A Phase II Trial of Neoadjuvant Gemcitabine,Epirubicin, and Docetaxel as Primary Treatment of Patients With Locally Advanced or Inflammatory Breast Cancer

BackgroundThree-drug regimens containing gemcitabine, an anthracycline, and a taxane produce response rates of 70%-90% in patients with metastatic breast cancer (MBC) although accompanied by considerable hematologic toxicity. We explored the combination of gemcitabine/epirubicin/docetaxel as neoadjuvant therapy. Docetaxel was administered weekly to decrease myelosuppression.Patients and MethodsA total of 110 patients with locally advanced or inflammatory breast cancer received neoadjuvant gemcitabine 800 mg/m² intravenously (I.V.) days 1 and 8, epirubicin 75 mg/m² I.V. day 1, and docetaxel 30 mg/m² I.V. days 1 and 8, repeated every 21 days for 4 cycles. Then patients had either mastectomy or breast conservation surgery, and pathologic treatment responses were assessed. After surgery, 4 cycles of adjuvant gemcitabine 1000 mg/m² I.V. days 1 and 8 and docetaxel 35 mg/m² I.V. days 1 and 8 were administered at 21-day intervals. After patients completed chemotherapy, locoregional radiation therapy and/or anti-estrogen therapy was administered per standard guidelines.ResultsTreatment with 4 cycles of neoadjuvant gemcitabine, epirubicin, and weekly docetaxel resulted in an objective response in 79 of 110 patients enrolled (72%; 95% CI, 63-80%). Twenty of 103 patients (19%) who had surgery had pathologic complete response (pCR). Moderate hematologic toxicity was evident during neoadjuvant therapy, with grade 3/4 neutropenia in 41% and febrile neutropenia in 11% of the patients. Protocol-specified dose modifications were required in 35% of the patients, and 58% of the patients used myeloid growth factors.ConclusionThe pCR rate of 19% achieved with gemcitabine, epirubicin, and weekly docetaxel confirms previous reports with similar 3-drug regimens. The use of a weekly schedule of docetaxel did not appear to reduce the incidence of grade 3/4 hematologic toxicity.     

多西紫杉醇加表柔比星治疗局部晚期乳腺癌的多中心Ⅱ期临床研究

目的观察多西紫杉醇加表柔比星(ET方案)新辅助化疗方案治疗局部晚期乳腺癌(LABC)后的病理完全缓解率、客观缓解率、手术切除率以及毒性反应。方法2001年3至12月间共有40例IABC患者入组,中位年龄48(28～67)岁。Ⅲa期20例,Ⅲb期15例,单纯同侧锁骨上淋巴结转移5例。化疗剂量为表柔比星60mg/m^2,多西紫杉醇75mg／m^2,静脉点滴,每3周为1个周期。化疗中预防性应用粒细胞集落刺激因子(DCSF)。在2个周期ET方案之后,由研究者对病灶进行首次评估,以决定是否再给予1～2个周期ET后再接受手术或放射治疗。结果38例患者接受2～4个周期ET方案的新辅助化疗,病理完全缓解率、临床完全缓解率以及临床部分缓解率分别为15．0％、20．0％和52．5％。本组的手术切除率为92．5％。Ⅲ、Ⅳ度中性粒细胞减少症的发生率分别占总周期数的8.4％和14.0％,3例患者出现中性粒细胞减少性发热。常见的非血液系统不良反应为脱发、恶心或呕吐、体液潴留、肌肉关节疼痛以及指甲改变,但多呈轻、中度反应。结论多西紫杉醇联合表柔比星是针对LABC的一种安全而有效的新辅助化疗方案。     

Docetaxel plus epidoxorubicin as neoadjuvant treatment in patients with large operable or locally advanced carcinoma of the breast: a single-center, phase II study

