Therapy For Early-stage Breast Cancer Research Articles

Favorable Proliferative Response Using Ki-67 in Patients Prospectively Treated With Preoperative Accelerated Partial-Breast Radiation Therapy for Early-Stage Breast Cancer

Forest School of Medicine. J. Strasser: None. G. Enevold: None. M. Naughton: Committee leadership; Alliance for Clinical Trials in Oncology. K.E. Weaver: None. K. Baglan: None. D. Bryant: None. C. Langefeld: None. T. Lad: None. L. Lee: None. G.P. Rine: None. A.E. Curtis: None. C.D. Koprowski: None. W.V. Tomlinson: None. G.J. Lesser: Employee; Wake Forest School of Medicine. Leader of research program; Wake Forest NCORP. E.G. Shaw: None. J. Hu: None.

Socioeconomic Factors Impact Probability of Receiving Radiation As Part of Breast Conserving Therapy for Early-Stage Breast Cancer

Socioeconomic Factors Impact Probability of Receiving Radiation As Part of Breast Conserving Therapy for Early-Stage Breast Cancer

Definitive Radiation Therapy for Early-Stage Breast Cancer: Dosimetric Feasibility of Stereotactic Ablative Radiosurgery (SABR) for Intact Breast Tumors

Definitive Radiation Therapy for Early-Stage Breast Cancer: Dosimetric Feasibility of Stereotactic Ablative Radiosurgery (SABR) for Intact Breast Tumors

Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages.

Zoledronic acid (ZA) has been tested in clinical trials as an additive therapy for early-stage breast cancer. However, the mechanism by which ZA exerts its antitumor activity is still unclear. The aim of this study is to investigate whether the prevention of tumor growth by ZA is through regulating the mesenchymal stem cells (MSC)-monocyte chemotactic protein 1 (MCP-1)-macrophages axis in the tumor microenvironment. To address this issue, MDA-MB-231-FLUC human breast cancer cells were cultured and injected either alone, or coupled with MSC into the mammary fat pads of nude mice. MSC were treated with either ZA or untreated. Tumor growth was determined by using an in vivo bioluminescence imaging (BLI) and the tumor-associated macrophages (TAMs) in tumor tissues were immunohistochemically analyzed by using CD206 antibody. The effects of ZA on the cytokine related gene expression of MSC were assessed by using real-time PCR. In this study, we found that ZA-treated mice showed a significant delay in tumor growth. In addition, our data revealed that ZA weakened the ability of MSC to promote tumor growth by impairing TAMs recruitment and tumor vascularization. Furthermore, it was found that ZA decreased MCP-1 expression of MSC, and therefore reduced the recruitment of TAMs to the tumor sites and hence inhibited the tumor growth. Altogether, our study demonstrated ZA can prevent the tumor-promoting effects of MSC. The antitumor effects of ZA were caused by decreasing the MCP-1 expression of MSC, which further decreased the infiltration of TAMs into tumor sites, and therefore inhibited the tumor growth.

Abstract 3327: Metabolomics: Potential molecular mechanisms of radiotherapy (RT)-related normal tissue toxicities in breast cancer

Abstract Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in American women. Clinical guidelines recommend that when breast-conserving surgery is provided as a primary therapy for early-stage breast cancer, RT should follow to improve clinical outcome. Although well tolerated by most patients, even with improved RT technology, breast cancer patients experience moist desquamation as early adverse skin reactions. To elucidate the molecular mechanisms involved in RT-related normal tissure toxicity, global metabolomic profiles were determined in urine samples comparing across paired pre-RT and post-RT samples from 60 breast cancer patients exhibiting low (n = 30) or high (n = 30) skin toxicity in response to RT. The extracted samples were split into equal parts for analysis on the GC/MS and LC/MS platforms. The dataset comprises a total of 478 compounds of known identity. Preliminary data suggest that pre-RT glucose and a variety of derivatives linked to the pentose phosphate pathway, such as ribulose, or the consumption of pyruvate in the mitochondrial tricarboxylic acid cycle, including citrate and succinate, were significantly elevated in the high toxicity group. Multiple metabolites derived from the oxidation of aromatic compounds such as amino acids and dietary polyphenolics - vanillate, 3-hydromandelate, tyramine, 3-methoxy-4-hydroxyphenylglycol, and 2-hydroxyphenylacetate - were elevated in a trending or significant fashion at the pre-RT baseline in the high toxicity relative to the low toxicity group. Pre-RT ascorbate depletion and accumulation of tobacco metabolites were associated with radiation sensitivity. Ascorbate was significantly decreased at baseline in the high toxicity group and its pre-RT levels were negatively correlated with post-RT skin toxicity. Nicotine derivatives were only detected in 12% of the pre- and post-RT samples but their presence seemed to be a risk factor that could predispose smokers to unfavorable outcomes during radiation therapy. Histamine breakdown markers provided an indication of a heightened inflammatory activity in individuals who experienced toxicity as suggested that anti-histamines might be useful to prevent sensitivity. Our preliminary data suggest the potential application of metabolomics in predicting and monitoring RT-related normal tissue toxicities; future larger studies are warranted to confirm out promising findings and identify targeted metabolic pathways for effective intervention. Citation Format: Jennifer J. Hu, Eunkyung Lee, Cristiane Takita, Jean L. Wright, Omar L. Nelson. Metabolomics: Potential molecular mechanisms of radiotherapy (RT)-related normal tissue toxicities in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3327. doi:10.1158/1538-7445.AM2015-3327

