Influence of depression on breast cancer treatment and survival: A Kentucky population-based study.

BACKGROUND: Depression is common among breast cancer patients and can affect concordance with guideline-recommended treatment plans. Yet, the impact of depression on cancer treatment and survival is understudied, particularly in relation to the timing of the depression diagnosis. METHODS: The Kentucky Cancer Registry data was used to identify female patients diagnosed with primary invasive breast cancer who were 20 years of age or older in 2007-2011. Patients were classified as having no depression, depression pre-cancer diagnosis only, depression post- cancer diagnosis only, or persistent depression. The impact of depression on receiving guideline-recommended treatment and survival was examined using multivariable logistic regression and Cox regression, respectively. RESULTS: Of 6054 eligible patients, 4.1%, 3.7%, and 6.2% patients had persistent depression, depression pre-diagnosis only, and depression post-diagnosis only, respectively. A total of 1770 (29.2%) patients did not receive guideline-recommended cancer treatment. Compared to patients with no depression, the odds of receiving guideline-recommended treatment were decreased in patients with depression pre-diagnosis only (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.54-1.04) but not in patients with post-diagnosis only or persistent depression. Depression post-diagnosis only (hazard ratio, 1.51; 95% CI, 1.24-1.83) and depression pre-diagnosis only (hazard ratio, 1.26; 95% CI, 0.99-1.59) were associated with worse survival. No significant difference in survival was found between patients with persistent depression and patients with no depression (p > .05). CONCLUSIONS: Neglecting depression management after a breast cancer diagnosis may result in poorer cancer treatment concordance and worse survival. Early detection and consistent management of depression is critical in improving patient survival.

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.

Systemic therapy for HER2-positive early-stage breast cancer.

The advent of the targeted monoclonal antbody trastuzumab for treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer marked a revolution in the understanding and management of mammary carcinoma and, in practice, separated this subtype from other kinds of primary breast malignancy. Long term follow-up from the initial large adjuvant trials continue to show remarkably positive results. Currently, at least four additional agents targeting this receptor, using different and complementary mechanisms of action compared with trastuzumab, have been incorporated into clinical trials. The small molecule tyrosine kinase inhibitors lapatinib and neratinib, in addition to the antibody pertuzumab and the antibody-drug conjugate trastuzumab-ematansine, have shown efficacy in metastatic breast cancer and are being evaluated both in neoadjuvant and adjuvant trials for early stage disease. The cytotoxic chemotherapy regimens used in combination with these agents also are evolving and different therapeutic approaches are emerging for patients depending on their relative level of risk from their cancers, thus moving clinical management toward individualized therapy. Much has been learned about managing the toxicities of treatment and pre-operative approaches have provided a means of assessing the sensitivity of individual patients' cancers to specific treatment regimens. This review traces the development of these studies and focuses on improvements in adjuvant and neoadjuvant therapy for patients with HER2-positive disease whose prognosis has changed in the last decade from dire to favorable. A path forward has been set by which the goal of cure is attainable for almost all patients faced with this aggressive form of breast cancer.

Body Mass Index at Diagnosis and Breast Cancer Survival Prognosis in Clinical Trial Populations from NRG Oncology/NSABP B-30, B-31, B-34, and B-38.

BACKGROUND: Body mass index (BMI) has been associated with breast cancer outcomes. However, few studies used clinical trial settings where treatments and outcomes are consistently evaluated and documented. There are also limited data assessing how patient/disease characteristics and treatment may alter the BMI-breast cancer association. METHODS: We evaluated 15,538 breast cancer participants from four NSABP protocols. B-34 studied early-stage breast cancer patients (N = 3,311); B-30 and B-38 included node-positive breast cancer patients (N = 5,265 and 4,860); and B-31 studied node-positive and HER2-positive breast cancer patients (N = 2,102). We used Cox proportional hazards regression to calculate adjusted hazards ratios (HR) for risk of death and recurrence, and conducted separate analyses by estrogen receptor (ER) status and treatment group. RESULTS: In B-30, increased BMI was significantly related to survival. Compared with BMI < 25, HRs were 1.04 for BMI 25 to 29.9 and 1.18 for BMI ≥ 30 (P = 0.02). Separate analyses indicated the significant relationship was only in ER-positive disease (P = 0.002) and the subgroup treated with doxorubicin/cyclophosphamide (P = 0.005). There were no significant trends across BMI for the other three trials. Similar results were found for recurrence. Increased BMI was significantly related to recurrence in B-30 (P = 0.03); and the significant relationship was only in ER-positive breast cancers (P = 0.001). Recurrence was also significant among ER-positive disease in B-38 (P = 0.03). CONCLUSIONS: In our investigation, we did not find a consistent relationship between BMI at diagnosis and breast cancer recurrence or death. IMPACT: This work demonstrates that the heterogeneity of breast cancer between different breast cancer populations and the different therapies used to treat them may modify any association that exists between BMI and breast cancer outcome.

