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PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Purpose CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age ≥ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival. Methods Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance. Results Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose. Conclusion Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients.

Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

Background: Pertuzumab (P), a monoclonal antibody that binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupts HER2 dimerization and signaling. Dual anti-HER2 therapy with HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) in the placebo-controlled CLEOPATRA phase III trial. We report matured results of a phase II study to evaluate the efficacy and cardiac safety of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) were eligible. Pts received weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint was PFS at 6 months (mo). Secondary endpoints included response, safety (including cardiac events), and tolerability. Evaluable pts were those who had started study Rx and were able to be assessed at 6 mo for PFS. Safety and toxicity are reported for all enrolled patients. Left ventricular ejection fraction (LVEF) was monitored by echocardiogram (ECHO) every 3 mo. Cardiac enzymes including troponin I (TNI) and brain natriuretic peptide (BNP) were measured every other cycle x6. Cardiac events (CE) were defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of June 10th 2013, 63 pts were enrolled; 50 pts have reached the primary endpoint and were assessed at 6 mo for PFS. At 6 mo, 38/50 pts (76%) are progression-free (5 CR, 20 PR and 13 SD); 9 pts progressed; 3 pts were non-evaluable. The 6 mo PFS results for all patients will be updated. Of all enrolled pts (n = 63), median age was 52 years (range 26 to 72). A total of 28 pts (44%) previously received H in the adjuvant or metastatic setting, and 15 pts (24%) were being treated in the second-line metastatic setting. Safety and toxicity were assessed in all enrolled patients; G 3/4 toxicities were fatigue (3 pts, 5%), neutropenia (3 pts, 5%), peripheral neuropathy (2 pts, 3%), diarrhea (1 pt, 2%), hypomagnesium (1 pt, 2%), sepsis (1 pt, 2%), cellulitis (1 pt, 2%), and dry skin (1 pt, 2%). There were no febrile neutropenic (FN) events. Median LVEF was 64% at baseline (range 50% to 72%), 64% at 3mo (range 50% to 73%), 63% at 6mo (range 49% to 68%), 63% at 9 mo (range 47% to 68%), 64% at 12 mo (range 52% to 69%), 63% at 15 mo (range 55% to 69%), and 63% at 18 mo (range 56% to 68%). There were no CEs and no significant changes in TNI levels. Only 1 pt had a transient rise in BNP after cycle 1, but she did not have a CE. Conclusions: Six-month PFS is 76% (95% CI 62-87%) in evaluable pts. Treatment is safe, with few grade 3/4 toxicities, no FN events, no CEs, and no significant or persistent elevation in TNI or BNP, respectively. THP is endorsed by the NCCN as a treatment option for pts with HER2+ MBC, as supported by this study. This study also suggests that intense serial LVEF monitoring may not be necessary with THP based on the cardiac safety results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-07.

Capecitabine is widely used in the management of metastatic breast cancer; however, drug delivery is limited by gastrointestinal and other toxicity. We employed mathematical modeling to rationally design an optimized dose and schedule for capecitabine of 2,000 mg twice daily, flat dosing, 7 days on, 7 days off. Preclinical data suggested increased efficacy and tolerability with this novel dosing, and three early-phase clinical trials have suggested a favorable toxicity profile. To further define the tolerability of this regimen, we conducted a systematic review of the gastrointestinal adverse events of patients on these studies. This review demonstrated a favorable gastrointestinal toxicity profile with capecitabine in this novel schedule when given as single agent or in combination therapy with either bevacizumab or lapatinib. No patients discontinued therapy for gastrointestinal toxicity, and there were no grade 4 or 5 gastrointestinal toxicities reported. Grade 3 or greater diarrhea occurred in two (2%); grade 2 or greater mucositis, constipation, and vomiting were reported in three (4%) patients. We conclude that capecitabine administered on a 7 days on, 7 days off schedule has limited gastrointestinal toxicity. Our methodology was based on an analysis of individual patient toxicity data from one phase I single-agent capecitabine and two phase II capecitabine combination studies (with bevacizumab and lapatinib, respectively), focusing specifically on gastrointestinal toxicity.

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0–1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6–1-12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-20.

Background We tested whether an educational video on the goals of care in advanced cancer (life-prolonging, basic or comfort care) can help patients understand these goals and impact preferences for resuscitation.

Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7-7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7-7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7-7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥ 6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2-96+), five patients had partial responses (23; 95 CI, 7-44%) and six (27; 95 CI, 10-48%) had stable disease ≥ 6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥ 3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7-7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC.

