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p53 mutations are associated with resistance to platinum-based chemotherapy in ovarian cancer
PROGNOSIS
p53 mutations are associated with resistance to platinum-based chemotherapy in ovarian cancer Abstracted from: Reles A, Wen WH, Schmider A, Gee C, Runnebaun IB, Kilian U, Jones LA, El-Naggar A, Minguillon C, Schonborn I, Reich O, Kreinberg R, Lichtenegger W, Press MF. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res 2001; 7: 2984^2997.
BACKGROUND The p53 tumor suppressor gene is the most frequently mutated gene in cancers, playing a central role in cell cycle regulation and induction of apoptosis.
METHOD Cohort analysis.
MAIN RESULTS p53 mutations were found in 56% of tumors. Time to progression (p = 0.029) and overall survival (p = 0.014) was shorter in women with p53 mutations compared to wild-type p53.Time to progression (p = 0.010) and overall survival (p = 0.007) were also shorter for women with mutations in highly conserved domains compared to all women. Time to progression (p = 0.071) and overall survival (p = 0.056) tended to be shorter in those with p53 overexpression (63% of women) compared to those without p53 overexpression. Women with overexpression (p = 0.001) or missense mutations (p = 0.008) were more likely to resist platinum-based chemotherapy.
PARTICIPANTS One hundred and seventy-eight women with invasive epithelial ovarian carcinoma; average age 57 years (range 23 to 84 years). Fifty percent of participants were resistant to chemotherapy at baseline.
AUTHORS’ CONCLUSIONS p53 mutations in tumors correlate with shortened time to progression and overall survival.The sensitivity of ovarian cancer cells to cisplatin and carboplatin may depend on a functional p53 protein to enable apoptosis induction.
OBJECTIVE To clarify the role of p53 alterations and their impact on response to chemotherapy. SETTING United States and Germany;1972 to 1995.
ANALYSIS All participants underwent surgery for ovarian cancer (exploratory laparotomy with bilateral salpingo-oophorectomy, hysterectomy, infracolic omentectomy, maximal tumor debulking). Snap-frozen carcinoma were analyzed for mutations of the p53 gene (exons 2 to 11) by single-strand conformation polymorphism and DNA sequencing. Immunohistochemistry was used to analyze p53 overexpression. Seventy-six percent of those with tumor stages 1b-IVreceived adjuvant chemotherapy. Of these, 47% received cisplatin^ cyclophosphamide and 36% received other regimens. Response to chemotherapy was classi¢ed as platinum refractory, platinum resistant and platinum sensitive. Twenty-four percent did not receive chemotherapy because of early stage disease, old age or refusal. Median follow-up was 31 months for the total cohort and 52 months for survivors. OUTCOMES Evidence of p53 mutations in tumors; time to progression; resistance to platinum-based chemotherapy; overall survival. 1363- 4054/02/$-see front matter & 2002 Elsevier Science Ltd. Allrights reserved doi:10.1054/ebon.37, available online at http://www.idealibrary.com.on
METHOD NOTES Power Blinding Randomization Other
No power calculation Not applicable Not applicable Most earlier studies on p53 used archival formalin-¢xed, para⁄nembedded tissue.This reduced immunoreactivity of many proteins after the ¢xation process. Only frozen tissue was used in this study
Sources of funding: The National Cancer Institute; The American Cancer Society; The Molecular Core Laboratory Facilities of the GCRC;The Deutsche Forschungsgemeinschaft; University of Southern California Overian CancerResearch Fund. Correspondence to: Norris Comprehensive Cancer Center, Norris ToppingTower, Mailslot # 73, University of Southern California Los Angeles, 1441 Eastlake Avenue, Los Angeles, CA 90033 (E-mail: [email protected]). Evidence-based Oncology (2002) 3,141^142
141
