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Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

ABSTRACT: Early-stage breast cancer (BC) is a curable disease with many patients dying of causes other than BC. The influence of non-BC death and other competing risks on the interpretation of Kaplan-Meier (KM)-based analyses for BC-specific outcomes are unknown. We searched the Oxford University website to identify all meta-analyses published by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) between 2005 and 2018. The potential influence of competing risks was estimated using a validated multivariable linear model that predicts the difference between KM and cumulative incidence function (CIF) on estimates of BC-specific outcomes. The initial search identified 14 EBCTCG papers, 10 (71%) reported data on BC and competing events. Eight (80%) had a relative difference between KM and the competing risk adjusted estimates exceeding 10%. The median relative difference was 28.4% for local-recurrence; 16.8% for distant-recurrence, and 6.7% for BC-specific mortality. There was a 18.9% relative difference between KM and CIF adjusted analyses beyond 10 years. The use of KM-based methods when competing risks are present biases risk estimates in studies of early BC especially for uncommon outcomes such as local recurrence. The use of CIF to calculate BC-specific outcomes may be preferable in this setting.

SUBMITTER: Saleh RR

PROVIDER: S-EPMC7058037 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

Saleh Ramy R RR Nadler Michelle B MB Desnoyers Alexandra A Rodin Danielle L DL Abdel-Qadir Husam H Amir Eitan E

Scientific reports 20200305 1

Early-stage breast cancer (BC) is a curable disease with many patients dying of causes other than BC. The influence of non-BC death and other competing risks on the interpretation of Kaplan-Meier (KM)-based analyses for BC-specific outcomes are unknown. We searched the Oxford University website to identify all meta-analyses published by the Early Breast Cancer Trialists Collaborative Group (EBCTCG) between 2005 and 2018. The potential influence of competing risks was estimated using a validated ...[more]

PMID: 32139756

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Project description:AimTo show a new paradigm of simultaneously testing whether breast cancer therapies impact other causes of death.MethodsMA.14 allocated 667 postmenopausal women to 5 years of tamoxifen 20 mg/daily ± 2 years of octreotide 90 mg, given by depot intramuscular injections monthly. Event-free survival was the primary endpoint of MA.14; at median 7.9 years, the tamoxifen+octreotide and tamoxifen arms had similar event-free survival (P = 0.62). Overall survival was a secondary endpoint, and the two trial arms also had similar overall survival (P = 0.86). We used the median 9.8 years follow-up to examine by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa) and other cause (OC) mortality with log-normal survival analysis adjusted by treatment and stratification factors. We tested whether baseline factors including Insulin-like growth factor 1 (IGF1), IGF binding protein-3, C-peptide, body mass index, and 25-hydroxy vitamin D were associated with (1) all cause mortality, and if so and (2) cause-specific mortality. We also fit step-wise forward cause-specific adjusted models.ResultsThe analyses were performed on 329 patients allocated tamoxifen and 329 allocated tamoxifen+octreotide. The median age of MA.14 patients was 60.1 years: 447 (82%) < 70 years and 120 (18%) ≥ 70 years. There were 170 deaths: 106 (62.3%) BrCa; 55 (32.4%) OC, of which 24 were other malignancies, 31 other causes of death; 9 (5.3%) patients with unknown cause of death were excluded from competing risk assessments. BrCa and OC deaths were not significantly different by treatment arm (P = 0.40): tamoxifen patients experienced 50 BrCa and 32 OC deaths, while tamoxifen + octreotide patients experienced 56 BrCa and 23 OC deaths. Proportionately more deaths (P = 0.004) were from BrCa for patients < 70 years, where 70% of deaths were due to BrCa, compared to 54% for those ≥ 70 years of age. The proportion of deaths from OC increased with increasing body mass index (BMI) (P = 0.02). Higher pathologic T and N were associated with more BrCa deaths (P < 0.0001 and 0.002, respectively). The cumulative hazard plot for BrCa and OC mortality indicated the concurrent accrual of both types of death throughout follow-up, that is the existence of competing risks of mortality. MA.14 therapy did not impact mortality (P = 0.77). Three baseline patient and tumor characteristics were differentially associated with cause of death: older patients experienced more OC (P = 0.01) mortality; patients with T1 tumors and hormone receptor positive tumors had less BrCa mortality (respectively, P = 0.01, P = 0.06). Additionally, step-wise cause-specific models indicated that patients with node negative disease experienced less BrCa mortality (P = 0.002); there was weak evidence that, lower C-peptide (P = 0.08) was associated with less BrCa mortality, while higher BMI (P = 0.01) was associated with worse OC mortality.ConclusionWe demonstrate here a new paradigm of simultaneous testing of therapeutics directed at multiple diseases for which postmenopausal women are concurrently at risk. Octreotide LAR did not significantly impact breast cancer or other cause mortality, although different baseline factors influenced type of death.

