|Year : 2017 | Volume
| Issue : 1 | Page : 280-284
Repeat biopsy in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer: Feasibility, limitations, and clinical utility in Indian patients
S Zanwar1, V Noronha1, A Joshi1, VM Patil1, A Chougule2, R Kumar3, S More1, S Goud1, A Janu4, A Mahajan4, K Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Molecular Laboratory, Mumbai, Maharashtra, India
3 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||1-Dec-2017|
Dr. K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
INTRODUCTION: The feasibility and success rate of repeat biopsy for epidermal growth factor receptor (EGFR) mutation-positive lung cancers that have progressed on tyrosine kinase inhibitors (TKIs) are varied and merits further assessment. MATERIALS AND METHODS: EGFR mutation-positive lung cancers were offered repeat biopsy upon progression on TKIs. Two groups of patients, first one on a clinical trial and second one from a database, were included for analysis. The feasibility to perform a repeat biopsy was analyzed in the first group. Success rate of biopsy and tissue adequacy for molecular testing was analyzed in both groups. Descriptive statistics were used for analyzing the demography, EGFR mutation type, tissue adequacy, and molecular profile at repeat biopsy. Kolmogorov–Smirnov test was used to assess normality of data. Two sample t-tests were used for comparison of proportions. RESULTS: The feasibility of undergoing repeat biopsy was 77% (95% confidence interval [CI] of 69.4%–83.5%) in the first group (114/148 patients). Feasibility was not analyzed in the second group of patients. Out of 196 patients who underwent a repeat biopsy, 154 patients (78.6%; 95% CI: 72.2%–84.1%) had tumor tissue adequate for performing molecular testing. 27/196 (13.8%) patients did not have any evidence of malignancy on repeat biopsy whereas 15/196 (7.6%) patients had scanty tissue on repeat biopsy prohibiting molecular testing. Six patients (3.06%; 95% CI: 1.1%–6.5%) had small cell transformation. T790M mutation was detected in 12 out of the 42 patients (28.6%; 95% CI: 15.7–44.6) in whom EGFR testing was performed on repeat biopsy specimen. CONCLUSION: Repeat biopsy was able to provide adequate tissue acquisition in only two-thirds of the patients. Liquid biopsy represents an important tool to bridge this gap.
Keywords: Epidermal growth factor receptor mutation, rebiopsy success rate, repeat biopsy, T790M
|How to cite this article:|
Zanwar S, Noronha V, Joshi A, Patil V M, Chougule A, Kumar R, More S, Goud S, Janu A, Mahajan A, Prabhash K. Repeat biopsy in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer: Feasibility, limitations, and clinical utility in Indian patients. Indian J Cancer 2017;54:280-4
|How to cite this URL:|
Zanwar S, Noronha V, Joshi A, Patil V M, Chougule A, Kumar R, More S, Goud S, Janu A, Mahajan A, Prabhash K. Repeat biopsy in epidermal growth factor receptor mutation-positive nonsmall cell lung cancer: Feasibility, limitations, and clinical utility in Indian patients. Indian J Cancer [serial online] 2017 [cited 2019 Aug 19];54:280-4. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/280/219568
| » Introduction|| |
Tumor tissue acquisition is vital for personalized medicine approach in cancer. Epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) represents an important example of this approach. Despite the substantial progress made in the first-line treatment of these patients, majority will have disease progression at 8–14 months with EGFR directed therapies., Molecular and histologic analyses have identified various mechanisms of resistance leading to progression on tyrosine kinase inhibitors (TKIs)., A repeat biopsy at progression can play a critical role in directing further treatment of these patients as a substantial proportion of these mutations can be targeted with specific drugs., Success rates of repeat biopsy in acquiring tissue for molecular testing and subsequent impact on therapy have varied in previous reports., This study analyses the feasibility and success rate of repeat biopsy for pathologic and molecular testing.
| » Materials and Methods|| |
Between 2012 and 2016, EGFR mutation-positive NSCLCs treated at our center that had progressed on TKIs in any line were evaluated for the potential of a repeat biopsy at the time of progression. This cohort included two groups of patients. First group was that of patients who were being treated on a randomized clinical trial that was being conducted at our center. Their data, including the reasons for inability to perform a repeat biopsy, were collected prospectively. The second group included patients who were part of a database maintained by the Medical Oncology Department of thoracic disease management group. This is depicted in [Figure 1].
The decision to offer repeat biopsy in this group was based on the treating physician. The reasons for inability to perform a repeat biopsy in this group were not recorded prospectively. The denominator for analyzing feasibility of repeat biopsy is not available for the second group and has not been included for the analysis of feasibility of repeat biopsy. T790M mutation analysis was performed in the second group for patients who were potentially amenable for treatment with osimertinib.
