Efficacy In Advanced Breast Cancer Research Articles

360P Identification of circulating immune factors as predictive biomarkers of CDK4/6i treatment efficacy in advanced breast cancer

360P Identification of circulating immune factors as predictive biomarkers of CDK4/6i treatment efficacy in advanced breast cancer

Absolute lymphocyte count and neutrophil-to-lymphocyte ratio as predictors of CDK 4/6 inhibitor efficacy in advanced breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the standard agents for treating patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (ER + HER2 - ABC). However, markers predicting the outcomes of CDK4/6i treatment have yet to be identified. This study was a single-center retrospective cohort study. We retrospectively evaluated 101 patients with ER + HER2 - ABC receiving CDK4/6i in combination with endocrine therapy at Fukuyama City Hospital between November 2017 and July 2021. We investigated the clinical outcomes and the safety of CDK4/6i treatment, and the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) as predictive markers for CDK4/6i. We defined the cut-off values as 1000/μL for ALC and 3 for NLR, and divided into "low" and "high" groups, respectively. We evaluated 43 and 58 patients who received abemaciclib and palbociclib, respectively. Patients with high ALC and low NLR had significantly longer overall survival than those with low ALC and high NLR (high vs. low; ALC: HR 0.29; 95% CI 0.12-0.70; NLR: HR 2.94; 95% CI 1.21-7.13). There was no significant difference in efficacy between abemaciclib and palbociclib and both had good safety profiles. We demonstrated that ALC and NLR might predict the outcomes of CDK4/6i treatment in patients with ER + HER2 - ABC.

Ginsenoside Rh2-Based Multifunctional Liposomes for Advanced Breast Cancer Therapy.

Most solid tumors are not diagnosed and treated until the advanced stage, in which tumors have shaped mature self-protective power, leading to off-target drugs and nanomedicines. In the present studies, we established a more realistic large tumor model to test the antitumor activity of a multifunctional ginsenoside Rh2-based liposome system (Rh2-lipo) on advanced breast cancer. Both cholesterol and PEG were substituted by Rh2 to prepare the Rh2-lipo using ethanol-water system and characterized. The effects of Rh2-lipo on cell uptake, penetration of the tumor spheroid, cytotoxicity assay was investigated with 4T1 breast cancer cells and L929 fibroblast cells. The 4T1 orthotopic-bearing large tumor model was established to study the targeting effect of Rh2-lipo and inhibitory effect of paclitaxel loaded Rh2-lipo (PTX-Rh2-lipo) on advanced breast tumors. Rh2-lipo exhibit many advantages that address the limitations of current liposome formulations against large tumors, such as enhanced uptake in TAFs and tumor cells, high targeting and penetration capacity, cytotoxicity against TAFs, normalization of the vessel network, and depletion of stromal collagen. In in vivo study, PTX-Rh2-lipo effectively inhibiting the growth of advanced breast tumors and outperformed most reported PTX formulations, including Lipusu® and Abraxane®. Rh2-lipo have improved drug delivery efficiency and antitumor efficacy in advanced breast cancer, which offers a novel promising platform for advanced tumor therapy.

Alpelisib Efficacy in Advanced Breast Cancer

Breast cancer is one of the popular problems related to the medical field. Breast cancer become more aggressive, and the incidence rate keeps increasing yearly. The incidence indicates the slow progression of the disease. Yearly, there are more than one million new cases that get worse. Probably the incidence rate will increase significantly in the next years. Breast cancer develops silently without medical attention, and most cases are discovered during a routine clinic visit. While other cases may accidentally discover breast lumps, changes in breast shape or size, and nipple discharge. Breast cancer highly affects women worldwide. Mortality rates of breast cancer are improving, but still, the survival rate in the advanced stage is decreasing. Nowadays, Chemotherapy is considered the gold-standard approach for most cancer types and a modest improvement in both survival rates and toxicity reduction. Therefore, this article aims to focus on the use of one of the modest drugs that treat advanced breast cancer, which is Alpelisib, and highlight the mechanism of action, indication, contraindication, pharmacodynamic, pharmacokinetic, dose, and its side effects. Alpelisib is being developed by Novartis company. The first clinical trials started in Oct 2010. It was approved in the USA on May 24th, 2019. Alpelisib works by inhibiting the phosphatidylinositol 3-kinase (PI3K) which leads to inhibiting the activation of some signaling pathways. Alpelisib is used in combination with fulvestrant to treat advanced breast cancer in postmenopausal women with some genetic mutations.

