from University of Nebraska Medical Center).

This discussion is built upon a hypothetical, lung cancer 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.

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Comments

15521

ASCO University
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 11, 2018 9:14 AM

Patient Case

A 70-year-old never smoker male patient was in his normal state of health until approximately 2 months ago when he developed progressively worsening low back pain. He did not have any radiating symptoms of sciatica, lower extremity weakness, incontinence or saddle anesthesia. He was then referred to Orthopedic Surgery for further evaluation. He had a lumbar spine MRI that displayed multiple lesions. A biopsy of the lumbar spine confirmed adenocarcinoma, most likely, lung primary. Immunostaining showed that the tumor was diffusely positive for keratins (AE1/3, K903 and CK7), TTF-1 and napsin, and negative for CK20, PSA, PAP, CDX-2, CD10, ERG and CD45.  CT scan showed mediastinal and hilar adenopathy, micro-nodularity in the lung along with patchy consolidation in the lower lobes. He was started on palliative radiation to his lumbar spine for pain control. He received a lung biopsy, which was positive for rearrangement of the ALK (2p23) locus (40.5%). He was started on crizotinib and showed a partial response. His functional status improved significantly (PS ECOG -2 to ECOG – 0 in about 3 months) and he remained on it for 20 months.

15526

ASCO University
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 11, 2018 9:14 AM

Discussion Questions

1. What is the optimal specimen for molecular testing?
2. Should testing for ALK translocation be conducted?
3. What is the optimal first line therapy for ALK-translocated lung cancer?

15531

Anis Toumeh, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 11, 2018 6:54 PM

1- I usually try to target a non-bony lesion in order to avoid not having adequate tissue for testing with the decalcification process with bone biopsies. 

2- I prefer to send NGS for metastatic non small cell carcinomas of the lung. If NGS is not available or can not be done for some reason, then testing for EGFR, ALK, ROS1 and BRAF along with PD-L1 should be done. Testing for MET exon 14 and HER2 could be helpful mostly for clinical trials purposes

3- I am quite impressed with the ALEX / J-ALEX data and now I prefer to use Alectinib as first line in ALK positive cases

15536

Youxin Ji
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 12, 2018 3:12 AM

1. bony specimen can be used for molecular testing if other sample is not available.

2. For ALK rearrangement, I perfer IHC, it's simple and unexpensive. For tiny tissue or diffcult to obtain tissue, NGS is a good choice.

3. According to ALEX of J-ALEX, Alectinib in first-line therapy is an optimal method for benefit patient's survival, and may reduce the posibility of brain metastasis in the future.

15541

Satyanarayan K. Reddy, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 12, 2018 10:42 AM

Our pathologists tell us that soft tissue component associated with bone metastases could be used for molecular testing (where you do not need decalcification process).  Any further comments on this issue, specifically, can you do NGS on decalcified tissue? 

15551

Lynette M. Sholl, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 16, 2018 9:11 AM

Course Faculty Response

The patient was initially diagnosed with metastatic carcinoma based on a bone biopsy.  In the pathology laboratory, bone specimens must undergo some form of chemical treatment to dissolve calcium salts before the sample is sectioned for histopathologic evaluation.  Many labs have historically relied on the use of strong acids to rapidly decalcify specimens, however these low pH substances (including hydrochloric acid and nitric acid) degrade cellular proteins and nucleic acids and therefore may interfere with immunohistochemical, cytogenetic, and molecular assays.  As a result, molecular testing guidelines discourage the use of decalcification agents for specimens that require biomarker testing and many patients, as in this scenario, may need to undergo a repeat biopsy of a soft tissue or visceral site to obtain adequate tissue for molecular testing (Lindeman, et al). Alternatively, when bone biopsies are obtained for a suspicion of metastatic carcinoma, laboratories may consider used a neutral-pH chelating agent such as EDTA; EDTA-based decalcification solutions are less efficient than those using acids but can effectively remove calcium salts from small core needle biopsies in a relatively short period of time while preserving protein antigenicity and nucleic acid integrity.  Studies of breast cancer samples undergoing neutral decalcification indicate that quantitative immunohistochemistry (IHC) and fluorescence in in situ hybridization (FISH) results are comparable to those for standardly processed formalin-fixed paraffin embedded (FFPE) tissue (Schrijver, et al).  The need for any decalcification can be circumvented entirely by performing cytology-type touch preps or smears of the bone specimen; these can be stained to confirm adequate tumor cellularity and then used directly for nucleic acid extraction or for FISH or IHC. These types of cytology preparations do not require formalin fixation—methanol fixation is commonly used instead—and as a result may actually have superior quality nucleic acids than FFPE samples.  Current molecular testing guidelines advise that such cytology preparations may be used in lieu of other samples such as core biopsies or cell blocks, however individual laboratories should ensure that each sample type accepted for testing is specifically evaluated in the course of assay validation.  In patients with an established diagnosis of lung adenocarcinoma but whose tumor specimens are inadequate for molecular testing, plasma-based next generation sequencing may be considered to determine the status of essential biomarkers, however this is recognized to have inferior sensitivity relative to tumor tissue testing.  