Time-Varying Effects of Breast Cancer Adjuvant Systemic Therapy.

BACKGROUND: The benefits of breast cancer adjuvant systemic treatments are generally assumed to be proportional (or constant) over time, but limited data suggest that some treatment effects may vary with time. We therefore systematically assessed the proportional hazards assumption across all 19 breast cancer adjuvant systemic therapy trials in the National Surgical Adjuvant Breast and Bowel Project (NSABP) database. METHODS: The NSABP breast cancer trials were tested for the proportionality of hazard rates between randomized treatment groups for five endpoints: overall survival, disease-free survival and recurrence, local-regional recurrence, or distant recurrence as first events. When the proportional hazards assumption did not hold, a "change point for the relative risk" technique was used to identify the temporal breakdown of the treatment effect. RESULTS: Time-varying treatment effects were observed in nearly half of the trials (nine of 19). In six (B-05, B-11, B-12, B-14, B-16, and B-20), novel treatment benefits diminished statistically significantly at specific time points following surgery. In B-09 and B-31, novel treatment benefits were delayed and emerged more than one year after surgery (1.57 and 1.32 years correspondingly), but the benefit in B-09 reversed after the third year of follow-up. In one trial (B-23), the initial advantage and subsequent disadvantage of one of the regimens was evident. CONCLUSIONS: Breast cancer adjuvant systemic therapy can have statistically significant time-varying effects, which should be considered in the design, analysis, reporting, and translation of clinical trials. These time-dependent effects will have greater relevance as the number of long-term breast cancer survivors increases.

Everolimus-induced hematologic changes in patients with metastatic breast cancer.

BACKGROUND: Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists. PATIENTS AND METHODS: We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests. RESULTS: Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils. CONCLUSION: In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.

PURPOSE: Positive interim analysis findings from four large adjuvant trials evaluating trastuzumab in patients with early-stage human epidermal growth factor receptor 2 (HER2) -positive breast cancer were first reported in 2005. One of these reports, the joint analysis of North Central Cancer Treatment Group NCCTG N9831 (Combination Chemotherapy With or Without Trastuzumab in Treating Women With HER2-Overexpressing Breast Cancer) and the National Surgical Adjuvant Breast and Bowel Project NSABP B-31 (Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2), was updated in 2011. We now report the planned definitive overall survival (OS) results from this joint analysis along with updates on the disease-free survival (DFS) end point. METHODS: In all, 4,046 patients with HER2-positive operable breast cancer were enrolled to receive doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in both trials. The required number of events for the definitive statistical analysis for OS (710 events) was reached in September 2012. Updated analyses of overall DFS and related subgroups were also performed. RESULTS: Median time on study was 8.4 years. Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (hazard ratio [HR], 0.63; 95% CI, 0.54 to 0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. These results were accompanied by an improvement in DFS of 40% (HR, 0.60; 95% CI, 0.53 to 0.68; P < .001) and increase in 10-year DFS rate from 62.2% to 73.7%. All patient subgroups benefited from addition of this targeted anti-HER2 agent. CONCLUSION: The addition of trastuzumab to paclitaxel after doxorubicin and cyclophosphamide in early-stage HER2-positive breast cancer results in a substantial and durable improvement in survival as a result of a sustained marked reduction in cancer recurrence.

Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research.

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

Metastatic angiosarcoma and kasabach-merritt syndrome.

