Agents In Metastatic Breast Cancer Research Articles

Abstract P5-09-02: Impact of therapeutic complexity on practice patterns for metastatic breast cancer (MBC) in the United States: Results of a 2-phase national study

Abstract Background: The rapidly changing clinical management of MBC has challenged the ability of clinicians to understand and integrate new data, which relates directly to the quality of clinical care and is a key determinant of patient outcomes. This study was designed to determine the potential impact of the increased clinical complexity of decision making in MBC on optimal patient care by quantifying professional practice gaps and barriers among oncology specialists at academic medical centers and community clinic settings in the United States. Methods: From October 2014 to February 2015, 216 actively practicing US oncology specialists with a caseload of ≥1 patient/year with MBC were recruited to participate in a 2-phase national needs assessment study. In the first, qualitative phase, 35 participants consented to a 45-minute telephone interview focused on the personal, contextual, and behavioral factors that influence their clinical reasoning process in diagnosis and treatment of MBC. Findings from this initial phase informed the second phase of the study. This quantitative phase included an online survey comprising specific multiple choice questions, semantic differential rating scales, and case vignettes. Respondents' (N = 181) answers to these questions were compared with optimal answers, as identified by treatment guidelines and MBC experts. Results: Eight core practice gaps were identified through combined analysis of data from the in-depth interviews and online surveys. Of note, only 15% of respondents agreed with the experts' choice of letrozole + palbociclib as initial treatment for a postmenopausal patient with HR+ MBC with bone and visceral lesions after a prolonged response to adjuvant endocrine therapy. Survey respondents indicated that they use chemotherapy substantially more frequently than experts when treating patients with HR+ MBC. Only 36% of respondents' current practice matched expert recommendations regarding management of toxicity associated with exemestane + everolimus and 32% opted for management strategies with a risk of worsening treatment-related toxicity. Just over 30% of respondents agreed with the expert choice of ado-trastuzumab emtansine as second-line therapy for HER2+ MBC after progression on trastuzumab/paclitaxel. In addition, a minority of respondents knew the mechanisms of action of newly approved (palbociclib [45%]) and investigational agents, including dovitinib (19%), neratinib (30%), pembrolizumab (49%), and pictilisib (28%). Conclusions: A significant percentage of US oncology specialists are not applying optimal care in patients with MBC. Most notably, this study indicated that participants overuse chemotherapy in patients with HR+ MBC, suboptimally manage treatment-related toxicities, and are challenged to select optimal therapy for HER2+ MBC patients who progress on previous therapy. Finally, a lack of familiarity with mechanisms of action of approved and promising investigational agents in MBC may lead to delays in the appropriate integration of new agents or indications into clinical practice. A full review of the study results and recommendations will be presented. Citation Format: Quill TA, Jahanzeb M, Obholz KL, Brady E, Howson A, Rasulina M, Willis C, Hurvitz S. Impact of therapeutic complexity on practice patterns for metastatic breast cancer (MBC) in the United States: Results of a 2-phase national study. [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 P5-09-02.

Abstract 279: Bexarotene increases tumor CD8+ T cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model TgMMTV-neu

