| Background:Neoadjuvant chemotherapy(NCT) has become an important part in the comprehensive treatment of breast cancer,patients classified with pathological complete remission(pCR) after NCT have superior outcome.However,there is no standard NCT regimen for breast cancer,thus anthracyclines and taxanes-containing regimens are recommended.Weekly paclitaxel has been demonstrated as an effective regimen in the adjuvant setting.Furthermore,with the better recognition of breast cancer biology,several clinical trials conducted to compare the anthracyclines and taxanes,and the clinical implication of trastuzumab,the role of anthracyclines in adjuvant treatment of breast cancer has been challenged in recent years.Now,there is no available data reported the non-anthracycline-containing weekly PCb(paclitaxel plus carboplatin) in the NCT for breast cancer.Objective:A single center,prospective phaseⅡstudy was initiated to evaluate the activity and safety of non-anthracycline-containing weekly PCb regimen in NCT for breast cancer,which may help our further clinical usage and research.Methods:Eligible patients with clinical stageⅡA～ⅢC breast cancer were assigned to receive four cycles of PCb with the dose of P(Paclitaxel) 80 mg/m2 and Cb (Carboplatin) AUC=2,given day 1,day 8 and day 15,out of every 4 weeks.Clinical response and extent of residual disease in breast and axillary lymph nodes(ALN) in surgical removed sample were assessed after completion of NCT,pCR was defined as no invasive cancer in breast and axillary.Estrogen(ER),Progesterone(PR) receptor and HER2 status were detected before treatment by immunohistochemistry,HR (hormonal receptor) was defined positive as either or both ER/PR positive.Results:From Dec.2007 to Dec.2008,107 breast cancer patients received weekly PCb NCT and one with bilateral breast cancer.85.2%patients were initially diagnosed with stageⅢdiseases,83 patients had positive ALN confirmed by fine needle aspiration before NCT.94.4%(102) patients have completed all of 4 cycles weekly PCb treatment.Clinical response rate was 86.1%with clinical complete remission rate 32.4%.21 patients achieved pCR,with pCR rate 19.4%.30 cases who had positive ALN before NCT showed negative result in the surgery specimen with ALN downstage rate 36.6%.The incidence of grade 3-4 neutropenia was 40.2%and only 1 patient was reported with febrile neutropenia.Severe thrombocytopenia and anemia occurred in 0.9%and 4.7%of patients,respectively.No episode of symptomatic cardiac adverse event was recorded.Peripheral neuropathy was frequent, but never severe,only 5(4.7%) patients recorded had more than grade 1 toxicity. Patients with ER- disease had superior pCR rate than ER+patients(32.6%vs.9.7%, P=0.005).Patients with PR- disease had higher pCR rate than PR+patients(30.6%vs. 10.2%,P=0.010).pCR rate was 33.3%(8/24) and 15.5%(13/84) in HER2+and HER2- patients.Furthermore,We used ER,PR and HER2 status to construct molecular classification of breast cancer,patients classified with Luminal A (HR+/HER2-) subtype had the lowest pCR rate,which was 8.3%less than 22.2%in Luminal B(HR+/HER2+),33.3%in triple-negative(HR-/HER2-) and 40.0%in HER2 positive(HR-/HER2+) subtype patients,P=0.017.Conclusions:Weekly PCb regimen was very active and tolerable as NCT for breast cancer.ER-,PR-,HER2+ and triple negative breast cancer were more likely to achieve pCR.This weekly PCb regimen should consider as a reasonable non-anthracycline-containing option in NCT setting of breast cancer. Background:Neoadjuvant chemotherapy has become standard option for locally advanced breast cancer.Patients classified with pathological complete remission (pCR) after neoadjuvant chemotherapy have superior outcome.Approximately 15% to 25%breast cancer patients are HER2 overexpressed which was associated with poor prognosis.Trastuzumab(Herceptin?) which targets the HER2 gene has been demonstrated with great efficacy in treatment of HER2 positive metastatic or early breast cancer,however,trastuzumab concurrent with anthracyclines led to high incidence of cardiotoxicity.Trastuzumab had additional or synergistic interaction with paclitaxel or carboplatin in vitro study and response rate was as high as 78%when HPCb(Herceptin?