Potent CYP2D6 Inhibiting drugs do not increase relapse rate in early breast cancer patients treated with adjuvant tamoxifen

Endoxifen, the most active metabolite of the prodrug tamoxifen, is produced by cytochrome P450 CYP2D6. Breast cancer patients treated with tamoxifen who have reduced CYP2D6 activity, related to either genetic variation or drug inhibition, may have inferior outcomes. To assess the effect of concomitant CYP2D6 inhibiting drug use on clinical outcomes of breast cancer patients treated with adjuvant tamoxifen. We conducted a retrospective database analysis. Women with non-metastatic estrogen receptor positive tumors who had completed adjuvant tamoxifen therapy for 2 years, without treatment with adjuvant aromatase inhibitors or early relapse, were included. Patients were classified as users of CYP2D6 inhibitors if they purchased strong CYP2D6 inhibiting drugs for ≥4 consecutive months during tamoxifen treatment. Tumors were classified as “high risk” if adjuvant chemotherapy was prescribed. Primary endpoint was disease free (DFS) and secondary endpoint was overall survival (OS). 902 patients treated with tamoxifen (median duration, 4.9 years) were followed for a median period of 5.9 years. Fifty-nine (6.5%) patients were users of CYP2D6 inhibitors (median duration, 23 months). DFS at 3 years (corresponding to 5 years after tamoxifen initiation) did not differ between users and non-users of CYP2D6 inhibiting drugs (92.7 vs. 93.0%, respectively; adjusted P = 0.44). OS at 3 years was lower in the patients using CYP2D6 inhibiting drugs: 89.4 vs. 93.8%, but after adjustment for age and comorbidities this difference was not significant (P = 0.20). Overall recurrence rates did not differ between users and non-users of CYP2D6 inhibiting drugs (11.8 vs. 19.0% respectively, P = 0.23). Concomitant prolonged therapy with strong CYP2D6 inhibiting drugs does not affect adversely DFS and recurrence rates in tamoxifen-treated early breast cancer patients.     

Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis

Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96–4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73–2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69–2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.     

CYP2D6 phenotype indicative for optimized antiestrogen efficacy associates with outcome in early breast cancer patients

Background

Endoxifen serum concentrations seem to correlate with outcome in breast cancer (BC) patients. Concurrently, cytochrome P450 2D6 (CYP2D6) enzyme activity and dextromethorphan (DM) metabolism are deemed a surrogate marker for the formation of endoxifen. Here, we conducted a matched cohort study to determine the impact of an extensive CYP2D6 phenotype on relapse in patients with early-stage estrogen receptor (ER)-positive BC and adjuvant tamoxifen intake.

Methods

CYP2D6 extensive metabolism was determined upon appropriate dextromethorphan/dextrorphan (DM/DX) urinary excretion ratios (≤0.30). Fifty-nine BC patients were identified as extensive phenotype metabolizers, while for 148 matched controls, CYP2D6 was not determined. Patients and controls did not differ with respect to age, stage, hormone receptor status, HER2, grade, menopausal status, chemotherapy and antihormonal therapy. Survival analysis was performed according to clinical follow-up.

Results

Disease-free survival (DFS) of patients identified as extensive CYP2D6 metabolizers did not differ significantly from controls (p = 0.10). However, when patients with ER expression of ≤20 % were excluded from the analysis, DFS was associated with a more favorable outcome (p = 0.06).

Conclusions

This study suggests a positive association between extensive CYP2D6 metabolism and outcome in early-stage ER-positive BC patients using tamoxifen and in particular, when a sufficient number ERs are represented on the primary tumor.     

CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients: a meta-analysis

Purpose

To evaluate whether breast cancer (BC) patients with CYP2D6 gene variation have different clinical tamoxifen (TAM) treatment outcomes to those with normal function of CYP2D6.

Methods

Systematic searches of the PubMed up to February 21, 2013, were retrieved. The study end points were disease-free survival (DFS) and overall survival (OS). Fixed or random-effects meta-analytical models were used to calculate summary hazard ratio (HR) and corresponding 95 % confidence intervals (CIs). Meta-regression, Galbraith plots, subgroup analysis, and sensitivity analysis were also performed.

