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Introduction: Triple negative breast cancer (TNBC) is highly heterogeneous, but still most of the patients are treated by the anthracycline/taxane-based neoadjuvant therapy (NACT). Tumor-infiltrating lymphocytes (TILs) are a strong predictive and prognostic biomarker in TNBC, however not always available due to organizational and analytical issues. Peripheral blood counts, which reflect the systemic inflammatory/immune status, are easier to obtain than TILs. We investigated whether baseline white cell or platelet counts, as well as Neutrophil-to-Lymphocyte Ratio (NLR) or Platelet-to-Lymphocyte Ratio (PLR) could replace baseline TILs as predictive or prognostic biomarkers in a series of TNBC treated by standard NACT. Patients and methods: One hundred twenty patients uniformly treated by FEC/taxane NACT in a tertiary cancer care center were retrospectively analyzed. The presence of pathological complete response (pCR: ypT0/Tis, ypN0) or the presence of pCR and small residual disease (ypT0/Tis/T1ab, ypN0) were considered as good responses in data analysis. Baseline/pre-NACT blood count, NLR, PLR and TILs were evaluated as predictors of response, distant recurrence rate and distant recurrence-free survival (DRFS). TILs were assessed on breast tumor biopsies according to the recommendations of the International Immuno-Oncology Biomarker Working Group (www.tilsinbreastcancer.org). Results: TILs ≥30% and ≥1.5% were best predictors of pCR and distant recurrence risk, respectively (p=0.007, p=0.012). However, in this cohort, pCR status was not significantly associated with recurrence. Only the ensemble of patients with pCR and small residual disease had lower recurrence risk and longer survival DRFS (p=0.042, p=0.024, respectively) than the rest of the cohort (larger residual disease). The only parameter which could predict the pCR/small residual disease status was PLR: patients with values lower than 133.25 had significantly higher chance of reaching that status after NACT (p=0.045). However, no direct correlation could be established between baseline PLR and metastatic recurrence. No correlation either was found between TIL and individual blood counts, or between TILs and NLR or PLR. Conclusion: In this cohort, TILs retained their pCR predictive value, however PLR was better predictor of the ensemble of responses which had good outcome in terms of less distant recurrences or longer DRFS (pCR or small residual disease). Thus, baseline PLR is worth further, prospective investigation together with baseline TILs, as it might indicate a good TNBC response to NACT when TILs are unavailable. Citation Format: Nina Radosevic-Robin, Sejdi Lusho, Xavier Durando, Marie-Ange Mouret-Reynier, Myriam Kossai, Nathalie Lacrampe, Ioana Molnar, Frederique Penault-Llorca, Catherine Abrial. Platelet-to-lymphocyte ratio is worth using with tumor-infiltrating lymphocytes to predict good response to neoadjuvant chemotherapy in triple negative breast cancer: A study on 120 patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-24.

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.

Purpose The proportion of older populations living with cancer is on the increase. Maintaining or improving their quality of life (QoL) has become an important goal in the treatment of cancer and has become an endpoint in clinical trials. Melatonin regulates a wide variety of physiological functions and is involved in the initiation of sleep and the improvement of QoL. With age, the secretion of melatonin decreases and could lead to a deterioration in QoL. Methods Literature searches were conducted using the PubMed database. The search terms and derivatives of “metastatic cancer”, “older patients”, “quality of life” and “melatonin” were used. Titles and abstracts were screened to identify whether studies were relevant for full-text screening. Results There is major concern about the symptoms older cancer patients encounter during treatment because they can impact their QoL. Melatonin supplementation presents several benefits for older patients: improvement in survival, decrease in symptoms induced by cancer and cancer treatment, and also improvements in quality of life. Conclusion It therefore seems appropriate to study the impact of melatonin supplementation during cytotoxic therapy on QoL among elderly patients with metastatic cancer. The use of melatonin as a therapeutic strategy seems particularly suitable for elderly patients, a population known to secrete significantly less melatonin. However, to date, no studies have been conducted in this population.

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.

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.

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.

