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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 4  |  Page : 678-680
 

Efficacy of crizotinib in ALK mutant non-small cell lung cancers that are positive by IHC but negative by FISH compared to FISH positive cases


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication30-Jul-2018

Correspondence Address:
Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_532_16

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 » Abstract 


BACKGROUND: A small proportion of Non-Small Cell Lung Cancers (NSCLC) are detected with Anaplastic Lymphoma Kinase (ALK) mutation by immunohistochemistry (IHC) but are negative by Fluorescence in situ Hybridization (FISH). Data on responses and outcome of this subset of patients when treated with crizotinib is limited. We analyzed the outcomes of such patients who received crizotinib. PATIENTS AND METHODS: Demographics, treatment details, response to treatment, date of progression and date of death were collected for patients who were IHC positive and FISH negative for ALK mutation from a prospectively maintained database. Depending upon feasibility, patients received either platinum based doublet chemotherapy or the ALK inhibitor crizotinib as first line therapy. Outcomes were compared to our previously published historical cohort of FISH positive patients who were treated with crizotinib. RESULTS: Thirteen patients were detected to be IHC+/FISH- and out of these seven received crizotinib. Objective response rate for crizotinib was 57.15% with an estimated mean PFS of 9.6 months (95% CI 3.8 -15.5 months). The difference in ORR of ALK IHC+/FISH- when compared to our historical cohort of ALK FISH positive treated with crizotinib was not statistically significant (57.15% vs 69.8%; P = 0.265). Estimated mean and median PFS was similar between the two cohorts (median PFS 6.0 months vs 14 months; mean PFS 9.6 months versus 14.7 months; P = 0.467). CONCLUSION: NSCLCs positive for ALK mutation by IHC but not detected by FISH show good response to crizotinib and merit treatment with the same.


Keywords: Anaplastic lymphoma kinase positive, crizotinib, fluorescence in situ hybridization, immunohistochemistry


How to cite this article:
Zanwar S, Noronha V, Joshi A, Patil VM, Kaushal R, Chougule A, Janu A, Mahajan A, Kapoor A, Prabhash K. Efficacy of crizotinib in ALK mutant non-small cell lung cancers that are positive by IHC but negative by FISH compared to FISH positive cases. Indian J Cancer 2017;54:678-80

How to cite this URL:
Zanwar S, Noronha V, Joshi A, Patil VM, Kaushal R, Chougule A, Janu A, Mahajan A, Kapoor A, Prabhash K. Efficacy of crizotinib in ALK mutant non-small cell lung cancers that are positive by IHC but negative by FISH compared to FISH positive cases. Indian J Cancer [serial online] 2017 [cited 2019 Aug 24];54:678-80. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/678/237905





 » Introduction Top


Fluorescence in situ hybridization (FISH) testing using the Vysis ALK Break Apart Probe Kit (2p23/ALK translocation detection, Abbott Molecular, Des Plaines, IL, USA) and immunohistochemistry (IHC) testing with the Ventana Anti-ALK (D5F3) rabbit monoclonal primary antibody (Roche Diagnostics, SW) using the OptiView DAB IHC Detection Kit and the OptiView Amplification Kit (Ventana) are considered standard methods for detecting anaplastic lymphoma kinase (ALK) mutation in lung cancer, and there is good concordance between these two methods.[1],[2],[3] However, there is a subset of patients who are IHC positive and FISH negative (IHC+/FISH−) on testing, which has been recognized as an important issue in recent publications.[4] Data regarding the efficacy of crizotinib in IHC+/FISH− patients are limited. This study tries to understand the efficacy of crizotinib in these patients.


 » Materials and Methods Top


Patient selection

Between July 2014 and December 2015, consecutive patients with ALK-mutant metastatic non-small cell lung cancer (NSCLC) who underwent testing for ALK mutation concurrently with IHC and FISH technique were identified from a prospective lung cancer audit database maintained in the Department of Medical Oncology. The lung cancer audit is an Institutional Ethics Committee-approved observational protocol registered with the Clinical Trials Registry India (registration number: CTRI/2013/01/003335). Patients signed written informed consent before their information was recorded as part of the lung cancer audit. IHC+/FISH− ALK-positive patients were selected from this database. A historical cohort of ALK-mutated NSCLCs that were positive on FISH testing and treated with crizotinib was selected from our previously published data on ALK-mutated NSCLCs for comparison of response rates and progression-free survival (PFS) with the current cohort of IHC+/FISH − patients.[5]