BACKGROUND: The objective of this study was to test the activity and toxicity of epirubicin plus docetaxel as primary chemotherapy for women with large, operable (T2; > 3 cm) or locally advanced (Stage III) breast carcinoma, including patients with inflammatory breast carcinoma. METHODS: In this single-center, open-label, single-stage, Phase II trial, epirubicin (75 mg/m(2); intravenous bolus) followed by docetaxel (80 mg/m(2); 1-hour intravenous infusion) was administered on Day 1 of each cycle for four cycles. RESULTS: Nine of 30 patients (30%) had inflammatory breast carcinoma. Twenty-three patients (76.7%; 95% confidence interval, 57.7-90.1) had a clinical objective response that was complete in 6 patients (20%). Twenty-seven patients (90%) underwent surgery that was conservative in 5 patients (16.7%). Pathologic response evaluation revealed four complete responses (13.3%; 95% confidence interval, 3.8-30.7). Grade 4 neutropenia was recorded in 80.0% of patients, and febrile neutropenia was recorded in one-third of patients. Anemia and thrombocytopenia were never severe. Other side effects were diarrhea (26.6%), oral mucositis (43.3%), and emesis (26.6%). CONCLUSIONS: Neoadjuvant chemotherapy with epirubicin plus docetaxel was a feasible treatment and was active in an unfavorable series of patients with locally advanced breast carcinoma, including patients with inflammatory breast carcinoma.     

Docetaxel plus epirubicin is a highly active, well-tolerated, first-line chemotherapy for metastatic breast cancer: results of a large, multicentre phase II study

Purpose In this multicentre phase II study, the efficacy and safety profile of the combination of docetaxel and epirubicin as first-line chemotherapy for metastatic breast cancer (MBC) were evaluated.Methods Epirubicin (75 mg/m²) and docetaxel (75 mg/m²) were given intravenously once every 3 weeks for six cycles to 133 patients with MBC.Results The overall clinical response rate was 67% (complete and partial responses were 23% and 44%, respectively). The median time to progression was 10.8 months (95% CI 9.7–12.6) and the median overall survival was 19.5 months. Granulocyte colony-stimulating factor support was administered to 32% of patients and in 22% of cycles. Grade 3/4 neutropenia occurred in 35% of patients and febrile neutropenia in 19%. The most frequent grade 3/4 non-haematological toxicities (as percent of patients) were asthenia (6%), vomiting (5%) and nausea (5%). No patients developed congestive heart failure.Conclusions The combination of docetaxel and epirubicin was highly active as first-line treatment for MBC and showed a manageable toxicity profile.     

Primary systemic chemotherapy with sequential, dose-dense epirubicin and docetaxel for inoperable, locally advanced inflammatory breast cancer: a phase II study

Sequential, dose-dense epirubicin plus docetaxel was evaluated as primary systemic therapy for women with inoperable, locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients (LABC n=27; IBC n=7) received 3 cycles of epirubicin 120 mg/m2 every 2 weeks followed by 3 cycles of docetaxel 100 mg/m2 every 2 weeks, with granulocyte colony-stimulating factor. Grade 3-4 toxicities were observed in 21 of 195 cycles (10.8%). Grade 3 anemia and leukopenia each occurred in 1% of cycles. Following chemotherapy, all patients underwent surgery. Eight patients (23.5%) had a clinical complete response and 15 (44.1%) had a partial response. In patients with IBC, median skin thickness decreased from 5.85 mm (range: 3.1-6.2 mm) to 4 mm (range: 2.7-5.1 mm) (p<0.005). Sequential, dose-dense epirubicin plus docetaxel achieved a high response rate among patients with LABC or IBC with only moderate toxicity.     

