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La chimiotherapie neoadjuvante du cancer du sein correspond a l’utilisation d’un traitement cytostatique systemique avant le traitement locoregional (chirurgie et/ou radiotherapie). Initiee dans les annees 1970 pour le traitement des formes localement avancees et/ou inflammatoires, la chimiotherapie d’induction s’est etendue au debut des annees 1980 aux cancers dits operables, de taille superieure a 3 cm et/ou de position centrale afin de permettre une chirurgie conservatrice plus frequente. Cet objectif est obtenu dans environ 75 % des cas sans augmentation du risque de rechute locale et sans effet deletere sur la survie globale, malgre le retard du traitement locoregional. La chimiotherapie neo–adjuvante a bien sur evolue au fur et a mesure de l’avenement des drogues majeures du cancer du sein que sont les anthracyclines, la vinorelbine et les taxanes. Mais a ce jour, aucun protocole ne s’est impose comme un standard inconteste. Toutefois, il semble que l’obtention d’une reponse complete clinique soit le meilleur garant pour eviter la rechute. Et cela semble ne pouvoir s’observer qu’apres 6 cycles, voire 8 cycles de chimiotherapie combinant au minimum 2 des 3 drogues majeures du traitement du cancer du sein dont le docetaxel qui parait, aujourd’hui, avoir une place incontournable surtout lorsqu’il est utilise en sequentiel apres un traitement a base d’anthracyclines en dehors de toute contre–indication cardiaque.

Objectif L’activation de la telomerase est essentielle pour la survie des cellules tumorales. L’expression de sa sous-unite catalytique hTERT est le facteur limitant pour cette activation. Notre objectif etait d’etudier les mecanismes de la surexpression de hTERT et leur impact clinique dans le cancer du sein. Materiel et methodes Le statut mutationnel du promoteur de hTERT a ete determine par sequencage de l’ADN tumoral chez 104 patientes atteintes de carcinomes canalaires invasifs et traitees par chimiotherapie neoadjuvante. Le nombre de copies du locus hTERT a ete evalue par CGH array (8 × 60 K, Agilent). Les donnees obtenues ont ete correlees a l’expression de hTERT et aux parametres cliniques (reponse therapeutique, survie). Resultats Aucune des mutations somatiques decrites comme responsables de la surexpression de hTERT n’a ete mise en evidence. En revanche, le gain du locus hTERT a ete correle a une surexpression du gene ( p = 0,0092). Le SNP rs2853669 a ete retrouve chez 40 % des patientes mais n’etait pas correle a la surexpression de hTERT . Par contre, il etait associe a une reponse histologique incomplete ( p = 0,019) et une diminution de la survie sans rechute ( p = 0,026). Discussion Dans le cancer du sein, le gain du locus hTERT semble plus implique dans la surexpression du gene que le statut du promoteur. Zhang et al. ont montre que l’amplification du gene hTERT participait a l’activation de la telomerase sur une petite cohorte de 19 cancers du sein [1] . Par ailleurs, il a ete montre que le SNP rs2853669, dont la presence interrompt un site de fixation du facteur de transcription Ets2, affectait l’expression de hTERT dans le glioblastome [2] et la survie dans le cancer de la vessie [3] lorsqu’il etait associe aux mutations. Nous mettons en evidence un impact clinique significatif de ce SNP isole dans le cancer du sein.

Background Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline–taxane-based chemotherapy in patients with operable, stage II–III, TNBC. Patients and methods Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m2) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m2) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody. Results Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR. Conclusions Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC. Clinical Trial Number NCT00933517.

Classical prognostic factors of breast cancer are correlated to disease-free survival and overall survival (OS); their precise role is less known on metastatic disease. A total of 511 breast cancer patients without initial metastasis were treated. OS was divided in time to distant recurrence and metastatic survival (MS). Age, Scarff–Bloom–Richardson (SBR) grade, hormone receptor, axillary node involvement, and Nottingham prognostic index predicted MS in univariate analysis. Multivariate analysis retained age, SBR grade, and axillary lymph node involvement as significant independent prognostic factors. Interactions are still present between initial parameters and MS. The clinician has to take into account for treatment choice.

Temozolomide (TMZ) was first known to be useful as a radiosensitiser in both primary brain tumours like glioblastoma multiforme and oligodendroglioma. Later, TMZ proved its efficacy in the treatment of melanoma. Multiple publications have demonstrated the benefit of TMZ in terms of efficacy and tolerance (used as mono-therapy or as adjuvant chemotherapy) compared to the "gold standard" treatment of this kind of tumours. Furthermore, several recent clinical trials have shown the particular importance of TMZ in other types of cancer. This publication deals with the use of TMZ in cancers which are not formal indications for TMZ (excluding glioblastoma multiforme, oligodendroglioma and melanoma). It also includes a necessary review of recent literature about the role of TMZ in the treatment of brain metastases, lymphomas, refractory leukaemia, neuroendocrine tumours, pituitary tumours, Ewing's sarcoma, primitive neuroectodermal tumours, lung cancer and other tumours.

Background Weight change during chemotherapy is reported to be associated with a worse prognosis in breast cancer patients, both with weight gain and weight loss. However, most studies were conducted prior to the common use of anthracycline-base chemotherapy and on North American populations with a mean BMI classified as overweight. Our study was aimed to evaluate the prognostic value of weight change during anthracycline-based chemotherapy on non metastatic breast cancer (European population) with a long term follow-up. Methods Patients included 111 women diagnosed with early stage breast cancer and locally advanced breast cancer who have been treated by anthracycline-based chemotherapy regimen between 1976 and 1989. The relative percent weight variation (WV) between baseline and postchemotherapy treatment was calculated and categorized into either weight change (WV > 5%) or stable (WV < 5%). The median follow-up was 20.4 years [19.4 - 27.6]. Cox proportional hazard models were used to evaluate any potential association of weight change and known prognostic factors with the time to recurrence and overall survival. Results Baseline BMI was 24.4 kg/m2 [17.1 - 40.5]. During chemotherapy treatment, 31% of patients presented a notable weight variation which was greater than 5% of their initial weight. In multivariate analyses, weight change (> 5%) was positively associated with an increased risk of both recurrence (RR 2.28; 95% CI: 1.29-4.03) and death (RR 2.11; 95% CI: 1.21-3.66). Conclusions Our results suggest that weight change during breast-cancer chemotherapy treatment may be related to poorer prognosis with higher reccurence and higher mortality in comparison to women who maintained their weight.

This retrospective study analyzed, in metastatic breast cancer (MBC), overall survival (OS) related to each subsequent line of chemotherapy (CT). We evaluated 578 patients with a MBC. Among these patients, 558 patients were stratified according to the number of differents CT lines received. Median OS decreased from 22.5 to 12.3 months. Nevertheless, survival was rather stable for subsequent lines after the third line of CT around 8 months. In our study, it appeared useful to give several CT lines when possible. Subsequent lines of CT could have a beneficial effect on the survival for some patients with MBC.

