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Background: The American Joint Committee on Cancer (AJCC) 8th edition pathologic prognostic staging (PPS) incorporates anatomic and biologic factors. The OncotypeDX Breast Recurrence Score (RS) was included based on the initial report of the TAILORx trial, with T1-2N0 hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancer patients who had a RS < 11 staged as PPS 1A. This study examined whether the RS criteria for PPS 1A can be further expanded using patients enrolled in the TAILORx trial. Methods: The TAILORx trial enrolled 10,273 HR+HER2− T1-2N0 patients. Those with incomplete HR-status/grade and T3 disease were excluded for analysis. The recurrence-free interval (RFI) was compared between the patients who did and those who did not fall into the current PPS 1A category using the Kaplan-Meier method. Results: The study enrolled 9535 patients for analysis. The RS was < 11 in 16.1%, 11–17 in 35.9%, 18–25 in 32.4%, and > 25 in 15.6% of the patients. The majority (91.2%) of the patients (including all the T1N0 patients regardless of RS) were PPS 1A, and 8.8% were not-PPS 1A. The median follow-up time was 95 months. The PPS 1A patients had an 8-year RFI of 94.2%, which was similar to that of the patients with a RS of 11–17 who were not-PPS 1A (91.7%; p = 0.07) and better than that of the patients with a RS ≥ 18 who were not-PPS 1A (85.4% for a RS of 18–25, 76.0% for a RS > 25; both p < 0.01). Similar RFI trends were seen in patients who received endocrine therapy or chemotherapy followed by endocrine therapy. Conclusions: Patients with T1-2N0 HR+HER2− breast cancer and a RS < 18 have an RFI similar to that of patients staged as PPS 1A by the current AJCC staging system, regardless of treatment, suggesting that the criteria for PPS 1A can be expanded to include a RS < 18. [ABSTRACT FROM AUTHOR]

Purpose: The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib, are generally well tolerated; however, neutropenia is a common toxicity. Within the general population, neutropenia has been shown to be more common in individuals of African descent. The landmark CDK4/6i trials in MBC lacked racial diversity in their patient populations. We aimed to assess the toxicity profiles of CDK4/6is in a racially diverse population. Methods: We conducted a retrospective study at Montefiore Medical Center in patients with HR-positive/HER2-negative MBC prescribed CDK4/6i as first or subsequent line therapy between January 2015 and April 2020. Baseline characteristics and laboratory data at various treatment timepoints were collected. Results: The final analysis included 182 patients, of whom 46% were Black. Baseline absolute neutrophil count (ANC) was lower in the Black vs. Non-Black cohort (p = 0.001) but the change in ANC from baseline (delta-ANC) was smaller in the Black cohort, and the ANC at different treatment timepoints was similar between groups. There was no difference in the rate of infection or number of dose delays/reductions between racial groups. We did not find any difference in PFS between Black and Non-Black groups, regardless of the presence of CDK4/6i-induced neutropenia. Conclusion: We analyzed toxicity profiles of 182 patients with HR-positive/HER2-negative MBC treated with CDK4/6i. Despite the lower baseline ANC seen in our Black cohort, treatment toxicities were similar between racial groups. Long-term outcomes with CDK4/6i therapy, measured by PFS, were similar between Black vs. Non-Black patients. [ABSTRACT FROM AUTHOR]