Objective: This study is a longitudinal follow-up of metastatic breast cancer patients treated with ixabepilone as first-line chemotherapy, with the aim to evaluate the association between a mechanism-based neurotoxicity and the efficacy of ixabepilone. Patients and Methods: At the 2 main investigational sites of a phase II clinical trial, 50 patients previously treated with anthracycline received ixabepilone. A chart review was performed to evaluate overall survival (OS) and time to progression (TTP) and to describe the subsequent treatments. Results: The severe neurotoxicity induced by ixabepilone (38%) is correlated with a higher overall response rate to ixabepilone (79 vs. 48%; p = 0.042), a longer TTP (11.4 vs. 6.8 months; p = 0.023) and a longer OS (36.6 vs. 19.9 months; p = 0.05). After ixabepilone discontinuation, patients received a median of 4 subsequent chemotherapy lines (range 1-12). Among the 31 patients who received taxanes, neither the neurotoxicity incidence under treatment with taxanes nor the response was affected by a previous occurrence under ixabepilone treatment. Conclusion: These findings suggest that neurotoxicity development under ixabepilone treatment is a predictor of treatment outcomes as well as a favorable prognostic factor. It highlights the risk-to-benefit ratio issue of ixabepilone. We noticed the possibility to treat patients with taxanes after ixabepilone without systematic recurrent neurotoxicity. © 2014 S. Karger AG, Basel

Introduction/Objectifs La dysfonction des telomeres, comme des mecanismes de reparation de l’ADN, joue un role majeur dans la progression tumorale. Nous avons etudie les parametres telomeriques et l’expression d’ERCC1, une proteine impliquee a la fois dans de nombreux mecanismes de reparation de l’ADN et dans la maintenance des telomeres, pour evaluer leur valeur pronostique dans 90 residus tumoraux de cancer du sein apres chimiotherapie neoadjuvante. Materiels/Patients et methodes Le statut d’ERCC1 a ete evalue a differents niveaux moleculaires (expression proteique, expression du gene et nombre de copie du gene) par immunohistochimie, qRT-PCR et QMF-PCR. Une analyse globale des parametres telomeriques a ete realisee par qPCR pour la longueur des telomeres et qRT-PCR pour l’expression de TERT et des genes codant la tankyrase (TNKS) et les proteines du complexe shelterin (TRF1, TRF2, POT1, TPP1, RAP1 and TIN2). Resultats Nous avons montre que des telomeres courts, une surexpression de TERT et de TNKS et une sous-expression d’ERCC1 sont des marqueurs de mauvais pronostic independants. Un clustering non supervise comprenant les parametres telomeriques et les differentes valeurs d’ERCC1 a permis d’identifier 2 sous-groupes associes, independamment du stade et du grade tumoral, a la survie sans maladie nettement diminuee (HR = 5,41, p = 0,004). Le 1er sous-groupe presente une sous-expression d’ERCC1, des alterations du nombre de copie d’ERCC1, des telomeres courts et une surexpression de TERT et le 2e une surexpression de TNKS et des genes codant les proteines du complexes shelterin. Conclusions Cette etude montre que la dysfonction simultanee des telomeres et des mecanismes de reparation de l’ADN peut contribuer de facon synergique a la resistance tumorale. Ces parametres ont une valeur pronostique dans le cancer du sein traite par chimiotherapie neoadjuvante et pourraient etre utilises cliniquement comme biomarqueurs utiles au choix de la chimiotherapie adjuvante.

Background: Our group has previously reported (SABCS 2012, abstract 1081) a 2-fold higher pathologic complete response (pCR) rate in TNBC treated with panitumumab+FEC100 (47%) than with the standard therapy alone. However, in a half of the patients (pts) a residual tumor (RT) was detected. Having in mind the detrimental impact of resistant TNBC on patient outcome, we have investigated the tumor tissue factors that might have been important in development of resistance to this treatment. Methods: 40 TNBC pts, treated with 8 cycles the anti-EGFR antibody panitumumab combined with FEC 100 for the first 4 and with docetaxel only for the last 4 cycles, were eligible. All pts underwent breast surgery after the neoadjuvant chemotherapy (NACT) completion. Formalin-fixed, paraffin-embedded tumor samples were collected before and after NACT for biomarker analysis. EGFR, HER3, IGF-1R, MET and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry (IHC). Expression of the kinases was graded semi-quantitatively (histoscores). Results: Out of 40 treated pts, 21 demonstrated a RT (53%, according to the Chevallier classification, PMID 8338056). The IHC data were available for 17 pts. Since high EGFR expression was important for pCR achievement in this study (SABC 2012), we first investigated the expressions of EGFR, HER3 and MET in the RT. The results are presented in Table 1. Table 1post-NACT RTn = 17EGFR down or flatEGFR up143HER3 upHER3 flatHER3 upHER3 flat8512MET upMET down or flatMET upMET down or flatMET upMET down or flatMET upMET down or flat17220120 Overall, among the 9 cases (cs) with increased post-NACT HER3 expression (HER3 up), only 1 had increased MET (MET up), while among the 7 cs with no change in HER3 post-CTNA (HER3 flat), 4 had MET expression increased. Interestingly, although the pre-NACT IGF-1R expression was a strong predictor of pCR (p = 0.028, SABCS 2012), no significant changes in this kinase expression were observed in the RT, compared to the pre-NACT levels. Most RT had low IGF-1R scores ( The density of TIL post-NACT correlated principally with the% of tumor mass (TM) reduction. Among the 7 pts with average reduction of 20%, there was only 1 cs with a good InSitu Immune Response (ISIR: dense TIL, with CD8+/FOXP3+ > 1.2). On the contrary, among the 9 pts with average TM reduction of 90%, 8 demonstrated a good ISIR. Conclusion: The results indicate that HER3 and MET play significant roles in development of TNBC resistance to the anti-EGFR agents. Those molecules seem to drive 2 different resistance pathways in TNBC, as it has been shown in other malignancies. As several anti-HER3 or anti-MET drugs are nowadays available, we find very important investigating the expression of HER3 and MET in each TNBC pt pre- and post-NACT, in order to rapidly detect and combat the resistance. The ISIR-stimulating agents may bring an additional therapeutic benefit to those patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-07.

