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Background: Triple negative breast cancer (TNBC) is the most heterogeneous subtype of breast cancer. However, the initial treatment of this disease is still dichotomous: 1st-line surgery (Surg1) followed by adjuvant chemotherapy, or neoadjuvant chemotherapy (NACT) followed by surgery. After radiotherapy, most of the patients (pts) are only observed until recurrence. Our team has pointed earlier (SABCS 2017) that some TNBCs recur very rapidly, in less than 12 months (mo) after NACT. Pts with those tumors have a very poor prognosis (overall survival < 6 mo). On the other side, a recent study has revealed a TNBC subgroup with late recurrences (> 5 yrs post-diagnosis, Rueda et al, Nature 2019). Neither of those groups is currently recognized in clinical practice nor specifically managed. In this study, we analyzed pattern and potential clinico-pathological biomarkers of recurrence in a large TNBC patient cohort treated at a specialized cancer center in France, to get a better insight into the need and possibilities for specific prevention of recurrent TNBC. Pts and methods: The study retrospectively included 305 pts, treated between 2000 and 2015 in Centre Jean Perrin, Clermont-Ferrand (stage I-III: 135 pts by Surg1; 146 pts by NACT; stage IV: 24 pts). The following putative biomarkers were evaluated: breast tumor size, number of involved nodes, tumor histograde, presence of lympho-vascular invasion (LVI), tumor-infiltrating lymphocytes (TILs, according to PMIDs 25214542, 29024776), presence of epithelial-mesenchymal transition (expression of Zeb1 protein by immunohistochemistry) - all at the Surg1 and post-NACT residual tumor (RT), as well as pathological complete response to NACT (pCR). Median follow-up of the pts was 4.8 yrs. The biomarkers were evaluated by univariate and multivariate analysis. Results: Recurrence-free survival (RFS) rate was significantly higher in Surg1 than in NACT cohort (76% vs 62%, resp., p=0.016). Early recurrence rate (RR) (< 12 mo post-Dg) was higher in the latter (5.6%) than in the former (2.4%), whereas the standard and the late RRs were comparable (RR 1-5 yrs post-Dg: 21.4% vs. 32.5%, p=0.05; > 5 yrs: 7.0% vs 6.7%, Surg1 vs NACT, resp.) In Surg1 cohort, the independent recurrence biomarkers were pN (pN0 vs pN+, p=0.003) and LVI+ (LVI+ vs LVI-, p=0.005). In NACT cohort, the only independent recurrence biomarkers were post-NACT RT size (p=0.009) and number of the involved nodes (LN) (p1cm≤2cm/LN=0, n=36; any RT/LN=1, n=18; RT≤2cm/LN≥2, n=11; RT>2cm/LN≥2, n=16, with significantly different 5-year RFS rates (92%, 62%, 54%, 30%, 13%, p2cm), with median TILs 5yrs) recurrences exist too, in up to 15% pts. The early recurrences are more frequent in the pts treated by NACT, and reflect high baseline metastatic capacity of the tumors. Big post-NACT RT size (> 2 cm), TILs < 5% and ≥ 2 LN+ are worth validation on larger cohorts as biomarkers of TNBC early and standard (1-5 yrs) recurrence. These 3 parameters, easily assessable in routine clinical practice, could help selecting pts with high risk of recurrence for specific therapies. To discover biomarkers of late TNBC recurrence, additional analyses are needed. Citation Format: Judith Passildas-Jahanmohan, Mona Ouled Dhaou, Fabrice Kwiatkowski, Wilfrid Finck, Camille Poirier, Marie-Ange Mouret-Reynier, Xavier Durando, Catherine Abrial, Frederique Penault-Llorca, Nina Radosevic. Pattern and biomarkers of recurrence in 305 triple negative breast cancer patients treated in a French comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-45.

To find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (SOX2 and CXCR4. Our results indicate that high expression of cell cycle genes, combined with cold immunological phenotype, may predict strong TNBC resistance to NAT and rapid progression after it. This biomarker combination is worth validation in larger studies.