EGFR and BRAF mutation as well as ALK and ROS1 rearrangement testing is advised for all patients with a new diagnosis of advanced non-squamous non-small cell lung carcinoma.  ALK rearrangements are found in about 3-5% of this population; the relative rarity of this event poses some operational challenges for laboratories.  FISH, the historic gold standard test for identification of patients for ALK targeted therapy, is a relatively expensive and labor-intensive technique, and the common EML4-ALK fusion associated with oncogenic activity in lung cancers results from an intrachromosomal inversion event that can be difficult to interpret in clinical practice.  Therefore, alternative approaches such as IHC, PCR, and sequencing have been widely adopted in practice.  Immunohistochemistry, in particular, can be readily implemented in surgical pathology laboratories, is typically less expensive than FISH, and facilitates reflexive testing protocols.  Using established antibodies (5A4 or D5F3) with well-validated protocols, ALK IHC generates a binary readout, with fusion negative cases showing no staining and fusion positive cases typically showing diffuse and often strong cytoplasmic staining.  Pooled analyses of studies examining the performance characteristics of ALK IHC show a sensitivity of 97% and specificity of 99% relative to FISH (Lindeman, et al).  Small studies of IHC-FISH discrepant cases tend to show that FISH+/IHC- tumors do not respond to ALK inhibitor therapy and the FISH results in these cases likely represent nonspecific structural variants that interrupt the FISH probe binding sites (Gao, et al). ALK IHC is, therefore, considered to be robust enough to serve as a standalone predictive marker and indeed one ALK IHC assay has been approved as a companion diagnostic for both crizotinib and alectinib.  Molecular assays, including hybrid capture DNA-based next generation sequencing or RNA-based sequencing, reverse-transcriptase PCR, or anchored-multiplex PCR, also appear to be effective in the detection of ALK rearrangements.  An ALK rearrangement event detected using one of these methods, assuming it shows a predicted functional, in-frame fusion (e.g., retained ALK kinase domain in the same reading frame as the fusion partner), can generally be considered to be a true positive.  Sequencing and PCR-based methods can, however, be falsely negative if the fusion involves unusual gene breakpoints not covered by a targeted assay.  

In general, many molecular diagnostics laboratories require at least 20% tumor cell content in any tissue specimen, however individual labs may develop targeted assays that detect mutations and structural variants in specimens with lower tumor content.  NCCN guidelines recommend up-front testing of any non-squamous non-small cell carcinoma for EGFR, BRAF, ALK, ROS1, and PD-L1; reporting of the PD-L1 tumor proportion score requires at least 100 tumor cells, thus providing a minimal absolute requirement for biomarker testing.

15556

Apar Kishor Ganti, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 16, 2018 9:12 AM

Course Faculty Response

The last few years have seen a tremendous increase in our understanding of the molecular pathogenesis of lung cancer, especially adenocarcinoma. The identification of driver mutations has led to the development of new agents targeting these molecular pathways. Based on clinical trial data with these agents, molecularly targeted agents are the recommended treatment options for patients with metastatic lung cancer whose tumors harbor these driver mutations. Therefore, it is important to test for molecular abnormalities prior to initiation of therapy for metastatic lung adenocarcinoma. This is especially important in patients who have never smoked or have a light/remote history of smoking, since the more common abnormalities (i.e., EGFR activating mutations and ALK translocations) are seen in never/light smokers.

Since this patient has evidence of a rearrangement of the ALK (2p23) locus in his tumor, he would be a candidate for therapy with an ALK inhibitor. ALK inhibitors have been shown to be superior to chemotherapy in terms of PFS, but not OS, for these patients. Crizotinib was the first drug approved for this population based on the results of the PROFILE 1004 study comparing crizotinib to platinum-pemetrexed chemotherapy (Solomon, et al). In this study of 343 patients, crizotinib had a superior progression-free survival (PFS) compared to cytotoxic chemotherapy (10.9 vs. 7 months). There was however no difference in overall survival. Since then, there have been two other randomized phase III studies in patients with treatment naïve, ALK rearrangement positive non-small cell lung cancer. The ASCEND-4 trial compared ceritinib, a second-generation ALK inhibitor to chemotherapy (Soria, et al). Ceritinib was associated with a doubling of PFS (16.6 vs. 8.1 months). The ALEX study compared alectinib with crizotinib and found a significant improvement in PFS with alectinib (25.7 vs. 10.4 months; HR - 0.47; 95% CI, 0.34 to 0.65) (Peters, et al). Based on these results, the current NCCN guidelines list all three agents as being appropriate for the up-front management of ALK positive non-small cell lung cancer, but based on the improved PFS and better side effect profile seen in the ALEX study, alectinib has become the preferred therapeutic option amongst the three agents.

