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Purpose: To report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in cautionary (as described in 2017 revised ASTRO APBI guidelines) and high-risk women (age Methods and Material: Between March 2004 and April 2016 patients were enrolled in two APBI breast protocols (Phase II NCT01185145 and Phase III NCT01185132). Patients were treated with 38.5 Gy IMRT or 3D-CRT APBI w/ 3.85 Gy fraction/BID fractionation for 10 fractions. Patients who were ER/PR negative, ER negative, PR negative, HER2 positive, ≥2 cm primary tumors, or triple negative were compared to a total of 543 patients who were enrolled in the Phase II and Phase III trials. High risk patients were defined as those who possess one or more high risk criteria: triple negative (n=30), ER-/PR- (n=40), tumor size ≥2 cm Results: Median follow up was 4.0 years for all patients. No significant difference was found for this cautionary/high risk cohort at 5 years for ipsilateral breast, or regional recurrences. However, axillary recurrence was significantly adversely impacted by triple negative status, as well as both ER- and combined ER/PR- status (p=0.01, p=0.04, p=0.03, respectively). On multivariate analysis, the only significant correlations were between triple negative type and axillary recurrence (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories. Estimated Recurrence-free and Overall Survival at 5 years VariableIpsilateral breast recurrencepAxillary recurrencepRegional recurrencepAll Patients OSpHER-2/neupositive100%0.45100%0.64100%0.3895.3%0.88negative98%99.5%97.4%95.8%Size Triple negativeyes100%0.3496.7%0.0196.7%0.9384.3%0.16no98%99.7%97.6%95.9%HistologyIDCA98%0.4599.7%0.0797.7%0.7595.8%0.14ILCA100%97.5%97.5%88.9%Age> 5098%0.2899.5%0.4597.8%0.5595.2%0.10≤ 5097%100%97%96.6%ERpositive97.9%0.399.7%0.0497.6%0.9496%0.29negative100%97.5%97.5%87.5% Conclusion: There were no statistically significant differences in clinical local ipsilateral breast or regional recurrence outcomes at 5 years for patients currently considered to be cautionary/high risk. Axillary recurrence, however, was adversely impacted by triple negative, ER-, and combined negative ER/PR status. ER- and ER/PR- status similarly affected axillary recurrence. In light of these differences, however, the actual increase in axillary recurrence ranges from 2.4%-3% and are of questionable clinical significance. These data suggest that women possessing cautionary/high risk features are at no more risk for ipsilateral breast recurrence than other patients considered to be acceptable for APBI treatment. Citation Format: Anabel Goulding, Charles Leonard, Shannon Tole, Lora Barke, Jodi Widner, Lina Asmar, Yunfei Wang. Outcomes after accelerated partial breast irradiation in “high risk” and women categorized as cautionary in the ASTRO guidelines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-05.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Background: Candida bloodstream infection (BSI) remains one of the leading causes of BSI in critically ill and immunosuppressed cancer patients. In light of the changing epidemiology and rising resistant species, duration of treatment and appropriate timing of stepdown therapy from intravenous (IV) to oral antifungal agents are crucial for utmost disease control and overall survival. Method: We performed a multicenter retrospective study, with 119 non-neutropenic patients enrolled from four different medical institutions in Brazil, Lebanon ,Spain and the United States, to assess the duration of IV therapy and appropriate time to step down to oral therapy in adult patients, 14 years of age and older, with documented candidemia. The analysis was done using the statistical program R and SAS v9.4. Descriptive statistics are presented as frequencies and tables and the Fisher exact test was used to test the association between the categorical variables: organism, cancer, country, antifungal drug and duration of therapy, and time of step-down. Results: Candida albicans contributed to 45% bloodstream infection versus 55% infection caused Candida non-albicans. The three most common Candida non-albicans are: Candida glabrata 24%, Candida parapsilosis 13% and Candida tropicalis 8%. Most (57%) of the patients were admitted to ICU whereas 52% had underlying malignancy. Multivariate analysis showed that a stay at ICU or an underlying cancer requiring chemotherapy were independently associated with failure and death (p 5 days of treatment (24% mortality - p = 0.75). Conclusion: Our data support the IDSA guidelines in that the total duration of treatment for candidemia should be at least 14 days after a negative blood culture. However, in non-neutropenic cancer patients with candidemia, a step down to oral azole therapy can safely take place early (within 4 days of initiating IV therapy) as long as the patient had clinical and microbiologic resolution of the bloodstream infections.

PurposeTo report a primary objective clinical outcome of ipsilateral breast recurrence following accelerated partial breast irradiation (APBI) in women with triple negative and other high risk breast cancer (as described in 2017 ASTRO guidelines) (i.e., age 40–49, size 2.1–3.0 cm, estrogen receptor negative and invasive lobular breast cancer). Secondary objectives of axillary and regional failure as well as overall survival are also reported.Methods and MaterialPatients from two clinical trials (NCT01185145, NCT01185132) were treated with 38.5 Gy IMRT or 3D-CRT APBI w/3.85 Gy fraction/BID fractionation for 10 fractions. Triple negative and other high risk patients (n=269) were compared to a total of 478 low risk patients which ASTRO defined as “suitable” for APBI. High risk patients, for the purpose of this study, were defined as those who possess one or more high risk criteria: triple negative (n=30), tumor size >2 cm ResultsMedian follow up was 4.0 years for all patients. No significant difference was found for this high-risk cohort at 5 years for ipsilateral breast, or regional recurrences. Axillary recurrence was significantly adversely impacted by triple negative and ER- statuses (p=0.01, p=0.04). There were significant correlations between triple negative type and axillary recurrence on multivariate analysis (p=0.03). Overall survival for all patients was unaffected by any of the high-risk categories.ConclusionThe data from this study suggests that women possessing high risk features are at no more meaningful risk for recurrence than other patients considered to be acceptable for APBI treatment. However, the finding of axillary recurrence in patients with triple negative breast cancer does warrant a degree of caution in proceeding with accelerated partial breast irradiation technique in this patient group.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Background Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2 − metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. Patients and Methods In the present prospective analysis of hormone receptor-positive (HR + )/HER2 − and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m 2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. Results We enrolled 54 HR + and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR + and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR + and TN patients, respectively). The median OS was 17.9 months for HR + patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. Conclusion Ixabepilone plus carboplatin is active even in later-line HR + and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