Background: Durable responses of triple negative breast cancer (TNBC) to pembrolizumab (anti-PD-1) or atezolizumab (anti-PD-L1) have been reported in the metastatic setting. Moreover, it is currently being hypothesized that immune checkpoint inhibitors might be more effective in the neoadjuvant setting, due to better preserved anti-tumor immunity in early TN disease. However, biomarkers predictive of response to anti-PD-1 or anti-PD-L1 agents, as well as biomarker-based strategies for testing those drugs in the neoadjuvant setting are still lacking. We evaluated PD-L1 protein expression and the composition of tumor-infiltrating lymphocytes (TILs) in untreated TNBC, in order to get a better insight into the TNBC sub-population(s) which would be suitable for neoadjuvant anti-PD-1 or anti-PD-L1 therapy evaluation. Methods: TNBC patients consecutively treated at the Jean Perrin Comprehensive Cancer Centre (Clermont-Ferrand, France), from 01/01/2010 to 12/31/2014, were included. FFPE tumor tissues were assessed for PD-L1 expression by immunohistochemical (IHC) laboratory-developed test (clone 28-8, Abcam), in tumor cells (tPD-L1) and in TILs. Positivity cut-offs evaluated were ≥1%, ≥5% and ≥10%. The amount CD8+, CD4+, FoxP3+ or PD-1+ TILs was determined by counting those cells, detected by IHC methods, within 5 consecutive HPFs (x400), from tumor invasive front toward tumor center. Clinical disease stage was determined using the TNM system. Results: One hundred and two TNBCs were assessed. There were 28.4%, 23.5% or 16.7% tPD-L1-positive cases (cs), for cut-offs ≥1%, ≥5% or ≥10%, respectively. Similarly, 32.4%, 15.7% or 5.9% of cs were positive for PD-L1 in TILs, using the same cut-offs. With ≥5% as cut-off, positivity for tPD-L1 significantly correlated with the amount of CD8+ (p=0.023), FoxP3+ (p=0.0036) or PD-1+ TILs (p=0.043). The same cut-off, applied to TILs, revealed significant correlations between PD-L1 positivity and the amount of each CD8+, CD4+ or PD-1+ TILs (p=0.025, 0.039 and 0.0042, respectively). Interestingly, when the ≥5% cut-off was used, tumors of T2 size were most frequently tPD-L1+ (11/41 cs, 26.8%), compared with the T1 (3/35 cs, 8.6%) and T3+T4 (3/18 cases, 16.7%) (p=0.04). With regards to TILs, with the ≥5% cut-off, the PD-L1+ cases belonged exclusively to the T1+T2 group (15/76), whereas the T3+T4 group was PD-L1-negative (0/18 cs). Other two cut-offs revealed only occasional correlations. Conclusion: This single-center, real-world TNBC cohort contained a high number of smaller tumors (T1-T2). The IHC-based PD-L1 assessment, with ≥5% as the positivity cut-off, revealed that approximately 1/4 of TNBC could be candidates for neoadjuvant anti-PD-1/anti-PD-L1 approaches. Combined with the amount of CD8+ and PD-1+ TILs, tumor PD-L1 positivity might make an easy-to-use composite biomarker for the 1st-level patient selection for PD-1 or PD-L1 inhibitors in neoadjuvant TNBC treatment. The 2nd level could exploit, for example, the assessment of mutation burden in tumors with low tPD-L1 or amount of CD8+ or PD-1+ TILs. Such tumors might be more frequent among larger TNBC (T3-T4). Citation Format: Finck W, Passildas J, Poirier C, Kwiatkowski F, Abrial C, Durando X, Penault-Llorca F, Radosevic-Robin N. The ≥5% cut-off reveals tumor PD-L1 positivity as potential selection biomarker for patient enrollment into the trials evaluating anti-PD-1 or anti-PD-L1 agents in neoadjuvant treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-09.

BackgroundTriple negative breast cancer (TNBC) accounts for 10-20% of breast cancers but has no specific therapy. While TNBC may be more sensitive to chemotherapy than other types of breast cancer, it has a poor prognosis. Most TNBC relapses occur during the five years following treatment, however predictive biomarkers of metastatic relapse are still lacking. High tumour-infiltrating lymphocytes (TILs) levels before and after neo-adjuvant chemotherapy (NAC) are associated with lower relapse risk and longer survival but TILs assessment is highly error-prone and still not introduced into the clinic. Therefore, having reliable biomarker of relapse, but easier to assess, remains essential for TNBC management. Searching for such biomarkers among serum/plasma proteins, circulating tumoral DNA (ctDNA) and blood cells appear relevant.MethodsThis single-centre and prospective study aims to discover predictive biomarkers of TNBC relapse and particularly focuses on plasma proteins. Blood samples will be taken at diagnosis, on the day of first-line or post-NAC surgery, on the day of radiotherapy start, then 6 months and one year after radiotherapy. A blood sample will be taken at the time of metastatic relapse diagnosis. Blood samples will be used for circulating protein quantification, blood cell counts and circulating tumour DNA quantification. A tumour RNA signature, based on the analysis of the RNA expression of 6 genes, will also be tested from the initial biopsy taken routinely. In NAC patients, TILs quantity will be assessed on TNBC pre-treatment biopsy and surgical specimen.Ethics and DisseminationINSTIGO belongs to category 2 interventional research on humans. This study has been approved by the SUD-EST IV ethics committee and is conducted in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study findings will be published in peer-reviewed medical journals.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04438681.