Studies have demonstrated the feasibility and accuracy of sentinel lymph node (SLN) biopsy after neoadjuvant chemotherapy (NAC) in breast cancer. Some SLN-positive patients have low risk of nonsentinel lymph node (non-SLN) involvement. Our goal was to determine clinicopathological factors correlating with the presence of non-SLN metastases in patients after NAC and to assess the validity of nomograms predicting additional axillary metastases.Patients with infiltrating breast carcinoma (n = 132) were studied prospectively. All patients received NAC. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. Lymphatic mapping was done using the isotope method. Fifty-one patients were SLN positive.In univariate analysis, tumor size (P = 0.016) and the size of SLN metastases (P = 0.0055) were significantly correlated with the presence of non-SLN metastases. In multivariate analysis, SLN macrometastases (P = 0.047) conferred significantly increased risk of non-SLN metastases. The Memorial Sloan-Kettering Cancer Center nomogram was not reliably predictive for non-SLN metastases (area under the receiver operating characteristic curve, AUC, of 0.542), whereas the MD Anderson (AUC 0.716) and Tenon scoring systems (AUC 0.778) were validated.Our results suggest that clinicopathological factors predicting non-SLN involvement in SLN-positive patients with and without NAC are essentially the same. The risk of involvement may be assessed using existing nomograms, but additional large prospective studies are needed to determine their accuracy in patients after NAC.

Metabolic abnormalities of tumor cells offer opportunities of therapeutic targeting. In contrast to normal cells, tumor cells have absolute requirement for methionine (Met), an essential amino acid. Many molecular mechanisms have been considered to explain Met dependency. Several approaches have been used To reduce Met in vivo. As the main Met source was food, synthetic Met free diet were widely used. Alternatively, Met restriction was archived by the use of Met analogs or enzymatic degradation by methioninase. In animal models, Met restriction permit to limit tumor growth and to reduce tumor volume. However, interruption of Met restriction induce the regrowth of tumor. Moreover Met restriction induce several cells modifications suggesting its use in association with conventional chemotherapy. Preclinical studies have shown synergistic effect of the association of Met restriction and different cytostatic agents. Currently, few clinical investigations have been realised to test this therapeutic strategy.

The aim of this study was to detect and analyze changes in hormone receptor (HR) status after treatment of operable breast cancer with neoadjuvant chemotherapy (NCT). Patients were treated from 1982 to 2004 with different NCT combinations, mainly in successive prospective phase II trials. HR status before and after NCT was retested and reviewed in a blinded fashion by two pathologists, for 420 patients from a database of 710 patients. Among these 420 tumors, 145 (35%) were HR negative and 275 (65%) were HR positive before NCT. The HR status had changed after treatment in 98 patients (23%): 61 patients (42%) initially HR negative became HR positive. This HR-positive switch was significantly correlated with better overall survival (OS), compared with patients with unchanged HR-negative tumors. Moreover, this HR-positive switch also had an effect on disease-free survival (DFS). Conversely, 37 patients (13%) initially HR positive became HR negative after NCT. However, this group of previously positive patients still had a survival advantage for OS, but not for DFS. The Allred score was evaluated before and after chemotherapy. An increase in Allred score after NCT was significantly correlated with better DFS but not OS. It was previously shown, for other tumor parameters, that residual disease after NCT, rather than parameters evaluated on the initial biopsy, must be considered for patient prognosis. In this work, NCT induced variations in HR status in 23% of patients. A positive switch in HR status after NCT could be an indicator of better prognosis for patient outcome.

Pathologic complete response (pCR) is linked to a better outcome, but its definition varies among working groups. We performed this study to validate different expressions of pCR as well as to determine the role of in situ and isolated tumor cell residues. A pathologic review was conducted on 710 operable patients with breast cancer to assess the residual disease in breast and in nodes according to the Chevallier (Ch) and Sataloff's (Sa) classifications. The pCR rate was 14.3% according to the Chevallier and 25.8% according to the Sataloff's classification. Overall survival and disease-free survival have been compared according to the pathologic response. There were significant differences between the pCR Ch(1+2) or Sa(A) and the non-pCR group. No significant difference was found between classes Ch(1) versus Ch(2) and between class Sa(A) without isolated cells versus class Sa(A) with isolated cells. Conversely, tumors histologically modified by chemotherapy were associated with a better prognosis than unmodified tumors. Finally, evidence of pCR in nodes was associated with a better prognosis. pCR should be defined as an absence of node invasion, and in the breast, either absence of tumor or tumor residue less than 5% of the tumor.

Recent trials of induction chemotherapy in bulky operable breast cancer have shown much higher pathological complete response (pCR) rates with trastuzumab-driven combinations. However, it is useful to take into account the specific chemosensitivity of HER-2–positive tumors. The aim of this study was to assess the pCR rate according to HER-2 status in response to chemotherapy, without an anti–HER-2 specific biological agent, in 710 operable breast cancer patients. Since 1982, these patients have been treated with several different neoadjuvant chemotherapy combinations. During this period, HER-2 overexpression was most often not assessed. Subsequently, we assessed HER-2 expression using archival paraffin-embedded tissue. A technically usable specimen was available for 413 of the 710 patients. Before treatment, 51 patients were HER-2 positive, 287 patients were HER-2 negative, and the results were inconclusive for 75 patients. Of these patients, a pCR in breast and nodes was obtained in 94 patients (14.3%), but this event was threefold more frequent for HER-2–positive patients (23.5%) than for HER-2–negative patients (7%). The overall survival (OS) and disease-free survival (DFS) rates at 10 years were 66.6% and 57.4%, respectively. The DFS rate was, as expected, better for HER-2–negative patients, with HER-2 status assessed before as well as after chemotherapy. A significant difference was found for OS in favor of HER-2–negative patients only with postchemotherapy assessment of HER-2, a fact similar to our previous findings. Finally, there was a tendency toward a higher DFS rate for HER-2–positive patients who achieved a pCR compared with HER-2–positive patients who did not.

e11526 Background: Everolimus, in combination with exemestane, is indicated to treat hormone receptor-positive, HER2-negative metastatic breast cancer (MBC), in postmenopausal women without symptom...

Breast cancer is the most common malignancy and the second most common cause of cancer-related death in women. Endocrine therapy has been used for more than a century to treat advanced-stage breast cancer. The results obtained with the third-generation aromatase inhibitor letrozole demonstrated an actual improvement in patient outcome compared with tamoxifen. This benefit translates into disease-free survival improvement for adjuvant treatment and overall survival in patients with metastatic disease. The present clinical situation of hormonal therapy is stable; however, recently, new anticancer agents (temsirolimus and everolimus) that inhibit mammalian target of rapamycin protein kinase have been developed and seem to be very promising because of their synergistic activity with letrozole. The phase II study of a combination of temsirolimus or everolimus with letrozole demonstrated a better progression-free survival in the combination arm than in the letrozole alone arm. Consequently, the results of ongoing phase III studies are eagerly awaited.