A phase II trial of capecitabine and docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) as preoperative treatment in women with stage II/III breast cancer

BackgroundCapecitabine (X) and docetaxel (T) have demonstrated a synergistic effect in preclinical models and a survival benefit in metastatic breast cancer. This study's purpose was to determine the efficacy of X and T followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) in the preoperative setting.Patients and methodsPatients with stage II/III breast cancer received four cycles of XT (capecitabine 1650 mg/m² on days 1–14 and docetaxel 60 mg/m² on day 8 every 3 weeks), followed by four cycles of FEC (5-fluorouracil 500 mg/m², epirubicin 90 mg/m², and cyclophosphamide 500 mg/m² on day 1 every 3 weeks). Primary end points were the pathological complete response (pCR) rate and adverse drug reactions.ResultsSeventy-four patients were enrolled and 71 patients were assessable for clinical and pathological responses. The overall response rate was 91.5%. The pCR rate was 14.1% (10 of 71). Grade 3/4 neutropenia was observed in 32.4% of patients. The most common grade 3/4 non-hematologic adverse event was hand–foot syndrome, observed in 11.3% of patients. With 29 months median follow-up, 2-year disease-free survival was estimated 85% for all patients.ConclusionThese data indicate that the sequential combination of XT followed by FEC is a well-tolerated, effective neoadjuvant treatment of stage II/III breast cancer.     

Taxane and Anthracycline Based Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer : Institutional Experience

Background: The aim of this study was to assess the response rates (clinical and pathological ) with docetaxeland epirubicin combination chemotherapy and its effect on outcome. Materials and Methods: We retrospectivelyanalysed locally advanced breast cancer (LABC) patients who received NACT from January 2008 to December2012 in our tertiary care centre. LABC constituted 37% of all breast cancer cases and 120 patients fulfilled theeligibility criteria. The regimens used for NACT were, six cycles of DEC (docetaxel 75 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 500 mg/m2 on Day 1, 3 weekly) and a sequential regimen (4 cycles of FEC, 5-flurouracil600 mg/m², epirubicin 75 mg/m², cyclophosphamide 600 mg/m² followed by 4 cycles of docetaxel 85 mg/m2).Results: The median age was 47 years (range 23-72). Ninety six ( 80 %) had T4 disease and 90% had clinicallypalpable lymph nodes at diagnosis. The median size of primary tumor at presentation was 5.9 cm. Hormonereceptor positivity was seen in 55% and HER2/neu positivity, in 25%. Triple negative breast cancers constituted25 % of the cases. The overall clinical response rate ( complete or partial ) was 85% and pathological completeresponses were obtained in 15%. Four cases defaulted, 5 patients died of treatment related toxicity and 15%developed febrile neutropenia on DEC. The median duration of follow up was 22 months. The median time torelapse was 20 months and the 3 year relapse free and overall survival rates were 50% and 70% respectively.Conclusions: LABC constituted 37% of all breast cancer cases at our institute. With NACT, pCR was seenin 15% of the cases. Sequential chemotherapy was better tolerated than concurrent anthracyline and taxanechemotherapy with a similar pCR.     

Comparison of 6 cycles versus 4 cycles of neoadjuvant epirubicin plus docetaxel chemotherapy in stages II and III breast cancer

Background

This phase III clinical study was designed to investigate whether 6 cycles of epirubicin plus docetaxel (ED) is more effective than 4 cycles of ED as neoadjuvant chemotherapy (NC) in patients with stage II or III breast cancer.

Patients and methods

Women with breast cancer that had tumors larger than 3 cm were prospectively randomized to receive 4 or 6 cycles of epirubicin 75 mg/m² and docetaxel 75 mg/m² every 3 weeks. The primary end point was the clinical response to NC.

Results

A total of 176 patients were randomly assigned, and 150 patients were assessable for efficacy and toxicity. Groups were well balanced for clinicopathologic parameters. The median age was 42 years (range 30–58). Overall clinical response was observed in 72% with ED4 and 82% with ED6. pCR was observed in 11% with ED4 and in 24% with ED6 (p = 0.047). 47% of the ED4 group underwent breast conserving surgery (BCS) whereas 58% of ED6 group underwent BCS. Grade 3/4 neutropenia was observed in 27% in ED4 and 31% in ED6. Febrile neutropenia occurred in 17% with ED4 and 19% with ED6. Grade 3 mucositis was observed in 8% with ED4 and in 6% with ED6.