PURPOSE: Primary objective: patient self-assessment of breast pain between 3-dimensional radiotherapy (3D-CRT) versus intensity modulated radiotherapy (IMRT). Secondary objectives: breast cosmesis as well as local-regional recurrence and survival statistics. METHODS AND MATERIALS: 656 patients (3D-CRT n=325; IMRT n=331) were prospectively randomized to either IMRT or 3D-CRT accelerated partial breast radiotherapy to 38.5 Gy in 10 BID 3.85 Gy fractions. Follow-up was: 1, 4, 8, 12, 16, 20, 24 months then yearly. At follow-up, patients completed a cosmesis/pain self-assessment form and physicians completed a cosmesis and disease-status form. RESULTS: 636 patients completed treatment (3D-CRT n=316; IMRT n=320). Median age was 62. Mean tumor size was 1.1 cm. Mean margin was 7mm. Histology was: 74.5% IDCA, 7% ILCA, 17% DCIS, 0.5% Tubular, 1% Mucinous. 99% were ER+. HER2/neu status by IHC was 3+ in 16% of patients. Median follow-up is 2 years. Tables 1 and 2 show there is no significant difference in patient-assessed pain and cosmesis between the two treatment arms (p=0.14, =0.68 respectively). Decreasing pain and worsening cosmesis as reported by the patient were significantly related to time (p Patient breast pain by follow-up interval12 Months (3D n=167 and IMRT n=163)Rx ModalityNoneMildModerate-Severep value3D50.9%47.3%1.8%0.44IMRT52.1%44.2%3.7% 24 Months (3D n=111 and IMRT n=109)3D52.3%47.7% 0.07IMRT66.1%33.9% 36 Months (3D n=50 and IMRT n=34)3D60.0%40.0% 0.37IMRT58.8%41.2% 48 Months (3D n=12 and IMRT n=123D25.0%75.0% 0.19IMRT58.3%41.7% Results from mixed model for pain gradeEffectEstimateSELowerUpperp value3D vs IMRT0.0810.055-0.0260.1890.14Visit (Baseline, 12, 24, 36, 48 month-0.1010.019-0.137-0.064 Patient breast cosmesis by follow-up interval12 Months (3D n=162 and IMRT n=158)Rx ModalityNo changeSlight changeObvious changeDrastic changep value3D40.1%38.3%19.1%2.5%0.83IMRT41.8%40.5%15.2%2.5% 24 months (3D n=108 and IMRT n=108)3D38.9%40.7%18.5%1.9%0.30IMRT41.7%29.6%26.9%1.9% 36 Months (3D n=50 and IMRT n=34)3D38.0%34.0%28.0%0%0.37IMRT32.4%35.3%26.5%5.9% 48 Months (3D n=10 and IMRT n=12)3D10.0%30.0%60.0% 0.10IMRT50.0%8.3%41.7% Patient breast cosmoses by follow-up intervalEffectEstimateSELowerUpperp value3D vs IMRT0.0260.064-0.1000.1530.68All Visit (Baseline, 12, 24, 36, 48 month)-0.0530.021-0.095-0.0120.01Table 2. Conclusion: T here were no significant differences in patient-assessed pain and cosmesis between the two treatment arms (p=0.14, =0.68 respectively) and no significant increase in pain over time. However, MD assessed cosmesis showed worsening cosmesis in the IMRT cohort compared to the 3D-CRT cohort wen compared to baseline. Citation Format: Leonard CE, Sobus RD, Fryman S, Sedlacek S, Kercher J, Widner J, Asmar L, Wang Y, Howell K, Barke L, Carter D. A randomized trial of accelerated breast radiotherapy utilizing either 3-dimensional radiotherapy versus intensity modulated radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-03.

Purpose This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor–positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. Patients and Methods Women age 40 to 49 with estrogen receptor–positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. Results The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. Conclusion These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Background: Pertuzumab was FDA-approved in 6/2012 for use in first-line in combination with trastuzumab (H) and docetaxel for patients (pts) with HER2-positive mBC. This retrospective study investigated the clinical characteristics, treatment patterns, safety, and outcomes for pts with HER2-positive mBC who received a P-containing regimen in first-line in US community oncology practices. Methods: This study utilized iKnowMed electronic health records, Claims Data Warehouse, and Social Security Death Index. Pts with HER2-positive mBC, who received a P-containing regimen between 6/2012 and 6/2014 and were followed through 12/2014, had ≥2 visits within the McKesson Specialty Health/US Oncology Network, and were not on clinical trials during the study period, were eligible. Results: Of the 322 pts who received a P-containing regimen in the first-line setting, 25% were ≥65 years of age, 63% were post-menopausal, 61% had hormone receptor-positive mBC, 84% had a performance status of 0 or 1, and 76% had a Charlson Comorbidities Index of 0. Twenty-one percent of pts had 1 site of metastasis noted, 32% had 2 sites, and 47% had 3 or more sites. Pts with de novo mBC made up 40% of this cohort. Of the pts with recurrent mBC, over 60% received H in the early-stage BC setting. In the first-line mBC setting, 93% of the 322 pts received H+P+taxane, and 7% received H+P with other chemotherapy agent(s). Common adverse events reported included: fatigue (49%), diarrhea (44%), nausea (33%), peripheral neuropathy (33%), neutropenia (24%), and rash (22%). Further analyses including outcomes of these 322 pts will be presented. Conclusions: First-line P was given in combination with H and chemotherapy agent(s) (93% taxane). No new safety signals were observed. More details on the clinical characteristics, specific treatment patterns, and safety will be presented, along with the progression-free survival of these pts receiving first-line P-containing therapy in a real-world setting. Citation Format: Robert N, Goertz H-P, Asmar L, Tseng W-Y, Jiao X, Portera C, Yoo B, Patt D, Antao V. Pertuzumab (P) use in first-line HER2-positive metastatic breast cancer (mBC) in US community oncology practices: Treatment patterns and outcomes. [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 P4-14-13.

Background Early stage HER2 amplified breast cancer has a generally favorable prognosis with over 95% of patients showing 2-year disease free survival (DFS) when treated with adjuvant trastuzumab. However, a subset of these tumors are refractory to treatment and present a challenge for the oncologist, particularly when clinical and histologic parameters, including the patient’s nodal and hormonal status, are indicative of lower-risk HER2 positive disease. In this study we describe the genomic landscape of three clinically lower-risk patients with HER2 amplified tumors who relapsed on adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). All patients’ tumors showed high-level HER2 amplification ratios by FISH (8.51-14.46) and were analyzed in parallel with a fourth clinically matched 2-year DFS patient’s tumor from the same trial with high HER2 gene amplification (FISH ratio 11.38). Methods Primary tumor genomic DNA analysis was performed from archival tissue by next generation sequencing (NGS) on the Illumina HiSeq 2500 platform in a CLIA certified laboratory. Tumors were screened for point mutations and copy number alterations (CNAs) by NGS using a targeted-whole exome 613 gene panel. CNAs detected by NGS were confirmed on a DNA microarray featuring high-density probe coverage of the same 613 genes on the targeted panel. CGH chromosome ratio plots were overlaid with algorithmically derived NGS copy number data to generate a map of the chromosomal genomic landscape for each patient’s tumor. Results High-level HER2 gene amplification status was confirmed, and co-amplified chromosome 17 genomic regions were detected in all three relapsed patients’ tumors. High-level HER2 amplification was also confirmed in the non-relapsed patient’s tumor but co-amplified regions were not detected on chromosome 17 or elsewhere in this patient’s tumor genome. Two of the relapsed ER negative tumors shared focal high-level CCNE1 gene amplifications on chromosome 19. High-level MAP3K3 gene amplification on chromosome 17 was detected in the one ER positive tumor from a relapsed patient. Focal PIK3CA gene amplifications were not identified in any of these tumors, but two tumors (one from the relapse group and one non-relapse) were positive for activating H1047R mutations. Conclusions Combined NGS and CGH analysis of HER2 positive early stage breast cancer can be performed in the clinical laboratory to reveal the tumor’s chromosomal genomic landscape. Combined with other test results, this tumor map can help identify patients at high-risk for relapse and reveal alternative predictive biomarkers of therapeutic response. Citation Format: Shelly Gunn, Chris McCaskill, Linda Daley, Agnes Puskas, Lina Asmar, Yunfei Wang, Stephen Jones. The chromosomal genomic landscape and targetable co-amplified genes in HER2 positive breast cancer patients who relapsed on an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-18.