Emerging evidence shows that tumor cells secrete extracellular vesicles (EVs) that carry bioactive cell surface markers, such as programmed death-ligand 1 (PD-L1), which can modulate immune responses and inhibit anti-tumor responses, potentially playing a role in lymphomagenesis and in promoting the growth of these cancers. In this study, we investigated the role of EVs expressing cell surface molecules associated with B cell activation and immune regulation. We measured levels of EVs derived from plasma from 57 subjects with AIDS-related non-Hodgkin lymphoma (AIDS-NHL) enrolled in the AIDS Malignancies Consortium (AMC) 034 clinical trial at baseline and post-treatment with rituximab plus concurrent infusional EPOCH chemotherapy. We found that plasma levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII were significantly reduced after cancer treatment. AIDS-NHL patients with the diffuse large B cell lymphoma (DLBCL) tumor subtype had decreased plasma levels of EVs bearing PD-L1, compared to those with Burkitt's lymphoma. CD40, CD40L and TNF-RII-expressing EVs showed a significant positive correlation with plasma levels of IL-10, CXCL13, sCD25, sTNF-RII and IL-18. Our results suggest that patients with AIDS-NHL have higher levels of EVs expressing PD-L1, CD40, CD40L or TNF-RII in circulation before cancer treatment and that levels of these EVs are associated with levels of biomarkers of microbial translocation and inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical data demonstrate STAT3 as an important regulator in HER2+ tumors, and disruption of the IL6-JAK2-STAT-S100A8/S100A9 signaling cascade reduces HER2+ cell viability. Ruxolitinib is an FDA approved inhibitor of JAK1 and JAK2. We performed a phase I/II trial investigating the safety and efficacy of the combination of trastuzumab and ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. Methods: Patients with metastatic HER2+ breast cancer progressing on at least 2 lines of HER2-directed therapy were eligible. The phase I portion determined the tolerable dose of ruxolitinib in combination with trastuzumab. The primary objective of the phase II was to assess the progression free survival (PFS) of the combination of ruxolitinib plus trastuzumab compared to historical control. Results: Twenty-eight patients were enrolled, with a median number of prior therapies of 4.5. Ruxolitinib 25 mg twice daily was the recommended phase II dose with no dose limiting toxicities (DLTs). Of 26 evaluable patients in phase II, the median PFS was 8.3 weeks (95% CI 7.1, 13.9). Among the 14 patients with measurable disease, 1 patient had a partial response and 4 patients had stable disease. Most of the adverse events were hematologic. Conclusion: While well tolerated with a strong preclinical rationale, the combination of ruxolitinib and trastuzumab did not lead to an improvement in PFS compared to historical control in patients with trastuzumab-resistant metastatic HER2+ breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. Patients and methods: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. Results: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52–1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. Conclusion: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. Clinical trial registry: ClinicalTrials.gov Identifier: NCT00684983 [ABSTRACT FROM AUTHOR]

Objective: Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.Methods: Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.Results: 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.Conclusions: The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy. [ABSTRACT FROM AUTHOR]

Black race compared to white race is associated with more advanced stage and biologically aggressive breast cancer. Consequently, black patients are more frequently treated with neoadjuvant chemotherapy (NAC) than white patients. However, it is unclear how distant recurrence-free survival (DRFS) of black patients treated with NAC, compares to DRFS of black patients treated with adjuvant chemotherapy (AC). We evaluated the association between race, distant recurrence, and type of chemotherapy (AC or NAC) in localized or locally advanced breast cancer. We evaluated DRFS in 807 patients, including 473 black, 252 white, 56 Hispanic, and 26 women of other or mixed race. The association between AC or NAC and DRFS was examined using multivariate Cox proportional hazard models that included race, age, stage, estrogen receptor (ER) and triple negative (TN) status. When the black and white subjects were pooled for the analysis the features associated with worse DRFS included stage III disease and age < 50 years, but not ER-negative disease, TN disease, the use of NAC, or black race. However, in the analysis stratified by race NAC was associated with worse DRFS compared to AC in black (HR 2.70; 95% CI 1.73-4.22; p < 0.0001), but not in white women (HR 1.29, 95% CI 0.56-2.95; p = 0.36). Black patients treated with NAC had worse DRFS than black patients treated with AC, or white patients treated with either NAC or AC. These findings need to be validated in a large-scale observational study and the effect of NAC on the breast cancer microenvironment in black women needs to be further evaluated. [ABSTRACT FROM AUTHOR]

Purpose: Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. Methods: In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. Results: The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle ( n = 6). The Phase II study ( n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. Conclusions: In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients. [ABSTRACT FROM AUTHOR]