Background Capecitabine (C) administered for 14 days followed by a 7 day rest (14—7) in combination with lapatinib (L) improved TTP in patients (pts) with HER2(+) metastatic breast cancer (MBC) that progressed following trastuzumab (T). Our mathematical modeling of C dosing predicted 7 days of therapy followed by 7 days of rest (7—7) to maximize efficacy and minimize drug-related toxicity. In xenograph models, C (7—7) was better tolerated than C (14—7) at higher doses and led to improved survival. We established the maximum tolerated dose of C (7—7) to be 2,000 mg twice daily and have studied C (7—7) in combination with targeted therapies. We now report the results of C (7—7) with L in pts with trastuzumab-refractory HER2(+) MBC. Methods Eligible pts had measurable, HER2(+) MBC with progression following T. HER2(+) is defined as 3+ on IHC or FISH-amplified. Pts had normal LVEF by MUGA, ECOG performance status (PS) ≥2, and 6 months, and progression free survival (PFS). Using a Simon optimal 2-stage design, with alpha 10% and power 90% to discriminate between RR 10% and 25%, 21 pts were planned for the 1st stage. If >2 pts responded, then 29 additional pts were to have been enrolled to 2nd stage. If >7/50 pts responded, C (7—7) with L would be considered worthy of further study. Results As of 6/14/10, 22 pts were enrolled on study with the following characteristics: median (med) age 55 years (42-72), med PS 0 (0-2), ER/PR(+) 12, HER2(+) 22, med LVEF 64% (51-70%). Sites of MBC include viscera 16, brain 3. Prior therapy includes 8 pts with adjuvant anthracycline and taxane exposure, 4 pts with adjuvant T, 18 pts with metastatic T, and a med of 1 CRx for MBC. After a med of 5 cycles (1-16), 18 patients are evaluable for response: 0 CR, 3 PR, 6 SD >6 months, 9 SD 10% of patients include: hand-foot syndrome (gr 3: 5%, gr2: 41%), diarrhea (gr 3: 0%, gr 2: 23%), elevated AST/ALT or bilirubin (gr 3: 0%, gr 2: 18%). There have been no declines in LVEF. Conclusion Due to slower than expected accrual and an anticipated randomized, phase III trial comparing C (7—7) with C (14—7), we closed this study to further accrual. However, our data suggests that C (7—7) with lapatinib is active, well-tolerated, feasible and associated with mild gastrointestinal toxicity in pts with trastuzumab-refractory, HER2(+) MBC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-11-12.

Background—To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-totoxicity ratios. Methods—We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14 - 7). Results—The model predicted that 7 days of treatment followed by a 7-day rest (7 - 7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions—We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development.

Breast tumor volume measured on MRI has been used to assess response to neoadjuvant chemotherapy. However, accurate and reproducible delineation of breast lesions can be challenging, since the lesions may have complicated topological structures and heterogeneous intensity distributions. In this article, the authors present an advanced computerized method to semiautomatically segment tumor volumes on T1-weighted, contrast-enhanced breast MRI. The method starts with manual selection of a region of interest (ROI) that contains the lesion to be segmented in a single image, followed by automated separation of the lesion volume from its surrounding breast parenchyma by using a unique combination of the image processing techniques including Gaussian mixture modeling and a marker-controlled watershed transform. Explicitly, the Gaussian mixture modeling is applied to an intensity histogram of the pixels inside the ROI to distinguish the tumor class from other tissues. Based on the ROI and the intensity distribution of the tumor, internal and external markers are determined and the tumor contour is delineated using the marker-controlled watershed transform. To obtain the tumor volume, the segmented tumor in one slice is propagated to the adjacent slice to form an ROI in that slice. The marker-controlled watershed segmentation is then used again to obtain a tumor contour in the propagated slice. This procedure is terminated when there is no lesion in an adjacent slice. To reduce measurement variations possibly caused by the manual selection of the ROI, the segmentation result is refined based on an automatically determined ROI based on the segmented volume. The algorithm was applied to 13 patients with breast cancer, prospectively accrued prior to beginning neoadjuvant chemotherapy. Each patient had two MRI scans, a baseline MRI examination prior to commencing neoadjuvant chemotherapy and a 1 week follow-up after receiving the first dose of neoadjuvant chemotherapy. Blinded to the computer segmentation results, two experienced radiologists manually delineated all tumors independently. The computer results were then compared with the manually generated results using the volume overlap ratio, defined as the intersection of the computer- and radiologist-generated tumor volumes divided by the union of the two. The algorithm reached overall overlap ratios of 62.6%±9.1% and 61.0%±11.3% in comparison to the two manual segmentation results, respectively. The overall overlap ratio between the two radiologists’ manual segmentations was 64.3%±10.4%. Preliminary results suggest that the proposed algorithm is a promising method for assisting in tumor volume measurement in contrast-enhanced breast MRI.

Purpose This study was conducted to determine, in patients with advanced-stage breast cancer, the maximum tolerated dose (MTD) of capecitabine administered orally for 7 days followed by a 7-day rest (7/7), a schedule based on a mathematical method for the optimization of anticancer drug scheduling. Patients and Methods Eligible patients had measurable, metastatic breast cancer. There was no limit to number of prior treatments. A standard, three-patients-per-cohort dose-escalation scheme used flat-dose capecitabine beginning at 1,500 mg orally twice daily (bid) on a 7/7 schedule. Each cohort was monitored for 28 days before escalation to the next cohort to assess for delayed toxicity. Response was evaluated radiographically every 12 weeks; toxicity was assessed every 2 weeks. Results Twenty-one patients were treated on study. The most frequently reported treatment-related grade 2/3 adverse events were hand-foot syndrome (29%), leukopenia/neutropenia (24%), and fatigue (19%). Grade 3 toxicity was transient and easily managed. Three patients experienced grade 3 hand-foot syndrome; one of these patients had grade 3 diarrhea. There were no grade 4 events. The MTD of capecitabine 7/7 is 2,000 mg twice daily. Conclusion As predicted by mathematical modeling, capecitabine dosing for 7 days followed by a 7-day rest is well tolerated. Efficacy of this schedule is being determined in a phase II clinical trial in patients with advanced breast cancer.