Commentary A number of factors contribute to the poor prognosis of women with advanced ovarian cancer. There is an intrinsic resistance to adjuvant chemotherapy in over half of women with ovarian cancer. Chemoresistance develops in nearly half of those initially responsive to treatment. Clinicopathological characteristics such as clinical stage, histological grade and residual disease after debulking surgery also have prognostic value. Most anticancer agents induce tumor regression by triggering apoptosis. Factors which affect apoptosis, such as p53 status, are therefore likely to affect treatment sensitivity and overall prognosis. p53 mutations may encourage clones resistant to chemotherapy. These mutations are mostly missense and occur within conserved sequences of the p53 gene. They are the most common genetic alterations in human malignancies and have been detected in approximately 50% of epithelial ovarian cancers.1,2 Reles and colleagues evaluated p53 mutations and overexpression in a large series of fresh frozen specimens. p53 abnormalities were identified using DNA sequencing (exons 2 to 11) and immunohistochemical staining techniques. p53 mutation status and protein evaluation were correlated with resistance to platinumbased chemotherapy. Combination therapy with carboplatin^paclitaxel, the current gold standard in ovarian cancer treatment, was not in£uenced by p53 mutation status. This suggests that apoptosis induced by paclitaxel is independent of the p53 gene. Other literature has suggested that chemotherapy-induced apoptosis may occur in the absence of functional p53 and that cisplatin resistance may develop independent of p53 alterations.2 In order to clarify the role of p53 in predicting chemoresponse in epithelial ovarian cancer, p53 status could be evaluated in large randomized trials testing currently available drugs (carboplatin,
142
Evidence-based Oncology (2002) 3,141^142
paclitaxel, topotecan, encapsulated doxorubicin and gemcitabine). This may allow us to identify subgroups of patients who could benefit from alternative therapy regimens. Quality assessment (scale 1 = fair, 4 = excellent) Relevance 4 Validity 4 Applicability 2 Feasibility 2 Impact 2 Knowledge context 3 Dionyssios Katsaros, MD, PhD University of Turin Turin, Italy Literature cited 1. Levesque MA, Katsaros D, Yu H, Zola P, Sismondi P, Giardina G, Diamandis EP. Mutant p53 protein overexpression is associated with poor outcome in patients with well or moderately di¡erentiated ovarian carcinoma. Cancer 1995; 75(6): 1327^1338. 2. Levesque MA, Katsaros D, Massobrio M, Genta F, Yu H, Richiardi G, Fracchioli S, Durando A, Arisio R, Diamandis EP. Evidence for a dose^response e¡ect between p53 (but not p21WAF1/Cip1) protein concentrations, survival, and responsiveness in patients with epithelial ovarian cancer treated with platinum-based chemotherapy. Clin Cancer Res 2000; 6(8): 3260^3270. Level and Quality of Evidence: 1C
p53 mutations are associated with resistance to platinum-based chemotherapy in ovarian cancer Abstracted from: Reles A, Wen WH, Schmider A, Gee C, Runnebaun IB, Kilian U, Jones LA, El-Naggar A, Minguillon C, Schonborn I, Reich O, Kreinberg R, Lichtenegger W, Press MF. Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res 2001; 7: 2984^2997.
BACKGROUND The p53 tumor suppressor gene is the most frequently mutated gene in cancers, playing a central role in cell cycle regulation and induction of apoptosis.
METHOD Cohort analysis.
MAIN RESULTS p53 mutations were found in 56% of tumors. Time to progression (p = 0.029) and overall survival (p = 0.014) was shorter in women with p53 mutations compared to wild-type p53.Time to progression (p = 0.010) and overall survival (p = 0.007) were also shorter for women with mutations in highly conserved domains compared to all women. Time to progression (p = 0.071) and overall survival (p = 0.056) tended to be shorter in those with p53 overexpression (63% of women) compared to those without p53 overexpression. Women with overexpression (p = 0.001) or missense mutations (p = 0.008) were more likely to resist platinum-based chemotherapy.
PARTICIPANTS One hundred and seventy-eight women with invasive epithelial ovarian carcinoma; average age 57 years (range 23 to 84 years). Fifty percent of participants were resistant to chemotherapy at baseline.
AUTHORS’ CONCLUSIONS p53 mutations in tumors correlate with shortened time to progression and overall survival.The sensitivity of ovarian cancer cells to cisplatin and carboplatin may depend on a functional p53 protein to enable apoptosis induction.
OBJECTIVE To clarify the role of p53 alterations and their impact on response to chemotherapy. SETTING United States and Germany;1972 to 1995.
