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Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.Experimental Design: We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28).Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.

CCR Translation for This Article from HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab

AimsThe most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer.Methods and resultsUsing a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens—concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20–50 min at 55%–100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, −0.88 mL O2·kg−1·min−1; 95% confidence interval (CI): −3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg−1·min−1, P < 0.001).ConclusionThere was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.

Dalam dunia pendidikan keperawatan, pembelajaran klinik merupakan salah satu upaya untuk membantu mahasiswa dalam proses perubahan menjadi perawat yang profesional. Mahasiswa D3 Keperawatan merupakan perawat vokasi dengan pembelajaran teori 40 % dan pembelajaran klinik 60 %. Tujuan penelitian untuk mengetahui tingkat kepuasan mahasiswa tingkat III Program Studi Diploma Tiga Keperawatan terhadap lingkungan pembelajaran klinik di Rumah Sakit. Penelitian ini merupakan jenis penelitian deskriptif kuantitatif pendekatan survey dengan teknik sampling menggunakan total sampling dengan jumlah 84 responden. Instrumen penelitian menggunakan instrumen baku (Clinical Learning Environment, Supervision And Nurse Teacher – Cles+T) yang dialih bahasakan oleh Puji Priyanti & Naharian(2016), uji validitas instrumen mengunakan PCA (Principal Component Analysis)dengan N=46, uji reliabiliti dengan Cronbach alpha, Hasil eigenvalue dan explanation percentage diperoleh 67%, maka dengan demikian instrumen tersebut dinyatakan valid dan reliable. Berdasarkan hasil penelitian diperoleh bahwa mahasiswa Tingkat III Program Studi Diploma Tiga Keperawatan, sebagian besar menyatakan puas terhadap lingkungan pembelajaran klinik sebanyak 81 responden dengan presentase 96.4% dan sebagian kecil tidak puas sebanyak 3 responden dengan presentase 3,6%. Dengan demikian diharapkan institusi mengadakan evaluasi dan perbaikan secara terus menerus sehingga kepuasan pembelajaran klinik tercapai.

Important counter measures to combat an infectious disease pandemic include vaccination, antiviral therapy, and immunomodulation therapy. Vaccinations are disease specific and moreover strain specific, so the protection provided is also specific and limited. Antiviral therapies are costly and require bulk production of drugs, hence globally there is an increased interest toward low-risk, cost-effective complementary alternative therapies, such as Yoga and Ayurveda to tackle the infectious pandemic, coronavirus disease 2019 (COVID-19). There is clinical evidence available on the potential complementary role of yogic practices in the management of noncommunicable and communicable diseases. Various online databases were searched for articles published between 2000 and 2020. Databases explored were Medline, EMBASE, Indian Citation Index, PsycINFO, Index Medicus for South-East Asia Region, and Google Scholar. All search results were screened, and articles related to keywords such as COVID-19, yoga therapy, and Sudarshan Kriya Yoga (SKY) were selected for data extraction. Quality of the studies included was evaluated on the basis of the construct validity, content validity, relevance, bias, credibility relating to information, and data sources. SKY is a unique yogic practice that includes specific sequential breathing techniques. It balances the autonomic nervous system and thus can alleviate anxiety, routine stress, depression, stress-related medical disorders, and posttraumatic stress. It potentiates natural host immune defenses that are essential to tackle a plethora of microbial infections. This narrative review article provides an overview of potential therapeutic benefits that SKY can offer to the population at large during this COVID-19 pandemic.

Background Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial. Patients and Methods Patients had received ≤ 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit. Results From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL. Conclusion This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned.

Background Genomic profiling is increasingly incorporated into oncology research and the clinical care of cancer patients. We sought to determine physician perception and use of enterprise-scale clinical sequencing at our center, including whether testing changed management and the reasoning behind this decision-making. Patients and methods All physicians who consented patients to MSK-IMPACT, a next-generation hybridization capture assay, in tumor types where molecular profiling is not routinely performed were asked to complete a questionnaire for each patient. Physician determination of genomic ‘actionability’ was compared to an expertly curated knowledgebase of somatic variants. Reported management decisions were compared to chart review. Results Responses were received from 146 physicians pertaining to 1932 patients diagnosed with 1 of 49 cancer types. Physicians indicated that sequencing altered management in 21% (331/1593) of patients in need of a treatment change. Among those in whom treatment was not altered, physicians indicated the presence of an actionable alteration in 55% (805/1474), however, only 45% (362/805) of these cases had a genomic variant annotated as actionable by expert curators. Further evaluation of these patients revealed that 66% (291/443) had a variant in a gene associated with biologic but not clinical evidence of actionability or a variant of unknown significance in a gene with at least one known actionable alteration. Of the cases annotated as actionable by experts, physicians identified an actionable alteration in 81% (362/445). In total, 13% (245/1932) of patients were enrolled to a genomically matched trial. Conclusion Although physician and expert assessment differed, clinicians demonstrate substantial awareness of the genes associated with potential actionability and report using this knowledge to inform management in one in five patients. Clinical Trial number NCT01775072.

