\\MENT OF HEALTH & HUMAN
SERVICES . USA
Published in final edited form as: Clin Genitourin Cancer. 2015 February ; 13(1): e19-e26. doi:10.1016/j.clgc.2014.06.017.
MET abnormalities in patients with genitourinary malignancies and outcomes with c-MET inhibitors
Denis L. F. Jardim1, Débora de Melo Gagliato1, Gerald Falchook1, Ralph Zinner1, Jennifer J. Wheler1, Filip Janku1, Vivek Subbiah1, Sarina A. Piha-Paul1, Siqing Fu1, Nizar Tannir2, Paul Corn2, Chad Tang3, Kenneth Hess4, Sinchita Roy-Chowdhuri4, Razelle Kurzrock5, Funda Meric-Bernstam1, and David S. Hong, MD1
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, USA
2Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
3Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
4Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
5Department of Medicine, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, USA
Abstract
Purpose-To determine the prevalence of MET amplification and mutation among genitourinary (GU) malignancies and its association with clinical factors and responses to c-MET inhibitors.
Methods-Patients with genitourinary (GU) malignancies referred to the Phase I Clinic were evaluated for MET mutation and amplification and outcomes on protocols with c-MET inhibitors.
Results-MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 RCC [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients testing positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild-type MET). Median overall
Corresponding author: Denis L. F. Jardim, MD, Department of Investigational Cancer Therapeutics; The University of Texas MD Anderson, Cancer Center; 1515 Holcombe Blvd., FC8.3050, Box 0455; Houston, TX 77030, denis.ljardim@hsl.org.br; Phone 713-563-5844; Fax 713-563-0566.
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survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio [HR] = 2.8; 95% CI, 1.1 to 6.9; P =. 034). Twenty-nine (25%) patients were treated on a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (0.4 - 19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment.
Conclusion-MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs.
Graphical abstract
MET mutation and/or amplification can be found in diverse GU malignancies, and is potentially targetable. We explored the prevalence of MET abnormalities and its association with demographics and targeted therapy response in patients with GU tumors. We found that patients with a MET alteration present poor survival in a phase I setting. Although c-MET inhibitors showed activity, efficacy of these drugs was more pronounced when combined with other targets and in the absence of MET alterations.
Keywords
bladder cancer; c-MET inhibitor; MET mutation; MET amplification; prostate cancer; renal cell cancer
Introduction
The MET oncogene encodes a transmembrane receptor with intrinsic tyrosine kinase activity.1 The c-MET receptor is activated by its physiological ligand, hepatocyte growth factor (HGF)2, leading to downstream signaling events involved in cancer growth, migration, metastasis and angiogenesis.3-5 Recent data have shown that many solid tumors display MET/HGF pathway deregulation, actuated by various mechanisms, including c-MET overexpression, MET mutation, amplification and increased HGF secretion by the tumor microenvironment.6-9
Genitourinary (GU) malignancies frequently involve c-MET deregulation. In prostate cancer, c-MET overexpression is associated with higher Gleason grade and development of resistance to anti-hormonal therapies.10,11 MET mutations are described both in hereditary and sporadic papillary renal cell carcinoma (RCC)12; in addition, MET amplification and overexpression is a newly described mechanism of resistance in RCC patients undergoing VEGFR inhibitor treatment.13,14 In bladder cancers, phosphorylation of HGF/c-MET is associated with the development of metastasis and poor survival.15 c-MET inhibitors are currently being tested for treating GU malignancies with promising initial results in prostate cancer and RCC.16,17
Although much of the available data highlight the importance of protein overexpression as a mechanism of c-MET deregulation in GU malignancies, genetic abnormalities, including mutation and amplification, may also play a role.18 Additionally, molecular biomarkers that
Clin Genitourin Cancer. Author manuscript; available in PMC 2016 December 08.
could be used to select optimal patients for treatment with c-MET inhibitors are lacking. These limitations call for a better understanding of MET genetic abnormalities to further efficacious treatment with c-MET inhibitors in GU malignancies.8
We investigated MET status, including mutation and amplification, in patients with advanced RCC, prostate cancer, urothelial cancer and adrenocortical carcinoma referred to our Phase I Clinical Trials Program. We also explored the relationship between MET status, demographic and molecular data, and patient outcomes with c-MET inhibitor treatment.