Synergistic strategy with hyperthermia therapy based immunotherapy and engineered exosomes-liposomes targeted chemotherapy prevents tumor recurrence and metastasis in advanced breast cancer.

Advanced breast cancer with recurrent and distal organ metastasis is aggressive and incurable. The current existing treatment strategies for advanced breast cancer are difficult to achieve synergistic treatment of recurrent tumors and distant metastasis, resulting in poor clinical outcomes. Herein, a synergistic therapy strategy composed of biomimetic tumor‐derived exosomes (TEX)‐Liposome‐paclitaxel (PTX) with lung homing properties and gold nanorods (GNR)‐PEG, was designed, respectively. GNR‐PEG, with well biocompatibility, cured recurrent tumors effectively by thermal ablation under the in situ NIR irradiation. Meanwhile, GNR‐mediated thermal ablation activated the adaptive antitumor immune response, significantly increased the level of CD8+ T cells in lungs and the concentration of serum cytokines (tumor necrosis factor‐α, interlekin‐6, and interferon‐γ). Subsequently, TEX‐Liposome‐PTX preferentially accumulated in lung tissues due to autologous tumor‐derived TEX with inherent specific affinity to lung, resulting in a better therapeutic effect on lung metastasis tumors with the assistance of adaptive immunotherapy triggered by GNR in vivo. The enhanced therapeutic efficacy in advanced breast cancer was a combination of thermal ablation, adaptive antitumor immunotherapy, and targeted PTX chemotherapy. Hence, the synergistic strategy based on GNR and TEX‐Liposome provides selectivity to clinical treatment of advanced breast cancer with recurrent and metastasis.

Doxorubicin response prediction in neoadjuvant breast cancer therapy.

e12119 Background: Neoadjuvant treatment for breast cancer (BC) is an important remedy if the tumors are responding adequately. Still, there is no biomarker guidance resulting in many patients receiving chemotherapy with no efficient antitumor effect. We study a multigene mRNA-based technology for drug response prediction (DRP). DRP has been thoroughly validated in other settings, latest in prediction of epirubicin efficacy in advanced BC [1]. Here are the results of the DRP method in the prediction of response to neoadjuvant doxorubicin in early BC. Methods: The DRP correlates sensitivity of the applicable drug in cell lines with background mRNA. This is combined with gene expression patterns from >2.000 tumors of different origin to ensure clinically usefulness. The higher DRP score, the higher likelihood of response. Blinded predictions of doxorubicin DRP scores were compared to response data which originated from a phase II trial [2], where the study population received neoadjuvant doxorubicin and cyclophosphamide (N=279). The patients had histologically confirmed primary invasive breast adenocarcinoma (T2-3, N0-3, M0, tumor size ≥ 2.0 cm, ER+/- and HER2+/-). Statistical analysis was done using logistic regression. Results: Table shows the distribution of response and DRP scores, showing higher DRPs are correlated to better clinical outcome. This is demonstrated by logistic regression ( p=0.002), odds ratio for response 2.2 (95% CI:1.3-3.4). Multivariate analysis showed that the DRP was independent of other covariates. Conclusions: The DRP can predict which patients will be high likelihood responders to neoadjuvant doxorubicin. Modern multigene technologies may help assist clinicians in choosing between upfront surgery or neoadjuvant chemotherapy. Complete response (CR), Partial response (PR), Stable disease (SD), Progression of Disease (PD). 1. Buhl ASK, et al. (2018): Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study. Breast cancer research and treatment. doi: 10.1007/s10549-018-4918-4. 2. Horak CE et al. (2013): Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clinical cancer research. doi: 10.1158/1078-0432.ccr-12-1359.[Table: see text]

Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer

BackgroundEverolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. Patients and methodsTumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). ResultsA total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. ConclusionsA positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.

Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Phase Ib study of sorafenib and vinorelbine as first-line treatment in patients with metastatic breast cancer.

