A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer

Modi, Shanu; Seidman, Andrew D.; Dickler, Maura N.; Moasser, Mark M.; D’Andrea, Gabriella; Moynahan, Mary Ellen; Menell, Jennifer H.; Panageas, Katherine S.; Tan, Lee K.; Norton, Larry; Hudis, Clifford A.

doi:10.1007/s10549-004-3974-0

Cited by 84 publications

(67 citation statements)

References 18 publications

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“…However, in contrast to GIST, for which imatinib has proved to be an efficient tailored therapy, experience with imatinib therapy in breast cancer is limited. A trial conducted by Modi et al (2005) did not establish clinical benefit. However, in that study, no c Kit expression was detected in 8 out of the 11 patients enroled with available tissue.…”

Section: Discussionmentioning

confidence: 99%

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome

et al. 2009

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BACKGROUND: c Kit (CD117) expression in tissues has been reported as a relevant target for specific therapy in some human malignancies, but has been poorly documented in breast carcinomas METHODS: The prognostic significance of c Kit in a series of 924 breast carcinomas (mean follow-up, 79 months) was investigated using standardised high-throughput quantitative densitometry of immunohistochemical precipitates in tissue microarrays. RESULTS: c Kit was expressed in 14.7% breast carcinomas (and in 42 out of 586 node-negative tumours). In univariate analysis, (log-rank test) the score of c Kit expression correlated with poor patient outcome P ¼ 0.02 and particularly in node-negative cases (P ¼ 0.002). In multivariate Cox analysis, c Kit was an indicator of metastasis independent of 25 other concomitantly evaluated markers of prognosis. Logistic regression showed that c Kit ranked 10 out of 25 (P ¼ 0.041), and was included in a 10-marker signature that allowed 79.2% of the patients to be correctly classified in the metastatic or metastasis-free categories independently of hormone receptors and HER-2 status. Interestingly, c Kit was also a significant predictor of metastasis in node-negative tumours (2 out of 25 ranking, Po0.0001) and included in a six-marker signature of prognosis, correctly classifying 88.6% of the patients (Po0.0001). CONCLUSION: We concluded that, as assessed by quantitative immunohistochemistry, c Kit is an independent prognostic indicator that could also potentially serve as a target for specific therapy in breast carcinomas.

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Section: Discussionmentioning

confidence: 99%

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome

et al. 2009

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“…The tumor microenvironment is PDGFR-rich, and activation of PDGFR has been implicated in playing an important role in elevating the IFP (38). High IFP, in turn, could decrease the uptake of chemotherapeutic drugs (41).…”

Section: Discussionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors

Ali

Lin

Gharibo

et al. 2007

Clinical Cancer Research

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Purpose: Preclinical data shows improvements in response for the combination of imatinib mesylate (IM, Gleevec) and gemcitabine (GEM) therapy compared with GEM alone. Our goals were to determine the maximum tolerated dose of GEM and IM in combination, the pharmacokinetics of GEM in the absence and in the presence of IM, and IM pharmacokinetics in this combination. Patients and Methods: Patients with refractory malignancy, intact intestinal absorption, measurable/evaluable disease, adequate organ function, Eastern Cooperative Oncology Group PS 0-2, and signed informed consent were eligible. Initially, treatment consisted of 600 mg/m 2 of GEM (10 mg/m 2 /min) on days 1, 8, and 15, and 300 mg of IM daily every 28 days. Due to excessive toxicity, the schedule was altered to IM on days 1to 5 and 8 to 12, and GEM on days 3 and 10 every 21days. Two final cohorts received IM on days 1to 5, 8 to 12, and 15 to 19. Results: Fifty-four patients were treated. IM and GEM given daily at 500 to 600 mg/m 2 on days 1, 8, and 15 produced frequent dose-limiting toxicities.With the modified scheduling, GEM given at 1,500 mg/m 2 /150 min was deliverable, along with 400 mg of IM, without dose-limiting toxicities.Three partial (laryngeal, renal, and mesothelioma) and two minor (renal and pancreatic) responses were noted at GEM doses of 450 to 1,500 mg/m 2 . Stable disease >24 weeks was seen in 17 patients. CA19-9 in 7 of 10 patients with pancreatic cancer was reduced by f90%. IM did not significantly alter GEM pharmacokinetics. Conclusion: The addition of intermittently dosed IM to GEM at low to full dose was associated with broad antitumor activity and little increase in toxicity.

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“…15,19,20 As a result, it is not that surprising that multiple clinical trials have observed only minimal or no clinical efficacy of imatinib mesylate (Gleevec) in various types of tumors expressing KIT detected by immunohistochemical staining but lacking activating mutations, such as adenoid cystic carcinomas of the salivary gland, 22 pulmonary small cell carcinomas, 32,33 breast carcinomas, 34 ovarian carcinomas 35 and melanomas. 36 These studies 15,19,20,22,[32][33][34][35][36] support the concept that mutation-mediated activation of KIT or PDGFRA is a prerequisite for successful treatment with imatinib mesylate. 37 This conclusion is further supported by a recent study in which clinical response to imatinib mesylate was observed in a patient with metastatic thymic carcinoma harboring an activating KIT mutation.…”

Section: Discussionmentioning

confidence: 99%

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

et al. 2006

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Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in 450% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.

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A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer

Abstract: Imatinib therapy at doses of 800 mg/day was associated with significant toxicity in patients with heavily pre-treated MBC. Our results do not indicate activity for imatinib monotherapy in these unselected patients.

Cited by 84 publications

References 18 publications

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome

Quantitative immunohistochemical expression of c Kit in breast carcinomas is predictive of patients' outcome

Phase I and Pharmacokinetic Study of Imatinib Mesylate (Gleevec) and Gemcitabine in Patients with Refractory Solid Tumors

Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

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