Patients and Methods
Patients
We retrospectively reviewed the electronic medical records of consecutive patients with advanced prostate, RCC, urothelial and adrenocortical carcinoma referred to the Phase I at The University of Texas MD Anderson Cancer Center starting in May 2010 until January 2013. Patients were eligible for inclusion in data analysis if a primary diagnosis of any of these GU malignancies was confirmed and a tumor sample from a primary site or metastatic lesion was sent for evaluation of MET mutation or amplification. This study and all associated treatments were conducted in accordance with the guidelines of the MD Anderson Institutional Review Board.
Tissue samples and molecular analysis
MET mutation/variant and amplification were investigated in archival formalin-fixed, paraffin-embedded tissue blocks obtained from diagnostic and/or therapeutic procedures. Samples from primary or metastatic lesions were accepted. All histologies were centrally reviewed at MD Anderson. MET mutation or variant analysis was performed in different Clinical Laboratory Improvement Amendment-certified laboratories as part of a gene panel analysis or in a single test. Information about mutations in additional oncogenes was also included for analysis.
MET amplification was analyzed via fluorescence in situ hybridization (FISH). Copy numbers were expressed as gene copy number in relation to CEP7, a gene located near the centrosome of the same chromosome. MET was considered amplified when the MET/CEP7 signal ratio was ≥ 2.0 or when this ratio was < 2.0 but there were > 20 copies of MET signals and/or clusters in > 10% of the tumor nuclei counted.
Treatment and evaluation
Patients referred to the Phase I Clinic were enrolled in clinical trials judged to be clinically appropriate by attending physicians. Treatment continued until disease progression, withdrawal of consent by the patient, clinical judgment deeming the necessity of removing a patient from a clinical trial, or development of unacceptable toxicity or death. Clinical assessments were performed as specified in each protocol, typically before the initiation of therapy and then at a minimum at the beginning of each new treatment cycle. All radiographs were read in the Department of Radiology at MD Anderson and reviewed in the
Phase I Department tumor measurement clinic. Responses were categorized using RECIST on the basis of specific protocol requirements19,20 and were reported as best response.
Statistical analysis
All statistical analysis was reviewed by our statistician (KH). Patient characteristics including demographics, tumor type, MET mutation and/or amplification status and associated genetic abnormalities were summarized using frequency distributions and percentages. Time to tumor progression (TTP) was defined as the interval from the start of therapy to treatment discontinuation for disease progression or death related to disease progression. Overall survival (OS) was assessed starting from the date of the first appointment in the Phase I Clinic using Kaplan-Meier curve analysis.
Results
Patient characteristics
A total of 118 patients with advanced RCC, prostate cancer, urothelial and adrenocortical cancers were analyzed for MET mutation/variant (53 patients) or amplification (97 patients). Among these patients, 33 were tested simultaneously for both genetic abnormalities. Thirty- eight (32%) patients had RCC (21 clear cell, 5 papillary, 3 medullary, 2 chromophobe, 2 Xp11 translocation, 2 sarcomatoid-predominant and 3 unclassified histologic subtypes), 46 (39%) prostate cancer, 22 (19%) urothelial cancer, and 12 (10%) adrenocortical cancer. Their median age at diagnosis was 55 years (range 16-75 years), and 99 (84%) were Caucasians, 11 (9%) were black, and 8 (7%) were Hispanic. Detailed patient characteristics according to MET status are shown In Table 1.
Met abnormalities
Seven out of 97 (7.2%) patients demonstrated a MET gene amplification by FISH. The prevalence of MET amplification was 14.8% (4 out of 27) in RCC (all clear cell), 5.5% (1 out of 18) in urothelial cancer and 17% (2 out of 12) in adrenocortical cancer. None of the 40 patients with prostate cancer tested positive for amplification. The copy number of the MET gene in relation to CEP7 ranged from 1.1 to 6.8 (Table 2). Of note, the patient with a ratio of 1.1 was positive because more than 10% of cancer cells had more than 20 copies of the MET gene. A MET mutation/variant was detected in 3 out of 54 patients (5.6%), 2 out of 20 (10%) with RCC (one with clear cell and one with papillary RCC) and 1 out of 16 (6.2%) with prostate cancer. All mutations detected were N375S, which was previously described as germline in nature21 (Table 2).