1093 Background: Sorafenib is an oral inhibitor of Raf and VEGFR/PDGFR. In preclinical models, favorable effects were noted combining sorafenib and vinorelbine. Both vinorelbine and sorafenib undergo hepatic metabolism. We aimed to determine the recommended doses in a phase 1b study. Methods: Patients were eligible with HER2-negative metastatic breast cancer, measurable (RECIST), not previously treated with chemotherapy for advanced stage; ECOG PS 0-1, adequate renal, liver and bone marrow functions, and LVEF ≥50%. Treatment was in two subsequent cohorts of 6 patients each: vinorelbine (30 mg/m2 days 1, 8 every 21) + sorafenib 200 mg BID continuously (cohort 1); vinorelbine (same as cohort 1) + sorafenib 400 mg BID continuously (cohort 2). Patients still benefiting after 8 cycles of treatment were allowed to continue on single-agent sorafenib. Results: Six patients in each cohort (n=12) were evaluated. Patients received a median of 8 cycles of treatment. Dose-limiting toxicities with the first cycle included: grade 3 (G3) pancreatitis + cholangitis (n=1, cohort 1; gallstones were also found), and asymptomatic G4 increase in serum amylase/lipase (n=1, cohort 2; spontaneously resolved). With repeated cycles, other significant (G2-4) toxicities included: uncomplicated G3-4 neutropenia (92%); G3 enteritis (8%); G2-3 diarrhea (33%); G2-3 AST/ALT increase (33%); G2 bilirubin increase (25%), fatigue (50%), stomatitis (25%), vomiting (17%), hand-foot syndrome (17%), dyspepsia, nausea, anorexia, dry skin, sensorial neuropathy (8% each); G2 alopecia (17%). One patient discontinued treatment for recurrent G2 LVEF decrease after 8 cycles. Of 12 patients 50% showed a partial response, and 92% had clinical benefit (including stable disease after 4 cycles of treatment). Conclusions: The combination of vinorelbine and sorafenib is feasible, and shows promising efficacy in advanced breast cancer. Toxicity is quite variable, with uncomplicated neutropenia being very common. Full doses of both agents are tolerated in most patients, but patients at high risk for toxicity can more safely start on a lower dose. We recommend close monitoring for the first 2 cycles, including amylase and lipase. No significant financial relationships to disclose.

Ixabepilone and lapatinib for HER2-positive advanced breast cancer: Preclinical rationale and phase I trial

2582 Trastuzumab with or without taxanes are the cytotoxic therapies of choice for advanced Her-2 positive breast cancer. Ixabepilone and lapatinib have demonstrated clinical efficacy in advanced breast cancer that is resistant to taxanes and trastuzumab. We have compared the therapeutic potential of ixabepilone, lapatinib, paclitaxel and trastuzumab, in vitro, prior to commencing a phase I clinical trial. Three different breast cancer cell lines SK-BR3, BT-474 and MCF-7 (control; non-Her-2 amplified), were seeded 96-well plates, cultured for 24 hours and different concentrations of ixabepilone or paclitaxel and trastuzumab or lapatinib were added. Experiments were performed in triplicate. A MTT viability assay was used to measure the activity of live cells after 0, 3, 24, 48 and 120 hours. The cells and vehicle control wells were averaged and normalized to 100% for comparison to the average value of the 6 replicate wells graphed over time for each cell line, drug concentration and cell density. Student-t test was used to determine the level of significance comparing the 0 hour time point in a pair-wise, pooled variance manner to each other time point. Paclitaxel + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Paclitaxel + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Dose response curves were clearly evident for all combinations. Of note proliferation was reduced earlier and at lower drug concentrations with lapatinib combinations than with trastuzumab combinations. The drugs whose efficacy was proven in MCF-7 cells were studied in detail on the xCELLigence cell analysis system. These data recapitulated the MTT data and provided in depth detail of the rate of drug action. An international multicentre phase I trial of Ixabepilone with lapatinib ± capecitabine has commenced in patients with Her-2 positive taxane and trastuzumab resistant advanced breast cancer. Toxicity has been as previously described with fatigue, arthralgias, onycholysis and rash occurring. No DLTs have occurred. RECIST responses have been confirmed in 2 of the first 3 patients enrolled. [Table: see text]

Proactive Management of Adverse Events Maintains the Clinical Benefit of Ixabepilone