Background Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL ( ClinicalTrials.gov identifier, NCT01827163 ). Patients and Methods Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m2 × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate Results From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34-74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity. Conclusion The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made it unlikely that full accrual would demonstrate feasibility.

OBJECTIVES: To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL). DESIGN: A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later. SETTING: This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York. PARTICIPANTS: Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable. MEASUREMENTS: The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times. RESULTS: Patients (mean age 68, range 65–84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (IV), methotrexate 40 mg/m2 IV, 5-fluorouracil 600 mg/m2 IV every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL. CONCLUSION: Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

Purpose This study was designed to evaluate the efficacy and safety of single-agent gemcitabine for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Eligible patients were required to have bidimensionally measurable MBC that had been treated with 2–4 prior chemotherapy regimens that included an anthracycline and a taxane. Gemcitabine was delivered at a dose of 800 mg/m 2 on days 1, 8, and 15 of a 28-day cycle until evidence of disease progression. Patients and Methods Twenty-two patients were enrolled and included in the safety analysis; 18 patients were evaluable for response. The median age of patients was 54 years (range, 36–70 years). The mean number of prior chemotherapy regimens for metastatic disease was 2.3, and the mean dose of gemcitabine delivered was 911 mg/m 2 (range, 600–1600 mg/m 2 ). Results Overall, gemcitabine was well tolerated with minimal grade 3 toxicities; the only grade 4 toxicity was 1 case of pulmonary embolus. Three patients had evidence of partial tumor regression (17%; 95% CI, 4%–41%), and 1 patient had a 41% decrease in tumor volume, including liver metastasis. Conclusions Gemcitabine is active and well tolerated as monotherapy given in heavily pretreated patients with MBC after anthracyclines and taxanes. The activity and safety reported in this trial are consistent with previous reports in similar patients.

In this study, 275 women with breast cancer attending ambulatory breast cancer clinics in two sites were evaluated for psychological distress by using three self-report instruments: a visual analogue scale for psychological distress, the Hospital Anxiety and Depression Scale, and the Brief Symptom Inventory. Results suggest that significant psychological distress exists in ambulatory women with breast cancer; all three instruments effectively measured that level of distress. Implications for the use of these instruments in educating oncological staff members, documenting need for psychiatric services in a period of capitation, and providing quality assurance evaluations of psychiatric services are discussed.

Purpose: Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin–cyclophosphamide (ddAC) → nanoparticle albumin–bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer. Experimental Design: Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted. Results: The median age was 48 years (range, 27–75 years), and baseline LVEF was 68% (53%–82%). After 39 months' median follow-up (5–45 months): median LVEF was 68% (53%–80%) at 2 months (n = 78), 64% (51%–77%) at 6 months (n = 66), 63% (48%–77%) at 9 months (n = 61), and 66% (42%–76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively. Conclusions: Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials. Clin Cancer Res; 17(10); 3398–407. ©2011 AACR.

Background SRC activation is associated with cell migration, proliferation, and metastasis. Saracatinib is an oral tyrosine kinase inhibitor (TKI) selective for SRC. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER) – and progesterone receptor (PR) – metastatic breast cancer (MBC). Patients and Methods Patients who had undergone ≤ 1 previous chemotherapy regimen for measurable ER – and PR – MBC received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 months. Secondary endpoints included toxicity and progression-free survival (PFS). Levels of circulating tumor cells (CTCs) in response to therapy were measured over time. Results Nine patients were treated on study. After a median of 2 cycles (range 1-3), no patient had achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12-109 days).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient acquired potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from the study. Common adverse events included fatigue, elevated liver enzymes, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency. Conclusions These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER − /PR − MBC.

BACKGROUND: Capecitabine has antitumor activity in metastatic breast cancer (MBC); however, its optimal dose and schedule remain unclear. Mathematical modeling predicts that a capecitabine schedule 7 days of treatment followed by 7 days of rest (7—7) will improve efficacy and minimize toxicity. Bevacizumab has demonstrated the ability to improve outcomes when it is added to chemotherapy, including capecitabine, in the first-line and second-line settings. METHODS: Patients with measurable MBC received oral capecitabine (2000 mg twice daily; 7—7), and intravenous bevacizumab (10 mg/kg every 2 weeks). The primary endpoint was the response rate. Secondary endpoints included toxicity, the clinical benefit rate, and progression-free survival (PFS). RESULTS: Forty-one patients were treated. After a median of 7 cycles (range, 1-32 cycles), partial responses were observed in 20% of patients, and stable disease for ≥6 months was noted in 35% patients. The median PFS was 8 months. The most common treatment-related toxicities were hand-foot syndrome (49% grade 2, 20% grade 3/4) hypertension (12% grade 2, 10% grade 3/4), and fatigue (12% grade 2, 2% grade 3/4). Diarrhea (5% grade 2, 0% grade 3/4), nausea (0% grade 2-4), and vomiting (0% grade 2-4) were rare. CONCLUSIONS: Capecitabine administered for 7 days followed by a 7-day rest in combination with bevacizumab had modest efficacy and an acceptable toxicity profile in patients with MBC. Gastrointestinal toxicity with this schedule was minimal. Cancer 2011;. © 2011 American Cancer Society.

