5580
`
`‘Z138
`
`TUMOR BlOLOGY/HUMAN GENETICS
`
`Proceedings of ASCO Volume I 7 I 998
`
`IN WOMEN
`PROPHYLACTIC MASTECTOMY (PM) AND OOPHORECTOMY (PO)
`UNDERGOING BRCA1/2 TESTING. D. Schrag, K.J. Kalkbrenner, T.L. Light,
`K.A. Schneider, J.E. Garber. Dana Farber Cancer Institute, Boston, MA.
`Women tested for BRCA1/2 mutations may consider PM and/or P0 based
`on the results of genetic testing for predisposing mutations. A cohort of 88
`women with at least 10% risk of inherited breastlovarian cancer provided
`information about attitudes towards PM and PO before testing and again at
`mean 5.5 months following results disclosure. 46 women had prior
`breast/ovarian cancer (CA); 42 women had not had cancer (NC). Before
`genetic testing, 8 women had had PM, 12 PO and 5 therapeutic
`oophorectomy. At baseline, 37/80 had discussed PM with a physician and
`33/71 had discussed PO 8/80 were considering PM and 24/71 P0.
`Following BRCA disclosure, 6 women underwent PM (3 CA, 3 NC) and 5
`had PO (2 CA, 3 NC); one woman (NC) had both procedures. Mutations
`were identified in all women having prophylactic surgery following results
`disclosure except for 2 who had PM with indeterminate results but
`abnormal breast biopsies.
`In addition, 13 were still considering PM (8+,
`4?) and 19 were considering P0 (12+, 6?, 1-) For the entire cohort, no
`cancers have been detected at PM; one borderline ovarian cancer was
`found at PO. PM and P0 are often considered by women who have BRCA1l2
`mutation testing even with indeterminate test results.
`
`*2I39
`
`LY231514 (MTA): RELATIONSHIP OF VITAMIN METABOLITE PROFILE TO TOXIC-
`ITY. C. Niyikiza, J. Walling, D. Thornton, D. Seltz, and R. Allen. Eli Lillyand
`Company, Indianapolis, IN, and Univ of Colorado Health Science Center,
`Denver, CO.
`
`LY231514 (MTA) is a new generation multitargeted antifolate antimetabo-
`lite with inhibitory activity against thymidylate synthase, dihydrofolate
`reductase and glycinamide ribonucleotide formyl transferase. Of a total of
`246 patients (pts) in phase II trials treated with MTA (600 mg/m2 IV over
`10 minutes once every 21 days) 118 pts also had vitamin metabolites
`measured. Because earlier studies with other antifolates had suggested
`that nutritional status may play a role in the likelihood that a patient will
`experience severe toxicity, levels of the vitamin metabolites homocysteine,
`cystathionine and methylmalonic acid were measured at baseline and once
`each cycle thereafter. A multivariate statistical analysis of the data was
`conducted in order to determine which among a set of pre-specified
`predictors (creatinine clearance, albumin levels,
`liver enzyme levels, and
`vitamin metabolites) might correlate with toxicity. There was a strong
`correlation between baseline homocysteine levels and the development of
`the following toxicities at any time during the study: CTC Grade 4
`neutropenia (57 pts, p < 0.0001), Grade 4 thrombocytopenia (13 pts,
`p < 0.0001), Grade 3 or 4 mucositis (8 pts, p < 0.0003), and Grade 3 or
`4 diarrhea (8 pts, p < 0.004). cystathionine levels did not correlate with
`hematologic toxicity or mucositis but were moderately correlated with
`fatigue (p < 0.04). Maximum cystathionine levels doubled from baseline
`during treatment with MTA. No correlation between toxicity (CTC Grades as
`defined above) and the remaining pre»specified predictors was seen.
`Toxicity was seen in all patients with homocysteine levels above a threshold
`concentration of 10 pM. A correlation over time between homocysteine
`levels and CTC Grade 4 neutropenia and thrombocytopenia and CTC Grade
`3 or 4 mucositis was also observed, but only in the first two cycles of
`treatment. Maximum homocysteine levels did not appear to change from
`baseline during treatment with MTA.
`
`32140
`
`*2141
`
`PHASE I CHEMOPREVENTION CLINICAL TRIAL OF CURCUMIN A.L. Cheng, J.K.
`Lin, M.M. Hsu, IS. Sheri, J. l’. K0, J] Lin, B]. Lin, M.S. Wu, H. 5. Yu, S.H.
`Jee, G.S. Cheri, TM. Chen, C.A. Chen, M.K. Lai, KS. Pu, M.H. Pan,
`)’.J.
`Wang, C.C. Isai, C.l’. Hsieh. National Taiwan University College of Medi-
`cine, Taipei, Taiwan; and Kaohsiung Medical College, Kaohsiung, Taiwan.