Angiosarcomas are exceedingly rare tumors that are often difficult to diagnose. Exceptionally unusual is the presentation of these tumors with Kasabach-Merritt Syndrome, a curious form of intratumoral coagulation that can be impossible to distinguish from intravascular coagulation, which is more common. Instant recognition of this clinical association can help making a prompt diagnosis and timely initiation of therapy.

Impact of adding the multikinase inhibitor sorafenib to endocrine therapy in metastatic estrogen receptor-positive breast cancer.

BACKGROUND: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure.

Fulvestrant, which degrades ER, is used after AI failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using everolimus to inhibit mTOR, a key signaling pathway in endocrine resistance, may delay fulvestrant resistance in patients and thus improve its efficacy. We conducted a phase II trial of combined fulvestrant and everolimus in postmenopausal women with disease progression or relapse after an AI. Primary endpoint was time to progression (TTP) and secondary endpoints included objective response rate, clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were collected and biopsy of accessible tumor was done for future biomarker analysis. Of 33 patients enrolled two were ruled ineligible after enrollment and were excluded from study analysis, for a total of 31 evaluable patients. Median age was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy (71 %), with 26 % of patients having received 3 or more endocrine agents. Median TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to study treatment with disease progression as their best response. Most common adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs were grade 1 or 2 and largely reversible with infrequent need for everolimus dose reduction. To conclude, everolimus plus fulvestrant is effective after AI failure in heavily pretreated metastatic ER-positive breast cancer and has manageable toxicity. Further study of this combination is warranted in randomized studies. Since not all patients experience benefit, and in view of potential toxicities, biomarker examination is critical to help select patients most likely to benefit from this strategy in future studies.

Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31.

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31 suggested the efficacy of adjuvant trastuzumab, even in HER2-negative breast cancer. This finding prompted us to develop a predictive model for degree of benefit from trastuzumab using archived tumor blocks from B-31. METHODS: Case subjects with tumor blocks were randomly divided into discovery (n = 588) and confirmation cohorts (n = 991). A predictive model was built from the discovery cohort through gene expression profiling of 462 genes with nCounter assay. A predefined cut point for the predictive model was tested in the confirmation cohort. Gene-by-treatment interaction was tested with Cox models, and correlations between variables were assessed with Spearman correlation. Principal component analysis was performed on the final set of selected genes. All statistical tests were two-sided. RESULTS: Eight predictive genes associated with HER2 (ERBB2, c17orf37, GRB7) or ER (ESR1, NAT1, GATA3, CA12, IGF1R) were selected for model building. Three-dimensional subset treatment effect pattern plot using two principal components of these genes was used to identify a subset with no benefit from trastuzumab, characterized by intermediate-level ERBB2 and high-level ESR1 mRNA expression. In the confirmation set, the predefined cut points for this model classified patients into three subsets with differential benefit from trastuzumab with hazard ratios of 1.58 (95% confidence interval [CI] = 0.67 to 3.69; P = .29; n = 100), 0.60 (95% CI = 0.41 to 0.89; P = .01; n = 449), and 0.28 (95% CI = 0.20 to 0.41; P < .001; n = 442; P(interaction) between the model and trastuzumab < .001). CONCLUSIONS: We developed a gene expression-based predictive model for degree of benefit from trastuzumab and demonstrated that HER2-negative tumors belong to the moderate benefit group, thus providing justification for testing trastuzumab in HER2-negative patients (NSABP B-47).

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

A prognostic model of early breast cancer relapse after standard adjuvant therapy and comparison with metastatic disease on initial presentation.