Breast tumor volume measured on MRI has been used to assess response to neoadjuvant chemotherapy. However, accurate and reproducible delineation of breast lesions can be challenging, since the lesions may have complicated topological structures and heterogeneous intensity distributions. In this article, the authors present an advanced computerized method to semiautomatically segment tumor volumes on T1-weighted, contrast-enhanced breast MRI. The method starts with manual selection of a region of interest (ROI) that contains the lesion to be segmented in a single image, followed by automated separation of the lesion volume from its surrounding breast parenchyma by using a unique combination of the image processing techniques including Gaussian mixture modeling and a marker-controlled watershed transform. Explicitly, the Gaussian mixture modeling is applied to an intensity histogram of the pixels inside the ROI to distinguish the tumor class from other tissues. Based on the ROI and the intensity distribution of the tumor, internal and external markers are determined and the tumor contour is delineated using the marker-controlled watershed transform. To obtain the tumor volume, the segmented tumor in one slice is propagated to the adjacent slice to form an ROI in that slice. The marker-controlled watershed segmentation is then used again to obtain a tumor contour in the propagated slice. This procedure is terminated when there is no lesion in an adjacent slice. To reduce measurement variations possibly caused by the manual selection of the ROI, the segmentation result is refined based on an automatically determined ROI based on the segmented volume. The algorithm was applied to 13 patients with breast cancer, prospectively accrued prior to beginning neoadjuvant chemotherapy. Each patient had two MRI scans, a baseline MRI examination prior to commencing neoadjuvant chemotherapy and a 1 week follow-up after receiving the first dose of neoadjuvant chemotherapy. Blinded to the computer segmentation results, two experienced radiologists manually delineated all tumors independently. The computer results were then compared with the manually generated results using the volume overlap ratio, defined as the intersection of the computer- and radiologist-generated tumor volumes divided by the union of the two. The algorithm reached overall overlap ratios of 62.6% +/- 9.1% and 61.0% +/- 11.3% in comparison to the two manual segmentation results, respectively. The overall overlap ratio between the two radiologists' manual segmentations was 64.3% +/- 10.4%. Preliminary results suggest that the proposed algorithm is a promising method for assisting in tumor volume measurement in contrast-enhanced breast MRI.

PurposePreclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC).MethodsPatients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease.ResultsForty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months.ConclusionCombination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

This was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity.Forty patients (median age, 48 years; range, 30-74 years) with HER2/neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they receivedor= 1 previous trastuzumab regimen,or= 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline dosesor= 240 mg/m2. The study regimen comprised NLD 60 mg/m2 every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receivingor= 1 cycle. Cardiac safety was assessed after completingor= 4 full treatment cycles.Thirty out of 40 patients (75%) receivedor= 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia.Nonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.

Older women with breast cancer are underrepresented in clinical trials, and data on the effects of adjuvant chemotherapy in such patients are scant. We tested for the noninferiority of capecitabine as compared with standard chemotherapy in women with breast cancer who were 65 years of age or older.We randomly assigned patients with stage I, II, IIIA, or IIIB breast cancer to standard chemotherapy (either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide plus doxorubicin) or capecitabine. Endocrine therapy was recommended after chemotherapy in patients with hormone-receptor-positive tumors. A Bayesian statistical design was used with a range in sample size from 600 to 1800 patients. The primary end point was relapse-free survival.When the 600th patient was enrolled, the probability that, with longer follow-up, capecitabine therapy was highly likely to be inferior to standard chemotherapy met a prescribed level, and enrollment was discontinued. After an additional year of follow-up, the hazard ratio for disease recurrence or death in the capecitabine group was 2.09 (95% confidence interval, 1.38 to 3.17; P0.001). Patients who were randomly assigned to capecitabine were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (P=0.02). At 3 years, the rate of relapse-free survival was 68% in the capecitabine group versus 85% in the standard-chemotherapy group, and the overall survival rate was 86% versus 91%. Two patients in the capecitabine group died of treatment-related complications; as compared with patients receiving capecitabine, twice as many patients receiving standard chemotherapy had moderate-to-severe toxic effects (64% vs. 33%).Standard adjuvant chemotherapy is superior to capecitabine in patients with early-stage breast cancer who are 65 years of age or older. (ClinicalTrials.gov number, NCT00024102.)

Purpose The objective of this study was to assess the efficacy and safety of pemetrexed in pretreated patients with advanced-stage breast cancer. Patients and Methods Patients with advanced-stage or metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-2, and progressive or relapsed disease after treatment with regimens containing anthracyclines and taxanes were eligible. Pemetrexed 500 mg/m 2 was administered as a 10-minute intravenous infusion on day 1 every 21 days. Results Seventy-nine women were enrolled. After protocol amendment, 43 patients received folic acid and vitamin B 12 supplementation to control pemetrexed-related toxicity. A median of 4 cycles (range, 1-23 cycles) was administered. Overall response rate was 9% (95% confidence interval, 3.7%-17.6%), median duration of response was 5.5 months, median progression- free survival was 3.1 months, and median survival was 10.5 months. Major grade 3/4 toxicities were lymphopenia (53.3%), neutropenia (36.4%), leukopenia (26.9%), and anemia (7.7%). In general, the toxicities were less frequent in patients who received vitamin supplementation than in those who did not receive vitamin supplementation. Conclusion The response to pemetrexed salvage treatment was low in this study of heavily pretreated patients with breast cancer. Pemetrexed was generally well tolerated in patients with previously treated breast cancer. Vitamin supplementation appeared to ameliorate toxicity.