Purpose: To determine the recommended phase II dose (RPTD) of a 96-h continuous intravenous infusion (CIVI) of cyclophosphamide (200, 300, or 400 mg/m2/d) and etoposide (60 or 90 mg/m2/d) when used in conjunction with doxorubicin (12.5 mg/m2/d) (CDE) given every 28 d plus granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with poor prognosis non-Hodgkin's lymphoma (Group A), and the same regimen given every 21 d (Group B).Methods: In Group A, infusional CDE was repeated every 28 d, GM-CSF (250 microg/m2) was given subcutaneously from d 6 until neutrophil recovery, with dose escalation in cohorts of three to six evaluable patients. The RPTD of cyclophosphamide and etoposide established in Group A was then used with CDE given every 3 wk (Group B) with GM-CSF given on d 6-20, and dose escalation was attempted again.Results: In Group A, the RPTD of cyclophosphamide and etoposide were 300 mg/m2/d and 90 mg/m2/d, respectively; prolonged neutropenia was the dose-limiting toxicity. In Group B, use of GM-CSF on d 6-20 did not facilitate dose escalation above the RPTD established in Group A. Complete response occurred in 13/26 patients (50%) with no prior chemotherapy, and in 4/16 patients (25%) who had relapsed after prior chemotherapy.Conclusions: Because of the increase in dose and dose-density afforded by the administration of GM-CSF, the relative dose intensity was increased by twofold for cyclophosphamide (400 vs 200 mg/m2/wk) and etoposide (120 vs 60 mg/m2/wk), and by 1.3-fold for doxorubicin (16.7 vs 12.5 mg/m2/wk). [ABSTRACT FROM AUTHOR]

Fludarabine is an active agent in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Paclitaxel is also active in patients with refractory lymphoma, and preclinical data suggest an additive effect with fludarabine in vitro. We performed a phase I trial of fludarabine (25 mg/m(2) d 1-3) plus a 3-h infusion of paclitaxel (125, 150, or 175 mg/m(2)) on d 3 every 28 d in 13 patients with non-Hodgkin's lymphoma. The paclitaxel dose was escalated in cohorts of 3-4 patients using standard phase I design schema. Dose-limiting toxicity was defined as febrile neutropenia, platelet nadir less than 50,000/microL, or grade 3-4 nonhematologic toxicity. Thirteen patients were accrued to the study, 8 of these 13 patients (62%) had received prior chemotherapy. At the 125-, 150-, and 175-mg/m(2) dose levels of paclitaxel, dose-limiting toxicity occurred in 1/4, 0/4, and 0/4 patients, respectively. The single patient with dose-limiting toxicity had febrile neutropenia. Partial response occurred in two of eight patients with low-grade lymphoma and none of five patients with other types of lymphoma. A paclitaxel dose of 175 mg/m(2) given as a 3-h infusion on d 3 in conjunction with fludarabine (25 mg/m(2) d 1-3 every 4 wk) is a well-tolerated regimen for non-Hodgkin's lymphoma. Further study will be required in order to determine whether the fludarabine paclitaxel is more active than fludarabine alone in patients with low-grade lymphoma and chronic lymphocytic leukemia [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo. [ABSTRACT FROM AUTHOR]

Purpose To determine the effectiveness of bortezomib plus irinotecan and bortezomib alone in patients with advanced gastroesophageal junction (GEJ) and gastric adenocarcinoma. We also sought to explore the effect of these therapeutics on tumor and normal gene expression in vivo. Methods Forty-one patients with advanced GEJ (89 %) or gastric (11 %) adenocarcinoma received bortezomib (1.3 mg/m days 1, 4, 8, 11) plus irinotecan (125 mg/m days 1, 8) every 21 days as first line therapy ( N = 29), or bortezomib alone as second line therapy ( N = 12). The trial was designed to detect a 40 % response rate for the combination, and 20 % response rate for bortezomib alone. Affymetrix HU133A gene chip arrays were used for gene expression studies. Results Objective response occurred in 3 of 29 patients (10 %, 95 % confidence intervals [CI] 2 %, 27 %) treated with bortezomib plus irinotecan, and in 1 of 12 patients (8 %, 95 % CI 0 %, 39 %) with bortezomib alone. Due to the limited number of responders, there were no significant correlations with response found in the gene expression profiles of 12 patients whose tumors were sampled before and 24 h after therapy with bortezomib alone ( N = 2) or the combination ( N = 10). Conclusions We conclude that bortezomib is not effective for the treatment of advanced adenocarcinoma of the GEJ or stomach, whether used alone or in combination with irinotecan, in an unselected patient population. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether pre-chemotherapy anti-mullerian hormone (AMH) is a biomarker for chemotherapy-related amenorrhea (CRA) in breast cancer patients. A multicenter randomized controlled trial, ECOG5103, assigned patients with early stage breast cancer to standard doxorubicin-cyclophosphamide followed by paclitaxel with either placebo or one of two durations of bevacizumab therapy. Five hundred ninety-one patients were part of the decision-making/quality of life substudy, in which there were surveys from baseline through 18-month follow-up. One hundred twenty-four women were included in this analysis of menses data because they were premenopausal at enrollment, responded to the 12-month survey, had not undergone bilateral oophorectomy or ovarian function suppression before that survey, and had serum banked for research before chemotherapy. One hundred of the 124 also responded to the 18-month survey. Median age was 45 years (range 25-55), and median serum AMH level was 0.11 ng/mL (range 0.01-8.63) prior to treatment. Eighty-two percent had CRA at 12 months, and 81 % at 18 months. In multivariate analyses, older age ( p = 0.0003) was the only statistically significant predictor of 12-month CRA, but at 18-months, lower pre-chemotherapy AMH ( p = 0.04) and older age ( p = 0.008) were both statistically significant predictors of CRA. Race, bevacizumab therapy, and tamoxifen use were not statistically significantly associated with CRA after adjustment for AMH and age. Pre-chemotherapy AMH level is a potential novel biomarker for CRA in premenopausal women with early stage breast cancer. Further research to evaluate the clinical utility of AMH testing is warranted. [ABSTRACT FROM AUTHOR]

