***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    ***EXAMPLES*** 
    Input: Introduction The Preoperative Chemotherapy in Primary Operable Breast Cancer ( POCOB ) study was design ed to compare preoperative with postoperative chemotherapy in patients with early breast cancer concerning breast conserving therapy ( BCT ) procedures ,  disease free survival ( DFS ) and overall survival ( OS ) . Methods Patients ( n = 698 ) with early breast cancer were enrolled between 1991 and 1999 and r and omized between  preoperative versus postoperative chemotherapy ( four cycles of fluorouracil , epirubicin , and cyclophosphamide ) . Endpoints were BCT procedures , DFS , OS , and tumor response to preoperative chemotherapy .  In addition , tumor tissue was collected for translational research and the following markers were examined : ER , PgR , HER2 , p21 , p53 , and bcl-2 expression . Results With a median follow-up of 10 years , there was no statistically significant difference between the two treatment arms for OS ( HR = 1.09 ; 95%CI 0.83–1.42 ; P = 0.54 ) , DFS ( HR = 1.12 ; 95%CI 0.90–1.39 ; P = 0.30 ) , or locoregional recurrences ( LRR , HR = 1.16 ; 95%CI 0.77–1.74 ) . Preoperative chemotherapy was associated with an increase in BCT rates . BCT in part feasible due to tumor downsizing after preoperative chemotherapy was not correlated with higher LRR or worse OS compared to BCT which was feasible without downsizing of the tumor . Using available tumor material , only tumor stage , nodal stage , and grade were independent prognostic factors for overall survival . Conclusions Preoperative chemotherapy does not result in a difference in OS or DFS compared to postoperative chemotherapy in patients with early breast cancer . Moreover , it increases BCT rates with no significant increase of LRR . This implies that preoperative chemotherapy is a safe procedure for patients with early breast cancer , even after a follow-up period of 10 years Expression of the Bcl-2 protein confers resistance to chemotherapy-mediated apoptotic signals in patients with breast cancer . We investigated effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies . Oblimersen targets Bcl-2 messenger RNA ( mRNA ) , down-regulates Bcl-2 protein translation and enhances antitumor effects of subtherapeutic chemotherapy doses . Within a phase I trial , we administered escalating doses of oblimersen ( 3 , 5 or 7 mg/kg/day ) as continuous infusion on days 1 - 7 in combination with st and ard-dose docetaxel ( Taxotere ) , Adriamycin and cyclophosphamide ( TAC ) on day 5 as preoperative chemotherapy in 28 patients with T2 - 4 tumors . Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells ( P BMC s ) 4 days after start of oblimersen and before TAC treatment by quantitative microfluidic real-time PCR . Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 putative predictive markers . Two of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day . P BMC s could not be evaluated as a surrogate tissue because no qualified RNA could be isolated . Nevertheless , we demonstrated feasibility to process clinical sample s and to obtain good quality RNA from tumor biopsies and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer Background To define protein molecular characteristics of tumor cells prior to , and immediately following , preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response ( pCR ) or non response ( no pCR ) to preoperative HER2-directed therapy and chemotherapy . Methods This open-label , phase II study r and omized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab , lapatinib , or both , 2 weeks prior to and during chemotherapy with FEC75 for 4 courses ; then paclitaxel 80 mg/m2 weekly for 12 courses , then surgery . Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy . Data were correlated with pCR , defined as absence of invasive tumor in breast and lymph nodes . Results Of 100 enrolled patients , the analysis population included those who had surgery and received ≥75 % chemotherapy ( 78 % [ n = 78 ] ) . pCRs by arm are : trastuzumab ( n = 26 ) , 54 % [ n = 14 ] ; lapatinib ( n = 29 ) , 45 % [ n = 13 ] ; trastuzumab plus lapatinib ( n = 23 ) , 74 % [ n = 17 ] ) . Paired biopsy specimens were available for 49 patients ( 63 % ) . Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO , phosphorylated Stat5 , and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3 K and autophagy proteins compared with no pCR . Conclusion In this exploratory study , pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells . These data may provide c and i date biomarkers to stratify initial treatment and potential combination therapies for future study . Tissue preservation technology introduced here makes this procedure widely feasible . Trial registration Clinical Trials.gov : Purpose : To evaluate study feasibility , toxicity , drug concentrations , and activity of escalating doses of the synthetic retinoid fenretinide [ N-(4-hydroxyphenyl)retinamide ( 4-HPR ) ] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment . Methods : Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0 , 400 , 600 , and 800 mg/d for 1 to 4 weeks before surgery . Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables ( nuclear area , DNA index , and chromatin texture ) were determined in ascitic cells . Drug levels were measured by high-performance liquid chromatography . Results : Doses up to 800 mg/d were well tolerated , and no adverse reactions occurred . There was no effect of 4-HPR on changes in serum CA125 , Ki67 expression , which were assessed in 75 % of subjects , and cytomorphometric variables , which were assessed in 80 % of subjects . Plasma retinol levels were significantly lower in affected women than healthy donors .  