Background Among 493 patients with early stage, lower risk (70% node negative), HER2 positive breast cancer, the 2-year DFS was 97% with adjuvant docetaxel and cyclophosphamide plus 1 year of trastuzumab (TCH) in a phase 2 study (Jones et al, Lancet Oncology 14: 1121, 2013). The objective of this work was to investigate the presence of ERBB2 specific DNA biomarkers in HER2 amplified tumors associated with relapse compared to those which did not recur during 3 years of followup. Methods The 26 coding exons of the ERBB2 gene were analyzed by next generation sequencing (NGS) on the HiSeq-2500 (Illumina) platform using DNA samples from the primary tumors of 13 of the 493 patients who progressed. Treatment refractory cases were analyzed in parallel with a clinically and pathologically matched group of 11 patients from the same trial with 2-year relapse free survival (RFS). Results ERBB2 gene variants were detected in all 11 relapse-free patients and 10/13 patients with relapse. Heterogeneity for sub-clonal ERBB2 variants at 30 ERBB2 SNVs. These sub-clonal ERBB2 SNVs were not detected in a comparison set of non-HER2 positive solid tumors. We did find variants that seem to be associated with later relapse, of which one is statistically significant (I655V; p=1.2%, Fisher exact test, no compensation for multiple testing), and further 5 have p Conclusions We find no evidence for known activating HER2 mutations to confer increased (nor decreased) risk of relapse after TCH therapy (p=30.0%). Remarkably, I655V is found significantly less often in the relapse group. This variant is known to increase BC risk by activating HER2 dimerization; an effect that may be muted by trastuzumab, in contrast to some other causes of BC. Moreover, I655V mutations with high TVF (>75%, hence suggesting homozygous germline presence) are exclusively found in the no-relapse group (p=3.1%). These biomarkers in combination with other molecular studies including immune function gene status may help define the subset of patients at risk for relapse during TCH therapy. The hyper-mutability genotype does not seem to correlate with later relapse, so it may be hypothized that the low TVF mutations are passengers rather than drivers. Further studies are needed to verify and precisely define the role of these ERBB2 biomarkers in HER2 positive breast cancer. Citation Format: Shelly Gunn, Alexander Zien, Markus Hartenfeller, Francesca Diella, Stephan Brock, Martin Stein, Sasha Badbanchi, Anja Doerks, David Jackson, Lina Asmar, Yunfei Wang, Steve Jones. Identification of ERBB2 gene variants in HER2 positive disease associated with trastuzumab response in an adjuvant trastuzumab chemotherapy trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-22.

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer compared with the TC6 regimen.

Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+ breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity. Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy. Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p = .05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction. Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p = .05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.

This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versustwo prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.

Summary Background Previous results suggest that docetaxel plus cyclophosphamide improves disease-free survival (DFS) and overall survival compared with doxorubicin plus cyclophosphamide in early stage breast cancer. We assessed the addition of 1 year of trastuzumab to a non-anthracycline regimen, docetaxel plus cyclophosphamide, in patients with HER2 -amplified early stage breast cancer and examined whether this regimen was equally effective in patients with TOP2A -amplified and TOP2A -non-amplified disease. Methods This was an open-label, single-group, phase 2 study. Eligible patients were aged 18–75 years; had Eastern Cooperative Oncology Group performance status of 1 or less; HER2 -amplified early stage breast cancer; operable, histologically confirmed, invasive carcinoma of the breast; adequate tumour specimen available for FISH analysis of TOP2A status; and adequate haematological, renal, hepatic, and cardiac function. Patients received four 21-day cycles of intravenous docetaxel 75 mg/m 2 , plus intravenous cyclophosphamide 600 mg/m 2 , plus intravenous trastuzumab 4 mg/kg (loading dose) on day 1 and 2 mg/kg on days 1, 8, and 15 during chemotherapy, followed by trastuzumab 6 mg/kg every three weeks for the remainder of 1 year. The primary endpoint was 2-year DFS in TOP2A -amplified and TOP2A -non-amplified patients; the primary analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00493649. Findings 493 patients were enrolled between June 15, 2007, and Aug 5, 2009. After a median follow-up of 36·1 months (IQR 35·5–36·7), 2-year DFS was 97·8% (95% CI 94·2–99·2) and 2-year overall survival was 99·5% (95% CI 96·2–99·9) for the 190 patients with TOP2A -amplified disease; 2-year DFS was 97·9% (95% CI 94·9–99·1) and 2-year overall survival was 98·8% (95% CI 96·2–99·6) for the 248 patients with TOP2A -non-amplified disease; 55 patients were not assessable for TOP2A status. In the 486 patients who received at least one dose of study drug, the most common adverse events of any grade were fatigue (284 patients, 58·4%), neutropenia (250, 51·4%), and nausea (217, 44·7%). The most common grade 3–4 toxic effects were neutropenia (229, 47·1%), febrile neutropenia (30, 6·2%), fatigue (21, 4·3%), and diarrhoea (16, 3·3%). Cardiac dysfunction occurred in 29 (6·0%) patients (12 [2·5%] grade 1, 15 [3·1%] grade 2, and two [0·4%] grade 3). 23 patients had at least one study-related serious adverse event. 16 patients stopped trastuzumab because of cardiac dysfunction. Interpretation A short, four-cycle regimen of docetaxel and cyclophosphamide combined with trastuzumab could be an option for adjuvant treatment of women with lower risk HER2 -amplified early breast cancer, irrespective of TOP2A status. Funding Sanofi.

