Fabrice Andre

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer

PURPOSEnTriple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC.nnnPATIENTS AND METHODSnAnalysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC.nnnRESULTSnTwo hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001).nnnCONCLUSIONnPatients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell–mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN–related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such viral mimicry constitutes a hallmark of successful chemotherapy.

Biomarker studies: a call for a comprehensive biomarker study registry

Tumor biomarker studies may generate insights into the biological characteristics that drive the clinical behavior of a cancer. Publication bias and hidden multiple hypotheses testing distort the assessment of the true value of biomarkers. Publication bias from preferential reporting of positive findings is well recognized. Hidden multihypothesis testing arises from several biomarkers being tested by different teams using the same samples. The more hypotheses (that is, biomarker association with outcome) tested, the greater the risk of false-positive findings. These biases inflate the potential clinical validity and utility of published biomarkers while negative results often remain hidden. Trial registries have been developed where all phase II and phase III trials should be listed regardless of study outcome. However, such steps have not been taken to reduce such bias in tumor biomarker research. We propose that a registry should be created for biomarker studies initially focused on studies that use specimens from randomized trials. Further development could include nonrandomized studies and deposition of raw data similar to existing genomic data repositories. The benefits of a comprehensive biomarker study registry include more balanced evaluation of proposed markers, fewer false positive leads in research, and hopefully more rapid identification of promising candidate biomarkers.

Brain metastases at the time of presentation of non-small cell lung cancer: a multi-centric AERIO * analysis of prognostic factors

A multi-centre retrospective study involving 4 French university institutions has been conducted in order to identify routine pre-therapeutic prognostic factors of survival in patients with previously untreated non-small cell lung cancer and brain metastases at the time of presentation. A total of 231 patients were recorded regarding their clinical, radiological and biological characteristics at presentation. The accrual period was January 1991 to December 1998. Prognosis was analysed using both univariate and multivariate (Cox model) statistics. The median survival of the whole population was 28 weeks. Univariate analysis (log-rank), showed that patients affected by one of the following characteristics proved to have a shorter survival in comparison with the opposite status of each variable: male gender, age over 63 years, poor performance status, neurological symptoms, serum neuron-specific enolase (NSE) level higher than 12.5 ng ml–1, high serum alkaline phosphatase level, high serum LDH level and serum sodium level below 132 mmol l−1. In the Cox’s model, the following variables were independent determinants of a poor outcome: male gender: hazard ratio (95% confidence interval): 2.29 (1.26–4.16), poor performance status: 1.73 (1.15–2.62), age: 1.02 (1.003–1.043), a high serum NSE level: 1.72 (1.11–2.68), neurological symptoms: 1.63 (1.05–2.54), and a low serum sodium level: 2.99 (1.17–7.62). Apart from 4 prognostic factors shared in common with other stage IV NSCLC patients, whatever the metastatic site (namely sex, age, gender, performance status and serum sodium level) this study discloses 2 determinants specifically resulting from brain metastasis: i.e. the presence of neurological symptoms and a high serum NSE level. The latter factor could be in relationship with the extent of normal brain tissue damage caused by the tumour as has been demonstrated after strokes. Additionally, the observation of a high NSE level as a prognostic determinant in NSCLC might reflect tumour heterogeneity and understimated neuroendocrine differentiation.

Evaluating beauty care provided by the hospital to women suffering from breast cancer: qualitative aspects

Goals of workCancer patients are offered more and more access to beauty care during their stay in the hospital. This kind of intervention has not been evaluated yet. Primary objective of our research was to determine what type of evaluation strategy to be implemented (as a supportive care with quality of life and/or medical benefits; as a service providing immediate comfort); intermediate objective was to investigate in scientific terms (psychological, sociological) the experience of beauty care by patients.Patients and methodsSixty patients (all users of beauty care provided by hospital, 58 female, most of them treated for breast cancer, two male, mean age 53xa0years) and 11 nurses and physicians, from four French cancer centres were included. We used direct observation and semi-structured interviews, conducted by a sociologist and a psychologist; different types of beauty care were concerned.ResultsAll the interviewed patients were satisfied. Patients appreciated acquiring savoir-faire on how to use make-up and on personal image enhancement. Psychological and social well-being benefits were mentioned. The beauty care was not alleged to be reducing the side effects of the treatments, but it had helped patients to accept or bear the burden of them. Providing care beyond that which is directly curative was appreciated by the patients as a sign that they were treated as a “whole” person.ConclusionThe survey brings valuable clues concerning beauty care experience by cancer patients; it suggests the relevance of quantitative evaluation of the immediate and long-term effects on the quality of life.