Optimal Systemic Therapy for Early Breast Cancer in Women: A Clinical Practice Guideline

The Breast Cancer Disease Site Group of Cancer Care Ontario identified the need for new guidelines for the adjuvant systemic therapy of early-stage breast cancer. The specific question to be addressed was "What is the optimal adjuvant systemic therapy for female patients with early-stage operable breast cancer, when patient and disease factors are considered?" A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period January 2008 to March 5, 2012, and updated to May 12, 2014. Guidelines were located from that search, from the Standards and Guidelines Evidence directory of cancer guidelines, and from the Web sites of major guideline organizations. The literature located was subdivided into the broad categories of chemotherapy, hormonal therapy, and therapy targeted to her2 (human epidermal growth factor receptor 2). Although several of the systemic therapies discussed in this guideline can be considered in the neoadjuvant setting, the review focused on trials with rates of disease-free and overall survival as endpoints and thus excluded several trials that used pathologic complete response as a primary endpoint. Based on the systematic review, the working group drafted recommendations on the use of chemotherapy, hormonal therapy, and targeted therapy; based on their professional experience, they also drafted recommendations on patient and disease characteristics and recurrence risk. The literature review and draft recommendations were circulated to a consensus panel of medical oncologists who had expertise in breast cancer and who represented the regions of Ontario. Items without initial consensus were discussed at an in-person consensus meeting held in Toronto, November 23, 2012. The final recommendations are those for which consensus was reached before or at the meeting. Some of the key evidence was revised after the updated literature search. Evidence reviews for systemic chemotherapy, endocrine therapy, and targeted therapy for her2-positive disease are reported in separate articles in this supplement. The full three-part 1-21 evidence-based series, including complete details of the development and consensus processes, can be found on the Cancer Care Ontario Web site at https://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs.

Incorporating microarray assessment of HER2 status in clinical practice supports individualised therapy in early-stage breast cancer

Accurate determination of human epidermal growth factor receptor-2 (HER2) status is essential for optimal selection of breast cancer patients for gene targeted therapy. The analytical performance of microarray analysis using TargetPrint for assessment of HER2 status was evaluated in 138 breast tumours, including 41 fresh and 97 formalin-fixed paraffin embedded (FFPE) specimens. Reflex testing using immunohistochemistry/in situ hybridization (IHC/ISH) in four discordant cases confirmed the TargetPrint results, achieving 100% agreement regardless of whether fresh tissue or FFPE specimens were used. One equivocal IHC/ISH case was classified as HER2-positive based on the microarray result. The proven clinical utility in resolving equivocal and borderline cases justifies modification of the testing algorithm under these circumstances, to obtain a definitive positive or negative test result with the use of microarrays. Determination of HER2 status across three assay platforms facilitated improved quality assurance and led to a higher level of confidence on which to base treatment decisions.

Adoption of Intensity Modulated Radiation Therapy For Early-Stage Breast Cancer From 2004 Through 2011

Intensity modulated radiation therapy (IMRT) is a newer method of radiation therapy (RT) that has been increasingly adopted as an adjuvant treatment after breast-conserving surgery (BCS). IMRT may result in improved cosmesis compared to standard RT, although at greater expense. To investigate the adoption of IMRT, we examined trends and factors associated with IMRT in women under the age of 65 with early stage breast cancer. We performed a retrospective study of early stage breast cancer patients treated with BCS followed by whole-breast irradiation (WBI) who were ≤65 years old in the National Cancer Data Base from 2004 to 2011. We used logistic regression to identify factors associated with receipt of IMRT (vs standard RT). We identified 11,089 women with early breast cancer (9.6%) who were treated with IMRT and 104,448 (90.4%) who were treated with standard RT, after BCS. The proportion of WBI patients receiving IMRT increased yearly from 2004 to 2009, with 5.3% of WBI patients receiving IMRT in 2004 and 11.6% receiving IMRT in 2009. Further use of IMRT declined afterward, with the proportion remaining steady at 11.0% and 10.7% in 2010 and 2011, respectively. Patients treated in nonacademic community centers were more likely to receive IMRT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.30-1.43 for nonacademic vs academic center). Compared to privately insured patients, the uninsured patients (OR, 0.81; 95% CI, 0.70-0.95) and those with Medicaid insurance (OR, 0.87; 95% CI, 0.79-0.95) were less likely to receive IMRT. The use of IMRT rose from 2004 to 2009 and then stabilized. Important nonclinical factors associated with IMRT use included facility type and insurance status.

