Adherence Outcomes and Risk Factors Predicting Nonadherence to Active Surveillance in Patients With Stage 1 Testicular Germ Cell Tumors.

PURPOSE: Adherence to active surveillance in patients with stage 1 testicular cancers may be influenced by factors affecting capacity and motivation to attend appointments. The aims of this study were to assess adherence to active surveillance and analyze factors which may impact adherence. PATIENTS AND METHODS: A retrospective cohort study was conducted in patients diagnosed with stage 1 testicular cancer between 2005 and 2020, and managed with active surveillance at 3 institutions in South Western Sydney, Australia. Adherence with active surveillance was followed to 2023 and patients were subsequently classified into 3 groups: "Optimal," "Adequate" or "Loss to follow-up" (LTFU). Factors for adherence were analyzed using multivariable logistic regression. Disease recurrence was analyzed using multivariable Cox regression. RESULTS: In 125 patients, adherence with active surveillance was assessed as "Optimal" in 64 (51%), "Adequate" in 14 (11%), and LTFU in 47 (38%). Multivariable analysis demonstrated that patients had higher odds of being in the "Optimal" or "Adequate" categories if they were from a culturally and linguistically diverse background (OR 4.86, P = .026), nonsmokers (OR 7.63, P = .0002), not employed (OR 4.93, P = .0085), had a partner (OR 2.74, P = .0326), or were diagnosed after June 2016 (OR 5.22, P = .0016). Recurrence occurred in 21 patients (17%). The risk of recurrence increased with the presence of multiple pathological risk factors (HR 5.77, P = .0032), if patients were unemployed (HR 2.57, P = .032), or if they had "Optimal" or "Adequate" adherence (HR 12.74, P = .0136). CONCLUSION: Adherence with active surveillance was poorer in this cohort of stage 1 testicular cancer patients. Patients from culturally and linguistically diverse backgrounds and those who were nonsmokers, unemployed, with a partner, and later date of diagnosis, were more likely to be adherent with active surveillance.

Review of Toxicities of PARP Inhibitors in Metastatic Castrate Resistant Prostate Cancer.

There is emerging evidence for the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with mCRPC with patients harboring germline or somatic mutations deriving clinical benefit. However, the toxicity profile of PARPi in mCRPC is not well established. In March 2022 a literature search was conducted across 4 databases - Medline, PubMed, Cochrane Library and Embase. In total, 14 relevant studies were identified cumulating in 2066 patients that were treated with PARPi. The overall ORR to PARPi alone or in combination with other therapy was 37% (246/666). In 5trials that investigated PARPi alone, the ORR was 39% (141/361). Treatment emergent adverse events (TEAEs) of any grade were reported in 96% (1034/1080) in PARPi treatment arms. TEAEs of grade >= 3 were reported in 57% (611/1080). 45% (457/1006) experienced treatment interruption whilst 31% (310/989) required dose reductions. 11% (114/1006) of patients had their treatment discontinued directly as the result of toxicity associated with the trial medications. The most common hematological toxicity was anemia, reported in 490/1160 (42%) patients. and lowered white blood cell count were the next 2most common toxicities, reported in 186/655 (28%) and 133/729 (18%) respectively. The 3most common non-hematological toxicities reported were nausea, fatigue and anorexia reported in 440/1013 (43%), 340/1013 (34%) and 274/1013 (27%) patients respectively. Overall, TRAEs associated with individual PARPi are still emerging with hematological toxicities being most apparent. Further toxicities will be informed from future clinical trials to allow improved treatment selection, education and management of toxicities in prostate cancer.

Choice of antibody is critical for specific and sensitive detection of androgen receptor splice variant-7 in circulating tumor cells.

Androgen receptor variant 7 (AR-V7) is an important biomarker to guide treatment options for castration-resistant prostate cancer (CRPC) patients. Its detectability in circulating tumour cells (CTCs) opens non-invasive diagnostic avenues. While detectable at the transcript level, AR-V7 protein detection in CTCs may add additional information and clinical relevance. The aim of this study was to compare commercially available anti-AR-V7 antibodies and establish reliable AR-V7 immunocytostaining applicable to CTCs from prostate cancer (PCa) patients. We compared seven AR-V7 antibodies by western blotting and immmunocytostaining using a set of PCa cell lines with known AR/AR-V7 status. The emerging best antibody was validated for detection of CRPC patient CTCs enriched by negative depletion of leucocytes. The anti-AR-V7 antibody, clone E308L emerged as the best antibody in regard to signal to noise ratio with a specific nuclear signal. Moreover, this antibody detects CRPC CTCs more efficiently compared to an antibody previously shown to detect AR-V7 CTCs. We have determined the best antibody for AR-V7 detection of CTCs, which will open future studies to correlate AR-V7 subcellular localization and potential co-localization with other proteins and cellular structures to patient outcomes.