Histology and epidermal growth factor receptor testing
All patients were histologically proven NSCLCs at baseline. EGFR mutation testing methodology has been described in detail in our previous publications., Repeat biopsy was offered at the time of progression as defined by the Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 criteria. At repeat biopsy, immunohistochemistry was used to supplement microscopic findings to determine the histology. Tissue adequacy for molecular testing was assessed by a dedicated thoracic oncopathologist. In 12 cases, cytological analysis showed malignancy and a cell block was prepared for molecular analysis purpose. Patients with only cytology done at progression were not included in the study.
Descriptive statistics were used for analyzing the demography, EGFR mutation type, tissue adequacy, and molecular profile at repeat biopsy. Microsoft Office Excel 2016 was used for descriptive analysis. Kolmogorov–Smirnov test was used to assess normality of data for tissue adequacy when repeat biopsy was performed from site/organ of progression or from other sites and baseline EGFR mutation type and its association with acquisition of T790M mutation. Two sample t-tests were used to compare tumor tissue adequacy when repeat biopsy was performed from site/organ of progression or elsewhere and rate of acquisition of T790M mutation with baseline EGFR mutation type.
| » Results|| |
Feasibility of repeat biopsy
One hundred and forty-eight EGFR mutation-positive patients in the first group of patients were offered a repeat biopsy at progression out of which 114 ultimately underwent the procedure. Thus, the feasibility of undergoing repeat biopsy was 77% (95% confidence interval [CI] of 69.4%–83.5%). Among the 34 patients who did not undergo a repeat biopsy, major reasons were patient refusal in 15 (44.1%) cases, technically difficult biopsy in 10 (29.4%) cases (8 - very small lesion, 1 - intracranial disease, 1 - preexisting hydropneumothorax), poor performance status at the time of progression in 6 (17.6%) cases, and clinician cancelling the procedure due to patient being symptomatic for disease and not stable enough to wait for the procedure in 3 (8.8%) cases. In the second group, 82 EGFR mutation-positive patients underwent repeat biopsy at progression on TKIs. In this group, the denominator (number of patients evaluated for repeat biopsy) was not available, and hence, feasibility of repeat biopsy was not analyzed. All patients, except one who underwent excision of fractured neck femur with placement of prosthesis, underwent nonsurgical procedures for tumor tissue acquisition at progression. In all the subsequent analysis, both the groups were combined. The demographics, baseline characteristics, EGFR mutation type, and site of repeat biopsy are shown in [Table 1]. There was a steady increase in the number of repeat biopsies performed each year over the course of the last 5 years [Figure 2]. This trend was more pronounced among the patients in group two. Sites of repeat biopsy are shown in [Figure 3].
Tissue adequacy and impact of site of biopsy
A total of 196 patients underwent a repeat biopsy. Out of these, 154 patients (78.6%; 95% CI: 72.2%–84.1%) had tumor tissue adequate for performing molecular testing. 27/196 (13.8%) patients did not have any evidence of malignancy on repeat biopsy whereas 15/196 (7.6%) patients had scanty tissue on rebiopsy prohibiting molecular testing. Among patients undergoing rebiopsy, six patients (3.06%; 95% CI: 1.1%–6.5%) had small cell transformation on rebiopsy. The findings of histopathology on rebiopsy are shown in [Table 2].
182 of 196 patients managed to undergo biopsy from the site/organ of progression. Among the 16 patients where biopsy was not performed from site of progression, 13 (81.2%; 95% CI: 54.4%–96%) patients had adequate tissue for molecular testing. Among the 182 rebiopsies performed from site/organ of progression, 141 (77.47%; 95% CI: 70.7%–83.3%) had tissue adequate for molecular testing. There was no statistically significant difference in the rates of tissue adequacy whether rebiopsy was performed from the site/organ of progression or not (P = 0.728). Among 12 patients in whom cell block preparation was used for testing adequacy of tumor tissue, 7 patients (58.3%; 95% CI: 27.7%–84.8%) had tissue adequate for molecular testing. All five cell block preparations where tissue was inadequate were from pleural fluid.
