Steven W. Corso

Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin’s Lymphoma

PURPOSE To evaluate response to single-agent rituximab in patients with indolent non-Hodgkins lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy. PATIENTS AND METHODS Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m(2) intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses. CONCLUSION Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.

Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study

PURPOSE We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. PATIENTS AND METHODS One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. RESULTS As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. CONCLUSION This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

Phase III Trial of Gabapentin Alone or in Conjunction With an Antidepressant in the Management of Hot Flashes in Women Who Have Inadequate Control With an Antidepressant Alone: NCCTG N03C5

PURPOSE Despite the utility of newer antidepressants for alleviating hot flashes, antidepressants do not work adequately enough in many patients. Gabapentin is a nonhormonal agent that also can reduce hot flashes. No data have been available to address whether the combination of both agents would more effectively alleviate hot flashes, compared with gabapentin alone, in patients with inadequate hot flash control with an antidepressant alone. PATIENTS AND METHODS This was a randomized trial in which 118 patients with inadequate hot flash control on an antidepressant were randomly assigned to receive both an antidepressant and gabapentin versus being weaned off the antidepressant and receiving gabapentin alone. Patients were observed for 5 weeks (including a baseline week in which patients continued on their current antidepressant without gabapentin) during which time they completed validated daily hot flash diaries. RESULTS Ninety-one patients provided complete data at the 5-week assessment. Regardless of whether or not the antidepressant was continued when gabapentin was started, there was an approximately 50% median reduction in hot flash frequencies (54%; 95% CI, 34% to 70% for combined treatment v 49%; 95% CI, 26% to 58% for gabapentin alone) and scores (56%; 95% CI, 26% to 71% for combined treatment v 60%; 95% CI, 33% to 73% for gabapentin alone). CONCLUSION Gabapentin seems to decrease hot flashes by approximately 50% in women with inadequate hot flash control who were using an antidepressant. This study saw no significant additional hot flash reduction from continuation of the antidepressant.

In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles

AIMS A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. METHODS Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen : N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. RESULTS Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). CONCLUSION The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.

Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity

BACKGROUND Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races. METHODS PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months. RESULTS In 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients. CONCLUSION Differences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy. IMPLICATIONS FOR PRACTICE This secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life.

Validating CYP2D6 Genotype-Guided Tamoxifen Therapy for a Multiracial U.S. Population.

Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective agent for hormone sensitive breast cancer with documented efficacy in prevention, treatment of preneoplasia, and treatment in both the adjuvant and metastatic settings. However, tamoxifen is a prodrug, and up to half of those taking it may not receive the full benefit because of genetic differences in CYP2D6 that affect metabolism to its active form, endoxifen. Tamoxifen is FDA approved for use at both 20mg/day and 40 mg/day, however by convention is dosed at 20mg. We aimed to determine if endoxifen levels can be manipulated by genotype-guided dosing of tamoxifen.Methods: 118 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the CYP450 Amplichip® (Roche Diagnostics) for 2D6 alleles: *1-11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41 XN. Tamoxifen dose was increased from 20mg to 40mg in patients with any intermediate or poor metabolizing (IM or PM) alleles [but not in patients homozygous for extensive metabolizing (EM) alleles]. Endoxifen levels were drawn at baseline and 4 months later. Assuming that endoxifen levels in IM pts are 40% lower than EM at baseline (Jin et al., 2005) and with a one-sided significance level of 0.025 and a sample size of 40 patients with intermediate metabolizing CYP2D6 genotypes, this study would have 84% power to detect a 40% increase in endoxifen.Results: Of the 118 patients, 25 withdrew or were removed from study, leaving 93 who have completed this study and who are evaluable for the primary analysis. Genotyping results were presented at 2009 ASCO meeting (Irvin et al.). For this analysis, 19 (20%) are African-American, 69 (74%) are non-Hispanic white, 2 are Hispanic, and 3 are Asian. For the 93 evauable patients, genotyping revealed 31 (33%) EM/EM, 1 EM/UM (ultra-rapid), 20 (22%) EM/IM, 19 (20%) EM/PM, 4 (4%) IM/IM, 9 (10%) IM/PM, 9 (10%) PM/PM and 1 unknown. The primary outcome, the tamoxifen metabolite levels, including endoxifen, will be available in July.(Supported by NC University Cancer Research Fund, NCI SPORE, Laboratory Corporation of America, Roche Diagnostics) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 410.

Patients' Understanding of a CYP2D6 Tamoxifen Genotyping Study.

