In postmenopausal women at increased risk for breast cancer, exemestane reduced the annual incidence of invasive breast cancer by 65% after a median follow-up of only 3 years. Exemestane caused no ...serious toxic effects and only minimal changes in quality of life.
Estrogens contribute to normal breast development but can also promote breast cancer in preclinical models and in women with high circulating plasma estrogen levels.
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To date, chemoprevention of breast cancer has focused on the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene, which exert antiestrogenic effects on the breast, as well as agonist or antagonist effects on other organs. In the National Surgical Adjuvant Breast and Bowel Project P-1 trial, tamoxifen significantly reduced the number of invasive breast cancers, by 49% (P<0.001) as compared with placebo.
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A meta-analysis of trials comparing tamoxifen with placebo showed that tamoxifen reduced the incidence . . .
Summary Background Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline ...and gabapentin compared with each drug given alone. Methods In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0–10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636. Findings 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0–10; numerical rating scale) was 5·4 (95% CI 5·0 to 5·8) at baseline, and at maximum tolerated dose, pain was 3·2 (2·5 to 3·8) for gabapentin, 2·9 (2·4 to 3·4) for nortriptyline, and 2·3 (1·8 to 2·8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (−0·9, 95% CI −1·4 to −0·3, p=0·001) or nortriptyline alone (−0·6, 95% CI −1·1 to −0·1, p=0·02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0·0001) or combination treatment (p<0·0001). No serious adverse events were recorded for any patients during the trial. Interpretation Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain. Funding Canadian Institutes of Health Research.
An additional 5 years of adjuvant aromatase-inhibitor therapy in women with early hormone-receptor–positive breast cancer resulted in longer disease-free survival and a lower incidence of ...contralateral breast cancer than placebo, but not in longer overall survival.
The risk of recurrence of hormone-receptor–positive early breast cancer continues indefinitely.
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Long-term reduction in the risk of recurrence has been achieved with the antiestrogen agent tamoxifen, aromatase inhibitors, or a combination of the two. These treatments are administered in a variety of adjuvant regimens, including tamoxifen for 10 years, tamoxifen for up to 5 years followed by an aromatase inhibitor for 5 years, or an initial aromatase inhibitor for 5 years.
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Extrapolating from these results, many patients have chosen to continue taking an aromatase inhibitor for more than 5 years (if they do not have unacceptable side effects), despite . . .
Purpose
Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help ...researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs.
Methods
We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin’s lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data.
Results
Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12).
Conclusion
Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.
In this paper, we introduce a single‐index threshold Cox proportional hazard model to select and combine biomarkers to identify patients who may be sensitive to a specific treatment. A penalized ...smoothed partial likelihood is proposed to estimate the parameters in the model. A simple, efficient, and unified algorithm is presented to maximize this likelihood function. The estimators based on this likelihood function are shown to be consistent and asymptotically normal. Under mild conditions, the proposed estimators also achieve the oracle property. The proposed approach is evaluated through simulation analyses and application to the analysis of data from two clinical trials, one involving patients with locally advanced or metastatic pancreatic cancer and one involving patients with resectable lung cancer.
This study examined the mutation status of the
K-ras
gene in colorectal tumors from patients who were enrolled in a trial of cetuximab, a monoclonal antibody against the epidermal growth factor ...receptor (EGFR). A survival benefit was found among patients with tumors bearing wild-type
K-ras
but not among patients with tumors bearing mutated
K-ras
. Wild-type
K-ras
is essential in transmitting signals initiated by EGFR.
This study examined the mutation status of the
K-ras
gene in colorectal tumors from patients who were enrolled in a trial of cetuximab. A survival benefit was found among patients with tumors bearing wild-type
K-ras
but not among patients with tumors bearing mutated
K-ras
.
A randomized trial (CO.17) conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) in collaboration with the Australasian Gastro-Intestinal Trials Group (AGITG) showed that among patients with colorectal cancer that had not responded to advanced chemotherapy, monotherapy with cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), improved overall survival and progression-free survival and preserved the quality of life better than did best supportive care alone.
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However, resistance to cetuximab was common: at the first assessment of disease response, the disease had progressed in more than 50% of treated patients.
K-ras
, a . . .
CONTEXT Patients with metastatic colorectal cancer who have KRAS codon 12– or KRAS codon 13–mutated tumors are presently excluded from treatment with the anti–epidermal growth factor receptor ...monoclonal antibody cetuximab. OBJECTIVE To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. DESIGN, SETTING, AND PATIENTS We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received off-study treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. MAIN OUTCOME MEASURES The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. RESULTS In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n = 32) treated with cetuximab had longer overall survival (median, 7.6 95% confidence interval {CI}, 5.7-20.5 months vs 5.7 95% CI, 4.9-6.8 months; adjusted hazard ratio HR, 0.50; 95% CI, 0.31-0.81; P = .005) and longer progression-free survival (median, 4.0 95% CI, 1.9-6.2 months vs 1.9 95% CI, 1.8-2.8 months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P = .004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P = .003). In vitro and mouse model analysis showed that although p.G12V-mutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. CONCLUSIONS In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.
In clinical research, it is important to study whether certain clinical factors or exposures have causal effects on clinical and patient-reported outcomes such as toxicities, quality of life, and ...self-reported symptoms, which can help improve patient care. Usually, such outcomes are recorded as multiple variables with different distributions. Mendelian randomization (MR) is a commonly used technique for causal inference with the help of genetic instrumental variables to deal with observed and unobserved confounders. Nevertheless, the current methodology of MR for multiple outcomes only focuses on one outcome at a time, meaning that it does not consider the correlation structure of multiple outcomes, which may lead to a loss of statistical power. In situations with multiple outcomes of interest, especially when there are mixed correlated outcomes with different distributions, it is much more desirable to jointly analyze them with a multivariate approach. Some multivariate methods have been proposed to model mixed outcomes; however, they do not incorporate instrumental variables and cannot handle unmeasured confounders. To overcome the above challenges, we propose a two-stage multivariate Mendelian randomization method (MRMO) that can perform multivariate analysis of mixed outcomes using genetic instrumental variables. We demonstrate that our proposed MRMO algorithm can gain power over the existing univariate MR method through simulation studies and a clinical application on a randomized Phase III clinical trial study on colorectal cancer patients.
Identification of a subset of patients who may be sensitive to a specific treatment is an important problem in clinical trials. In this paper, we consider the case where the treatment effect is ...measured by longitudinal outcomes, such as quality of life scores assessed over the duration of a clinical trial, and the subset is determined by a continuous baseline covariate, such as age and expression level of a biomarker. A threshold linear mixed model is introduced, and a smoothing maximum likelihood method is proposed to obtain the estimation of the parameters in the model. Broyden-Fletcher-Goldfarb-Shanno algorithm is employed to maximize the proposed smoothing likelihood function. The proposed procedure is evaluated through simulation studies and application to the analysis of data from a randomized clinical trial on patients with advanced colorectal cancer.
Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of ...tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry.
Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2-enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes.
Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit DFS: HR, 0.52; 95% confidence interval (CI), 0.32-0.86 vs. HR, 0.80; 95% CI, 0.50-1.29 for nonluminal subtypes, although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease.
In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen.
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