or metastatic salivary gland carcinomas: A phase II study

Oral Oncology 45 (2009) 574–578

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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study L.D. Locati a, P. Bossi a, F. Perrone b, P. Potepan c, F. Crippa d, L. Mariani e, P. Casieri b, M. Orsenigo b, M. Losa b, C. Bergamini a, C. Liberatoscioli a, P. Quattrone f, R.G. Calderone a, G. Rinaldi a, S. Pilotti b, L. Licitra a,* a

Head and Neck Cancer Medical Oncology Unit, Cancer Medicine Department, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy Unit of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy c Department of Radiology, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy d PET Unit, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy e Medical Statistics and Biometry, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy f Department of Pathology, Fondazione IRCCS ‘‘Istituto Nazionale dei Tumori”, via Venezian 1, Milan, Italy b

a r t i c l e

i n f o

Article history: Received 2 July 2008 Accepted 21 July 2008 Available online 18 September 2008 Keywords: Cetuximab Metastatic disease Palliative treatment Salivary gland cancer Target therapy Head and neck squamous cell carcinoma

s u m m a r y EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for P6 months was investigated. From April to December 2005, 30 patients [23 adenoid cystic carcinoma (ACC) and 7 non-ACC] were treated with cetuximab at 400 mg/m2/week followed by 250 mg/m2/week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5–54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash PG2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC. Ó 2008 Elsevier Ltd. All rights reserved.

Introduction Salivary gland carcinomas (SGCs) are no longer curable in presence of metastases and/or bulky recurrence. In few cases local-regional relapses can be managed with further surgery and/ or radiotherapy. The frequency of distant metastases depends on histotype and on its grading, reaching 40% of cases in patients with ACC.1 Most salivary gland cancers, in particular ACC, have an indolent course. First-line treatment is chemotherapy, although with current treatment response rates are generally poor. Moreover, there is no clear association with any survival advantage.2 EGFR is expressed on many normal human tissues and on a large variety of epithelial tumors, including SGCs.3–7 In SGCs, EGFR overexpression rate is about 70%3 making it an attractive therapeu-

* Corresponding author. Tel.: +39 02 23903352; fax: +39 02 23903353. E-mail address: [email protected] (L. Licitra). 1368-8375/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2008.07.010

tic target. Its expression varied markedly among different histotypes as well as within the same category, with a maximum of 85% ACCs overexpressing it.4,7,8 The unsatisfactory results in SGCs with chemotherapy, along with the presence of a biological rational, prompted us to evaluate cetuximab as single agent. The antitumor activity of cetuximab has been demonstrated in preclinical and clinical models in head and neck squamous cell carcinoma (HNSCC) as single agent9 and in association with chemotherapy10 and radiotherapy.11 Cetuximab was generally welltolerated, the most common adverse event is skin toxicity, which occurred in at least 80% of treated patients. Presence and severity of acneiform rash have been predictive of response and survival in patients with colorectal cancer.12 In the present paper, we report the results, including the biological correlative studies, of a phase II monoinstitutional study that investigated the activity of cetuximab defined as the rate of patients obtaining clinical benefit in relapsed and/or metastatic salivary gland cancers (RMSGCs).