Conclusion

Six cycles of ED enhanced the rates of pCR and BCS compared with 4 cycles without increasing treatment-related toxicities.     

Evaluation of ER,PgR, HER-2, Ki-67, cyclin D1, and nm23-H1 as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with locally advanced breast cancer (LABC). Two hundred and twenty consecutive patients with LABC who had received neoadjuvant chemotherapy (NCT) with docetaxel and epirubicin from March 2006 to March 2009 were included in this retrospective study. The pre- and post-neoadjuvant chemotherapy (NCT) treatment expression levels and changes of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). The pCR rate was 9.1% (95% CI, 5.3–12.9%). In univariate analysis, poor tumor differentiation, OR after 2 cycles of NCT, both negative of ER/PgR, negative HER-2, positive cyclin D1, and positive nm23-H1 were found to be significantly predictive of a pCR. Histological grade and ER/PgR status were significant for pCR on multivariate analysis (P = 0.023 and 0.003, respectively). The expression levels of cyclin D1 (median, 8% vs. 9%; P = 0.016) after NCT treatment increased significantly, while the median Ki-67 proliferation index was dramatically decreased after NCT treatment from 35 to 15% (P = 0.036). However, after a Bonferroni adjustment, only the difference of Ki-67 proliferation index was still significant (P = 0.026). Histological grade and ER/PgR status are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in locally advanced breast cancer. Expression of HER-2, Ki-67, cyclin D1, and nm23-H1 were not predictive for pCR.

     

ER,PgR, HER-2, Ki-67, topoisomerase IIα, and nm23-H1 proteins expression as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in patients with locally advanced breast cancer (LABC) One hundred and twelve consecutive patients with clinical stage III LABC who had received NCT with docetaxel and epirubicin from March 2006 to March 2009 were included in this retrospective study. The pre-NCT treatment expression levels of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), Topoisomerase II alpha (Topo-II), and nm23-H1 were detected by immunohistochemistry (IHC). A total of 361 cycles were administered with the median number of three cycles per patient (range, 2–6). The pCR rate was 9.8% (95% CI, 4.3–15.3%). In univariate analysis, poor tumor differentiation, both negative of ER/PgR, negative Topo-II, and positive nm23-H1 were found to be significantly predictive of a pCR. ER/PgR status and nm23-H1 were significant for pCR on multivariate analysis (P = 0.006 and 0.025, respectively). ER/PgR status and nm23-H1 are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with LABC.     

Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated,advanced breast carcinoma

BACKGROUND: The objective of this study was to evaluate the activity and safety of oral capecitabine in combination with docetaxel and epirubicin (TEX) as first-line treatment for patients with locally advanced/metastatic breast carcinoma. METHODS: This open-label, Phase II study was conducted at six Italian centers. Treatment consisted of epirubicin, 75 mg/m(2) (intravenous bolus), and docetaxel, 75 mg/m(2) (1-hour infusion), both administered on Day 1, plus oral capecitabine, 1000 mg/m(2) twice daily, on Days 1-14 of each 3-week treatment cycle. RESULTS: A total of 67 patients received 392 cycles of treatment, with a median of 6 cycles in patients with Stage III disease (n = 34 patients) and a median of 8 cycles in patients with Stage IV disease (n = 33 patients). The objective response rate was 82%, including complete responses in 21% of patients. A greater proportion of patients with Stage III disease achieved tumor responses compared with patients who had Stage IV disease (97% vs. 67%, respectively). Among 34 patients with Stage III disease, pathologic complete responses were confirmed in 10 patients (29%). TEX chemotherapy demonstrated an acceptable safety profile. There was a low incidence of Grade 3 adverse events, and Grade 4 adverse events were particularly rare (4%). The most common Grade 3-4 adverse event was febrile neutropenia, which occurred in 16% of patients. CONCLUSIONS: TEX combination therapy has important antitumor activity and an acceptable safety profile in this setting. A large, randomized, Phase III trial is ongoing to compare TEX chemotherapy with an epirubicin plus docetaxel regimen in patients with untreated, advanced breast carcinoma.     

