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Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O'Shaughnessy, Javier Cortés, Michaela Tsai, Linda Vahdat, Véronique Diéras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-06.

PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.

Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

Background Increased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC. Patients and Methods Patients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition. Results Fifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET. Conclusion These results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy.

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Background: Increased signaling through growth factor pathways including PI3K/Akt/mTOR and HER2 have been implicated in hormone resistance. Everolimus (EVE) improves outcomes when added to endocrine therapy for patients with HR-positive MBC. This study evaluated the efficacy of everolimus (EVE) and trastuzumab (TRAS) in hormone refractory HER2-normal metastatic breast cancer. Methods: Eligible patients had HR-positive, HER2/neu-negative (IHC +1 or +2, HER2-non-amplified) MBC that had progressed within 6 months of the most recent endocrine therapy. Patients continued on the most recent endocrine therapy they received and were randomized to receive EVE 10 mg oral daily or TRAS IV (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks). At progression, the other agent was added (TRAS in the EVE arm and EVE in the TRAS arm). Patients were followed until disease progression or death. Results: 54 eligible patients were included in the analysis, and were randomized to EVE (n=30) or TRAS (n=24). 33% of patients were on fulvestrant, 31% exemestane, 22% tamoxifen and 7% letrozole, which were continued. The median PFS was 5.7 months for EVE vs. 2 months for TRAS until first progression or death with hazard ratio of 0.45 (95% CI 0.25-0.81, p=0.008). Among 48 patients who had disease progression, EVE was added to 16 patients who were originally treated by TRAS, and TRAS was added to 12 patients who were originally treated by EVE; the median time to the second progression was 6.3 months for the arm where EVE was added vs. 3.1 months in the arm where TRAS was added. Three patients were taken off study due to decrease in ejection fraction. Conclusions: This trial demonstrates the efficacy of EVE alone or in combination with TRAS in patients with hormone refractory HR-positive, HER2-negative metastatic breast cancer, who remained on the endocrine therapy they had experienced disease progression on. This suggests that mTOR inhibition has the potential of restoring sensitivity to endocrine therapy and potentially allows the re-use of endocrine agents. Updated results and correlative studies will be presented. Clinical trial information: NCT00912340. Citation Format: Paplomata E, Gogineni K, Meisel J, Santa-Maria C, Yuan L, Kramer J, Bill Li X, Zelnak A, Pakkala S, Kaklamani V, O'Regan R. Phase 2 trial of everolimus and/or trastuzumab in hormone refractory, hormone receptor (HR)-positive, HER2-normal metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-03.

Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.

Background Neoadjuvant chemotherapy is widely used to downstage breast cancers before surgery and is an accepted standard of care among patients with early-stage breast cancer in whom adjuvant chemotherapy would be recommended. Pathologic complete response (pCR) rate is a robust predictor of outcome for certain breast cancer subtypes, including Her2-overexpressing breast cancer. The incorporation of Her2-targeted therapies has significantly increased the pCR rate in the neoadjuvant setting. Although regimens composed of trastuzumab, nab-paclitaxel, and vinorelbine have demonstrated clinical efficacy in patients with metastatic breast cancer, few studies have examined this combination in early-stage Her2+ breast cancer. We hypothesized that the combination of neoadjuvant nab-paclitaxel followed by vinorelbine could represent a nonanthracycline-based treatment option for early-stage Her2-overexpressing breast cancer. Patients and Methods Patients received 4 cycles of nab-paclitaxel 260 mg/m2 intravenously (IV) every 14 days for 4 cycles followed by vinorelbine 25 mg/m2 IV weekly for 12 weeks with concurrent trastuzumab (4 mg/kg loading dose, and then 2 mg/kg/wk). The primary endpoint was the rate of pCR. Secondary endpoints included clinical response, toxicity, and survival rates. Results A total of 27 patients were accrued to the trial. The median tumor size was 4.0 cm, and more than 50% of patients had axillary lymph node involvement. The pCR rate was 48.1%. Among the 40% of patients who had hormone receptor–positive disease, the pCR rate was 18.2%, compared with 68.8% among patients with estrogen receptor/progesterone receptor–negative tumors. Conclusions The combination of trastuzumab with nab-paclitaxel followed by vinorelbine was well tolerated and had promising activity in the neoadjuvant setting.

Long-term outcomes for early-stage breast cancer have continued to improve, and more patients are becoming long-term survivors. In addition to patients' concern about risk of developing recurrent disease, they are also concerned about potential toxicities of treatment. Current guidelines for long-term follow-up are reviewed. Potential toxicities of tamoxifen and aromatase inhibitors are reviewed. Management of menopausal symptoms, cancer-related fatigue, and cognitive function is discussed.

Background: Trastuzumab targets the human epidermal growth factor receptor-2 (HER2). Cardiotoxicity is a potential adverse effect, manifesting as either an asymptomatic decline in left-ventricular ejection fraction or infrequently as largely reversible symptomatic heart failure (HF). Monitoring recommendations differ between product labeling and 2012 guidelines, and the clinical utility of serial cardiac monitoring in patients with metastatic breast cancer remains controversial. Objective: The objectives of this study were to describe the frequency of monitoring, incidence of symptomatic or asymptomatic HF, overall effect on treatment, and cost of monitoring for cardiotoxicity. Methods: We preformed an institutional review board–approved retrospective chart review of breast cancer patients receiving trastuzumab from January 1, 2009, through January 1, 2014, at an academic medical center. Results: Out of 154 treatments, 72% were adjuvant, and 28% were metastatic. In the adjuvant setting, a mean of 4.5 (interquartile range [IQR] = 4-5) echocardiograms (echos) over a mean of 11.5 (IQR = 11-12) months were performed. In the metastatic setting, a mean of 3.1 (IQR = 1-5) echos over a mean of 20.2 (IQR = 9-31) months were performed. Symptomatic HF events occurred in 4 adjuvant (3.6%) and 2 metastatic patients (6.5%); 10 patients (6.5%) had a treatment interruption, with 9 (90%) tolerating restart of trastuzumab. Two patients (1.3%) changed treatment as a result of cardiotoxicity. Using population incidence of HER2-positive breast cancer, $13 million could be saved if monitoring were reduced by 1 echo per patient. Conclusions: Given the low incidence of clinically significant HF and cost of monitoring, less frequent monitoring may be justified.