Obesity is associated with an increased risk of breast cancer, and increased risk of recurrence in women who develop breast cancer. Evidence suggests that the risk of estrogen-receptor (ER)-positive breast cancer is increased in obese postmenopausal women, whereas in premenopausal women the risk of triple negative breast cancer is increased. Nonetheless, the presence of obesity at diagnosis, and possibly weight gain after diagnosis, may independently contribute to an individual’s risk of recurrence of both pre- and postmenopausal breast cancer. Factors associated with adiposity that are likely contributing factors include hyperinsulinemia, inflammation, and relative hyperestrogenemia. Some studies suggest that some aromatase inhibitors may be less effective in obese women than lean women. Clinical trials have evaluated pharmacologic (eg, metformin) and dietary/lifestyle interventions to reduce breast cancer recurrence, although these interventions have not been tested in obese women who may be most likely to benefit from them. Further research is required in order to identify adiposity-associated factors driving recurrence, and design clinical trials to specifically test interventions in obese women at highest risk of recurrence. [ABSTRACT FROM AUTHOR]

Tipifarnib (T) is a farnesyl transferase inhibitor (FTI) that enhances the antineoplastic effects of cytotoxic therapy in vitro, has activity in metastatic breast cancer, and enhances the pathologic complete response (pCR) rate to neoadjuvant doxorubicin-cyclophosphamide (AC) chemotherapy. We, therefore, performed a phase I-II trial of T plus neoadjuvant sequential weekly paclitaxel and 2-week AC chemotherapy in locally advanced breast cancer. Eligible patients with HER2-negative clinical stage IIB-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m) followed by AC (60/600 mg/m every 2 weeks and filgrastim), plus T (100 or 200 mg PO on days 1-3 of each P dose, and 200 mg PO on days 2-7 of each AC cycle). The trial was powered to detect an improvement in breast pCR rate from 15 to 35 % ( α = 0.10, β = 0.10) in two strata, including ER and/or PR-positive, non-inflammatory (stratum A) and inflammatory carcinoma (stratum B). Of the 60 patients accrued, there were no dose-limiting toxicities among the first six patients treated at the first T dose level (100 mg BID; N = 3) or second T dose level (200 mg BID; N = 3) plus paclitaxel. Breast pCR occurred in 6/33 patients (18 %, 95 % confidence intervals (CI) 7-36 %) and 1/22 patients (4 %, 95 % CI 0-8 %) in stratum B. Combination of the FTI T with weekly paclitaxel-AC is unlikely to be associated with a breast pCR rate of 35 % or higher in patients with locally advanced HER2/neu-negative inflammatory or non-inflammatory ER- and/or PR-positive breast carcinoma. [ABSTRACT FROM AUTHOR]

Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to eribulin mesylate (1.4 mg/m, 2-5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m, 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with eribulin and resolve later. [ABSTRACT FROM AUTHOR]

Anthracyclines and taxanes are cytotoxic agents commonly used for treatment of breast cancer, including in adjuvant, neoadjuvant, and metastatic settings. Each drug class is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agent have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps for patients with rapidly progressive disease and/or high tumor burden. [ABSTRACT FROM AUTHOR]