Results

A total of 11,701 BC patients from 20 trials were included. Compared with reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR = 1.37, 95 % CI 1.12–1.69, P = 0.002) and OS (HR = 1.25, 95 % CI 1.03–1.50, P = 0.021). We found significant heterogeneity between studies. When the analysis was stratified into subgroups, significantly worse DFS was found in the groups of intermediate metabolizer versus extensive metabolizer (HR = 1.65, 95 % CI 1.04–2.64, P = 0.035), Asian population (HR = 3.29, 95 % CI 1.64–6.63, P = 0.001), 5 years TAM treatment duration (HR = 1.59; 95 % CI 1.14–2.22, P = 0.006), concomitant chemotherapy (HR = 1.35, 95 % CI 1.04–1.76, P = 0.025), and TAM alone (HR = 1.44, 95 % CI 1.44–2.06, P = 0.045). With respect to OS, no significant association was demonstrated in stratified analyses.

Conclusions

We concluded that CYP2D6 polymorphisms may influence tamoxifen treatment outcomes of DFS in BC patients.     

Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment

BackgroundHuman cytochrome P450 2D6 (CYP2D6) genotype may affect the efficacy of tamoxifen treatment in Caucasian women with breast cancer. The most common polymorphism of CYP2D6 in Chinese women is variant 10 (188 C to T).Patients and methodsTamoxifen and 4-hydroxytamoxifen (4OHtam) were measured in the serum of 37 women with breast cancer who were receiving tamoxifen treatment. The association between CYP2D6 *10 genotype and survival was determined in a cohort of 293 women with breast cancer who received tamoxifen (n = 152) or who did not (n = 141).ResultsThe serum 4OHtam concentrations were significantly lower in women with the CYP2D6 *10 homozygous variant T/T genotype than in those with the homozygous wild-type C/C genotype (P = 0.04). Among tamoxifen-treated women, women with the T/T genotype had a significantly worse disease-free survival (DFS) than those with the C/C or C/T genotype, and the T/T genotype remained an independent prognostic factor of DFS in multivariate analysis (hazard ratio = 4.7; 95% confidence interval = 1.1–20.0; P = 0.04). Among women who did not receive tamoxifen, there was no significant association between CYP2D6 *10 genotype and survival.ConclusionIn tamoxifen-treated patients, women with the CYP2D6 *10 T/T genotype have a lower 4OHtam level in the serum and a worse clinical outcome.     

Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols

Background

Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread.

Methods

A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998– 2019 was performed (n = 447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival.

Results

Median overall survival (mOS) improved over time (6.7 months in 1998–2007 to 11.8 months in 2008–2019, p = .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2–2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4–3.0], disease-free interval (DFI) ≤6 months (HR, 1.4 [1.02–2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1–3.4). In this cohort, 50.6% of recurrences occurred within 6 months of treatment completion, 72.5% occurred within 1 year, and 88.6% occurred within 2 years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4–4.0]), DFI >6 months (OR, 2.4 [1.5–4.0]), and body mass index ≥30 (OR, 2.3 [1.1–4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24–0.55).

Conclusion

These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials.

Plain Language Summary

• After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body.
• This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns.
• Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients.
• These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests.

     

Breast cancer in young women

The aim of this study is to evaluate the impact of CYP2D6 genotyping in predicting disease-free survival and toxicity in breast cancer patients treated with adjuvant tamoxifen. DNA from 91 patients was genotyped using the AmpliChip CYP450 GeneChip^®, Roche that facilitates the classification of individuals by testing 27 alleles. When patients were grouped into group 1 (*4/*4, *4/*41, *1/*5 and *2/*5) and group 2 (the remaining genotypes), a significant difference in disease-free survival (DFS) was observed between groups (P = 0.016). The mean DFS in group 1 was 95 months in contrast with 119 months in group 2. No significant relationship was found between the CYP2D6 genotype classification and severe, mild or no toxicity (P = 0.2). Nevertheless, severe, and mild toxicity was more frequent among poor metabolizer patients than in patients with a normal metabolizer pattern (18.8 and 43.8% vs. 10.7 and 36%, respectively). In breast cancer, patients treated with adjuvant tamoxifen, non-functional and severely impaired CYP2D6 variants are associated with a worse DFS and with a higher frequency of severe and mild toxicities. Larger studies of the CYP2D6 genotype-clinical outcomes association are needed to complement initial results.     