Abstract In breast cancer, increased immune infiltrate prior to neoadjuvant chemotherapy predicts improved pathologic complete response (pCR) and improved survival, however almost half of breast tumors have no CD8+ T cell infiltrate. Evidence has emerged that conventional breast cancer chemotherapy can increase CD8+ T cells (doxorubicin) and decrease the immunosuppressive regulatory CD4+ T cells (paclitaxel and cyclophosphamide); therefore discovering well tolerated agents that further enhance the anti-tumor immune function of these chemotherapies may further improve response in breast cancer patients. The oral agent bexarotene (a retinoic receptor agonist) showed a 20% disease response as a single agent in metastatic breast cancer and has been shown to increase CD8+ T cell tumor infiltration and decrease CD8+ T cell apoptosis in vitro. The goal of this study is to demonstrate whether this well tolerated oral agent can enhance the anti-tumor response of conventional chemotherapy through increasing intratumoral CD8+ T cells in TgMMTV-neu transgenic mice that are immunologically competent and genetically similar to human luminal B breast cancer. Two of the most active chemotherapies in human breast cancer, doxorubicin and paclitaxel, each could inhibit tumor growth by 70-80% and increase CD8+ T cell tumor infiltrate by approximately 40% in tumor bearing TgMMTV-neu mice, a third breast cancer chemotherapy cyclophosphamide increased CD8+ tumor infiltrate by 45% (p = 0.011) but did not show a statistically significant decrease in tumor volume. When TgMMTV-neu mice with ∼100 mm3 tumors were treated with 50 mg/m2 bexarotene for four weeks they demonstrated a 44% increase in CD8+ tumor infiltrate (p = 0.05) and 60% decrease in mean tumor growth (p = 0.03) compared to control. However, the addition of bexarotene to chemotherapy was superior to chemotherapy alone, and significantly more effective than bexarotene alone. This enhanced anti-tumor function was even seen with cyclophosphamide that by itself had not inhibited tumor growth. Adding bexarotene to weekly doxorubicin decreased tumor growth by 98% (p = 0.008 compared to doxorubicin alone), adding bexarotene to weekly paclitaxel decreased tumor growth by 86% (p = 0.02 compared to paclitaxel alone), and adding bexarotene to weekly cyclophosphamide inhibited tumor growth by 82% (p = 0.04 compared to cyclophosphamide alone). Further studies are now ongoing to identify the anti-tumor role of bexarotene particularly its immune modulatory role. These results suggest that the addition of bexarotene, a relatively well-tolerated oral agent, may modify the immune environment and improve tumor response to chemotherapy in breast cancer possibly improving response to neoadjuvant chemotherapy. Citation Format: Sasha E. Stanton, Ekram Gadd, Edmond Marzbani, Lauren Rastetter, Mary L. Disis. Bexarotene increases tumor CD8+ T cells and improves response to conventional breast chemotherapy in the transgenic mouse mammary tumor model TgMMTV-neu. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 279. doi:10.1158/1538-7445.AM2015-279

Combination of eribulin (E) and capecitabine (C) in elderly metastatic breast cancer (MBC): Update of a new option suitable in older elderly.

9540 Background: E mesylate, a nontaxane microtubule dynamics inhibitor is widely prescribed for MBC pts pretreated with at least 1-2 lines of chemotherapy, including anthracyclines and taxanes (A&...

Abstract SY45-02: Evaluation of targeted therapies in advanced breast cancer

Abstract SY45-02: Evaluation of targeted therapies in advanced breast cancer

394P - Eribulin in Her2 Negative Metastatic Breast Cancer, Assessment of Overall Survival in Real World

ABSTRACT Aim: Recently new chemotherapeutic agents for metastatic breast cancer (MBC) have been developed and introduced to bedside. Some of them improved overall survival (OS) in clinical trial, however, it is still unclear those agent(s) improve OS of MBC patients in real world. Methods: HER2 negative MBC (HER2-MBC) patients who received chemotherapy (-ies) in our institute from September 2002 to March 2014 were reviewed. Kaplan-Meier method was utilized to estimate median OS and log-rank test was used to compare OS between subgroups. Univariate and multivariate Cox regression analyses were preformed to find significant factor(s) concerning OS. Results: Upon checking our medical record, 446 HER2-MBC patients, median age of 55 (range 25-85) at their diagnosis of MBC were found, and 397 patients were receiving/received chemotherapy (-ies). Disease statuses were as follows; 105 (26.4%) advanced, 292 (73.6%) recurrent, 321 (80.9%) luminal, 76 (19.1%) triple-negative, 149 (37.5%) with visceral disease at MBC diagnosis. Multivariate COX regression analysis disclosed use of eribulin, triple-negative status and liver involvement at the diagnosis of MBC influenced OS significantly. (HR = 2.29; 95% confidence interval [CI] 1.73-3.04; P Conclusions: According to our retrospective, multivariate analyses of house data, eribulin significantly improved OS of HER2-MBC patients. We have to reassess the value of new chemotherapeutic agents continuously. Disclosure: All authors have declared no conflicts of interest.

Eribulin (E) and capecitabine (C), a combined treatment schedule in elderly metastatic breast cancer (EMBC): Efficacy and safety evaluation (E&S).

e20513 Background: E mesylate, a nontaxane microtubule dynamics inhibitor, was approved in the U.S in 2010 for the treatment of MBC who have previously received at least 2 MBC chemo regimens, inclu...