Background Patients with advanced adenocarcinoma of the gastroesophageal junction/stomach are treated by combination chemotherapy, with minimal improvements in survival. We evaluated adding cetuximab to combination chemotherapy in these patients. Methods The primary objective was progression-free survival. Secondary objectives were response rate, time to response, duration of response and safety. Treatment Arm 1: docetaxel + oxaliplatin (DOCOX) = docetaxel 60 mg/m 2 plus oxaliplatin 130 mg/m 2 on Day 1 of each 21-day cycle. Arm 2: docetaxel + oxaliplatin + cetuximab (DOCOX + C) = DOCOX with C 400 mg/m 2 first dose then 250 mg/m 2 weekly. The protocol was amended to allow collection of tissue to correlate responses with KRAS status. Findings One hundred fifty patients were enrolled (75/arm). DOCOX/DOCOX + C: gastric 44%/41%, gastroesophageal junction 51%/55%, both 5%/4%. Response rate/arm: 26.5%/38.0%. Median progression-free survival: 4.7/5.1 months (95% confidence interval (CI) 3.0–5.6/4.3–5.9); 1 year survival: 39.1%/33.0%, median overall survival: 8.5/9.4 months; median duration of response: 7.3/5.6 months. Grade 3–4 treatment-related adverse events (%) included neutropenia (50%/44%), febrile neutropenia (13%/19%), diarrhoea (12%/17%), fatigue (12%/17%) and leukopenia (7%/14%). Discontinuation was due to progressive disease 39/32 and adverse events 21/34. KRAS was collected on some patients 2 years into the study because of new American Society of Clinical Oncology (ASCO) findings. Interpretation Cetuximab added to DOCOX may improve response rate minimally; there appears to be no improvement in progression-free survival, overall survival or 1-year survival. Cetuximab added to DOCOX did not produce clinically significant outcomes. Toxicities were consistent with the study drugs’ known safety profiles. KRAS mutation was infrequent; no conclusions can be drawn from KRAS response data. ClinicalTrial.gov Identifier: NCT00517829 .

Background We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin). Patients and methods Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status. Treatment: PLD 30 mg/m2 followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab. Results Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3–4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%. Conclusions PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity.

Cetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy.Eligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU. L (folinic acid), oxaliplatin (O) + bevacizumab), administered days 1 and 15 of each 28-day cycle as bevacizumab 5 mg/kg, oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), and 5-FU 400 mg/m(2) then 1200 mg/m(2)/day for 48 hours, or arm B (FOLF-CB), which included bevacizumab, leucovorin, and 5-FU as in arm A and cetuximab 400 mg/m(2) day 1 cycle 1; all other weekly cetuximab doses were 250 mg/m(2).Two hundred forty-seven patients (arm A/arm B 124/123) were enrolled, and 239 were treated (118/121). Twelve-month progression-free survival (PFS) was 45%/32%, objective response rates (ORR) (complete response [CR] + partial response [PR]) were 52%/41%, disease control rates (CR+PR+stable disease [SD]) were 87%/83%, and median overall survival (OS) was 21/19.5 months, respectively. Grade 3-4 neutropenia was higher in arm A (28%/7%), as was grade 3 fatigue (12%/3%), and grade 3 neuropathy (11%/1%), whereas acneiform rash was confined to arm B. Retrospective analysis of KRAS mutational status did not demonstrate KRAS as a meaningful determinant of activity, except in arm B patients with KRAS-mutated tumors, which resulted in inferior PFS. Patient satisfaction favored the control (mFOLFOX6-B).FOLF-CB was not superior to mFOLFOX6-B in terms of 12-month PFS and ORR, and was not more acceptable to patients. This trial supports the conclusion of other recently reported trials that concurrent cetuximab+bevacizumab should not be routinely used in metastatic CRC.

Background In our original doxorubicin-cyclophosphamide/docetaxel-cyclophosphamide (AC/TC) adjuvant study (JCO 27: 1177–1183, 2009), we reported an incidence of febrile neutropenia (FN) of 5% (8% in women ≥65 years) with the TC regimen without prophylactic WBC growth factors but with a recommendation for prophylactic antibiotics. There is a paucity of data on the incidence of FN with the TC regimen aside from this clinical trial. Because we have been conducting a randomized adjuvant study of TC compared to other regimens, we used this opportunity to analyze the incidence of FN during the first course of chemotherapy with TC in the first cohort of randomized patients (US Oncology Network study 06090). The prophylactic use of WBC growth factors was at the investigator's discretion. Patients and Methods The study included 1298 patients entered between May 2007 and May 2009. Of these, 649 were included in the TC arm. Median age was 54 years (range 27–71), 75.5% were Caucasian, 561 (86.4%) were in PS 0 at baseline, and about half were node negative. Eight patients did not receive study treatment for various reasons. Among the 641 patients who received TC; 213 (33.3%) received pegfilgrastim, 48 (7.5%) received filgrastim and were not included in this analysis, and 380 (59.2%) patients did not receive either during the first cycle. Thus, this analysis focused on 593 women who did or did not receive prophylactic pegfilgrastim in cycle 1. Results: All patients with a reported adverse event of FN or with a reported AE of fever with some degree of neutropenia (in order to capture all possible cases of FN) during the first cycle of TC were identified [Table 1]. FN and fever + neutropenia occurred in a total of 6 (2.8%) patients who received pegfilgrastim and 36 (9.5%) patients who did not. A comparison of age, race, performance status and stage of disease between these 2 groups revealed that they were similar. The 213 patients who received pegfilgrastim were slightly older (median 56 years, range 27–71) compared to those who did not (median 53 years, range 30–71). During all 6 cycles, 41 patients reported FN, and 30 (73%) of these patients experienced FN during cycle 1. Conclusion: Among 593 women who received TC as adjuvant chemotherapy, the incidence of FN during the first cycle was under 10% whether or not the patients received prophylactic pegfilgrastim. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-09.

Introduction: Ixabepilone adds to the antitumor effectiveness of capecitabine in both ER+ and triple negative (TN) breast cancer. Ixabepilone has antitumor activity in taxane-refractory patients, and novel combinations are needed in this poor prognosis population. Carboplatin combined with gemcitabine or paclitaxel has activity in metastatic breast cancer; there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus TN subsets. A Phase I study of ixabepilone + carboplatin in solid tumor patients demonstrated the safety of this combination.1 We conducted a Phase II trial of ixabepilone + carboplatin at the doses and schedule used in the Phase I trial to determine its effectiveness in hormone receptor positive (HR+) and TN patients. Methods: This was a Phase II, open label, nonrandomized parallel, noncomparative study of 2 groups. Patients could have received up to 2 lines of treatment for metastatic disease. All patients received ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients were stratified as either (HR+) (n=50) or (TN) ER-/PR-/HER2− (n=53). Patients received drug until PD or intolerable toxicity. Patients continued treatment for as long as they responded (CR, PR, or SD). The primary objective was to evaluate objective response rate (ORR). Secondary objectives included evaluation of clinical benefit rate (CBR) defined as ORR (CR+PR)+SD≥6 months, progression-free survival (PFS), overall survival (OS), duration of responses, and toxicity. Results: Based on preliminary data, 96 patients (55 [57.3%] HR+ and 40 [41.7%] TN) received study treatment, with 1 patient found ineligible. Median age was 55.2 years; all were females; baseline PS of 0/1/2 was 50/44/2; stage at diagnosis I/II/III/IV/unknown was 12/38/23/21/2, respectively. PR was 26.3% overall. There were no CRs. CBR overall was 41.1% (39), 52.7% (29) for HR+ patients, and 25.6% (10) for TN patients. Median PFS was 7.6 months, and median OS was 12.7 months. The median time to response and duration of response in patients achieving a PR was 1.7 and 6.5 months, respectively. Grade 3/4 hematological toxicities included 49% neutropenia, 10.4% anemia, and 4.2% thrombocytopenia. The most common grade 3/4 non-hematologic toxicities included fatigue (8.3%), nausea (6.3%), neuropathy (6.3%), vomiting (5.2%), and dehydration (5.2%). Of 32 deaths during the study, one was due to neutropenic sepsis, and 25 were due to PD. Conclusion: The combination of ixabepilone plus carboplatin was a tolerable and active regimen for both HR+ and TN breast cancer. In general, it had expected hematologic and manageable non-hematological toxicities. Further follow-up of the remaining 12 patients still on treatment is ongoing. 1. Plummer R, et al. Clin Cancer Res. 2008 Dec 15;14(24):8288–8294. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-09.

Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT)3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥ 3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m(2) was administered subcutaneously on days 1-5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥ 30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).Azacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.

Purpose: This phase III study compared the efficacy and tolerability of gemcitabine and oxaliplatin (GEMOX) with paclitaxel and carboplatin (PCb) in chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer. Patients and Methods: Patients aged 18 years or older were randomized to PCb (paclitaxel 225 mg/m 2 followed by carboplatin area under the curve=6 on day 1 every 3 weeks) or GEMOX (gemcitabine 1,000 mg/m 2 on days 1 and 8 followed by oxaliplatin 130 mg/m 2 on day 1 every 3 weeks) for up to six cycles. The primary end point was progression-free survival (PFS), with tumor response rate, overall survival (OS), and quality of life as secondary end points. Results: The study was terminated after 383 patients had been randomized (371 received treatment) as the incidence of adverse events had exceeded the protocol-specified safety threshold (≥20% in either arm). No formal statistical comparisons were conducted. Median PFS was 4.44 months and 4.67 months in the GEMOX and PCb groups, respectively. Objective response rates (complete or partial) were 15.2% and 22.4% in the GEMOX and PCb arms, respectively. Median OS was 9.90 months (GEMOX) and 9.24 months (PCb); post hoc analyses showed median OS in patients aged 70 years or older to be similar to those younger than 70 years. PFS was similar in both groups of patients with adenocarcinoma histology, although OS favored the GEMOX group. Quality of life was improved from baseline in both groups. Toxicity profiles were comparable between the groups. Conclusion: PFS, OS, and objective response rates with GEMOX were similar to PCb. Nevertheless, toxicities limit the adoption of this regimen for routine use in advanced non-small cell lung cancer.

Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range,1-22.4). Median overall survival (OS) was 18.9 months (range,1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

Background: TEAM is the largest AI phase III trial comparing exemestane with tamoxifen followed by exemestane as adjuvant breast cancer therapy in postmenopausal women. We performed a meta-analysis of three randomized sub-studies of the TEAM trial conducted in Germany, the Netherlands/Belgium and the United States to determine the effects on bone health. Methods: Patients were randomised to exemestane or tamoxifen as adjuvant therapy for hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12 and 24 months’ treatment. Bone turnover markers were also measured. Results: 412 patients were evaluable. Patients in the tamoxifen group showed a mean increase in lumbar spine BMD of 1.2% from baseline to month 12 and 0.2% to month 24. Patients in the exemestane group showed a mean decrease from baseline of 2.6% after 12 months and 3.5% after 24 months. There were significant differences in the changes in BMD at the lumbar spine between treatment groups (P Conclusions: After 24 months, exemestane treatment resulted in decreases in BMD and increases in bone turnover markers. In contrast, BMD was increased and bone turnover markers were decreased with tamoxifen. BMD and bone turnover changes appeared to stabilise after initial treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-08.

Background A majority of multiple myeloma (MM) patients fail to achieve complete response (CR) to peripheral blood stem cell transplantation (PBSCT); effective options following autologous transplantation are needed. Bortezomib (B) is active against MM. This study was conducted to determine the feasibility, safety, tolerability, and efficacy of B following high-dose melphalan therapy and PBSCT. Methods Fifty patients enrolled (48 evaluable) and 49 were treated (safety population). Treatment: 4 cycles B 1.3 mg/m2 Days 1, 4, 8, and 11/21-days; 4 additional cycles were permitted for stable or responding patients. Results Median age was 55 years (range, 38–73), 68% male, 64% ECOG PS = 0, 44% Durie-Salmon Stage IIIA prior to induction, 42% had symptomatic IgG MM; 74% had prior single transplant (26% tandem). Responses post-transplant: 70% PRs, 18% MRs. A median of 4 cycles (range, 2–8) of B were administered. Responses: CR 8%, uCR 2%, PR 23%, uPR 19%, MR 10%, and no change 35%; median time-to-treatment failure (TTF) was 6.2 months (range, 1.0–19.4). Three deaths occurred (n = 1 sepsis, n = 2 disease progression). Grade 3–4 treatment-related toxicities included: thrombocytopenia, neuropathy (14%, each); asthenia, neutropenia (10%, each); and nausea (4%). Twelve patients (24%) discontinued treatment due to toxicity and 30 patients (60%) completed the study; 20 patients started new treatment (median 5.8 months [range, 1.5–20.3]). Conclusions The study closed early due to widespread availability of B, and the lack of B-naive patients. Bortezomib monotherapy after melphalan and autologous PBSCT was feasible, safe and well-tolerated (toxicities were manageable), but failed to produce the hypothesized response rates.

Purpose This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer. Methods Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor. Treatments were as follows: arm 1 was doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles followed by paclitaxel 175 mg/m2 every 3 weeks for four cycles (ie, AC-P); and arm 2 was doxorubicin 50 mg/m2 plus paclitaxel 200 mg/m2 every 3 weeks for four cycles followed by paclitaxel 80 mg/m2 weekly for 12 weeks. Results Overall, 1,830 patients were enrolled and 1,801 were treated: arm 1 (n = 906; AC→P) and arm 2 (n = 895; AP-WP). Overall, patients had a PS of 0 (88%), had estrogen receptor and progesterone receptor–positive disease (52%), had one to three positive nodes (46%), and were postmenopausal (57%); the median age was 52 years. Currently, 1,640 patients (90%) are alive. The 6-year DFS was 79% to 80% in both groups. Disease relapse was the cause of death for 83 patients in arm 1 and in 66 patients of arm 2. Overall 6-year survival rates were 82% and 87% in arms 1 and 2, respectively. Reasons for patients being taken off study treatment included toxicity (13% in arm 1 v 20% in arm 2), progressive disease or recurrence (7% v 5%), and consent withdrawn (9% v 8%), respectively. The most frequent toxicities were hematologic, including neutropenia and leukopenia followed by neuropathy, myalgia, nausea, fatigue, headache, arthralgia, and vomiting. Conclusion The results indicate that the AP-WP regimen is an equally effective and tolerable option for the adjuvant treatment of patients with high-risk breast cancer. The substitution of paclitaxel for cyclophosphamide results in comparable effectiveness of the regimen.