Neoadjuvant chemotherapy in breast cancer corresponds to the use of a systemic treatment applied before loco-regional treatment (surgery and/or radiotherapy). Initiated in the seventies for treatment of the locally advanced and/or inflammatory breast cancers, induction chemotherapy has been extended in the beginning of eighties for cancers known as operable (size higher than 3 cm and/or in central position) in order to allow a more frequent conservating surgery. This objective is obtained in 75% of the cases approximately without increase in the risk of local relapse and without noxious effect on overall survival, in spite of the delay of the loco-regional treatment. Neo-adjuvant chemotherapy progressively moved with the advent of major drugs in breast cancer which are anthracyclins, vinorelbine and taxans. But to date, no protocol was essential like an uncontested standard. However, it seems that obtaining a complete clinical response is the best guarantor to avoid relapse. That seems to be observed only after 6 cycles, even 8 cycles of chemotherapy, each cycle combining the 2 major drugs for the treatment of breast cancer of which are anthracyclins and taxanes employed according a sequential scheme after a based-anthracyclins treatment, except any cardiac contra-indication. Moreover, the use of targeted therapeuticals like Herceptin, with a chemotherapy, seems to be promising and should be more studied. Finally, when a neoadjuvant chemotherapy is administered, the evaluation of the pre-treatment biopsy helps to establish key patient-management parameters such as tumour type, SBR grade and immunohistochemical parameters. This evaluation provides predictive parameters with regards to drug response (hormonal status, overexpression of Her2). The further studies realised in this way will permit to improve the results yet obtained.

The pathologist plays a key role in the optimal management of patients receiving an induction or a neoadjuvant chemotherapy. The evaluation of the pre-treatment biopsy helps to establish key patient-management parameters such as tumor type, SBR grade and immunohistochemical parameters. This evaluation provides predictive parameters with regards to drug response such as hormonal status, proliferation factors and overexpression of Her-2. The evaluation of the post-treatment tumour residue helps to determine tumour response to treatment and prognosis, as well as to adjust adjuvant regimens. It is essential to standardize these histopathological procedures.

This phase II study investigated the efficacy and tolerability of a primary chemotherapy regimen combining vinorelbine, epirubicin, and paclitaxel (VEP protocol) in women with stage II/III operable breast cancer. Patients (n = 50) were treated with six cycles of VEP according to the following schedule: vinorelbine (Navelbine®; Pierre Fabre, Boulogne, France; http://www.pierre-fabre.com) 20 mg/m2, epirubicin (Farmorubicin®; Pharmacia, New York, NY; http://www.pnu.com) 35 mg/m2 given on days 1 and 8, paclitaxel (Taxol®; Bristol-Myers Squibb, New York, NY; http://www.bmsoncology.com) 175 mg/m2 given on day 9, and G-CSF 5 mg/kg/day given on days 10–20 of a 21-day cycle, followed by surgery and radiotherapy. After six cycles of VEP, the pathological response rate (pCR) in breast was confirmed in six patients (12%; 95% confidence interval [CI]: 3–21)) using Chevallier's classification and in nine patients (18%; 95% CI: 7.4–28.6) using Sataloff's classification. The clinical response rate was 42% (95% CI: 28.3–55.7), including 26% complete responses. Breast conservation was achieved in 68% of patients. After a median follow-up of 48 months (range, 34–62 months), 16 relapses were observed. The overall and disease-free survivals at 5 years were 54.1% (95% CI: 40.3–67.9) and 38% (95% CI: 24.1–51.9), respectively. The principal toxicities of VEP were grade 3/4 neutropenia observed in 30% of patients and grade 3 anemia observed in 12% of patients. There was no case of severe cardiac toxicity, thrombocytopenia, or any other serious adverse events. In conclusion, whereas this regimen was relatively well tolerated, it appears inferior to other regimens and its use is not recommended.

This study investigated the efficacy and tolerability of FEC 100 (epirubicin 100 mg/m2 with 5-fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2) every 21 days as neoadjuvant chemotherapy in women with stage I-III primary operable breast cancer. Forty patients were treated with 6 cycles of FEC 100, followed by surgery and radiation therapy. In addition, most patients also received an adjuvant treatment for residual disease (11 chemotherapies and 31 tamoxifen). After 6 cycles of FEC 100, the overall clinical response rate of 75% (CI 95%, 61.6-88.4) was achieved, 22.5% of which were complete responses. Breast conservation was achieved in 70% of patients. A pathologic complete response was confirmed in 6 patients (15%; CI 95%, 3.9-26.1) using Chevallier's classification and in 10 patients (25%; CI 95%, 11.6-38.4) using Sataloff's classification. After a median follow-up of 29.5 months, 3 metastatic relapses were observed. The principal toxicity of FEC 100 was myelosuppression; 51.3% of patients developed grade 3/4 neutropenia. Neoadjuvant FEC 100 was both effective and well tolerated in patients with early-stage operable breast cancer.

Background: We have recently demonstrated (AACR 2013, abstract 4669) that antibody (Ab)-based EGFR targeting, sequentially combined with cytotoxic agents, can achieve pathologic complete response in almost 50% of triple-negative breast cancer (TNBC) patients (pts). However, the pts left with a residual tumor (RT), need a modification of treatment approach. We investigated whether expression of EGFR and two of its major cooperators, HER3 and MET, can offer a simple and practical base for neoadjuvant therapy (NAT) improvement in TNBC. Methods: The study included pts with a post-NAT RT in 2 pilot clinical trials of anti-EGFR Abs in TNBC, conducted from 2009 to 2011 by our team. One trial combined panitumumab with standard fluorouracil-epirubicin-cyclophosphamide and docetaxel (P-FEC-T) while another applied cetuximab with docetaxel (C-T). EGFR, HER3 and MET were assessed by immunohistochemistry (IHC) on pre- and post-NAT BC tissue. Expressions were evaluated by Quick score (% of positive cells x stain intensity as 0, 0.5, 1, 1.5, 2, 2.5 or 3; score range 0-300). At least 30 points of difference qualified the post-NAT score as changed, compared to the pre-NAT level. Results: 44 pts were eligible (P-FEC-T: 26 pts, C-T: 18 pts). Using 150 (the middle of the score range) as cut-off, we separated the tumors in each study on pre-NAT EGFR-high (score ≥ 150) and EGFR-low (score < 150). The P-FEC-T trial had 13 EGFR-high tumors (median score 220) and 13 EGFR-low ones (median score 0). After NAT, the pre-NAT EGFR-high BC most frequently showed EGFR decrease (9/13), HER3 increase (6/10) and MET decrease (7/12). However, the pre-NAT EGFR-low tumors showed no change in EGFR (7/13) and HER3 (6/11) post-NAT, but most of them increased MET (7/11). The C-T trial had 7 EGFR-high (median score 210) and 11 EGFR-low cases (median score 70). The EGFR-high BC from that trial showed a similar pattern of score changes as the same group from the P-FEC-T trial: frequent EGFR decrease (4/7), HER3 increase (5/7) and MET decrease (4/7). The EGFR-low BC were more heterogeneous than in P-FEC-T: most frequently EGFR, HER3 and MET were increased (4/11, 5/11, 5/11 respectively) or unchanged (4/11, 4/11, 3/11 resp.). Conclusion: Our results indicate that: a) there is a TNBC subgroup with relatively high EGFR expression (score ≥ 150, median around 200) which resist to anti-EGFR treatment mainly by downregulating EGFR and upregulating HER3; b) TNBC with low EGFR expression (score < 150) are a heterogeneous subgroup, which will frequently upregulate HER3 and/or MET after exposure to the anti-EGFR agents. The IHC assessment of EGFR, HER3 and MET before and on-NAT can help improving TNBC treatment by introduction of currently available anti-EGFR/HER3, anti-HER3 and anti-MET agents. Citation Format: Nina Radosevic-Robin, Catherine Abrial, Marie-Melanie Dauplat, Matthieu Roche, Anne Cayre, Maud Privat, Fabrice Kwiatkowski, Nassera Chalabi, Marie-Ange Mouret-Reynier, Yves-Jean Bignon, Philippe Chollet, Jean-Marc Nabholtz, Frederique Penault-Llorca. Heterogeneity of triple-negative breast cancer response to neoadjuvant treatment: tumor EGFR, HER3 and MET expressions can provide clues for therapy tailoring. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1819. doi:10.1158/1538-7445.AM2014-1819