Assessment of HER2 testing patterns, HER2+ disease, and the utilization of HER2-directed therapy in early breast cancer.

ContextDetermining human epidermal growth factor receptor 2 (HER2) status is critical for the management of early-stage breast cancer (ESBC). An understanding of HER2 testing practices can provide insight into how test results influence the use of HER2-directed therapy.ObjectiveTo assess HER2 testing, HER2+ disease, and HER2-directed therapy in ESBC at the Huntsman Cancer Institute before and after the 2007 American Society of Clinical Oncology and College of American Pathologist (ASCO/CAP) guidelines on HER2 testing were published.MethodsPatients were identified from an institutional tumor registry. HER2 testing patterns and results were examined using a chart review of pathology and clinical notes. Patient characteristics, HER2+ rate, and trastuzumab use were evaluated descriptively. Discordance rate with reflex testing (immunohistochemistry [IHC]2+ retested by fluorescence in situ hybridization [FISH]) was also evaluated.ResultsA total of 1,459 women were included (mean age: 57 years). The rate of HER2+ disease was 17% (number [N] =245). The discordance rate between IHC2+ and FISH was 10%. After the 2007 ASCO/CAP guidelines, fewer tumors were classified as IHC3+ (16% post- versus 21.9% pre-2007), more tumors were characterized as IHC2+ (26.4% post- versus 20.7% pre-2007), and the overall HER2+ rate was decreased (18.7% versus 21.9%), but this was not statistically significant (P=0.519). Most patients with HER2+ ESBC received HER2-targeted therapy (N=185).ConclusionThe HER2+ rate was 17% and within the range of the reported rates in the literature. Reflex testing identified additional HER2+ tumors by approximately 10%, and should be considered a potential quality indicator. ASCO/CAP HER2 testing guidelines in 2007 appeared to impact the interpretation and classification of HER2+ tumors.

Cognitive function after the initiation of adjuvant endocrine therapy in early-stage breast cancer: an observational cohort study.

This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET.

Outcomes after local recurrence following breast-conserving therapy for early-stage breast cancer.

66 Background: Limited data exist for patients who develop local recurrence (LR) following breast conserving therapy (BCT) for early stage breast cancer (ESBC). This study is to evaluate outcomes and predictors of failure following LR in patients treated with BCT. Methods: 1,654 women with ESBC underwent BCT from 1980 – 2013 at a single institution. All patients had breast-conserving surgery followed by whole breast irradiation (WBI) or accelerated partial breast irradiation (APBI). Subset analysis was performed for patients who developed LR as a first event. Clinical outcomes analyzed include contralateral breast failure (CLBF), regional recurrence (RR), distant metastases (DM), cause-specific survival (CSS), and overall survival (OS). Continuous variables were analyzed with an independent samples t-test and categorical variables with χ2. Univariate analysis was performed to determine factors predictive for events after LR. Results: 112 (7%) patients developed LR (87 WBI; 25 APBI), with median time to LR of 6.6 yrs (0.1-28). Median follow-up for the LR group was 14 yrs (0.7-31) overall; 10 (0.7-19) and 16 yrs (1.4-31) for APBI and WBI, respectively (p=0.01). A change from initial to LR pathology was seen for: ER status 21%, PR status 25%, HER2 status 13%, grade 38%, histology 40%, and LVSI 38%. Salvage treatment following LR was mastectomy ± chemotherapy (CHT) in 75%, wide local excision ± RT in 19%, CHT in 2%, and other in 4%. Outcomes following salvage treatment for LR are shown in the table. No differences were seen in outcomes between patients treated with APBI v WBI. Univariate analysis failed to demonstrate any factors predictive for events following LR. Conclusions: Patients who developed LR following BCT for ESBC had excellent clinical outcomes at 5 and 10 yrs, demonstrating effective salvage treatment in this cohort of patients. No differences were noted between patients undergoing APBI v WBI. Further identification of histopathologic patterns between first cancer and LR is currently underway. [Table: see text]

Utilization of Hypofractionated Radiation Therapy for Early-Stage Breast Cancer in the Elderly Population: A National Cancer Data Base Analysis

Hypofractionated whole breast irradiation (HF-WBI) following breast conserving surgery for early stage breast cancer is well-supported by the literature. The rate of HF-WBI utilization and associated patterns of care for the elderly population is not known and was the subject of this study.

