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Bianchini G.,IRCCS Ospedale San Raffaele | Pusztai L.,Yale University | Pienkowski T.,Centrum Onkologii | Im Y.-H.,Samsung | And 13 more authors.
Annals of Oncology | Year: 2015

Background: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). Patients and methods: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon- inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation. Results: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. Conclusions: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors. © The Author 2015.


Mackey J.R.,Cross Cancer Institute | Martin M.,Complutense University of Madrid | Pienkowski T.,European Health Center | Rolski J.,Podkarpackie Centrum Onkologii | And 26 more authors.
The Lancet Oncology | Year: 2013

Background: We compared standard adjuvant anthracycline chemotherapy with anthracycline-taxane combination chemotherapy in women with operable node-positive breast cancer. Here we report the final, 10-year follow-up analysis of disease-free survival, overall survival, and long-term safety. Methods: BCIRG 001 was an open label, phase 3, multicentre trial in which 1491 patients aged 18-70 years with node-positive, early breast cancer and a Karnofsky score of 80% or more were randomly assigned to adjuvant treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC) every 3 weeks for six cycles. Randomisation was stratified according to institution and number of involved axillary lymph nodes per patient (one to three vs four or more). Disease-free survival was the primary endpoint and was defined as the interval between randomisation and breast cancer relapse, second primary cancer, or death, whichever occurred first. Efficacy analyses were based on the intention-to-treat principle. BCIRG 001 is registered with ClinicalTrials.gov, number NCT00688740. Findings: Enrolement took place between June 11, 1997 and June 3, 1999; 745 patients were assigned to receive TAC and 746 patients were assigned to receive FAC. After a median follow-up of 124 months (IQR 90-126), disease-free survival was 62% (95% CI 58-65) for patients in the TAC group and 55% (51-59) for patients in the FAC group (hazard ratio [HR] 0·80, 95% CI 0·68-0·93; log-rank p=0·0043). 10-year overall survival was 76% (95% CI 72-79) for patients in the TAC group and 69% (65-72) for patients in the FAC group (HR 0·74, 0·61-0·90; log-rank p=0·0020). TAC improved disease-free survival relative to FAC irrespective of nodal, hormone receptor, and HER2 status, although not all differences were significant in these subgroup analyses. Grade 3-4 heart failure occurred in 26 (3%) patients in the TAC group and 17 (2%) patients in the FAC group, and caused death in two patients in the TAC group and four patients in the FAC group. A substantial decrease in left ventricular ejection fraction (defined as a relative decrease from baseline of 20% or more) was seen in 58 (17%) patients who received TAC and 41 (15%) patients who received FAC. Six patients who received TAC developed leukaemia or myelodysplasia, as did three patients who received FAC. Interpretation: Our results provide evidence that the initial therapeutic outcomes seen at the 5-year follow-up with a docetaxel-containing adjuvant regimen are maintained at 10 years. However, a substantial percentage of patients had a decrease in left ventricular ejection fraction, probably caused by anthracycline therapy, which warrants further investigation. Funding: Sanofi. © 2013 Elsevier Ltd.


PubMed | Hospital Ernesto Dornelles, Hospital Reina Sofia, Centrum Onkologii, Center des maladies du sein and 10 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP).Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation.TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only.The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.


PubMed | University of Paris 13, Service de Biologie Cellulaire, French Institute of Health and Medical Research, Center des Maladies du Sein and Laboratoire des Urgences et Gardes
Type: Journal Article | Journal: Reproductive biomedicine online | Year: 2014

Anti-Mllerian hormone (AMH) levels fall during chemotherapy. Treatment-induced amenorrhoea is a reversible phenomenon, but few data are available on long-term AMH changes in breast cancer. The aim of the study was to describe serum AMH levels before, during and in the long term after chemotherapy, and to show a potential AMH recovery. Between May 2010 and June 2011, we selected 134 women aged 18-43 years at the time of breast cancer diagnosis who received chemotherapy between 2005 and 2011, and had not undergone an oophorectomy or had previous cytotoxic treatment. The AMH levels were assessed before, during and 4 months to 5.5 years after the end of chemotherapy. During chemotherapy, AMH was undetectable in 69% of women. After chemotherapy, a significant increase in AMH was found, with an average magnitude of +1.2% per month (95% credibility interval: 0.7 to 1.6). Older age and 12 monthsof amenorrhoea were found to be associated with a lower AMH recovery rate, whereas baseline AMH and number of chemotherapy cycles were not. The process of AMH changes during and after chemotherapy is dynamic, and shows recovery after ovarian injury. Caution should be exercised in interpreting individual AMH assessment in this context.