Background. Triple negative breast cancers (TNBC) represent about 15 % of invasive breast carcinomas. These tumors are identified in clinical practice according to their “triple negative” immunophenotype (estrogen receptor, progesterone receptor and HER2 negative). TNBC show aggressive behavior and an unusual sarcoma-like pattern of metastasis. Identification of predictive biomarkers is critical to optimal therapeutic management of these tumors. TNBC are characterized by increased genomic instability. These tumors present complex pattern of numerous low-amplitude genomic gains and losses as well as shorter telomeres. Aim. Identification of predictive biomarkers of response to neoadjuvant chemotherapy in TNBC by evaluating telomeric parameters and genomic instability. Methods. We studied 38 TNBC patients treated with neoadjuvant chemotherapy according to the TVA protocol (FEC 100, docetaxel, panitumumab). DNA and RNA were extracted from snap-frozen tumor samples obtained before neoadjuvant therapy. The pathological response to treatment was evaluated according to Chevallier's and Sataloff's classifications and correlated with aCGH profiles (8x60K, Agilent) and telomere characteristics, including telomere length (qPCR) and expression (qRT-PCR) of telomerase (hTERT) and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2). Results. Telomere shortening and high hTERT expression were found in more aggressive tumors according to TNM classification (P< 0.04), and hTERT expression was also highly correlated with an increased tumor size (P= 0.0058). Short telomeres were strongly associated with incomplete histological response to neoadjuvant therapy according to Chevallier's (P= 0.0004) and Sataloff's classifications, (P= 0.0007). hTERT expression was significantly increased in cases with incomplete response (P< 0.04). Among shelterin complex genes, TRF2 and TPP1 overexpression was found in more aggressive TNBC (according to TNM classification and SBR grading, P< 0.05), but there was no correlation with pathological response. aCGH data indicated that genomic instability in non-responders was mainly represented by genomic gains. In particular, cases with incomplete therapeutic responses showed significantly larger size of gains than cases with complete responses. (P= 0.0089). Short telomeres were also associated with larger gains of genomic material (P= 0.0067). Of note, telomere shortening has been previously described as one of the mechanisms of genomic gains and amplifications. Conclusions. Telomere shortening and hTERT overexpression were observed in resistant TNBC. Genomic profile of non-responding tumors was characterized by larger genomic gains. Telomere length, hTERT expression and genomic instability profiles may represent predictive biomarkers of response to neoadjuvant chemotherapy in TNBC. Citation Format: Mathilde Gay-bellile, Nina Radosevic-Robin, Eleonore Eymard-Pierre, Fabrice Kwiatkowski, Marie-Mélanie Dauplat, Maud Privat, Catherine Abrial, Patricia Combes, Gwendoline Soler, Yves-Jean Bignon, Jean-Marc Nabholtz, Philippe Vago, Frédérique Penault-Llorca, Andreï Tchirkov. Genomic instability and telomere characteristics as predictive biomarkers of therapeutic response in triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 550. doi:10.1158/1538-7445.AM2014-550

e11615 Background: Gene expression studies have demonstrated that breast cancer can be divided into three major subgroups : Luminal, Human Epidermal Growth Factor Receptor-2 (HER2) over-expression and Oestrogen negative (ER-). Luminal breast cancer is well known for its better prognosis compared with the other types. Conversely, response is less effective by pCR criteria after chemotherapy. This work aimed to evaluate if pCR could still be considered as a surrogate marker in luminal subgroup according to immunohistochemical classification : Hormonal receptor positive and HER2 negative (HR+HER2-). Methods: All 132 luminal early breast cancer patients treated by neo-adjuvant chemotherapy (NAC), in our institution from 2001 to 2007 were included in this study. NAC treatment comprised anthracycline alone, taxotere alone or sequential use of these two drugs. Survival curves have been established according to the Kaplan-Meier’s method. Comparison of curves were performed in using Log-rank test. The median of follow-up was 102 months (range 59 – 142 months) in October 2012. Results: Median age was 53.5 (range 34–78) years and median initial tumor size was 4cm (range 1-10). Objective response rate was 65% (86 patients), of which 8% (10 patients) had a complete response after 6 courses. One hundred and six (80%) underwent breast conservation surgery. Seven patients (5%) and ten patients achieved pCR (8%) according to Chevallier and Satatloff’s classification, respectively. Twenty patients did relapse and 18 patients died. At 10 years, Disease-free survival (DFS) and overall survival (OS) rate was 81% and 84%, respectively. All pCR patients, regardless of classification, did not relapse. However, the patients who achieved a pCR had not a significant difference in DFS and OS compared to the patients who did not. Conclusions: pCR was not a surrogate marker after a relatively short survey of 100 months for luminal breast cancers, who have generally late relapses. However, sixty five percent of patients had >50% reduction in primary tumor and 80% of patients had a breast conservation. Further studies are needed to identify new markers able to predict patients’ survival.

e16021 Background: Prostate cancer is a major problem in the aging male population. Docetaxel, the first-line reference treatment in CRPC induces a prostate-specific antigen (PSA) response in 45% of patients and an objective tumor response in 12%. Preclinical studies suggested that curcuminoids inhibit tumor metastasis, invasion and angiogenesis and reverse drug resistance. We wanted to potentiate docetaxel by curcuminoïds in CRPC first line. Our previous phase I study showed the safety and the tolerability of CCM associated to docetaxel for advanced breast cancers. We have conducted in 2009-2010 a phase II study to assess the response of CRPC to this combination. Methods: Patients (n=30) with progressing CRPC and rising PSA were enrolled to receive the experimental treatment. Docetaxel was given in standard conditions (75mg/m², 1h i.v infusion every 3 weeks for 6 cycles + prednisolone) with CCM orally at the dose of 6gr/day (7 days by cycle: d-4 to d+2). The primary endpoint was response rate assessed by biological and paraclinical examinations. The secondary endpoints included safety, time to progression and compliance. Twenty nine patients were evaluable on PSA assessment and 15 on RECIST criteria. Results: 26 patients received the treatment totality and 4 withdrew prematurely. No patient withdrew for toxicity (2 deaths and 2 PSA progressions). A PSA response was observed in 17/29 patients (59%) (4 complete and 13 partial) observed rapidly (before the 3rd cycle) for 15 patients. The median time to subsequent PSA progression (TTP) was 5.8 months. Six patients (40%) had a partial objective response and 9 (60%) a stable disease. The median TTP on targets was 7.85 months (n=13/15). The regimen was well tolerated, with uncommon grade 3/4 toxicity; no adverse event was attributed to CCM. Of 169 cycles, 150 (89%) were completed with perfect compliance. Overall survival was 19 months (mean) and 24 months (median) with 17 events as of december 2012. Conclusions: These results are promising in improving the response rate to docetaxel in terms of both PSA decrease and objective response, with good tolerability and acceptability of CCM. A randomized trial is necessary to confirm this results. Clinical trial information: NCT01012141.