The safety and efficacy of skin-sparing mastectomy (SSM) with immediate reconstruction (IR) in patients with locally advanced breast cancer are unclear. The purpose of this study is to compare the outcomes of women with noninflammatory Stage III SSM with IR vs. non-SSM-treated women who underwent neoadjuvant chemotherapy and adjuvant radiation therapy (XRT).Between October 1997 and March 2010, 100 consecutive patients (40 SSM with IR vs. 60 non-SSM) with Stage III breast cancer received anthracycline- and/or taxane-based neoadjuvant chemotherapy, mastectomy, and adjuvant XRT. Clinical stage (SSM with IR vs. for non-SSM) was IIIA (75% vs. 67%), IIIB (8% vs. 18%), and IIIC (8% vs. 8%). Tumors greater than 5 cm were found in 74% vs. 69%; 97% of patients in both groups were clinically node positive; and 8% vs. 18% had T4b disease.The time from initial biopsy to XRT was prolonged for SSM-IR patients (274 vs. 254 days, p = 0.04), and there was a trend toward XRT delay of more than 8 weeks (52% vs. 31%, p = 0.07) after surgery. The rate of complications requiring surgical intervention was higher in the SSM-IR group (37.5% vs. 5%, p0.001). The 2-year actuarial locoregional control, breast cancer-specific survival, and overall survival rates for SSM with IR vs. non-SSM were 94.7% vs. 97.4%, 91.5% vs. 86.3%, and 87.4% vs. 84.8%, respectively (p = not significant).In our small study with limited follow-up, SSM with IR prolonged overall cancer treatment time and trended toward delaying XRT but did not impair oncologic outcomes. Complication rates were significantly higher in this group. Longer follow-up is needed.

BACKGROUND: African American (AA) women experience higher breast cancer mortality than white (W) women. These differences persist even among estrogen receptor (ER)-positive breast cancers. The 21-gene recurrence score (RS) predicts recurrence in patients with ER-positive/lymph node-negative breast cancer according to RS score—low risk (RS, 0-18), intermediate risk (RS, 19-31), and high risk (RS, >31). The high-risk group is most likely to benefit from chemotherapy, to achieve minimal benefit from hormonal therapy, and to exhibit lower ER levels (intrinsically luminal B cancers). In the current study, the authors investigated racial differences in RS testing, scores, treatment, and outcome. METHODS: Tumor registry data from 3 Atlanta hospitals identified women who were diagnosed with breast cancers during 2005 through 2009. Medical record abstraction provided information on RS and other tumor/treatment factors. Statistical analyses used chi-square/exact tests and logistic regression. RESULTS: Of 2186 patients, including 1192 AA women and 992 W women, 853 women had stage I or II, ER-positive/lymph node-negative disease and, thus, were eligible for RS testing (AA = 372 [31.2%]; W = 481 [48.5%]; P < .0001); and 272 women (31.8%) received testing (AA = 76 [20.4%]; W = 196 [40.7%]; P < .0001). Tumors were distributed into the following groups according to risk: low risk (n = 133), medium risk (n = 113), and high risk (n = 26). The mean RS did not differ by race, but risk groups did (low-risk group: 46.1% vs 50% for AA women and W women, respectively; high-risk group: 15.8% vs 7.1%, respectively; P = .043). In multivariate analyses, AA race (odds ratio, 3.6) was associated independently with high risk scores. CONCLUSIONS: AA women were half as likely as W women to receive 21-gene RS testing but were 2-fold more likely to be categorized as high risk. The current data suggested that testing guidelines are not applied equivalently, testing bias may attenuate racial differences in RS, and disparate outcomes may be explained in part by differences in RS, although compliance and pharmacogenomics also may play a role. Cancer 2012;. © 2011 American Cancer Society.

In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for stage I, II, and III breast cancer. The purpose of this study was to document compliance with the 3 NQF breast quality indicators during 2 time intervals in a metropolitan public hospital.Tumor registry and medical records were used to identify patient demographics and treatments before (2005-2006) and after (2008) implementations in 2007 as a result of the NQF audit. Program changes included: hiring a dedicated medical oncology nurse practitioner, requiring the radiation oncology case manager to attend weekly multidisciplinary conferences, educating Patient Navigators of the importance of multimodal care, and providing support groups for patients addressing importance of completion of all treatment options.A total of 213 female patients were diagnosed with and treated for stage I, II, or III breast cancer in 2005-2006 and 2008. Of these, 189 (89%) were African American (AA) women. Also, 70 patients of 86 (81.3%) received radiation therapy, 60 of 77 (77.9%) received or were considered for adjuvant chemotherapy, and 124 of 144 (86.1%) for hormonal therapy according to NQF indicators. After 2007, patients receiving radiation therapy increased from 75.8 to 95.8%. Patients receiving or considered for adjuvant chemotherapy or hormonal therapy increased from 73.7 to 93.7% and from 84.1 to 90.0%, respectively.NQF breast cancer indicators provided a mechanism to improve compliance of multimodal treatment in our center. Raising awareness of these indicators in the multidisciplinary conference, hiring dedicated personnel, and educating patients has led to major improvements in breast cancer care.