Assessment of different criteria for the pathological complete response (pCR) to primary chemotherapy in breast cancer: standardization is needed

Purpose Evaluation of the safety and efficacy of a combination of docetaxel and doxorubicin in breast cancer patients. Evaluation and comparison of the pathological complete response (pCR) to this regimen according to various definitions in different clinical trials. Utilize the data to propose standardization of definitions. Patients and Methods Between 1998 and 2001, 141 patients with stage II (tumor size >3.0 cm) or III breast cancer were treated with doxorubicin 50 mg/m² followed by docetaxel 60 mg/m² (AT) on day 1. A total of 4 courses of AT were administered as primary chemotherapy with intervals of 3 weeks. Additionally, 2 cycles of the same regimen were administered after surgery when clinical CR or PR was achieved; otherwise, 4 cycles of CMF were added postoperatively. Results 141 patients were enrolled in this trial. A clinical response rate was 86%. Seven patients (5%) achieved pCR according to the Japanese Breast Cancer Society classification, 14 patients (10%) fulfilled the University of Texas M.D. Anderson Cancer Center trial’s pCR criteria, and 19 patients (14%) met the NSABP trial pCR definition. NCI CTC version 2 grade 3/4 toxicities included leucopenia (26%), neutropenia (85%) and febrile neutropenia (12%). Conclusion Primary chemotherapy with AT induced modest tumor responses with tolerable toxicity. Differences in the definition of pCR among clinical trials caused substantial confusion in interpreting the trial results. Therefore, standardization of the pCR definition after primary chemotherapy is needed.     

Luminal B型局部晚期乳腺癌新辅助化疗疗效预测基因的研究

目的 筛选Luminal B型局部晚期乳腺癌新辅助化疗疗效预测基因。方法 收集10例Luminal B型乳腺癌患者,均行DA方案新辅助化疗（多西他赛 75mg／m2静滴,d1;表阿霉素80mg／m2 静滴d1,21天为1周期,共4个周期）,根据化疗疗效分为完全病理缓解（pCR）组（n=3）和非完全病理缓解（npCR）组（n=7）。采用人基因表达谱cDNA芯片从10例乳腺癌患者中筛选新辅助化疗疗效相关基因,荧光定量PCR验证差异表达基因。结果 pCR组与npCR组癌组织相比,上调基因231个,下调基因195个;pCR组癌组织与癌旁组织相比,上调的基因357个,下调的基因544个;npCR组癌组织与癌旁组织相比,上调基因143个,下调基因101个;pCR组与npCR组癌旁组织比较,上调基因98个,下调基因67个。pCR组与npCR组癌组织比较,筛选出6个与肿瘤有关的基因,其中上调基因为CYP4Z1、FGFL6、BCAR4,下调基因为FABP4、S100B、ALPH1L1。荧光定量PCR进一步验证显示,两组mRNA表达差异的基因为CYP4Z1和BCAR4,pCR组两种基因表达均显著低于npCR组（P＜0.05）。结论 对局部晚期Luminal B型乳腺癌低表达BCAR4和CYP4Z1的患者新辅助治疗选择采用DA方案化疗更有可能获得pCR。     

CK5/6, EGFR, Ki-67, cyclin D1, and nm23-H1 protein expressions as predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer patients

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in patients with locally advanced triple-negative breast cancers (TNBCs). Forty-one patients (18.6%) among 220 breast cancer patients were identified as TNBCs from March 2006 to 2009 were included in this prospective study. The pre-NCT treatment expression levels of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), CK5/6, epidermal growth factor receptor (EGFR), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). A total of 180 cycles were administered with the median number of four cycles per patient (range, 4-6). The pCR rate was 34.1% (95% CI, 19.6-48.6%). In univariate analysis, early T stage, clinical response after 2 cycles, negative basal-like, negative EGFR, high Ki-67 proliferation index, and positive nm23-H1 were found to be significantly predictive of a pCR (P = 0.010, 0.040, 0.007, 0.001, 0.019, and 0.010, respectively). Basal-like status and nm23-H1 status were significant for pCR on multivariate analysis (P = 0.004 and 0.031, respectively). Basal-like status and nm23-H1 are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with TNBCs.     

