Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis.

BACKGROUND: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance. METHODS: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. RESULTS: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001). CONCLUSIONS: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.

Mogamulizumab in Combination with Nivolumab in a Phase I/II Study of Patients with Locally Advanced or Metastatic Solid Tumors.

PURPOSE: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. PATIENTS AND METHODS: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. RESULTS: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6-17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3-3.1) months, and median overall survival was 9.5 (95% CI, 5.9-13.5) months. CONCLUSIONS: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.

BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

PURPOSE: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA). METHODS AND MATERIALS: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months. CONCLUSIONS: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.

IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405.

Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided. Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; P nonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; P trend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; P trend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; P trend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (P nonlinearity = .03). Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405.

BACKGROUND: In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. METHODS: We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided. RESULTS: Among 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted P trend = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; P trend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; P trend = .006). CONCLUSIONS: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.

Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial.

Importance: Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited. Objective: To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer. Design, Setting, and Participants: This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018. Exposures: Participants completed a validated food frequency questionnaire within 4 weeks after initiation of first-line treatment for metastatic colorectal cancer. Diets were categorized according to the Alternative Healthy Eating Index (AHEI), Alternate Mediterranean Diet (AMED) score, Dietary Approaches to Stop Hypertension (DASH) score, and Western and prudent dietary patterns derived using principal component analysis. Participants were categorized into sex-specific quintiles. Main Outcomes and Measures: Multivariable hazard ratios (HRs) and 95% CIs for overall survival. Results: In this cohort study of 1284 individuals with metastatic colorectal cancer, the median age was 59 (interquartile range [IQR]: 51-68) years, median body mass index was 27.2 (IQR, 24.1-31.4), 521 (41%) were female, and 1102 (86%) were White. There were 1100 deaths during a median follow-up of 73 months (IQR, 64-87 months). We observed an inverse association between the AMED score and risk of death (HR quintile 5 vs quintile 1, 0.83; 95% CI, 0.67-1.04; P = .04 for trend), but the point estimates were not statistically significant. None of the other diet scores or patterns were associated with overall survival. Conclusions and Relevance: In this prospective analysis of patients with metastatic colorectal cancer, diet quality assessed at initiation of first-line treatment for metastatic disease was not associated with overall survival.

Diabetes and Clinical Outcome in Patients With Metastatic Colorectal Cancer: CALGB 80405 (Alliance).

BACKGROUND: Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear. METHODS: This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network. The primary exposure was physician-documented diabetes at the time of enrollment. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS) and adverse events. Tests of statistical significance were two-sided. RESULTS: Among 2326 patients, 378 (16.3%) had diabetes. The median follow-up time was 6.0 years. We observed 1973 OS events and 2173 PFS events. The median time to an OS event was 22.7 months among those with diabetes and 27.1 months among those without diabetes (HR = 1.27, 95% CI = 1.13 to 1.44; P < .001). The median time to a PFS event was 9.7 months among those with diabetes and 10.8 months among those without diabetes (HR = 1.16, 95% CI = 1.03 to 1.30; P = .02). Patients with diabetes were more likely to experience no less than grade 3 hypertension (8.1% vs 4.4%; P = .054) but were not more likely to experience other adverse events, including neuropathy. CONCLUSIONS: Diabetes is associated with an increased risk of mortality and tumor progression in patients with advanced or metastatic CRC. Patients with diabetes tolerate first-line treatment with chemotherapy and monoclonal antibodies similarly to patients without diabetes.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2.

PURPOSE: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.

Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405.

PURPOSE: Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored. PATIENTS AND METHODS: We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850), a National Cancer Institute-sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss. RESULTS: The final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend = .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend = .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend < .001). CONCLUSION: Among patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

Dietary Fat Intake after Colon Cancer Diagnosis in Relation to Cancer Recurrence and Survival: CALGB 89803 (Alliance).