Modern field-programmable gate arrays offer dynamic partial reconfiguration (DPR) capabilities, a characteristic that opens new scheduling opportunities for real-time applications running on heterogeneous platforms. To evaluate when it is really useful to exploit a DPR, in this letter, we present the characterization of its reconfiguration cost in terms of time and a definition of the “DPR Profitability” concept targeting real-time systems. To obtain such results, the components involved in a DPR process have been identified and an innovative approach to calculate the DPR time and its worst-case bound is provided. We validate our approach on a real DPR-compliant platform, showing that our proposal is general enough to be applied to modern DPR-compliant platforms.

e15016 Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4. Capecitabine (X) at optimal dose of 7 days on and 7 days off schedule (7/7) is well-tolerated with low rates of ≥ grade (G3) diarrhea. Methods: We conducted phase Ib/II study of N with X (7/7) with loperamide and colestipol prophylaxis in patients (pts) with pretreated HER2+ MBC (NCT03377387). Eligible pts had normal left ventricular ejection fraction (≥ 50%), any and < 4 prior chemotherapy-based treatments in phase Ib and II, respectively. Primary endpoint of phase Ib is maximum tolerated dose (MTD) and phase II is response rate. Secondary endpoints are safety, tolerability, and progression-free survival. Exploratory endpoint is to quantify cell-free DNA (cfDNA), correlating with response. Phase Ib follows traditional 3+3 design with 4 dose levels. In phase II, if > 3/9 respond, study is expanded to 24. If > 10/24 respond, study is deemed successful. Results: As of 2-4-2021, 10 pts were enrolled in phase Ib. 4 pts were treated at dose level 1 (X at 1500 mg BID at 7/7 and N at 240 mg daily); 2/4 pts experienced with G3 diarrhea during cycle 1. Six pts were treated at dose level -1 (X at 1000 mg BID 7/7 and N at 240 mg daily); 1 (17%) developed G3 diarrhea. The MTD is X at 1000 mg BID 7/7 and N at 240 mg daily. Twenty-two of 24 pts have been enrolled in phase II. Of 22 pts, data show 6 with partial response, 8 with stable disease, 3 with progressive disease, and 5 have not been assessed radiographically. Overall, 6/22 (27.3%) and 1/22 (4.5%) had all G and G3 diarrhea, respectively. Other significant toxicities at MTD included G2 hand foot syndrome (n = 1, 4.5%), G1 fatigue (n = 1, 4.5%) and G1 nausea (n = 4, 18%). Conclusions: The MTD is X at 1000 mg BID at 7/7 and N at 240 mg daily. This combination is safe and well tolerated with G3 diarrhea rate of 4.5%, which is significantly lower than the X 14/7 schedule in NALA study. The phase II portion of the study is near completion and updated result will be presented. Analysis of cfDNA, to correlate with response for phase II portion, is ongoing. Clinical trial information: NCT03377387.