`Curcumin (diferuloylmethane), a yellow substance from the root of the
`plant Curcuma longa Linn., has been demonstrated to inhibit murine
`carcinogenesis of skin, stomach, intestine and oral cavity. A phase-I clinical
`trial was conducted to examine the toxicology, the pharmacokinetics and
`the biologically effective dose of curcumin in humans. Five types of
`high-risk individual were eligible: 1. recently-resected urinary bladder
`cancer (BC), 2. arsenic Bowen's disease (BD), 3. uterine cervical intraepi—
`thellal neoplasia (CIN). 4. oral leukoplakia (OL), and 5. intestinal metap|a-
`sia of gastric mucosa (IM). The starting dose was 500 mg/day, taken orally
`for 3 months. If no any 2 Grade II toxicity was noted in at least 3 p’ts, the
`dose was escalated successively to 1000 (level II), 2000 (level III), 4000
`(level IV), and 8000 mg/day (level V). Lesion sites were biopsied before and
`3 months aftertaking curcumin. Serum curcumin was quantitated by HPLC
`method. In a total of 25 pts enrolled, no treatment—re|ated toxicity was
`noted up to 8000 mg/day (level V). Serum concentration usually peaked at
`1 to 2 hours after oral intake, and gradually declined within 12 hours. The
`average peak serum concentrations after taking 4000 mg, 6000 mg and
`8000 mg of curcumin were 0.41 : 0.07 ;1M, 0.57 1 0.05 LLM, and
`1.75 : 0.80 p.M, respectively. Although 3 of 25 p'ts proceeded to develop
`frank malignancies, histological improvement of the precancerous lesions
`was seen in 1 (level III) of the 2 pts with BC, 2 (both level IV) of 7 p'ts with
`0L, 1 (level II) of 6 p'ts with IM, 1 (level I) of 4 p'ts with CIN, and 2 (level I
`and III) of 6 p‘ts with BD. Although curcumin is probably non—toxic even up
`to more than 8000 mg/day, the bulky volume of drug tablets became a
`limiting factor itself. Therefore, for future phase II studies, doses close to
`8000 mglday may be recommended.
`
`FACTORS INFLUENCING THE DECISION T0 UNDERGD BRCA1/2 GENE TESTING: A .
`STUDY OF ASHKENAZI JEWISH WOMEN WITH A PERSONAL HISTORY OF BREAST
`CANCER (BC), ENROLLED IN AN ONTARIO CANCER GENETICS NETWORK
`PRUTUCDL. K.A. Philligs, J. Hunter, E. Warner; W. Meschino, G. Glendon,
`l.L. Andrulis and RJ. Goodwin. Mt Sinai Hospital, Princess Margaret
`Hospital, Toronto—Sunnybrook Regional Cancer Center, North York General
`Hospital, Toronto, Ontario, Canada.
`
`The purpose of this study was to examine the contribution of demographic,
`medical, psychosocial, and cultural/religious factors in decision making
`regarding testing for BRCAI and BRCA2 mutations,
`in Canadian Jewish
`women with BC, unselected for family history. A self-administered question-
`naire was developed and distributed, (after genetic counseling), to 134
`individuals enrolled in a research—based testing program for Ashkenazi
`women. Data for the first 52 participants are presented. The response rate
`was 40 (77%). Respondents had the following demographic features: age
`40-75 years (median = 59), married 83%, had children 92%, post-
`secondary education 55%, practicing Jew 88%, extra health insurance
`77%, median age of BC diagnosis = 50. No patient had ovarian cancer
`(OC). 45% had at least one 1st degree relative with BC or OC (median
`perceived risk for being a gene carrier 50%). 35% had no affected relatives
`(median perceived risk for being a carrier = 15%). The 5 factors most
`frequently identified as “definitely an important factor in my decision
`making" were, desire to contribute to research (90%), curiosity (77%),
`potential benefit to other family members (64%), potential for personal
`cancer prevention (59%), and impact on ovarian cancer screening practice
`(41%). 53% and 38% of women respectively, identified a potential change
`in their perspective on prophylactic oophorectomy and mastectomy as at
`least “somewhat important." Main concerns related to insurance discrimi-
`nation (35%), confidentiality (30%), accuracy and interpretability of
`results (33%), potential impact on marriage prospects for family members
`(20%), and focus on the Jewish community (15%). Potential employer
`discrimination and impact on life planning were “not a factor" for most
`(90%,82%). The focus on factors unrelated to personal physical health is
`notable. The generalisability of these results to women not affected by BC
`requires further study. Final results for the 134 patients will be presented.