Ixabepilone is a novel microtubule-stabilizing agent with clinical efficacy in advanced breast cancer, including patients whose disease has progressed on prior anthracyclines and taxanes. The safety profile of single-agent ixabepilone and combination ixabepilone plus capecitabine therapy is reviewed, outlining the steps to effectively manage and prevent common adverse events. Ixabepilone is generally well tolerated, and importantly, its toxicity profile does not overlap with that of capecitabine. Peripheral sensory neuropathy and neutropenia are the most common toxicities associated with ixabepilone; both can be effectively managed by monitoring patients and then, depending on severity, instituting a treatment delay until recovery and reducing the ixabepilone dose for subsequent treatment cycles. Ixabepilone dose reductions are recommended for most grade 3 events, excluding transient fatigue, arthralgia, and myalgia, whereas treatment discontinuation is recommended for persistent grade 3 neuropathy or any grade 4 nonhematological toxicity. Because ixabepilone exposure is greater in patients with hepatic impairment and those receiving concomitant strong cytochrome P-450 CYP3A4 inhibitors, dose adjustments and restrictions are recommended according to the degree of hepatic impairment, whether ixabepilone is administered alone or in combination with capecitabine, and whether a strong CYP3A4 inhibitor is being coadministered. Patients should be premedicated with oral H(1) and H(2) antihistamines to prevent hypersensitivity reactions. Unlike taxanes, corticosteroid premedication is not required unless a hypersensitivity reaction occurred during a previous cycle or during treatment with another Cremophor-containing agent. By effectively managing adverse events and taking steps to minimize them, clinicians can ensure that patients derive the maximum benefit from ixabepilone therapy.

Doxorubicin (Dox), cyclophosphamide (Cyc) and weekly docetaxel (Doc) as first-line treatment of advanced breast cancer (ABC)

11516 Background: The breast is one of the leading cancer sites in women. ABC is essentially incurable with standard therapy and have a median survival of approximately 2 years. Dox, Cyc and Doc showed better efficacy results but also an increased rate of neutropenia and febrile neutropenia with respect to FAC (which is considered one of the most used standard option). The substitution of 5- fluorouracil with docetaxel resulted in an increase in the efficacy parameters but showed a higher hematological toxicity. One possible approach to reduce the rate of neutropenia is the administration of weekly docetaxel wich demostrated efficacy in ABC. Methods: ABC patients (pts) were enrolled in an open, single arm, non-randomized phase I escalation trial in 3 to 6 pts/cohorts. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity.*The treatment schedule was: Doc 20 mg/m2 (or 25, depending on dose level assignment) on day 1, 8, 15; Dox 40 mg/m2 (or 50, depending on dose level assignment) and Cyc 500 mg/m2 on day 1, every four weeks. Results: Eleven pts, median age 56 yrs, were enrolled. Five pts were allocated to dose level 20/50 (Doc/Dox) and six pts to dose level 20/40. At the dose level 20/50 febrile neutropenia (DLT) occurred in 2 pts. Other 3 pts experienced neutropenia WHO grade 4 (not DLT). Six patients were allocated at previous dose level and MTD was defined at Doc 20 mg/m2 in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 Conclusions: We didn’t observe toxic deaths and all the toxicity was limited and resolved. The accrual was stopped and we are waiting for one patient to end the treatment in order to analyse the final data and to design the phase II study a the dose Doc 20 mg/m2 (days 1, 8 and 15) in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 (day 1) every 4 weeks. No significant financial relationships to disclose.

Efficacy in advanced breast cancer should be evaluated by time to progression

对一个复发转移的晚期乳腺癌患者来讲,要达到根治的效果是非常困难的.即使病灶切除或放疗消退,也无法抑制已经播散出去的亚临床病灶;即使通过全身药物治疗达到完全缓解(CR),也很可能药物一停,肿瘤又再度进展.这是每个从事乳腺癌专业医生都会经常遇到的难题。