Background: TNBC is a heterogenous group of tumors for some of which the Epithelial Growth Factor Receptor pathway (EGFR) may play an important role. We evaluated the efficacy and toxicity of an anti-EGFR antibody (cetuximab) combined with docetaxel, which were given to the TNBC patients (pts) in the neoadjuvant setting. A biomarker analysis accompanied this trial, aiming to identify predictors of response. Methods: 35 patients with stage II-IIIA TN breast disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 6 cycles of docetaxel (100 mg/m2) each 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. Patient characteristics : mean age 48 [28-67]; TNM: T1: 3%, T2: 73%, T3: 24%; N0: 61%, N1-N2: 39%; mean tumor size 40 mm [15-100]; SBR: grade III: 73%, grade II: 27%. The median number of cycles was for docetaxel 6 [1-6] and for cetuximab 15 [1-18]. Pathological complete response (pCR) rate was 24% according to the Chevallier and Sataloff classifications; 28% if we consider breast pCR only. Overall clinical response rate was 57% (22% CR). Conservative surgery was performed in 75% of cases. The main side effect was skin toxicity: grade II: 39%, grade III: 36%, grade IV: 3%. Other side effects were: neutropenia grade IV: 12.7%, febrile neutropenia: 1.3%, hand-foot syndrome grade III: 3%, grade II: 3%, ungueal toxicity grade III: 3%, grade II: 33%. Paraffin-embedded and frozen samples were systematically collected before and after ST for biomarker studies. Germinal BRCA1 mutations and EGFR, KRAS, BRAF and PI3KCA somatic mutations were analyzed by NGS. EGFR, MET, cytokeratins 5/6 and 8/18, PTEN, P-cadherin, ALDH1, Ki67, p53 and the number of FOXP3+ or CD8+ tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry. Results: The biomarker analysis was interpretable on the samples from 21 pts (3 pCR and 18 non-pCR). We applied the ROC curve to identify the best cut-off value for Ki67, EGFR, MET, cytokeratin 5/6 and 8/18, p53, ALDH1, PTEN, P-cadherin and the FOXP3+ or CD8+ TIL counts. None of these biomarkers was predictive of pCR except for the CD8+/FOXP3+ TIL count ratio. pCR rate was higher in the pts with the ratio equal or higher than 2.75 than in the others (43% versus 0%, p = 0.047). BRCA1 mutations were detected in 16% of pts. PI3K and EGFR somatic mutations were observed in 1 and 3 patients, respectively. The presence of the mutations was not predictive of pCR. Conclusion: Similarly to the previously reported trial by our group (SABCS 2012, abstract 1081), the immune component of the tumor microenvironment plays a very important role in the TNBC response to cytotoxic therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-34.