1017 Background: Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR) +, estrogen receptor (ER)/progesterone receptor (PR)- breast cancer (BC). The functional role of AR was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy. TBCRC011 established the safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with AR+/ER/PR- metastatic BC (MBC) with a median progression free survival (PFS) of 12 weeks (wks) (95% CI, 11–22 wks). In preclinical data, palbociclib (P) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 BC cells. It has been shown that AR+ triple negative BC (TNBC) expresses a luminal profile and has intact Rb protein, the target of P activity. We conducted this Phase I/II trial of the AR inhibitor B in combination with the CDK4/6 inhibitor P in pts with AR+/ER/PR/HER2- BC (NCT02605486) to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in pts with androgen-dependent BC. Methods: Postmenopausal pts with AR+ TN MBC defined as IHC ≥ 1% nuclear staining (DAKO, Clone AR441 (5/2016-11/2016) then Ventana AR SP107 (11/2016-6/2018), ECOG ≤2, measurable/non-measurable disease were eligible for enrollment. Any number of prior regimens was permitted. Pts received B 150 mg daily and P 125 mg daily 3 wks on 1 wk off. Pts were evaluated for toxicity every 2-4 wks and for response every 8-12 wks. Primary endpoint: 6 month (mo) PFS. Secondary endpoints: clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC. A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If ≥ 11/33 pts were PF at 6 mo then B+P would warrant further study. Results: As of 1.1.20 33 pts were enrolled on study with median (med) age 67 (42-79), performance status 0 (0-1). Number of pts with visceral metastases: 20, measurable disease: 22. AR% 1-9: 3, 10-50: 6; 51-100: 24. Med prior lines for MBC: 3 (0-9). Best response: (31 evaluable pts): 11 pts PF at 6mo: 10 SD > 6mo, 1 PR. Med wks on study: 14 (2-101). Toxicity > 10% grade >3 related: Number of pts with leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3. One pt with febrile neutropenia. One death due to disease progression within 30 days off study. Conclusions: In this selected subset of pts with AR+ TN MBC, this study met its prespecified endpoint with 11 pts PF at 6 mo on B 150 mg + P 125 mg. B+P has been well tolerated with no unexpected toxicity observed. Clinical trial information: NCT02605486 .

Introduction: Targeted therapies in HER2+ MBC significantly improve outcomes but efficacy is limited by therapeutic resistance. HSP90 is a molecular chaperone involved in the stability and function of multiple signaling onco-proteins. HER2 is an acutely sensitive HSP90 client and HSP90 inhibition can overcome trastuzumab resistance. Our group reported objective responses with 17-AAG plus trastuzumab in HER2+ MBC. Ganetespib, a synthetic, second generation HSP90 inhibitor has increased potency and tolerability compared with earlier agents. We reported anti-tumor activity in metastatic HER2+ and triple negative breast cancer with single agent ganetespib. Preclinically, HSP90 inhibition has synergistic anti-tumor activity with taxanes and trastuzumab. This study will define the MTD and RP2D of ganetespib plus paclitaxel and trastuzumab in HER2+ MBC. Methods: In this 3+3 phase I dose escalation study, patients with trastuzumab-resistant HER2+ MBC receive weekly trastuzumab and paclitaxel (80mg/m2) with ganetespib on day 1, 8, 15 of a 28 day cycle. HR+ positive patients are required to have at least one prior line of endocrine therapy. DLT of ganetespib monotherapy is diarrhea and therefore patients receive prophylactic anti-motility agents. Based on prior experience with ganetespib plus docetaxel in NSCLC, only 3 dose levels of ganetespib were explored: 100mg/m2, 150mg/m2 and a 3rd cohort of 125mg/m2, if needed. Secondary endpoints include evaluation of effects of ganetespib on the pharmacokinetics (PK) of paclitaxel and preliminary efficacy assessment. Results: The dosing cohorts (100 mg/m2 (n=3) and 150 mg/m2 (n=6)) have been completed without any DLTs. Median age was 46 years (range 29-65), median prior lines of chemotherapy and anti-HER2 therapy were 3 (range 2-6) and 3 (range 2-4) respectively, including prior pertuzumab in 9/9 and T-DM1 in 8/9 patients. There were no grade 3/4 adverse events (AEs) related to ganetespib. Most common AEs related to ganetespib were diarrhea, fatigue, anemia and rash. Paclitaxel PK data available from 6/9 patients are not appreciably different from those reported in literature. Overall response rate was 25% (2/8 had PR in 150 mg/m2 cohort; 1 patient was not evaluable), SD in 63% (5/8), and clinical benefit rate (CR+PR+SD>24 weeks) was 50% (4/8). 3 patients remain on study. Conclusion: The RP2D of ganetespib is 150mg/m2 in combination with paclitaxel and trastuzumab. The combination was safe and well tolerated. Updated PFS and PK data will be presented. Despite prior taxanes, pertuzumab and T-DM1, clinical activity of this triplet regimen in this heavily pre-treated cohort is very promising and together with our prior experience with 17-AAG plus trastuzumab and single agent ganetespib warrants further study in HER2+ MBC. A phase 2 trial is being planned in trastuzumab-refractory HER2+ MBC who have progressed on prior pertuzumab and T-DM1. Additionally, the protocol is amended to assess the safety of ganetespib in combination with paclitaxel, trastuzumab and pertuzumab in the first-line setting. Citation Format: Jhaveri K, Teplinsky E, Chandarlapaty S, Solit D, Cadoo K, Speyer J, D'Andrea G, Adams S, Patil S, Haque S, Friedman K, Neville D, Esteva F, Hudis C, Modi S. A phase I trial of ganetespib (heat shock protein 90 inhibitor) in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 positive (HER2+) metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-21.