Capecitabine: Efficacy in advanced breast cancer

827 Background: Capecitabine is a 5 flouropyrimidine derivative that is an orally administered, tumor activated and tumor selective agent. The drug has shown an excellent response in anthracycline and taxane refractory metastatic breast cancer patients (pts). Methods: Pts of advanced breast cancer were treated with capecitabine alone or in combination with other agents.The response rate, toxicity, and time to tumor progression (TTP) was evaluated. Results: : 23 pts (between jan'2000 to march'03) with metastatic breast cancer were treated with capecitabine. The mean age was 55 years. All except one patients had received prior chemotherapy either as adjuvant and or for metastatic disease. Mean number of prior chemotherapy regimens received were two. 5-flurouracil was part of prior chemotherapy in ten patients. Mean number of metastatic sites were two. Only six patients had single site of metastasis. Site of metsastasis was lungs in 12, liver in 10, bones in 12, skin in 5. Sixteen patients received capecitab...

Treatment of metastatic breast cancer with alternative vinorelbine and gemcitabine

800 Background: In Romania, most breast cancer cases are locally advanced or metastatic. Single agent therapy with gemcitabine or vinorelbine showed good tolerability and efficacy in advanced breast cancer. Methods: to evaluate safety profile and efficacy of alternatively gemcitabine and vinorelbine regimen in pretreated metastatic breast cancer. 32 patients were included between October 2001 -October 2002. All patients had prior chemotherapy with antracicline or taxane. They had progression or recurrence within 6 month of prior treatment. They had measurable or evaluable disease. Median age was 52 years. Performance status was ECOG 0–2. Metastatic sites: liver -9 patients, lung -8 patients, bone -17 patients, soft tissue -6 patients. Treatment schedule: Gemcitabine 1000 mg/m2 given on day 1, 15, 29, 43, 57, etc and vinorelbine 25 mg/m2 given on day 8, 22, 36, 50, etc. until disease progression; the median duration of administration was six month. Results: The treatment was well tolerated. Grade 1–2 myelosuppression was commonly observed; grade 3–4 neutropenia - 4 patients (12.5%), never complicated with septicaemia, grade 3 anemia - 2 patients (6.25%), grade 3 trombocitopenia -1 patient (3.12%). Grade 2 neurotoxicity was observed in 3 patients (9.37%). Grade 1–2 gastrointestinal toxicity (nausea/emesis) occurred in 13 patients (40.62%). Malaise or flu-like syndrome were mild and occurred in 9 patients (28.12%). No treatment-related death was observed with gemcitabine -vinorelbine alternative regimen. No patients required dose reduction. One patient was not evaluable for tumor response. Overall response rate was 31.25% (2 patients (6.25%) complete response, 8 patients (25%) partial response); 12 patients had stable disease (37.5%) and 9 patients progressive disease (31.25%). The median time to progression was 8,3 month. Conclusion: Our results suggest that gemcitabine and vinorelbine alternative administration has an acceptable efficacy and a favorable safety profile. No significant financial relationships to disclose.

Capecitabine: Efficacy in advanced breast cancer

827 Background: Capecitabine is a 5 flouropyrimidine derivative that is an orally administered, tumor activated and tumor selective agent. The drug has shown an excellent response in anthracycline ...

Breast cancer prevention—clinical trials strategies involving aromatase inhibitors