Comparison of clinical and mutational characteristics
In the overall study population, 94 (80%) patients were male and 24 (20%) were female. The 3 patients with a MET variant, but only 4 (57%) out of 7 patients with amplification, were male. There were no differences in ethnicity among the patients with a MET abnormality and the overall population (Table 1). Patients harboring a MET abnormality had a median of 4 (3-5) metastatic sites compared to 3 (0-6) sites in wild-type patients; of note, all patients with a MET variant presented with bone metastasis and 2 out of 3 (67%) had brain metastasis, while only 2 out of 50 (4%) in the MET wild-type group developed central
Clin Genitourin Cancer. Author manuscript; available in PMC 2016 December 08.
metastasis. A lower proportion of bone metastasis (2 out of 7, 29%) and a higher proportion of lung metastasis (6 out of 7, 85%) were seen in MET amplified patients.
Concomitant mutations
MET amplification and mutation were mutually exclusive in the 33 patients tested for both abnormalities simultaneously. Five out of 10 patients with MET abnormalities had concomitant mutations, including p53 mutations (2 patients), PTENloss (3 patients) and a VHL mutation (1 patient with RCC) (Table 2). These mutations were also detected in MET wild-type patients, suggesting no differences between groups. The prevalence of mutations in other important oncogenes in the overall patient population was: 0 out of 81 patients for KRAS, 1 out of 66 (1.5%) for EGFR; 2 out of 77 (2.6%) for BRAF, and 5 out of 101 (5%) for PIK3CA. None of the patients positive for those mutations had a MET genetic abnormality, although not all of them were tested for both mutation and amplification.
Analysis of survival of MET positive patients
For survival analysis we compared the group of patients who tested positive for either a MET mutation/variant or amplification (MET positive group, 10 patients) with patients who tested negative for both abnormalities (MET negative group, 28 patients). Patients with MET mutation and MET amplification were grouped altogether after considering that individual survival data was similar between both groups (Table 2). Median OS from the day patients were initially seen in our Phase I Clinic was 6.1 and 11.5 months, for MET positive and negative patients, respectively, with an estimated hazard ratio (HR) of 2.8 (95% CI, 1.1 to 6.9; P =. 034; Figure1). Patients received different treatments after phase I consult at the discretion of the physician.
Treatment of patients with c-MET inhibitors
Of the 118 study patients, 29 were treated on phase I protocols that contained a c-MET inhibitor (16 prostate cancer, 9 RCC, 3 urothelial cancer and 1 adrenocortical cancer). We further divided these patients into those treated on protocols with c-MET-specific inhibitors as a single agent (9 patients) and protocols targeting pathways in addition to c-MET. These included protocols containing multikinase inhibitors (with c-MET inhibitory activity) or treatment combinations containing a c-MET inhibitor (20 patients). Response rates were recorded according to RECIST criteria and are shown in Figure 2A. Six patients (21%) had a partial response and 10 (34%) had stable disease as their best response. Responses varied according to tumor type (25% for prostate and 22% for RCC, whereas no responses were registered for other GU malignancies), and all responses occurred in patients who had no MET genetic abnormalities and who had been treated with either a multikinase inhibitor or on a combination protocol (Table 3). The median TTP on c-MET inhibitors was 2.3 months (range, 0.4 - 19.7). An apparently shorter TTP was observed in patients harboring MET abnormalities (median TTP of 1.6 months, range 0.9-3.1) versus wild-type patients (median TTP 4.3 months, range 0.7-19.7) and when treated with single-agent c-MET-specific inhibitors (median TTP 1.43 months, range 0.7-3.1) versus when treated with combined targets (median TTP 5.4, range 0.7-19.7) (Table 3 and Figure 2B). We analyzed the prevalence of concomitant mutations in subgroups with different responses to c-MET inhibitors. The only apparent difference was on TP53 prevalence. Three out of four (75%) of
Clin Genitourin Cancer. Author manuscript; available in PMC 2016 December 08.
patients with PD on a c-MET protocol and tested for TP53 alteration were positive for mutation, while none of the four patients with SD or PR tested positive.