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 Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. Patients and Methods Patients were treated with single agent ganetespib at 200 mg/m2 once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. Results Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). Conclusion The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.

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.

Introduction: The role of dasatinib, an oral SRC inhibitor is being explored for the treatment of metastatic breast cancer. In a phase I study, we previously established that the combination of dasatinib and weekly paclitaxel was feasible. The activity of this combination is currently being explored in an ongoing phase II trial. Since Src kinase has a major role in osteoclast function and dasatinib has established anabolic and anti-resorptive effects in bone in vitro, we hypothesized that patients receiving this combination would have good control of osseous metastases and primarily develop progression of disease in sites other than bone. Patients and methods: Patients were included in this analysis if they participated in the phase I or II metastatic breast cancer studies and received dasatinib at or above the recommended phase II dose of 120mg with paclitaxel (80mg/m2 day 1 and 8 of each 21day cycle). Patients who discontinued therapy for reasons other than progression were excluded. Per protocol, patients were required to discontinue bisphosphonates or other bone modulating agents for the first 8 weeks of study due to the potential for hypocalcaemia. Thereafter, they were permitted to receive these agents at the discretion of their treating physician. Patients provided serum samples for correlative studies. Assessment of N-telopeptide of type 1 collagen (NTX), a product of mature bone collagen that reflects bone specific resorption, is planned. Results: The median age of the 24 patients who met criteria for analysis was 50y (37 - 66y). Of these, 15 (63%) had ER+ disease, and 24 (100%) were negative for human epidermal growth factor receptor (HER2). At study entry, 17 (71%) patients had bone involvement. Following the initial eight week moratorium, 7 (29%) patients received a bisphosphonate or rank ligand inhibitor during treatment with dasatinib + paclitaxel. Patients received a median 2 months (range 1-23) of dasatinib + paclitaxel therapy. To date, 3 (13%) continue on therapy, and 21 (88%) have had progression of disease. Among patients who progressed, 18 (86%) have progressed in visceral sites and only 3 (14%) progressed in bone. Analyses of serum NTX levels are ongoing and will be compared by site of progression. Conclusion: The potential role of serum NTX as a predictive biomarker of benefit from dasatinib and paclitaxel is being explored and updated results will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-12.

Background Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. Methods In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. Results Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55). Conclusion The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. Trial registration ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

In premenopausal women with hormone dependent breast cancers, ovarian suppression is an important part of treatment, and is often achieved with a bilateral salpingo-oophorectomy (BSO). However, this procedure can lead to ovarian remnant syndrome (ORS), a rare condition where the adnexal tissue is not completely removed and can produce estrogen. We describe a case of ORS in a patient with estrogen receptor positive (ER+) breast cancer who had progression of disease after undergoing a BSO, despite optimal therapy. ORS therefore poses a significant treatment challenge in premenopausal ER+ breast cancer patients thought to be rendered menopausal with a BSO.