1057 Background: Cetuximab is an antiboby targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Therefore, we evaluated the combination of docetaxel with cetuximab as neoadjuvant therapy of operable TNBC. Methods: 35 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 6 cycles of T (100 mg/m2) q.3 weeks, in combination with weekly cetuximab (first dose : 400mg/m², then : 250 mg/m²/week) for 6 cycles. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff : J Am Coll Surg 1995 ; Chevallier : Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints. Results: Patients characterisctics are as follows : mean age 48 [28-67] ; T1 : 3%, T2 : 73%, T3 : 24% (mean tumor size : 40 mm [15-100]) ; N0 : 61% and N1-N2 : 39%; invasive ductal carcinoma : 100%; Scarff-Bloom-Richardson Grade III : 73%, grade II : 27%. The median number of cycles was : T : 6 [1-6], cetuximab : 15 [1-18]. Pathological complete response was 24% according to Chevallier and Sataloff’s classifications and 28% if we consider response in breast. Preliminary results on 23 patients show an overall clinical response rate of 57% (22% CR). Conservative surgery was performed in 75% of cases. Skin toxicity was the main side-effect : grade II : 39%, grade III : 36%, grade IV : 3%. Neutropenia grade IV : 12.7%, febrile neutropenia : 1.3%, infection : 0%. Hand-foot syndrome grade III : 3%, grade II : 3%. Ungueal toxicity grade III : 3%, grade II : 33%. Conclusions: These preliminary results suggest that cetuximab in combination with Tappears to have a modest efficacy in operable TNBC. Clinical trial information: NCT00600249.

1058 Background: EGFR overexpression is one of the hallmarks of the “basal-like” TNBC definition by immunohistochemistry (IHC). In a phase II neoadjuvant clinical trial targeting EGFR in TNBC, we investigated various biomarkers to better identify an EGFR-sensitive population for potential further regimen development. Methods: Sixty patients (pts) with stage II-IIIA TNBC were prospectively included. Systemic treatment (ST) consisted of the anti-EGFR antibody panitumumab combined with FEC 100, followed by 4 cycles of docetaxel. All pts underwent surgery after ST completion. Patient characteristics: median tumor size: 40 mm (20-120); invasive ductal carcinoma: 96.7%; SBR grade III: 71.7%; complete pathological response (pCR) rate: 55.3% and 46.8% (according to Sataloff’s and Chevallier’s classifications, respectively). Paraffin-embedded and frozen tumor samples were collected before and after ST for biologic studies. Germinal BRCA1 mutations, and EGFR, KRAS, BRAF and PI3KCA somatic mutations were analyzed by NGS. EGFR, IGF-1R, MET, cytokeratins 5/6 and 8/18, PTEN, P-cadherin, ALDH1, Ki-67, p53, tumoral FOXP3 expression and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TILs) were evaluated by IHC. Results: High CD8+ TILs was response-predictive (p=3.4.10-6). Tumor FOXP3 expression and high FOXP3 TILs tended to be predictive. High IGF-1R expressors responded better than low expressors (p = 0.028). Comparison of EGFR, IGF-1R and Her3 in biopsies versus surgical samples showed reduced EGFR levels in non-responders (p = 0.037), while Her3 (p = 0.049) and IGF-1R (p = 0.08) increased. Sequencing revealed BRCA1 mutations in 10% of pts. No difference of response (pCR) was observed between mutated patients and others. Somatic mutations of PI3K were observed in 6 pts. No mutations were observed in BRAF, KRAS, or EGFR. Conclusions: The CD8+ TIL count seems to predict the response to panitumumab. Tumor FOXP3 expression and high FOXP3 TILs also tended to be predictive. Tumor levels of IGF-1R seem to play a determinant role in TNBC response to anti-EGFR antibodies, in concordance with our observations in a head-and-neck cancer cohort. Clinical trial information: NCT00933517.

Background In breast cancer, positive Hormone Receptors (HR) constitute a favourable prognostic factor whereas HER-2 overexpression is an adverse prognostic factor associated with a more aggressive tumor. In a retrospective database of 282 breast cancer patients diagnosed from 1991 to 2006, we analysed the overall survival (OS) and the disease-free survival (DFS) of 4 phenotypes: HR-/HER-2- (triple negative, TN); HR + /Ki-67 20% or Her2+ (luminal B) and HER-2 overexpression (HER-2 + /HR-). Patients and methods Median diameter of the invasive tumour was 40 mm [10-130]. 231 (82%) patients had a canalar carcinoma. 33% of the tumours were grade III SBR. Patients received either an anthracycline-based chemotherapy (47%), a taxane-based chemotherapy (21%) or a combination of both (32%). The median number of NCT courses was 6 [1-8] followed by a surgery for 97.6%, a radiotherapy for 93%, an adjuvant chemotherapy for 20% and/or an hormonotherapy for 56%. Only 5 patients received adjuvant herceptin for 1 year. In the different subgroups, we had 123 luminal A tumors (44%), 67 luminal B tumours (24%), 21 Her2+ tumours (7%) and 71 TN tumours (25% of patients). Results According to tumour's phenotype, the pCR (Chevallier's classes 1 + 2) was: 3.3% for luminal A, 16.6%, for luminal B, 33.3% for Her2+ HR- and 26% for triple negative tumours. On 2 April 2012, the median follow-up was 148 months (range, 63- 252). We evaluated the OS and the DFS in the four subgroups, at 10 years. -For TN: OS and DFS were 58.5% and 56.2%. -For luminal A: OS and DFS were 76.1% and 64.7%. -For luminal B: OS and DFS were 81.7% and 72.4%. -For Her2 + HR- subgroup: OS and DFS were 64.5% and 56.4%. pCR is an objective method improvement after NCT, but it is variable among subsets, and may constitute an acquired prognostic factor. However, it was much smaller in hormonal-positive tumors subsets and may there not be an endpoint per se. We observed a significant improvement of DFS and OS for patients who reached a pCR only in TN breast cancer. However Her2 subset may be too small to reach significance here. Conclusion OS and DFS were better in luminal A and B subgroups. Conversely OS and DFS decreased for TN and Her2+ subtypes. When TN breast cancer patients reached a pCR, OS and DFS were significantly improved. Disclosure All authors have declared no conflicts of interest.