Background Filgrastim decreases the time to neutrophil recovery after autologous peripheral blood stem cell transplantation (PBSCT). We hypothesized that single-dose pegfilgrastim would mimic multiple daily doses of filgrastim, resulting in an equivalent shortening of post-PBSCT neutropenia. Patients and Methods Patients who were eligible for PBSCT and aged ≥ 18 years were identified before high-dose chemotherapy, after the harvesting and cryopreservation of peripheral blood progenitor cells (ie, > 2.5 × 10 6 CD34-positive cells/kg). Eligible patients received either standard carmustine/etoposide/cytarabine/melphalan (BEAM) or carmustine/etoposide/cytarabine/cyclophosphamide (BEAC) high-dose chemotherapy. Before high-dose chemotherapy, patients were randomly assigned to receive pegfilgrastim 6 mg on day 1 (arm A) or weight-based, dose-adjusted filgrastim beginning on day 1 (arm B) after transplantation until neutrophil engraftment. Results One-hundred and one patients were enrolled between April 2003 and April 2007. Three patients were not treated. Demographics were well-balanced in terms of stage at diagnosis, Eastern Cooperative Oncology Group performance status, histology, and lines of previous therapy. Results (arm A/arm B) pertained to mean doses received (1.0/12.6), mean absolute neutrophil count recovery days (9.3/9.8), red blood cell transfusions (1.7/1.9), red blood cell transfusion units (3.1/3.8), platelet transfusions (3.1/2.8), positive blood culture rate (18%/29.2%), febrile neutropenia (FN; 18%/16.7%), and duration of FN (days; 7.1/6.9). Transplantation-related mortality and grade 3 or 4 adverse events were comparable between arms. Conclusion Pegfilgrastim after PBSCT appears equivalent to multiple daily doses of filgrastim. This approach might be considered in lieu of filgrastim, thus obviating the need for multiple daily injections.

Background Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. Patients and methods Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. Results Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a ≥50% prostate-specific antigen (PSA) decline and seven (21.2%) had a ≥30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score ≥2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. Conclusion Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

This study evaluated the efficacy and safety of single-agent bortezomib in indolent B-cell lymphoma that had relapsed from or was refractory to rituximab. Sixty patients enrolled: 59 were treated with bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 for up to eight 21-day cycles; responders could receive 4 additional cycles; maintenance was optional. Fifty-three evaluable patients completed more than 2 cycles. The median age was 70 years, 53% female, Ann Arbor stage III-IIIE (28%) and IV (65%); 43 patients (72%) had more than 2 prior regimens; and 6 patients went on to maintenance. Overall responses are as follows: 1 complete response (1.9%), 3 unconfirmed complete response (5.7%), 3 partial response (5.7%), 34 stable disease (64.2%), and 12 progressive disease (22.6%). Median time to response = 2.2 months (range, 1.2-5.3 months); duration of response = 7.9 months (2.8-21.3 months); 1-year survival was 73% and 2-year survival was 58%; median survival = 27.7 months (range, 1.4-30.9 months); median progression-free survival = 5.1 months (range, 0.2-27.7 months), median time to progression = 5.1 months (range, 0.2-27.7 months), and median event-free survival = 1.8 months (range, 0.2-27.7 months). Treatment-related grade 3 or 4 adverse events included: thrombocytopenia (20%), fatigue (10%), neutropenia (8.5%), and neuropathy and diarrhea (6.8% each). This study demonstrates that bortezomib has modest activity against marginal zone and follicular lymphoma; it has the potential for combination with other agents in low-grade lymphomas. Maintenance therapy should be explored further.

IntroductionCarboplatin/paclitaxel chemotherapy with bevacizumab is an accepted standard treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). The development of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has circumvented many of the infusion difficulties associated with standard solvent-based paclitaxel (in Cremophor) and offers theoretical advantages in efficacy. This trial evaluated the combination of nab-paclitaxel, carboplatin, and bevacizumab in advanced (stage IIIB/IV) nonsquamous NSCLC.MethodsFifty patients with stage IIIB/IV NSCLC were enrolled between October 2005 and April 2006; 48 were treated with nab-paclitaxel 300 mg/m2, carboplatin area under the curve = 6, and bevacizumab 15 mg/kg every 21 days until progression or intolerable toxicity, up to 4 cycles; an additional 2 cycles could be administered to responding patients and the physician's discretion; maintenance bevacizumab was not administered. Patient demographics included: 56% female, median age 67 years (range, 32–83), performance status 0 (52%) or 1 (48%), adenocarcinoma 86%, and stage IV disease 82%. Responding patients received a minimum of 4 cycles. The primary end point was response rate.ResultsResponse rate was 31% with a stable disease rate of 54%. No complete responses were observed. Median progression-free survival was 9.8 months (range

Purpose Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCβ and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. Methods Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg PO daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m2 IV Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. Results Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3–4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3β trended toward greater OS with GE treatment. Conclusions OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

Purpose Patients with recurrent ovarian, peritoneal, or fallopian tube cancer have limited therapeutic options. There are no reports of nanoparticle albumin–bound paclitaxel (nab-paclitaxel) in patients with recurrent platinum-sensitive disease. We report efficacy and toxicity with nab-paclitaxel in this group. Patients and Methods Forty-seven patients enrolled (44 assessable patients). Main inclusion criteria were histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2 to 3 if stage I) and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) or elevated CA-125 (> 70 U/mL) in patients without measurable disease. Patients received nab-paclitaxel 260 mg/m2 administered intravenously for 30 minutes on day 1 of a 21-day cycle for six cycles or until disease progression. Results Median age was 65.5 years; 76% of patients had stage IIIC or IV disease, 81% had Eastern Cooperative Oncology Group performance status of 0, and 94% had prior surgery. For assessable patients, the objective response rate (ORR) was 64% (15 complete responses [CR] and 13 partial responses [PR] among 44 assessable patients). In patients evaluated with RECIST only, the ORR was 45% (one CR and four PR of 11 patients). In patients with only elevated CA-125, ORR was 82% (seven CRs and two PRs of 11 patients). In patients meeting both RECIST and CA-125 criteria, the ORR was 64% (seven CRs and seven PRs of 22 patients). Median time to response was 1.3 months (range, 0.5 to 4.8 months). Estimated median progression-free survival was 8.5 months. The most frequent grade 3 to 4 treatment-related toxicities were neutropenia (24%) and neuropathy (9%). Conclusion Nab-paclitaxel is active in this group of patients with recurrent ovarian, peritoneal, or fallopian tube cancer. The ORR was 64%. Toxicities were manageable. Further studies of nab-paclitaxel in combination with platinum are warranted.