Background: Higher intake of long-chain ω-3 polyunsaturated fatty acids and nuts, rich plant sources of unsaturated fats, after colon cancer diagnosis are associated with improved survival. It is not known whether the amount or the distribution of other types of fat is associated with survival after colon cancer.Methods: We prospectively examined postdiagnostic total, animal, and vegetable fats, as well as the saturated, monounsaturated, polyunsaturated, and trans fat in relation to disease-free survival among 1,011 patients with stage III colon cancer. Patients were enrolled between 1999 and 2001 at the onset of adjuvant chemotherapy and followed for recurrence or death through 2009.Results: During median follow-up of 7 years, we observed 305 deaths and 81 recurrences (total events: 386). Neither total nor any specific type of dietary fat examined was statistically significantly associated with risk of cancer recurrence or death from any cause (disease-free survival) after stage III colon cancer.Conclusions: The amount and type (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer does not appear to be substantially associated with risk of recurrence or survival.Impact: Neither total nor major types (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer was associated with cancer recurrence or survival. Cancer Epidemiol Biomarkers Prev; 27(10); 1227-30. ©2018 AACR.

Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Purpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. Clin Cancer Res; 24(19); 4734-44. ©2018 AACR.

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2.

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.

BACKGROUND: Prior studies with the use of a prospective-retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. METHODS: We performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence). RESULTS: Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6). CONCLUSIONS: Among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Effects of yoga on cancer-related fatigue and global side-effect burden in older cancer survivors.

BACKGROUND: Sixty percent of cancer survivors are 65years of age or older. Cancer and its treatments lead to cancer-related fatigue and many other side effects, in turn, creating substantial global side-effect burden (total burden from all side effects) which, ultimately, compromises functional independence and quality of life. Various modes of exercise, such as yoga, reduce cancer-related fatigue and global side-effect burden in younger cancer survivors, but no studies have specifically examined the effects of yoga on older cancer survivors. OBJECTIVES: The purpose of this study was to assess the effects of a 4-week yoga intervention (Yoga for Cancer Survivors: YOCAS©®) on overall cancer-related fatigue, and due to its multidimensional nature, the subdomains of cancer-related fatigue (general, physical, emotional, and mental) and global side-effect burden in older cancer survivors. MATERIALS AND METHODS: We conducted a secondary analysis on data from a multicenter phase III randomized controlled clinical trial with 2 arms (standard care and standard care plus a 4-week YOCAS©® intervention). The sample for this secondary analysis was 97 older cancer survivors (≥60years of age), between 2months and 2years post-treatment, who participated in the original trial. RESULTS: Participants in the YOCAS©® intervention arm reported significantly lower cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden than participants in the standard care arm following the 4-week intervention period (p<0.05). CONCLUSIONS: YOCAS©® is an effective standardized yoga intervention for reducing cancer-related fatigue, physical fatigue, mental fatigue, and global side-effect burden among older cancer survivors.

Comparative effectiveness of sphincter-sparing surgery versus abdominoperineal resection in rectal cancer: patient-reported outcomes in National Surgical Adjuvant Breast and Bowel Project randomized trial R-04.

OBJECTIVE: National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 was a randomized controlled trial of neoadjuvant chemoradiotherapy in patients with resectable stage II-III rectal cancer. We hypothesized that patients who underwent abdominoperineal resection (APR) would have a poorer quality of life than those who underwent sphincter-sparing surgery (SSS). METHODS: To obtain patient-reported outcomes (PROs) we administered two symptom scales at baseline and 1 year postoperatively: the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) and the European Organization for the Research and Treatment of Cancer module for patients with Colorectal Cancer Quality of Life Questionnaire (EORTC QLQ-CR38). Scoring was stratified by nonrandomly assigned definitive surgery (APR vs SSS). Analyses controlled for baseline scores and stratification factors: age, sex, stage, intended surgery, and randomly assigned chemoradiotherapy. RESULTS: Of 1,608 randomly assigned patients, 987 had data for planned analyses; 62% underwent SSS; 38% underwent APR. FACT-C total and subscale scores were not statistically different by surgery at 1 year. For the EORTC QLQ-CR38 functional scales, APR patients reported worse body image (70.3 vs 77.0, P = 0.0005) at 1 year than did SSS patients. Males undergoing APR reported worse sexual enjoyment (43.7 vs 54.7, P = 0.02) at 1 year than did those undergoing SSS. For the EORTC QLQ-CR38 symptom scale scores, APR patients reported worse micturition symptoms than the SSS group at 1 year (26.9 vs 21.5, P = 0.03). SSS patients reported worse gastrointestinal tract symptoms than did the APR patients (18.9 vs 15.2, P < 0.0001), as well as weight loss (10.1 vs 6.0, P = 0.002). CONCLUSIONS: Symptoms and functional problems were detected at 1 year by EORTC QLQ-CR38, reflecting different symptom profiles in patients who underwent APR than those who underwent SSS. Information from these PROs may be useful in counseling patients anticipating surgery for rectal cancer.

Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.

BACKGROUND: We studied the effect on tumour response to neoadjuvant therapy of the substitution of lapatinib for trastuzumab in combination with weekly paclitaxel after doxorubicin plus cyclophosphamide treatment, and of the addition of lapatinib and trastuzumab combined after doxorubicin plus cyclophosphamide treatment in patients with HER2-positive operable breast cancer to determine whether there would be a benefit of dual HER2 blockade in these patients. METHODS: For this open-label, randomised phase 3 trial we recruited women aged 18 years or older with an ECOG performance status of 0 or 1 with operable HER2-positive breast cancer. Each received four cycles of standard doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously on day 1 every 3 weeks followed by four cycles of weekly paclitaxel (80 mg/m(2)) intravenously on days 1, 8, and 15, every 4 weeks. Concurrently with weekly paclitaxel, patients received either trastuzumab (4 mg/kg load, then 2 mg/kg intravenously) weekly until surgery, lapatinib (1250 mg orally) daily until surgery, or weekly trastuzumab plus lapatinib (750 mg orally) daily until surgery. After surgery, all patients received trastuzumab to complete 52 weeks of HER2-targeted therapy. Randomisation (ratio 1:1:1) was done centrally with stratification by clinical tumour size, clinical nodal status, hormone-receptor status, and age. The primary endpoint was the pathological complete response in the breast, and analysis was performed on an intention-to-treat population. FINDINGS: Patient accrual started on July 16, 2007, and was completed on June 30, 2011; 529 women were enrolled in the trial. 519 patients had their pathological response determined. Breast pathological complete response was noted in 93 (52·5%, 95% CI 44·9-59·5) of 177 patients in the trastuzumab group, 91 (53·2%, 45·4-60·3) of 171 patients in the lapatinib group (p=0·9852); and 106 (62·0%, 54·3-68·8) of 171 patients in the combination group (p=0·095). The most common grade 3 and 4 toxic effects were neutropenia (29 [16%] patients in the trastuzumab group [grade 4 in five patients (3%), 28 [16%] in the lapatinib group [grade 4 in eight patients (5%)], and 29 [17%] in the combination group [grade 4 in nine patients (5%)]) and grade 3 diarrhoea (four [2%] patients in the trastuzumab group, 35 [20%] in the lapatinib group, and 46 [27%] in the combination group; p<0·0001). Symptomatic congestive heart failure defined as New York Heart Association Class III or IV events occurred in seven (4%) patients in the trastuzumab group, seven (4%) in the lapatinib group, and one (<1%) in the combination group; p=0·185). INTERPRETATION: Substitution of lapatinib for trastuzumab in combination with chemotherapy resulted in similar high percentages of pathological complete response. Combined HER2-targeted therapy produced a numerically but insignificantly higher pathological complete response percentage than single-agent HER2-directed therapy; these findings are consistent with results from other studies. Trials are being undertaken to further assess these findings in the adjuvant setting.

Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial.