Testing methodology

FISH was the routinely used diagnostic test for the detection of ALK mutation at our center. We started performing IHC testing following its standardization and approval in 2014. In the initial year and a half from the implementation of IHC testing, concurrent FISH testing was also performed to validate the results of IHC testing at our center. Data of patients who concurrently underwent FISH and IHC were retrieved from the database for analysis. The procedure for FISH and IHC testing has been elaborated in our previous publication.[5]

Treatment details

All patients, who could afford the treatment and were deemed fit, with ALK mutation detected by either IHC or FISH were offered targeted therapy with crizotinib. If crizotinib was logistically not feasible, patients received either platinum-based doublet regimen or oral tyrosine kinase inhibitor with palliative intent. Data regarding demography, date of diagnosis, treatment planned, best response to treatment, date of progression, date of death, and date of the last follow-up were collected. Dose modifications and toxicity management were as per the standard practice guidelines. Response assessment was done using contrast-enhanced computed tomography 2–3 months' post start of the therapy. Response was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease using RECIST 1.1 criteria. Objective response rate (ORR) was defined as CR plus PR, and disease control rate (DCR) was defined as CR plus PR plus SD.

Statistical analysis

Descriptive statistics were used for expressing demographic data and response rates. PFS was calculated from the date of start of treatment till date of progression or loss to follow-up or date of death if there was no progression or change in treatment. Data were censored on the last follow-up on September 30, 2016 for analysis. Patients lost to follow-up were censored and considered as progressed at the time of last visit for the purpose of calculation of PFS. Time to event endpoints was calculated using Kaplan–Meier method. Chi-square test with Yates correction was applied for comparing the response rates with the historical cohort of ALK mutation-positive NSCLCs who were positive on FISH testing and treated with crizotinib.


 » Results Top


A total of 13 ALK-mutant metastatic NSCLC patients were positive by IHC and negative by FISH testing. The median age of the cohort was 51 years with a male/female ratio of 6:7. The median follow-up time for the whole cohort was 9.6 months. Seven out of 13 patients received crizotinib at some point in time during their therapy, whereas six patients did not receive crizotinib due to logistic constraints. Among patients not receiving crizotinib, two were offered supportive care only in view of poor performance status and patients unwilling for treatment and four patients received platinum-based doublet therapy as the first line. The demographics, treatment details, response to crizotinib, and outcomes of all the patients are presented in [Table 1].
Table 1: Details of individual patients

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Among patients treated with crizotinib, four out of 7 (57.15%) achieved a PR, one had SD, and two patients progressed at first evaluation giving an ORR of 57.15% and DCR of 71.4%. Three of the four patients achieving PR still continue to be on treatment while one patient was lost to follow-up. The estimated mean PFS for patients receiving crizotinib was 9.6 months (95% confidence interval [CI] 3.8–15.5 months) and estimated median PFS was 6 months (CIs not available due to low number of events). The overall survival data were not mature at the time of analysis.

The ORR for a previously published historical cohort of ALK-mutated NSCLCs with FISH positivity who were treated with crizotinib was 69.8%. The difference in ORR of ALK IHC+/FISH− and FISH-positive cohort was not statistically significant (P = 0.265) [Table 2]. There was no statistically significant difference in the estimated median PFS for patients treated with crizotinib in the IHC+/FISH− group versus the historical cohort of FISH-positive group (median PFS 6 months vs. 14 months; mean PFS 9.6 months versus 14.7 months; P = 0.467) [Figure 1].
Table 2: Comparisonof ORR with historical cohort of FISH positive patients

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Figure 1: Kaplan–Meier survival curve of progression-free survival for patients treated with crizotinib in the immunohistochemistry-positive/fluorescence in situ hybridization-negative group versus the historical cohort of fluorescence in situ hybridization-positive group

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 » Discussion Top


Cases are being reported with discrepancy between IHC and FISH techniques for ALK mutation testing, with discordance ranging from 1% to 10% in various series.[4],[6] There is evidence of activity of crizotinib in the form of case reports in patients positive by IHC but negative by FISH in few reports.[7] However, large series reporting outcomes with crizotinib in this patient population are lacking and its clinical implications remain uncertain. Here, we attempt to report the activity of crizotinib in this group of IHC+/FISH− patients.

