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.

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.

Patient navigation and the quality of breast cancer care: an analysis of the breast cancer care quality indicators.

PURPOSE: Patient navigation programs are initiated to help guide patients through barriers in a complex cancer care system. We sought to analyze the impact of our patient navigator program on the adherence to specific Breast Cancer Care Quality Indicators (BCCQI). METHODS: A retrospective cohort of patients with stage I-III breast cancer seen the calendar year prior to the initiation of the patient navigation program were compared with patients treated in the ensuing two calendar years. Quality indicators deemed appropriate for analysis were those associated with overcoming barriers to treatment and those associated with providing health education and improving patient decision-making. RESULTS: A total of 134 consecutive patients between January 1, 2006 and December 31, 2006 and 234 consecutive patients between January 1, 2008 and December 31, 2009 were evaluated for compliance with the BCCQI. There was no significant difference in the mean age or race/ethnic distribution of the study population. In all ten BCCQI evaluated, there was improvement in the percentage of patients in compliance from pre and post implementation of a patient navigator program (range 2.5-27.0 %). Overall, compliance with BCCQI improved from 74.1 to 95.5 % (p < 0.0001). Indicators associated with informed decision-making and patient preference achieved statistical significance, while only completion axillary node dissection in sentinel node-positive biopsies in the process of treatment achieved statistical significance. CONCLUSIONS: The implementation of a patient navigator program improved breast cancer care as measured by BCCQI. The impact on disease-free and overall survival remains to be determined.

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update.

PURPOSE: To update recommendations on appropriate use of breast cancer biomarker assay results to guide adjuvant endocrine and chemotherapy decisions in early-stage breast cancer. METHODS: An updated literature search identified randomized clinical trials and prospective-retrospective studies published from January 2016 to October 2021. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert Panel members used informal consensus to develop evidence-based recommendations. RESULTS: The search identified 24 studies informing the evidence base. RECOMMENDATIONS: Clinicians may use Oncotype DX, MammaPrint, Breast Cancer Index (BCI), and EndoPredict to guide adjuvant endocrine and chemotherapy in patients who are postmenopausal or age > 50 years with early-stage estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+ and HER2-) breast cancer that is node-negative or with 1-3 positive nodes. Prosigna and BCI may be used in postmenopausal patients with node-negative ER+ and HER2- breast cancer. In premenopausal patients, clinicians may use Oncotype in patients with node-negative ER+ and HER2- breast cancer. Current data suggest that premenopausal patients with 1-3 positive nodes benefit from chemotherapy regardless of genomic assay result. There are no data on use of genomic tests to guide adjuvant chemotherapy in patients with ≥ 4 positive nodes. Ki67 combined with other parameters or immunohistochemistry 4 score may be used in postmenopausal patients without access to genomic tests to guide adjuvant therapy decisions. BCI may be offered to patients with 0-3 positive nodes who received 5 years of endocrine therapy without evidence of recurrence to guide decisions about extended endocrine therapy. None of the assays are recommended for treatment guidance in individuals with HER2-positive or triple-negative breast cancer. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.Additional information is available at www.asco.org/breast-cancer-guidelines.

Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer.

The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.

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.

A phase I trial of oblimersen sodium in combination with cisplatin and 5-fluorouracil in patients with advanced esophageal, gastroesophageal junction, and gastric carcinoma.

PURPOSE: To determine the maximum tolerated dose of oblimersen, an antisense oligonucleotide directed to the Bcl-2 mRNA, in combination with cisplatin and 5-flourouracil in patients with advanced gastric and esophageal carcinoma. METHODS: Patients were treated with escalating doses of oblimersen administered by continuous intravenous infusion (CIVI) days 1 to 7, CIVI 5-fluorouracil (5-FU) days 4 to 7, and cisplatin on day 4 every 3 weeks. RESULTS: Fifteen patients received a total of 49 courses of oblimersen at doses of 3, 5, or 7 mg/kg/d given as a 7 day CIVI in combination with 4 or 5 day CIVI of 5-FU (1000 or 750 mg/m2/d) plus intravenous cisplatin (100 or 75 mg/m2 over 2 hours). The recommended phase II dose of oblimersen was 5 mg/kg/d in combination with 5-FU (750 mg/m2/d for 4 days) and cisplatin (75 mg/m). The most common grade 3 to 4 adverse events that occurred in at least 10% of patients at all dose levels included neutropenia (33%), hypokalemia (27%), infection (20%), and mucositis, fatigue, dizziness, thrombosis, and dehydration (in 13% for each category). CONCLUSION: The combination of oblimersen with 5-FU and cisplatin chemotherapy is feasible in patients with advanced upper gastrointestinal cancer, with antitumor activity observed in gastric carcinoma.