L.D. Locati et al. / Oral Oncology 45 (2009) 574–578

Patients and methods Patient selection Inclusion criteria were histologically proven RMSGCs with no other available curative option; the presence of at least one measurable lesion according to RECIST criteria, the availability of archival and/or fresh tumor tissue for the EGFR analysis; age P18 years; Karnofsky performance status of >70; life expectancy >3 months; laboratory values as following: neutrophils P1.0  109/L, platelets P100  109/L, hemoglobin P9 g/dl; ALAT and ASAT 62.5  ULN (<5  ULN if liver metastases are present); total bilirubin 61.5  ULN and serum creatinine 6 1.5  ULN. Prior radiotherapy was allowed on the only target lesions if they had either progressed or re-appeared. One prior chemotherapy regimen was allowed whenever performed, except for patients with ACC and acinic cell carcinoma, for whom two previous chemotherapy lines were authorized. Brain metastasis, bone metastasis as single tumor evidence; previous exposure to EGFR inhibitors, clinically relevant coronary artery disease or myocardial infarction within the last 12 months and any previous malignancy (except concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix) with no evidence of disease for 65 years were considered exclusion criteria. Progression of disease documented by radiographic images as defined by RECIST criteria was not considered as an inclusion criteria for study entry. The study was revised and approved by the internal institutional studies review committee and by the ethic committee. All patients signed an informed consent before study entry. Study therapy The loading starting dose of cetuximab was 400 mg/m2. All patients received premedication before cetuximab administration. The first time cetuximab was administered over a 2-h period (maximum rate of 5 ml/min) and saline solution (0.9%) was used to flush the line at the end of infusion. Vital signs were checked before the administration of cetuximab as well as during, post and 1 h postvolume infusion. The weekly dose (all further infusions) was 250 mg/m2 (=125 ml/m2) and it was administered over a 1-h period (maximum rate of 5 ml/min). Toxicity assessment and dose modifications Treatment-related toxicity was graduated according to Common Toxicity Criteria Adverse Event (CTCAE) version 3.0. Cetuximab was deferred for up to two consecutive infusions without changing the dose level in case of grade P3 skin toxicity. If the toxicity resolved to grade 2 or less by the following treatment period, the treatment was resumed. With the second and third occurrences of grade P3 skin toxicity, cetuximab therapy was deferred for up to two consecutive weeks with concomitant dose reductions to 200 mg/m2 and 150 mg/m2, respectively. Cetuximab dose reductions, if occurring, were permanent. Patients stopped cetuximab if more than two consecutive infusions were withheld or a fourth event of grade P3 skin toxicity occurred despite an appropriate dose reduction. Patients experiencing a grade 3 allergic, a grade 4 anaphylactic and a grade 5 reaction stopped study treatment.C Response evaluation Patients were considered evaluable if at least one assessment of objective response was available. Clinical evaluation was performed every week. A baseline radiological tumor evaluation by

575

CT scan and/or MRI was performed; objective response was assessed every 6 weeks for four times, thereafter every 12 weeks according to RECIST criteria.13 Cetuximab was discontinued in case of progressive disease, voluntary interruption or severe non-compliance to protocol. The primary endpoint of the study was to assess the activity of cetuximab in terms of clinical benefit (CB) defined as the occurrence of objective response, complete or partial response (CR or PR) or stable disease (SD) for at least 6 months in RMSGCs patients. EGFR immunocytochemistry (IHC) and fluorescence in situ hybridization (FISH) Both analyses were performed as previously described protocols.14 Briefly, IHC was performed on 2 lm cut fixed tumor section using the EGFR-DAKO kit and a final score of low, intermediate and high expression was calculated combining the scores relative to staining intensity and percentage of immunopositive cells. FISH was performed on sections from fixed tumors using LSI EGFR dual-colour probe (Vysis). In each nucleus, the EGFR copy number was assessed in respect to chromosome 7 copy number. A distinction was made among trisomy, three gene copies in more than 10% of cells; low polysomy, P4 gene copies in more than 10% of cells but less than 40%; high polysomy P4 gene copies in more than 40%. Gene amplification was defined as presence of amplification clusters or ratio gene/chromosome more than 2 or P15 gene copies in P10% of cells. Non-evaluable cases where those for which the archival material was unsuitable for analysis.

Statistical considerations The clinical benefit rate (CBR) and corresponding 95% exact confidence limits were estimated on the overall sample of 30 patients. Furthermore, the possible dependence of the CBR on EGFR expression by IHC, EGFR copy number by FISH or skin toxicity was investigated by means of the Fisher’s exact test for contingency tables. Originally, a sample of 20 patients had been planned. With such a number, the power to detect an increase in the CBR from 20%, indicating the lack of a worthwhile antitumor activity, to 50%, indicating that the treatment is promising and warrants further investigation, with a one-sided test at the 10% significance level was above 90%. In consideration of the lack of important therapeutic alternatives in the specific setting and the possibility to accrue additional patients in a relatively short time interval, a sample size extension up to 30 patients was decided during the study. With such a number, the null hypothesis of a 20% CBR can be rejected if 10 or more patients over a total of 30 show a response in terms of CB. Additional analyses were carried out to better describe the duration of disease stabilization. In particular, the Kaplan–Meier product-limit method15 was adopted to estimate time to progression (TTP) survival curves either overall or splitting the series into ACC and non-ACC histotypes.

