Estrogen Receptor Status by Immunohistochemistry Is Superior to the Ligand-Binding Assay for Predicting Response to Adjuvant Endocrine Therapy in Breast Cancer.

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Prophylactic Use of Compression Sleeves Reduces the Incidence of Arm Swelling in Women at High Risk of Breast Cancer-Related Lymphedema: A Randomized Controlled Trial.

PURPOSE: To determine whether prophylactic use of compression sleeves prevents arm swelling in women who had undergone axillary lymph node dissection for breast cancer surgery. METHODS: Women (n = 307) were randomly assigned to either a compression or control group. In addition to usual postoperative care, the compression group received two compression sleeves to wear postoperatively until 3 months after completing adjuvant treatments. Arm swelling was determined using bioimpedance spectroscopy (BIS) thresholds and relative arm volume increase (RAVI). Incidence and time free from arm swelling were compared using Kaplan-Meier analyses. Hazard ratios (HRs) were estimated from Cox regression models for BIS and RAVI thresholds independently. In addition, time to documentation of the first minimally important difference (MID) in four scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the breast cancer-specific (BR23) questionnaire was analyzed. RESULTS: The HR for developing arm swelling in the compression group relative to the control group was 0.61 (95% CI, 0.43 to 0.85; P = .004) on the basis of BIS and 0.56 (95% CI, 0.33 to 0.96; P = .034) on the basis of RAVI. The estimated cumulative incidence of arm swelling at 1 year was lower in the compression group than the control group on the basis of BIS (42% v 52%) and RAVI (14% v 25%). HRs for time from baseline to the first change of the minimally important difference were not statistically significant for any of the four scales of EORTC QLQ-30 and BR23 questionnaires. CONCLUSION: Prophylactic use of compression sleeves compared with the control group reduced and delayed the occurrence of arm swelling in women at high risk for lymphedema in the first year after surgery for breast cancer.

A Grant-Based Experiment to Train Clinical Investigators: The AACR/ASCO Methods in Clinical Cancer Research Workshop.

To address the need for clinical investigators in oncology, American Association for Cancer Research (AACR) and American Society for Clinical Oncology (ASCO) established the Methods in Clinical Cancer Research Workshop (MCCRW). The workshop's objectives were to: (i) provide training in the methods, design, and conduct of clinical trials; (ii) ensure that clinical trials met federal and international ethical guidelines; (iii) evaluate the effectiveness of the workshop; and (iv) create networking opportunities for young investigators with mentoring senior faculty. Educational methods included: (i) didactic lectures, (ii) Small Group Discussion Sessions, (iii) Protocol Development Groups, and (iv) one-on-one mentoring. Learning focused on the development of an Institutional Review Board (IRB)-ready protocol, which was submitted on the last day of the workshop. Evaluation methods included: (i) pre- and postworkshop tests, (ii) students' workshop evaluations, (iii) faculty's ratings of protocol development, (iv) students' productivity in clinical research after the workshop, and (v) an independent assessment of the workshop. From 1996 to 2014, 1,932 students from diverse backgrounds attended the workshop. There was a significant improvement in the students' level of knowledge from the pre- to the postworkshop exams (P < 0.001). Across the classes, student evaluations were very favorable. At the end of the workshop, faculty rated 92% to 100% of the students' protocols as ready for IRB submission. Intermediate and long-term follow-ups indicated that more than 92% of students were actively involved in patient-related research, and 66% had implemented five or more protocols. This NCI-sponsored MCCRW has had a major impact on the training of clinicians in their ability to design and implement clinical trials in cancer research.

Redefining adequate margins in oral squamous cell carcinoma: outcomes from close and positive margins.

PURPOSE: Adequacy of surgical margins impacts outcomes in oral cancer. We sought to determine whether close and positive margins have different outcomes in patients with oral cancer. METHODS: Retrospective data from 612 patients with oral carcinoma were analyzed for the effect of margin status on locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 90 cases (14.7%) had close margins and 26 patients (4.2%) had positive margins. Recurrences were documented in 173 patients (28%), of which 137 (22% of the study sample) were locoregional, and 164 patients (27%) had died. Among patients with close or positive margins, a cutoff of 1 mm optimally separated LRFS (adjusted p = 0.0190) and OS curves (adjusted p = 0.0168) whereas a cutoff of 2 mm was sufficient to significantly separate DFS curves (adjusted p = 0.0281). CONCLUSIONS: Patients with oral carcinoma with positive margins (< 1 mm) had poorer outcomes compared to those with close margins (1-5 mm) in terms of LRFS, DFS and OS. There is a suggestion that a cutoff of < 2 mm might provide slightly more separation for DFS.