Background: Panitumumab is an antibody targeting the epidermal growth factor receptor (EGFR) for which an important role has been suggested in TNBC. Consequently, we evaluated a combination of the standard chemotherapy (FEC 100 followed by docetaxel) with panitumumab as neoadjuvant therapy of operable TNBC. Complete pathologic response (pCR) was the primary endpoint, with clinical response, toxicity, and outcome as secondary endpoints. An investigation of biomarkers possibly predictive of pCR accompanied this trial. Here we focus on tumor recurrence, after a median follow up of 33 months [25-40] as on April, 1, 2013. Methods: Sixty patients (pts) with stage II-IIIA TNBC were prospectively included. Systemic neoadjuvant 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]; SBR grade III: 71.7%; pCR rate: 55.3% and 46.8% (the Sataloff and the Chevallier classifications, respectively). Paraffin-embedded and frozen tumor samples were collected before and after ST for biomarker analysis. 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 (TIL) were evaluated by immunohistochemistry. Results :.We have observed 9 recurrences: 1 local and 8 distant recidives, including 1 both local and distant. The distant recidives (metastases) were as follows: brain (4 pts); brain and lungs (1 pt); lungs only (1 pt), pleura (1 pt); liver (1 pt). 6 out of the 8 metastatic pts died and all were non-pCR post-ST. The 2 alive pts had brain metastases, but reached a pCR after the ST. Among the 9 relapsed pts 6 were 55 years old or less at the diagnosis. Seven out of those 9 pts had tumors with the clinical size equal or higher than 4 cm. As previously reported (SABCS 2012, abstract 1081), the pCR-predictive biomarkers in this study were high CD8+ TIL count (p = 3.4.10−6) and high ratio between the CD8+ and FOXP3+ TIL counts (CD8+/FOXP3+ > 1.23, p = 8.5.10−5). With this in mind, we have evaluated whether those parameters, assessed before or after the ST, could predict the recurrences. No difference was found in the preoperative CD8+ and the FOXP3+ TIL counts, as well as in the CD8+/FOXP3+ ratio, between the patiens who have recurred and the others. Conclusion : As it has been reported in previous studies, in our cohort of TNBC pts, the relapses occurred early after the administration of the last systemic treatment. The patients who relapsed died rapidly and most of them have not reached pCR after the ST. In addition, half of the metastatic pts got brain deposits. This implies that research on the resistance factors in TNBC should focus on those important for seeding of the “sanctuaries”, like brain. This research is ongoing in our group. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-19.

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.

Background: TNBC is an heterogeneous group of tumors for some of which the Epithelial Growth Factor Receptor pathway (EGFR) may play an important role. We evaluated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant chemotherapy in order to identify predictive biomarkers of efficacy and target biologically defined subpopulations for potential further development. Methods: Sixty patients with stage II-IIIA disease were prospectively included in this multicentre neoadjuvant study. Systemic therapy (ST) consisted of panitumumab (9 mg/kg q.3 weeks x8) combined with FEC 100 (500/100/500 mg/m2q.3 weeks x4) followed by 4 cycles of T (100 mg/m2 q.3weeks x4). All patients underwent surgery at completion of ST. Paraffin-embedded and frozen samples were systematically collected before and after ST for biologic studies. Patients characteristics are as follows: mean age 50 [27–72]; median tumor size: 40 mm [20–120]; invasive ductal carcinoma: 96.7%; Scarff-Bloom-Richardson Grade III: 71.7%, grade II: 28.3%. Complete pathological response (pCR) rate was 52.3% [95% IC: 37.3–67.5] (Sataloff's classification) and 46.7% [95% IC: 31.6–61.4](Chevallier's classification). Conservative surgery was performed in 88% of cases. 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 performed a ROC curve to identify the best cut-off value for KI-67, EGFR, cytokeratin 5–6 and p53 in order to predict a pCR. Tumors with more than 40% of positive cells for KI-67 and tumors with a score for EGFR greater than 70 tend to be associated with pCR according to Chevallier's classification (p = 0.06). No predictive value was identified for Cytokeratin 5–6 and p53 (p = 0.61 and p = 0.27, respectively). Immunohistochemistry results show that two thirds of tumors have more than 40% of positive cells for KI-67 and that two thirds of tumors present a score for EGFR greater than 70. About half of the tumors express cytokeratin 5–6 and p53 (cut off: 1%). Chi-squared tests were performed to assess relations between cutaneous toxicities and pCR. The cutaneous toxicities were not predictive of pCR (p = 0.94) and no correlations were found with KI-67, EGFR, Cytokeratin 5–6 and p53. In terms of BRCA1 and BRCA2 status, 35 tumors were analysed so far: BRCA1: 6 mutations (17%); BRCA2 (30 patients): 1 mutation (3.3%). Conclusions: These results suggest the possibility to identify a subpopulation with high probability of pCR (KI-67 > 40%, EGFR score > 70). Further biological studies are ongoing and will be presented at the meeting, including EGFR polymorphisms, C-met, ALDH1, pCadherine and PTEN. This will help us further define subpopulations of TNBC patients, potential targets for antiEGFR development. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-20.

