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PURPOSE Patients with locally advanced breast cancer (LABC) typically undergo staging tests at presentation. If staging does not detect metastases, treatment consists of curative intent combined modality therapy (neoadjuvant chemotherapy, surgery, and regional radiation). Positron emission tomography-computed tomography (PET-CT) may detect more asymptomatic distant metastases, but the evidence is based on uncontrolled studies. METHODS For inclusion, patients had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1). Consenting patients from six regional cancer centers in Ontario were randomly assigned to 18F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of the chest/abdomen and pelvis). The primary end point was upstaging to stage IV. A key secondary outcome was receiving curative intent combined modality therapy (ClinicalTrials.gov identifier: NCT02751710 ). RESULTS Between December 2016 and April 2022, 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging. Forty-three (23%) PET-CT patients were upstaged to stage IV compared with 21 (11%) conventional staged patients (absolute difference, 12.3%; 95% CI, 3.9 to 19.9; P = .002). Consequently, treatment was changed in 35 (81.3%) of 43 upstaged PET-CT patients and 20 (95.2%) of the 21 upstaged conventional patients. Subsequently, 149 (81%) patients in the PET-CT group received combined modality treatment versus 165 (89.2%) patients in the conventional staging group (absolute difference, 8.2%; 95% CI, 0.1 to 15.4; P = .03). CONCLUSION In patients with LABC, PET-CT detected more distant metastases than conventional staging, and fewer PET-CT patients received combined modality therapy. Our randomized trial demonstrates the utility of the PET-CT staging strategy.

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Survival analysis showing the primary endpoint of disease-free survival for patients receiving tamoxifen (red lines) vs. placebo (black lines) in the MA.12 translational study cohort.

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Purpose:Accurate IHC biomarkers incorporating nestin positivity or inositol polyphosphate-4-phosphate (INPP4B) loss have recently been optimized to identify the basal-like intrinsic breast cancer subtype regardless of estrogen, progesterone, or Her2 status. We examined the predictive capacity of these basal biomarkers in the CCTG MA.5 chemotherapy and MA.12 endocrine therapy trials.Experimental Design:Formalin-fixed paraffin embedded blocks of primary tumors from patients randomized in the two trials were used to build tissue microarrays. IHC staining for nestin and INPP4B followed published methods and REMARK criteria. A prespecified statistical plan tested the hypothesis that patients with basal breast cancer (nestin+ or INPP4B−) would not benefit from anthracycline substitution in MA.5 or from tamoxifen in MA.12.Results:Nestin positivity or INPP4B loss was observed in 110/453 (24%) interpretable samples from MA.5 and 47/366 (13%) from MA.12, and was associated with high grade, younger age, estrogen receptor negativity, triple-negative, core basal, and PAM50 basal-like subtypes. In the MA.5 trial, patients assigned as basal experienced lower benefit from anthracycline versus nonanthracycline adjuvant chemotherapy [HR, 1.49; 95% confidence interval (CI), 0.72–3.10] when compared with non-basal (nestin− and INPP4B+) cases where there was a higher benefit from anthracyclines (HR, 0.75; 95% CI, 0.54–1.04; Pinteraction = 0.01). In the MA.12 trial, patients assigned as basal did not demonstrate a benefit from adjuvant tamoxifen versus placebo (HR, 0.48; 95% CI, 0.12–1.86; P = 0.29), whereas nonbasal cases displayed significant benefit (HR, 0.66; 95% CI, 0.45–0.98; P = 0.04), although the interaction test was not significant.Conclusions:The nestin/INPP4B IHC panel identifies women with basal breast cancers who benefit from nonanthracycline chemotherapy but not endocrine adjuvant treatments.

Supplementary Table S1: Patient characteristics in the CCTG MA.5 original trial versus the CCTG MA.5 translational study cohort classifiable by immunohistochemistry; Supplementary Table S2: Patient characteristics in the CCTG MA.12 original trial versus the CCTG MA.12 translational study cohort classifiable by immunohistochemistry; Supplementary Table S3: The distribution of the possible Nestin/INPP4B IHC staining categories in the translational study cohorts of MA.5 and MA.12; Supplementary Table S4: The distribution of the different combinations of nestin/INPP4B IHC staining according to "PAM50 basal-like vs. non basal-like" in MA.5 and MA.12; Supplementary Table S5: Performance characteristics of the IHC basal panel against the intrinsic PAM50 breast cancer subtype assay as a gold standard

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Purpose: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.Experimental Design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan–Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.Results: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non–HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6–2.1 for RFS and HR, 1.3; 95% CI, 0.7–2.5 for OS].Conclusion: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required. Clin Cancer Res; 18(8); 2402–12. ©2012 AACR.