Background Triple negative breast cancer affects 10% to 20% of all women diagnosed with breast cancer. Due to its characteristics, treatment strategies are limited and metastatic recurrences are common in the first 5 years after treatment. However, not all patients affected by this disease develop metastases. Tumor-infiltrating lymphocytes have shown to be reliable predictive biomarkers of treatment response and metastatic recurrences. However, we need to develop simpler and faster ways to predict response to cytotoxic treatment and the possibility of eventual cancer relapse by identifying new biomarkers. Recently, new studies are emerging, suggesting a predictive role of circulating blood cells in different types of cancer. In this study, we will assess the correlation between tumor-infiltrating lymphocytes and different elements of the blood count in patients diagnosed with triple negative breast cancer. Methods The main objective of this study is to evaluate the correlation between the peripheral neutrophil-to-lymphocyte ratio and the amount of tumor-infiltrating lymphocytes, assessed in triple negative breast cancer patients at diagnosis. Secondary objectives include evaluation of the correlation between tumor-infiltrating lymphocytes at diagnosis and the baseline absolute neutrophil, lymphocyte, and platelet counts, as well as the platelet-to-lymphocyte ratio. The triple negative breast cancer patients will be enrolled in the PERCEPTION trial during the first year after the treatment completion. Two supplementary blood tests, at 12 months after the end of treatment and at the time of the first metastatic recurrence, will be performed. Discussion The discovery of new prognostic and predictive biomarkers is crucial for triple negative breast cancer. We set up the PERCEPTION clinical trial in order to evaluate certain blood counts as early biomarkers and to assess their correlation with tumor-infiltrating lymphocytes. Demonstration of comparative predictive and/or prognostic capacities of peripheral blood counts and tumor-infiltrating lymphocytes would allow introduction of the former as simple and cheap biomarkers in triple negative breast cancer patient management. Trial registration The PERCEPTION study has been registered in the French National Agency of Medical Security registry on the 2nd of July 2019 under the number 2019-A01861-56 and in the ClinicalTrials.org registry under the number NCT04068623.

Background: Epidermal growth factor receptor (EGFR) is expressed in ˜50% of triple negative breast cancer (TNBC) and has been proposed as a therapeutic target in this disease. However, trials testing EGFR blockade in TNBC failed to show significant clinical benefit. Probable reasons for such results were patient selection based on EGFR expression and the enrollment of heavily pretreated metastatic patients. Our team has conducted two neoadjuvant trials testing the activity of the anti-EGFR antibodies panitumumab (PTB) and cetuximab (CTX) combined with chemotherapy in locally advanced TNBC. Biomarkers predictive of pathological complete response (pCR) were the level of tumor cell EGFR protein expression and tumor-infiltrating lymphocytes' (TILs) profile (PMIDs 24827135, 26649807). The PTB-treated pts had a higher pCR rate (47%) than the CTX-treated pts (24%), but also a twice higher relapse rate, after 5 years of follow-up. Here we report results of genomic and TILs studies, performed in order to reveal possible determinants of recurrences in those trials. Methods: Tumor tissues sampled before and after neoadjuvant therapy (NAT) have been analyzed by next generation sequencing (NGS) using a targeted exome panel (MSK-IMPACT) of 410 cancer-related genes. Gene expression was evaluated by Affymetrix arrays. TIL density was assessed on pre-NAT samples according to Salgado et al, 2014 (PMID 25214542). The correlation between response, recurrences, genomic and TIL findings was analyzed in a case-by-case fashion. Results: Sixteen tumors that achieved pCR (PTB: 11, CTX: 5) and 23 non-pCR tumors (PTB: 11, CTX: 12) have been analyzed. For 14 non-pCR tumors (PTB: 6, CTX: 8) data have been obtained both from the pre-NAT and the post-NAT sample. Among those tumors, 6 recurred within 2 years after surgery (PTMB: 3, CTX: 3) and assays are on-going on several others that relapsed. Several genomic aberrations that potentially played a causative role in opposing to therapy were identified. We observed multiple mutations in the PI3K pathway in several non-pCR or relapsing pts. Interestingly, in a residual tumor (RT) of a non-pCR patient we found 3 different activating mutations in PIK3CA and one in PTEN. Another example of genomic selection induced by pharmacological pressure is the emergence of a HRAS G12S mutation in a RT after CTX. Additional novel findings include in-frame mutations and deletions in ARID1B and PARP1 amplification in non-pCR pts. Most of the tumors which recurred had ≤10% TILs (9/13) and only 4/13 had ≥30%. Among the tumors with a post-NAT RT but without recurrence, 17/33 had ≤10% TILs and 16/33 ≥30%. No particular link between TIL density and mutation pattern was observed. Conclusions: This is an example of a case-by-case approach where we captured the intrinsic inter-tumor heterogeneity, which is likely responsible for the different responses to EGFR-targeting in TNBC. Genes/pathways candidate of resistance to therapy are currently being validated. Citation Format: Radosevic-Robin N, Cocco E, Privat M, Abrial C, Penault-Llorca F, Scaltriti M. Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-29.