Results Series characteristics and treatment From April until December 2005, 30 patients with RMSGCs were enrolled. Patient’s characteristics are listed in Table 1. ACC was the main histology, representing 76% of the enrolled cases. Lung was the most frequent metastatic site, being involved in 18 (60%)

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Table 1 Series characteristics and response

100 Non-ACC No. 7

45 years (19–67) 14:9

22 years (18–62) 6:1

23

0 2 3 1 1

Non-ACC

80

Percent

Median age (range) F:M ratio Histotypes Adenoid cystic (ACC) Mucoepidermoid Myoepithelial Acinic cell carcinoma Cystoadenocarcinoma Primary site Major salivary gland Minor salivary gland Site of relapse Local-regional Local-regional + distant Distant PD at time of study entry Yes No Unknown Previous local-regional treatment Surgery (S) S + Radiotherapy (R) S + R + concomitant chemo Number of prior regimens 0 1 2 Response to cetuximab SD P6 months SD <6 months PD

ACC No. 23

ACC

60 p=0.3081 40 20 0 0

4

8

12

16

Months Figure 1 Time to treatment progression according to histotype.

11 12

4 3

1 13 9

2 4 1

11 6 6

5 1 1

7 15 1

3 4

10 6 7

3 2 2

12 8 3

3 1 3

regional and metastatic sites) were spared from skin eruption16 and one patient developed benign naevi on the trunk. Among 10 patients who experienced a skin rash PG2, six patients had a SD P6 months. None statistically correlation between skin toxicity PG2 and CBR was observed (p = 1.00). Clinical benefit and survival

F: female; M: male; ACC: adenoid cystic carcinoma; S: surgery; R: radiotherapy; PD: progression of disease; SD: stable of disease.

All patients were considered evaluable for the study objectives. Series characteristics and response are reported in Table 1. No objective response was observed. SD was recorded in 24 (80%) patients. Among those, a SD P6 months was observed in 15 cases, thus achieving a CBR of 50% (95% CL, 31–69%). According to the observed CBR the 50% study target was met. Median TTP was 6 months (range 1–15). TTP is reported in Figure 1. Eight patients, who have withheld cetuximab, for reasons other than progressive disease, had a stable disease after the end of treatment lasting for a median of 4.5 months (range 1+ to 7+ months). EGFR IHC and FISH analysis

patients, followed by bone in five patients; skin, soft tissues and kidney were also involved. A median of 14 courses of cetuximab (range 5–54) were infused. Cetuximab dose reduction at 200 mg/m2 was applied in six cases. Twenty-two patients stopped cetuximab for disease progression, seven patients voluntarily interrupted cetuximab after a median number of 22 courses (range 6–45). One patient experienced an acute psychiatric episode after 17 drug courses, which led to treatment interruption. Toxicity All patients were evaluable for toxicity. Toxicities are summarized in Table 2. Skin toxicity was the main adverse event. Interestingly in four patients, previously irradiated areas (both loco-

Table 2 Toxicities

Rash desquamations Dry skin Pruritus Hair loss Nail changes Hypertrichosis Trichomegalia Rhagades Paronychia Fatigue Keratitis Congiuntivitis

G1 n (%)

G2 n (%)

G3 n (%)

20 (67) 6 (20) 4 (13) 1 (3) – 6 (20) 9 (30) 3 (10) 4 (13) – – 3 (10)

6 (20) 4 (13) – – 3(10) 1 (3) – 1 (3) – 2 (7) – –

4 (13) – – – – – – – – 1 (3) 1 (3)

To study the correlation between EGFR expression/status and response to cetuximab, EGFR IHC and FISH analyses were performed in 25 and 24 tumors samples, respectively. The results are listed in Table 3. Eight out of 15 cases (53%) with SD P6 months had a high IHC EGFR expression. FISH analysis revealed a normal disomic EGFR/chromosome 7 pattern in most of tumors (21/24 = 88%). No EGFR gene amplification was found, but three cases (12%) showed trisomy or low polisomy of chromosome 7. Similarly to HNSCC14, EGFR FISH status does not seem to correlate with EGFR immunoreactivity, since two cases with an increased EGFR gene copy number showed a null EGFR immunophenotype, while 12 samples carrying EGFR disomy had high EGFR overexpression. Although, a slight correlation between EGFR expression and CBR was observed, none statistically association was recorded between EGFR expression, EGFR copy number and CBR (p = 0.2016 and p = 0.2222, respectively).

Table 3 Tumor samples EGFR IHC and FISH analysis Histotype

IHC

FISH

ACC = 23

High = 11 Moderate = 3 Negative = 5 n.e. = 4

10 3 3 1

High = 2 Moderate = 2 Low = 1 Negative = 1 n.e. = 1

2 1 1

Disomy

Non-ACC = 7

Trisomy

Low polysomy

n.e. 1

1

ACC: adenoid cystic carcinoma; n.e.: not evaluable.