Biomarkers of Castrate Resistance in Prostate Cancer: Androgen Receptor Amplification and T877A Mutation Detection by Multiplex Droplet Digital PCR.

Androgen Receptor (AR) alterations (amplification, point mutations, and splice variants) are master players in metastatic castration resistant prostate cancer (CRPC) progression and central therapeutic targets for patient management. Here, we have developed two multiplexed droplet digital PCR (ddPCR) assays to detect AR copy number (CN) and the key point mutation T877A. Overcoming challenges of determining gene amplification from liquid biopsies, these assays cross-validate each other to produce reliable AR amplification and mutation data from plasma cell free DNA (cfDNA) of advanced prostate cancer (PC) patients. Analyzing a mixed PC patient cohort consisting of CRPC and hormone sensitive prostate cancer (HSPC) patients showed that 19% (9/47) patients had AR CN amplification. As expected, only CRPC patients were positive for AR amplification, while interestingly the T877A mutation was identified in two patients still considered HSPC at the time. The ddPCR based analysis of AR alterations in cfDNA is highly economic, feasible, and informative to provide biomarker detection that may help to decide on the best follow-up therapy for CRPC patients.

A Rare Case of Castrate-Resistant Prostate Adenocarcinoma with a Unilateral Testicular Metastasis Mimicking a Primary Testicular Tumour.

Prostate adenocarcinoma with testicular metastasis is rare, present in up to 4% of autopsy diagnoses, and presents symptomatically in less than 0.5% of cases. We report an unusual case of a 55-year-old male who developed a symptomatic testicular metastasis from primary prostate cancer 4 years after initial diagnosis of metastatic castrate-sensitive prostate cancer with nodal and bone-only involvement. The patient had orchidectomy, histologically confirming the metastasis and revealing sparing of the spermatic cord. Prior treatment for his metastatic castrate-sensitive prostate cancer had included androgen deprivation therapy and upfront docetaxel chemotherapy. He had received palliative radiotherapy for symptomatic bone metastasis and managed on enzalutamide for castrate-resistant disease for the preceding 22 months with ongoing PSA response at the time of diagnosis of new testicular metastasis, with a further significant PSA response following his "testicular metastasectomy." At the time of diagnosis of testicular metastasis, he did not have any evidence of other visceral metastases, and his metastatic disease otherwise remained radiologically stable. We describe his disease course, treatment and outline the rare nature of his case of testicular metastasis from prostate cancer.

Patterns of care and outcomes of men with germ cell tumors in a high-volume Australian center.

AIM: To evaluate disease presentation, treatment practices, and outcomes of patients with germ cell tumor (GCT) treated in a high-volume cancer center in Australia. METHODS: This is a retrospective analysis of 609 patients diagnosed with GCT in the Sydney West Cancer Network between 1990 and 2013. Cause and date of death, and second malignancy information was sourced from The Centre for Health Record Linkage. RESULTS: The median age was 33 years (range, 14-85). Primary site was testis in 590 (96.9%), mediastinum in nine (1.5%), and retroperitoneum in nine (1.5%). History of undescended testis was present in 48 (7.9%). Pure seminoma was seen in 334 (54.8%), with 274 (82.0%) being stage I. There was a decline in use of adjuvant radiotherapy from 83% in 1990-1997 to 29% in 2006-2013. Nonseminoma GCT (NSGCT) was diagnosed in 275 (45.2%), with 162 (58.9%) being stage 1. Active surveillance has increased as the initial treatment, from 58% between 1990 and 1997 to 89% between 2006 and 2013. Metastatic disease at presentation was seen in 162 (26.6%): 55 (34.0%) seminoma and 107 (66.0%) NSGCT. With median of 15-year follow-up, 18 (3.0%) have died from GCT and 70 (11.5%) from all causes. Ten-year overall survival was 93% and GCT-specific survival was 97%. Forty patients developed a secondary malignancy, with 38 receiving chemotherapy, radiotherapy, or both. CONCLUSIONS: This large Australian series illustrates a changing pattern of care and outcomes and compares them favorably with other series. This serves as a basis for future comparison of outcomes for this malignancy.

PD-L1 Detection on Circulating Melanoma Cells.