1022 Background: CALGB 49907 compared capecitabine (X) with standard (S) chemotherapy in BC patients (pts) 65 yrs and older. Initial results: inferiority of X for both RFS and OS at 2.4 yrs median ...

To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL).A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later.This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York.Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable.The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times.Patients (mean age 68, range 65-84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (i.v.), methotrexate 40 mg/m2 i.v., 5-fluorouracil 600 mg/m2 i.v. every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL.Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

Purpose: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. Experimental Design: Patients with ≥4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m2, respectively, ×6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m2) alternating with docetaxel (35 mg/m2) ×18. Results: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26–63 years), median number of positive nodes was 9 (range, 4–32), and median tumor size was 2.5 cm (range, 0.6–11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. Conclusion: FEC ×6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.

Purpose: Preclinical studies demonstrate a link between overexpression of HER-2/neu and cyclooxygenase-2 (COX-2) activity. To explore the possibility that COX-2 is a therapeutic target, we conducted a phase II study of celecoxib, a selective COX-2 inhibitor, and trastuzumab in patients with HER-2/neu-overexpressing metastatic breast cancer that had progressed while receiving trastuzumab. Experimental Design: Eligible patients had bi-dimensionally measurable or evaluable HER-2/neu-overexpressing metastatic breast cancer. HER-2/neu overexpression, defined as 2+ or 3+ by the HercepTest, was required. Patients had to have progressed despite prior trastuzumab-based therapy. Treatment consisted of celecoxib (400 mg twice daily) and trastuzumab. Results: Twelve patients were enrolled (42% status post 1 regimen for metastatic disease 58% status post > 2 prior regimens (range of 2–6). Eleven patients were evaluable. There were no responses. Median duration of treatment was 9 weeks. One patient had stable disease at 3 months but progressed at 6 months. A second patient stopped treatment at 3 months because of unresolved grade 2 rash, felt to be related to celecoxib. Toxicities were generally grade 1 or 2. One patient (8%) experienced grade 3 toxicity (abdominal pain). Conclusions: Celecoxib combined with trastuzumab is well tolerated. However, this combination in patients with HER2/neu-overexpressing, trastuzumab-refractory disease, was not active.

Although conventional doxorubicin is associated with favorable clinical outcomes in patients with a variety of tumor types, it long has been associated with the risk of development of cardiotoxicity. Therefore, researchers have focused their efforts on the development of new formulations to improve efficacy while minimizing associated toxicities. The most successful strategy reported to date has been liposomal encapsulation, which alters the pharmacokinetics of the drug, with the goal of maintaining efficacy and improving the therapeutic index. The cardiac profiles of three liposomal anthracyclines, liposomal daunorubicin, nonpegylated liposomal doxorubicin, and pegylated liposomal doxorubicin, were reviewed. More studies will be needed to determine the cardiac safety of liposomal daunorubicin. Although nonpegylated liposomal doxorubicin demonstrated more favorable cardiac safety compared with conventional doxorubicin, its cardiac safety appeared to be mitigated when high bolus doses were administered. Of the liposomal formulations, the strongest evidence of cardiac safety was observed with pegylated liposomal doxorubicin. Compared with conventional doxorubicin, pegylated liposomal doxorubicin was associated with a significantly lower risk of development of cardiac events (P0.001). Moreover, the risk of cardiotoxicity was not increased in patients who were treated with pegylated liposomal doxorubicin at cumulative doses450 mg/m(2) or in patients at increased risk for cardiotoxicity, such as those with prior adjuvant doxorubicin use. Liposomal doxorubicin formulations provided a favorable advantage over conventional doxorubicin in terms of cardiac safety. Recent evidence also suggests that the improved cardiac safety of liposomal doxorubicin formulations is reflected by their successful use in combination with trastuzumab and other chemotherapy agents.

Adjuvant chemotherapy is an established standard of care for most patients diagnosed with early breast cancer, and its popularity is gaining worldwide. The systemic armamentarium presently includes anthracyclines and taxanes, alkylating agents, fluoropyrimidines, and antimetabolites; in the future, it may include platinum compounds and the recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, as well. Anti-estrogens continue to play an important role in the adjuvant setting for hormone-sensitive primary breast cancer. Adjuvant radiotherapy is common in the setting of early-stage disease as breast conservation gains popularity, and radiation is often employed in the postmastectomy setting as well. As treatment guidelines continue to evolve with newer data, the relative benefits of treatment in many situations continues to grow. Refinement of the optimal identification of patients at risk for local and distant relapse is a continued challenge facing the treating clinician. Parallel to this effort, and of equal importance, is the ability to shield patients that will gain little, if any, benefit from treatment and to identify those who may be at greater risk to suffer from potential toxicities. Until these factors are better defined, the recognition by clinicians of long-term side effects associated with adjuvant therapy is obligatory. Acute toxicities from treatment are often reversible, but late onset adverse effects of therapy can increase morbidity and mortality in long-term survivors, and continue to be of concern. One of the most serious side effects of adjuvant therapy of early breast cancer is cardiac toxicity. This article will provide an overview of the cardiac effects of adjuvant therapy in the treatment of early breast cancer.

6601 Background: With an increasing complexity and number of endocrine, molecularly-targeted and immunotherapeutic clinical trial and standard-of-care therapies available for patients with metastat...