Background: Numerous studies have shown important impact of tumor-infiltrating lymphocytes (TILs) on natural or therapeutically-modified evolution of invasive breast cancer (IBC), however knowledge about TIL role in breast ductal carcinoma in situ (DCIS) is still limited. Because of the lack of reliable prognostic parameters, DCIS treatment is much less personalized than IBC therapy. BONBIS is a phase 3 French multicenter randomized trial designed to compare 2 schemes of adjuvant radiotherapy (adjRT) for DCIS (Azria et al, ASCO meeting 2011, TPS 131). It is accompanied by a translational study of DCIS pathobiology, aimed to discover predictive or prognostic biomarkers. Here we present results of TIL density (TIL-d) assessment, its correlation with pathobiology of the lesions and preliminary clues for further biomarker search in this DCIS cohort. Methods: Formalin-fixed, paraffin-embedded DCIS surgical specimens, obtained before adjRT, were prospectively collected and centrally reviewed for histology (architectural pattern, nuclear grade, proliferation, presence of necrosis), receptor status (ER, PR, HER2) and TIL-d. TIL-d was assessed on H&E-stained DCIS sections and reported as percentage of the DCIS specialized stroma area occupied by lymphocytes, lympho-plasmocytes and plasmocytes. Tumors were classified using the St Gallen 2011 criteria for IBC (PMID 21709140). For purpose of this study, the HER2+ category included all cases with HER2 protein expression scored 2+ and 3+, irrespective of the ERBB2 amplification status. Results: TIL-d was assessed in 495 cases, with distribution as follows: 0-4% TILs (D1): 85.5% (n=423); 5-9% TILs (D2): 9.3% (n=46); ≥10% TILs (D3): 5.2% (n=26). Molecular subclasses of those cases were: luminal A (LumA): 39% (n=192); luminal B (LumB): 25.5% (n=126), HER2+: 28.5% (n=141) and triple-negative (TN): 7% (n=33). TIL-d significantly correlated with molecular subclass: ≥5% TILs (D2) were found in 39.4% (13/33) TN, 22.7% (32/141) HER2+, 18.2% (23/126) LumB and only in 1% (2/192) LumA cases (p Citation Format: Bayol B, Tixier-Deves L, Dauplat M, Kwiatkowski F, Cayre A, Abrial C, Azria D, Penault-Llorca F, Radosevic-Robin N. Tumor-infiltrating lymphocytes in breast ductal carcinoma in situ: Correlations with tumor pathobiology in a French cohort of 495 cases (BONBIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-15-03.

International audience; Upregulation of the telomerase reverse transcriptase (TERT) gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of TERT upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the TERT promoter, evaluated TERT copy number changes and assessed the expression of the MYC oncogene, a known transcriptional TERT regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating TERT promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in TERT upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with TERT expression, but T349C carriers had significantly shorter disease-free survival. TERT gains (15-25% of cases) were strongly correlated with increased TERT mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of TERT gains with MYC overexpression. These results evidence a significant effect of gene copy number gain on the level of TERT expression and provide a new insight into the clinical significance of TERT and MYC upregulation in breast cancer.

International audience; Physical activity is known to prevent the occurrence of cancer and decrease the risk of breast cancer. At diagnosis of breast cancer, fewer than half of the patients reach the international recommendation for physical activity. However, breast cancer patients, and particularly HER2+ breast cancer patients, are exposed to treatment-induced cardiotoxicity because of a side effect of 2 molecules used in standard therapy to treat these tumors, i.e., anthracycline and trastuzumab. Cardiotoxicity can sometimes lead to discontinuation of the treatment and even to the development of cardiovascular diseases. Exercise is known to protect the cardiovascular system in the healthy population. Consequently, being physically active during treatment appears to be a way to prevent the negative impact of cancer treatment on the heart in this population. In particular, aerobic exercising could have a protective effect against treatment-induced cardiotoxicity. A supervised physical activity program seems to be the best way for breast cancer patients to be active during treatment. However, there is very little information, and in particular a lack of guidelines, on exercising available to patients. The interventional trials that have been conducted on this topic are very heterogeneous and no standard recommendations have been made available for cancer patients thus far. An effective physical activity program needs to take each patient’s barriers and motivations into account in order to encourage the practice of physical activity throughout treatment. To ensure the success of the program, it is essential to facilitate adherence and especially maintain motivation. Further studies are needed to determine what practice guidelines oncologists should give their patients.