Mutational profile at recurrence
Among the 82 patients who were being treated in the clinic and underwent repeat biopsy, repeat EGFR testing was performed in 42 patients. T790M mutation was detected on 12/42 (28.6%; 95% CI: 15.7%–44.6%). The details of EGFR testing along with baseline EGFR status are shown in [Table 3]. There was no statistically significant association between acquisition of T790M resistant mutation and presence of baseline EGFR exon 19 or exon 21 mutation (P = 0.150). The mutational profile analysis of 114 patients who underwent repeat biopsy while on a clinical trial is being conducted as a separate project.
|Table 3: Epidermal growth factor receptor mutation status at repeat biopsy with corresponding epidermal growth factor receptor mutation at baseline|
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Serious complication rates of rebiopsy procedure
Out of 164 patients who underwent rebiopsy from lung or pleura, there was no report of any serious pneumothorax requiring chest tube placement or severe pulmonary hemorrhage. There was no incidence of postprocedure hospitalization due to complications.
| » Discussion|| |
Extensive translational research on the tumor specimens' postprogression has elucidated various mechanisms for the development of resistance. The presence of T790M mutation is the most common mechanism of resistance accounting for approximately half of the cases at progression with MET mutation, HER2 mutation, and small cell transformation accounting for the other prominent mutations.,, The fact that most of these targets are amenable to inhibition by specific drugs makes molecular profiling critically important in the management of these patients.,,,, An obvious limitation in performing a repeat biopsy is the invasive nature of the procedures involved. Bronchoscopy or computerized tomography (CT)-guided procedures are the commonly used techniques for sampling. These procedures, although relatively safe, carry the risk of pneumothorax and pulmonary bleeding among others. Furthermore, acquiring adequate tissue at the time of repeat biopsy for performing molecular testing can be a challenge. Success rates of repeat biopsy have varied between 70% and 95% in previous reports.,,, Furthermore, the improvement in techniques of liquid biopsy in the past few years has meant that there is a potential to do away with an invasive procedure.,,, Thus, performing an invasive procedure should be undertaken when there is evidence of a substantial impact on clinical decision-making.
In our study, 34 patients could not undergo a repeat biopsy due to various reasons elaborated earlier. Out of the remaining 196 patients, only 154 had tissue that was adequate for molecular testing. Thus effectively, repeat biopsy was not able to address the issue of tissue acquisition in 33% (76/230) of the cases. In one of the largest series of repeat biopsy at progression on EGFR directed therapy, Nosaki et al. reported a success rate of 79.5%. The success rate in this study was reported as the number of patients in whom tumor cells were detected out of the number of patients who underwent a biopsy. However, a key aspect to understand here is that patients who have refused a rebiopsy considering the invasive nature of the procedure or did not undergo a rebiopsy due to technical constraints are not accounted for by this method of assessment of success rate. Indeed, this is what was seen in a previous prospective study of repeat biopsy, wherein 25.4% (94/126) patients did not undergo a repeat biopsy after careful review of CT scans. Moreover, only 75/94 patients had adequate tissue on rebiopsy. Thus effectively, repeat biopsy managed to provide adequate tissue acquisition for molecular testing in only 60% (75/126) cases in this study. In another prospective study looking at feasibility and clinical impact of repeat biopsy, 19.5% patients could not undergo the procedure. Among those who underwent a repeat biopsy, 25.6% had insufficient tissue for testing and a repeat biospy an overall clinical impact of 30.4% in terms of deciding further therapy.
These high percentages where repeat biopsy is unable to address tissue acquisition are a concern. The improvements in techniques of liquid biopsy hope to bridge this gap. Liquid biopsy, using the cobas EGFR mutation test v2, has been approved by the United States Food and Drug Administration in newly diagnosed NSCLCs for detecting EGFR mutation has been approved in newly diagnosed NSCLCs. Compared to activating EGFR mutations, there are concerns regarding the lower concordance rate of T790M detection in liquid biopsy compared with tissue. However, with use of techniques such as the BEAMing digital polymerase chain reaction, the concordance rate and sensitivity seem to be reasonable with studies reporting concordance rates of 70%–80% for detection of T790M compared with tissue., Thus, liquid biopsy is an important tool in the setting of progression on TKIs and may well supplant tissue biopsy in the years to come.