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: Heat shock protein 90 (Hsp90) is a molecular chaperone that maintains the stability of a number of key cellular oncoproteins (client proteins). When Hsp90 is inhibited, its client proteins undergo ubiquitination and degradation. HER2 is one of the most sensitive client proteins of Hsp90 and we have previously shown that tanespimycin, a geldanamycin-based Hsp90 inhibitor, is active in trastuzumab-refractory HER2+ MBC, with a RR of 22% and clinical benefit rate of 59%. Ganetespib is a synthetic, small molecule, IV administered, non-geldanamycin Hsp90 inhibitor which has broader inhibitory effects on oncoproteins with pre-clinical antitumor activity in more breast cancer (BC) subtypes, including triple negative breast cancer (TNBC). We therefore tested ganetespib in an unselected cohort of patients with advanced BC. Methods: Pts with locally advanced or MBC were treated with single agent ganetespib at 200mg/m2 once weekly for 3 weeks, on a 28 day cycle. The primary endpoint of the trial was overall response rate using RECIST 1.1. Pts with HER2+ BC were required to have received prior therapy with trastuzumab. No more than 3 lines of chemotherapy in the metastatic setting were permitted and there was no limit on prior lines of hormone therapy. Pts were evaluated for response after 2 cycles. The trial used a Simon two-stage design requiring at least 3 responses among the first 22 pts, to allow expansion to a total of 40 pts. Results: A total of 14 pts have been treated thus far with a median age of 45.3 years (36.6 to 59.1) and the following subtypes: 8 ER+/HER2+, 3 ER-/HER2+, 1 ER+/HER2− and 2 TNBC. Pts received a median of 1.84 cycles (0.33 to 4). The most common treatment-related AEs were Grade 1/2 and included the following: diarrhea (64%), fatigue (50%), nausea (35%), vomiting (14%), insomnia (14%) and hypersensitivity reactions (35%). The diarrhea had an early onset (< 24 hrs) and lasted up to 48 hrs post-infusion and was managed with either Imodium or similar anti-diarrheal medication. Pts who developed a hypersensitivity reaction were successfully re-challenged following pre-medication using dexamethasone plus H1/H2 antagonists. Grade 3 AEs were limited to 2 pts: 1 with an asymptomatic and reversible elevation in serum amylase, and the other with abdominal pain and diarrhea requiring a dose reduction to 175mg/m2. Of the 10 pts evaluable for efficacy, there is 1 confirmed partial response (PR), 1 minor response (MR) and 2 pts with stable disease (14%). The pt with MR had TNBC and was taken off-study due to a complicated pneumonia requiring hospitalization (unrelated). The remaining 3 pts had HER2+ BC; 2 of these 3 pts (1 PR, 1 SD) are continuing on study and have completed 4 cycles thus far. Updated toxicity and efficacy data will be presented. Conclusions: These data show activity for single agent ganetespib in different subtypes of breast cancer. Ganetespib was well tolerated, with expected gastrointestinal toxicity that was mild in nature and manageable in all patients. Accrual continues and we will present updated data at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-17-08.

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: Inhibition of SRC is a novel approach for MBC. D is an inhibitor of multiple tyrosine kinases, including the SRC family. Pre-clinical data show D inhibits multiple breast cancer cell lines, including those of “basal-like” subtype. In preclinical models D + P had superior antitumor activity to either agent alone. We designed this phase I-II study to translate this observation. Methods: For phase I: pts with MBC, ECOG PS 0-1, normal hepatic, renal, marrow function were eligible. Pts with pleural/pericardial effusions were excluded. For phase II: pts had measurable, HER2-negative MBC, ≥2 prior rx for MBC. Prior taxanes, stable brain metastases and baseline neuropathy grade ≥1 were allowed. Cycle (C) consisted of wP 80 mg/m2 IV 3/4 weeks + D 70mg orally daily; escalating to 100 mg, 120 mg and 150 mg in cohorts of 3pts. Toxicity was assessed by CTCAE v3.0, response by RECIST. Results: 17 pts enrolled (15 phase I; 2 phase II); median age 54 (range 35-74), median PS=1 (range 0-1). 12 (71%) pts rcvd prior adjuvant chemoRx. Pts rcvd a median of 3 prior rx for MBC (range 0-12). Pts rcvd median of 2 C of D + P (range 1-14). One DLT occurred at 150mg (G3 fatigue); this cohort was expanded with no further DLTs. However 3 pts on this dose level withdrew;1 pt delayed hypersensitivity rash (grade 1), 1 pt febrile neutropenia (grade 3), 1 pt paclitaxel pneumonitis (grade 3). Therefore the phase II dose is D 120mg. Overall the most common toxicities have been hematologic and low G (table). 13 pts are assessable for response; 4 patients (31%) had a PR, including 3 patients previously treated with taxanes. 5 pts (29%) had stable disease. Toxicities > Grade 1 Conclusion: Treatment with wP and D is feasible in pts with MBC. In the phase I study, 1 DLT occurred at D 150mg but due to cumulative toxicities the recommended dose for the ongoing phase II study is 120mg. Preliminary evidence of activity has been seen in taxane-pretreated pts at the phase II dose. Identification of biomarkers to select appropriate pts for this therapeutic approach is the subject of ongoing correlative studies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-09.

This multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC).We treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m2 and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6-8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles.The overall response rate (ORR) was 62.5% (95% CI, 45.7%-79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%).Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.