With more and more breast cancer (BC) patients receiving taxanes and anthracyclines in the adjuvant setting, the number of patients resistant to these drugs is rising. Herein, we review cellular mechanisms (e.g., overexpression of drug efflux pumps) that are associated with clinical anthracycline and/or taxane-resistant BC. We also discuss therapeutic approaches that have received Food and Drug Administration approval in this setting or are in clinical development, including targeted agents that do not employ a cytotoxic mechanism, as well as novel chemotherapeutics such as the epothilones, a class of microtubule stabilizers less susceptible to common cellular resistance mechanisms.

Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)].163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type.Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease,2 mm surgical margins, and received chemotherapy as directed by RS. While an RS25 did not predict for a higher rate of LRR, an RS24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT.Breast cancer patients treated with mastectomy for tumors that have an RS24 are at high risk of LRR and may benefit from post-mastectomy radiation.

Objectives: We compared outcomes in post-menopausal estrogen receptor-positive (ER+) breast cancer patients treated with neoadjuvant hormonal therapy (NAHT) or neoadjuvant chemotherapy (NACT).Methods: We retrospectively identified post-menopausal women who received either NAHT or NACT for non-metastatic, non-inflammatory, ER+, Her2neu negative breast cancer from 2004 to 2011. We compared long-term rates of locoregional relapse free survival (LRFS), distant metastasis free survival (DMFS), and overall survival (OS) using the Kaplan-Meier method. The Cox proportional hazards model was used to identify patient and disease factors significantly associated with these endpoints. Results: We identified 99 patients in our study, including 27 who received NAHT and 72 who received NACT. There were no differences in 4-year LRFS, DMFS, or OS between groups. On Cox proportional hazards modeling, the type of systemic therapy (NAHT vs. NACT) was not associated with OS. However, patients with progesterone receptor (PR) positive disease had a 92% lower risk of death compared to patients with PR negative disease.Conclusions: Our data suggest that outcomes are not adversely affected by NAHT in post-menopausal women with ER+ breast cancer. Therefore, NAHT is a viable and potentially less toxic option than NACT in appropriately selected patients. Furthermore, although PR negative disease appears to be associated with poor prognosis, intensification of systemic treatment with chemotherapy may not be associated with improvement of disease-related outcomes in this patient population.

Background: There is extensive crosstalk between the cyclin D–CDK4/6–inhibitor of CDK4–retinoblastoma and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways at the G1/S cell-cycle checkpoint. Both pathways are frequently dysregulated in hormone receptor-positive (HR+) breast cancer and have been associated with endocrine therapy (ET) resistance. CDK4/6 and PI3K/mTOR inhibitors have demonstrated clinical activity in combination with ET. Although CDK4/6 inhibitors combined with ET significantly improve progression-free survival (PFS) in ABC, disease progression eventually occurs, highlighting the need for effective treatment options following doublet therapy. Ribociclib (LEE011; CDK4/6 inhibitor; 3-weeks-on/1-week-off) + EVE (mTOR inhibitor) + EXE triplet therapy has shown preliminary clinical activity in heavily pretreated HR+, human epidermal growth factor receptor 2-negative (HER2–) ABC including patients (pts) with prior exposure to CDK4/6 inhibitors, suggesting this combination may restore sensitivity to CDK4/6 inhibitor-based therapy. Trial design and objectives: TRINITI-1 (NCT02732119) is a US-based, phase I/II, single arm, open-label study of ribociclib (continuous daily dosing) + EVE (2.5 mg/day) + EXE (25 mg/day) in men and postmenopausal women with HR+, HER2– ABC refractory to ≥1 line of ET. Phase I dose escalation consists of 2 ribociclib dose-level cohorts (250 and 300 mg/day), followed by a Simon Two-Stage phase II trial in pts with disease progression on prior CDK4/6 inhibitor-based therapy. No more than 3 lines of therapy for ABC, including ≤1 prior chemotherapy regimen, are permitted. Previous EXE treatment of >28 days for metastatic disease, prior mTOR inhibitors, and progression on >1 CDK4/6 inhibitor are prohibited. All pts in phase II must have progressed on a CDK4/6 inhibitor as the last regimen before study entry. Additional eligibility criteria include measurable disease or lytic/mixed bone lesions and Eastern Cooperative Oncology Group performance status of ≤1. Exclusion criteria include visceral crisis, unstable CNS metastases, and clinically significant heart disease. Phase I primary objective: maximum tolerated dose and/or recommended phase II dose of the triplet combination. Phase II primary objective: clinical benefit rate (CBR) at 24 weeks (0.1 significance level, 80% power to test CBR ≤15% against CBR ≥30%) with centrally-assessed PFS as a key secondary objective. Other secondary objectives include preliminary antitumor activity (phase I), safety and pharmacokinetics (phase I/II), and overall response rate, overall survival, and duration of overall response (phase II). Tumor assessments (RECIST v1.1) will be performed every 8 weeks for the first 12 months, and every 12 weeks thereafter until disease progression. Exploratory analyses include biomarkers potentially predictive of response and mechanisms of resistance. Target accrual: Approximately 52 pts at ∼30 sites; 3–6 pts per cohort in phase I, an initial 19 in phase II with another 20 enrolled upon demonstration of clinical benefit in ≥4 pts. Citation Format: Bardia A, Hurvitz S, Yardley DA, Zelnak A, DeMichele A, Clark AS, Warsi G, Small T, Tucci C, Moulder S. TRINITI-1: Ribociclib + everolimus (EVE) + exemestane (EXE) triplet combination in men or postmenopausal women with HR+, HER2– advanced breast cancer (ABC) following progression on a cyclin-dependent kinase (CDK) 4/6 inhibitor [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-05.