Two different doses of fulvestrant (F) as second- or further-line hormone therapy (HT) in elderly patients with metastatic breast cancer (MBC).

e11547 Background: Fulvestrant (F) is a pure antiestrogen drug approved for MBC of postmenopausal women with estrogen receptor positive disease. The CONFIRM trial has recently demonstrated that a double dose (500 mg/monthly) of F is superior to 250 mg/monthly dose as PFS in MBC. In elderly (age >65 years) patients (pts) HT is the preferred choice when disease is hormone sensitive. The aim of our study was to determine the comparative activity, toxicity and feasibility of two different schedule of F in elderly women with MBC. Methods: A retrospective study was carried out in elderly MBC pts treated between 2006-2013 with F after at least one HT. Pts received F 250 or 500 mg im every 28 days until progression. Median age was 70,5 years (66-84). ER e PR status was known in all pts: ER+/PR+ were 56 (94%), ER+/PR- 4 (6%). Histological type were: ductal 52 (86,6%), lobular 8 (13,4%). HER 2 was positive in 4 (6%) pts. All pts were metastatic: 20 (33%) with bone metastasis alone, 40 (66%) with visceral involvemen...

Bleomycin electrochemotherapy in elderly metastatic breast cancer patients: clinical outcome and management considerations.

To evaluate the efficacy and toxicity of electrochemotherapy (ECT) in elderly metastatic breast cancer (BC) patients. Retrospective analysis of 55 patients with superficial metastases who underwent ECT according to the European Standard Operative Procedures of electrochemotherapy. Treatment schedule consisted of intravenous or intratumoral bleomycin followed by locally delivered electric pulses. Statistical comparisons were performed between two groups: the patients aged <70years (n=27) and those ≥70years (n=28). Treatment outcomes were as follows: complete response (CR) rate, local progression-free survival (LPFS), new lesions-free survival (NLFS), toxicity and patient compliance. Patient groups were comparable for clinical-pathological features, except for the number of comorbidities (P<.001). The median follow-up was 32months (range 6-53). Overall, CR rate was 40% and was significantly higher in elderly patients (57 vs. 26%, P=.023) and in patients with better performance status (PS=0-1, 53 vs. PS=2, 21%, P=.048), although local tumor control showed a trend for lower values (2-year LPFS, 67 vs. 93% among elderly and young patients, respectively; P=.061). Older women seemed less likely to progress outside the ECT field (2-year NLFS, 39 vs. 30%, P=.075), but discontinued treatment more frequently due to impaired performance status (P=.002). Local pain was graded ≥3, according to a 10-point visual analog scale, by 16/28 (57.1%) and 8/28 (28.6%) elderly patients at 4 and 8weeks, respectively. Wound debridement was required in 5/28 (18%) older women, due to G3 skin ulceration. Elderly BC patients are highly responsive to ECT and achieve durable local tumor control. Physicians should be aware of possible debilitating side effects, such as pain and skin toxicity. Performance status and frailty screening could be a helpful addition to improve patient selection.

Abstract P4-12-09: Results from a phase 2a study of trastuzumab emtansine, paclitaxel, and pertuzumab in patients with HER2-positive metastatic breast cancer