Cancer patients commonly use dietary supplements to "boost immune function". A polysaccharide extract from Grifola frondosa (Maitake extract) showed immunomodulatory effects in preclinical studies and therefore the potential for clinical use. Whether oral administration in human produces measurable immunologic effects, however, is unknown.In a phase I/II dose escalation trial, 34 postmenopausal breast cancer patients, free of disease after initial treatment, were enrolled sequentially in five cohorts. Maitake liquid extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for 3 weeks. Peripheral blood was collected at days -7, 0 (prior to the first dosing), 7, 14, and 21 for ex vivo analyses. The primary endpoints were safety and tolerability.No dose-limiting toxicity was encountered. Two patients withdrew prior to completion of the study due to grade I possibly related side effects: nausea and joint swelling in one patient; rash and pruritus in the second. There was a statistically significant association between Maitake and immunologic function (p0.0005). Increasing doses of Maitake increased some immunologic parameters and depressed others; the dose-response curves for many endpoints were non-monotonic with intermediate doses having either immune enhancing or immune suppressant effects compared with both high and low doses.Oral administration of a polysaccharide extract from Maitake mushroom is associated with both immunologically stimulatory and inhibitory measurable effects in peripheral blood. Cancer patients should be made aware of the fact that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function.

Purpose Granulocyte-colony stimulating factor (G-CSF) was used in CALGB 9741 to support dose-dense sequential chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) (Citron et al. J Clin Oncol 21:1431–1439, 2003). However, myelosuppression is not known to be dose or schedule limiting for paclitaxel. We therefore conducted this trial to determine the need for routine G-CSF, using the pegylated product (pG-CSF), support during the paclitaxel component of dose-dense sequential chemotherapy in women with early stage breast carcinoma (BC). Patients and methods Eligible patients received dose-dense chemotherapy consisting of four cycles of AC followed by four cycles of P at two week intervals. pG-CSF (NeulastaTM) was administered after each of four cycles of AC but was held after P. Planned enrollment was 59 pts. Results Of the first 15 patients, nine completed therapy without delays due to neutropenia but 6 (40%) did not, leading to implementation of the pre-specified early termination rule. Overall, 85% of P doses were successfully delivered on time. The mean treatment delay for the entire group due to neutropenia was 0.75 days. There was no significant correlation between neutropenia and prior WBC, ANC, or concurrent treatment with trastuzumab. Pts with neutropenia tended to be younger (Mean age 43.5) and have a lower BSA (1.65 m2). There were no febrile episodes due to omission of pG-CSF. Conclusion When paclitaxel is administered in a dose-dense fashion without growth factor support brief treatment delays are common. Further study is needed to identify the minimal pG-CSF administration that will avoid treatment delays.

Purpose Dose-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 trastuzuamb (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. Methods Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of ≥ 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m2) × 4 followed by P (175 mg/m2) × 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T ×1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. Results From 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 conestive heart failure (CHF). There were no cardiac deaths. Conclusion Dose-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.

Purpose To determine the immediate and long-term effects of true acupuncture versus sham acupuncture on hot flash frequency in women with breast cancer. Patients and Methods Seventy-two women with breast cancer experiencing three or more hot flashes per day were randomly assigned to receive either true or sham acupuncture. Interventions were given twice weekly for 4 consecutive weeks. Hot flash frequency was evaluated at baseline, at 6 weeks, and at 6 months after initiation of treatment. Patients initially randomly assigned to the sham group were crossed over to true acupuncture starting at week 7. Results The mean number of hot flashes per day was reduced from 8.7 (standard deviation [SD], 3.9) to 6.2 (SD, 4.2) in the true acupuncture group and from 10.0 (SD, 6.1) to 7.6 (SD, 5.7) in the sham group. True acupuncture was associated with 0.8 fewer hot flashes per day than sham at 6 weeks, but the difference did not reach statistical significance (95% CI, −0.7 to 2.4; P = .3). When participants in the sham acupuncture group were crossed over to true acupuncture, a further reduction in the frequency of hot flashes was seen. This reduction in hot flash frequency persisted for up to 6 months after the completion of treatment. Conclusion Hot flash frequency in breast cancer patients was reduced following acupuncture. However, when compared with sham acupuncture, the reduction by the acupuncture regimen as provided in the current study did not reach statistical significance. We cannot exclude the possibility that a longer and more intense acupuncture intervention could produce a larger reduction of these symptoms.

Purpose: Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. Experimental Design: Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m2 paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 μg s.c. daily) from day 2 to 24 h before the next treatment. Results: Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38°C with absolute neutrophil count Conclusions: Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The ∼30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.

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.