Gemcitabine/epirubicin/paclitaxel as neoadjuvant chemotherapy in locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group

BACKGROUND: This phase II protocol of neoadjuvant chemotherapy with gemcitabine/epirubicin/paclitaxel (GET) was designed to determine the pathologic complete response (pCR) rate in the breast, clinical response rate, disease-free survival, and overall survival at 2 years as well as toxicity in patients with locally advanced breast cancer. This trial also evaluated the feasibility of tissue collection for gene-expression profiling. PATIENTS AND METHODS: Seventy-six women with stage IIB, IIIA, and IIIB breast cancer were entered into this trial. Patients received a maximum of 6 cycles of neoadjuvant GET chemotherapy every 21 days (gemcitabine 1000 mg/m2 intravenously [i.v.] on days 1 and 4, epirubicin 90 mg/m2 i.v. bolus on day 1, and paclitaxel 175 mg/m2 i.v. on day 1). After chemotherapy, patients underwent surgery and were assessed for pathologic response. RESULTS: The pCR rate among the 74 patients evaluable for efficacy was 23% (95% CI, 14%-34.2%). Adverse events among the 76 patients evaluable for toxicity included anemia requiring transfusion (14.5%), infection with grade 3/4 neutropenia (10.5%), febrile neutropenia (7.9%), and platelet transfusion (6.6%). Infectious complications occurred in 24 patients (31.6%), of whom 18.4% were in the setting of neutropenia. High-quality RNA and successful probe synthesis were obtained from all pretreatment core biopsy specimens that contained tumor cells (n=66; 88%). CONCLUSION: Neoadjuvant GET chemotherapy is an active regimen but with substantial toxicity. Tissue collection for gene-expression profiling is feasible in a multi-institutional setting.     

High pathologic complete response in HER 2-positive locally advanced breast cancer after primary systemic chemotherapy with weekly docetaxel and epirubicin

Background: To evaluate pathological complete response rate and to identifythe predictor of response after primary systemic chemotherapy(PST) with weekly docetaxel and epirubicin for locally advancedbreast cancer. Methods: Sixty-three patients with locally advanced breast cancer receivedthree cycles PST on day 1 and 8 of each 3-week cycle with epirubicinand docetaxel (epirubicin 45 mg/m² intravenous bolus, docetaxel35 mg/m² in 100 ml normal saline infused 1 h), followed by surgeryand adjuvant chemotherapy with cyclophosphamide, epirubicinand 5-fluorouracil. The pathological complete response was definedas no invasive carcinoma in breast and axillary nodes afterPST. Results: The median tumor sizes (by ultrasound) before and after PSTwere 6.2 and 2.5 cm, respectively. The negative estrogen receptor(ER) by immunochemical stain was found in 33 (52.4%) patientsand HER-2/neu-overexpression in 12 (19.0%) patients. Clinicaloverall response rate (ORR) was 89% (95% confidence intervals(95% CI: 81–97), including 38% complete response (95%CI: 26–50), sonographical ORR was 97% (95% CI: 93–100).The pathological complete response were found in 11 patients(18%, 95% CI: 9–27), and 15(24%, 95% CI: 13–35)patients achieved breast only pathological complete response.Nine (27.3%) of thirty-three ER (–) patients and 5 (41.7%)of 12 HER2-positive patients achieved pathological completeresponse. Conclusion: PST with weekly docetaxel and epirubicin were well-toleratedand very high pathological complete response rate was achievedin HER-2/neu-overexpression tumors.     