The advent of personalized medicines targeting cell signaling pathways has radically improved melanoma patient outcomes. More recently, immune-modulating therapies disrupting the PD-1/PD-L1 axis have become a powerful tool in the treatment of a range of melanoma, showing a profound improvement in the overall survival outcomes. However, immune checkpoint inhibitors (ICIs) are associated with considerable toxicities and appear to only be efficacious in a subset of melanoma patients. Therefore, there is an urgent need to identify biomarkers that can determine if patients will or will not respond to ICI therapy. Here, we describe an optimized method for analyzing PD-L1 expression on circulating melanoma cells following immunomagnetic enrichment from patient blood samples.

Single-Cell Analysis of BRAFV600E and NRASQ61R Mutation Status in Melanoma Cell Lines as Method Generation for Circulating Melanoma Cells.

Molecular testing of tumor biopsies allows for the identification of the key mutations driving a patient's cancer. However, this is limited to singular nodes and may not accurately reflect cancer heterogeneity. Circulating tumor cell (CTC) analyses offer a noninvasive method of interrogating the genomic profile of patient-derived tumor material. To date, molecular analysis of CTCs has relied on the characterization of bulk or pooled CTC lysates, limiting the detection of minor tumorigenic CTC subclones. Here, we show a workflow enabling BRAFV600E/NRASQ61R mutation detection from single cultured melanoma cells by combining micromanipulation and genomic material amplification methods. This workflow can be directly integrated into circulating tumor cell analysis applications.

Simplified phenotyping of CYP2D6 for tamoxifen treatment using the N-desmethyl-tamoxifen/ endoxifen ratio.

INTRODUCTION: CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. MATERIALS AND METHODS: A target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into 'Normal' (NM) and 'Slow' (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA. RESULTS: A target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. CONCLUSIONS: The simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered.

Endocrine Resistance in Breast Cancer: The Role of Estrogen Receptor Stability.

Therapy of hormone receptor positive breast cancer (BCa) generally targets estrogen receptor (ER) function and signaling by reducing estrogen production or by blocking its interaction with the ER. Despite good long-term responses, resistance to treatment remains a significant issue, with approximately 40% of BCa patients developing resistance to ET. Mutations in the gene encoding ERα, ESR1, have been identified in BCa patients and are implicated as drivers of resistance and disease recurrence. Understanding the molecular consequences of these mutations on ER protein levels and its activity, which is tightly regulated, is vital. ER activity is in part controlled via its short protein half-life and therefore changes to its stability, either through mutations or alterations in pathways involved in protein stability, may play a role in therapy resistance. Understanding these connections and how ESR1 alterations could affect protein stability may identify novel biomarkers of resistance. This review explores the current reported data regarding posttranslational modifications (PTMs) of the ER and the potential impact of known resistance associated ESR1 mutations on ER regulation by affecting these PTMs in the context of ET resistance.

Detection of AR-V7 in Liquid Biopsies of Castrate Resistant Prostate Cancer Patients: A Comparison of AR-V7 Analysis in Circulating Tumor Cells, Circulating Tumor RNA and Exosomes.

Detection of androgen receptor (AR) variant 7 (AR-V7) is emerging as a clinically important biomarker in castrate resistant prostate cancer (CRPC). Detection is possible from tumor tissue, which is often inaccessible in the advanced disease setting. With recent progress in detecting AR-V7 in circulating tumor cells (CTCs), circulating tumor RNA (ctRNA) and exosomes from prostate cancer patients, liquid biopsies have emerged as an alternative to tumor biopsy. Therefore, it is important to clarify whether these approaches differ in sensitivity in order to achieve the best possible biomarker characterization for the patient. In this study, blood samples from 44 prostate cancer patients were processed for CTCs and ctRNA with subsequent AR-V7 testing, while exosomal RNA was isolated from 16 samples and tested. Detection of AR and AR-V7 was performed using a highly sensitive droplet digital PCR-based assay. AR and AR-V7 RNA were detectable in CTCs, ctRNA and exosome samples. AR-V7 detection from CTCs showed higher sensitivity and has proven specificity compared to detection from ctRNA and exosomes. Considering that CTCs are almost always present in the advanced prostate cancer setting, CTC samples should be considered the liquid biopsy of choice for the detection of this clinically important biomarker.

Tamoxifen-induced severe hot flashes and endoxifen levels: is dose reduction a safe and effective strategy?