Abstract Introduction The antibody-drug conjugate trastuzumab emtansine (T-DM1) combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1 via a stable linker. T-DM1 prolonged PFS and OS vs standard therapy in a phase 3 study of patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with H and a taxane. Preclinical data suggest synergy when T-DM1 is combined with paclitaxel (T) or pertuzumab (P). In the phase 1b study TDM4652g, the maximum tolerated doses of T-DM1 + T ± P were defined. Here we present results from the phase 2a expansion, which further explored feasibility and safety. Methods TDM4652g is a phase 1b/2a open-label study of pts with HER2-positive locally advanced or MBC. Pts had no prior T-DM1 or P, no baseline peripheral neuropathy (PN; phase 2a only), and had LVEF ≥50%. Pts in phase 2a were randomized to T-DM1 3.6 mg/kg q3w + T 80 mg/m2 qw ± P 840 mg loading dose [LD], then 420 mg q3w. The primary objective, feasibility, was assessed by the percent of evaluable pts receiving ≥12 doses of T within 15 weeks of cycle 1, day 1, and those receiving 12 consecutive weeks of T. Results Forty-four pts were enrolled (T-DM1 + T, n = 22; T-DM1 + T + P, n = 22); the data snapshot date was May 23, 2013. Median age was 52.5 years (range, 35–81); median number of prior agents for MBC was 6 (range, 0–12). 43 (98%) pts had previously received H, and 36 (82%) pts had received taxane therapy. Median dose intensities were T-DM1, 94% (range 54–105); T, 50% (range 9–100) and P, 100% (range 67–100). 2 pts were not evaluable for feasibility (progressive disease [PD] before receiving 12 doses of T). 21/42 (50%) pts received ≥12 doses of T within 15 weeks; 6/42 (14%) pts received 12 consecutive doses by week 12, and 33/42 (79%) pts received ≥8 doses within 12 weeks. Grade 3/4 adverse events (AEs) were reported for 18 (82%) and 17 (77%) pts in the T-DM1 + T and T-DM1 + T + P groups, respectively (see Table for AEs and best responses). Ten pts discontinued early due to PD (n = 6), PD-related death (n = 2), AEs (n = 1), or withdrawal from the study (n = 1). 21 pts discontinued T due to AEs, most commonly PN (n = 12). Grade 3/4 AEs occurring in &amp;gt;1 patientAE, n (%)All patients (N = 44)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw (n = 22)TDM1 3.6 mg/kg q3w + T 80 mg/m2 qw + P 840 mg LD, 420 mg q3w (n = 22)Neutropenia10 (23)6 (27)4 (18)Peripheral neuropathy9 (20)3 (14)6 (27)Fatigue6 (14)3 (14)3 (14)Thrombocytopenia6 (14)5 (23)1 (5)Anemia3 (7)2 (9)1 (5)Abdominal pain2 (5)2 (9)0Decreased hemoglobin2 (5)1 (5)1 (5)Muscosal inflammation2 (5)1 (5)1 (5)Muscular weakness2 (5)02 (9)Nausea2 (5)1 (5)1 (5)Best response,* n (%)CR2 (5)1 (5)1 (5)CR confirmed1 (2)1 (5)0PR27 (61)13 (59)14 (64)PR confirmed8 (18)3 (14)5 (23)SD10 (23)6 (27)4 (18)PD3 (7)1 (5)2 (9)*At any time point with responses ordered CR&amp;gt;PR&amp;gt;SD&amp;gt;PD. Conclusions Overall, 50% of pts received ≥12 doses of T within 15 weeks. Adding P to the combination of T-DM1 + T did not appear to increase the incidence of grade 3/4 AEs. Data support further investigation of T-DM1 + T ± P in larger studies in early breast cancer. Final data from all phase 2a patients will be available for the full report. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-09.

Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: Results from the OMEGA study of the Dutch Breast Cancer Trialists' Group

AimTo evaluate the association between baseline comprehensive geriatric assessment (CGA) or the Groningen Frailty Indicator (GFI) and toxicity in elderly metastatic breast cancer (MBC) patients treated with first-line palliative chemotherapy. Patients and methodsMBC patients (≥65 years) were randomized between pegylated liposomal doxorubicine or capecitabine. CGA included instrumental activities of daily living (IADL), cognition using the mini-mental state examination (MMSE), mood using the geriatric depression scale (GDS), comorbidity using the Charlson index, polypharmacy and nutritional status using the body mass index. Frailty on CGA was defined as one or more of the following: IADL ≤ 13, MMSE ≤ 23, GDS ≥ 5, BMI ≤ 20, ≥5 medications or Charlson ≥2. The cut-off for frailty on the GFI was ≥4. ResultsOf the randomized 78 patients (median age 75.5 years, range 65.8–86.8 years), 73 were evaluable for CGA; 52 (71%) had one or more geriatric conditions. Grade 3–4 chemotherapy-related toxicity was experienced by 19% of patients without geriatric conditions compared to 56% of patients with two geriatric conditions and 80% of those with three or more (p = 0.002). Polypharmacy was the only individual factor significantly associated with toxicity (p = 0.001). GFI had a sensitivity of 69% and a specificity of 76% for frailty on CGA, and was not significantly associated with survival or toxicity. ConclusionIn this study of elderly patients with MBC, the number of geriatric conditions correlated with grade 3-4 chemotherapy-related toxicity. Therefore, in elderly patients for whom chemotherapy is being considered, a CGA could be a useful addition to the decision-making process.