Background The epidermal growth factor receptor (EGFR) is part of the ErbB family of receptor tyrosine kinases and is known to be variably expressed in breast cancers. Cetuximab is a humanized monoclonal antibody directed against the EGFR that works by blocking the downstream signaling function of this protein and thereby interfering with cancer cell proliferation. Preclinical studies have indicated a synergistic effect for the combination of anti-EGFR therapy plus paclitaxel in breast cancer models. Patients and Methods Hence, we conducted a dose-escalation phase I trial using cetuximab/paclitaxel in patients with metastatic breast cancer to evaluate the feasibility of this combination. Patients with EGFR-positive metastatic breast cancer treated with=1 previous therapy, excluding taxanes, were eligible. Treatment consisted of weekly cetuximab therapy and every-3-week paclitaxel, with dose escalation of cetuximab until the maximum tolerated dose was reached. Results Twelve patients were enrolled to 3 treatment cohorts. Two of 6 patients on the second cohort (cetuximab 100 mg/m 2 ) developed dose-limiting toxicities, presenting as grade 3 rash. The third cohort was amended to allow the same cetuximab dose but to modify the paclitaxel to a weekly schedule. Despite this, 1 of 3 patients in this group also developed grade 3 skin toxicity as a dose-limiting toxicity; thus, the trial was stopped. Ten of the 12 patients were evaluable for response, and of these, 2 patients experienced stable disease, and 8 patients experienced disease progression. Conclusion Because of prohibitive dermatologic toxicity and disappointing preliminary efficacy, the combination of paclitaxel/cetuximab was not considered promising in this population, although further study of this regimen might be warranted.

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.

OBJECTIVES: To report on the longitudinal cognitive functioning of older women receiving adjuvant chemotherapy for breast cancer. DESIGN: Neuropsychological and functional status testing were performed before chemotherapy and 6 months after chemotherapy. SETTING: Cancer center. PARTICIPANTS: Thirty-one patients aged 65 and older with Stage I to III breast cancer. Of the 31 patients enrolled, three refused posttesting, and 28 were evaluable. MEASUREMENTS: The following domains of cognitive function were examined: attention; verbal memory; visual memory; and verbal, spatial, psychomotor, and executive functions. RESULTS: Participants had a mean age of 71 (range 65–84): 39% Stage I, 50% Stage II, and 11% Stage III. The number of scores 2 standard deviations (SDs) below the norm were calculated for each patient before and 6 months after chemotherapy; 14 (50%) had no change, 11 (39%) worsened, and three (11%) improved (P=.05). Seven patients (25%) experienced a decline in cognitive function, defined as a 1-SD decline from pre- to posttesting in two or more neuropsychological domains. Exploratory analyses revealed no significant difference between functional status, comorbidity, and depression scale scores and change in overall quality-of-life scores before and after chemotherapy. CONCLUSION: In this cohort of older women receiving adjuvant chemotherapy, a subset experienced a decline in cognitive function from before chemotherapy to 6 months after chemotherapy. Further prospective study is needed to confirm these observations and to identify the subgroup at special risk.

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.

At Memorial Sloan Kettering, we have used a clinically validated custom hybridization capture-based NGS assay (MSK-IMPACT) to sequence the tumors of more than 10,000 patients. We sought to determine physician perception and use of these results, including whether they changed management and the reasoning behind this decision-making. All physicians who ordered MSK-IMPACT testing for patients where it was not considered routine were asked to complete a questionnaire quarterly (Table). Physician determination of genomic “actionability” was compared to OncoKB, a curated knowledge base of somatic variants (OncoKB.org). Responses were received from 146 of 258 physicians emailed (57%) regarding 1932 of 9147 patients (21%). Physician respondents comprised a diversity of cancer specialties including medical oncology (67%), pediatric oncology (8%), surgery (6%), radiation oncology (5%), and neuro-oncology (5%). A total of 49 cancer types were represented. Physicians indicated that sequencing altered management in 331 (20%) of profiled patients in need of a treatment change. Among those in whom treatment was reportedly not altered, physicians indicated the presence of at least one actionable alteration in 55% (805/1474) of cases. However, only 45% of these cases harbored a genomic variant annotated as actionable by OncoKB. Among patients in whom physicians deemed the report non-actionable, 12% had OncoKB annotated actionable variants. Across the cases annotated as potentially actionable by OncoKB, physicians identified an actionable alteration in 81% of cases. At the time of data analysis, 297 (15%) patients had been enrolled in at least one clinical trial of targeted therapy at MSKCC including 224 (12%) patients on genomically-matched trials, 76% of whom participated after IMPACT profiling. As the clinical adoption of NGS panels expands, continued education of physicians as well as maintained knowledge bases for annotation will be necessary to expand the utility of this approach and the opportunity for precision medicine. QuestionsResponses, N (%)DID alter treatment, as follows:1. Patient enrolled to a therapeutic protocol at MSKCC265 (14)2. Patient enrolled to a therapeutic protocol at another institution15 (1)3. Patient treated with off-label use of an FDA approved therapy43 (2)DID NOT alter treatment, as follows:4. Actionable mutation(s) identified, but no therapeutic protocol was available175 (9)5. Actionable mutation(s) identified, but patient declined participation in, or was ineligible for, available therapeutic protocol115 (6)6. Actionable mutation(s) identified, but patient deteriorated, progressed, or died before results could be used176 (9)7. Actionable mutation(s) identified and therapeutic study available, but patient has not recurred/progressed since MSK-IMPACT result339 (18)8. No actionable mutation identified669 (35)Other135 (7)TOTAL1932 Citation Format: Alison M. Schram, Dalicia Reales, Jesse Galle, Roy Cambria, Robert Durany, Darren Feldman, Eric Sherman, Jonathan Rosenberg, Gabriella D'Andrea, Shrujal Baxi, Yelena Janjigian, William Tap, Maura Dickler, José Baselga, Barry Taylor, Debyani Chakravarty, Jianjiong Gao, Nikolaus D. Schultz, David B. Solit, Michael F. Berger, David M. Hyman. Oncologist use and perception of large panel next generation tumor sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 375. doi:10.1158/1538-7445.AM2017-375