BACKGROUND: There have been few studies evaluating the day-to-day effects of advanced breast cancer (ABC) and its treatment on patients in a real-world setting.Palbociclib is a novel CDK4/6 inhibitor approved in the US for hormone-receptor positive, human epidermal growth factor receptor negative (HR+, HER2-) ABC/metastatic breast cancer (MBC) in combination with letrozole as initial endocrine based therapy in postmenopausal women or with fulvestrant in women with disease progression following endocrine therapy. With the introduction of this first-in-class drug it is important to understand the experiences of patients initiating ABC therapies including palbociclib in real-world settings and to document the management of these therapies. A smartphone-based mobile application has been developed to collect patient-reported outcome (PRO) data to assess the impact of ABC and associated treatment on symptoms, functioning and quality of life (QOL) as reported by patients. The application is further designed to provide patients initiating palbociclib with a virtual community to connect to others enrolled in the study for peer support. Additionally, clinical data on therapy management (e.g. dose modifications, interruptions, discontinuations, adverse event management and monitoring) will be obtained from patients' medical records to explore the association between patient reported functioning and neutropenia. Study Design: A prospective, observational, non-interventional study. PROs collected via a mobile application and clinical data via case report forms completed by investigator. Eligibility Criteria: Women with HR+/HER2– ABC receiving palbociclib in combination with letrozole or fulvestrant as per US label (Group 1) orapproved therapies for ABC other than palbociclib (Group 2). No comparison is intended between the 2 groups. Specific Aims: The primary goals are to describe changes in patients' general health status as measured by monthly administration of the 12-Item Short Form Health Survey, describe changes in patients' psychological distress as measured by monthly administration of the Center for Epidemiological Studies Depression Scale, and describe the extent to which ABC and its treatment are associated with changes in patients' lives in terms of symptoms, functioning and QOL as measured by daily and weekly administration of targeted patient-reported questions. Additionally, for patients who are employed at baseline, time lost from work in relation to breast cancer and its treatment will be quantified.Data from patients' medical records will be used to document changes in therapy as well as the incidence, severity, and duration of neutropenia. The association between patient reported functioning and neutropenia will also be assessed. Finally, real-world monitoring patterns will be assessed. Statistical Methods: Descriptive statistics will be used to summarize all endpoints. Meta-data regarding use of virtual community resources will be explored for relationships to PRO data. Present Accrual and Target Accrual: Approximately 450 patients from up to 30 US sites will be enrolled. Study duration will be approximately 12 months assuming 6 months of recruitment. It is expected the study will start enrollment Q3 2016. Sponsor: Pfizer. Citation Format: McRoy LL, Mitra D, Hollis K, Kaye JA, Zelnak A, Cheyl J. MADELINE: A prospective observational study of mobile app-based patient reported outcomes in advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-03-01.

Neoadjuvant chemotherapy is widely used to downstage breast cancers before surgery. The addition of capecitabine to chemotherapy may improve the pathologic complete response rate (pCR), a robust predictor of outcome for certain breast cancer subtypes. This phase II neoadjuvant trial incorporated capecitabine either in combination with or sequentially after treatment with docetaxel. Background: The combination of docetaxel and capecitabine has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer compared with docetaxel alone. We hypothesized that the combination of docetaxel and capecitabine, given concomitantly or sequentially, would present a nonanthracycline-based treatment option for patients with early stage and locally advanced breast cancer. Patients and Methods: Patients with stage I to stage IIIC, human epidermal growth factor receptor 2–negative (HER2) breast cancer were randomly assigned to receive either docetaxel followed by capecitabine (D i C) or docetaxel administered concomitantly with capecitabine (DC). Results: Between April 2007 and July 2009, 51 patients were accrued to the trial at an academic center, a county hospital, and community sites. Median tumor size was 3.8 cm and 70% of patients had axillary lymph node involvement. Fifty-seven percent of patients accrued were African American. Twenty-one of the 51 subjects had triple-negative breast cancer. The pathologic complete response (pCR) rate was 8% in the D i C arm; 12% in the DC arm. The pCR rate among patients with triple-negative breast cancer was 19%. Conclusion: The combination of docetaxel and capecitabine has modest activity in the neoadjuvant setting. These results are consistent with other trials using this combination in the neoadjuvant setting.

The treatment of women with estrogen receptor-positive breast cancer has advanced significantly in the past decade. Tamoxifen was the gold standard hormonal therapy for breast cancer until the introduction of aromatase inhibitors and fulvestrant. Many of these new treatments are useful only for patients who are postmenopausal. There are data to support the use of these new agents both in the metastatic and adjuvant settings. Here, we briefly review the recent clinical trials supporting the use of these agents in both the adjuvant and metastatic settings. We will discuss possible mechanisms of resistance to endocrine agents that could be exploited therapeutically to improve the outcome for patients with hormone receptor-positive breast cancers.

Angiogenesis, the process of new blood vessel formation, is required for tumor growth and metastasis. There is substantial preclinical and clinical evidence supporting the central role of angiogenesis in tumor formation and metastasis. Thus, the inhibition of angiogenesis may provide more effective treatment for patients with advanced breast cancer. Several chemotherapeutic and hormonal agents routinely used in the treatment of advanced breast cancer have anti-angiogenic properties. Novel anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) ligand and receptor tyrosine kinase inhibitors are being developed. Recently, a large phase III clinical trial demonstrated a significant benefit in progression-free survival with the addition of anti-VEGF monoclonal antibody bevacizumab to paclitaxel for first-line treatment of advanced breast cancer. This study established that antiangiogenic therapy is effective in breast cancer, and additional studies of bevacizumab and other antiangiogenic agents are underway. This article reviews the evidence for the role of angiogenesis in breast cancer pathogenesis, the challenges of developing antiangiogenic agents, and current agents in clinical trials.