OBJECTIVES: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM. MATERIALS AND METHODS: Twenty patients with severe HFs on 20 mg TAM had CYP2D6genotype, trough level tamoxifen and metabolites measured with Loprinzi HF scores (HFS) derived before and after DR of tamoxifen to 10 mg. Other data collected included demographics, smoking, alcohol, menstrual and breast cancer history, previous chemotherapies, concurrent medications, BMI and other tamoxifen toxicities. RESULTS: At the 20 mg tamoxifen dose, endoxifen levels were 25.6, 0-91.9 nM (median, range) with HFS 131, 22-1482 (median, range). Upon DR to 10 mg, median endoxifen level fell to 14.1, 0.6-71.9 nM (difference in means p = 0.11, two-tailed T test) with HFS 47, 5-864 (difference in means p = 0.24, two-tailed T test). Despite lacking statistical significance, 85% of patients reported subjective improvement of HFs with DR. After DR, the proportion of patients with endoxifen level <15 nM increased from 20% to 50%. HFS did not correlate with any other parameter. CONCLUSION: DR of tamoxifen from 20 mg to 10 mg daily resulted in halving of endoxifen levels and subjective improvement of HF. While half the dose-reduced patients were below a potential therapeutic level of endoxifen, other recent studies suggest that low endoxifen levels may not indicate reduced effectiveness of tamoxifen.

Patterns of Presentation and Treatment Outcomes of Non-clear-cell Renal Cell Carcinoma and Sarcomatoid Renal Cell Carcinoma Patients in 2 Tertiary Referral Centers in Sydney, Australia.

BACKGROUND: Non-clear-cell renal cell carcinoma (nccRCC) and renal cell carcinoma with sarcomatoid features (scRCC) are rare, and represent subtypes with less defined treatment strategies. The aim of this study is to describe the patterns of care and outcomes of these patients in 2 tertiary referral centers in South Western Sydney Local Health District over a 10-year period. PATIENTS AND METHODS: Patients with RCC seen at South Western Sydney Local Health District from January 1, 2005 to December 31, 2015 were identified from electronic medical records. For each patient, we extracted details regarding demographics, tumor characteristics, treatment, recurrences, and survival, which was analyzed using the Kaplan-Meier method. RESULTS: Of 178 patients with RCC identified between 2005 and 2015, 23% (n = 41) had nccRCC and 8% (n = 15) had scRCC. Twenty-five patients in total had de novo metastatic disease or disease recurrence. The median follow-up was 46 and 16 months for nccRCC and scRCC, respectively. The median overall survival for nccRCC with metastatic disease was 34 months (range, 14 months to not reached). Seventy percent of these patients received systemic therapy. By contrast, the median overall survival for scRCC with metastatic disease was 10 months (range, 1.6-89 months). Less than one-half of the patients with scRCC received systemic therapy in our cohort, with only 34% receiving no more than 1 line of treatment. CONCLUSIONS: Our data confirm the rapid and aggressive course of scRCC, highlighting the need for more effective therapeutic strategies in this rare patient population.

Patterns of immunotherapy use and management of toxicities in regional and tertiary settings.

BACKGROUND: The introduction of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) immune checkpoint inhibitors and their subsequent listing on the Pharmaceutical Benefits Scheme for use in metastatic melanomas, renal cell carcinomas and non-small-cell lung cancers has resulted in routine use of these agents in oncology practices, including in regional areas. Although immunotherapeutic agents generally have a favourable toxicity profile compared to chemotherapy, they can provoke immune-related adverse effects (irAE) caused by an unregulated and hyperstimulated immune response. Some of these effects can be serious and life-threatening. AIMS: To compare the utilisation of immunotherapy and the rates, management and outcomes of irAE between a regional oncology service and a tertiary service. METHODS: We reviewed the medical records for all patients treated with immunotherapy in the participating services for the 5-year period from 31 July 2012 to 31 July 2017. RESULTS: Data demonstrated that rates of immunotherapy use are both similar and increasing across the tertiary and regional services. The rates, types and severity of irAE are equivalent and in concordance with pre-existing literature. Immune-related adverse events appear to be identified and treated earlier in the regional service with the corresponding reduction in the duration of immunosuppression and requirement for inpatient management. CONCLUSION: The use of immunotherapy in a regional setting is safe and equivalent to that of a tertiary centre.

Dose individualization of sunitinib in metastatic renal cell cancer: toxicity-adjusted dose or therapeutic drug monitoring.