Background Young patients with breast cancer treated with chemotherapy can experience ovarian failure, which can lead to chemotherapy-induced menopause (CIM) impacting the quality of life (QoL). A prospective study was set out to evaluate the impact of CIM on QoL in women of childbearing age with non-metastatic breast cancer, and this article reports results of the interim analysis conducted to evaluate feasibility and to see preliminary results. Patients and Methods A total of 58 women (age, 18-46 years) with newly diagnosed breast cancer and treated with chemotherapy were eligible. QoL was assessed by self-administered questionnaires (Quality of Life Questionnaire-Core 30 [QLQ-C30], Quality of Life Questionnaire-Breast 23 [QLQ-BR23], and Kupperman index) and hormonal variations (anti-Mullerian hormone [AMH], follicle-stimulating hormone, and estradiol) were explored. We compared patients with ≥ 12 months amenorrhea (CIM) (n = 41) to patients with Results A good inclusion rate (approximately 4/month) and sufficient data enabled us to perform this analysis. QLQ-C30 failed to show any difference between CIM and non-CIM patients (P = .5). In contrast, at 6 months post-chemotherapy, CIM patients tended to have lower QoL as shown by QLQ-BR23 (P = .16) and more severe climacteric symptoms (P = .01). Regarding hormonal variations, AMH pre-treatment level was higher in non-CIM patients (P = .0032). We also noted that CIM patients were older (P = .00013), had shorter menstruation cycle (P = .082), and experienced faster amenorrhea (P = .088). Conclusions The study is technically feasible, and our preliminary results underline that age in association with pre-treatment AMH level could be helpful to predict ovarian function. QLQ-BR23 seemed to be stronger, more precise, and appropriate to evaluate QoL changes in patients with breast cancer than the QLQ-C30.

Background Weight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. Patients and Methods Dual-energy x-ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. Results During endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 ± 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (≥ 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 ± 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. Conclusion Endocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy.

Breast cancer is heterogeneous in clinical, morphological, immunohistochemical and biological features, as reflected by several different prognostic subgroups. Neoadjuvant approaches are currently used for the "in vivo" efficacy assessment of treatments. Pathological complete response (pCR) has been reported as a reliable predictive factor of survival in that setting. However, pCR remains a subject of controversy in terms of definition and its evaluation methods. In addition, its predictive value for patient outcome in various breast cancer biological subtypes has been under debate. In this review, we will present the existing definitions of pCR, the impact of its evaluation methods on its rate and the assessment of its predictive value for patient outcome in the molecular subtypes of breast cancer (luminal A and B, Triple Negative and HER2-positive).

Objective: Neoadjuvant chemotherapy (NACT) allows for a more frequent use of breast-conservative surgery; it is also an in vivo model of individual tumor sensitivity which permits to determine new prognostic factors to personalize the therapeutic approach. Methods: Between 2000 and 2012, 318 patients with primary invasive breast cancer were treated with a median of 6 cycles of NACT; they received either an anthracycline-based FEC 100 protocol (31.1%), or anthracyclines + taxanes (53.5%), with trastuzumab if indicated (15.4%). Results: After a median follow-up of 44.2 months, the pathological complete response rate according to the classification of Chevallier et al. [Am J Clin Oncol 1993;16:223-228] was 19.3%, and overall (OS) and disease-free survival (DFS) at 10 years were 60.2 and 69.6%, respectively. Univariate analyses demonstrated that the Residual Disease in Breast and Nodes (RDBN) index was the most significant prognostic factor for OS (p = 0.0082) and DFS (p = 0.0022), and multivariate analyses mainly revealed that the residual tumor size, residual involved node number and post-chemotherapy Scarff-Bloom-Richardson (SBR) grading were the most significant prognostic factors. Conclusions: In a cohort of patients who were all homogeneously treated with some of the most common drugs for breast cancer, we demonstrate that NACT may provide additional prognostic factors and confirm the RDBN index. As this index allows for the prediction of survival with different breast cancer subtypes, we suggest that it should be calculated routinely to help clinicians to select patients who need adjuvant treatments.

Objective: Young breast cancer (BC) patients receiving chemotherapy are at risk of chemotherapy-induced menopause (CIM). We sought to define the incidence rate of premature menopause after chemotherapy and to retrospectively investigate factors related to the onset of menopause. Methods: We identified BC patients who had received chemotherapy at the Cancer Center (Centre Jean-Perrin). We selected premenopausal women aged between 18 and 50 years at the moment of diagnosis who received chemotherapy between 1994 and 2012. Results: Of the 345 selected patients, the median age was 42 years (interquartile range: 38-46). CIM was defined as amenorrhea for at least 2 years following the end of chemotherapy. A total of 260 premenopausal women versus 85 menopausal women were included. Among the 85 menopausal women, only 46 were in the CIM group (13.3%). This rate increased in the group of women aged >43 years at diagnosis and with early hot flushes. Conclusion: CIM occurred in 13.3% of BC patients after chemotherapy. Age >43 years and early hot flushes were significantly associated with the risk of CIM. We suggest that the definition of CIM should be standardized in the literature: “amenorrhea of at least 2 years” seems a good cutoff, although 2 patients recovered their menstrual cycles beyond this limit.