Inflammatory breast cancer (IBC) is an uncommon and aggressive presentation of locally advanced breast cancer that is potentially curable when localized but may be associated with distant metastasis in up to one-third of patients at presentation. The diagnosis of IBC is made based on clinical features, including the presence of skin edema and erythema involving at least one-third of the breast, with or without a mass, and usually associated with dermal lymphatic invasion (DLI) on skin biopsy. Management requires combined modality therapy, including neoadjuvant chemotherapy with an anthracycline and taxane-based regimen, followed by surgery and radiotherapy, plus concurrent anti-HER2 therapy for HER2-positive disease, and endocrine therapy for at least 5 years after surgery for estrogen-receptor-positive disease (Fig. 1). There have been few large clinical trials focused on IBC; therefore, most data regarding treatment are derived from retrospective analyses, small studies, and extrapolation of results from trials of noninflammatory locally advanced breast cancer. Patients with IBC should be encouraged to enroll in clinical trials whenever possible. In addition, further research into the biology of IBC may help to elucidate the mechanisms underlying its aggressive clinical behavior and to assist in the development of therapies targeted for this specific population. [ABSTRACT FROM AUTHOR]

Although pathologic complete response after neoadjuvant systemic chemotherapy (NST) is associated with an excellent prognosis, the prognosis for patients with residual disease is variable. The mitotic count (MC) is commonly used in the evaluation of histologic tumor grade, but its prognostic value relative to other factors when determined after NST has not been studied. We evaluated MC in the residual tumor after NST in order to determine whether it provided prognostic information independent of other factors, including the residual cancer burden (RCB). We retrospectively reviewed pathologic specimens from 80 patients with localized breast cancer who received standard NST, of whom 61 had residual disease evaluable for MC analysis and RCB score. The exact number of mitotic figures was counted in 10 high power (40×) fields (hpf). We classified tumors as having high (≥13 per 10 hpf) and low (<13 per 10 hpf) MC because this threshold fell at the midpoint for an intermediate MC score in the Nottingham combined histologic grade. Distant metastases developed in 2 of 32 (6.3 %) patients with a low MC compared with 18 of 29 (62.1 %) with a high MC (log-rank test, p < 0.001). When adjusted for other covariates, including age, estrogen receptor, HER2/neu expressions, and RCB score, a high MC was associated with a significantly higher risk of developing distant metastases (hazard ratio 11.21, 95 % CI [2.19, 57.37]; p = 0.004). Our findings indicated that evaluation of MC after NST warrants validation and further evaluation as a prognostic marker in breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. Methods: We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. Results: Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. Conclusions: PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays. [ABSTRACT FROM AUTHOR]

The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local-regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1-3 positive lymph nodes or negative lymph nodes with tumor size >1.0 cm. The study population was a subset of 388 patients with known 21-gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7-11.6 years). The 10-year rates of local recurrence and local-regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local-regional recurrence on univariate or multivariate analyses (all P ≥ 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2-negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors ( P = 0.76), and the 10-year rates of local-regional recurrence were 6.3, 6.9, and 7.2 %, respectively ( P = 0.79). For hormone receptor-positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively ( P = 0.17), and the 10-year rates of local-regional recurrence were 3.8, 5.1, and 12.0 %, respectively ( P = 0.12). For hormone receptor-positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local-regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local-regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation. [ABSTRACT FROM AUTHOR]

Capecitabine produces an objective response rate of up to 25 % in anthracycline-treated, taxane-resistant metastatic breast cancer (MBC). The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has clinical activity when used alone in MBC. The objective of this study was to determine the efficacy and safety of tipifarnib-capecitabine combination in MBC patients who were previously treated with an anthracycline and progressed on taxane therapy. Eligible patients received oral capecitabine 1,000 mg/m twice daily plus oral tipifarnib 300 mg twice daily on days 1-14 every 21 days. The primary endpoint was ORR. The trial was powered to detect an improvement in response rate from 25 to 40 %. Among 63 eligible, partial response occurred in six patients (9.5 %; 90 % CI 4.2-17.9 %), median progression-free survival was 2.6 months (95 % CI 2.1-4.4), and median overall survival was 11.4 months (95 % CI 7.7-14.0). Dose modifications were required for 43 patients (68 %) for either tipifarnib and/or capecitabine. Grades 3 and 4 toxicities were seen in 30 patients (44 %; 90 % CI 44.4-67.0 %) and 11 patients (16 %; 90 % CI 10.8-29.0 %), respectively. The most common grade 3 toxicities included neutropenia, nausea, and vomiting; and the most common grade 4 toxicity was neutropenia (8 out of 11 cases). The tipifarnib-capecitabine combination is not more effective than capecitabine alone in MBC patients who were previously treated with an anthracycline and taxane therapy. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a heterogeneous disease that is usually associated with poor prognosis, and frequently associated with the basal-like breast cancer gene expression profile. There are no targeted therapeutic modalities for this disease, and no useful biomarkers. High GRB7 RNA expression levels are associated with an elevated risk of recurrence in patients with operable TNBC treated with standard adjuvant anthracycline and taxane therapy. To determine whether GRB7 is involved in the pathobiology of TNBC, we evaluated the biological effects of GRB7 inhibition in a panel of triple-negative cell lines-MDA-MB-468, MDA-MB-231, HCC70, and T4-2. We found GRB7 inhibition reduced cell motility and invasion of these cell lines and promoted cell death by apoptosis in 3D culture. These data suggest that GRB7 itself, or GRB7-dependent pathways, may prove to be important therapeutic targets in this disease. [ABSTRACT FROM AUTHOR]

