Loic Campion

Bortezomib Plus Dexamethasone Induction Improves Outcome of Patients With t(4;14) Myeloma but Not Outcome of Patients With del(17p)

PURPOSE Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic parameters. PATIENTS AND METHODS A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p). RESULTS We found that both t(4;14) and del(17p) remain prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prognosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induction therapy. In contrast, no improvement was observed for del(17p) patients. CONCLUSION Short-term bortezomib induction improves outcome of patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS despite bortezomib induction.

Prognostic Significance of Copy-Number Alterations in Multiple Myeloma

PURPOSE Chromosomal aberrations are a hallmark of multiple myeloma but their global prognostic impact is largely unknown. PATIENTS AND METHODS We performed a genome-wide analysis of malignant plasma cells from 192 newly diagnosed patients with myeloma using high-density, single-nucleotide polymorphism (SNP) arrays to identify genetic lesions associated with prognosis. RESULTS Our analyses revealed deletions and amplifications in 98% of patients. Amplifications in 1q and deletions in 1p, 12p, 14q, 16q, and 22q were the most frequent lesions associated with adverse prognosis, whereas recurrent amplifications of chromosomes 5, 9, 11, 15, and 19 conferred a favorable prognosis. Multivariate analysis retained three independent lesions: amp(1q23.3), amp(5q31.3), and del(12p13.31). When adjusted to the established prognostic variables (ie, t(4;14), del(17p), and serum beta(2)-microglobulin [Sbeta(2)M]), del(12p13.31) remained the most powerful independent adverse marker (P < .0001; hazard ratio [HR], 3.17) followed by Sbeta(2)M (P < .0001; HR, 2.78) and the favorable marker amp(5q31.3) (P = .0005; HR, 0.37). Patients with amp(5q31.3) alone and low Sbeta(2)M had an excellent prognosis (5-year overall survival, 87%); conversely, patients with del(12p13.31) alone or amp(5q31.3) and del(12p13.31) and high Sbeta(2)M had a very poor outcome (5-year overall survival, 20%). This prognostic model was validated in an independent validation cohort of 273 patients with myeloma. CONCLUSION These findings demonstrate the power and accessibility of molecular karyotyping to predict outcome in myeloma. In addition, integration of expression of genes residing in the lesions of interest revealed putative features of the disease driving short survival.

Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy for Advanced Breast Cancer: Results of Ganglion Sentinelle et Chimiothérapie Neoadjuvante, a French Prospective Multicentric Study

PURPOSE To determine the detection rate, the false-negative rate, and the accuracy of sentinel lymph node (SLN) detection after neoadjuvant chemotherapy (NAC) for advanced breast cancer. PATIENTS AND METHODS A prospective multicentric study was initiated to evaluate the results of SLN biopsy with the combined method after NAC for advanced large operable breast cancer. RESULTS From September 2003 to March 2007, 195 patients enrolled from 12 institutions were found suitable for evaluation. The detection rate was 90% (176 of 195 patients), and the false-negative rate was 11.5% (six of 52 patients). Patients without axillary palpable nodes (N0) before NAC had a better detection rate compared with patients with axillary suspicious nodes (N1, 94.6% v 81.5%; P = .008). The false-negative rate was not correlated with clinical nodal status before NAC (9.4% v 15%; P = .66). CONCLUSION This study confirms the feasibility of SLN biopsy after NAC in the case of large operable breast cancer. The detection rate, false-negative rate, and accuracy do not differ from those obtained in the case of early breast cancer without NAC, thus demonstrating the feasibility of SLN biopsy after NAC.

Long-Term Analysis of the IFM 99 Trials for Myeloma: Cytogenetic Abnormalities [t(4;14), del(17p), 1q gains] Play a Major Role in Defining Long-Term Survival

PURPOSE In multiple myeloma, many prognostic parameters have been proposed. However, all of these predict shorter survival. To identify patients with a longer life expectancy, we updated the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials. PATIENTS AND METHODS A series of 520 patients was analyzed. Median follow-up was 90.5 months. To perform a comprehensive analysis of the major prognostic factors, we reanalyzed all patients for 1q gains [in addition to updating del(13), t(4;14), and del(17p) analyses]. RESULTS It was possible to identify a subgroup of patients (representing 20% of total patients) with an 8-year survival of 75%. These patients were defined by the absence of t(4;14), del(17p), and 1q gain and β(2)-microglobulin less than 5.5 mg/L. CONCLUSION We propose that all patients with newly diagnosed multiple myeloma be evaluated for these three chromosomal changes, not only to define high-risk patients but also to identify those with a longer life expectancy.

Mutations in TP53 are exclusively associated with del(17p) in multiple myeloma

Deletion of the 17p13 chromosomal region [del(17p)] is associated with a poor outcome in multiple myeloma. Most of the studies have targeted the TP53 gene for deletion analyses, although no study showed that this gene is the deletion target. In order to address this issue, we sequenced the TP53 gene in 92 patients with multiple myeloma at diagnosis, 54 with a del(17p) and 38 lacking del(17p). At least one mutation was found in 20 patients, all of them presenting a del(17p). The analysis of the mutation location showed that virtually all of them occurred in highly conserved domains involved in the DNA-protein interactions. In conclusion, we showed that 37% of the myeloma patients with del(17p) present a TP53 mutation versus 0% in patients lacking the del(17p). The prognostic significance of these mutations remains to be evaluated.

Translocation t(14;16) and multiple myeloma: is it really an independent prognostic factor?