The T790M mutation rate in our study was 28.6% (95% CI: 15.7%–44.6%) which is lower to previously reported literature.,, However, the lower numbers meant that CIs were wide. Although T790M was more commonly detected in patients with baseline exon 19 mutation compared to exon 21, this difference did not reach statistical significance. The rate of small cell transformation was 3.1% in our study. This figure is comparable to that reported in recent large studies., There is a steady increase seen in the number of patients who are treated in the clinic that are being offered a repeat biopsy, suggesting the growing awareness and importance of the same among treating physicians. There was no serious complication requiring hospitalization due to the biopsy procedures in this cohort. At our center, we have performed over 10,000 CT-guided biopsies over the past 6 years. There has not been a single mortality with the rate of pneumothorax requiring pigtail insertion was 2.9% (unpublished data). CT-guided biopsy seems to be a relatively safe procedure in experienced hands. The key issue, however, is the relatively inability to offer it to all the patients. In our study, the major reason for not undergoing a repeat biopsy was patient refusal in 44%, thereby emphasizing the need for noninvasive options. The site of biopsy, whether from progression or elsewhere, does not seem to impact tissue acquisition.
| » Conclusion|| |
Repeat biopsy, although extremely important in guiding treatment at progression on TKIs in EGFR mutated NSCLCs, was able to provide adequate tissue acquisition in only two-third of the patients. Liquid biopsy represents an important tool to bridge this gap.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al.
Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al.
Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7.
Jekunen AP. Role of rebiopsy in relapsed non-small cell lung cancer for directing oncology treatments. J Oncol 2015;2015:809835.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al.
Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N
Engl J Med 2017;376:629-40.
Yoshimura K, Inui N, Karayama M, Inoue Y, Enomoto N, Fujisawa T, et al.
Successful crizotinib monotherapy in EGFR-mutant lung adenocarcinoma with acquired MET amplification after erlotinib therapy. Respir Med Case Rep 2017;20:160-3.
Chouaid C, Dujon C, Do P, Monnet I, Madroszyk A, Le Caer H, et al
. Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: A prospective multicenter study in a real-world setting (GFPC study 12-01). Lung Cancer Amst Neth 2014;86:170-3.
Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N, et al.
Re-biopsy status among non-small cell lung cancer patients in Japan: A retrospective study. Lung Cancer 2016;101:1-8.
Chougule A, Prabhash K, Noronha V, Joshi A, Thavamani A, Chandrani P, et al.
Frequency of EGFR mutations in 907 lung adenocarcioma patients of Indian ethnicity. PLoS One 2013;8:e76164.
Noronha V, Prabhash K, Thavamani A, Chougule A, Purandare N, Joshi A, et al.
EGFR mutations in Indian lung cancer patients: Clinical correlation and outcome to EGFR targeted therapy. PLoS One 2013;8:e61561.
Kuiper JL, Heideman DA, Thunnissen E, Paul MA, van Wijk AW, Postmus PE, et al.
Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer 2014;85:19-24.
Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol 2016;9:34.
Peters S, Zimmermann S. Targeted therapy in NSCLC driven by HER2 insertions. Transl Lung Cancer Res 2014;3:84-8.
Waqar SN, Morgensztern D, Sehn J. MET mutation associated with responsiveness to crizotinib. J Thorac Oncol 2015;10:e29-31.
Manhire A, Charig M, Clelland C, Gleeson F, Miller R, Moss H, et al.
Guidelines for radiologically guided lung biopsy. Thorax 2003;58:920-36.
Kirita K, Izumo T, Matsumoto Y, Hiraishi Y, Tsuchida T. Bronchoscopic re-biopsy for mutational analysis of non-small cell lung cancer. Lung 2016;194:371-8.
Alix-Panabières C, Pantel K. Circulating tumor cells: Liquid biopsy of cancer. Clin Chem 2013;59:110-8.
Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al.
Detection of mutations in EGFR in circulating lung-cancer cells. N
Engl J Med 2008;359:366-77.
Diaz LA Jr., Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol 2014;32:579-86.
Rolfo C, Castiglia M, Hong D, Alessandro R, Mertens I, Baggerman G, et al.
Liquid biopsies in lung cancer: The new ambrosia of researchers. Biochim Biophys Acta 2014;1846:539-46.
Yoon HJ, Lee HY, Lee KS, Choi YL, Ahn MJ, Park K, et al.
Repeat biopsy for mutational analysis of non-small cell lung cancers resistant to previous chemotherapy: Adequacy and complications. Radiology 2012;265:939-48.
Wang W, Song Z, Zhang Y. A Comparison of ddPCR and ARMS for detecting EGFR T790M status in ctDNA from advanced NSCLC patients with acquired EGFR-TKI resistance. Cancer Med 2017;6:154-62.
Karlovich C, Goldman JW, Sun JM, Mann E, Sequist LV, Konopa K, et al.
Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase i study of rociletinib (CO-1686). Clin Cancer Res 2016;22:2386-95.
Thress KS, Brant R, Carr TH, Dearden S, Jenkins S, Brown H, et al.
EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer 2015;90:509-15.
Ko R, Kenmotsu H, Serizawa M, Koh Y, Wakuda K, Ono A, et al
. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. BMC Cancer 2016;16:864.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]