Discussion
We detected MET gene amplification in 7.2% of 97 patients and a MET genetic mutation/ variant in 5.6% of 54 patients with GU malignancies. The prevalence of MET amplification was highest in RCC (14.8%) and adrenocortical carcinoma (17%), whereas a genetic variant was more frequent in RCC (10%). These abnormalities were mutually exclusive among patients tested simultaneously for both. Of the 29 patients treated on a protocol containing a c-MET inhibitor, 21% had a partial response.
Data from the Catalog of Somatic Mutations in Cancer (COSMIC) database revealed a low prevalence of MET mutations in prostate cancer (3.6%), in which c-MET activation was especially mediated by c-MET overexpression in the setting of androgen deprivation.11,22 In addition, there was a 2.3% prevalence of MET mutations in urothelial cancers, 3% in RCC and none in adrenocortical carcinomas. The MET mutation has been described as being germline in virtually all patients with hereditary papillary RCC and somatic in up to 13% of patients with sporadic papillary renal cell cancer (PRCC).23 Data concerning MET gene amplification in GU malignancies is however very scarce in the literature. Trisomy of chromosome 7, where the MET gene is located, has been detected in some patients with PRCC.24 We described a higher prevalence of MET genetic abnormalities in GU malignancies than previous reports, which could be due to selection bias as our patient population was composed of those with advanced disease.
All mutations described here were N375S, which occurs in the extracellular semaphorin domain of the MET gene. This alteration was previously described as a germline mutation (variant)21, and for this reason we did not perform a matched normal tissue analysis for confirmation. Although considered to be germline, it has functional implications through conferring a reduced affinity of the c-MET receptor to HGF and resistance to the apoptotic effects of a c-MET inhibitor.21 Therefore, this variant is important for patients with GU malignancies especially when using a c-MET inhibitor for treatment is being considered. Accordingly, the 2 patients with this variant in our study had no responses to c-MET inhibitor treatment. It is important to note that only one of the 2 patients with RCC and a N375S mutation/variant had a papillary subtype. This patient had no personal history of multiple tumors or a family history of papillary RCC, which precludes the diagnosis of the hereditary form of the disease.
Substantial data correlate activation of the c-MET pathway with aggressiveness and a worse prognosis in different malignancies. A retrospective series of patients with gastroesophageal tumors showed MET amplification associated with a higher tumor grade and worse survival.25 A deleterious effect of MET genetic abnormalities was also described in ovarian cancer26. In prostate cancer, c-MET overexpression is associated with a higher Gleason grade, whereas c-MET activation conferred a worse prognosis in urothelial cancer.10,15 Our series also demonstrated a shorter OS for patients with either a MET mutation/variant or amplification compared to wild-type patients (6.1 months vs. 11.5 months) after they
presented to our Phase I Clinic. This finding highlights the inherent challenges that these patients represent vis-à-vis treatment selection.
Interestingly, despite the promising activity of c-MET inhibitors in the overall patient population with GU malignancies reported in our study, these agents showed no activity in the few patients presenting with MET genetic abnormalities. As demonstrated in preclinical models, the N375S mutation may confer resistance to c-MET inhibitors 21 and our data suggest that resistance might also occur in vivo. Additionally, two patients with MET amplification were treated with c-MET inhibitors and both presented tumor progression as best response. There is debate about the threshold of MET gene amplification that can cause c-MET addiction by cancer cells and susceptibility to c-MET inhibitors. Of note, the RCC patient with the highest detected FISH ratio in our series (MET/CEP7 = 6.8) received a c- MET inhibitor and developed tumor progression within 2 months of therapy. It is important to note that in our study patients had access to c-MET inhibitors during dose escalation of phase I trials, and optimal biologic dose might not be reached yet. In a phase II study of foretinib (a dual c-MET/VEGFR2 inhibitor) in PRCC no responses were seen in the 2 patients with MET amplification.16 In the same study, MET germline mutations were greatly associated with better activity of the drug, but they were all considered activating mutations of MET gene, which are different than N375S variant as previously discussed. Therefore, further prospective data are warranted to better correlate MET genetic abnormalities with responses to c-MET inhibitors. It is important to note that this correlation may also be tissue dependent, as illustrated in gastroesophageal cancers.27
Finally, all responses in our study were observed when a c-MET inhibitor was combined with another targeted agent, either using a combination of drugs or a multikinase inhibitor. Some of the promising c-MET inhibitors in development are, in fact, multikinase inhibitors, including cabozantinib, which produced responses in prostate cancer17 and RCC,28 and foretinib, which showed activity in PRCC.16 Although further prospective data are needed, this observation has importance for the development of c-MET inhibitors.