Dose-adjustment study of tamoxifen based on <Emphasis Type="Italic">CYP2D6</Emphasis> genotypes in Japanese breast cancer patients

CYP2D6 is a key enzyme responsible for the metabolism of tamoxifen to active metabolites, endoxifen, and 4-hydroxytamoxifen. The breast cancer patients who are heterozygous and homozygous for decreased-function and null alleles of CYP2D6 showed lower plasma concentrations of endoxifen and 4-hydroxytamoxifen compared to patients with homozygous-wild-type allele, resulting in worse clinical outcome in tamoxifen therapy. We recruited 98 Japanese breast cancer patients, who had been taking 20 mg of tamoxifen daily as adjuvant setting. For the patients who have one or no normal allele of CYP2D6, dosages of tamoxifen were increased to 30 and 40 mg/day, respectively. The plasma concentrations of tamoxifen and its metabolites were measured at 8 weeks after dose-adjustment using liquid chromatography–tandem mass spectrometry. Association between tamoxifen dose and the incidence of adverse events during the tamoxifen treatment was investigated. In the patients with CYP2D6*1/*10 and CYP2D6*10/*10, the mean plasma endoxifen levels after dose increase were 1.4- and 1.7-fold higher, respectively, than those before the increase (P < 0.001). These plasma concentrations of endoxifen achieved similar level of those in the CYP2D6*1/*1 patients receiving 20 mg/day of tamoxifen. Plasma 4-hydroxytamoxifen concentrations in the patients with CYP2D6*1/*10 and CYP2D6*10/*10 were also significantly increased to the similar levels of the CYP2D6*1/*1 patients according to the increasing tamoxifen dosages (P < 0.001). The incidence of adverse events was not significantly different between before and after dose adjustment. This study provides the evidence that dose adjustment is useful for the patients carrying CYP2D6*10 allele to maintain the effective endoxifen level.     

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

Background:

Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.

Methods:

We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.

Results:

OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06–4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared with patients without CYP2D6 inhibitors.

Conclusion:

CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.     

The relationship between the CYP2D6 polymorphisms and tamoxifen efficacy in adjuvant endocrine therapy of breast cancer patients in Chinese Han population

Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)‐treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease‐free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5‐year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients.     

Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study

Background  

In vitro data indicate that the sorafenib is a moderate inhibitor of cytochrome P450 (CYP) enzymes, including CYP3A4, CYP2C19, and CYP2D6. This phase I/II study in patients with advanced melanoma evaluated the potential effect of sorafenib on the pharmacokinetics of midazolam, omeprazole, and dextromethorphan, specific substrates of CYP3A4, CYP2C19, and CYP2D6, respectively.     

Analysis of prognosis and prognostic factors of cervical adenocarcinoma and adenosqumous carcinoma of the cervix

OBJECTIVE To analyze clinical characteristics and treatment methods of the patients with adenocarcinoma of the uterine cervix （AUC） and adenosquamous carcinoma of the cervix （ASCC）. To compare the survival time of the patients in 2 groups and analyze the prognostic factors. METHODS Clinical data of both 123 patients with AUC and 32 patients with ASCC treated at the Cancer Hospital, Chinese Academy of Medical Science （CAMS） ＆ Peking Union Medical College （PUMC）, were retrospectively analyzed.
RESULTS The median age of the AUC patients was 50 years, and that of the ASCC patients was 44, P = 0.019. Poorly-differentiated （grade 3） cases accounted for 59.5% of the total ASCC patients, while only 32.5% of the AUC patients were in grade 3, P = 0.002. In 123 AUC patients, relapse or failure of the treatment occurred in 63 of the patients （51.2%）, and the median relapse time was 6 months （0-59 months）. In 32 ASCC patients, relapse or failure of the treatment occurred in 8 of these patients （51.2%）, with a median relapse time of 4.5 months （0-52 months）. The overall 5-year survival rate of the AUC patients was 49.8%, which was significantly lower than that of the ASCC patients （74.1%）, P = 0.015. The 5-year survival rates of the ASCC patients in Stage Ⅰ-Ⅲ were higher than that of the AUC patients with the same stages. However, statistical significant difference could only be found among the patients in Stage II, P = 0.006. The 5-year survival rates of the ASCC patients with various differential grade were higher than those of the AUC patients with the same differential grade, but statistical significant difference could only be found among the patients in the two groups with moderately differentiation, P = 0.039. It was found by Cox regression analysis that only clinical stage （P 〈 0.001） and histological type （P = 0.046） were the independent prognostic factors.
CONCLUSION Clinical stage and histological type were the independent prognostic factors of the AUC and ASCC patients. The prOgnosis of ASCC patients is better than that of the AUC patients.     