Prognostic factors are used to help clinical decision-making in selecting the appropriate treatment for individual patients. The purpose of this retrospective study was to identify one or more factors associated with overall survival (OS) and disease-free survival (DFS), in 710 patients with operable breast cancer, subjected to neoadjuvant chemotherapy followed by surgery, radiotherapy and adjuvant treatments. At a median follow-up of 7.6 years, univariate analysis showed that pathological complete response (pCR) was significantly related to survival (p < 0.003), as well as accepted prognostic factors, as SBR and MSBR grades, hormonal receptors or node involvement at surgery, who remained significant in our study (p < 0.001). The revised Nottingham prognostic index (NPI) and related indices (BGI, MNPI and MBGI) were also significantly associated to survival (p < 0.003). In multivariate analysis, node involvement and MSBR grade remained prognostic factors for OS and DFS (p < 0.0003 and p < 0.02, respectively). The MNPI and pCR were significantly related with OS (p = 0.04) and pts with hormonal receptor-positive tumours had a better DFS than others (p = 0.004). Among all clinical and pathological parameters, axillary dissection after neoadjuvant chemotherapy is still important to determine node involvement, a major prognostic factor. Moreover, MSBR grade seemed to be more accurate and predictive of long-term outcome than the standard SBR grade. It is concluded that, outside any other 'biological' factor, residual disease in breast and nodes must be strongly considered after an induction chemotherapy so as to choose adjuvant treatment for the individual patient.

International audience; Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR). A comprehensive analysis of telomere characteristics was performed using qPCR for telomere length and qRT-PCR for telomerase (hTERT), tankyrase 1 (TNKS) and shelterin complex (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2) gene expression. Short telomeres, high hTERT and TNKS expression and low ERCC1 protein expression were independently associated with worse survival outcome. Interestingly, ERCC1 gains and losses correlated with worse disease-free (p = 0.026) and overall (p = 0.043) survival as compared to survival of patients with normal gene copy-numbers. Unsupervised hierarchical clustering of all ERCC1 and telomere parameters identified four subgroups with distinct prognosis. In particular, a cluster combining low ERCC1, ERCC1 gene alterations, dysfunctional telomeres and high hTERT and a cluster with high TNKS and shelterin expression correlated with poor disease-free (HR= 5.41, p= 0.0044) and overall survival (HR= 6.01, p= 0.0023) irrespective of tumour stage and grade. This comprehensive study demonstrates that telomere dysfunction and DDR can contribute synergistically to tumour progression and chemoresistance. These parameters are predictors of clinical outcome in breast cancer patients treated with NCT and could be useful clinically as prognostic biomarkers to tailor adjuvant chemotherapy post-NCT.

Purpose of the study: In a new database harbouring the patients of several prospective phase II neoadjuvant trials (fec 50–100, net, tncf, taxotere/tncf, taxotere alone), the predictive value of tumour factors (SBR grade, RH, Her2, Ki-67 and cycline D1) was studied in 466 women with stage II-III operable breast cancer treated between 1991 and 2006. Patients and methods: Median age of the patients was 48 years [27-76]. Median diameter of the invasive tumour was 40 mm [10-130]. 382 (82%) patients had a canalar, 57 (12.2%) a lobular, 14 (3%) a mixed or invasive carcinoma, 3 (0.6%) neoplasic cells only and 10 (2.2%) another carcinoma. Before chemotherapy, 33% were grade III SBR. The median number of NCT courses was 6 [1-8] followed by a surgery for 98%, a radiotherapy for 93%, an adjuvant chemotherapy (20%) and/or a hormonotherapy (56%). Results: Overall response rate was 73% (18% complete). The complete pathological response (pCR) rate was 17.2% according to Chevallier's classification. On 455 patients operated, 324 (71%) had a conservative surgery. On 390 patients with an axillary dissection, 195 (50%) had involved nodes (median number: 2 [1-20]). After a median follow-up of 135 months, DFS and actuarial survival at 120 months were 61.9% and 73%, respectively. After chemotherapy, we found a significant variation for SBR grade ***: there was five fold more patients for whom we observed a down grading of the SBR grade (grade 2/3 to grade 1) than up grading (grade 1 to grade 2/3), p=6.1.10−6. For patients in objective response, we observed a significant decrease of SBR grade (p=1.7.10−3). Moreover, the variation of SBR grade was also pronostic. Indeed, the disesase-free survival for patients who presented a SBR down grading after chemotherapy was significantly better (p=0.031) compared to patients for whom SBR grade remained stable or was in up grading. There was a tendancy for overall survival (p=0.15). Conclusion: Down grading of SBR grade appears linked to response and so may constitute a parameter of better prognostic. At the opposite, up grading of SBR grade is an adverse prognostic factor. To conclude, it is interesting to emphasize that SBR grade variations can be assessed when patients are not in pCR, ie plays a complementary role. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-20.