The demographic characteristics were similar to the previous reports of ALK-mutated NSCLCs. The ORR to crizotinib in our study was 57.15% and DCR was 71.4%, which is quite similar to the response rates seen in the pivotal PROFILE 1001 trial.[8] There was no statistically significant difference in the ORR compared to our historical cohort of ALK-mutant NSCLCs positive by FISH testing when treated with crizotinib.[5] Activity of crizotinib in this patient population suggests that there are possible mechanisms for failure of FISH to detect the ALK mutation. Some of these IHC+/FISH− cases can be attributable to complex intrachromosomal ALK translocations, which can be missed on FISH but expressing the mutant protein or novel mutations for ALK and represent important shortcomings of FISH testing.[9],[10]

The demonstration of efficacy of crizotinib in IHC+/FISH− cases is of clinical relevance. It will help in exposing these cases to targeted therapy that might have been otherwise deprived of benefit from crizotinib if only FISH-positive cases had been treated with crizotinib. This study reassures us that IHC+/FISH− are responsive to crizotinib and need to be treated with the same.


 » Conclusion Top


NSCLCs positive for ALK mutation by IHC but not detected on FISH show good response to crizotinib and merit treatment with the same.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Alì G, Proietti A, Pelliccioni S, Niccoli C, Lupi C, Sensi E, et al. ALK rearrangement in a large series of consecutive non-small cell lung cancers: Comparison between a new immunohistochemical approach and fluorescence in situ hybridization for the screening of patients eligible for crizotinib treatment. Arch Pathol Lab Med 2014;138:1449-58.  Back to cited text no. 1
    
2.
Minca EC, Portier BP, Wang Z, Lanigan C, Farver CF, Feng Y, et al. ALK status testing in non-small cell lung carcinoma: Correlation between ultrasensitive IHC and FISH. J Mol Diagn 2013;15:341-6.  Back to cited text no. 2
    
3.
Wynes MW, Sholl LM, Dietel M, Schuuring E, Tsao MS, Yatabe Y, et al. An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol 2014;9:631-8.  Back to cited text no. 3
    
4.
Ilie MI, Bence C, Hofman V, Long-Mira E, Butori C, Bouhlel L, et al. Discrepancies between FISH and immunohistochemistry for assessment of the ALK status are associated with ALK 'borderline'-positive rearrangements or a high copy number: A potential major issue for anti-ALK therapeutic strategies. Ann Oncol 2015;26:238-44.  Back to cited text no. 4
    
5.
Noronha V, Ramaswamy A, Patil VM, Joshi A, Chougule A, Kane S, et al. ALK positive lung cancer: Clinical profile, practice and outcomes in a developing country. PLoS One 2016;11:e0160752.  Back to cited text no. 5
    
6.
Cabillic F, Gros A, Dugay F, Begueret H, Mesturoux L, Chiforeanu DC, et al. Parallel FISH and immunohistochemical studies of ALK status in 3244 non-small-cell lung cancers reveal major discordances. J Thorac Oncol 2014;9:295-306.  Back to cited text no. 6
    
7.
Sun JM, Choi YL, Won JK, Hirsch FR, Ahn JS, Ahn MJ, et al. A dramatic response to crizotinib in a non-small-cell lung cancer patient with IHC-positive and FISH-negative ALK. J Thorac Oncol 2012;7:e36-8.  Back to cited text no. 7
    
8.
Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol 2012;13:1011-9.  Back to cited text no. 8
    
9.
Togashi Y, Mizuuchi H, Kobayashi Y, Hayashi H, Terashima M, Sakai K, et al. An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer. Ann Oncol 2015;26:1800-1.  Back to cited text no. 9
    
10.
Sholl LM, Weremowicz S, Gray SW, Wong KK, Chirieac LR, Lindeman NI, et al. Combined use of ALK immunohistochemistry and FISH for optimal detection of ALK-rearranged lung adenocarcinomas. J Thorac Oncol 2013;8:322-8.  Back to cited text no. 10
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

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