Fahmy J.,Service de Dermatologie | Halabi-Tawil M.,Service de Dermatologie | Bagot M.,Service de Dermatologie | Tournant B.,Center des Maladies du Sein | Petit A.,Service de Dermatologie
Annales de Dermatologie et de Venereologie | Year: 2015

Background.-Idiopathic granulomatous mastitis (IGM) is a benign, aseptic inflammatorydisease of unknown origin, which must be distinguished from tumoral and infectious processesthat affect the breast, including tuberculosis. IGM is a rare cause of erythema nodosum, but itis useful for dermatologists to be aware of this association.Patients and methods.-A 32-year-old nulliparous woman presented with erythema nodosum,arthralgia and fever. On examination, she had a firm and painful mass of 5 cm in the rightbreast with retraction and axillary adenopathy. The breast lump developed gradually over thepreceding 4 months. Although two biopsies showed no evidence of atypical cells, inflammatoryareas and a granulomatous process were seen. Culture of breast tissue for mycobacteria wasnegative. A diagnostic of idiopathic granulomatous mastitis was made. Systemic corticosteroidsled to a reduction in size of the mass, but relapse occurred in the contralateral breast ondose-reduction of the corticosteroids.Discussion.-IGM is a rare disease of unknown aetiology. Diagnosis is based on characteristichistological features and exclusion of other granulomatous diseases. Extra-mammary signs arerare and include erythema nodosum, arthralgia and episcleritis. Management is poorly codified. © 2014 Elsevier Masson SAS. All rights reserved.


PubMed | CHRU, AP HP, University Paris Diderot and Center des maladies du sein
Type: Journal Article | Journal: Bulletin du cancer | Year: 2016

Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12mg/day (days: 1-5) and then 15mg/week until progression or toxicity. Between 2003and 2015, 41patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0mois [CI95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression.


Gougis P.,Center Dinvestigation Clinique Paris Est | Teixeira L.,Center des maladies du sein | Teixeira L.,University Paris Diderot
Oncologie | Year: 2016

The use of virus to treat cancer is an old idea. Although many viruses, wild type and later genetically modified, have been tested since the 1950s, the results were often disappointing. It was not until 2015 that the first authorisation by American and European agencies was given. Talimogene laherparepvec or T-VEC has been validated for the treatment of locally advanced and metastatic melanoma following the results of a phase 3 study. This breakthrough in cancer treatment is an opportunity to discuss the history of those therapies, the rationale for their use, the main oncolytic viruses in development and finally the clinical singularities and outcomes of those treatments. © 2016 Lavoisier


PubMed | Center des maladies du sein
Type: Journal Article | Journal: Presse medicale (Paris, France : 1983) | Year: 2013

Low vitamin D plasmatic rates have been correlated to an increased risk of developing cancer. It has been proved that vitamin D could facilitate cell differentiation and have anti-inflammatory, anti-angiogenic and pro-apoptotic effects. Epidemiological studies are likely to show a protective role regarding colon cancer and possibly towards breast cancer.


PubMed | University Paris Diderot and Center des maladies du sein
Type: Journal Article | Journal: Gynecologie, obstetrique & fertilite | Year: 2014

Trastuzumab improves care of patients with HER2+ breast cancer and allows a major gain in terms of survival. T-DM1 and pertuzumab are two new treatments, which give very encouraging results in metastatic breast cancer. Their place in neo-adjuvant and adjuvant setting still remains to be defined. Bevacizumab have its place in metastatic breast cancer. In adjuvant setting, results are disappointing and in neo-adjuvant setting, we need more studies on subgroups, which can benefit more. Development of the PARP inhibitors was slowed down by recent negative results in metastatic breast cancer but studies continue with more targeted patients. Finally, everolimus, inhibitor of mTOR, allows to by pass the hormono-resistance in metastatic phase. Its toxicity must be taken into account in particular in adjuvant setting.


PubMed | French Institute of Health and Medical Research and Center des Maladies du Sein
Type: Journal Article | Journal: Reproductive biomedicine online | Year: 2016

Few studies have reported reproductive outcomes after breast cancer chemotherapy. The relationship between anti-Mllerian hormone (AMH) concentrations and the occurrence of subsequent pregnancies in women after chemotherapy for breast cancer was investigated. Women aged 18-43 years treated with chemotherapy for invasive breast cancer between May 2005 and January 2011 were retrospectively identified. Exclusion criteria were previous gonadotoxic treatment, oophorectomy or hysterectomy. Measurement of AMH took place before, during chemotherapy and at distant time points after the end of chemotherapy (4 months to 5.5 years). Seventeen out of 134 patients experienced 28 spontaneous pregnancies (median follow-up: 59 months). Neither baseline AMH (divided into quartiles) nor end-of-chemotherapy AMH (detectable versus undetectable) were significantly associated with the occurrence of pregnancy. Chemotherapy regimen with anthracyclines was associated with a greater probability of pregnancy compared with a taxane-containing regimen (hazard ratio 4.75; (95% CI 1.76 to 12.8); P = 0.002). Five-year disease-free survival and overall survival rates were 60% (95% CI: 51 to 70; relapse, n = 48) and 88% (95% CI 82 to 95; deaths, n = 21), respectively. AMH did not predict the occurrence of pregnancy. Additional studies assessing ovarian reserve and reproductive outcomes after breast cancer are required.

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