1051 Background: We evaluated the combination of a standard chemotherapy with panitumumab as neoadjuvant therapy of operable TNBC. Complete pathologic response (pCR) was the primary endpoint, with toxicity and biologic ancillary studies as secondary endpoints. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Paraffin-embedded samples and frozen samples have been systematically realised before and after neaodjuvant treatment in order to evalutate the biological profile of the tumor. Patients characteristics are : median age 50 ; median tumor size : 40 mm ; invasive ductal carcinoma : 96% ; Scarff-Bloom-Richardson Grade III : 70%, grade II : 30%, ki-67-positive : 100%, EGFR-positive : 78%, cytokeratine5-6-positive : 48% and p53-positive : 59%. Pathological response showed a pCR according to Sataloff’s classification of 52.38% and according to Chevallier’s classification of 46.52%. Skin toxicity was the main side-effect : Cutaneous toxicity grade IV : 5%, grade III : 30%, grade II : 20%. Neutropenia grade IV : 27% ; febrile neutropenia : 5%. Infection : 0%. Hand-foot syndrome grade III : 3.3%. Ungueal toxicity grade III : 1.6%, grade II : 20%. Results: We have tested the predictive value of ki-67, EGFR, cytokeratine 5-6 and p53. Only ki-67 is predictive of a pCR according to Chevallier’s classification (p=0.026), with a cut-off of 40% of positive cells (ROC curve): 62% of pCR if ki-67> 40% versus 23% if not (relative risk : 2.7). Low EGFR, high p53, and high cytokeratine 5-6 tended to be associated with poor reponse. No correlations were found between cutaneous toxicities and these biomarkers. The cutaneous toxicities were not predictive. Conclusions: HighKi-67 is predictive of more pCR. High EGFR, low p53 and low cytokeratine 5-6 tended to be associated with better response, but the data are not significant.

Background &Aims: Curcumin, a polyphenol derived from Curcuma Longa is known for his anti-cancer activity and may exert synergic effects with cytotoxic agents. In parallel, neuroendocrine differentiation in castration-resistant prostate cancer provides an aggressive phenotype to disease. In this prospective phase II study, we assessed the impact of a new combination, docetaxel plus curcumin, in patients with or without neuroendocrine features. Methods: In this phase II study, thirty patients received docetaxel 75 mg/m*2 (perfusion given every 3 weeks) in combination with curcumin orally at 6 g/day (day-4 to day+2 of docetaxel). Neuroendocrine features were determined by serum chromogranin A and neuron-specific enolase, before each cycle. Variations were divided in 3 groups: an increase > 25%, a decrease of 50% or greater and stability. Treatment response were measured by PSA >50% decrease (PSA response) and objective response rate on evaluable metastatic lesions. Results: Initially, 53% of patients had an elevated chromogranin A and 33% an elevated neuron-specific enolase. During treatment, 7% performed a > 50% chromogranin A decrease and 30% a neuron-specific enolase decrease. PSA response was observed in 59% of patients and 40% out of patients with evaluable targets had a partial response. PSA and objective response rate were identical whatever neuroendocrine feature. A positive correlation was found between chromogranin A and PSA, age, weight and palliative radiotherapy. Conversely, neuron-specific enolase was negatively correlated with PSA and patients'age. Conclusions: Curcumin and docetaxel had a global action on tumors with or without neuroendocrine features. Chromogranin A was the best neuroendocrine marker in correlation with clinical parameters. This association delivered then remarkable results on neuroendocrine differentiation of castration-resistant prostate cancer, in comparison with pivotal study data with docetaxel alone (TAX 327). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2694. doi:1538-7445.AM2012-2694

Purpose: As a contribution to the discussion of pathological complete response (pCR) as surrogate end-point, after neo-adjuvant chemotherapy (NACT), we studied disease-free survival (DFS) and overall survival (OS) at 15 years with THP-doxorubicin, vinorelbine, 5-Fluorouracil and cyclophosphamide (TNCF regimen). Patients and methods: This retrospective cohort study has been done in 61 patients treated with neo-adjuvant semi-intensive chemotherapy. PCR rate was analysed separately in breast (no histological evidence of invasive tumor cells and / or presence of in situ carcinoma tumor cells) and in nodes (no metastasis). Univariate and multivariate analysis (COX regression) have been used to assess the potential prognostic factors with a median follow up of 13.8 years. Results: Thirty two patients relapsed and 21 died. At 15 years, DFS and OS were 53% and 88% respectively for the patients who achieved pCR compared to 33% and 53% respectively for those who did not achieve pCR. Multivariate analysis with COX model showed that pCR in breast and the number of involved nodes at surgery were 2 factors who can significant predict patients’ DFS and these two factors were significantly related. Conclusion: In this current study, pCR in breast can be used as surrogate marker to predict survival outcome, even with a long-term follow-up of 15 years. When pathological response was incomplete in primary tumor, the number of involved nodes (n > 4 vs n Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2707. doi:1538-7445.AM2012-2707

1121 Background: Metastatic breast cancer (MBC) is an incurable disease in most cases; then treatment is palliative, to prolong overall survival (OS) and control clinical symptoms. Progressively the figures obtained have improved with time. However, the optimal duration of therapy is unknown. Few authors have considered the treatment globally versus for each line and fewer have demonstrated the interest of chemotherapy (CT) after the third line. The aim of this study was to assess tumoral response and OS of patients treated with more than 3 lines of treatment, for each line given. We selected recent patients treated during “taxanes/anti-aromatase era (TAA)” corresponding to an important progress in breast cancer therapy. Methods: Our metastatic database recorded 590 patients with MBC. Among these patients, 530 received at least one line of CT and 383 an hormonotherapy (HT). TAA was defined from December 31th, 1993, as from this date they became available for the french patients. Results: Median OS surviva...

e11574 Background: Panitumumab is an antiboby targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Consequently, we evaluated the combination of a standard chemotherapy (FEC100 followed by T) with panitumumab as neoadjuvant therapy of operable TNBC. Methods: 58 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff : J Am Coll Surg 1995 ; Chevallier : Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints. Results: Patients characterisctics are as follows : mean age 50 [38-64] ; T2 : 81%, T3 : 19% (mean tumor size : 42 mm [25-80]) ; N0 : 73% and N1 : 27%; invasive ductal...

e15069 Background: Prostate cancer is the most frequent tumor in men from developed countries. A previous phase I study showed the feasability of curcuminoids in association with docetaxel for adva...

683 Background: We report an extended experience of TNCF protocol as semi-intensive primary chemotherapy for high risk operable breast cancer (Eur J Cancer. 1997;33:862-866). Methods: Between 04-91...

648 Background: In a new database harbouringthe patients of several prospective phase II neoadjuvant trials (fec 50-100, net, tncf, taxotere/tncf, taxotere alone), the predictive value of tumour fa...