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.

Background: Panitumumab is an antibody 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 (FEC 100 followed by T) with panitumumab as neoadjuvant therapy of oprable TNBC. Methods: 60 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. 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 characteristics are as follows: mean age 47 [27-72]; T2: 74%, T3: 26%, (mean tumor size: 40 mm [20-120]); N0: 65%, N1: 28% and N2: 7%; invasive ductal carcinoma: 96%; Scarff-Bloom-Richardson Grade III: 72%, grade II: 28%. The median number of cycles was: FEC 100: 4 [2-4], T: 4 [0-4], Panitumumab: 7 [1-8]. Pathological response showed a pCR according to Sataloff's classification of 57.1% [95% IC: 40.7−73.5] and according to Chevallier's classification of 51.4% [95% IC: 34.8−68.0] with an overall clinical response rate of 60% (29% CR) [95% IC: 43.8−76.2]. Conservative surgery was performed in 79% of cases. Skin toxicity was the main side-effect: Cutaneous toxicity grade IV: 12%, grade III: 26%, grade II: 23%. No ocular complications have been reported. Neutropenia grade IV: 23.7%; febrile neutropenia: 4.2%. Infection: 0%. Hand-foot syndrome grade III: 4%. Ungueal toxicity grade IV: 2.5%, grade II: 25 .5%. Conclusions: These results suggest that Panitumumab in combination with FEC100 followed by T appears efficacious with acceptable toxicity in the neoadjuvant therapy of operable TNBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-01.

Metastatic breast cancer is mostly incurable. Progressively overall survival (OS) has improved but few authors have studied treatment globally versus for each line and demonstrated the interest of chemotherapy (CT) after the third line. We selected recent patients treated during the "taxane/anti-aromatase era" for each line given. 529 received CT and 383 hormonotherapy. OS was assessed; from the date of first metastasis and from Day 1 of each CT line. Median OS was 34.1 months; 226 patients received >3 lines of CT with a steady median OS for late lines, 11.4 months per line (range 10.4–12.6). Clinical benefit after the third line of CT was obtained for 29.2–36.6% of patients. CT lasted 11.7 months "on" versus 20.6 months "off" CT. These results may support the use of more than 3 CT lines; each line can contribute to a longer survival.

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.

The methionine (MET) dependency of tumor cells opens interesting perspectives for targeting tumor cells and potentiating chemotherapy treatment, like 5-fluorouracil (5-FU) and platinum compound. Since MET deprivation can individually potentiate the different chemotherapeutic agents used in the 48-hour combined regimen of 5-FU, leucovorin and oxaliplatin (FOLFOX) regimen, we initiated a feasibility study associating dietary MET restriction with the FOLFOX regimen in patients with metastatic colorectal cancer. Objectives: (i) To evaluate the depletion in the plasma MET concentration, and (ii) to assess the feasibility of this combination. Methods: Eleven patients were enrolled in this study. They received a median number of 3 two-week cycles of a MET-free diet (3 consecutive days) and FOLFOX6 regimen. Results: The plasma MET concentration was reduced by dietary MET restriction, with a depletion of 58% on the 1st day of MET-free diet. Indeed, we demonstrated the feasibility and good tolerance (nutritional status and toxicity) of the association of a MET-free diet with the FOLFOX regimen. Despite good compliance to the diet, this study revealed the difficulty of administering this combination during further months. Among the 4 patients evaluable for response, 3 experienced a partial response and 1 patient a disease stabilization.