Estrogens and their metabolites have been implicated in both the initiation and the prevention of breast cancer. The reduction in breast cancer incidence seen in the tamoxifen arms of the four prospective trials to date has established the proof of principle that antagonizing estrogen is a potential means of reducing breast cancer risk. However, the areas to improve on these results include: (a) enhanced efficacy, (b) reduction in the incidence of receptor-negative tumors, (c) improved overall and endocrinological side effects, and (d) improved function on end-organs other than the breast. The aromatase inhibitors offer the potential to achieve these goals in part in the following ways: (a) greater reduction in risk of disease as evidenced by superior efficacy in advanced breast cancer and by inhibition of both initiation and promotion of breast cancer, (b) reduction in receptor-negative tumors by synergy with COX-2 inhibitors resulting in growth factor inhibition, anti-angiogenesis and inhibition of tumor-associated aromatase expression, (c) fewer vasomotor and urogenital abnormalities, and (d) reduced thromboembolism and cardiovascular complications and satisfactory effects on bone metabolism. Important differences may exist between non-steroidal reversible inhibitors and steroidal irreversible inactivators in particular related to the androgenic/anabolic effects of the steroidal inactivators. Pilot studies of aromatase inhibitors described elsewhere in this session have begun in healthy women with dense mammography, or a high-risk genetic and/or histocytopathologic profile, to determine potential efficacy, as well as effects on end-organ function. A number of phase three trials with aromatase inhibitors are also underway or in planning. Among these are the BRCA 1 and 2 study of exemestane versus placebo in unaffected postmenopausal carriers, the International Breast Intervention Study 2 (IBIS 2) of anastrozole versus placebo in women with a high-risk profile, and the National Cancer Institute of Canada’s Clinical Trial Group (NCIC CTG) study of exemestane with or without celecoxib versus placebo in women at risk of the disease. For premenopausal women, combination strategies of gonadotrophin agonists and aromatase inhibitors are being investigated. The potential of using low doses of aromatase inhibitors to lower “in breast” estrogen levels without unduly perturbing plasma concentrations is also being explored. The potential of the aromatase gene functioning as an oncogene within the breast may be tied to breast density which in turn may represent both a selection tool for elevated risk and an intermediate marker of prevention. The strong link between postmenopausal estrogen levels and breast cancer risk suggests the possibility that plasma estrogen levels may be a useful intermediate marker of prevention. The aromatase inhibitors offer us the first ever tool to render women virtually free of estrogen and are potentially an exciting tool for the prevention of breast cancer.

Single-agent estramustine phosphate (EMP) is active in advanced breast cancer after failure with anthracyclines and taxanes

Estramustine phosphate (EMP) is an oral cytotoxic agent that depolymerizes tubuline, a mechanism of action that has been revisited during the last decade. Because of its lack of haematological toxicity and favourable tolerance profile, EMP is a good candidate for palliative chemotherapy. The aim of the study was to assess its tolerance and efficacy in advanced breast cancer after failure with usual regimens. Patients with a life expectancy of at least 12 weeks and bi-dimensionally measurable disease having received at least 1 line of chemotherapy (including taxanes and/or anthracyclines) for advanced breast cancer (ABC) were eligible. EMP was given daily at a dose of 10 mg/kg until disease progression, unacceptable toxicity or patient refusal to continue chemotherapy. Forty patients were included between June 1998 and December 1999. Patients had previously received one to eight chemotherapy regimens (median is two) for ABC. Twenty-two patients (55%) had visceral involvement and eighteen patients (45%) had osseous, chest wall or soft tissue metastases. Adverse events leading to early interruption of EMP were grade 2 allergy (n = 1), grade 2-3 nausea (n = 6), deep-vein thrombosis (n = 1), grade 3 sepsis (n = 1). One patient died at twenty-four weeks from pulmonary embolism, and another at fourteen weeks from unknown cause. Seven objective responses were observed (17.5%; 95% confidence interval (CI): 6%-30%). Median time to failure was 24 weeks (14-52+) in responding patients. All objective responses but one were observed in patients with visceral metastases. In 10 other patients (25%), disease remained stable with a median time to failure of 27 weeks (16-50); 6 of these experienced a decrease of consumption of analgesics or an improvement of performance status. EMP is an active drug in ABC after failure with taxanes and anthracyclines, whose tolerance profile appears favourable.

Tamoxifen Efficacy in Advanced Breast Cancer Previously Treated with Endocrine and Cytotoxic Therapy

Sixty-nine postmenopausal women with disseminated breast cancer previously treated with endocrine and cytotoxic therapy were treated with tamoxifen (20 mg/day). Complete plus partial response (CR+PR) was observed in 29 % (CR 16 %) and stable disease in 28 %. The objective response was higher in soft tissue sites (52 %) compared to osseous (12 %) and visceral (13 %) disease. No regression or disease stabilization was observed in the presence of liver involvement. Free-interval, length and type of menopause, and estrogen receptor status (carried out only 26 patients) did not statistically influence the percent of objective response. Only 1 of 16 patients (6 %) who did not respond to previous endocrine therapy responded to tamoxifen, while 3 of 9 previous hormonal responders (33 %) achieved objective regression with antiestrogen therapy. On the contrary, the response to previous chemotherapy failed to influence the subsequent response to tamoxifen. The median duration of the response was more than 12 months and the median survival more than 18 months. Treatment was generally very well tolerated and in only one patient was temporarily discontinued because of thrombocytopenia.