Many patients being treated for cancer use dietary supplements, particularly antioxidants, in the hope of reducing the toxicity of chemotherapy and radiotherapy. Some researchers have claimed, furthermore, that antioxidants also increase the effectiveness of cytotoxic therapy and have explicitly recommended their use. However, mechanistic considerations suggest that antioxidants might reduce the effects of conventional cytotoxic therapies. Preclinical data are currently inconclusive and a limited number of clinical studies have not found any benefit. Clinicians should advise their patients against the use of antioxidant dietary supplements during chemotherapy or radiotherapy. Such caution should be seen as the standard approach for any unproven agent that may be harmful.

Background SRC 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. Patients and methods Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m2 was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme. Results Fifteen 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. Conclusion In 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.

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.

Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule.Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%.The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals.Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.

Purpose: To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway. Experimental Design: Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg p.o. daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg i.v. every 3 weeks). Patients had one to two prior chemotherapy regimens for metastatic disease. The primary end point was response rate by Response Evaluation Criteria in Solid Tumors criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression, response duration, and stabilization of disease of ≥26 weeks. Correlative studies were done on tumor tissue, including EGFR expression and mutation analysis. Results: One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median time to progression was 11 weeks (95% confidence interval, 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy. Conclusions: The combination of erlotinib and bevacizumab was well-tolerated but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.

Purpose We conducted a pilot study of dose-dense epirubicin/cyclophosphamide (EC) × 6 → paclitaxel (P) × 6 with pegfilgrastim. A previous dose-dense trial of FEC (5-fluorouracil [5-FU]/EC) × 6 with filgrastim → by weekly paclitaxel alternating with docetaxel × 18 was not feasible because of pneumonitis (with dose-dense FEC) and pericardial/pleural effusion (taxane phase). Dose-dense EC (without the 5-FU) is not associated with pneumonitis, and dose-dense paclitaxel (alone) is feasible. Primary objective was feasibility. Patients and Methods Patients with resectable breast cancer were enrolled, regardless of surgery status, tumor size, or nodal status. Treatment regimen consisted of every-2-week EC (100/600 mg/m 2 ) × 6 → by 2-weekly P (175 mg/m 2 ) × 6 with pegfilgrastim 6 mg on day 2. Results Between November 2004 and May 2005, 38 patients were enrolled. The median age was 47 years (range, 30-72 years); 33 of 38 (87%) were treated in the adjuvant setting and 27 of 33 (81%) had involved nodes (range, 1-46); 5 of 38 (13%) were treated pre-operatively; 33 of 38 (87%) completed all chemotherapy as planned; the remaining patients (13%) had treatment modifications for toxicity. Febrile neutropenia occurred in 6 of 38 patients (16 %) and only during EC. There were 12 hospitalizations in 9 of 38 patients (24%) enrolled. Conclusion Dose-dense every-2-week EC × 6 → P × 6 with pegfilgrastim is feasible based on our prospective definition.

Purpose: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy. Experimental Design: Twenty patients ages ≥65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board–approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel. Results: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade ≥3 toxicity: 16% (3 of 19) grade ≥3 hematologic toxicity, and 53% (10 of 19) grade ≥3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade ≥3 toxicity. Conclusions: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade ≥3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.

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.