Introduction: Relationships between overweight and cancer have been described for a long time. First, obesity increases the risk of cancer at several sites, including breast cancer. Furthermore, overweight has been linked to adverse outcome in women with breast cancer, which mecanisms are not completely understood. After breast cancer development, numerous studies report a weight gain due in part to the effects of some treatment regimens, most notably chemotherapy. As observed in few studies, especially in US population, weight gain after breast cancer diagnosis may have an adverse effect on survival and recurrence of breast cancer. The aim of our study was to evaluate whether weight variations during chemotherapy are predictive of breast cancer survival and recurrence in an european population.Materials and methods : between 1976 and 1989, 141 women treated at Centre Jean Perrin (Clermont-Ferrand, France) for non-metastatic breast cancer by adjuvant or neo-adjuvant chemotherapy have been included in our series to have at least 20 years of follow-up for the study. The median follow-up was 20.4 years [19.4-32.5]. Weight was measured prospectively at baseline and at each cycle of chemotherapy. Patient were included if they had received neoadjuvant or adjuvant anthracycline-based chemotherapy, and if weight assessement included at least 3 measurements with necessary one at baseline and another at the end of chemotherapy. Body mass index (BMI) and weight variation (WV) on overall survival (OS) and disease free survival (DFS) (local recurrence and distant metastasis) were explored. Threshold of WV was fixed at 5% (gain or loss) of the initial body weight.Results : Median age of patients was 54 years [32- 75] and 57% were menopaused. Patients received a median of 6 cycles [2-15] of anthracycline-based chemotherapy. Initial median BMI was of 24.4 kg/m2 [16.6 -40.5]. During chemotherapy treatment, weight was stable (median of relative WW of 0% [-10.9-15.4]), 17% of patients lost weight (WV < -5%), 68% were stable (-5 5%).In the univariate analysis, patients with a baseline BMI lesser than 24 kg/m2 had a better OS than those with initial BMI higher than 24 kg/m2 (p = 0.026). Indeed, there was a significant difference in DFS between these two groups (p = 0.027).Moreover, there was a significant difference in OS between patients whose weight varied beyond 5% compared to patients who maintained their weight (p = 0.048). This effect was also observed on DFS (p = 0.033).In a multivariate analysis, that included tumor size and node involvement, we found that WV more than 5% was associated with a significantly OS decrease (risk ratio, 1.83; 95% CI, 1.08 to 3.08; p = 0.024) and a higher risk of recurrence (DFS: risk ratio, 1.95; 95% CI, 1.14 to 3.32; p = 0.014).Conclusion : our study showed that weight variations were associated with a higher risk of death and recurrence (local and distant metastasis) in breast cancer patients. Consistent with these results, weight management should be directed to maintain weight during chemotherapy treatment of non-metastatic breast cancer in future interventional studies. Moreover, further studies are needed to explore biological mecanisms of such a clinical observation. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6049.

e11502 Background: NCT is increasingly used for operable breast cancer to allow breast conservation. Our objective was to evaluate clinical and pathological response after sequential NCT of FEC 100-T. This chemotherapy is currently the reference in the adjuvant setting in France.In PACS 01 trial (Roche et al. J Clin Oncol, 2006) FEC followed by T significantly improved 5 years overall survival rates (90.7%) compared to 6 FEC 100 in node-positive breast cancer. However this combination has not yet been evaluated in NCT. Methods: 101 patients (pts) from February 2005 to September 2008 with stage II-III operable breast cancer received 3 cycles (c) of FEC 100 (epirubicin 100 mg/m2 + 5-fluorouracil and cyclophosphamide 500mg/m2) followed by 3 c of T (100mg/m2) every 3 weeks. pCR was defined according to Chevallier's (Am J Clin Oncol, 1993) as level 1 and 2 and to Sataloff's classification (J Am Coll Surg, 1995) as grade A. A clinical, mammography and ultrasound breast evaluation was performed at baseline, after 3 or 4 c and before surgery. Results: Median age was 52.3 years [32–71]. Median diameter of the tumor was 42 mm [15–100]. 83 pts had a ductal, 14 a lobular, 3 ductal and lobular, 1 another carcinoma. 8.9% were grade I SBR, 58.4% grade II SBR, 28.7% grade III SBR and 4% unspecified. 74 (73.3%) tumors were HR+, 9(8.9%) Her-2 + and 18(17.8%) triple negative. Ultrasound objective response rate (ORR) was 66.3%: 6 pts had a complete response and 53 pts had a partial response. 77pts (76.2%) underwent breast-conserving surgery After the completion of NCT, complete histologic data were available for 92 pts. 10 (10.8%) achieved pCR using Chevallier's classification and 9 (9.8%) using Sataloff's classification. The pCR rate was superior in triple negative (4/12) and Her2+ (2/6) tumors than in patients with HR+/Her-2- according to Chevallier's classification (p=0.034) and to Sataloff's classification (p=0.014). Conclusions: Sequential NCT with FEC followed by T was active and significantly improved pCR in patients with triple negative and Her-2+ tumors without an anti-Her2 specific biological agent. Breast-conserving rate appeared satisfactory. No significant financial relationships to disclose.

e11560 Background: Trastuzumab plus chemotherapy has become the standard of care for Her-2-positive breast cancer. Recent trials have shown higher pCR rates in Her2-positive tumors with trastuzumab-driven combinations (Buzdar, JCO 2005; Coudert, Ann Oncol, 2006). The purpose of this study was to review efficacity of sequential FEC followed by D+T. Methods: 21 patients (pts) with Her2-positive breast cancer (defined as either immunohistochemical 3+ or fluorescence in situ hybridization-positive) from June 2006 to September 2008 with breast cancer received 3 cycles (c) of FEC 100 ( epirubicin 100 mg/m2 + 5-fluorouracil and cyclophosphamide 500mg/m2) followed by 3 c of D (100mg/m2) every 3 weeks +T 2mg/kg weekly or 6mg/kg every 3 weeks (9 weeks of T). pCR was defined according to Chevallier's (Am J Clin Oncol, 1993) as level 1 and 2 and to Sataloff's classification (J Am Coll Surg, 1995) as grade A. A clinical, mammography and ultrasound breast evaluation was performed at baseline, after 3 or 4 c and before surgery. Cardiac evaluation (ejection fraction) was performed at baseline, after 3 c of FEC, before surgery and every 3 months after. Results: Median age was 52.1 years [27–71]. Median diameter of the tumors was 45 mm [10–160]. All pts had a ductal carcinoma. 5 pts had inflammatory breast cancer. 1 pts were grade I SBR, 13 grade II SBR, 6 grade III SBR and 1 unspecified. 5 tumors were HR+, 15 HR- and 1 unspecified. After FEC 100 x3, a clinical partial response (PR) was obtained in 4 pts (19%). After completion of NCT,clinical objective response rate was 95.2%: 13 pts had a complete response and 7 pts a partial response. 13 pts (62%) underwent breast-conserving surgery. 10 pts (47.6%) achieved pCR using Chevallier's classification (1 HR+ and 9 HR-) and 12 pts (57.1%) using Sataloff's classification (2 HR+ and 10 HR-). At the time of the analysis for cardiac evaluation, 8 pts continued to receive adjuvant T. 1 pt was lost for follow-up. 5 pts (25%) had an asymptomatic drop of ejection fraction greater than 10%. Conclusions: This regimen with only 9 weeks preoperative trastuzumab resulted in a high rate of pCR in Her2-positive tumors, without clinical cardiac events until now. No significant financial relationships to disclose.