Our study is limited by its retrospective nature and because the small number of patients with MET mutation or amplification did not provide sufficient statistical power for drawing definitive conclusions. Indeed, most of our analysis is essentially descriptive and statistical tests were not applied due to insufficient power to draw conclusions. Further collaborative efforts are necessary to include a higher number of patients in order to confirm some of the possible findings suggested based on our results. Additionally, we did not compare MET genetic alterations with c-MET receptor expression levels, limiting some of our comparisons with previous studies.
These limitations notwithstanding, we showed that abnormalities of MET gene might be detected in GU malignancies and that patients with them had a worse prognosis, especially those being treated in a phase I setting. However, c-MET inhibition has promise, especially in prostate cancer and RCC, but further exploration of biomarkers of response and combined treatments is needed.
Acknowledgments
the authors acknowledge Joann Aaron, MA, in the Department of Investigational Cancer Therapeutics for editorial support. Dr Hess would like to acknowledge his support funding (MDACC CCSG (P30 CA016672)).
David S. Hong received research support from Amgen and Dr. Gerald Falchook research funding, travel reimbursement and honoraria from EMD Serono.
References
1. Park M, Dean M, Kaul K, et al. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A. 1987; 84:6379- 83. [PubMed: 2819873]
2. Bottaro DP, Rubin JS, Faletto DL, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991; 251:802-4. [PubMed: 1846706]
3. Weidner KM, Di Cesare S, Sachs M, et al. Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature. 1996; 384:173-6. [PubMed: 8906793]
4. Paliouras GN, Naujokas MA, Park M. Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor. Mol Cell Biol. 2009; 29:3018-32. [PubMed: 19289496]
5. Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and progress. Nat Rev Cancer. 2012; 12:89-103. [PubMed: 22270953]
6. Ma PC, Tretiakova MS, Mackinnon AC, et al. Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008; 47:1025-37. [PubMed: 18709663]
7. Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002; 109:863-7. [PubMed: 11927612]
8. Blumenschein GR Jr. Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor- cMET axis in cancer therapy. J Clin Oncol. 2012; 30:3287-96. [PubMed: 22869872]
9. Graveel C, Su Y, Koeman J, et al. Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele. Proc Natl Acad Sci U S A. 2004; 101:17198-203. [PubMed: 15557554]
10. Jacobsen F, Ashtiani SN, Tennstedt P, et al. High c-MET expression is frequent but not associated with early PSA recurrence in prostate cancer. Exp Ther Med. 2013; 5:102-106. [PubMed: 23251249]
11. Verras M, Lee J, Xue H, et al. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res. 2007; 67:967-75. [PubMed: 17283128]
12. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997; 16:68-73. [PubMed: 9140397]
13. Powles T, Sarwar N, Stockdale A, et al. Pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer: A clinical and biomarker study. ASCO Meeting Abstracts. 2013; 31:4508.
14. Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012; 30:4026-34. [PubMed: 23008289]
15. Miyata Y, Sagara Y, Kanda S, et al. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin. Hum Pathol. 2009; 40:496-504. [PubMed: 19121849]
16. Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 2013; 31:181-6. [PubMed: 23213094]
17. Hussain M, Smith MR, Sweeney C, et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized discontinuation trial. ASCO Meeting Abstracts. 2011; 29:4516.