Clinical response to neoadjuvant docetaxel predicts improved outcome in patients with large locally advanced breast cancers

Summary Purpose In the adjuvant setting, taxanes modestly improve clinical outcome and survival. The goal of the present study was to define the efficacy of neoadjuvant docetaxel in treatment-na?ve large, locally advanced breast cancers and to better understand docetaxel’s mechanism of action by evaluating biomarker modulation in response to treatment. Patients and methods Fifty-one patients were enrolled. Patients received four cycles of docetaxel (100 mg/m² q3weeks) followed by surgery and four cycles of doxorubicin and cyclophosphamide (60/600 mg/m² q3weeks). Radiation and hormonal therapy were given if clinically indicated. Clinical responses were assessed at completion of neoadjuvant docetaxel. Pathological responses were considered complete (pCR) if no tumor cells were identified in the surgical specimen or near complete (npCR) if only occasional scattered tumor cells were seen. Proliferation (Ki-67) and apoptosis (cleaved caspase-3) were measured by IHC in tissue obtained at baseline and at surgery. Results The median tumor size was 9 cm (range 4–30 cm). Objective response rate was 75% with clinical complete response in 27%, partial response in 48%, and stable disease in 25% of the patients. pCR/npCR was reported in 20% of patients. With a median follow up of 28 months, 98 and 78% of the patients were alive at 12 and 24 months, respectively. Overall survival at 24 months was significantly better in patients who achieved a clinical response, 85 versus 51%, p=0.008, but pCR/npCR was not a significant predictor of outcome. Apoptosis was induced in clinical responders (p=0.002), while the proliferation index did not change significantly. In patients who had no clinical response to docetaxel, neither apoptosis nor proliferation changed significantly. Conclusion Neoadjuvant single agent docetaxel is effective in treating patients with large locally advanced breast cancer and clinical response is associated with improved survival. Docetaxel acts therapeutically by inducing apoptosis and this can be used as a marker of response. Joint first authors     

Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil–epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy

This randomized, multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide (FEC) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker. Patients were randomized to 4 cycles of docetaxel/capecitabine (docetaxel: 75 mg/m² on day 1; capecitabine: 1,650 mg/m² on days 1–14 every 3 weeks) or docetaxel alone (75 mg/m² on day 1 every 3 weeks) after completion of 4 cycles of FEC (5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m² on day 1 every 3 weeks). The primary endpoint was the pathological complete response (pCR) rate. Predictive factor analysis was conducted using clinicopathological markers, including hormone receptors and Ki67 labeling index (Ki67LI). A total of 477 patients were randomized; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 %, respectively. There were no significant differences in the pCR rate (docetaxel/capecitabine: 23 %; docetaxel: 24 %; p = 0.748), disease-free survival, or overall survival. However, patients with mid-range Ki67LI (10–20 %) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone. Furthermore, multivariate logistic regression analysis showed pre-treatment Ki67LI (odds ratio 1.031; 95 % CI 1.014–1.048; p = 0.0004) to be a significant predictor of pCR in this neoadjuvant treatment setting. Docetaxel/capecitabine (after 4 cycles of FEC) did not generate significant improvement in pCR compared to docetaxel alone. However, exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer.     

CK5/6, EGFR,Ki-67, cyclin D1, and nm23-H1 protein expressions as predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer patients

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in patients with locally advanced triple-negative breast cancers (TNBCs). Forty-one patients (18.6%) among 220 breast cancer patients were identified as TNBCs from March 2006 to 2009 were included in this prospective study. The pre-NCT treatment expression levels of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), CK5/6, epidermal growth factor receptor (EGFR), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). A total of 180 cycles were administered with the median number of four cycles per patient (range, 4–6). The pCR rate was 34.1% (95% CI, 19.6–48.6%). In univariate analysis, early T stage, clinical response after 2 cycles, negative basal-like, negative EGFR, high Ki-67 proliferation index, and positive nm23-H1 were found to be significantly predictive of a pCR (P = 0.010, 0.040, 0.007, 0.001, 0.019, and 0.010, respectively). Basal-like status and nm23-H1 status were significant for pCR on multivariate analysis (P = 0.004 and 0.031, respectively). Basal-like status and nm23-H1 are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with TNBCs.