`
`ACCORD EX 1006
`
`‘Z138
`
`TUMOR BlOLOGY/HUMAN GENETICS
`
`Proceedings of ASCO Volume I 7 I 998
`
`IN WOMEN
`PROPHYLACTIC MASTECTOMY (PM) AND OOPHORECTOMY (PO)
`UNDERGOING BRCA1/2 TESTING. D. Schrag, K.J. Kalkbrenner, T.L. Light,
`K.A. Schneider, J.E. Garber. Dana Farber Cancer Institute, Boston, MA.
`Women tested for BRCA1/2 mutations may consider PM and/or P0 based
`on the results of genetic testing for predisposing mutations. A cohort of 88
`women with at least 10% risk of inherited breastlovarian cancer provided
`information about attitudes towards PM and PO before testing and again at
`mean 5.5 months following results disclosure. 46 women had prior
`breast/ovarian cancer (CA); 42 women had not had cancer (NC). Before
`genetic testing, 8 women had had PM, 12 PO and 5 therapeutic
`oophorectomy. At baseline, 37/80 had discussed PM with a physician and
`33/71 had discussed PO 8/80 were considering PM and 24/71 P0.
`Following BRCA disclosure, 6 women underwent PM (3 CA, 3 NC) and 5
`had PO (2 CA, 3 NC); one woman (NC) had both procedures. Mutations
`were identified in all women having prophylactic surgery following results
`disclosure except for 2 who had PM with indeterminate results but
`abnormal breast biopsies.
`In addition, 13 were still considering PM (8+,
`4?) and 19 were considering P0 (12+, 6?, 1-) For the entire cohort, no
`cancers have been detected at PM; one borderline ovarian cancer was
`found at PO. PM and P0 are often considered by women who have BRCA1l2
`mutation testing even with indeterminate test results.
`
`*2I39
`
`LY231514 (MTA): RELATIONSHIP OF VITAMIN METABOLITE PROFILE TO TOXIC-
`ITY. C. Niyikiza, J. Walling, D. Thornton, D. Seltz, and R. Allen. Eli Lillyand
`Company, Indianapolis, IN, and Univ of Colorado Health Science Center,
`Denver, CO.
`
`LY231514 (MTA) is a new generation multitargeted antifolate antimetabo-
`lite with inhibitory activity against thymidylate synthase, dihydrofolate
`reductase and glycinamide ribonucleotide formyl transferase. Of a total of
`246 patients (pts) in phase II trials treated with MTA (600 mg/m2 IV over
`10 minutes once every 21 days) 118 pts also had vitamin metabolites
`measured. Because earlier studies with other antifolates had suggested
`that nutritional status may play a role in the likelihood that a patient will
`experience severe toxicity, levels of the vitamin metabolites homocysteine,
`cystathionine and methylmalonic acid were measured at baseline and once
`each cycle thereafter. A multivariate statistical analysis of the data was
`conducted in order to determine which among a set of pre-specified
`predictors (creatinine clearance, albumin levels,
`liver enzyme levels, and
`vitamin metabolites) might correlate with toxicity. There was a strong
`correlation between baseline homocysteine levels and the development of
`the following toxicities at any time during the study: CTC Grade 4
`neutropenia (57 pts, p < 0.0001), Grade 4 thrombocytopenia (13 pts,
`p < 0.0001), Grade 3 or 4 mucositis (8 pts, p < 0.0003), and Grade 3 or
`4 diarrhea (8 pts, p < 0.004). cystathionine levels did not correlate with
`hematologic toxicity or mucositis but were moderately correlated with
`fatigue (p < 0.04). Maximum cystathionine levels doubled from baseline
`during treatment with MTA. No correlation between toxicity (CTC Grades as
`defined above) and the remaining pre»specified predictors was seen.
`Toxicity was seen in all patients with homocysteine levels above a threshold
`concentration of 10 pM. A correlation over time between homocysteine
`levels and CTC Grade 4 neutropenia and thrombocytopenia and CTC Grade
`3 or 4 mucositis was also observed, but only in the first two cycles of
`treatment. Maximum homocysteine levels did not appear to change from
`baseline during treatment with MTA.
`
`32140
`
`*2141
`
`PHASE I CHEMOPREVENTION CLINICAL TRIAL OF CURCUMIN A.L. Cheng, J.K.
`Lin, M.M. Hsu, IS. Sheri, J. l’. K0, J] Lin, B]. Lin, M.S. Wu, H. 5. Yu, S.H.
`Jee, G.S. Cheri, TM. Chen, C.A. Chen, M.K. Lai, KS. Pu, M.H. Pan,
`)’.J.
`Wang, C.C. Isai, C.l’. Hsieh. National Taiwan University College of Medi-
`cine, Taipei, Taiwan; and Kaohsiung Medical College, Kaohsiung, Taiwan.