Background: Antitubulin agents exhibit antiangiogenic effects in vitro and in vivo. We evaluated the safety and feasibility of administering a metronomic schedule of oral vinorelbine designed to optimize its antiangiogenic effects. Methods: Patient with advanced cancer who had progressive disease after standard therapy received oral vinorelbine 3 times weekly (i.e., Monday, Wednesday, Friday) at the 6 dose levels ranging from 20 mg (1 week on, 1 week off) to 50 mg (3 weeks on, 1 week off) in cohorts of 3-6 patients at each dose level using a standard phase I design. Dose-limiting toxicity (DLT) during cycle 1 included: (1) neutrophil nadir < 500/μL attributed to therapy, (2) platelet nadir < 50,000/μL attributed to therapy, (3) grade 3-4 non-hematologic toxicity attributed to therapy, and (4) neutropenia associated with grade 2 fever (i.e., febrile neutropenia). Results: Nineteen patients received 50 cycles of therapy (range 1-11 cycles) at 6 dose levels. There were no dose-limiting toxic events. There were no consistent changes in serum TIE-2 or VCAM-1 levels, or urinary VEGF. One patient with renal cell carcinoma had stable disease for 9 months, and another patient with metastatic prostate cancer had a 70% decline in serum prostate-specific antigen, which lasted 4 months. Conclusions: Oral vinorelbine may be given using a metronomic schedule, 50 mg thrice weekly for three of 4 weeks, with minimal toxicity in patients with advanced cancer. [ABSTRACT FROM AUTHOR]

Purpose: Paclitaxel, a cytotoxic agent metabolized by cytochrome P450 hepatic enzymes, is active for the treatment of human immunodeficiency (HIV) associated Kaposi's sarcoma. Protease inhibitors are commonly used to treat HIV infection and are known to inhibit cytochrome P450. We sought to determine whether protease inhibitors alter the pharmacokinetics of paclitaxel. Methods: Patients with advanced HIV-associated KS received paclitaxel (100 mg/m) by intravenous infusion over 3 h, and plasma samples were collected to measure paclitaxel concentration. The area under the curve (AUC) was calculated using a combination of the log and linear trapezoidal rule, and clearance was calculated as the dose/AUC. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicity, Results: Thirty-four patients received paclitaxel, of whom 20 had no prior paclitaxel therapy and were assessable for response. Twenty-seven had pharmacokinetic studies performed. Paclitaxel exposure was higher in patients taking protease inhibitors compared to those who were not taking protease inhibitors. The increased exposure did not correlate with efficacy or toxicity. Of the 20 patients assessable for response, 6 (30%) had an objective response and median progression-free survival was 7.8 months (95% confidence interval, 5.6, 21.0 months). Conclusion: Despite higher exposure to paclitaxel, patients on protease inhibitors did not experience enhanced toxicity or efficacy. [ABSTRACT FROM AUTHOR]

Background: 3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma. Methods: Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000 mg/m on days 1, 8, and 15 every 28 days) 1 h after completing a 4-h infusion of 3-AP given at a dose of 105 mg/m in patients with normal liver function (stratum A) or 80 mg/m if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B. Results: Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3-4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24 h after 3-AP therapy showed increased R2 mRNA expression by in situ RT-PCR, suggesting RR inhibition. Conclusions: Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract. [ABSTRACT FROM AUTHOR]

Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky's performance status (KPS) 70-80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70-80 subset ( n = 606) or KPS 90-100 subset ( n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70-80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90-100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70-80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433). [ABSTRACT FROM AUTHOR]

DNA methylation, histone modification, and nucleosome remodeling are the three intercalated events that result in epigenetic modification, which in turn alters gene expression. Aberrant epigenetic regulation resulting in altered gene expression has been clearly implicated in the initiation and progression of breast cancer. Our understanding of the landscape of these changes in breast cancer has increased tremendously over the past decade. Significant advancement has been made in the preclinical arena to identify targets that are epigenetically altered in breast cancer and to modulate these targets with epigenetic therapies to improve tumor response. Clinical translation of these concepts is currently ongoing and shows promise in improving outcomes in breast cancer. This article provides a comprehensive review of the completed and ongoing clinical trials of epigenetic therapy in the management and prevention of breast cancer and the rationale leading to the design of these trials. [ABSTRACT FROM AUTHOR]

The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)–docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m2) and docetaxel (60 mg/m2) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in ~10% of patients. In conclusion, concurrent administration of trastuzumab with PLD–docetaxel was not associated with higher risk of cardiac toxicity compared with PLD–docetaxel alone, but led to excessive hand-foot syndrome. [ABSTRACT FROM AUTHOR]

Imaging and local therapy are important modalities for detection and management of localized breast cancer. Improvements in screening and local therapy have contributed to reduced breast cancer-associated morbidity and mortality. The Coalition of Cancer Cooperative Groups (CCCG) convened the Scientific Leadership Council (SLC) in breast cancer, an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for breast imaging and locoregional therapy, and also identified six trials judged to be of high priority. Current high priority trials included trials determining: (1) the role of accelerated partial breast versus whole-breast radiation (B39), (2) the feasibility, safety, and local and systemic control of small localized breast cancers treated with tumor ablation (Z1072), (3) the role of removal of the primary cancer in selected patients with metastatic disease (E2108), and (4) the clinical and biological effects of pre-operative anti-HER2-directed and ER-directed therapies in localized or locally advanced breast cancer (B41, Z1031, Z1041). Ongoing and future trials will further refine optimal locoregional management, and additional research is required to develop improved screening methods and identify high risk populations most likely to benefit from targeted screening. [ABSTRACT FROM AUTHOR]

Over 9,000 women with breast cancer are enrolled annually on clinical trials sponsored by the National Cancer Institute (NCI), accounting for about one-third of all patients enrolled on NCI-sponsored trials. Thousands are also enrolled on pharmaceutical-sponsored studies. Although breast cancer mortality rates have recently declined for the first time in part due to systemic therapeutic advances, coordinated efforts will be necessary to maintain this trend. The Coalition of Cancer Cooperative Groups convened the Scientific Leadership Council in breast cancer (BC), an expert panel, to identify priorities for future research and current trials with greatest practice-changing potential. Panelists formed a consensus on research priorities for chemoprevention, development and application of molecular markers for predicting therapeutic benefit and toxicity, intermediate markers predictive of therapeutic effect, pathogenesis-based therapeutic approaches, utilization of adaptive designs requiring fewer patients to achieve objectives, special and minority populations, and effects of BC and treatment on patients and families. Panelists identified 13 ongoing studies as High Priority and identified gaps in the current trial portfolio. We propose priorities for current and future clinical breast cancer research evaluating systemic therapies that may serve to improve the efficiency of clinical trials, identify individuals most likely to derive therapeutic benefit, and prioritize therapeutic strategies. [ABSTRACT FROM AUTHOR]

The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab. [ABSTRACT FROM AUTHOR]

Background and Objective: Preclinical data suggest gemcitabine may have schedule-dependent activity favoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h.Patients and Methods: Gemcitabine was initially given at 1 mg/m(2)/d for 48, then 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m(2)/d. Dose levels of 7, 8, 9 mg/m(2)/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule, we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk.Results: Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1-10 cycles). The RPTD was 8 mg/m(2)/d every 3 wk, and 6 mg/m(2)/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>or= grade 2) included fever (n = 14), dyspnea (n = 7), mucositis (n = 6), hypotension (n = 6), nausea/vomiting (n = 6), and fatigue (n = 5). Neutropenia and/or thrombocytopenia were uncommon.Conclusion: Administration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m(2)/d (32 mg/m(2)/course) when given every 3 wk, or 6 mg/m(2)/d (24 mg/m(2)/course) when given every 2 wk. [ABSTRACT FROM AUTHOR]