+Paclitaxle+Carboplatin) was used to treat HER2 positive metastatic breast cancer,however,there is no data reported about the HPCb regimen used in neoadjuvant setting.Objective:An open,prospective phaseⅡstudy was initiated to evaluate the activity and safety of weekly PCb(Paclitaxel+Carboplatin)+/- trastuzumab in neoadjuvant treatment of HER2 positive breast cancer,which may help our clinical application and further research.Methods:Eligible Patients with clinical stage ofⅡA～ⅢC breast cancer were assigned to receive four cycles of PCb with dose ofP(Paclitaxel) 80 mg/m2 and Cb (Carboplatin) AUC=2,given day1,day8 and day15 out of every 4 weeks,and patients were encouraged to receive additional weekly trastuzumab concurrent with PCb.The primary end point was pCR which defined as no residual invasive cancer in surgical removed breast and axillary lymph node(ALN).Results:From May 2007 to Dec.2008,38 patients with HER2 positive disease were enrolled.14 patients received weekly HPCb treatment and the rest treated with weekly PCb alone.Mean duration of trastuzumab treatment was 13 weeks(8-16 weeks).All of 14 patients were initially diagnosed with stageⅢdisease in HPCb treatment group who were demonstrated with positive ALN by fine neddle aspiration, which was higher than PCb arm(70.8%,17/24).A total of 15 patients achieved pCR, 7(50.0%) in HPCb arm and 8(33.3%) in PCb arm.12 cases who had positive ALN before neoadjuvant treatment showed negative result in surgery specimen,with ALN downstage rate 85.7%,which was apt to be higher than PCb group(52.9%,P=0.068). The incidence of severe hematological and non-hematological advert events was relatively low in both groups,none of them suffered from symptomatic severe cardiotoxicity.No one experienced left ventricular ejection fraction(LVEF) dropping larger than 15%or minimal LVEF＜50%before and after neoadjuvant HPCb treatment.Conclusions:This 4-cycle weekly HPCb regimen was highly effective and tolerable as neoadjuvant treatment for HER2 positive breast cancer,which deserves further validation. Background:Neoadjuvant chemotherapy(NCT) has become an important part in the comprehensive treatment of breast cancer,patients achieved pathological complete remission(pCR) after NCT have superior outcome.However,nowadays,the pCR rate was between 6%and 28%in NCT setting.We have previously reported the weekly PCb(Paclitaxel + Carboplatin) regimen in NCT for breast cancer,with pCR rate 19.4%,and there is still lack of reliable markers to predict the efficacy of weeldy PCb in NCT for breast cancer.Objective:To identify some markers which are associated with response of weekly PCb in NCT of breast cancer,then to built different models including various markers to predict the efficacy and to evaluate whether including candidate molecular markers can improve the predictive accuracy of model for predicting response of weekly PCb NCT.Methods:Retrospectively analyzed patients treated with weekly PCb NCT in Department of Breast Surgery,Fudan University Cancer Hospital,routine clinical and pathological markers as well as relative NCT response status were collected. According to ER(Estrogen Receptor,ER),PR(Progesterone Receptor,PR) and HER2 status,HR(Hormonal Receptor,HR) positive was defined as ER/PR positivity, we classified breast cancer into different molecular subtypes as follows:Luminal A (HR+/HER2-),Luminal B(HR+/HER2+),Triple-negative(HR-/HER2-) and HER2 positive(HR-/HER2+) subtype.11 candidate molecular biomarkers,which may be associated the response of weekly PCb NCT,including Tan,β-TubulinⅢ,PTEN, MAP4,Thioredoxin,MDR1,Ki67,p53,Bcl-2,BAX and ERCCl were detected by IHC(Immunohistochemical,IHC) in pre-NCT core needle biopsy specimens and we analyzed the relationship between these markers and pCR.Then we built different Logistic Regression Models including routine clinical,pathological markers and candidate molecular markers in various combinations,and to compare different predictive accuracy of models for predicting pCR.Results:91 patients had available core needle biopsy specimens for IHC evaluation, and 18 patients achieved pCR with pCR rate 19.8%.Univariate analysis showed that ER,PR,molecular classification(clinicopathological markers) and Tau,β-TubulinⅢ,p53,Bcl-2,ERCCl(candidate molecular markers) were associated with pCR; Multivariable analyze revealed thatβ-TubulinⅢ,Bcl-2 and ERCCl were independent pCR predictive markers,β-TubulinⅢ-negative,Bcl-2-negative or ERCCl-negative was associated with higher pCR rate,with OR 6.03(95%CI, 1.44-25.24,P=0.014),7.54(95%CI,1.52-37.40,P=0.013) and 4.09(95%CI, 1.17-14.30,P=0.028),respectively.To compare different Logistic Regression Models built with different combination of these variables,we found the model including routine clinical and pathological markers as well asβ-TubulinⅢ,Bcl-2,ERCCl candidate molecular markers had highest predictive power,area under ROC(Receiver Operating Characteristic,ROC) curve was 0.900(95%CI,0.831-0.968).Conclusions:β-TubulinⅢ,Bcl-2 and ERCCl candidate molecular markers were independent pCR predictive factors among breast cancer patients treated with weekly PCb regimen as NCT.Patients withβ-TubulinⅢ-negative,Bcl-2-negative or ERCCl-negative tumors had a higher pCR rate.Model integrating routine clinical, pathological andβ-TubulinⅢ,Bcl-2,ERCCl candidate molecular markers had highest power to predicte the pCR rate of this weekly PCb regimen. |