4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 μmol/L concentration with 800 mg/d . Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower , respectively , than in carcinoma cells treated in vitro with 1 μmol/L 4-HPR . Conclusions : Cell biomarkers can be measured in ascitic cells to assess drug activity . Under our experimental conditions , 4-HPR did not show activity in advanced ovarian cancer cells . However , clinical evidence supports further investigation of fenretinide for ovarian cancer prevention . ( Cancer Epidemiol Biomarkers Prev 2006;15(10):1914–9 BACKGROUND Some oestrogen-receptor ( ER ) positive breast cancers express epidermal growth factor receptor ( EGFR ) , but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known . METHODS In a double-blind , placebo-controlled r and omised trial of 56 postmenopausal patients with ER-positive and EGFR-positive primary breast cancer , 27 women were r and omly assigned to the tyrosine-kinase inhibitor of EGFR gefitinib ( 250 mg given orally once a day ) and the aromatase inhibitor anastrozole ( 1 mg given orally once a day ) , and 29 women to gefitinib ( 250 mg given orally once a day ) and placebo of identical appearance to anastrozole given orally once a day , all given for 4 - 6 weeks before surgery . Primary outcome was inhibition of tumour-cell proliferation , as measured by Ki67 antigen labelling index . Secondary outcomes were reduction in EGFR phosphorylation at Tyr 845 , reduction in ER phosphorylation at Ser 118 , tumour size , and toxic effects . Analyses were by intention to treat . FINDINGS Patients assigned gefitinib and anastrozole had a greater reduction from pretreatment values in proliferation-related Ki67 labelling index than did those assigned gefitinib alone ( mean % reduction 98.0 [ 95 % CI 96.1 - 98.9 ] vs 92.4 [ 85.1 - 96.1 ] ; difference between groups 5.6 % [ 5.1 - 6.0 ] , p=0.0054 ) . Tumour size was reduced by 30 - 99 % ( partial response ) in 14 of 28 patients assigned gefitinib and [corrected]in 12 of 22 assigned gefitinib , as assessed by ultrasonography . Reduction in phosphorylation of ER at Ser 118 was similar for both groups . Treatment was well tolerated and much the same for both groups . INTERPRETATION Single-agent gefitinib and gefitinib combined with anastrozole are well-tolerated and effective treatments for reducing the size of breast tumours and levels of ER phosphorylation when given as neoadjuvant therapy Background : Metformin has been associated with antitumour activity in breast cancer ( BC ) but its mechanism remains unclear . We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling ( TUNEL ) overall and by insulin resistance status in a presurgical trial . Methods : Apoptosis was analysed in core biopsies and in surgical sample s from 100 non-diabetic BC patients participating in a r and omised trial of metformin vs placebo given for 4 weeks before surgery . Results : Eighty-seven subjects ( 45 on metformin and 42 on placebo )  were assessable for TUNEL measurement at both time points . TUNEL levels at surgery were higher than that at baseline core biopsy ( P<0.0001 ) , although no difference between arms was noted ( metformin arm : median difference surgery-biopsy levels + 4 % , interquartile range ( IQR ) : 2–12 ; placebo arm : + 2 % , IQR : 0–8 , P=0.2 ) . Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery ( Spearman ’s r=0.51 , P<0.0001 ) . In the 59 women without insulin resistance ( HOMA index<2.8 ) , there was a higher level of TUNEL at surgery on metformin vs placebo ( median difference on metformin + 4 % , IQR : 2–14 vs + 2 % , IQR : 0–7 on placebo ) , whereas an opposite trend was found in the 28 women with insulin resistance ( median difference on metformin + 2 % , IQR : 0–6 , vs + 5 % , IQR : 0–15 on placebo , P-interaction=0.1 ) . Conclusion : Overall , we found no significant modulation of apoptosis  by metformin , although there was a trend to a different effect according to insulin resistance status , with a pattern resembling Ki67 changes . Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67 . Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status Purpose The primary aim of this trial was to assess the rate of pathologic complete responses ( pCR ) of doxorubicin/cyclophosphamide ( AC ) followed by bevacizumab/docetaxel ( BT ) , as neoadjuvant therapy for breast cancer ( BC ) . Furthermore , the association between biomarkers and the pCR was explored . Methods Patients with HER-negative operable stage II – III BC ≥2 cm were enrolled . Four cycles of AC ( A 60 mg/m2 and C 600 mg/m2 , every 3 weeks ) followed by 4 cycles of BT ( B 15 mg/kg and T 75 mg/m2 , every 3 weeks ) , were planned . A core-biopsy was performed for biological markers assessment . Results Seventy-two women were included . Forty-three ( 63 % ) patients were hormone receptor-positive . Sixty-four ( 89 % ) completed the planned treatment , and 66 evaluable patients underwent surgery ( 92 % ): a pCR was achieved in 16 of them ( 24 , 95 % CI 15–36 % ) . pCR was significantly higher in tumors hormone receptor 
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These trials often permit the identification of predictive and PD biomarkers