Race impacts outcome in stage III/IV squamous cell carcinomas of the head and neck after concurrent chemoradiation therapy

BACKGROUND:

The purpose of this study was to determine the impact of race on outcome in patients with stage III/IV squamous cell carcinoma of the head and neck (SCCHN) who have completed concurrent chemoradiotherapy.

METHODS:

The authors performed a retrospective analysis of 202 patients with stage III/IV SCCHN who were treated at the University of Maryland. Patients received daily radiation to a total dose of 70.2 Gray (Gy) (1.8 Gy/day), concurrently with weekly carboplatin (area under the curve [AUC] = 2) and paclitaxel (45 mg/m²) chemotherapy.

RESULTS:

There were 108 Caucasian (CA) and 94 African American (AA) patients. The median age was 56 years, and 81% were stage IV. The median follow‐up was 33 months. The median overall survival (OS) and disease‐free survival (DFS) were 33 months and 19 months, respectively. When analyzed by race, the median DFS was 33 months (CA) versus 12 months (AA) (P = .028). The median OS was 44 months (CA) versus 24 months (AA) (P = .071). The 3‐year DFS for stage IV AA versus stage IV CA was 29% versus 50% (P = .031). The 3‐year DFS for N2 disease in AA versus CA was 32% versus 51% (P = .046). The 3‐year DFS for AA versus CA with oropharyngeal tumors was 30% versus 60% (P = .006).

CONCLUSIONS:

This analysis documents the inferior outcome for AA patients. They had inferior DFS and a trend toward worse OS. When stratified by several prognostic variables, the mediocre DFS in the AA patients remains. These data suggest that further investigation into the genetic characteristics of SCCHN in AA patients is warranted. Cancer 2009. © 2009 American Cancer Society.     

Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) Polymorphisms in Breast Carcinoma

Background  

Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients.     

Analysis of the fecal metagenome in long-term survivors of pancreas cancer

Background

The 5-year overall survival of pancreas adenocarcinoma (PCa) remains less than 10%. Clinical and tumor genomic characteristics have not differentiated PCa long-term survivors (LTSs) from unselected patients. Preclinical studies using fecal transplant experiments from LTSs of PCa have revealed delayed tumor growth through unknown mechanisms involving the fecal microbiota. However, features of the fecal microbiome in patients with long-term survival are not well described.

Methods

In this cross-sectional study, comprehensive shotgun metagenomics was performed on stool from PCa patients with long-term survival (n = 16). LTS was defined as >4 years from pancreatectomy and all therapy without recurrence. LTSs were compared to control patients with PCa who completed pancreatectomy and chemotherapy (n = 8). Stool was sequenced using an Illumina NextSeq500. Statistical analyses were performed in R with MicrobiomeSeq and Phyloseq for comparison of LTSs and controls.

Results

All patients underwent pancreatectomy and chemotherapy before sample donation. The median time from pancreatectomy of 6 years (4–14 years) for LTSs without evidence of disease compared to a median disease-free survival of 1.8 years from pancreatectomy in the control group. No differences were observed in overall microbial diversity for LTSs and controls using Shannon/Simpson indexes. Significant enrichment of species relative abundance was observed in LTSs for the Ruminococacceae family specifically Faecalibacterium prausnitzii species as well as Akkermansia muciniphila species.

Conclusions

Stool from patients cured from PCa has more relative abundance of Faecalibacterium prausnitzii and Akkermansia muciniphila. Additional studies are needed to explore potential mechanisms by which the fecal microbiota may influence survival in PCa.