15561

ASCO University
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 16, 2018 9:13 AM

Patient Case Update

He developed progression and received palliative radiation to C2-3 vertebrae and 1st rib. He was switched to ceritinib and remained on it for 15 months. He had some problems with diarrhea and abdominal pain, but these symptoms improved gradually and he was able to tolerate the full dose. He then developed progressive disease, including development of brain metastases. He received palliative radiation to his whole brain left hemipelvis. He was then started on nivolumab and received six doses of that without a response. His performance status worsened and he succumbed to his disease 45 months after initial diagnosis.

15566

ASCO University
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 16, 2018 9:14 AM

Discussion Questions

1. What is the role of biopsy at progression?
2. What is the optimal choice of second-line therapy following failure of first-line options?
3. What is the role of checkpoint inhibitors in ALK-translocated lung cancer?

15576

Anis Toumeh, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 16, 2018 6:46 PM

I believe that, whenever possible, rebiopsy at progression should be standard for those progressing on ALK inhibitors. This helps identifying resistant mechanisms and mutations that may aid in selecting the next ALK inhibitor 

 

 

15581

Lynette M. Sholl, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 20, 2018 9:17 AM

Course Faculty Response

The mechanisms responsible for resistance in the setting of ALK-targeted therapy are diverse and including “on-target” ALK gene kinase domain mutations and amplification and “off target” alterations affecting other oncogenic pathways. ALK kinase domain mutations emerge in about 20-50% of patients at relapse and depend on the type of ALK inhibitor in use. The resistance conferred by some of the recognized mutations can be overcome with the use of an alternative ALK inhibitor (Gainor, et al). Other patients with relapsed/progressive disease and no detectable resistance mutation may respond to an alternative ALK inhibitor.  Given the lack of clear evidence suggesting a benefit for routine ALK resistance mutation testing, current biomarker testing guidelines do not recommend routine re-biopsy at the time of relapse following ALK targeted therapy (Lindeman, et al).

Retrospective analyses of patients receiving immune checkpoint inhibitor therapy for NSCLC have shown relative lack of benefit in patients with EGFR mutations or ALK rearrangements. Reasons for this lack of benefit are not fully established, but may be a reflection of the lower mutational rate in tumors with these alterations.  PD-L1 expression does not appear to be predictive of response to checkpoint blockade in ALK-rearranged tumors, possibly due to a relative lack of concomitant cytotoxic T cell infiltration (Gainor, et al).

15586

Apar Kishor Ganti, MD
Re: Lung Cancer (April 2018): Molecular Oncology Tumor Boards
Apr 20, 2018 9:18 AM

Course Faculty Response

Similar to the experience with EGFR TKIs, most patients develop resistance to ALK TKIs, especially crizotinib, after a while. However contrary to the EGFR mutation positive lung cancers, where most common mechanism of resistance is the development of resistance mutations in the EGFR gene, acquired secondary mutations within the ALK tyrosine kinase domain are seen in only about 20% of patients who develop resistance to crizotinib (Gainor, et al). The most common mutation seen after crizotinib is the L1196M mutation, while other common mutations include G1269A, C1156Y and I1171T/N/S. The common mutations seen after ceritinib use are G1202R, F1174C/L and V1180L mutations and deletion of G1202, while S1206Y, E1210K are commonly seen after alectinib use. Lorlatinib, an ALK inhibitor currently under investigation appears to have activity against many of these mutations.  

Currently patients who fail one ALK inhibitor may be treated with another agent and a repeat biopsy at progression is not routinely recommended. However, that may change with increased understanding of the resistance mechanisms. A recent case report described a patient who developed resistance to crizotinib, who did not respond to a second-generation agent, but did respond to lorlatinib (Shaw, et al). When the patient progressed on lorlatinib, the tumor was found to harbor an ALK mutation that predicted for sensitivity to crizotinib. The patient was treated with crizotinib with clinical response.

A retrospective analysis of EGFR-mutated and ALK-positive patients who received PD-1/PD-L1 inhibitors, found a response rate of 3.6% (Gainor, et al). The number of ALK-positive patients included in the large phase III trials of the PD-1/PD-L1 inhibitors are too small to make any specific conclusions regarding the efficacy in this sub-group. While there have been some reports speculating that the lack of response may be due to low PD-L1 expression in these tumors with oncogenic drivers, the data on PD-L1 expression in ALK positive patients are contradictory. A more plausible explanation for the lack of effect may be the presence of a lower tumor mutation burden in ALK-positive lung cancer.


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