BACKGROUND: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease with a poor clinical prognosis. While the primary therapeutic option for TNBC patients is pre-operative neo-adjuvant chemotherapy followed by surgical resection, about 60% of patients develop drug resistance and have a very high incidence of tumor recurrence and poorer prognosis. Given its poor survival and lack of available targeted therapeutics, the development of novel treatment options for chemo-resistant TNBC is critical. Cancer progenitor cells or stem-like cells (CSCs) are generally thought to contribute to the drug-resistant phenotype of TNBC which are typically identified as CD44+/CD24-. CSCs can also rely on activation of stem cell signaling through the Wnt/ β-catenin pathway. Components of the Wnt pathway, including Wnt ligands, have been shown to be over-expressed in human breast cancers. Our lab has developed urokinase plasminogen activator receptor (uPAR) targeted theranostic magnetic iron oxide nanoparticles (IONPs) carrying therapeutic agents that are clinically beneficial to TNBC patients such as doxorubicin (Dox). uPAR is an ideal target due to its high expression in malignant tumors including aggressive breast cancer tissues and tumor stromal cells that are enriched in TNBC tissues. METHODS: We generated patient derived xenografts of drug-resistant TNBC for testing the therapeutic efficacy of uPAR-targeted nanoparticle-drugs from tumor fragments from patients obtained from an ongoing Phase II clinical trial at Winship Cancer Institute. Histological analysis of post-chemotherapy TNBC with or without uPAR-targeted IONP-Dox was conducted using immunohistochemistry and immunofluorescence techniques. RESULTS: We have previously reported that treatment with uPAR-targeted IONP-Dox caused tumor growth inhibition following systemic delivery. We further investigated the effect of uPAR-targeted IONP on Wnt10b, a ligand of the Wnt signaling pathway. We observed that uPAR-targeted-IONP-Dox treatment decreases Wnt10b expression relative to the untreated and conventional Dox groups. We also investigated the level of CD44 expression, which is a target gene of the Wnt signaling pathway. We observed that Wnt10b and CD44 expression was co-localized and that treatment with uPAR-targeted IONP-Dox decreased the level of CD44 expression that is comparable to the level of decrease in Wnt10b expression. CONCLUSION: Our findings show that uPAR-targeted theranostic IONP can effectively target the Wnt activated CSC population. It is likely that uPAR expressing tumor cells are potential drug resistant cell populations with breast cancer stem-like cell properties. Our results support further investigation of theranostic nanoparticles as a viable therapeutic approach to overcome drug resistance in TNBC. Citation Format: Jasmine Miller-Kleinhenz, Weiping Qian, Ruth O'Regan, Toncred Styblo, Amelia Zelnak, Andrew Wang, Lily Yang. Down-regulation of Wnt10b following targeted theranostic nanoparticles in a patient derived xenograft model of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 691. doi:10.1158/1538-7445.AM2014-691

1112 Background: Taxanes are frequently used in the treatment of breast cancer. CHFR (checkpoint with forkhead and ringfinger domains) is a novel biomarker of resistance to microtubule targeting agents that can help individualize care and identify targets for overcoming this resistance. Our institution showed that high CHFR is associated with decreased response to taxanes and worse overall survival in patients with lung cancer. The current work evaluated the translational significance of CHFR in breast cancer. Methods: We studied a cohort of patients with triple negative breast cancer (TNBC), who were treated with pre-operative taxane-based chemotherapy followed by surgery. Archived paraffin-embedded tissue was stained for CHFR using immunohistochemistry. The level of protein expression was assessed by light microscopy and scored for intensity of staining and percentage of staining cells. CHFR expression was associated with pathologic complete response (pCR) and progression free survival (PFS). Covariates...

576^ Background: Increased signaling through growth factor receptor pathways, including HER2, has been demonstrated to play a role in resistance to endocrine therapy. Efficacy of inhibiting HER2 and mTOR in HER2-negative, hormone-resistant breast cancer has been previously demonstrated. We evaluated the ability of inhibition of HER2 with trastuzumab (TRAST) and/or mTOR with everolimus (EVER) to reverse resistance to endocrine therapy in patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (MBC). Methods: Eligibility included HR-positive, HER2-negative (IHC 1+ or 2+ and/or FISH negative) MBC on metastatic biopsy and documented progression within 6-months of starting an endocrine agent in the metastatic setting. Patients continued on the endocrine agent they had experienced disease progression on and were randomized to receive TRAST (8mg followed by 6mg every 3-weeks) or EVER 10mg daily. At disease progression the other agent (TRAST or EVER) was added. Biopsies of metastatic l...

BACKGROUND: The authors compared treatment adherence rates and outcome in Caucasian and African American patients with inflammatory breast cancer (IBC). METHODS: The records of 55 (25 Caucasian and 30 African American) IBC patients treated with curative intent from 1995 to 2009 were reviewed. All patients received neoadjuvant doxorubicin (Adriamycin) and/or taxane-based chemotherapy, and mastectomy with or without radiotherapy. The median follow-up period for Caucasian and African American patients was similar (39.5 months and 36.1 months, respectively). RESULTS: There was no difference between races in median age, tumor size, grade, and receptor status at diagnosis. The number of patients who completed neoadjuvant chemotherapy, surgery, and radiotherapy did not differ by race (84% of Caucasians vs 86.7% of African Americans) nor did the median length of time to complete trimodality treatment (263 [range, 207-422] days for Caucasians vs 262 [range, 165-371] days for African Americans). There was a trend toward slightly higher pathological complete response rates in Caucasian than African American women (20% in Caucasians vs 6.7% in African Americans, P = .23). Despite slightly better response rates to neoadjuvant chemotherapy, Caucasian patients did not have higher 3-year local control rates (70% in Caucasians vs 64% in African Americans, P = .73). However, there was a trend toward higher 3-year overall survival in Caucasian versus African American patients (73% in Caucasians vs 55% in African Americans, P = .09) and higher distant metastasis-free survival (60% in Caucasians vs 40% in African Americans, P = .19). CONCLUSIONS: This study is among the largest to examine patients with IBC by race. Being Caucasian or African American did not appear to impact treatment adherence. However, African American patients tended to have poorer response to standard treatment and worse outcome than Caucasian patients. Cancer 2011;. © 2011 American Cancer Society.