Sexual functioning in women after mastectomy versus breast conserving therapy for early-stage breast cancer: A prospective controlled study

IntroductionBreast cancer (BC) and/or its treatments may affect sexual functioning based on physiological and psychosocial mechanisms. The aim of this study was to prospectively investigate sexual adjustment of BC patients during a follow-up period of one year after mastectomy (ME) or breast conserving therapy (BCT). MethodsIn this prospective controlled study, women with BC and an age-matched control group of healthy women completed the Beck Depression Inventory Scale, World Health Organization 5 Well-being scale, Body Image Scale, EORTC QLQ questionnaire, Dyadic Adjustment Scale, Short Sexual Functioning Scale and Specific Sexual Problems Questionnaire to assess various aspects of sexual and psychosocial functioning before surgery, six months and one year after surgical treatment. ResultsIn total, 149 women with BC and 149 age-matched healthy controls completed the survey. Compared to the situation before surgery, significantly more BCT women reported problems with sexual arousal six months after surgery and significantly more women of the ME group reported problems with sexual desire, arousal and the ability to achieve an orgasm six months and one year after surgery. While in comparison with healthy controls, no significant differences in sexual functioning were found after BCT surgery, significantly more women who underwent ME reported problems with sexual desire, arousal, the ability to achieve an orgasm and intensity of the orgasm. ConclusionsAlthough little differences were seen in sexual functioning in the BCT group during prospective analyses and in comparison with healthy controls, analyses revealed that women who underwent a ME were at risk for post-operative sexual dysfunctions.

Adjuvant taxane therapy for early-stage breast cancer: A real-world comparison of chemotherapy regimens in Ontario.

1081 Background: FEC-D (5-FU, epirubicin, cyclophosphamide - docetaxel) and dd (dose-dense) AC-P (doxorubicin-cyclophosphamide - paclitaxel) are considered equally effective regimens in the adjuvan...

Social determinants and disparities in quality radiation therapy in early-stage breast cancer.

e17562 Background: Radiation therapy receipt and quality duration (QRTD, # days RT start to end) after breast conserving surgery (BCS) are associated with optimal outcomes in early-stage breast can...

The integration of locoregional with systemic adjuvant therapy for early-stage breast cancer: the shifting sands of decision-making

SUMMARY Given the generally excellent outcomes for modern breast cancer treatment, the recognition that overtreatment is commonplace is the driving force to reduce the treatment impact of surgery, radiation therapy and chemotherapy. Many recent trials have demonstrated that fewer axillary lymph node dissections, smaller radiation field sizes and less administration of chemotherapy are all feasible without compromising the long-term outcomes. However, each of these trials has studied a single modality while maintaining the intensities of the other modalities. There is a natural tendency, albeit controversial, to reduce more than one modality at a time. We review the literature, and counsel the breast cancer oncologist to work as a multimodality team to decide with the patient which modality can be reduced, and which should be preserved in its intensity.

Adjuvant Hypofractionated Versus Conventional Whole Breast Radiation Therapy for Early-Stage Breast Cancer: Long-Term Hospital-Related Morbidity From Cardiac Causes

The risk of cardiac injury with hypofractionated whole-breast/chest wall radiation therapy (HF-WBI) compared with conventional whole-breast/chest wall radiation therapy (CF-WBI) in women with left-sided breast cancer remains a concern. The purpose of this study was to determine if there is an increase in hospital-related morbidity from cardiac causes with HF-WBI relative to CF-WBI. Between 1990 and 1998, 5334 women ≤ 80 years of age with early-stage breast cancer were treated with postoperative radiation therapy to the breast or chest wall alone. A population-based database recorded baseline patient, tumor, and treatment factors. Hospital administrative records identified baseline cardiac risk factors and other comorbidities. Factors between radiation therapy groups were balanced using a propensity-score model. The first event of a hospital admission for cardiac causes after radiation therapy was determined from hospitalization records. Ten- and 15-year cumulative hospital-related cardiac morbidity after radiation therapy was estimated for left- and right-sided cases using a competing risk approach. The median follow-up was 13.2 years. For left-sided cases, 485 women were treated with CF-WBI, and 2221 women were treated with HF-WBI. Mastectomy was more common in the HF-WBI group, whereas boost was more common in the CF-WBI group. The CF-WBI group had a higher prevalence of diabetes. The 15-year cumulative hospital-related morbidity from cardiac causes (95% confidence interval) was not different between the 2 radiation therapy regimens after propensity-score adjustment: 21% (19-22) with HF-WBI and 21% (17-25) with CF-WBI (P=.93). For right-sided cases, the 15-year cumulative hospital-related morbidity from cardiac causes was also similar between the radiation therapy groups (P=.76). There is no difference in morbidity leading to hospitalization from cardiac causes among women with left-sided early-stage breast cancer treated with HF-WBI or CF-WBI at 15-year follow-up.