[Prevalence of elevated serum CA 15-3 at time of metastatic relapse of breast cancer and correlation with hormone receptor status].

CA15-3, a peptide derived from MUC-1, an hormonally-regulated protein, is the most widely used serum marker of breast cancer. CA15-3 level increases at the metastatic phase in 50-80% breast cancer patients. Although rise of CA15-3 precede symptoms of metastasis by a mean time of 2-9 months, current international guidelines do not recommend its routine use for screening for metastases because of moderate sensitivity and absence of clinical impact. We conducted a retrospective study among all patients with metastatic breast cancer seen by three senior breast oncologists during a 4-month period. We evaluated correlation of CA15-3 level at the time of metastatic relapse with ER, PgR and Her2 expressions, tumor type, size and nodal status at initial diagnosis, and sites of metastases. CA15-3 was increased in 168/272 patients (62%) at diagnosis of metastases. ER/PgR positivity was strongly correlated with elevated CA15-3 at this time (P < 0.0001). CA 15-3 was elevated in 69% of the cases of HR+ Her2- primary tumors at time of metastatic relapse. It was elevated in 56% of HR+ Her2+++, 46% of HR- Her2+++ cases and only in 41% of triple-negative cases (P = 0.003). these data confirm that CA 15-3 is very variably elevated at time of metastatic relapse of breast cancer, and this is dependant on HR status.

Targeting Toll like receptor 3 by double stranded RNA in breast cancer: Results from in vitro studies and randomized trial

9619 Background : Toll like receptor 3 (TLR3) is known to be expressed by myeloid dendritic cells (DC) and to induce their maturation following binding with double stranded RNA (dsRNA) or its synthetic homologues polyAU and polyI:C. Several clinical trials have reported that injection of dsRNA is associated with survival benefit in cancer patients. In the present study, we have asked whether dsRNA could act directly on tumor cells through TLR3.nnnPATIENTS AND METHODSn300 patients with early breast cancer have been included from 1972 to 1979 in a randomized trial comparing post-operative administration of polyAU with no treatment. Results have been reported that showed a trend for a survival benefit in patients with involved axillary lymph nodes (n=200). Tumor biopsies from these patients were stained with TLR3-specific mAb and correlation between TLR3 expression and polyAU efficacy was determined. To investigate directly the effects of dsRNA, both freshly isolated breast tumor cells and cancer cell lines were cultured with polyI:C, and apoptosis was measured. The involvement of TLR3 in cell response was established by TLR3 RNA interference.nnnRESULTSn182 tumor samples (91%) were available from the 200 pTxN+M0 patients included in this randomized trial. TLR3 was strongly expressed by tumor cells in 18 patients (10%). Table 1 reports the 20-year survival rates according to treatment and TLR3 expression. [Figure: see text] In vitro studies showed that breast cancer cell lines can express TLR3, and that dsRNA can induce up to 80% apoptosis in TLR3+ tumor cell lines within 48h of culture. This pro-apoptotic effect of double stranded RNA was specifically abolished by RNA interference for TLR3.nnnCONCLUSIONnThese data suggest that: i. TLR3 is expressed by breast cancer cells in a subset of patients, ii. its activation by dsRNA could lead to tumor cell apoptosis in vitro and survival benefit in patients with TLR3+ tumors. No significant financial relationships to disclose.

