Chau Dang

Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: A pilot prospective longitudinal study

OBJECTIVES: To report on the longitudinal cognitive functioning of older women receiving adjuvant chemotherapy for breast cancer.

A prospective, longitudinal study of the functional status and quality of life of older patients with breast cancer receiving adjuvant chemotherapy.

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).

Phase II Trial of Saracatinib (AZD0530), an Oral SRC-inhibitor for the Treatment of Patients with Hormone Receptor-negative Metastatic Breast Cancer

BACKGROUNDnSRC 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).nnnPATIENTS AND METHODSnPatients 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.nnnRESULTSnNine 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.nnnCONCLUSIONSnThese 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.

Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient’s perspective

SummaryPurposeThis longitudinal prospective study describes the older breast cancer patient’s perception of the cognitive impact of adjuvant chemotherapy.MethodsA total of 50 patients ≥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 6xa0months after chemotherapy, measured patients’ perceptions of the ability to learn new information, of working memory, and of remote learning capabilities.ResultsMean age was 70xa0years (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 6xa0months 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.ConclusionApproximately half of these older women perceived a decline in cognitive function from before to 6xa0months 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.

The Safety of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Trastuzumab in HER-2/neu Overexpressed/Amplified Breast Cancer

PURPOSEnDose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzumab (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival.nnnMETHODSnPatients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of >or= 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m(2)) x 4 followed by P (175 mg/m(2)) x 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T x1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18.nnnRESULTSnFrom January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced congestive heart failure (CHF). There were no cardiac deaths.nnnCONCLUSIONnDose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer

PURPOSEnPreclinical 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).nnnMETHODSnPatients 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.nnnRESULTSnForty-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 >or= 24 weeks was noted in 67%. Median PFS was 17.1 months.nnnCONCLUSIONnCombination 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).

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PURPOSEnThe 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.nnnPATIENTS AND METHODSnPatients 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/m(2) 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.nnnRESULTSnFrom 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.nnnCONCLUSIONnPaclitaxel 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.

Dose-Dense Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With Trastuzumab and Lapatinib in HER2/neu–Overexpressed/Amplified Breast Cancer Is Not Feasible Because of Excessive Diarrhea

PURPOSEnDose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).nnnPATIENTS AND METHODSnPatients with stages I to III, HER2-positive breast cancer and left ventricular ejection fraction (LVEF) of > or = 50% were enrolled. Treatment consisted of AC (60 mg/m(2) and 600 mg/m(2)) for 4 cycles every 2 weeks (with pegfilgrastim 6 mg on day 2) followed by paclitaxel (80 mg/m(2)) for 12 doses weekly plus trastuzumab and lapatinib. Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel) and lapatinib (1,000 mg daily) were given for 1 year. The primary end points were feasibility defined as > or = 80% patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of < or = 4%.nnnRESULTSnFrom March 2007 to April 2008, we enrolled 95 patients. Median age was 46 years (range, 28 to 73 years). At a median follow-up of 22 months, 92 were evaluable. Of the 92 patients, 41 patients (45%) withdrew for PTL-specific toxicities. Overall, 40 (43%) of 92 patients had lapatinib dose reductions, and 27 (29%) of 92 patients had grade 3 diarrhea. Three patients (3%) had congestive heart failure; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL.nnnCONCLUSIONnDose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction, mostly caused by unacceptable grade 3 diarrhea. Lapatinib (1,000 mg/d) was not feasible combined with weekly PT.

A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer

BACKGROUNDnSRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study.nnnPATIENTS AND METHODSnPatients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m(2) was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3u2009+u20093 dose-escalation scheme.nnnRESULTSnFifteen patients enrolled (median age 54 years, range 35-74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70-120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease.nnnCONCLUSIONnIn combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.

A Feasibility Study of Bevacizumab plus Dose-Dense Doxorubicin-Cyclophosphamide (AC) Followed by Nanoparticle Albumin-Bound Paclitaxel in Early-Stage Breast Cancer

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.