Many trials in myeloma are stratified on cytogenetic abnormalities. Among them, the most commonly chosen are the t(4;14), the del(17p), and the t(14;16). If data are well established for t(4;14) and del(17p), very few data support the use of t(14;16). To address this issue, we retrospectively analyzed 1003 patients with newly diagnosed myeloma for this abnormality. We identified 32 patients with the t(14;16). Compared with patients lacking the t(14;16), we did not observe any difference in overall survival (P = .28). Moreover, in multivariate analyses, the t(14;16) was not prognostic (P = .39). In conclusion, our data do not support the use of t(14;16)-specific probes in the diagnostic panels of multiple myeloma.

Investigation of FDG-PET/CT imaging to guide biopsies in the detection of histological transformation of indolent lymphoma

Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) has been successfully evaluated in the management of non-Hodgkin’s lymphoma (NHL).1–3 Histological transformation (HT) of indolent lymphoma is a dramatic event that occurs in 5–10% of the patients and carries a dismal prognosis.4,5 Previous studies prove that indolent lymphoma entities show a lower FDG uptake when compared with aggressive lymphomas.6–8 We therefore postulated that FDG-PET/CT identifies aggressive transformation sites and can guide biopsies.

Chromosomal Abnormalities Are Major Prognostic Factors in Elderly Patients With Multiple Myeloma: The Intergroupe Francophone du Myélome Experience

PURPOSE Chromosomal abnormalities, especially t(4;14) and del(17p), are major prognostic factors in patients with multiple myeloma (MM). However, this has been especially demonstrated in patients age < 66 years treated with intensive approaches. The goal of this study was to address this issue in elderly patients treated with conventional-dose chemotherapy. PATIENTS AND METHODS To answer this important question, we retrospectively analyzed a series of 1,890 patients (median age, 72 years; range, 66 to 94 years), including 1,095 with updated data on treatment modalities and survival. RESULTS This large study first showed that the incidence of t(4;14) was not uniform over age, with a marked decrease in the oldest patients. Second, it showed that both t(4;14) and del(17p) retained their prognostic value in elderly patients treated with melphalan and prednisone-based chemotherapy. CONCLUSION t(4;14) and del(17p) are major prognostic factors in elderly patients with MM, both for progression-free and overall survival, indicating that these two abnormalities should be investigated at diagnosis of MM, regardless of age.

Genetic polymorphism at the glutathione S-tranferase (GST) P1 locus is a breast cancer risk modifier

The isolation of full‐length cDNAs of naturally occurring GSTP1 gene variants, and the demonstration that these alleles are distributed in the normal population, have provided conclusive evidence that the human GSTP1 gene locus is polymorphic and that specific GSTP1 alleles may be associated with different risk for cancers or other diseases. Recent data have indicated that the different GSTP1 alleles encode proteins with different enzymatic activities against carcinogens. In this case‐control study, we examined the effect of the GSTP1 genetic polymorphism and its interaction with other factors to determine breast cancer risk. GSTP1 and GSTM1 genotypes of 220 breast cancer patients and 196 controls, all residents of western France, were examined. Data on menopausal status and family cancer history were obtained from 195 patients and 147 controls. Exons 5 and 6 of the GSTP1 gene, which contain the polymorphic nucleotide transitions, were analyzed by DNA polymerase chain reaction‐restriction fragment length polymorphism to distinguish between the GSTP1 alleles. In the control population, GSTP1 allelic frequencies were 64.3%, 26.0% and 9.7%, respectively, for GSTP1*A, GSTP1*B and GSTP1*C. In the breast cancer patients, the frequencies were 67.9% for GSTP1*A, 26.8% for GSTP1*B and 5.3% for GSTP1*C. In multivariate analysis, breast cancer risk increased by 7.7‐fold (p < 0.001) in women with a family history of cancers and 2.18‐fold (p = 0.026) in non‐GSTP1*C individuals. GSTM1 genotypes did not emerge as risk factor. Our results show that in addition to well‐known risk factors, in particular, a family history of cancer, GSTP1 allelopolymorphism is a significant modifier of breast cancer risk. The results also suggest a protective role against breast cancer for the GSTP1*C allele.

FDG PET evaluation of early axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients

PurposeRegional axillary lymph node status has remained the single most independent variable to predict prognosis both in terms of disease recurrence and survival. This study aimed to prospectively assess sequential [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) findings as early predictors of axillary lymph node response to neoadjuvant chemotherapy in stage II and III breast cancer patients.MethodsImages were acquired with a PET/CT scanner in 52 patients after administration of FDG (5 MBq/kg) at baseline and after the first, second, third and sixth course of chemotherapy before surgery. Clinical examination and ultrasound (US) were used to assess the size of axillary nodes. Decrease in the standardized uptake value (SUV) with PET corrected or not for partial volume effects was compared to the pathological response.ResultsThe sensitivity, specificity and accuracy of axillary node staging was higher with PET (75, 87 and 80%) than with US (50, 83 and 65%), and even more so when PET images were corrected for partial volume effects (86, 83 and 84%). While FDG uptake did not vary much in non-responders, as confirmed by histopathological analysis, it markedly decreased to baseline levels in responders (p < 10−5). Fifty per cent of baseline SUV was considered the best cutoff value to distinguish responders from non-responders. The sensitivity, specificity, negative predictive value and accuracy of FDG PET after one course of chemotherapy were, respectively, 96, 75, 95 and 84%.ConclusionThe pathological status of regional axillary lymph nodes in stage II and III breast cancer patients could be accurately predicted after one course of neoadjuvant chemotherapy based on FDG PET images.