`Curcumin (diferuloylmethane), a yellow substance from the root of the
`plant Curcuma longa Linn., has been demonstrated to inhibit murine
`carcinogenesis of skin, stomach, intestine and oral cavity. A phase-I clinical
`trial was conducted to examine the toxicology, the pharmacokinetics and
`the biologically effective dose of curcumin in humans. Five types of
`high-risk individual were eligible: 1. recently-resected urinary bladder
`cancer (BC), 2. arsenic Bowen's disease (BD), 3. uterine cervical intraepi—
`thellal neoplasia (CIN). 4. oral leukoplakia (OL), and 5. intestinal metap|a-
`sia of gastric mucosa (IM). The starting dose was 500 mg/day, taken orally
`for 3 months. If no any 2 Grade II toxicity was noted in at least 3 p’ts, the
`dose was escalated successively to 1000 (level II), 2000 (level III), 4000
`(level IV), and 8000 mg/day (level V). Lesion sites were biopsied before and
`3 months aftertaking curcumin. Serum curcumin was quantitated by HPLC
`method. In a total of 25 pts enrolled, no treatment—re|ated toxicity was
`noted up to 8000 mg/day (level V). Serum concentration usually peaked at
`1 to 2 hours after oral intake, and gradually declined within 12 hours. The
`average peak serum concentrations after taking 4000 mg, 6000 mg and
`8000 mg of curcumin were 0.41 : 0.07 ;1M, 0.57 1 0.05 LLM, and
`1.75 : 0.80 p.M, respectively. Although 3 of 25 p'ts proceeded to develop
`frank malignancies, histological improvement of the precancerous lesions
`was seen in 1 (level III) of the 2 pts with BC, 2 (both level IV) of 7 p'ts with
`0L, 1 (level II) of 6 p'ts with IM, 1 (level I) of 4 p'ts with CIN, and 2 (level I
`and III) of 6 p‘ts with BD. Although curcumin is probably non—toxic even up
`to more than 8000 mg/day, the bulky volume of drug tablets became a
`limiting factor itself. Therefore, for future phase II studies, doses close to
`8000 mglday may be recommended.
`
`FACTORS INFLUENCING THE DECISION T0 UNDERGD BRCA1/2 GENE TESTING: A .
`STUDY OF ASHKENAZI JEWISH WOMEN WITH A PERSONAL HISTORY OF BREAST
`CANCER (BC), ENROLLED IN AN ONTARIO CANCER GENETICS NETWORK
`PRUTUCDL. K.A. Philligs, J. Hunter, E. Warner; W. Meschino, G. Glendon,
`l.L. Andrulis and RJ. Goodwin. Mt Sinai Hospital, Princess Margaret
`Hospital, Toronto—Sunnybrook Regional Cancer Center, North York General
`Hospital, Toronto, Ontario, Canada.
`
`The purpose of this study was to examine the contribution of demographic,
`medical, psychosocial, and cultural/religious factors in decision making
`regarding testing for BRCAI and BRCA2 mutations,
`in Canadian Jewish
`women with BC, unselected for family history. A self-administered question-
`naire was developed and distributed, (after genetic counseling), to 134
`individuals enrolled in a research—based testing program for Ashkenazi
`women. Data for the first 52 participants are presented. The response rate
`was 40 (77%). Respondents had the following demographic features: age
`40-75 years (median = 59), married 83%, had children 92%, post-
`secondary education 55%, practicing Jew 88%, extra health insurance
`77%, median age of BC diagnosis = 50. No patient had ovarian cancer
`(OC). 45% had at least one 1st degree relative with BC or OC (median
`perceived risk for being a gene carrier 50%). 35% had no affected relatives
`(median perceived risk for being a carrier = 15%). The 5 factors most
`frequently identified as “definitely an important factor in my decision
`making" were, desire to contribute to research (90%), curiosity (77%),
`potential benefit to other family members (64%), potential for personal
`cancer prevention (59%), and impact on ovarian cancer screening practice
`(41%). 53% and 38% of women respectively, identified a potential change
`in their perspective on prophylactic oophorectomy and mastectomy as at
`least “somewhat important." Main concerns related to insurance discrimi-
`nation (35%), confidentiality (30%), accuracy and interpretability of
`results (33%), potential impact on marriage prospects for family members
`(20%), and focus on the Jewish community (15%). Potential employer
`discrimination and impact on life planning were “not a factor" for most
`(90%,82%). The focus on factors unrelated to personal physical health is
`notable. The generalisability of these results to women not affected by BC
`requires further study. Final results for the 134 patients will be presented.
`
`ACCORD EX 1006
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