Since the improvement of chemotherapy with safe molecules is needed for a better efficacy without supplementary toxicity, we investigated the feasibility and tolerability of the combination of docetaxel and curcumin, a polyphenolic derivative extracted from Curcuma longa root.Fourteen patients were accrued in this open-label phase I trial. At the last dose level of curcumin, three dose-limiting toxicities were observed and two out of three patients at this dose level refused to continue treatment, leading us to define the maximal tolerated dose of curcumin at 8,000 mg/d. Eight patients out of 14 had measurable lesions according to RECIST criteria, with five PR and three SD. Some improvements as biological and clinical responses were observed in most patients.Patients with advanced or metastatic breast cancer were eligible. Docetaxel (100 mg/m(2)) was administered as a 1 h i.v. infusion every 3 w on d 1 for six cycles. Curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d+2) and escalated until a dose-limiting toxicity should occur. The primary endpoint of this study was to determine the maximal tolerated dose of the combination of dose-escalating curcumin and standard dose of docetaxel chemotherapy in advanced and metastatic breast cancer patients. Secondary objectives included toxicity, safety, vascular endothelial growth factor and tumor markers measurements and assessment of objective and clinical responses to the combination therapy.The recommended dose of curcumin is 6,000 mg/d for seven consecutive d every 3 w in combination with a standard dose of docetaxel. From the encouraging efficacy results, a comparative phase II trial of this regimen plus docetaxel versus docetaxel alone is ongoing in advanced and metastatic breast cancer 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.

Objectives: Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC). Methods: Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron-specific enolase (NSE). Results: Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE. Conclusion: This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial.

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.

International audience; Objectives: Compare tomosynthesis to mammography, ultrasound, MRI, and histology for the detection and staging of BI-RADS 4—5 anomalies, as a function of breast composition, lesion location, size, and histology.Patients and methods: Seventy-five patients underwent mammography, tomosynthesis, ultrasound, and MRI. The diagnostic accuracy of the different examinations was compared.Results: The sensitivities for detection were as follows: 92.5% with MRI, 79% for ultrasound, 75% for tomosynthesis, and 59.5% for mammography. Tomosynthesis improves the sensitivity of mammography (P = 0.00013), but not the specificity. The detection of multifocality and multicentricity was improved, but not significantly. Tomosynthesis identified more lesions than mammography in 10% of cases and improved lesion staging irrespective of the density, but was still inferior to MRI. The detection of ductal neoplasia was superior with tomosynthesis than with mammography (P = 0.016), but this was not the case with lobular cancer. The visualization of masses was improved with tomosynthesis (P = 0.00012), but not microcalcifications. Tomosynthesis was capable of differentiating lesions of all sizes, but the smaller lesions were easier to see. Lesion sizes measured with tomosynthesis, excluding the spicules, concurred with histological dimensions. Spicules lead to an overestimation of the size.Conclusion: In our series, tomosynthesis found more lesions than mammography in 10% of patients, resulting in an adaption of the surgical plan.

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.

Influence of stress on immunity and pathogenesis relates to corticotropic axis: hypothalamus-hypophysis-surrenals (HHS). Its over-stimulation due to traumas during early childhood or before birth seems to generate brain abnormalities such as reduction of hippocampus volume. More typical of adult age, hypothalamus-pineal gland axis (HP), responsible for melatonin production, may be impaired because of chronic stress, mainly through sleep disturbances or addictive behaviours. Old age has been reported to produce same impairments. Circadian cycle of melatonin is closely related to immune functions and its disturbance seems to induce, among populations undergoing frequent changes of life rhythm, a significant raise of cancer incidence: night shift workers, air pilots... Stress then seems enable to increase cancer risk through its negative impact on HHS and HP axis and therefore on immunity. Immunotherapy, which was an interesting solution considering this, has not yield yet expected results. Upstream, other ways have been successfully investigated in prospective randomised trials, such as psychotherapeutic treatments, with positive effects on cellular immunity and survival. The ability to condition immune responses in animals allows thinking that hypnotherapy could also be used along with standard treatments.

Resume La melatonine est une petite molecule lipophile, secretee essentiellement dans la glande pineale. La synthese de cette hormone suit un rythme circadien avec un pic vers les 2–3 heures du matin. La melatonine possede de nombreux recepteurs dans l'organisme ce qui lui confere des fonctions multiples telles que la resynchronisation des rythmes biologiques, l'induction du sommeil, la vasoregulation mais aussi l'immunomodulation. De nombreuses experiences realisees dans ce domaine ont permis de decouvrir differentes interactions entre la melatonine et le systeme immunitaire, et surtout le lien qui existe entre la melatonine et la lutte anticancereuse de l'organisme via le systeme immunitaire. Des essais de phase II chez l'homme rapportent une diminution de la thrombocytopenie, une amelioration du taux de certaines cytokines et une augmentation de la reponse objective chez des patients atteints de cancer. Afin de confirmer et d'approfondir ces resultats, nous nous proposons de realiser un essai de phase II randomise melatonine versus placebo chez des patientes atteintes de cancers du sein metastatiques apres deux lignes de traitement.

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.