Radiofrequency ablation for early-stage breast cancer: Treatment outcomes and practical considerations

Radiofrequency ablation (RFA) for early-stage breast cancer has the potential advantage of being a less invasive treatment associated with improved cosmetic outcome. The aim of this review was to summarise the reported treatment outcomes of ultrasound-guided RFA for early-stage breast cancer and to highlight practical considerations with regard to this treatment. A search of the English-language literature concerning RFA for breast cancer treatment was performed. RFA is a technique that can be safely applied in patients with early-stage breast cancer, which is restricted to cT1-T2N0 ductal carcinoma with radiologically defined borders without any signs of multifocality or multicentricity. However, before RFA can be adopted as local therapy for early-stage breast cancer, more research is needed to assess the post-treatment pathological complete response and margin status, the long-term oncologic outcome in comparison to current standard breast conserving therapy and the potential cosmetic superiority of percutaneous RFA. RFA appeared to be a feasible technique for the treatment of early-stage breast cancer, but considerable practical considerations form an obstacle to introduce RFA as a standard of care.

Impact of endocrine therapy in early-stage breast cancer on time to locoregional recurrence.

64 Background: Locoregional recurrence (LR) remains a major source of morbidity and mortality in breast cancer. Our primary aim was to evaluate the impact of endocrine therapy (ET) on time to LR. Methods: A retrospective chart review of breast cancer patients (pts) treated with lumpectomy and locoregional radiation from 1999-2005 at the Princess Margaret Cancer Centre was carried out. LR was defined as ipsilateral breast or lymph node recurrence. Kaplan-Meier estimates of survival and univariate analyses were performed for age, menopausal status, tumor and nodal stage, grade, receptor status, adjuvant chemotherapy (AC) and ET. Results: Of 440 pts evaluated, the mean age at primary resection was 56 years (yrs) (range 40-79), and 67% were postmenopausal. The majority had ductal carcinomas (87%) and grade 1-2 (68%) tumors. Tumor distribution was 315 (72%) T1, 120 (27%) T2, 4 (1%) T3; 138 (31%) were node positive. Receptor status was ER/PR+HER2- 206 (47%), ER+PR+HER2unknown 80 (18%), ER-PR-HER2unknown 41 (9%), and triple negative 37 (8%). AC was used in 190 (43%). ET (tamoxifen and/or aromatase inhibitors) was initiated in 294 (84%) eligible pts, and 267/294 (91%) completed a minimum duration of ≥2 yrs. Overall, LR occurred in 24 (5%) pts, and 8/24 (33%) pts with LR also had distant metastases. Average time from surgery to LR was 5.4 yrs (range 8 months-12 yrs). The average duration of ET in pts with LR was 4.3 yrs (range 0-8), and 5.8 yrs (range 0-12) without LR. Of ER/PR+ pts with LR, 3/15 (20%) did not receive ET. At the time of LR, 5 (33%) pts were receiving ET. After stopping ET, 2 (13%) recurred 0-2 yrs, 3 (20%) at 4-5 yrs, and 2 (13%) at 7-8 yrs. Treatment with at least 2 yrs of ET predicted for fewer recurrences: at 2 yrs LR-free rate was 100% vs 90% for &lt;2 yrs ET; at 5 yrs 99.6% vs 84%; and at 8 yrs 98.2% vs 84% (p=0.0092). ER/PR+HER2- pts had lower LR risk (p=0.028), and ER-/PR-/HER+ had higher LR risk (p=0.029). The remaining variables were not associated with risk of LRs. Survival post-LR was 90% (95%CI 64-97%) at 2 yrs and 65% (95%CI 34-84%) at 5 yrs. Conclusions: Pts who completed at least 2 yrs of ET had significantly lower risk of LR. The average time to LR was 5.4 years, and pts with LR had decreased survival at 5 yrs post-recurrence.

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

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. 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. 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). 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.