Impact of geriatric risk factors on pegylated liposomal doxorubicin tolerance and efficacy in elderly metastatic breast cancer patients: Final results of the DOGMES multicentre GINECO trial

BackgroundMetastatic breast cancer chemotherapy in the elderly is considered effective in carefully selected patients, but there is little data regarding its effect in vulnerable patients. MethodsWe evaluated tumour response (primary endpoint), feasibility and outcomes after six courses of an adapted dose of pegylated liposomal doxorubicin (PLD) (40mg/m2 every 28 days) as first-line chemotherapy for hormone-resistant MBC. ResultsOf 60 patients >70 years (median 77 years), 15% had performance status ⩾2 and 73% had visceral metastases. Geriatric assessment included: ⩾2 comorbidities, 42%; ⩾1 deficiency in Activities of Daily Living (ADL), 10% and Instrumental ADL (IADL), 82%; living in residential homes, 12%; albumin <35g/L, 17%; body mass index (BMI) <21, 20%; depression, 17%; and lymphocytes ⩽1×103/mm3, 27%. Complete response, partial response and stable disease were observed in 5%, 15% and 60%, respectively, but only 48% completed six cycles. Treatment discontinuations were mostly due to disease progression (18%) and non-haematological (NH) toxicities (22%). Eight patients died during treatment (three possibly related to PLD), and 15 had unplanned hospital admissions. Exploratory analyses to identify geriatric covariates associated with treatment outcomes revealed severe haematological toxicities significantly correlated with lymphocytes ⩽1×103/mm3. NH toxicities correlated with age ⩾80 years and living in residential homes. Progression-free survival (median 6.1 months) decreased with age, deficiency in IADL, cardiac dysfunction and living in residential homes. Overall survival (median 15.7 months) also decreased with living in residential homes. ConclusionDespite manageable haematological toxicities and expected response rates, PLD feasibility was poor in unselected elderly patients.

Progression-free survival (PFS) as surrogate endpoint for overall survival (OS) in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer (MBC): An individual patient data (IPD) analysis.

610 Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2+ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2+ MBC patients (pts) in 1992-2008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r=0.66 (95% CI 0.65 to 0.66) corresponding to an r2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R2=0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R2=0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2+ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.

Emerging targeted agents in metastatic breast cancer

Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents.

Slow accrual of elderly patients with metastatic breast cancer in the Dutch multicentre OMEGA study

BackgroundIn a Dutch multicentre study, elderly (65 + year) metastatic breast cancer patients, eligible for first-line chemotherapy, were randomised between two types of single-agent chemotherapy. As accrual was slow, with 78 randomised patients between April 2007 and September 2011, we explored potential barriers in the accrual process and their consequences for characteristics of included patients. MethodsWe sent surveys on the reasons for non-inclusion to all coordinating investigators. We also examined inclusion in a concurrent, non-elderly breast cancer study of the trialists' group and analysed baseline geriatric characteristics of included patients. ResultsInvestigators from fifteen participating centres returned the survey. Most commonly reported barriers to inclusion were: patient's refusal of chemotherapy (n = 8) or of randomisation (n = 9), impaired cognition (n = 3) and insufficient cardiac function (n = 2). Oncologists' preference for combination regimens over single-agent chemotherapy was reported twice. Twenty-eight potentially eligible patients, aged 65–71 years, were included in a concurrent, study investigating combination chemotherapy in fit non-elderly patients with metastatic breast cancer. However, baseline characteristics of the included patients showed that the OMEGA study succeeded in including frail and older patients, with a performance status of 2 in 22% of patients and 54% of patients aged 75 years or older. ConclusionAccrual in this study was mainly hampered by patient's refusal or preference for a particular type of treatment, and an overall condition considered as too fit or too frail for inclusion. Future trials in elderly metastatic breast cancer patients should focus on non-restrictive inclusion criteria as well as on education of physicians and elderly patients on the advantages of trial participation.