Purpose We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were ≥ 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity. Patients and Methods Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m2; n = 510), or TC (75/600 mg/m2; n = 506), administered by intravenous infusion every 3 weeks. Results The median age in women younger than 65, was 50 years (range, 27 to 64) and for women ≥ 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio [HR], 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC. Conclusion With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.

XELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC.Subjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m2 (850 mg/m2 orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m2 intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m2 I.V. [120 minutes], subsequently 250 mg/m2 [30 minutes]).Baseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completingor = 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range,1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%).In summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.

Effective options are lacking for progressive castration-refractory prostate cancer (CRPC) after conventional chemotherapy. Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that is approved multinationally for renal cell carcinoma and gastrointestinal stromal tumors. A phase II trial was conducted to examine the efficacy and toxicities of sunitinib in metastatic CRPC progressing after 1-2 previous chemotherapy regimens including docetaxel. The primary objective was clinical progression-free survival (PFS) with a 12-week PFS ≤ 30% assumed to be of interest. Secondary objectives included prostate-specific antigen (PSA) response, modulation of PSA kinetics, objective response, quality of life, pain, survival, and toxicities. Sunitinib 50 mg daily was administered orally on days 1-28 of each 6-week cycle. Patients were treated to a maximum of 8 cycles or until clinically progressive disease or intolerable toxicity.

Purpose Aprepitant might offer an advantage in preventing acute/delayed chemotherapy-induced nausea and vomiting (CINV). This study integrated palonosetron and dexamethasone into the regimen to determine the efficacy and safety of this combination. Patients and Methods Fifty patients were enrolled; 49 were evaluable. Main inclusion criteria were (1) diagnosis of ovarian (OV), primary peritoneal (PP), or fallopian tube (FT) carcinoma (stage I-IV) or papillary serous cancer of the uterus (UPSC); (2) patients naive to emetogenic chemotherapy Hesketh ≥ level 4; (3) scheduled to receive paclitaxel 175 mg/m2 intravenously (I.V.) and carboplatin AUC 6 I.V.; able to read/understand the Functional Living Index–Emesis questionnaire. Results Median age was 61 years, 60% had Eastern Cooperative Oncology Group performance status of 0, 86% had previous surgery (74% OV, 12% PP, 8% UPSC, and 6% FT). The metastases rate was 30%; 21% were visceral metastasis. Eighty-six percent of patients reported no vomiting or use of rescue medications during cycle 1 (95% and 100% in cycles 2–3 and 4–6, respectively) and were deemed as complete responders. Grade 3/4 treatment-related adverse events limited to neutropenia (6%). Grade 1/2 toxicities > 5% included nausea (12%), alopecia, constipation, arthralgia (8% each), and anemia (6%). Some toxicities might have been related to chemotherapy and were not related to the aprepitant, palonosetron, or dexamethasone. Conclusion The addition of aprepitant to palonosetron and dexamethasone appears to be very well tolerated. This combination is effective in the prevention of chemotherapy-induced nausea and vomiting when used with emetogenic therapy (paclitaxel and carboplatin).

Background Gemcitabine and carboplatin have significant preclinical synergy, and both provide synergistic antitumor activity in metastatic breast cancer (MBC) when used in combination with trastuzumab. The gemcitabine/cisplatin combination is highly active in MBC with response rates (RRs) of approximately 50% in anthracycline-and taxane-pretreated patients and up to 80% in untreated subjects. This phase II trial studied the efficacy and safety of gemcitabine/carboplatin with or without trastuzumab in patients with MBC. Patients and Methods Patients were stratified into 3 groups: group 1, HER2-positive; group 2, HER2-negative and taxane-naive/remote (no taxanes within past 2 years); and group 3, HER2-negative and previous taxane therapy. Included were women aged ≥ 18 years, Eastern Cooperative Oncology Group performance status of 0-2, with Response Evaluation Criteria in Solid Tumors–defined measurable MBC; HER2-negative or HER2 (3+) by immunohistochemistry or fluorescence in situ hybridization positive. All cycles were repeated every 14 days. On day 1, gemcitabine 1500 mg/m2 over 30 minutes was administered followed by carboplatin area under the curve of 2.5. Group 1 also received trastuzumab 8 mg/kg on day 1 of each cycle followed by 4 mg/kg for every 2 weeks thereafter. Results One hundred fifty patients were registered (50, 51, and 49 in groups 1, 2, and 3, respectively). The overall RRs were 64%, 27%, and 32%, respectively, with median time to progression of 7.2, 5.5, and 4.4 months, respectively. Overall, grade 3/4 toxicities included neutropenia (45%), leukopenia (17%), and thrombocytopenia (7%). Alopecia was infrequent: grade 1 (34%) and grade 2 (3%), and there was no significant cardiac toxicity. Conclusion Gemcitabine/carboplatin/trastuzumab is highly active in patients with HER2-positive MBC. Gemcitabine/carboplatin is active in patients with HER2-negative MBC independent of previous taxane therapy. Gemcitabine/carboplatin with or without trastuzumab administered every 2 weeks is associated with a low frequency of serious toxicity.

Background Platinum-based chemotherapy is the standard treatment for advanced gastric cancer (GC). This trial explored the efficacy and tolerability of combined docetaxel (Taxotere) + oxaliplatin (DOCOX) in GC patients. Patients and methods Patients with untreated stage IV GC or adenocarcinoma of the gastroesophageal junction (AGEJ) received docetaxel 60 mg/m2 followed by oxaliplatin 130 mg/m2 on day 1 of each 21-day cycle until progression or unacceptable toxicity. The primary end points were response rate (RR), toxicity, progression-free survival (PFS), and overall survival (OS). Results Baseline characteristics (N = 71): median age 59 years, 72% male, 51% esophagogastric junction cancer, and Eastern Cooperative Oncology Group performance status of zero, one, two were 42%, 51%, 7%, respectively. The median number of cycles was 6 (range, 1–19). Grades 3–4 toxic effects: neutropenia (70%); vomiting (17%); nausea (16%); dehydration, fatigue, or diarrhea (13%, each); and thrombocytopenia or febrile neutropenia (7%, each). Sixty-six patients completed ≥2 cycles. The RR was 36% with 25 partial response (PR) and no complete responses (CRs); stable disease (SD) was 49%. Clinical benefit rate (CBR = CR + PR + SD ≥6 months) was 40%; median PFS was 4.3 months, and OS was 8.5 months. Conclusions DOCOX produced manageable toxicity in patients with advanced GC and AGEJ. The confirmed RR of 36%, CBR of 40%, and median survival of 8.5 months are encouraging and comparable to standard front-line regimens.