Plain Language Summary

• Although pancreatic cancer treatments have improved, the number of long-term survivors has remained stagnant with a 5-year overall survival estimate of 9%.
• Emerging evidence suggests that microbes within the gastrointestinal tract can influence cancer response through activation of the immune system.
• In this study, we profiled the stool microbiome in long-term survivors of pancreas cancer and controls.
• Several enriched species previously associated with enhanced tumor immune response were observed including Faecalibacterium prausnitzii and Akkermansia muciniphila.
• These findings warrant additional study assessing mechanisms by which the fecal microbiota may enhance pancreatic cancer immune response.

     

The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users

Cytochrome P450 2D6 (CYP2D6) plays an important role in the formation of endoxifen, the active metabolite of tamoxifen. In this study the association between the most prevalent CYP2D6 null-allele in Caucasians (CYP2D6*4) and breast cancer mortality was examined among all incident users of tamoxifen in a population-based cohort study. Breast cancer mortality was significantly increased in patients with the * 4/*4 genotype (HR = 4.1, CI 95% 1.1–15.9, P = 0.041) compared to wild type patients. The breast cancer mortality increased with a hazard ratio of 2.0 (CI 95% 1.1–3.4, P = 0.015) with each additional variant allele. No increased risk of all-cause mortality or all-cancer mortality was found in tamoxifen users carrying a CYP2D6*4 allele. The risk of breast cancer mortality is increased in tamoxifen users with decreased CYP2D6 activity, consistent with the model in which endoxifen formation is dependent on CYP2D6 activity.     

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

CYP2D6*4 allele and breast cancer risk: Is there any association?

Background  

CYP2D6 is an important cytochrome P450 enzyme. These enzymes catalyse the oxidative biotransformation of about 25% of clinically important drugs as well as the metabolism of numerous environmental chemical carcinogens. The most frequent null allele of CYP2D6 in European populations, CYP2D6*4, has been studied here in order to elucidate whether a relationship exists between this allele and the risk of developing breast cancer in a Spanish population.     

Real-world retrospective study of KRAS mutations in advanced non–small cell lung cancer in the era of immunotherapy

Background

KRAS mutation-positive (KRAS-positive), advanced nonsmall-cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real-world data by mutation subtype in the era of immunotherapy are still incomplete.

Methods

The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS-positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first-line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co-mutations.

Results

From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS-positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5–12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first-line treatment, the median OS was 12.2 months (95% CI, 8.3–16.1 months), and the median progression-free survival was 5.6 months (95% CI, 4.5–6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression-free survival and OS.

Conclusions

KRAS-positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype.

Plain Language Summary

This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes.

• The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations.
• These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

     

Chemoradiation versus local excision in treatment of stage I anal squamous cell carcinoma: A population-based analysis

IntroductionChemoradiation therapy (CRT) is the standard treatment for anal squamous cell carcinoma (ASCC) but can have significant treatment related toxicities. Recent studies have demonstrated the effectiveness of local excision (LE) for stage I ASCC with comparable oncologic outcomes to CRT. We aimed to evaluate this finding in a large population-based database.MethodsPatients diagnosed with stage I (T1N0M0) ASCC were identified from the Surveillance, Epidemiology, and End Results database, 2004–2015. Treatment approach was categorized as CRT or LE. Factors associated with treatment approach and cause-specific survival (CSS) were analyzed for the entire cohort and after stratification by tumor size (≤1 cm and 1–2 cm).ResultsAmong 883 patients, 56% had ASCCs 1–2 cm in size and 77% received CRT. Mean age was 60 years, 65% were female, and 90% were White. Factors independently associated with receiving CRT were, being female, higher tumor grade, and tumor size 1–2 cm. Unadjusted 5-year CSS for CRT was 96% while for LE it was 98% (p = 0.048). After adjusting for available confounders, treatment approach was not associated with worse CSS, however being Black (HR = 8.7) and uninsured (HR = 13.7) were independently associated with worse prognosis. After stratification by tumor size, there was still no significant difference in 5-year CSS by treatment approach.ConclusionsLE was performed in a significant proportion of patients but was not independently associated with worse CSS compared to CRT. In appropriately selected patients with well differentiated ASCCs ≤1 cm, LE could be an acceptable management option but studies measuring outcomes such as local recurrence are needed.