606 Background: Pertuzumab is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab, disrupting HER2 dimerization and signaling. Pertuzumab improves progression-free survival (PFS) and overall survival when combined with docetaxel/trastuzumab. We report results of a phase II study to evaluate the efficacy and safety of pertuzumab, trastuzumab and weekly paclitaxel. Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) were eligible. Rx is weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → 420mg). The primary endpoint is PFS at 6 months (mo). Evaluable pts are those who started study Rx and are assessed at 6 mo for PFS, including pts who progressed prior to 6mo. Secondary endpoints include response, safety (including cardiac events), and tolerability. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 1-18-13, 53 pts are enrolled; 36 are evaluable at 6 mo. At 6 mo, 29/36 pts (81%) are progression-free (4 CR, 14 PR and 11 SD); 7 pts progressed. The 6 mo PFS results for all patients will be updated. Median LVEF is 64% at baseline (range 50-72%), 63% at 3 mo (range 50-73%), and 62% at 6 mo (range 49-69%). There are no cardiac events to date. Of the 36 pts, grade 3/4 toxicities include fatigue (3 pts, 8%), peripheral neuropathy (2 pts, 6%), sepsis (1pt, 3%), cellulitis (1pt, 3%), neutropenia (1pt, 3%), and skin ulceration (1pt, 3%). There are no grade 3 diarrhea or febrile neutropenic events in the evaluable pts to date. Conclusions: The preliminary 6-month PFS is 81% (95% CI 67-91%) in evaluable patients. The study is closing to accrual. Treatment is ongoing, with few grade 3/4 toxicities and no signal of increased cardiac toxicity to date. This phase II study demonstrates efficacy and safety for pertuzumab with trastuzumab and weekly paclitaxel in HER2+ MBC. Clinical trial information: NCT01276041.

9515 Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(grade 3 non-hematologic toxicity vs. 14% with better function(p=0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.

134 Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ MBC prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel (T) with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0-1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 5-1-12, 33 of the planned 69 pts were enrolled; 16 were evaluable at 6 mo. Of the 16 pts, G 3/4 toxicities included sepsis (1pt, 6%), cholecystitis (1pt, 6%), fatigue (1pt, 6%), skin ulceration (1pt, 6%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 6%). G 1/2 toxicities included alopecia (16 pts, 100%), fatigue (15 pts, 94%), ALT/AST elevation (14 pts, 88%), neuropathy (14 pts, 88%), diarrhea (12 pts, 75%), rash (9 pts, 56%), nail changes (8 pts, 50%), nausea (7 pts, 44%), mucositis (7 pts, 44%), and dry skin (6 pts, 38%). Median LVEF was 63% at baseline, 60% at 3 mo and 58% at 6 mo. There were no cardiac events. At 6 mo, 12/16 pts (75%) were progression-free (2 CR, 7 PR and 3 SD); 4 pts progressed. Conclusions: Our single-center phase II study continues to accrue, with no significant diarrhea or signal of increased cardiac toxicity to date. If the estimate of activity is similar to results with docetaxel in CLEOPATRA, this will provide support for THP as an alternative option in this setting.

10514 Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE2. To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P

TPS122 Background: Patients with ER-/PR- MBC do not benefit from endocrine therapy. Doane et al. described a subgroup of ER-/PR- breast cancers with a gene expression profile similar to ER+ tumors but characterized by AR expression (Oncogene 2006). Farmer et al. identified an AR+ER-, non-basal-like group of breast tumors in a separate data set and termed them molecular apocrine breast cancer (Oncogene 2005). In vitro studies with the MDA-MB-453 cell-line, which is representative of this subtype, demonstrated AR-dependent growth and supported AR inhibition as a potential therapeutic approach for these patients (Doane et al., Oncogene 2006). We are testing the efficacy of the AR antagonist, bicalutamide (B) for patients with AR+/ER-/PR- MBC in a multicenter Phase II trial. Clinical trial registry #: NCT00468715. Methods: Patients with ER-/PR- (immunohistochemistry (IHC)

BackgroundCapecitabine (C) administered for 14 days followed by a 7 day rest (14—7) in combination with lapatinib (L) improved TTP in patients with HER2(+) metastatic breast cancer (MBC) that progressed following trastuzumab (T). We applied mathematical methods to C dosing which predicted 7 days of treatment (Tx) followed by 7 days of rest (7—7) to be optimal. In animal models, C(7—7) was better tolerated than C(14—7) at higher doses and led to improved survival. A phase I study in patients (pts) with MBC concluded the MTD of C(7—7) is 2,000mg BID. To optimize the combination of C+L, we are testing C(7—7) + L.MethodsEligible pts have measurable, HER2(+) MBC with progression following trastuzumab. HER2(+)=3+ or FISH-amplified. Pts have normal LVEF by MUGA, ECOG performance status (PS) ≤2 and normal organ function. Prior therapy is limited to 6 months and PFS. Using a Simon optimal 2-stage design, with alpha 10% and power 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the 1st stage. If >2 patients respond, 29 additional pts will be enrolled. If >7/40 pts respond, then C(7—7) + L will be considered worthy of further study.ResultsAs of 5/28/09, 12 pts are enrolled; 6 are evaluable for response. Median (med) age 61 years (41-71), med ECOG PS 0 (0-2), ER/PR(+) 5, HER2(+) 12. Sites of MBC: Viscera 5, Brain 2. Med LVEF 64% (51-71%). Prior Tx: Adjuvant: CRx (7), hormone Tx (3), T (4); MBC: CRx (6), hormone Tx (4), T (8). After a med of 3 cycles (1-8), 6 pts are evaluable for response: CR 0, PR 1, SD>6mo 2, SD10% of pts includes: hand-foot syndrome (Gr 3: 8%, Gr 2: 17%) and diarrhea (Gr 2: 17%). There were no declines in LVEF.ConclusionCapecitabine (7—7) plus lapatinib appears well-tolerated and demonstrates activity in pts with HER2(+) MBC that has progressed following trastuzumab based therapy. Additional efficacy and safety data is expected prior to this meeting. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5113.