Intraoperative imprint cytology (IC) is one of several accurate, proven methods to detect tumor cells in sentinel lymph nodes (SLN) from patients with operable breast cancer. In patients treated with neoadjuvant chemotherapy (NAC), studies have demonstrated the feasibility and accuracy of SLN biopsy procedure. We evaluated the validity of IC for SLN testing in patients after NAC. Patients with infiltrating breast carcinoma receiving NAC (n = 132) were studied prospectively. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. SLN were evaluated using IC in 80 of 132 patients (60%). The results of IC in the adjuvant setting (100 patients) were used for comparison. SLN metastases were correctly identified using IC in 58 of 80 (72%) patients. False negative results were observed in 21 patients. The sensitivity of IC testing was 38.2% and specificity 97.8%. The positive and negative predictive values (PPV and NPV) were 92.9% and 68.2%, respectively. In univariate analysis and multivariate logistic regression analysis, patients with micrometastases or isolated tumor cells in SLN have 2.3 times higher risk of a false negative IC result than patients with macrometastases in SLN (P = .00021; relative risk [RR] = 2.3; 95% confidence interval, 1.37–3.85). The non-NAC group, which contained fewer micrometastatic cases, showed better sensitivity (47.4%) and NPV (88.9%). NAC does not seem to influence the accuracy and sensitivity of IC. Variations in sensitivity are related to the proportion of cases with micrometastases and ITC, as it was also shown in chemonaive patients.

Background We hypothesized that, among molecular subclasses of breast cancer, p53 status may have a differential predictive value for the efficacy of anthracyclines/alkylating agents-based regimen. We analysed the efficacy of a preoperative combination between 5-fluorouracil, anthracyclines and cyclophosphamide according to both p53 status and molecular classification. Patients and methods Oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) expression and p53 status were determined by immunohistochemistry in 293 samples from two different centres. A logistic regression model was used for multivariate analysis of predictors for pathological complete response (pCR). Results p53 immunostaining (54%) was associated with high grade (P = 0.002) and ER negativity (P = 0.04). p53 was detected in 59% of triple-negative tumours (ER-/PgR-/HER2-, n = 120 patients). In the overall population, pCR (9.6%) was independently predicted by high tumour grade (P = 0.002) and ER/PgR/HER2 triple negativity (P = 0.0004), but not by p53 status (P = 0.12). p53 immunostaining was associated with a trend for a higher rate of pCR in triple-negative tumours [relative risk (RR) = 2.5, 95% confidence interval (CI) = 0.8–7.5, P = 0.09], but not in non-triple-negative tumours (RR = 0.73, 95% CI = 0.16–3.3, P = 0.69). Conclusion p53 status may have a different predictive value for efficacy of anthracycline/alkylating agents-based regimen in each molecular subclass, a result which may explain the different results reported in literature.

Purpose: Several factors have been shown to correlate with prognosis of patients with breast carcinoma. Among the most useful are node involvement, tumor size, and pathologic grade. These factors retained their prognostic value when assessed after neoadjuvant chemotherapy. Methods: Previously we used a revised Nottingham prognostic index and defined 3 related indices (breast grading index, modified Nottingham prognostic index, and modified breast grading index) that were also significantly related to overall survival and disease-free survival. To assess the postchemotherapy risk globally, we have combined the 3 pathologic factors to design a specific classification to evaluate residual disease. This new classification includes 4 risk levels (levels 1-4) according to residual disease magnitude after neoadjuvant chemotherapy in 710 patients with operable breast cancer. Results: This classification resulted in significantly different results for overall survival (P < 10 -7 ) and disease-free survival (P = 8.3 X 10- 7 ). Conclusion: This classification should help us in the selection of subgroups of patients for further adjuvant treatment.

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.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.The SLN identification rate was 93.8% (121/129). Fifty-six out of the 121 successfully 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.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.