1 3 1 1 1

L.D. Locati et al. / Oral Oncology 45 (2009) 574–578

Discussion The primary endpoint of the study defined as CBR derived from the observation of CRs, PRs, or SDs for at least 6 months in patients receiving cetuximab, was met in 15 cases (50%). No patient qualified for a response. According to RECIST criteria 24 (80%) patients showed SD and six had disease progression. After treatment interruption for reasons different from progressive disease, a prolonged SD was observed. Our clinical and biological results are consistent with other data obtained in RMSGCs with anti-EGFR therapies, where objective responses are virtually absent while prolonged disease stabilizations are observed at low toxicity costs. The activity of gefitinib was tested in a phase II trial.17 Twentyeight patients (19 ACC and 9 non-ACC) were enrolled to receive gefitinib at 250 mg daily. No objective response was observed. SD was achieved in 13 cases (46%), including 10 ACCs. Median duration of SD was 13 weeks (range 4–19 weeks). Forty patients were enrolled in a phase II study with lapatinib. No response was recorded.18 Among 19 evaluable ACC patients, 15 (79%) achieved a SD with a median TTP of 3.5 months, nine (47%) lasting P6 months. In 8 out of 17 evaluable non-ACC cases a SD was observed, four of which (25%) P6 months. There was a positive correlation between EGFR 3+ and SD P6 months. In our study we obtained very similar results with no responses and some patients obtaining a disease stabilization, particularly ACC patients, where SD was seen in almost all the patients (20/ 23 = 87%), with a SD P6 months in a relative high proportion (12/23 = 52%) of them. In our experience the median TTP was almost doubled as compared to that obtained by lapatinib and gefitinib, possibly suggesting a better positive interaction of cetuximab. Another possible explanation lies in the lack of patient’s selection in terms of disease progression. In fact, we treated also non progressive patients intrinsically represented by more favorable cases characterized by a prolonged TTP. In our series, 16 patients (53%) presented with a documented disease progression within 6 months at study entry. Eleven of progressing patients (69%) were ACC and all of them obtained a SD lasting P6 months, indicating that among progressive ACC, cetuximab offers a significant probability of obtaining a prolonged stabilization. Some authors suggested that the relative lack of tumor proliferation, as documented by the long doubling time of metastatic ACC ranging from 86 to 1064 days (average 393 days), might limit potential activity of target therapy in terms of response rate.19,20 On the other hand, the high variety of doubling times that represents high tumor heterogeneity among the same histotype may contribute, at least in ACC, to explain different results in terms of SD duration. It has been suggested that a better estimation of biological therapies activity in ACC17 would be obtained by treating only progressive patients whose tumor stabilization on treatment would indicate some therapeutic effect. Unfortunately, a clear cut definition of the optimal progression rate, at which single histotypes should be best treated, is still to be defined in SGCs. The underlying idea is that the progressive patient who achieves a disease stabilization of P6 months can account for some benefit in that, by representing his own internal control, the disease course was altered from the delivered treatment. Indeed, according to the gompertzian tumor kinetic hypothesis it can not be excluded that patients with documented progressive disease, achieving a SD with biological treatments, were those who were naturally destined to enter into a stabilization phase, irrespective of treatment interaction. Thus, we have decided to include in this trial both patients with a documented progressive disease and patients without a progressive disease.