1131 Background: Capecitabine (C) is active in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal schedule for C to be 7d followed by a 7d rest (7 - 7) (Norton et al, Amer Assn Can Res. 2005). The MTD of C(7 - 7) is 2,000mg BID (Traina et al, J Clin Oncol. April 2008). Lapatinib (L) improves time to progression when added to C(14 - 7) in patients (pts) with HER-2-positive (+) metastatic breast cancer (MBC) that progressed after trastuzumab (T). To optimize this effective combination, we are testing C(7 - 7) + L in a phase II trial. Methods: Eligible pts have measurable, HER-2(+) MBC that has progressed after T. HER-2(+)=IHC 3+ or FISH>2. Pts have normal LVEF by MUGA, ECOG performance status (PS) 6 months, PFS. Using a Simon optimal 2-stage design, with alpha = 10%, power = 90% to discriminate between RR 10% and 25%, 21 pts will be accrued to the first stage. If >2 pts respond, 29 additional pts will be enrolled. If >7/ 40 pts respond, then C(7 - 7) + L will be considered worthy of further study. Results: As of January 5, 2008, 6 pts are enrolled and evaluable. Median (med) age 64 yrs (42–71), med ECOG PS 1 (0–1), ER/PR(+) 3, HER-2(+) 6, sites of MBC: bone (2), viscera (4), soft tissue (5). Med baseline LVEF 62% (51–68%). Prior tx: Adjuvant: CRx (5), hormone tx (3), T (3); MBC: CRx (2), hormone tx (1), T (3). After a med of 3 cycles (1–4), there were no grade 3, 4, or 5 events. Tx-related toxicity is: Gr 2 fatigue (1); Gr 1 AST (4), diarrhea (3), ALT (2), vomiting (1), hand-foot (1), fatigue (1). No withdrawls due to reduced LVEF. Two pts evaluable for response: PR = 1, SD [Table: see text]

Abstract #6121 Background Capecitabine (Xeloda®,C) has activity in breast cancer when dosed for 14 days (d) followed by a 7d rest (14 - 7). Using mathematical methods, we predict the optimal dosing schedule of C to be 7d followed by a 7d rest (7 - 7) (Norton et al, AACR 2005). Xenograft studies show this schedule improves tolerability and survival. The MTD of C(7 - 7) is higher than that for conventional dosing (Traina et al, JCO 2008). Bevacizumab (B), an anti-VEGF antibody, improves response when added to capecitabine in pts previously treated for metastatic disease (Miller et al, JCO) and improves PFS when added to taxanes in the 1st-line treatment of advanced disease (Miller et al, NEJM 2007; Miles ASCO 2008). B + conventionally-dosed capecitabine modestly increased TTP when used as 1st-line therapy (Sledge, ASCO 2007). This study tests C(7 - 7) with bevacizumab (B) in a Phase II trial. Methods Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) ≤2 and normal organ function. Any number of prior chemotherapy (CRx) regimens is permitted. Pts with prior fluoropyrimidine or bevacizumab are excluded. Therapy (tx) consists of C (2,000mg BID, 7 - 7) and B (10mg/kg IV q2 weeks(wk)). Pts are evaluated for toxicity q2wk and for response q12wk. Cycle length: 4 wks. Primary endpoint: response rate (RR). Secondary endpoints: clinical benefit, TTP, PFS, toxicity. Using a mini-max, two-stage design, up to 40 patients will be enrolled. If >6/40 pts respond, then C(7 - 7) + B will be considered worthy of further study. If >11 pts experience Grade 3/4 capecitabine-related toxicity the trial will be stopped. Results Twenty-seven pts are enrolled. Median (med) age 57 yrs (29-71), med ECOG performance status 0 (0-2), ER/PR(+) 13, HER2(+) 1, sites of MBC: bone(13), liver/lung(13), soft tissue(12). Prior tx: Adjuvant: CRx (20), hormone tx (14); MBC: CRx (2), hormone tx (16). 27 pts are evaluable for toxicity. After a med of 6 (1-12) cycles: Twenty-three pts evaluable for response: PR=7 (confirmed=5), stable disease (SD) >6 mo =6, SD Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6121.