18. Yap TA, Sandhu SK, Alam SM, et al. HGF/c-MET targeted therapeutics: novel strategies for cancer medicine. Curr Drug Targets. 2011; 12:2045-58. [PubMed: 21777195]
19. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-47. [PubMed: 19097774]
20. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92:205-16. [PubMed: 10655437]
21. Krishnaswamy S, Kanteti R, Duke-Cohan JS, et al. Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res. 2009; 15:5714-23. [PubMed: 19723643]
22. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995; 147:386-96. [PubMed: 7639332]
23. Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto oncogene in papillary renal carcinomas. Oncogene. 1999; 18:2343-50. [PubMed: 10327054]
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25. Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011; 29:4803-10. [PubMed: 22042947]
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27. Okamoto W, Okamoto I, Arao T, et al. Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012; 11:1557-64. [PubMed: 22729845]
28. Vaishampayan U. Cabozantinib as a novel therapy for renal cell carcinoma. Curr Oncol Rep. 2013; 15:76-82. [PubMed: 23292795]
1.0
No Cmet Aberration, N = 28, median = 11.5
Cmet Aberration, N = 10, median = 6.1
0.8
HR = 2.8, 95% CI = (1.1, 6.9), p = 0.034
Survival
0.6
0.4
0.2
0.0
0
5
10
15
20
Months
50
c-Met ampl
c-Met ampl
40
c-Met variant
30
20
RECIST change (%)
c-Met variant
10
0
*
*
*
*
*
*
*
*
*
-10
20
-30
-40
☒ Renal Cell
☐ Prostate
-50
☐ Urothelial
-60 ☐ Adrenocortical
* c-MET selective inhibitor
+
+
Tumor Progression
c-Met variant
C-Met amplified
*
*
☒ Renal Cell
.
☐ Prostate
c-Met variant
☐ Urothelial
.
☐ Adrenocortical
* c-Met amplified
+
0
5
10
15
20
25
Time (months)
* c-MET selective inhibitor
+ treatment still ongoing at time of analysis
| Characteristic | Not mutated (n=50) (%) | Mutated (n=3) (%) | Not amplified (n=90) (%) | Amplified (n=7) (%) |
|---|---|---|---|---|
| Age At Diagnosis: Median (IQR) | 56 (25-72) | 56 (54-62) | 56 (16-75) | 48 (19-67) |
| Prior Therapies: Median (IQR) | 3 (0-8) | 3 (3-4) | 3 (0-10) | 3 (1-6) |
| Diagnosis (n) | ||||
| Renal Cell (38) | 18 (36) | 2 (67) | 23 (26) | 4 (57) |
| Urothelial (22) | 12 (24) | 0 (0) | 17 (19) | 1 (14) |
| Prostate (46) | 14 (28) | 1 (33) | 40 (44) | 0 (0) |
| Adrenocortical (12) | 6 (12) | 0 (0) | 10 (11) | 2 (29) |
| Gender | ||||
| Male | 40 (80) | 3 (100) | 75 (83) | 4 (57) |
| Female | 10 (20) | 0 (0) | 15 (27) | 3 (43) |
| Ethnicity (%) | ||||
| Black | 4 (8) | 0 (0) | 8 (9) | 0 (0) |
| Hispanic | 4 (8) | 1 (33) | 6 (7) | 1 (14) |
| Caucasian | 42 (84) | 2 (67) | 76 (84) | 6 (86) |
| Metastasis (%) | ||||
| # Metastatic sites - median | 3 (1-6) | 4 (3-5) | 2 (0-6) | 4 (3-4) |
| (range) | ||||
| Liver | 29 (58) | 1 (33) | 37 (41) | 4 (57) |
| Lungs | 26 (52) | 2 (67) | 35 (39) | 6 (85) |