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype that affects about 20% of breast cancer patients and has a high incidence in young African American women. Currently the only therapeutic options for TNBC patients is chemotherapy, however, more than 60% of TNBC patients are highly resistant to chemotherapeutic treatment. The development of novel therapeutic approaches is essential to enable treatment of patients with chemo-resistant TNBC. Our lab focuses on the development of receptor-targeted theranostic nanoparticles. We have developed a class of urokinase plasminogen activator receptor (uPAR) targeted theranostic magnetic iron oxide nanoparticles (IONPs) carrying therapeutic agents that are clinically beneficial to TNBC patients, including DNA damaging agents, such as doxorubicin (Dox) or cisplatin (Cis). We are targeting uPAR because it is highly expressed in malignant cancers including aggressive breast cancer tissues and tumor stromal cells that are enriched in TNBC tissues. Methods: Tumor fragments from TNBC patients, obtained from a Phase II clinical trial that is ongoing at the Breast Cancer Clinic in the Winship Cancer Institute, were implanted in the mammary fat pad of SCID mice. The tumor xenografts grew to about 1 cm in diameter in 12 to 15 weeks. Tumor fragments were then implanted into the mammary fat pad and passaged through nude mice for testing the therapeutic efficacy of the uPAR-targeted nanoparticle-drugs. Histological analysis of post-chemotherapy TNBC and primary tumor xenograft tissues with or without uPAR-targeted IONP-Dox was conducted using immunohistochemistry and dual immunofluorescence techniques. Results: We have previously reported that the uPAR-targeted IONP-Dox causes tumor growth inhibition following systemic delivery. Using CD44 and uPAR as biomarkers we also reported histological analysis of post-chemotherapy TNBC and primary tumor xenograft tissues showed high levels of CD44+/CD24- tumor cells and up-regulation of uPAR. Primary TNBC xenografts treated with conventional Dox had increased levels of CD44+/CD24- cells and strong uPAR expression. Conversely, the tumor tissues from the uPAR-targeted IONP-Dox treated group showed decreased levels of CD44+/CD24- and uPAR positive cells. We have further investigated the biomarkers insulin-like growth factor 1 receptor (IGF-1R) and Ki67. IGF-1R has been shown to be overexpressed in more than 50% of TNBCs and may be associated with the drug-resistant TNBC phenotype, while Ki67 is a conventional biomarker for proliferation. We observed that uPAR-targeted IONP- Dox treatment decreased IGF-1R expression compared to the control group and the group treated with conventional Dox. We also observed that Ki67 expression was decreased in the uPAR-targeted IONP- Dox treatment group compared to control group and the group treated with conventional Dox. Conclusions: Results of our study demonstrated that uPAR-targeted theranostic IONPs selectively delivers therapeutic payloads of the chemotherapeutic drug Dox to inhibit the growth of uPAR positive tumor cells. It is likely that uPAR expressing tumor cells are an aggressive and potentially drug resistant cell population that overexpress breast cancer stem-like cell biomarker (CD44+/CD24-) as well as up-regulation of a growth factor receptor, IGF-1R. These results support further investigation of theranostic nanoparticles as an approach to overcome drug resistance in TNBC. Citation Format: Jasmine M. Miller-Kleinhenz, Hongyu Zhou, Weiping Qian, Ruth O'Regan, Amelia Zelnak, Toncred Styblo, Lily Yang. uPAR-targeted theranostic nanoparticles effectively decrease expression of IGF-1R and Ki67 in drug-resistant triple-negative breast cancer human xenograft. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B045.

562 Background: Hormone receptor (HR)- positive breast cancer patients (pts) typically have lower pathological responses to pre-operative chemotherapy than HR-negative breast cancers. Objective: We evaluated the pathologic and radiologic response rates to pre-operative endocrine therapy or chemotherapy, as directed by RS, in pts with HR-positive resectable breast cancers. Methods: Pts with HR-positive breast cancers had RS performed on the initial diagnostic biopsy. Pts were treated pre-operatively as follows based on RS: ≤10, exemestane +/- goserelin for 6 to 12 months (ET); 11 to 25 randomized to ET or docetaxel-cyclophosphamide (TC) for 6 cycles (CT); ≥ 26, CT. Results: From 4/2009 to 12/2012, 66 pts signed consent for RS testing and 46 are evaluable for efficacy analysis. Median age is 57 (40 to 78); one-third of pts are African-American; 41% have clinically node positive disease. RS ranged from 2 to 57. 28 pts received CT: Pathologic complete response (PCR) rate was 10% and 60% of cancers were down-staged based on initial T-stage. Radiologic response is available for 20 pts: complete radiologic response (CRR) 15%, partial RR (PRR) 40%, progressive disease (PD) 5%. In 11 pts with RS 11 to 25: PCR 0%, down-staged 45%, up-staged 18%, radiologic responses: CRR 17%, PRR 50%, PD 17%. In 17 pts with RS ≥ 26: PCR 18%, down-staged 71%, up-staged 0%, radiologic responses: CRR 14%, PRR 36%, PD 0%. 18 pts received ET for between 6 to 22 months, 5 remain on study and have not had surgery: PCR 0%; down-staged 38%; up-staged 15%; radiologic responses: CRR 13%, PRR 40%, PD 0%. There was no correlation between RS and efficacy of ET. To date, 3 pts have relapsed, all of whom received CT. Conclusions: This is the first prospective use of the 21-gene RS to select pre-operative therapy for pts with HR-positive breast cancer. Pre-operative CT results in tumor down-staging in the majority of cancers with RS ≥ 11, though it appears to be more effective with RS ≥ 26. ET was moderately effective in down-staging cancers with RS ≤ 25. Updated results will be presented. Clinical trial information: NCT00941330, NCT00832338.