ANALYSIS All participants underwent surgery for ovarian cancer (exploratory laparotomy with bilateral salpingo-oophorectomy, hysterectomy, infracolic omentectomy, maximal tumor debulking). Snap-frozen carcinoma were analyzed for mutations of the p53 gene (exons 2 to 11) by single-strand conformation polymorphism and DNA sequencing. Immunohistochemistry was used to analyze p53 overexpression. Seventy-six percent of those with tumor stages 1b-IVreceived adjuvant chemotherapy. Of these, 47% received cisplatin^ cyclophosphamide and 36% received other regimens. Response to chemotherapy was classi¢ed as platinum refractory, platinum resistant and platinum sensitive. Twenty-four percent did not receive chemotherapy because of early stage disease, old age or refusal. Median follow-up was 31 months for the total cohort and 52 months for survivors. OUTCOMES Evidence of p53 mutations in tumors; time to progression; resistance to platinum-based chemotherapy; overall survival. 1363- 4054/02/$-see front matter & 2002 Elsevier Science Ltd. Allrights reserved doi:10.1054/ebon.37, available online at http://www.idealibrary.com.on
METHOD NOTES Power Blinding Randomization Other
No power calculation Not applicable Not applicable Most earlier studies on p53 used archival formalin-¢xed, para⁄nembedded tissue.This reduced immunoreactivity of many proteins after the ¢xation process. Only frozen tissue was used in this study
Sources of funding: The National Cancer Institute; The American Cancer Society; The Molecular Core Laboratory Facilities of the GCRC;The Deutsche Forschungsgemeinschaft; University of Southern California Overian CancerResearch Fund. Correspondence to: Norris Comprehensive Cancer Center, Norris ToppingTower, Mailslot # 73, University of Southern California Los Angeles, 1441 Eastlake Avenue, Los Angeles, CA 90033 (E-mail: [email protected]). Evidence-based Oncology (2002) 3,141^142
141
Commentary A number of factors contribute to the poor prognosis of women with advanced ovarian cancer. There is an intrinsic resistance to adjuvant chemotherapy in over half of women with ovarian cancer. Chemoresistance develops in nearly half of those initially responsive to treatment. Clinicopathological characteristics such as clinical stage, histological grade and residual disease after debulking surgery also have prognostic value. Most anticancer agents induce tumor regression by triggering apoptosis. Factors which affect apoptosis, such as p53 status, are therefore likely to affect treatment sensitivity and overall prognosis. p53 mutations may encourage clones resistant to chemotherapy. These mutations are mostly missense and occur within conserved sequences of the p53 gene. They are the most common genetic alterations in human malignancies and have been detected in approximately 50% of epithelial ovarian cancers.1,2 Reles and colleagues evaluated p53 mutations and overexpression in a large series of fresh frozen specimens. p53 abnormalities were identified using DNA sequencing (exons 2 to 11) and immunohistochemical staining techniques. p53 mutation status and protein evaluation were correlated with resistance to platinumbased chemotherapy. Combination therapy with carboplatin^paclitaxel, the current gold standard in ovarian cancer treatment, was not in£uenced by p53 mutation status. This suggests that apoptosis induced by paclitaxel is independent of the p53 gene. Other literature has suggested that chemotherapy-induced apoptosis may occur in the absence of functional p53 and that cisplatin resistance may develop independent of p53 alterations.2 In order to clarify the role of p53 in predicting chemoresponse in epithelial ovarian cancer, p53 status could be evaluated in large randomized trials testing currently available drugs (carboplatin,
142
Evidence-based Oncology (2002) 3,141^142
paclitaxel, topotecan, encapsulated doxorubicin and gemcitabine). This may allow us to identify subgroups of patients who could benefit from alternative therapy regimens. Quality assessment (scale 1 = fair, 4 = excellent) Relevance 4 Validity 4 Applicability 2 Feasibility 2 Impact 2 Knowledge context 3 Dionyssios Katsaros, MD, PhD University of Turin Turin, Italy Literature cited 1. Levesque MA, Katsaros D, Yu H, Zola P, Sismondi P, Giardina G, Diamandis EP. Mutant p53 protein overexpression is associated with poor outcome in patients with well or moderately di¡erentiated ovarian carcinoma. Cancer 1995; 75(6): 1327^1338. 2. Levesque MA, Katsaros D, Massobrio M, Genta F, Yu H, Richiardi G, Fracchioli S, Durando A, Arisio R, Diamandis EP. Evidence for a dose^response e¡ect between p53 (but not p21WAF1/Cip1) protein concentrations, survival, and responsiveness in patients with epithelial ovarian cancer treated with platinum-based chemotherapy. Clin Cancer Res 2000; 6(8): 3260^3270. Level and Quality of Evidence: 1C