507 Background: Older women with BC are underrepresented in clinical trials. Scant data exist on the effects of adjuvant chemotherapy (CRx) in these patients (pts). CALGB/CTSU 49907 was designed to compare the efficacy of capecitabine (X) with standard treatment (S) in BC pts ≥ 65 yrs old. Methods: Pts were randomized to X or S (CMF or AC per physician choice). Eligibility: Stage T1–4, N0–3, M0; PS 0–2, ≤ 84 days from surgery; adequate organ function. Regimens (all doses per M2): CMF (C, 100 mg d1–14 oral; M 40 mg d1,8; FU 600 mg d1,8) q4wk×6 cycles; AC (A 60 mg; C 600 mg) q3wk×4; X (2,000 d1–14) q3wk×6. Endocrine therapy was recommended after completion of CRx for hormone receptor positive (HR+) pts. A Bayesian design addressed equivalence of X to S; total sample size planned 600–1,800 pts with serial monitoring. The primary endpoint was relapse-free survival (RFS) defined as locoregional or distant relapse or death. We calculate Bayesian measures, including the probability of inferiority of X (that the ...

1101 Background: Capecitabine has activity in breast cancer and is usually dosed for 14 days (d) followed by a 7d rest (14 - 7). We described a mathematical method which predicts the optimal dosing...

1086 Background: BCBM are increasing in frequency possibly due to improved systemic therapies and few effective agents that cross the blood-brain barrier (BBB). Patupilone is a novel epothilone tha...

1049 Background: Mathematical methods applied to xenograft breast cancer models have determined that the maximum impact of C therapy occurs after ∼7 days (7d) of treatment (Norton AACR 2005). The model predicts that doses of C beyond 7d will contribute to toxicity without additional antitumor benefit. The tolerability and anti-tumor activity of C 7d on/7d off (7/7) in female nude mice bearing KPL-4 breast cancer xenografts has been established (SABCS 2006). We now report preclinical models of C7/7 with targeted therapies. Methods: We evaluated the tumor growth inhibition (TGI%) and increase in life span (ILS%) of C7/7 and B with or without T in female nude mice bearing KPL-4, HER2+ breast cancer xenografts. C at maximum tolerated dose (MTD) and ½MTD were tested in combination with conventional doses of the antibodies. Results: C7/7 at MTD is well tolerated in combination with conventional dose B + T. No toxicity was observed at any dose level. The addition of B ± T to C7/7 monotherapy significantly improves TGI%. Survival is significantly prolonged for the combination of C7/7 MTD with B ± T. Comparative results for C7/7 at MTD and ½ MTD are shown in the Table . Additional comparative data will be shown at the meeting. Assessment of ILS% is ongoing for the triplet C7/7 + B + T but has exceeded 463% and >152 days. Conclusions: The improvement in response and survival shown here supports the study of combination C7/7 with B and T. Combinations with B and anti-HER2 therapy will be tested in the clinical, Phase II program at MSKCC. [Table: see text] [Table: see text]

1045 Background: We have previously described a mathematical method to optimize chemotherapy dose and schedule (Norton et al, AACR 2005). Capecitabine (C) has activity in breast cancer when conventionally dosed for 14 days (d) q3 weeks (14/7). However, the predicted optimal dosing schedule for C using our model is 7d followed by a 7d rest (biweekly, 7/7). We tested this hypothesis in a Phase I/II study described below. Methods: Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) =2 and normal organ function. There is no limit to number of prior chemotherapy (CRx) regimens. Pts with prior fluoropyrimidine for MBC are excluded. HER2+ pts must not be candidates for trastuzumab. C is given in divided daily doses for 7d followed by a 7d rest. A standard “3+3” dose escalation scheme employs flat dosing which begins at 1,500mg BID and increases by 500mg/dose level. Primary endpoint is the maximum tolerated dose (MTD), defined as the highest dose for which the incidence of dose-limiting toxicity (DLT) is [Table: see text] No significant financial relationships to disclose.

633 Background: We previously demonstrated that weekly T + HL after anthracycline based therapy was not feasible due to high incidence of grade (G) 3 diarrhea, which led to modification of the ALTT...

Abstract #2108 Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety. Methods: Enrolled pts had HER2 (+) BC; LVEF > 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) > 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is < 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or < G 3 toxicity (unacceptable). Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline. Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (> 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.

This longitudinal prospective study describes the older breast cancer patient's perception of the cognitive impact of adjuvant chemotherapy.A total of 50 patientsor =age 65 with stage I to III breast cancer enrolled in this IRB-approved prospective study. Of the 50, 3 refused postchemotherapy testing and 2 had a cerebrovascular accident (CVA) during therapy, leaving 45 evaluable patients. The Squire Memory Self-Rating Questionnaire, given before and 6 months after chemotherapy, measured patients' perceptions of the ability to learn new information, of working memory, and of remote learning capabilities.Mean age was 70 years (range 65-84). Breast cancer stages were: I (33%), II (64%), III (2%). A 51% (23/45) of study participants perceived a decline in memory from before to 6 months after completion of chemotherapy. Patients who perceived a poorer memory than average before chemotherapy were more likely to report further memory deterioration after chemotherapy (19/30, 63%) than patients who perceived that their memory was average or better than average prior to chemotherapy (4/15, 27%). The memory domain most likely to be perceived as affected was the ability to learn new information (22/45, 49%) compared to remote memory (9/45, 20%) or working memory (13/45, 29%) capabilities.Approximately half of these older women perceived a decline in cognitive function from before to 6 months after chemotherapy. This perceived decline in cognitive function was most pronounced in patients with preexisting memory complaints. Further prospective study is needed to confirm these observations, correlate perceived memory changes with objective findings, and identify subgroups at special risk.

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.