| Bone | 29 (58) | 3 (100) | 60 (67) | 2 (29) |
| Central Nervous System | 2 (4) | 2 (67) | 4 (4) | 0 (0) |
| Peritoneum | 7 (14) | 0 (0) | 6 (7) | 2 (29) |
| Lymph nodes | 23 (46) | 2 (67) | 13 (14) | 2 (29) |
| Site of mutational analysis | ||||
| Primary tumor | 31 (62) | 0 (0) | 55 (61) | 5 (71) |
| Metastatic tumor | 19 (38) | 2 (67) | 35 (39) | 2 (29) |
| Unknown | 0 (0) | 1 (33) | 0 (0) | 0 (0) |
| Additional genetic alterations | ||||
| PIK3CA mutation | 2/47 (4) | 0/3 (0) | 4/79 (5) | 0/7 (0) |
| TP53 mutation | 7/31 (23) | 1/2 (50) | 5/21 (24) | 1/1 (100) |
| PTEN loss | 7/19 (37) | 1/2 (50) | 21/70 (30) | 2/6 (33) |
| HER amplification | 1/23 (4) | 0/1 (0) | 1/27 (4) | 0/0 (0) |
| EGFR mutation | 1/37 (3) | 0/3 (0) | 0/43 (0) | 0/5 (0) |
| BRAF mutation | 1/40 (3) | 0/3 (0) | 1/53 (2) | 0/5 (0) |
Table 2 Pathological and molecular characteristics of patients presenting MET abnormalities and outcomes on c-MET inhibitors
| Patient No. | Diagnosis | Histology | Grade | Mutation/ Copy Number | Concomitant Mutations | Best Response | TTP (mos) | OS (mos)" 1 |
|---|---|---|---|---|---|---|---|---|
| c-Met amplified | ||||||||
| 1 | RCC | Clear Cell | Fuhrman 4 | 2.27 | PTEN loss | - | - | 3.6 |
| 2 | RCC | Clear Cell | Fuhrman 4 | 2.7 | - | - | - | 7.5 |
| 3 | RCC | Clear Cell2 | Fuhrman 4 | 2.79 | - | PD | 1 | 2.5 |
| 4 | RCC | Clear Cell | Fuhrman 4 | 6.8 | TP53 | PD | 2 | 6.9 |
| 5 | Urothelial | TCC | High Grade | 5.91 | PTEN loss | - | - | 4.2 |
| 6 | Adrenocortical | Carcinoma | - | 1.13 | - | - | - | 12.7 |
| 7 | Adrenocortical | Carcinoma | - | 2.68 | - | - | - | 6.1 |
| c-Met Mutated | ||||||||
| 8 | RCC | Papillary | Fuhrman 3 | N375S | - | SD | 3 | 3.8 |
| 9 | RCC | Clear Cell | Fuhrman 4 | N375S | VHL | - | - | 4.4 |
| 10 | Prostate | Adenocarcinoma | Gleason 8 | N375S | PTEN loss, TP53 | PD | 1 | 3.6 |
Clin Genitourin Cancer. Author manuscript; available in PMC 2016 December 08.
1 OS was measured staring from phase I consult;
2 sarcomatoid differentiation;
3 more than 10% of cancer cells with more than 20 copies of the c-MET gene
| Characteristic | Response Rate (%) | Time to Tumor Progression Median/Range (mos) |
|---|---|---|
| All population (n=29) | 3.1 (0.7-19.7) | |
| PR | 6 (21) | |
| SD | 10 (34) | |
| PD | 13 (45) | |
| By tumor type | ||
| RCC | 2/9 (22) | 2.1 (0.9-6.6) |
| Prostate | 4/16 (25) | 5 (1-19.7) |
| Urothelial | 0/3 (0) | 0.73 (0.7-1.3) |
| Adrenocortical | 0/1 (0) | 2.2 |
| By MET abnormality | ||
| Variant/amplification | 0/4 (0) | 1.6 (0.9-3.1) |
| No abnormality 1 | 6/25 (24) | 4.3 (0.7-19.7) |
| By type of c-MET trial | ||
| c-MET specific inhibitor | 0/9 (0) | 1.43 (0.7-3.1) |
| Multi-kinase inhibitor or combination | 6/20 (30) | 5.4 (0.7-19.7) |
1 negative for either MET mutation or amplification or both
Clin Genitourin Cancer. Author manuscript; available in PMC 2016 December 08.