Background: The addition of trastuzumab to preoperative chemotherapy for Her2-positive breast cancers has been shown to increase pCR rate, which correlates with improved outcome. The purpose of this study was to evaluate the efficacy of trastuzumab in combination with dose-dense nab-paclitaxel followed by weekly vinorelbine. Methods: Patients with Stage I (>1.0 cm), II, or IIIA Her2-positive (defined as either immunohistochemical 3+ of fluorescence in situ hybridization-positive) breast cancer received nab-paclitaxel 260 mg/m2 iv every 2 weeks for 4 cycles in combination followed by vinorelbine 25 mg/m2 iv weekly with simultaneous trastuzumab (4 mg/kg loading dose then 2 mg/kg weekly) for 20 weeks. Tissue was collected at baseline, at optional midway biopsy, and post-therapy. Primary endpoint was pCR rate; secondary endpoints included response rate and toxicity. Cardiac evaluation was performed at baseline, after 4 cycles of nab-paclitaxel, after 12 weeks of vinorelbine and every 3 months thereafter per standard practice guidelines. Results: To date, 27 patients have been accrued (3/2008 to 6/2011). 24 patients are currently evaluable for primary endpoint. Patients were accrued from a university center (48.2%), county hospital (11.1%), and community sites (40.7%). Median age was 49.5 years (34-64). Median tumor size was 4.0 cm (1.5-7cm). 14 of 27 patients (51.9%) were clinically node-positive at study entry. 11 patients were African American (40.7%), 16 were Caucasian (59.3%). The regimen was well-tolerated: 3 patients experienced grade 3 neuropathy; 6 patients had grade 3 neutropenia; 1 patient had trastuzumab held for asymptomatic decrease in left ventricular ejection fraction. 18 of 24 patients (75%) had complete clinical response rate. 6 of 24 patients (25%) had partial clinical response. 11 of 24 patients (45.8%) had pCR. Conclusions: The combination of preoperative trastuzumab with dose-dense nab-paclitaxel followed by vinorelbine was well-tolerated and resulted in a high rate of pCR in Her2-positive, early-stage breast cancer. Final results and correlative studies will be reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2703. doi:1538-7445.AM2012-2703

1118 Background: Achievement of pathologic complete response (pCR) to preoperative therapy is a predictor of improved disease-free and overall survival. Sequential and concurrent regimens of D and C were evaluated in patients with Her2-negative breast cancers who were candidates for preoperative chemotherapy. Methods: Patients with Stage I (>1.0 cm), II or III, Her-negative breast cancer from Georgia-based oncology network were randomized between Arm A: sequential therapy with D 100 mg/m2 every 3 weeks for 4 cycles followed by C 1000 mg/m2 PO BID on days 1-14 of 3 week cycle for 4 cycles; Arm B: concurrent therapy with with D 50 mg/m2 on day 1 and C 1000 mg/m2 PO BID on days 1-7 of 2 week cycle for 8 cycles. Primary endpoint was pCR rate; secondary endpoints included response rate and toxicity. Results: 51 patients were accrued (4/2007–7/2009), Arm A (n=25) Arm B (n=26) and are evaluable for primary endpoint. Patients were accrued at academic center (45%), county hospital (33%), and community sites (22%)....

557 Background: AA patients have a worse outcome from breast cancer than their C counterparts, which is partly explained by their propensity to develop triple negative breast cancers. Additionally,...

625 Background: The addition of trastuzumab to preoperative chemotherapy for HER2-positive breast cancers has been shown to increase pCR rates. The purpose of this study was to evaluate the efficacy of trastuzumab in combination with dose-dense nab-paclitaxel followed by weekly vinorelbine. Methods: Patients with stage I (> 1.0 cm), II, or IIIA HER2-positive (by standard definitions) breast cancer received nab-paclitaxel 260 mg/m2 iv every 2 weeks for 4 cycles followed by vinorelbine 25 mg/m2 iv weekly with trastuzumab given weekly throughout chemotherapy (4 mg/kg loading dose then 2 mg/kg weekly) for 20 weeks. Tissue was collected at baseline, at optional midway biopsy, and post-therapy. Primary endpoint was pCR rate; secondary endpoints included response rate and toxicity. Cardiac evaluation was performed at baseline, after 4 cycles of nab-paclitaxel, after 12 weeks of vinorelbine and every 3 months thereafter. Results: To date, 21 of 50 planned patients have been accrued (3/2008 to 12/2009). 11 patient...