Background: Pharmacogenomics is an emerging area for breast cancer research. Little is known about how well patients understand pharmacogenomics or the rationale for research in this area. The objective of this study was to analyze patient understanding of a clinical trial involving CYP2D6 genotyping to guide tamoxifen (T) therapy for breast cancer.Methods: We conducted a survey of understanding of pharmacogenomics and the purposes of a clinical trial among patients (pts) eligible for LCCC0801, a prospective Phase 2 study of CYP2D6 genotype-guided therapy for pts on tamoxifen for breast cancer. In this trial, we evaluated baseline endoxifen (E) levels and the impact of increased T dose to 40 mg/day among pts with any dysfunctional CYP2D6 alleles. The primary endpoint of change in E levels is not yet reported. All trial participants and those who declined participation were eligible for this survey. The research nurse administered 11 written questions at time of consent related to the purpose of this study and the nature of pharmacogenomic research. Pts had unlimited time to complete the survey written in a 5 point scale (strongly agree, agree, not sure, disagree, strongly disagree). For pts declining to enroll in the parent study, we offered an identical companion survey to which they could separately give consent.Results: Of 118 pts in the parent study, 117 completed the survey. Following informed consent, all respondents expressed confidence that they understood the purpose of the trial, 75% strongly agreed that they understood the purpose of the study. 98% of participants understood that this was a study of how different people respond to T, but 42% also incorrectly felt that this was a study of how different types of breast cancer respond to T, and 30% incorrectly felt that this study evaluated genetic risk for developing breast cancer. Though the consent form clearly stated that there may be no direct benefit to participants and that the purpose of the study was to help future pts, 68% reported that they would benefit directly, and only 22% felt the study was designed only to help future pts. When asked if the study involved genetics, 14% of pts disagreed, or were unsure. 45% of participants were uncomfortable or unsure with “having your doctor determine your T dose from the results of a genetic test.” Among a small sample of pts who declined trial participation but consented to the survey (13/30 decliners, 43%), compared to trial participants, fewer reported strong confidence in understanding the purpose of the trial (38% vs. 75%, p=0.0034), and a greater percentage identified an inaccurate purpose of the trial (69% vs. 42%, p = 0.043).Conclusions: After informed consent, a high percentage of participants in a pharmacogenomic clinical trial are able to correctly identify the primary purpose of the research, but a substantial minority hold false views about what the trial is designed to investigate. The majority of participants believe that they will directly benefit from trial participation, and few may understand that the primary purpose of the study is to improve care for future patients. Opportunities exist for improved understanding and communication of pharmacogenomic research and further evaluation of this area is needed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6082.

Abstract P1-03-02: CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity

Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective hormonal agent for pre-menopausal hormone-receptor positive breast cancer patients. CYP2D6 activity phenotype, which is classified by genotype, predicts the extent of metabolic activation of tamoxifen to endoxifen. We previously reported that increasing the daily dose to 40 mg/day in intermediate metabolizers (IMs), but not poor metabolizers (PMs), achieves target endoxifen concentrations, defined as that of extensive metabolizers (EMs) on 20 mg/day. There was substantial endoxifen variability in the IM phenotype group, which is composed of several discrete diplophenotypes (EM/IM, EM/PM, IM/IM, IM/PM). We enrolled a second, larger cohort of patients in order to determine whether these diplophenotypes should be combined into a single IM phenotype or segregated. Methods: 380 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the Amplichip® CYP450 test (Roche Diagnostics) for CYP2D6, followed by systematic assignment of phenotype based on diplophenotype. Tamoxifen was increased from 20 to 40 mg/day in PMs and IMs. Endoxifen concentrations in IM diplophenotypes were compared with EM/EMs and PM/PMs at baseline and at 4 months (after dose increase in patients with IM and PM phenotypes). Results: After exclusion of UM patients and patients missing endoxifen data at baseline and/or 4 months, 295 patients were included in this analysis. At baseline the EM/IM patients had similar endoxifen level to the EM/EM patients while the IM/IM and IM/PM patients had similar levels to the PM/PMs. After 4 months on 40 mg/day the endoxifen concentrations in EM/IM patients were significantly greater than EM/EMs; EM/PM and IM/IM patients were similar to EM/EMs; but IM/PM patients remained significantly lower than EM/EMs and similar to PM/PMs (See Table 1 for results). Conclusions: The large group of patients currently defined as CYP2D6 intermediate metabolizers is comprised of four distinct CYP2D6 diplophentoypes. The most metabolically active diplophenotype (EM/IM) are very similar to EM/EMs while the least active diplophenotype (IM/PM) are similar to PM/PMs. A more accurate CYP2D6 activity classification system may be necessary if genetic association testing and genotype-guided therapy are pursued. Citation Format: Daniel L Hertz, Anna C Snavely, Howard L McLeod, Christine M Walko, Joseph G Ibrahim, Steven Anderson, Karen E Weck, Peter Rubin, Oludamilola Olajide, Susan Moore, Rachel Raab, Daniel R Carrizosa, Steven Corso, Gary Schwartz, Jeffrey M Peppercorn, James P Evans, Zeruesenay Desta, David A Flockhart, Lisa A Carey, William J Irvin Jr. CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-02.