Project description:BackgroundIn here, we constructed personalized models for predicting breast cancer (BC) recurrence according to timing of recurrence (as early and late recurrence).MethodsAn efficient algorithm called group LASSO was used for simultaneous variable selection and risk factor prediction in a logistic regression model.ResultsFor recurrence <?5 years, age (OR 0.96, 95% CI?=?0.95-0.97), number of pregnancies (OR 0.94, 95% CI?=?0.89-0.99), family history of other cancers (OR 0.73, 95% CI?=?0.60-0.89), hormone therapy (OR 0.76, 95% CI?=?0.61-0.96), dissected lymph nodes (OR 0.98, 95% CI?=?0.97-0.99), right-sided BC (OR 0.87, 95% CI?=?0.77-0.99), diabetes (OR 0.77, 95% CI?=?0.60-0.98), history of breast operations (OR 0.38, 95% CI?=?0.17-0.88), smoking (OR 5.72, 95% CI?=?2.11-15.55), history of breast disease (OR 3.32, 95% CI?=?1.92-5.76), in situ component (OR 1.58, 95% CI?=?1.35-1.84), tumor necrosis (OR 1.87, 95% CI?=?1.57-2.22), sentinel lymph node biopsy (SLNB) (OR 2.90, 95% CI?=?2.05-4.11) and SLNB+axillary node dissection (OR 3.50, 95% CI?=?2.26-5.42), grade 3 (OR 1.79, 95% CI?=?1.46-2.21), stage 2 (OR 2.71, 95% CI?=?2.18-3.35), stages 3 and 4 (OR 5.01, 95% CI?=?3.52-7.13), and mastectomy+radiotherapy (OR 2.97, 95% CI?=?2.39-3.68) were predictors of recurrence <?5 years. Moreover, relative to mastectomy without radiotherapy (as reference for comparison), quadrantectomy without radiotherapy had a noticeably higher odds ratio compared to quadranectomy with radiotherapy for recurrence <?5 years. (OR 17.58, 95% CI?=?6.70-46.10 vs. OR: 2.50, 95% CI?=?2-3.12). Accuracy, sensitivity, and specificity of the model were 82%, 75.6%, and 74.9%, respectively. For recurrence >?5 years, stage 2 cancer (OR 1.67, 95% CI?=?1.31-2.14) and radiotherapy+mastectomy (OR 2.45, 95% CI?=?1.81-3.32) were significant predictors; furthermore, relative to mastectomy without radiotherapy (as reference for comparison), quadranectomy without radiotherapy had a noticeably higher odds ratio compared to quadranectomy with radiotherapy for recurrence >?5 years (OR 7.62, 95% CI?=?1.52-38.15 vs. OR 1.75, 95% CI?=?1.32-2.32). Accuracy, sensitivity, and specificity of the model were 71%, 78.8%, and 55.8%, respectively.ConclusionFor the first time, we constructed models for estimating recurrence based on timing of recurrence which are among the most applicable models with excellent accuracy (>?80%).

Project description:BACKGROUND:The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. METHODS:In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years. RESULTS:Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. CONCLUSIONS:After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).

Dataset Information

Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

Publications

Influence of Competing Risks on Estimates of Recurrence Risk and Breast Cancer-specific Mortality in Analyses of the Early Breast Cancer Trialists Collaborative Group.

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