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Patient-reported outcome measures (PROMs), which are measures of symptom burden, health-related quality of life (HRQoL), and therapy effectiveness have become increasingly important in clinical research. They are unique in that they are reported directly from the patient, without clinician interpretation, thereby avoiding clinician bias. With an increased focus on the patient at the center of health care, PROMs have been increasingly incorporated into clinical research, systematic reviews, and clinical guidelines. Despite the recognition of the importance of including PROMs into clinical haematologic cancer research, barriers have prevented their integration into cancer research. This review highlights the value of including PROMs into clinical haematologic cancer research and addresses the methodological challenges in using and evaluating PROMs. We propose important questions for the malignant haematologist to consider when designing or evaluating a study that includes PROMs.

ObjectiveTo evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer.DesignPragmatic, cluster randomised trial.Setting20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care.ParticipantsAll patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires.InterventionsProactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle.Main outcome measuresThe primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life.ResultsBaseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively.ConclusionsProactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant.Trial registrationClinicalTrials.govNCT02485678.

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Purpose To provide recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. Prophylaxis in the outpatient, inpatient, and perioperative settings was considered, as were treatment and use of anticoagulation as a cancer-directed therapy. Methods A systematic review of the literature published from December 2007 to December 2012 was completed in MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed evidence to determine which recommendations required revision. Results Forty-two publications met eligibility criteria, including 16 systematic reviews and 24 randomized controlled trials. Recommendations Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for outpatients with cancer. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low–molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term (6 months) secondary prophylaxis. Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE. Anticoagulation should not be used for cancer treatment in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should provide patient education about the signs and symptoms of VTE.

2-[(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is potentially useful in assessing lymph nodes and detecting distant metastases in women with primary breast cancer.Women diagnosed with operable breast cancer within 3 months underwent FDG-PET at one of five Ontario study centers followed by axillary lymph node assessment (ALNA) consisting of sentinel lymph node biopsy (SLNB) alone if sentinel lymph nodes (SLNs) were negative, SLNB with axillary lymph node dissection (ALND) if SLNB or PET was positive, or ALND alone if SLNs were not identified.Between January 2005 and March 2007, 325 analyzable women entered this study. Sentinel nodes were found for 312 (96%) of 325 women and were positive for tumor in 90 (29%) of 312. ALND was positive in seven additional women. Using ALNA as the gold standard, sensitivity for PET was 23.7% (95% CI, 15.9% to 33.6%), specificity was 99.6% (95% CI, 97.2% to 99.9%), positive predictive value was 95.8% (95% CI, 76.9% to 99.8%), negative predictive value was 75.4% (95% CI, 70.1% to 80.1%), and prevalence was 29.8% (95% CI, 25.0% to 35.2%). Using logistic regression, tumor size was predictive for prevalence of tumor in the axilla and for PET sensitivity. PET scan was suspicious for distant metastases in 13 patients; three (0.9%) were confirmed as metastatic disease and 10 (3.0%) were false positive.FDG-PET is not sufficiently sensitive to detect positive axillary lymph nodes, nor is it sufficiently specific to appropriately identify distant metastases. However, the very high positive predictive value (96%) suggests that PET when positive is indicative of disease in axillary nodes, which may influence surgical care.