This study compares the outcome of 76 patients with N0 breast carcinoma, node-negative at axillary lymph node dissection (pN0) after neoadjuvant chemotherapy (NeoCT), treated with (RLNI+, 39 patients) or without (RLNI−, 37 patients) elective regional lymph node areas irradiation. For RLNI− and RLNI+ groups respectively at 10 years, survival without local-regional recurrence was 95% and 91% (p = .59), survival without distant metastasis was 97% and 78% (p = .018) and overall survival was 96% and 75% (p = .013). Clinical size < 4 cm was a strong pronostic factor.

Abstract #1020 Background: In breast cancer, neoadjuvant chemotherapy (NAC) is widely used in order to enable a conservative surgery. In patients treated with NAC, the use of sentinel lymph node (SLN) biopsy, which is a good predictor of the axillary nodal status in previously untreated patients, is still discussed. The aim of our study was to determine clinicopathological factors that may influence the accuracy of SLN biopsy after NAC. Patients and methods : Between March 2001 and December 2006, 129 patients with infiltrating breast carcinoma were studied prospectively. Preoperatively, all of them underwent NAC. At surgery, SLN biopsy followed by axillary lymph node (ALN) dissection was performed. Lymphatic mapping was done using the isotope method. Results : The SLN identification rate was 93.8% (121/129). Fifty-six out of the 121 sucessfully mapped patients had positive ALN. Eight out of these 56 patients had tumor-free SLN (false-negative rate of 14.3%). The false-negative rate was correlated with larger tumor size (T1-T2 versus T3; p=0.045) and positive clinical nodal status (N0 versus N1-N2; p=0.003) before NAC. In particular, the false-negative rate was 0% (0/29) in N0 patients and 29.6% (8/27) in N1-N2 patients. Clinical and pathological responses to NAC did not influence the accuracy of SLN biopsy. Conclusion : Our results show that clinical nodal status is the main clinicopathological factor influencing the false-negative rate of SLN biopsy after NAC for breast cancer. SLN biopsy after NAC can predict the ALN status with a high accuracy in patients who are clinically lymph node negative at presentation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1020.

11516 Background: To update the results of a phase II combining sequentially neoadjuvant docetaxel to a semi-intensive anthracycline-based regimen (TNCF); to compare these results to those of a larger 710 patients database in which patients were treated between 1982 and 2004 by several neoadjuvant chemotherapy protocols. Methods: From 2001 through 2003, 53 patients received four cycles of docetaxel, followed by a maximum of four cycles of TNCF every 21 days (Amat et al, Clin Breast Cancer, 2006). On completion of chemotherapy, patients underwent surgery and radiotherapy, then adjuvant treatment. Forty-four tumors (83%) were stage II disease (18 stage IIA and 26 stage IIB) and 9 (17%) were stage IIIa disease. In all, 43 (81%) patients had a canalar and 4 (7.5%) a lobular invasive carcinoma. 30% of the tumours were grade III SBR and 64% had at least one-positive HR. Patients received up to 8 cycles (median: 6 [range, 4–8]) ea. 21 days. Results: Clinical objective response rate (ORR) was 79% [CI 95% : 68–90]...

10579 Background: Pathological responses rates were studied in 710 women with stage II-III operable BC treated between 1982 and 2004. A pathological review was conducted to assess the residual disease in breast and nodes according to Chevallier's classification (Am J Clin Oncol 1993) and patients repartited according to 3 tumour phenotypes: Her2+ (Her2+ phenotype), Her2-HR+ (Hormonal Receptor; luminal phenotype) and Her2-HR- (triple negative phenotype). Methods: Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar, 90 (13%) a lobular, 18 (2.5%) a mixed or invasive carcinoma, 36 (5%) neoplasic cells only and 11 (1.5%) another carcinoma. 25.6% of the tumours were grade III SBR. The median number of NCT courses was 6 [1–9] followed by a surgery for 92%, a radiotherapy for 95%, an adjuvant chemotherapy for 17% and/or an hormonotherapy for 52%. A breast evaluation was realized before, during and after NCT. Results: Overall response rate was 68% (16% complete). The complete pathological response (pCR) rate was 14.2% according to Chevallier's classification. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes. After a median follow-up of 93 months, Disease-Free Survival (DFS) and Overall Survival (OS) at 120 months were 54.9% and 66.5%, respectively. According to tumour's phenotype, the pCR rate (Chevallier's classes 1+2) was: 24.5% in Her2+ phenotype, 14.8% in triple negative phenotype and 4.4% in luminal phenotype. These results showed that: -the pCR was three-fold more frequent in Her-2+ phenotype than in luminal one (p = 3.5.10-5) -the pCR was two-fold more frequent in triple negative phenotype than in luminal one (p = 3.10-3) -no significant pCR difference was found between Her2+ phenotype and triple negative one Furthermore, a significantly better DFS was found for luminal phenotype; DFS was intermediate for triple negative phenotype, and lower for Her2+ phenotype. Conclusions: The pCR rates were higher in Her2+ phenotype and in triple negative one. It is important to note that, in this series, most Her2+ patients did not receive any Herceptin treatment. No significant financial relationships to disclose.

673 Background: Positive HR constitutes by their presence a favourable prognosis factor and predicts response to an adjuvant hormonal therapy. In breast cancer treated by NCT, HR expression has been shown to be modified in residual disease after induction chemotherapy (Miyoshi Y and al., Clin Cancer Res. 2004). Methods: A second centralized comparative lecture of oestrogenic and progestative receptors was realized by IHC. HR status was evaluated in a blinded fashion by two pathologists, on 414 out of 710 patients from several prospective phase II trials. Cut off value for positivity was 10% tumor cells (Amat et al, Breast Cancer Res Treat 2005). Median age of patients was 49.5 years. 555 (78%) patients had a ductal, 90 (13%) a lobular and 65 (9%) other type carcinoma, with a median size of 40 mm. Response was evaluated before, during and after a median number of 6 courses (1–9) of NCT. Study is curently ongoing. Results: Among these414 tumors, 157 (38%) were HR negative and 257 (62%) positive before NCT. HR status was changed in 105 patients (25%): 75 patients (48%) initially HR negative became HR positive. This HR positive switch was significantly correlated with a better overall survival (OS), compared with the unchanged HR negative tumors (p=0.032). However, HR positive switch had no effect on the disease free survival (p=0.085). More details concerning RH status and effect on hormonal adjuvant treatment will be presented.Conversely, Among the 257 HR positive tumors, 30 (12%) became negative after NCT, without effect on OS (p=0.28). Conclusions: We have previously shown that residual disease after NCT, rather than parameters evaluated on initial biopsy, must be considered for patients’ prognosis. NCT induced variations in HR status in 25% of patients; a positive switch was a strong prognostic indicator for patients outcome. No significant financial relationships to disclose.

767 Background: Breast cancer, the most common feminine cancer, once metastatic, is incurable in most cases. While multiple treatments with various chemotherapy combinations and hormonotherapies ar...