Abstract P1-12-05: First-line chemotherapy with pegylated liposomal doxorubicin versus capecitabine in elderly patients with metastatic breast cancer: results of the phase III OMEGA study of the Dutch Breast Cancer Trialists' Group (BOOG)

Abstract Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m2, IV, q 4 wks) or capecitabine (Cape) (1000 mg/m2 PO bid, days 1–14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0–1 vs 2–3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65–86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0–1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42–1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49–1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1–2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3–4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21–4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31–4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-05.

New Vinca Alkaloids in Clinical Development

The most successful tubulin-targeting agents in the treatment of breast cancer are the taxanes and the Vinca alkaloids. Vinorelbine, a vinca alkaloid derivative, has remarkable clinical activity in advanced breast cancer patients, and is currently used. Among the most critical limitations of Vinca alkaloids in metastatic breast cancer are their sensitivity to multidrug resistance pumps and the development of drug resistance. So, there is a need for new efficacious Vinca alkaloids agents that are associated with increased response and limited and manageable toxicity. Vinflunine is a novel microtubule inhibitor of the Vinca alkaloid class obtained by semi-synthesis using superacidic chemistry to selectively modify the catharantine moiety. In preclinical models, vinflunine is more active in vivo than the other Vinca alkaloids and resistance to vinflunine develops more slowly than that to vinorelbine. In addition, vinflunine in-vitro neurotoxicity is lower than that of vincristine and of vinorelbine. Encouraging phase II results and the favorable safety profile of vinflunine warrant further investigation of this novel agent in combination with other active agents in metastatic breast cancer. Comparative clinical trials have been initiated.

Aromatase Inhibition in Obese Women: How Much Is Enough?

Aromatase Inhibition in Obese Women: How Much Is Enough?

Frondoside A has an anti-invasive effect by inhibiting TPA-induced MMP-9 activation via NF-κB and AP-1 signaling in human breast cancer cells

Metastasis and invasion are among the main causes of death in patients with malignant tumors. The aim of this study was to determine the anti-invasive activity of frondosideA against human breast cancer cells. We investigated the inhibitory effect of frondosideA on cell clonogenicity, invasion and migration in TPA-stimulated human breast cancer cells at non-cytotoxic concentrations. FrondosideA significantly attenuated TPA-induced colony formation, invasion and migration in MBA-MB-231 human breast cancer cells. Induction of MMP-9 is especially important for the metastasis of many cancer tumor cell types. Additionally, we found that frondosideA suppresses TPA-induced MMP-9 enzymatic activity, secretion and expression. This effect was associated with reduced activation of AP-1 and NF-κB, and correlated with enhanced expression of TIMP-1 and TIMP-2. FrondosideA significantly inhibited the TPA-induced MMP-9 expression possibly via the suppression of AP-1 and NF-κB signaling pathways. FrondosideA reduces the activation of the PI3K/Akt, ERK1/2 and p38 MAPK signals. These results suggest that the anti-metastatic effects of frondosideA on human breast cancer cells might result from inhibited TPA activation of AP-1 and NF-κB and reduced TPA activation of PI3K/Akt, ERK1/2 and p38 MAPK signals, ultimately leading to downregulation of MMP-9 expression. These results indicate the role of frondosideA in metastasis and its underlying molecular mechanisms, thus, suggesting frondoside A as a chemopreventive agent for metastatic breast cancer.

Baseline comprehensive geriatric assessment to predict for toxicity of single-agent chemotherapy in elderly metastatic breast cancer patients: Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group.

1080 Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m2every 4 weeks or capecitabine 2000 mg/m2 on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.

Lapatinib for advanced or metastatic breast cancer.

Lapatinib is a potent reversible and selective inhibitor of the tyrosine kinase domains of epidermal growth factor receptor and human epidermal growth factor receptor (HER)-2 that exerts its action by competitive binding to the intracellular ATP-binding site of the receptor. It is registered for the treatment of advanced or metastatic HER-2+ breast cancer in combination with capecitabine and for hormone receptor-positive breast cancer in combination with an aromatase inhibitor. Lapatinib administered orally once daily is moderately to well tolerated, with rash and gastrointestinal adverse events as the main toxicities. In studies on the efficacy of lapatinib, direct comparisons between lapatinib and trastuzumab are lacking. Results of ongoing randomized phase III studies with lapatinib or trastuzumab in combination with taxanes as first-line agents for metastatic breast cancer as well as in the neoadjuvant and adjuvant settings are awaited.