Breast cancer can metastasize at any time during its course, but timing of systemic relapse cannot be predicted by traditional TNM staging. Characteristics of distant recurrence within the first 3 years of diagnosis may identify a group of patients who could benefit from novel strategies to prevent systemic relapse. Of 1,089 patients with breast cancer treated at our institution between January 2007 and May 2011, we identified 76 with de novo metastases (on presentation) and 40 with systemic relapse after a median follow up of 2.2 years. Compared to relapse, de novo metastatic disease was more likely to be grade 1 or 2 (43.1 vs. 18.4 %, p = 0.032), estrogen receptor (ER) positive (69.7 vs. 47.5 %, p = 0.019), progesterone receptor (PgR) positive (56.6 vs. 32.5 %, p = 0.014), and HER2-positive (27.5 vs. 10.3 %, p = 0.035). In the 815 patients with stage I-III disease who were at risk of systemic relapse, univariate analyses were performed for age, tumor size, grade, ER, PgR, HER2, lymph nodes, and TNM stage. A multivariate Cox regression model was built using step-wise model selection and identified 4 covariates that were significantly associated with risk of early relapse: stage-III (p < 0.001), grade-III (p = 0.002), PgR-negative status (p = 0.014), and HER2-negative status (p = 0.033). A risk-score was developed based on the linear combination of these covariates and time-dependent predictive curves were used to evaluate the predictive accuracy of the proposed risk-score. The highest risk-score group had a 1, 2, and 3-year relapse probabilities of 11.5, 41.2, and 52.5 %, respectively. The corresponding 1, 2, and 3-year relapse probabilities for the overall population were 1.2, 4.4, and 6.3 %, respectively. Our proposed model can be used to select patients at high-risk of early relapse who could benefit from enrollment on clinical trials with novel therapies designed for this group.

Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: Cardiac dysfunction (CD) is a recognized risk associated with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer, especially when the treatment regimen includes anthracyclines. Given the demonstrated efficacy of trastuzumab, ongoing assessment of cardiac safety and identification of risk factors for CD are important for optimal patient care. PATIENTS AND METHODS: In National Surgical Adjuvant Breast and Bowel Project B-31, a phase III adjuvant trial, 1,830 patients who met eligibility criteria for initiation of trastuzumab were evaluated for CD. Recovery from CD was also assessed. A statistical model was developed to estimate the risk of severe congestive heart failure (CHF). Baseline patient characteristics associated with anthracycline-related decline in cardiac function were also identified. RESULTS: At 7-year follow-up, 37 (4.0%) of 944 patients who received trastuzumab experienced a cardiac event (CE) versus 10 (1.3%) of 743 patients in the control arm. One cardiac-related death has occurred in each arm of the protocol. A Cardiac Risk Score, calculated using patient age and baseline left ventricular ejection fraction (LVEF) by multiple-gated acquisition scan, statistically correlates with the risk of a CE. After stopping trastuzumab, the majority of patients who experienced CD recovered LVEF in the normal range, although some decline from baseline often persists. Only two CEs occurred more than 2 years after initiation of trastuzumab. CONCLUSION: The late development of CHF after the addition of trastuzumab to paclitaxel after doxorubicin/ cyclophosphamide chemotherapy is uncommon. The risk versus benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab.

Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31.

PURPOSE: Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials. Initial data of the combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial were reported in 2005. Long-term follow-up results on disease-free survival (DFS) and overall survival (OS) have been awaited. PATIENTS AND METHODS: Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials. The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis. RESULTS: At 3.9 years of median follow-up, there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm (P < .001). Similarly, there continues to be a statistically significant 39% reduction in death rate in favor of the trastuzumab-containing arm (P < .001). CONCLUSION: These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time, with the longest follow-up reported to date. The clinical benefits continue to outweigh the risks of adverse effects.

Should Histologic Grade Be Incorporated into the TNM Classification System for Small (T1, T2) Node-Negative Breast Adenocarcinomas?

Prognosis of invasive ductal carcinoma (IDC) strongly correlates with tumor grade as determined by Nottingham combined histologic grade. While reporting grade as low grade/favorable (G1), intermediate grade/moderately favorable (G2), and high grade/unfavorable (G3) is recommended by American Joint Committee on Cancer (AJCC) staging system, existing TNM (Primary Tumor/Regional Lymph Nodes/Distant Metastasis) classification does not directly incorporate these data. For large tumors (T3, T4), significance of histologic grade may be clinically moot as those are nearly always candidates for adjuvant therapy. However, for small (T1, T2) node-negative (N0) tumors, grade may be clinically relevant in influencing treatment decisions, but data on outcomes are sparse and controversial. This retrospective study analyzes clinical outcome in patients with small N0 IDC on the basis of tumor grade. Our results suggest that the grade does not impact clinical outcome in T1N0 tumors. In T2N0 tumors, however, it might be prognostically significant and relevant in influencing decisions regarding the need for additional adjuvant therapy and optimal management.