Purpose Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Patients and Methods Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor–positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Results Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. Conclusion At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

Purpose We conducted a multicenter phase II trial to determine the efficacy/safety of capecitabine and weekly paclitaxel, a combination with preclinical evidence of synergy, in patients with metastatic breast cancer (MBC) previously treated with a taxane. Patients and Methods Eligibility criteria included measurable MBC, history of every-3-week taxane therapy (adjuvant or for MBC), and no previous taxane on a weekly basis, capecitabine, or infusional 5-fluorouracil. Patients received capecitabine 825 mg/m2 per dose orally twice daily (1650 mg/m2 per day) on days 1–14 and weekly paclitaxel 80 mg/m2 intravenously on days 1 and 8, followed by a 1-week rest period (every-3-week cycle) until progression or intolerable toxicity. Fifty-four women were treated, most with previous every-3-week taxane exposure as adjuvant therapy (n = 43) rather than for MBC (n = 11). The median number of delivered cycles was 7, with dose modifications in 30 patients. The intent-to-treat objective response rate (primary study endpoint) was 59% (95% confidence interval, 46%–72%), including 7 complete and 25 partial responses. Results Three patients had stable disease for ≥ 6 months, for a clinical benefit rate of 65% (95% confidence interval, 51%–76%). Median objective response duration, time to progression, and overall survival were 8.1 months, 8.4 months, and 21.6 months, respectively. Grade 3/4 treatment-related adverse events consisted of neutropenia (13%), anemia (2%), hand-foot skin reaction (20%), fatigue (7%), diarrhea (4%), nausea/vomiting (4%), and pain (2%). No patients developed grade 3/4 neuropathy. Conclusion Capecitabine and weekly paclitaxel were highly active with acceptable tolerability in patients with MBC previously treated with a taxane, consistent with our recently published experience in taxane-naive women with MBC.

Optimal treatment for cancer of unknown primary (CUP) can challenge clinicians. This study sought to determine the efficacy and toxicity of weekly paclitaxel and carboplatin in CUP. Forty-two subjects enrolled. Treatment was intravenous paclitaxel (80 mg/m2) plus carboplatin (AUC = 2) on Days 1, 8, and 15 every 28 days. Seven (18 percent) responded (complete = 2, partial = 5); median survival was 8.5 months; estimated survival (12 and 24-month) was 33 and 17 percent, respectively. Median time to progression was 3.7 months, and estimated progression-free survival (12 and 24 months) was 14 and 7 percent, respectively. Median duration of response was 17.3 months. This combination produced modest antitumor activity in advanced CUP.

BACKGROUND A wide variety of myelosuppressive chemotherapy regimens are used for the treatment of cancer in clinical practice. Neutropenic complications, such as febrile neutropenia, are among the most common side effects of chemotherapy, and they often necessitate delays or reductions in doses of myelosuppressive agents. Reduced relative dose intensity (RDI) may lead to poorer disease-free and overall survival. METHODS Using the McKesson Specialty Health/US Oncology iKnowMed electronic health record database, we retrospectively identified the first course of adjuvant or neoadjuvant chemotherapy received by patients without metastases who initiated treatment between January 1, 2007, and March 31, 2011. For each regimen, we estimated the incidences of dose delays (≥7 days in any cycle of the course), dose reductions (≥ 15% in any cycle of the course), and reduced RDI (

Chemotherapy is often poorly tolerated in elderly patients or patients with poor performance status. This trial was designed to determine whether low-dose weekly docetaxel/estramustine was efficacious with acceptable toxicity.Dexamethasone was administered as premedication. Subjects received docetaxel 25 mg/m2 intravenously on days 2, 9, and 16 and estramustine 140 mg orally twice daily on days 1-3, 8-10, and 15-17. Cycles were 28 days. Participants receivedor = 6 cycles unless progression or intolerable toxicity occurred.Fifty-eight subjects were enrolled at 31 sites in the US Oncology Network. Median age was 78 years (range, 64-92 years); performance status scores (0, 1, 2, and 3) were 36%, 38%, 24%, and 2%, respectively; 55 subjects receivedor = 1 cycle of treatment; and 4 participants were nonevaluable because they completed2 cycles. Among the 56 treated subjects, 38 (68%) had a decreased prostate-specific antigen level (or = 50% compared with baseline level and maintained for 4 weeks). There were 40 subjects with measurable tumor(s). Responses, assessed using Response Evaluation Criteria in Solid Tumors, were 1 complete response (2.5%), 7 partial responses (17.5%), 26 stable diseases (65%), and 6 progressive diseases (15%). At 1 year, 17% of participants were progression free; median progression-free survival was 5.3 months (range, 1-14.5 months); estimated 1-year survival was 65%. There were no grade 4 treatment-related events. Grade 3 treatment-related events included fatigue/asthenia (11%) and arrhythmia, dehydration, cerebral ischemia, thrombocytopenia, and dyspnea (4% each). There was 1 treatment-related death (acute respiratory distress syndrome).These findings suggest that elderly men with advanced-stage prostate cancer tolerate this regimen, with significant responses and prolonged progression-free survival. These patients should not be excluded from chemotherapeutic interventions based on age alone.

Purpose To determine the response rate (RR), progression-free survival (PFS), and toxicity in patients with HER-2/neu–negative metastatic breast cancer treated with first-line paclitaxel in a de-escalating dosing schedule. Patients and Methods Between August 1999 and December 2000, 73 patients were enrolled. Paclitaxel was administered on day 1 (175 mg/m2) and on days 8 and 15 (80 mg/m2 each) in each 4-week cycle (1 week of rest). Doses were de-escalated with the aim of reducing toxicity. An Eastern Cooperative Oncology Group performance status of 0, 1, or 2 was found in 55%, 41%, and 4% of patients, respectively. Median age was 59 years (range, 38 to 84 years), and 86% of patients had received prior surgery; 60%, adjuvant chemotherapy; and 59%, radiation therapy. Results Based on an intention-to-treat analysis (N = 73), there were five patients with a complete response (6.8%), 16 with a partial response (21.9%), 17 with stable disease (23.3%), and 23 with progressive disease (31.5%) for an RR of 28.7%. Twelve patients (16.4%) were not assessable for response due to toxicity (seven patients, mainly neuropathy), withdrawal of consent (two patients), early death (two patients), or noncompliance (one patient). Median PFS was 6.5 months (range, < 1 to 36.1 months), median survival was 22.8 months (range, < 1 to 36.1 months), and median duration of response was 8.8 months (range, 3.0 to 31.8 months). Patients (n = 72) were evaluated for toxicity. Grade 3 to 4 treatment-related toxicities occurring in more than 5% of patients included neutropenia (22.2%), neuropathy (18.1%), fatigue (6.9%), and leukopenia (5.6%). Conclusion In a unique de-escalating schedule, this study of single-agent paclitaxel produced a response rate similar to other single-agent paclitaxel schedules, in first-line therapy for metastatic breast cancer, published in the literature. However, this schedule is not recommended for the therapy of metastatic breast cancer because of the higher rate of toxicity.

Purpose The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC). Patients and Methods Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity. Results Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each). Conclusion Capecitabine in combination with weekly paclitaxel is an active and tolerable regimen as first-line therapy for women with MBC.

Purpose This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2–overexpressing metastatic breast cancer (MBC). Patients and Methods HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2–overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone. Results Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01). Conclusion The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2–overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.