Background: Everolimus (Afinitor®) plus exemestane are indicated for hormone receptor-positive, HER2/neu-negative metastatic breast cancer (MBC), in menopausal women without symptomatic visceral disease after recurrence or progression following aromatase inhibitors. But everolimus efficacy as late treatment has not been explored. Methods: Sixty-three MBC patients progressing under hormonotherapy (HT; n = 30) or after chemotherapy (CT; n = 32) received everolimus plus HT (EHT) and were analyzed for safety, efficacy and overall survival (OS). This cohort was compared with our previous 530 MBC patients stratified by line (PMID 21852136). Results: The median duration of EHT was 27.8 weeks at 5-10 mg/day until clinical progression or toxicity. Median OS was not reached (median follow-up 18 months). Twelve-month survival was 100, 79 and 49% for patients treated with 0 (n = 13), 1-2 (n = 18) and >3 CT (n = 32), respectively. Median time-to-treatment failure was 6.4 months. In 62 EHT patients randomly matched 1:7 with 421 previous patients for age and number of CT, OS improved compared with patients receiving a new CT (p = 0.062). In patients pretreated with Conclusions: These results may support the use of EHT whatever the number of previous lines.

Author Summary Background. Neoadjuvant treatment provides a unique opportunity to evaluate individual tumor sensitivity. This study evaluated whether a response-guided strategy could improve clinical outcome compared with a standard treatment. Methods. Overall, 264 previously untreated stage II–III operable breast cancer patients were randomized to receive either standard treatment (arm A, n = 131), consisting of fluorouracil, epirubicin, and cyclophosphamide (FEC100: 500, 100, and 500 mg/m2, respectively, for 3 cycles) followed by docetaxel (100 mg/m2 for 3 cycles), or adapted treatment (arm B, n = 133), beginning with 2 cycles of FEC100 and switching to docetaxel if tumor size decreased by Results. Similar results were observed for clinical response (objective response was 54% vs 56%, p = .18), breast conservation surgery (BCS; 67% vs 68%, p = .97), and pathological complete response rate (Chevallier classification: 14% vs 11%, p = .68; Statloff classification: 16% vs 13%, p = .82) between arms A and B. Similar toxicities were observed, even with unbalanced numbers of FEC100 and docetaxel courses. Conclusion. Adapted and standard treatments had similar results in terms of tumor response, BCS rate, and tolerability. Further survival outcome data are expected.

Summary The clinical benefits of endocrine therapy for patients with hormonosensitive breast cancer are well established. For many years, five years’ treatment with tamoxifen was the gold standard of adjuvant treatment. The recent development of new endocrine agents provides physicians with the opportunity to take a more effective therapeutic approach. Nevertheless, the success of neoadjuvant endocrine therapy is much more recent and less frequently reported in the literature. This article reviews the studies published on neoadjuvant endocrine treatment (tamoxifen and aromatase inhibitors). According to the literature, neoadjuvant endocrine therapy seems to be effective and well tolerated. The newer generation of aromatase inhibitors (letrozole, anastrozole, exemestane) appear to result in better overall response rates and more conservative surgery than tamoxifen. Patients with an ER Allred score of 6 and over are most likely to respond and gain clinical benefit. The optimal duration of neoadjuvant therapy has not yet been investigated in detail. These preliminary results are interesting and should be confirmed by further studies.

The aim of the current study is an analysis of tumor parameters, clinical and pathological responses, medical management, and survival on 710 operable breast cancer patients who received neoadjuvant chemotherapy from 1982 to 2004 and were grouped into four successive periods according to diagnosis date: (1) 1982–1989; (2) 1990–1994; (3) 1995–1999; and (4) 2000–2004. Patients were treated by different neoadjuvant chemotherapies combinations : AVCF/M, TNCF, NEM, NET, TAXOTERE, FEC 50, 75, 100, FAC 50, and TAXOTERE-TNCF, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1–9). After primary chemotherapy, patients underwent a surgery and a radiotherapy. In case of significant residual disease, some patients received additional courses of chemotherapy. In addition, menopausal patients with hormonal receptor-positive tumors received tamoxifen for 5 yr. Clinical factors had some remarkable variations with time. The median age of the patients was 49.5 yr (range, 26–81). The size of the tumor was significantly greater from 1995; conversely, clinical lymph-node involvement was lower in period 4 than in the first period. The percentage of invasive ductal carcinoma and of SBR III tumors increased about 20% from 1982–1989 to 2000–2004. The number of positive hormonal receptors increased from 38.3% in period 1 to 74% in period 4. The clinical response rate improved recently from before 1990. The pathological response rate was greater in periods 2 and 3 than in periods 1 and 4. An adjuvant hormonotherapy became progressively more frequently given (44.7 for period 1 and 73.3% for period 4). Finally, no significant difference was found when we compared overall and disease-free survival through the four periods. It appears that the progressive increase of tumor burden was compensated by more effective treatments.

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.

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.

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.

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.

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.

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.

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.

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...

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.