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

BACKGROUND: There has been minimal research on the influence of delays for cancer treatments on patient outcomes. We measured the influence of delays to nonemergent colon cancer surgery on operative mortality, disease-specific survival and overall survival. METHODS: We used the linked Surveillance, Epidemiology and End Results (SEER)-Medicare databases (1993-1996) to identify patients who underwent nonemergent colon cancer surgery. We assessed 2 time intervals: surgeon consult to hospital admission for surgery and first diagnostic test for colon cancer to hospital admission. Follow-up data were available to the end of 2003. We selected the time intervals to create patient groups with clinical relevance and they did not extend past 120 days. RESULTS: We identified 7989 patients who underwent nonemergent colon cancer surgery. Median delays from surgeon consult to admission and from first diagnostic test to admission were 7 and 17 days, respectively. The odds of operative mortality were similar if the consult-to-admission interval was 22 days or more versus 1-7 days (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.6-1.8, p = 0.91) or if the test-to-admission interval was 43 days or more versus 1-14 days (OR 0.8, 95% CI 0.4-1.5, p = 0.51), respectively. For these same respective interval comparisons, disease-specific survival was not influenced by the consult-to-admission wait (hazard ratio [HR] 1.0, 95% CI 0.9-1.2, p = 0.91) or the test-to-admission wait (HR 1.0, 95% CI 0.8-1.1, p = 0.63). The risk of death was slightly greater if the consult-to-admission interval was 22 or more days versus 1-7 days (HR 1.1, 95% CI 1.0-1.2, p = 0.013) and if the test-to-admission interval was 43 days or more versus 1-14 days (HR 1.2, 95% CI 1.1-1.3, p = 0.003). CONCLUSION: It is unlikely that delays to nonemergent colon cancer surgery longer than 3 weeks from initial surgical consult or longer than 6 weeks from first diagnostic test negatively impact operative mortality, disease-specific survival or overall survival.

This chapter about hemorrhagic complications of anticoagulant treatment is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Bleeding is the major complication of anticoagulant therapy. The criteria for defining the severity of bleeding varies considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that vitamin K antagonist therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0), is associated with a lower risk of bleeding than therapy targeted at an INR3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism (VTE) is3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (70 years). Low molecular weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute VTE. UFH and LMWH are not associated with an increase in major bleeding in ischemic coronary syndromes, but are associated with an increase in major bleeding in ischemic stroke. Information on bleeding associated with the newer generation of antithrombotic agents has begun to emerge. In terms of treatment decision making for anticoagulant therapy, bleeding risk cannot be considered alone, ie, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk.

Abstract 4209 Background: The risk of recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, remains high even with the use of low molecular weight heparin (LMWH). However, due to the heterogeneity of the disease it is probable that recurrence risk varies widely. We have developed a prediction rule to classify risk of recurrence in the first 6 months of treatment: + 1 is scored for each of female gender, lung cancer and prior VTE and – 1 is scored for breast cancer and – 2 for TNM stage 1 disease. With a score of ≤ 0, 4.5% of patients recur (this represented 48% of the patient populations), and > 0, 19.7% recur. The rule was derived in a retrospective cohort study of patients followed at the Thrombosis unit of the Ottawa hospital and requires validation. Methods: We applied our rule in a new set of 819 consecutive patients with cancer-associated VTE from 2 multicentre randomized controlled trials comparing LMWH with vitamin K antagonists (VKA) (ClotCant group). In these studies the stage of disease was not separated by exact TNM classification, rather patients were classified as stage I, II (no metastasis) versus III, IV (metastasis). As such, we redid our derivation model with stage I and II grouped together, which gave this variable a score of – 1. This resulted in a prediction rule which gave a recurrence risk that no longer clearly dichotomized risk; rather gave a low, intermediate, and high risk groups. As in our derivation study, we evaluated patients' risk of recurrence regardless of type of anticoagulant use (VKA or LMWH). Results: Of 819 patients, 86 (10.5%) presented with a VTE recurrence during the anticoagulation period. When we applied our derivation rule in this population, we were able to demonstrate a significant difference in VTE recurrence risk dependent on gender, primary tumour site, stage and history of prior VTE. Patients with a score < 0 have low risk (5.1%) for VTE recurrence and this represented 19% of the patient population; patients with a score of 0 had a intermediate risk (9.8%) and this represented 42% of patients; a score ≥ 1 was high risk (13.9%), occurring in 38% of the population. Dichotomizing the results gave a recurrence risk of 8% in patients with a score ≤ 0 and a 15.2% recurrence risk with a score > 0. Conclusion: the validation dataset suggests reproducibility of our model. The dichotomized score is less discriminatory than our original model suggesting an advantage to classifying patients tumour stage as TNM stage I versus stage II, III and IV. Unfortunately, we could not test this hypothesis with the ClotCant dataset. Our model appears to differentiate risk for recurrence and should be utilized in treatment trials: attempting novel treatment strategies in high risk patients since LMWH alone does not seem to be enough; and using the less costly typical “LMWH followed by oral anticoagulants” in the low risk population to evaluate whether VKA can be as safe and effective as long term LMWH. Disclosures: Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.