Respective Prognostic Value of Genomic Grade and Histological Proliferation Markers in Early Stage (pN0) Breast Carcinoma

Genomic grade (GG) is a 97-gene signature which improves the accuracy and prognostic value of histological grade (HG) in invasive breast carcinoma. Since most of the genes included in the GG are involved in cell proliferation, we performed a retrospective study to compare the prognostic value of GG, Mitotic Index and Ki67 score.A series of 163 consecutive breast cancers was retained (pT1-2, pN0, pM0, 10-yr follow-up). GG was computed using MapQuant Dx(R).GG was low (GG-1) in 48%, high (GG-3) in 31% and equivocal in 21% of cases. For HG-2 tumors, 50% were classified as GG-1, 18% as GG-3 whereas 31% remained equivocal. In a subgroup of 132 ER+/HER2- tumors GG was the most significant prognostic factor in multivariate Cox regression analysis adjusted for age and tumor size (HR = 5.23, p = 0.02).In a reference comprehensive cancer center setting, compared to histological grade, GG added significant information on cell proliferation in breast cancers. In patients with HG-2 carcinoma, applying the GG to guide the treatment scheme could lead to a reduction in adjuvant therapy prescription. However, based on the results observed and considering (i) the relatively close prognostic values of GG and Ki67, (ii) the reclassification of about 30% of HG-2 tumors as Equivocal GG and (iii) the economical and technical requirements of the MapQuant micro-array GG test, the availability in the near future of a PCR-based Genomic Grade test with improved performances may lead to an introduction in clinical routine of this test for histological grade 2, ER positive, HER2 negative breast carcinoma

Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis

International audiencePurpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT).Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics.Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease.Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing.Registration identification: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1)

Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers

Triple-negative breast cancers (TNBC) are characterized by frequent alterations in the PI3K/AKT/mTOR signaling pathway. In this study, we analyzed PI3K pathway activation in 67 patient-derived xenografts (PDX) of breast cancer and investigated the anti-tumor activity of the mTOR inhibitor everolimus in 15 TNBC PDX with different expression and mutational status of PI3K pathway markers. Expression of the tumor suppressors PTEN and INPP4B was lost in 55% and 76% of TNBC PDX, respectively, while mutations in PIK3CA and AKT1 genes were rare. In 7 PDX treatment with everolimus resulted in a tumor growth inhibition higher than 50%, while 8 models were classified as low responder or resistant. Basal-like, LAR (Luminal AR), mesenchymal and HER2-enriched tumors were present in both responder and resistant groups, suggesting that tumor response to everolimus is not restricted to a specific TNBC subtype. Analysis of treated tumors showed a correlation between tumor response and post-treatment phosphorylation of AKT, increased in responder PDX, while PI3K pathway markers at baseline were not sufficient to predict everolimus response. In conclusion, targeting mTOR decreased tumor growth in 7 out of 15 TNBC PDX tested. Response to everolimus occurred in different TNBC subtypes and was associated with post-treatment increase of P-AKT

Development of sensitive and robust multiplex digital PCR assays for the detection of ESR1 mutations in the plasma of metastatic breast cancer patients

International audienceBACKGROUND: Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients. MATERIALS AND METHODS: Using the naica® three-color digital PCR platform, we developed a screening assay allowing the detection of 11 ESR1 mutations and designed a sequential strategy for precise mutation identification. We then applied this strategy in the analysis of plasma circulating cell-free DNA from 109 HR+/HER2- MBC patients and performed a double-blind comparison study on a subset of patients with the multiplex assay used at the Institut Curie (IC) for the PADA-1 study. RESULTS: Thirty-one patients (28.4%) harboured at least one ESR1 mutation, with the following frequencies: D538G (41.03%), Y537S (25.64%), E380Q (10.26%), Y537N (10.26%), "(536-540)" (7.69%), Y537C (2.56%), and L536R (2.56%). The presence of ESR1 mutation(s) was significantly associated with liver metastases (p = 0.0091). A very good agreement (91%) was observed with the IC assay. CONCLUSION: Our assays have proven to be robust and highly sensitive and are very well-suited for monitoring ESR1 mutations in the plasma of MBC patients

Impact of body mass index on overall survival in patients with metastatic breast cancer

International audienceBackground: High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC).Methods: The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers.Results: Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1-66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2-48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02-1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect.Conclusion: Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor

Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial

International audienc

Kaplan Meier Survival Curves.

<p>Distant Metastases Free Survival Analysis. 132 Estrogen Receptor positive HER2 negative samples. Logrank tests pvalue. <b>Top Left.</b> Genomic Grade (GG). Green: GG-1. Red: GG-3. (<i>p</i> = 0.007). <b>Bottom Left.</b> Histological Grade (HG). Green: HG-1. Red: HG-3. (<i>p</i>  = 0.15). <b>Top Right.</b> Ki67 score. Green: Ki67≤20%. Red: Ki67>20%. (<i>p</i> = 0.04). <b>Bottom Right.</b> Mitotic Index (MI). Green: MI I. Red: MI III. (<i>p</i> = 0.12).</p

A French prospective pilot study for identifying dihydropyrimidine dehydrogenase (DPD) deficiency in breast cancer patients (pts) receiving capecitabine (cap)

International audienceBackground: For fluoropyrimidines, and especially cap, Health Authorities point out that DPD deficiency confers a significant risk of major toxicity (tox). Identification of at-risk pts is thus relevant. This multicentric prospective study of the French GPCO group (Groupe de Pharmacologie Clinique Oncologique, Unicancer) evaluated the sensitivity, specificity and predictive values of DPD phenotyping and genotyping for predicting severe cap-related tox in metastatic breast cancer pts. Methods: 303 pts were included (15 institutions), 88% received cap as monotherapy, 28% were treated as first line (mean dose at 1st cycle 1957 mg/m2/d). Pre-treatment dihydrouracil (UH2) and uracil (U) plasma concentrations were measured in 286 pts (HPLC assay). DPD genotyping (IVS14+1G>A, 2846A>T, 1679T>G, 464T>A) was done on 281 pts. Severe tox (G3-4 CTCAE v3 criteria) was measured over cycles 1-2. Results: Grade 3-4 tox (diarrhea, vomiting, hematoxicity, hand-foot syndrome) was observed in 19.6% of pts (one toxic death). A marked trend for higher U (median 12.7 vs 10.2 ng/ml, p=0.014) and UH2 (median 110 vs 93 ng/ml, p=0.011) concentrations was observed in pts developing severe tox vs those who didn't. However, ROC curves showed that these differences were too small for use as reliable tox predictors. The distribution of UH2/U ratio was similar between pts with or without tox (median 9.1 vs 9.6, respectively, p=0.80). The patient with toxic death had a UH2/U ratio of 6.5 and U concentration of 17 ng/ml. Among the 7 pts with a DPD mutation (3 pts IVS14+1, 3 pts 2846A>T, one 1679T>G, all heterozygous), 5 developed severe tox (including toxic death, 2846A>T), one did not, and the last one was not documented. Relative risk for developing severe tox was 4.60 in mut pts vs wt pts (95%CI 2.95-7.16, p=0.001); positive and negative predictive values were 83.3% and 81.9%, respectively; specificity was 99.5% and sensitivity was 9.8%. Conclusions: These data point out that breast cancer pts harbouring a DPD variant allele are candidate to develop severe, up to lethal, cap-related tox. In contrast, pre-treatment UH2/U ratio and U measurements are not reliable predictors of cap tox. Clinical trial information: Eudract 2008-004136-20