PURPOSE: Anthracycline- and taxane-based three-drug chemotherapy regimens have proven benefit as adjuvant therapy for early-stage breast cancer. This trial (NSABP B-38; Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer) asked whether the incorporation of a fourth drug could improve outcomes relative to two standard regimens and provided a direct comparison of those two regimens. PATIENTS AND METHODS: We randomly assigned 4,894 women with node-positive early-stage breast cancer to six cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC), four cycles of dose-dense (DD) doxorubicin and cyclophosphamide followed by four cycles of DD paclitaxel (P; DD AC→P), or DD AC→P with four cycles of gemcitabine (G) added to the DD paclitaxel (DD AC→PG). Primary granulocyte colony-stimulating factor support was required; erythropoiesis-stimulating agents (ESAs) were used at the investigator's discretion. RESULTS: There were no significant differences in 5-year disease-free survival (DFS) between DD AC→PG and DD AC→P (80.6% v 82.2%; HR, 1.07; P = .41), between DD AC→PG and TAC (80.6% v 80.1%; HR, 0.93; P = .39), in 5-year overall survival (OS) between DD AC→PG and DD AC→P (90.8% v 89.1%; HR, 0.85; P = .13), between DD AC→PG and TAC (90.8% v 89.6%; HR, 0.86; P = .17), or between DD AC→P versus TAC for DFS (HR, 0.87; P = .07) and OS (HR, 1.01; P = .96). Grade 3 to 4 toxicities for TAC, DD AC→P, and DD AC→PG, respectively, were febrile neutropenia (9%, 3%, 3%; P < .001), sensory neuropathy (< 1%, 7%, 6%; P < .001), and diarrhea (7%, 2%, 2%; P < .001). Exploratory analyses for ESAs showed no association with DFS events (HR, 1.02; P = .95). CONCLUSION: Adding G to DD AC→P did not improve outcomes. No significant differences in efficacy were identified between DD AC→P and TAC, although toxicity profiles differed.

Diagnostic microRNA markers to screen for sporadic human colon cancer in stool: I. Proof of principle.

To present proof-of-principle application for employing micro(mi)RNAs as diagnostic markers for colon cancer, we carried out global microarray expression studies on stool samples obtained from fifteen individuals (three controls, and three each with TNM stage 0-1, stage 2, stage 3, and stage 4 colon cancer), using Affymetrix GeneChip miRNA 3.0 Array, to select for a panel of miRNA genes for subsequent focused semi-quantitative polymerase chain reaction (PCR) analysis studies. Microarray results showed 202 preferentially expressed miRNA genes that were either increased (141 miRNAs), or reduced (61 miRNAs) in expression. We then conducted a stem-loop reverse transcriptase (RT)-TaqMan® minor groove binding (MGB) probes, followed by a modified qPCR expression study on 20 selected miRNAs. Twelve of the miRNAs exhibited increased and 8 decreased expression in stool from 60 individuals (20 controls, 20 with tumor-lymph node-metastatic (TNM) stage 0-1, 10 with stage 2, five with stage 3, and 5 with stage 4 colon cancer) to quantitatively monitor miRNA changes at various TNM stages of colon cancer progression. We also used laser-capture microdissection (LCM) of colon mucosal epithelial tissue samples (three control samples, and three samples from each of the four stages of colon cancer, for a total of 15 samples) to find concordance or lack thereof with stool findings. The reference housekeeping pseudogene-free ribosomal gene (18S rRNA), which shows little variation in expression, was employed as a normalization standard for relative PCR quantification. Results of the PCR analyses confirmed that twelve miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p and miR214) had an increased expression in the stool of patients with colon cancer, and that later TNM carcinoma stages exhibited a more pronounced expression than did adenomas. On the other hand, eight miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, miR-222 and miR-938) had decreased expression in the stool of patients with colon cancer, which was also more pronounced from early to later TNM stages. Results from colon mucosal tissues were similar to those from stool samples, although with more apparent changes in expression. Cytological studies on purified stool colonocytes that employed Giemsa staining showed 80% sensitivity for detecting tumor cells in stool smears. The performance characteristics of the test confirmed that stool is a medium well-suited for colon cancer screening, and that the quantitative changes in the expression of few mature miRNA molecules in stool associated with colon cancer progression provided for more sensitive and specific non-invasive diagnostic markers than tests currently available on the market. Thus, a larger prospective and properly randomized validation study of control individuals and patients exhibiting various stages of colon cancer progression (TNM stages 0-IV) is now needed in order to standardize test conditions, and provide a means for determining the true sensitivity and specificity of a miRNA screening approach in stool for the non-invasive detection of colon cancer, particularly at an early stage (0-I). Eventually, we will develop a chip to enhance molecular screening for colon cancer, as has been accomplished for the detection of genetically-modified organisms (GMOs) in foods.