A perspective on challenges and issues in biomarker development and drug and biomarker codevelopment.

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized.

Erlotinib for advanced non-small-cell lung cancer in the elderly: an analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.

PURPOSE: National Cancer Institute of Canada Clinical Trials Group Study BR.21 established erlotinib as a standard of care in patients with non-small-cell lung cancer (NSCLC) after failure of first- or second-line chemotherapy. The current study analyzes the influence of age on outcomes in BR.21. PATIENTS AND METHODS: BR.21 was a double-blind phase III trial that randomly assigned 731 patients to erlotinib 150 mg daily or placebo. End points included progression-free survival and overall survival (OS), response, quality of life (QOL), drug exposure, and toxicity, which are analyzed in this retrospective study by the following two age groups: >or= 70 years (elderly) or less than 70 years (young). RESULTS: There were 163 elderly patients (112 on erlotinib, 51 on placebo) and 568 young patients (376 on erlotinib, 192 on placebo). There was no significant difference between age groups randomly assigned to erlotinib or placebo in progression-free survival (elderly: 3.0 v 2.1 months; hazard ratio [HR] = 0.63; 95% CI, 0.44 to 0.90; P = .009; young: 2.1 v 1.8 months; HR = 0.64; 95% CI, 0.53 to 0.76; P < .0001; interaction, P = .77) or OS (elderly: 7.6 v 5.0 months; HR = 0.92; 95% CI, 0.64 to 1.34; P = .67; young: 6.4 v 4.7 months; HR = 0.73; 95% CI, 0.61 to 0.89; P = .0014; interaction, P = .31). Response rates were similar between age groups. Elderly patients, compared with young patients, had significantly more overall and severe (grade 3 and 4) toxicity (35% v 18%; P < .001), were more likely to discontinue treatment as a result of treatment-related toxicity (12% v 3%; P < .0001), and had lower relative dose-intensity (64% v 82% received > 90% planned dose; P < .001). CONCLUSION: Elderly patients treated with erlotinib gain similar survival and QOL benefits as younger patients but experience greater toxicity.

Prognostic factors versus predictive factors: Examples from a clinical trial of erlotinib.

It would be helpful to have factors that could identify patients who will, or will not, benefit from treatment with specific therapies. Ideally, these should be molecular-based factors. When results with molecular-based factors are disappointing, physicians often use clinical characteristics to make treatment decisions. Several characteristics have been suggested to predict sensitivity to epidermal growth factor receptor inhibitors in patients with non-small lung cancer, including gender, histology, smoking history. This report demonstrates that gender and histology are actually prognostic, rather than predictive factors. Before biomarkers or clinical characteristics are included in guidelines for selecting patients for specific treatments, it is imperative that the prognostic effects of these factors are distinguished from their ability to predict a differential clinical benefit from the specific treatment.

Molecular heterogeneity of inflammatory breast cancer: a hyperproliferative phenotype.

PURPOSE: Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays. EXPERIMENTAL DESIGN: For gene expression analysis, IBC (n=14) was clinically defined as rapid-onset cancer associated with erythema and skin changes, whereas non-IBC patients (n=20) had stage III breast cancers, and cDNA analysis was carried out using the Affymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from>2,000 non-IBC. RESULTS: Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93% versus 11%; P<0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P<0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P=0.002; progesterone receptor, 68% versus 42%; P=0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different. CONCLUSION: This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.

REporting recommendations for tumor MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, pre-planned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Smoking history and epidermal growth factor receptor expression as predictors of survival benefit from erlotinib for patients with non-small-cell lung cancer in the National Cancer Institute of Canada Clinical Trials Group study BR.21.