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In our study non-ACC patients were few (seven cases). The number of non-ACC cases enrolled in the trials above17,18 is also very few and although the comparison of results among trials could be considered quite hazardable, the proportion of cases obtaining a CB (43%) was slightly superior in our series than in gefitinib17 and lapatinib18 trials. This data would suggest the importance of histotype in dictating drug activity. High EGFR expression, similarly to the study with lapatinib18 correlated with a prolonged disease stabilization in half of the cases. Consistent data on this issue would strongly advice the inclusion of immunohistochemical analysis when targeted therapies are applied to RMSGC. A high EGFR gene copy number has been reported to be a biomarker of response to cetuximab in colorectal carcinoma.21 In our study the EGFR FISH analysis demonstrated a normal EGFR disomic pattern in most specimens potentially justifying a lack of response to cetuximab. Remarkably, our tumor series encompasses mainly ACC, that in our hands, as opposed to other histotypes, is rarely associated with an increased EGFR copy number (data not shown). In conclusion, our results are consistent with other experiences with anti-EGFR therapies. Cetuximab provides a SD P6 months in half of the treated RMSGC patients. EFGR overexpression was not correlated with treatment outcome. In progressing ACC patients, SD P6 months occurred in every case. In RMSGCs further evaluation of EGFR targeting agents are advisable and should take place by differentiating ACC from other SGCs histotypes and by appropriate tumor biological selection. Conflict of interest statement Lisa Licitra, MD, has been serving as Advisory Board Member for AMGEN, GlaxoSmithKline and MERCK Serono. The remaining authors have no conflict of interest to be disclosed. Acknowledgements We thank all the Colleagues that have contributed to accrue Patients in this trial. Supported in part by Merck Serono and AIRC. References 1. Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston Park) 1998;12:671–80. 2. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 2006;24:2673–8. 3. Locati LD, Perrone F, Losa M, Mela M, Casieri P, Orsenigo M. Treatment relevant immunophenotyping of 139 salivary gland carcinomas (SGCs). AACR-NCIEORTC, Meeting proceedings, 2005, abs C252, 263. 4. Gibbons MD, Manne U, Carroll WR, Peters GE, Weiss HL, Grizzle WE. Molecular differences in mucoepidermoid carcinoma and adenoid cystic carcinoma of the major salivary glands. Laryngoscope 2001;111:1373–8. 5. Mori M, Naito R, Tsukitani K, Okada Y, Hayashi T, Kato K. Immunohistochemical distribution of human epidermal growth factor in salivary gland tumours. Virchows Arch A Pathol Anat Histopathol 1987;411:499–507. 6. Fan CY, Melhem MF, Hosal AS, Grandis JR, Barnes EL. Expression of androgen receptor, epidermal growth factor receptor, and transforming growth factor alpha in salivary duct carcinoma. Arch Otolaryngol Head Neck Surg 2001;127: 1075–9. 7. Yamada K, Iwai K, Okada Y, Mori M. Immunohistochemical expression of epidermal growth factor receptor in salivary gland tumours. Virchows Arch A Pathol Anat Histopathol 1989;415:523–31. 8. Vered M, Braunstein E, Buchner A. Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin. Head Neck 2002;24:632–6. 9. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Openlabel, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171–7. 10. Vermorken J, Mesia R, Vega V, Remenar E, Hitt R, Kawecki A, et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN

578

11.

12.

13.

14.

15. 16.

L.D. Locati et al. / Oral Oncology 45 (2009) 574–578 when added to first line platinum based therapy - Results of a randomized phase III (Extreme) study. J Clin Oncol ASCO annual meeting proceedings, vol. 25, 2007. p. 18S. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–78. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med 2004;351:337–45. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 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. Perrone F, Suardi S, Pastore E, Casieri P, Orsenigo M, Caramuta S, et al. Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. Clin Cancer Res 2006;12:6643–51. Kaplan EL, Meyer P. Non parametric estimation for incomplete observations. J Am Stat Assoc 1958;53:457–74. Bossi P, Liberatoscioli C, Bergamini C, Locati L, Fava S, Rinaldi G, et al. Previously irradiated areas spared from skin toxicity induced by cetuximab in six patients:

17.

18.

19.

20.

21.

implications for the administration of EGFR inhibitors in previously irradiated patients. Ann Oncol 2007;18:601–2. Glisson BS, Blumenschein G, Francisco M, Erasmus J, Zinner R, Kies M. Phase II trial of gefitinib in patients with incurable salivary gland cancer. ASCO annual meeting proceedings, vol. 23, 2005. p. 508s. Agulnik M, Cohen EW, Cohen RB, Chen EX, Vokes EE, Hotte SJ, et al. Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non adenoid cystic carcinoma malignant tumors of the salivary glands. J Clin Oncol 2007;25: 3978–84. Umeda M, Nishimatsu N, Masago H, Ishida Y, Yokoo S, Fujioka M, et al. Tumordoubling time and onset of pulmonary metastasis from adenoid cystic carcinoma of the salivary gland. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:473–8. Faivre S, Raymond E, Casiraghi O, Temam S, Berthaud P. Imatinib mesylate can induce objective response in progressing, highly expressing KIT adenoid cystic carcinoma of the salivary glands. J Clin Oncol 2005;23:6271–3. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di NF, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6:279–86.