Background: Radiotherapy has been shown to reduce local recurrence rates of breast cancer after treatment with surgery and adjuvant chemotherapy. Indications for postmastectomy radiation have historically been based on pathology, but indications for radiation in the setting of pathologic complete response (pCR) to neoadjuvant chemotherapy are not well defined. The aim of this study was to evaluate the rates of local regional recurrence (LRR) among patients with pCR to neoadjuvant chemotherapy followed by surgery with or without radiation (XRT).Patients and Methods: The case histories of 337 patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, surgery with or without radiation from October 1997 to December 2006 were analyzed. Median age at diagnosis was 50.6 years (range: 25-84). The clinical stage at diagnosis was I in 3 (1%), IIA in 105 (31%), IIB in 94 (28%), and III in 135 (40%) patients. All patients received preoperative systemic therapy with a doxorubicin-based regimen (92%) or a single-agent taxane regimen (7%) or CMF (1%). A total of 272 patients received radiation following surgery and 65 did not receive any radiation. Median follow-up time was 40 months among all patients. The Kaplan-Meier method and log rank test were used to evaluate LRR rates and overall survival among both groups.Results: Patients treated with neoadjuvant chemotherapy followed by surgery and XRT had a lower incidence of LRR at 3 years with 24 cases of local recurrence among 272 patients who received XRT compared with 12 cases of local recurrence among the 65 patients who did not receive XRT (8.9% v 18.5%, P=0.02). Radiation also reduced local regional recurrence at 3 years among a subset of patients with clinical stage T2N1 disease (4.9% v 28.6%, P=0.03). There was no difference in overall survival or disease free survival among patients who received XRT compared to patients who did not receive XRT. There were 62 (18%) patients who achieved a pCR to neoadjuvant chemotherapy. Among patients with a pathologic complete response, radiation appeared to reduce the risk of LRR compared to patients who did not receive XRT (7.4% v 25%, P=0.17).Conclusion: Radiotherapy significantly reduced local regional recurrence rate among patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery. Of particular interest, patients who achieve a pathologic complete response to neoadjuvant chemotherapy still had high LRR rates and may benefit from radiotherapy by lowering the risk of local regional recurrence. Further studies on the significance of LRR and overall survival among these patients are needed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4114.

Results: Median follow-up was 16 months. The minimum balloon-to-skin distance was\7 mm in 16% (7/45) of Contura patients and 12% (17/137) of MammoSite patients (p=0.78). The maximum skin dose was 100% of the prescribed dose with a Contura catheter vs. 145% of the prescribed dose with a MammoSite catheter. Air/fluid next to the Contura balloon was at least partially removed in 71% (32/45) of patients. The volume of air/fluid next to the Contura balloon was 5.0% ± 0.7% (mean ± standard error) of the planning target volume for plan evaluation (PTV_EVAL) before suctioning vs. 1.3% ± 0.2% after suctioning (p\ 0.001). Eighty-nine percent (40/45) of Contura plans satisfied both treatment planning goals vs. only 36% (16/45) of hypothetical MammoSite plans (p \ 0.0001). A Contura catheter did not require explantation in 16% (7/45) of patients where balloon-toskin spacing was only 3-6 mm and in 11% (5/45) of patients where there was an air/fluid pocket next to the balloon .10% of PTV_EVAL prior to suctioning. A MammoSite catheter was explanted in 10% (15/152) of cases where the minimum balloon-to-skin distance was \7 mm and in 13% (20/157) of cases where there was an air/fluid pocket next to the balloon .10% of PTV_EVAL. The incidence of acute toxicity with a Contura catheter was similar to that with a MammoSite catheter. Conclusions: A Contura catheter does not require explantation in cases where balloon-to-skin spacing is only 3-6 mm or an air/ fluid pocket next to the balloon is .10% of PTV_EVAL prior to suctioning, thereby increasing the applicability of accelerated partial breast irradiation. Phase III clinical trials will help to determine whether accelerated partial breast irradiation offers advantages over standard whole breast irradiation.

Abstract #5122 Background The efficacy of D and C as single agents and in combination is well established in the treatment of metastatic breast cancer. Novel sequential and concurrent regimens of D and C were evaluated in patients with her2-negative breast cancer eligible for preoperative therapy. MethodsPatients with Stage I (>1.0cm), II or III, Her2- breast cancer were randomized to two treatment arms: Arm A: sequential therapy with D 100 mg/m2 Q 3 weeks for 4 cycles, followed by C 1000mg/m2 BID on days 1-14 of a 3-week cycle, for 4 cycles; Arm B: concurrent therapy with D 50mg/m2 on day 1 and C 1000mg/m2 BID on days 1-7 of a 2-week cycle for 8 cycles. The planned total dose of D and C and number of cycles were identical on both arms. Tissue was collected at baseline, midway and post-therapy for correlative studies. Endpoints included pathologic complete response (pCR) rate, response rate, and toxicity. Results To date 38 of 80 planned patients have been accrued (4/07-6/08). Data are available for 33 patients; 16 African American (AA) (49%), 16 Caucasian (49%), and 1 Hispanic (2%). Patients were accrued from a university center (59%), county hospital (31%) and community sites (10%). Histology: Infiltrating ductal carcinoma (76%), infiltrating lobular carcinoma (15%), metaplastic tumors (6%), mucinous carcinoma (3%). Four patients had inflammatory breast cancer. 17 patients (52%) had ER+ or PR+ tumors and 16 (48%) had ER-/PR- tumors (triple negative tumors or TNT). The average tumor size at baseline was 4.0cm+/-3.0cm. In 29 patients who completed therapy, both regimens were relatively well tolerated: 9 patients (Arm A, N=3 (23%); Arm B, N=6 (38%)) had grade 3 toxicity, predominantly hand-foot syndrome, diarrhea or neuropathy. Dose reductions were required for 12 patients due to toxicity (11 required for C, 1 for D). To date, the pCR rate is 7%, observed only in AA patients with TNTs. In this subgroup the pCR rate was 18%. Discussion This study represents the first effort to accrue patients through a Georgia-based trial network, providing a unique opportunity to treat patients from a region with a large AA population. Our preliminary results suggest modest activity of D and C, with greater activity in the concurrent arm and in AA patients with TNTs. An official interim analysis is planned and updated results will be presented. Correlative studies which focus on molecular differences in responders and non-responders, particularly in the TNT group will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5122.