The challenge of rapid diagnosis in oncology: Diagnostic accuracy and cost analysis of a large-scale one-stop breast clinic

PURPOSEnRapid diagnosis is a key issue in modern oncology, for which one-stop breast clinics are a model. We aimed to assess the diagnosis accuracy and procedure costs of a large-scale one-stop breast clinic.nnnPATIENTS AND METHODSnA total of 10,602 individuals with suspect breast lesions attended the Gustave Roussys regional one-stop breast clinic between 2004 and 2012. The multidisciplinary clinic uses multimodal imaging together with ultrasonography-guided fine needle aspirationxa0for masses and ultrasonography-guided and stereotactic biopsies as needed. Diagnostic accuracy was assessed by comparing one-stop diagnosis to the consolidated diagnosis obtained after surgery or biopsyxa0or long-term monitoring. The medical cost per patient of the care pathway was assessed from patient-level data collected prospectively.nnnRESULTSnSixty-nine percent of the patients had masses, while 31% had micro-calcifications or other non-mass lesions. In 75% of the cases (87% of masses), an exact diagnosis could be given on the same day. In the base-case analysis (i.e. considering only benign and malignant lesions at one-stop and at consolidated diagnoses), the sensitivity of the one-stop clinic was 98.4%, specificity 99.8%, positive and negative predictive values 99.7% and 99.0%. In the sensitivity analysis (reclassification of suspect, atypical and undetermined lesions), diagnostic sensitivity varied from 90.3% to 98.5% and specificity varied from 94.3% to 99.8%. The mean medical cost per patient of one-stop diagnostic procedure was €420.nnnCONCLUSIONSnOne-stop breast clinic can provide timely and cost-efficient delivery of highly accurate diagnoses and serve as models of care for multiple settings, including rapid screening-linked diagnosis.

ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy

BACKGROUNDnWe recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy.nnnPATIENTS AND METHODSnIncidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs.nnnRESULTSnOf 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup.nnnCONCLUSIONSnThis study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies.

P4-20-01: Multicentric Phase II PACS 09/Beverly1 Trial: First Efficacy and Safety Results of Neoadjuvant Chemotherapy Combined with Bevacizumab in HER2−Negative Patients with Non-Metastatic Inflammatory Breast Cancer.

Background: Inflammatory breast cancer (IBC) is a relatively rare form of breast cancer. Because this disease exhibits angiogenic properties, bevacizumab (BEV) may improves the efficacy of neoadjuvant chemotherapy (CT) in IBC. Methods: Pts with HER2−negative IBC (IHC 0 or 1+ or FISH/CISH-, T4d, any N) were included to receive 4 cycles of FEC100 + BEV 15 mg/kg, d1 q3w, followed by 4 cycles of Docetaxel 100 mg/m2 + BEV 15 mg/kg q3w. Complete surgery was performed 4–6 weeks after the last dose of CT, followed by radiotherapy and endocrine therapy for hormone receptor positive (HR+) pts. BEV was re-introduced as adjuvant therapy for 10 cycles, giving a total of 18 cycles of BEV. The primary endpoint of the PACS09/Beverly1 trial was to evaluate the pathologic complete response (pCR; Sataloff classification) rate in HER2−negative non-metastatic IBC patients(pts). Results: Between Jan 2009 and Sep 2010, 101 pts were included (100 pts were evaluable). Main baseline characteristics were: median age 49 years; postmenopausal status, 39 pts; SBR 2, 32 pts SBR3 61 pts, both HR-negative, 55 pts. 85 pts completed neoadjuvant therapy according to the protocol, ***.90 pts underwent complete mastectomy, 4 had a breast-conservative surgery. After neoadjuvant treatment, investigator-assessed pCR rate was 27% (18%-36%, CI 95%). Interestingly, a significantly greater proportion of pCR rate was observed in the HR-negative group compared to HR-positive group (38% vs 13% respectively; p=0.007). Results from central review of pCR are currently in progress. Main Grade 3,4 toxicities were: neutropenia (61 pts),febrile neutropenia (36 pts),mucitis (23 pts) Neither gr3/4 HTA nor cardiac failure or proteinuria was reported. There were no treatment-related deaths. Conclusions: These data suggest that the use of BEV with neoadjuvant CT is active in HER2−negative IBC (pCR rate 27%), with an acceptable safety profile. Interestingly, the HR-negative subgroup is significantly more responsive than the HR-positive subgroup. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-20-01.