The anthracyclines are commonly used for the treatment of early stage and advanced stage breast cancer, but many patients develop resistance to therapy. The definition of anthracycline resistance varies considerably in the literature, but in most cases includes disease progression during or within 6–12 months after completion of anthracycline therapy. Some authors have distinguished true anthracycline resistance (defined as progression during anthracycline therapy) from anthracycline pretreatment (defined as progression after completion of therapy). Single agents that have demonstrated response rates of at least 15–20% in anthracycline pretreated or resistant disease include the antitubulin agents (docetaxel, paclitaxel, vinorelbine), antimetabolites (capecitabine, fluorouracil), nucleoside analogues (gemcitabine), and trastuzumab (for HER2/neu positive disease only). Phase III studies have demonstrated that docetaxel is more effective than paclitaxel, mitomycin/vinblastine, and methotrexate/fluorouracil, and that the docetaxel/capecitabine combination is more effective than docetaxel alone. The decision regarding which agent(s) to use should be based upon the patient’s prior treatment history, tumor biology (HER2/neu and hormone receptor expression), comorbid conditions (e.g. neuropathy, heart disease), and other considerations (e.g. insurance coverage for oral medication). The choice of a specific treatment regimen must be individualized based upon these considerations. [ABSTRACT FROM AUTHOR]

Several anticancer drugs have been associated with cardiac toxicity, especially the anthracyclines and trastuzumab. The pathogenesis of anthracycline-associated toxicity has been well described, whereas the mechanism of trastuzumab-associated toxicity is unknown. Although routine cardiac imaging studies (e.g. echocardiogram or multiple gated acquisition scans) may identify subclinical evidence of myocardial dysfunction, available data do not support their routine use for monitoring asymptomatic patients undergoing cancer therapy. Other modalities such as nuclear medicine scintigraphy with indium-111-antimyosin antibody and endomyocardial biopsy have been shown to be useful in identifying early cardiac damage, but their routine use is limited by practical considerations such as feasibility and cost. Consequently, there is significant interest in developing simple and reproducible methods for identifying patients at risk for treatment-induced myocardial damage. Available data suggest that circulating markers such as troponins and natriuretic peptides could potentially be useful for this purpose. Measurement of plasma troponin levels are commonly used in clinical practice in order to provide diagnostic and prognostic information in patients with myocardial ischaemia. Elevated levels may likewise correlate with anthracycline-induced cardiac damage, although plasma levels are only minimally elevated (well below that associated with ischaemia), and elevations may persist for weeks or months after anthracycline exposure. Clinical trials are currently evaluating the role of these markers in predicting both early and late, clinical and subclinical damage associated with anthracyclines and trastuzumab. [ABSTRACT FROM AUTHOR]

Echinomycin is a novel bifunctional intercalating agent derived from Streptomyces echinatus. A phase II clinical trial of echinomycin in patients with advanced, measurable colorectal cancer was initiated to determine the efficacy and toxicities of this agent. Echinomycin, 1.5 mg/m2, was given initially as a 30- to 60-min infusion every 4 weeks. After 4 episodes of anaphylaxis had occurred among the first 14 patients, the schedule was changed to a 24-h infusion, and an additional 16 patients were treated on this schedule. Treatment was given every 3 weeks. A total of 30 patients were eligible and evaluable; there were 3 (10%; 90% confidence interval, 3%-23%) clinical responses lasting 3, 3+, and 12 months, respectively. The most serious toxicity encountered was anaphylaxis, which occurred in 5 patients, although with no serious sequelae. A premedication regimen with dexamethasone, diphenhydramine, and cimetidine and a change of the duration of the infusion to 24 h reduced the incidence of this complication. Grade 2-3 vomiting occurred among earlier patients treated; however, with the 24-h schedule this toxicity was substantially reduced. The sole important case of hematologic toxicity was a single patient with grade 3 thrombocytopenia. Echinomycin employed in this dose and schedule had modest activity against colorectal cancer, comparable with that observed with 5-fluorouracil. Further studies in patients with gastrointestinal malignancies using a 24-h infusion with a dexamethasone premedication regimen similar to that employed prior to administration of taxol may be warranted. [ABSTRACT FROM AUTHOR]