PURPOSE: Dose individualization of sunitinib has been proposed using therapeutic drug monitoring (TDM) or toxicity-adjusted dose (TAD). We prospectively studied aspects of TDM and TAD to inform future trials, namely (1) intrapatient variability (CV) of sunitinib and (2) feasibility of a TAD protocol. METHODS: Sunitinib dose was adjusted to ensure grade 1 or 2 toxicity on 10-20 days of each 42-day cycle. Total trough levels (TTL) C min of sunitinib and its active metabolite were measured every 6 weeks. RESULTS: In 45 patients with mRCC, 283 TTL samples were assayed over a median 30 weeks (6-108 weeks). Fifteen patients (33%) had an intrapatient CV of >25% in TTL. Ninety-one percent achieved target toxicity with a final sunitinib dose of 25 mg (18%), 37.5 mg (27%), 50 mg (50%), and 62.5 or 75 mg (7%). TTL C min was <50, 50-100, and >100 ng/mL in 7 (15%), 31 (69%), and 7 patients (15.5%), respectively. The median overall survival was 32 months. CONCLUSIONS: Sunitinib level has minimal variability in the majority of patients on stable dose. A subset of patients had a significant intrapatient variation, so we recommend two samples 4 to 6 months apart. TAD is feasible for dosing sunitinib and showed a favourable outcome.

CTC-mRNA (AR-V7) Analysis from Blood Samples-Impact of Blood Collection Tube and Storage Time.

Circulating tumour cells (CTCs) are an emerging resource for monitoring cancer biomarkers. New technologies for CTC isolation and biomarker detection are increasingly sensitive, however, the ideal blood storage conditions to preserve CTC-specific mRNA biomarkers remains undetermined. Here we tested the preservation of tumour cells and CTC-mRNA over time in common anticoagulant ethylene-diamine-tetra-acetic acid (EDTA) and acid citrate dextrose solution B (Citrate) blood tubes compared to preservative-containing blood tubes. Blood samples spiked with prostate cancer cells were processed after 0, 24, 30, and 48 h storage at room temperature. The tumour cell isolation efficiency and the mRNA levels of the prostate cancer biomarkers androgen receptor variant 7 (AR-V7) and total AR, as well as epithelial cell adhesion molecule (EpCAM) were measured. Spiked cells were recovered across all storage tube types and times. Surprisingly, tumour mRNA biomarkers were readily detectable after 48 h storage in EDTA and Citrate tubes, but not in preservative-containing tubes. Notably, AR-V7 expression was detected in prostate cancer patient blood samples after 48 h storage in EDTA tubes at room temperature. This important finding presents opportunities for measuring AR-V7 expression from clinical trial patient samples processed within 48 h-a much more feasible timeframe compared to previous recommendations.

Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies.

Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies.

Patterns and trends in the incidence of paediatric and adult germ cell tumours in Australia, 1982-2011.

PURPOSE: Germ cell tumour (GCT) aetiology is uncertain and comprehensive epidemiological studies of GCT incidence are few. METHODS: Nationwide data on all malignant GCTs notified to Australian population-based cancer registries during 1982-2011 were obtained. Age- and sex-specific, and World age-standardised incidence rates were calculated for paediatric (0-14) and adult (15+) cases using the latest WHO subtype classification scheme. Temporal trends were examined using Joinpoint regression. RESULTS: There were 17,279 GCTs (552 paediatric, 16,727 adult). Age-specific incidence in males (all histologies combined) was bimodal, with peaks during infancy for most sites, and second, larger, peaks during young adulthood. Incidence of ovarian tumours peaked at age 15-19. Around half of paediatric tumours were extragonadal, whereas adult tumours were mostly gonadal. Yolk sac tumours and teratomas predominated in infants, whereas germinomas became more frequent towards adulthood. Increasing incidence trends for some adult gonadal tumours have stabilised; the trend for male extragonadal tumours is also declining. CONCLUSION: Broad similarities in the shape of age-specific incidence curves, particularly for gonadal, central nervous system, and mediastinal tumours provide epidemiological support for commonalities in aetiology among clinically disparate GCT subtypes. Differences in peak ages reflect underlying subtype-specific biological differences. Declining incidence trends for some adult gonadal tumours accords with the global transition in GCT incidence, and supports the possibility of a reduction in prevalence of shared aetiological exposures.

Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.

PURPOSE: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. EXPERIMENTAL DESIGN: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. RESULTS: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). CONCLUSIONS: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121.

Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study.

BACKGROUND AND OBJECTIVE: The wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib. METHODS: A correlation analysis was performed between sunitinib pharmacokinetics and 1'OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile ((99m)Tc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate. RESULTS: In 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4 ng/mL at day 1 of a cycle to 88.1 ng/mL in the fourth week of treatment. A trend for a correlation was observed between (99m)Tc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1'OH-midazolam/midazolam ratio and sunitinib clearance (P = 0.008) and day 1 N-desethylsunitinib trough concentrations (P = 0.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4 L/h; P = 0.025). CONCLUSIONS: Phenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure-toxicity relationship.