BACKGROUND: Erlotinib is an oral, reversible inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. A survival advantage for erlotinib compared with placebo was demonstrated in the National Cancer Institute of Canada Clinical Trials Group study BR.21, a randomized double-blind study of 731 patients with advanced-stage non-small-cell lung cancer. PATIENTS AND METHODS: In this retrospective, exploratory investigation, univariate and multivariate analyses of survival of the 311 patients with available EGFR status by immunohistochemistry and known smoking history were performed to determine which factor might be more important for predicting clinical outcome. RESULTS: A marginally significant interaction was observed between smoking history and treatment (P = 0.054). The hazard ratios (HRs) were 0.42 among never-smokers and 0.87 for smokers, indicating that erlotinib was beneficial in both subsets but more effective in patients who had never smoked. The HRs for patients with EGFR-positive and EGFR-negative tumors were 0.65 and 0.83, respectively; however, the interaction between EGFR status and treatment was not significant in univariate or multivariate analyses. Patients with EGFR-positive tumors who never smoked had the greatest survival benefit from erlotinib relative to placebo (HR, 0.28; P = 0.0007). CONCLUSION: These data suggest that never-smokers and patients with EGFR-positive tumors might experience an enhanced benefit from erlotinib compared with placebo but that smoking history might be more predictive of survival benefit than EGFR expression. Subset analyses of ever-smokers revealed significant survival advantages for men and patients with squamous cell histology. Male ever-smokers with squamous cell non-small-cell lung cancer derived a significant survival benefit from erlotinib (HR, 0.66; P = 0.015) despite a very low tumor response rate.

Effects of smoking on the pharmacokinetics of erlotinib.

PURPOSE: To compare the pharmacokinetic variables of erlotinib in current smokers with nonsmokers after receiving a single oral 150 or 300 mg dose of erlotinib. EXPERIMENTAL DESIGN: This was a single-center, open-label pharmacokinetic study in healthy male subjects. Subjects were enrolled into two treatment cohorts based on smoking status (current smokers and nonsmokers). The pharmacokinetic profile for erlotinib and its metabolite, OSI-420, was determined for each subject following each treatment. RESULTS: Current smokers achieved significantly less erlotinib exposure following a single 150 or 300 mg dose than nonsmokers. Following the 150 mg dose, the geometric mean erlotinib AUC(0-infinity) in smokers was 2.8-fold lower than in nonsmokers and similar to that of nonsmokers at the 300 mg dose. C(max) in smokers was two-thirds of that in nonsmokers, and C(24h) in smokers was 8.3-fold lower than in nonsmokers. The median C(24h) of smokers at the 300 mg dose was slightly less than the C(24h) of smokers at the 150 mg dose. The median C(max) was greater in smokers at the 300 mg dose than in nonsmokers at the 150 mg dose. CONCLUSION: This study confirms that the pharmacokinetics of erlotinib is different in current smokers and nonsmokers. The observation that AUC(0-infinity) and C(24h) were significantly decreased in smokers compared with nonsmokers, and a smaller decrease in C(max) was observed, is consistent with increased metabolic clearance of erlotinib in current smokers.

Breast tumors that overexpress nuclear metastasis-associated 1 (MTA1) protein have high recurrence risks but enhanced responses to systemic therapies.

Nuclear metastasis-associated 1(MTA1) protein is an estrogen receptor co-repressor that regulates transcription via chromatin remodeling, and MTA1 messenger ribonucleic acid (mRNA) levels are elevated in several kinds of locally advanced and metastatic tumors relative to non-metastatic tumors. Previous studies in our laboratory mapped MTA1 into a region showing significantly lower LOH (loss of heterozygosity) in primary breast cancers with metastases compared to node-negative tumors, suggesting that epigenetic alterations of MTA1 affect metastatic potential. The present study examined immunohistochemical expression of the MTA1 protein in treated and untreated primary human breast cancers to study the relationship between MTA1 expression and clinical outcome. Node-negative tumors that overexpress MTA1 protein had recurrence risks similar to node-positive tumors. In multivariate analysis of untreated node-negative tumors, highest expression of MTA1 was associated with increased relapse risk (hazard ratio (HR)=2.72, p=0.0003 for multivariate analysis). Tamoxifen and/or anthracylcene-based chemotherapies eliminated all MTA1 associations with clinical outcome, suggesting MTA1 overexpression predicts early disease relapse, but sensitizes breast tumors to systemic therapies.

Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib.

INTRODUCTION: Erlotinib (Tarceva) has demonstrated a survival benefit in unselected patients with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy. Because not all patients benefit from erlotinib, epidermal growth factor receptor (EGFR) protein expression may provide a basis for selecting patients for treatment with this EGFR inhibitor. METHODS: Tumor samples from patients who participated in National Institute of Canada Clinical Trials Group Study BR.21 were assayed by immunohistochemistry using Dako EGFR pharmDx kits. EGFR expression was scored as proportion of tumor cells with membrane staining, staining intensity, and combined proportion and intensity scores. All possible cutpoints were examined to determine whether EGFR protein expression status by immunohistochemistry might be useful for predicting patient survival. RESULTS: Three hundred twenty-five patients had evaluable assay results. The prognostic significance of EGFR protein expression was modest. Patients with EGFR-positive tumors who received placebo after failure of chemotherapy had slightly worse survival than patients with EGFR-negative tumors; however, the differences were not statistically significant for any cutpoint for any of the three measures of EGFR protein expression. The treatment benefits from erlotinib relative to placebo were greater for EGFR-positive patients compared with EGFR-negative patients, but they were not significantly different for any cutoff used to define EGFR positivity. Use of very high cutpoints to define patients with EGFR-rich tumors that might be especially sensitive to treatment with erlotinib cannot be supported by these data. CONCLUSIONS: Selection or exclusion of NSCLC patients for erlotinib therapy after failure of standard therapy for advanced or metastatic disease should not be based solely on EGFR protein expression as determined by immunohistochemistry.

Morphologic and immunophenotypic markers as surrogate endpoints of tamoxifen effect for prevention of breast cancer.

Prevention trials using incidence or mortality as endpoints require a large number of participants and long follow-up. Trials using biomarkers as endpoints would potentially require fewer participants, less time, and significantly less resources to test promising new agents for breast cancer prevention. To test this idea, a randomized trial of tamoxifen for 1 year versus observation for 1 year was conducted to determine whether tamoxifen can cause regression of hyperplastic breast tissue, whether it changes the biomarker phenotype of premalignant disease or normal breast epithelium, and if biomarkers can be used as early surrogate indicators of response to tamoxifen. Women were identified by having an abnormal mammogram and ductal hyperplasia diagnosed by core needle biopsy. Image-directed needle biopsy was repeated in the same site of the breast after 1 year. Approximately 3000 women were screened, and 265 were eligible. Sixty-three women were randomized and paired biopsies from 45 subjects were available for analysis. There was no evidence of substantial regression of hyperplasia--fewer samples showed hyperplasia at 1 year follow-up, but this was seen in both untreated and tamoxifen-treated women. There were trends for reductions in ER and PgR and trends for increases in bcl-2 in normal and hyperplastic tissue in the tamoxifen-treated arm, though these changes did not reach statistical significance. Proliferation, determined by Ki67 staining, was not significantly changed. Clinical trials of this type are difficult to carry out and modifications in trial design are needed to make this process more efficient.

REporting recommendations for tumor MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons why multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines provide helpful suggestions on how to present data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Reporting recommendations for tumor marker prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often, initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

REporting recommendations for tumour MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomised trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, pre-planned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Hazard rates of recurrence following diagnosis of primary breast cancer.

We calculated hazard rates for recurrence in patients with primary breast cancer (stage I, II; no adjuvant therapy). Previous publications have indicated a peak in hazard rates for recurrence (or death) at approximately 2-3 years after diagnosis of primary breast cancer. However, there have been conflicting reports concerning the presence of a second peak at 5-7 years after diagnosis. In this study, we estimated hazard functions by the Nelson-Aalen method and fit by cubic-linear and cubic-cubic-linear models to test for the presence of one or two peaks, respectively. We identified two peaks in hazard of recurrence, one at 2 years and another at 5 years. The 5-year peak, though statistically significant, represents very small differences in patient outcome. This additional peak may be an artifact of interval censoring due to a tendency to follow-up patients at specific bench-mark time points.