Rémi Dendale

Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity

IntroductionTypical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC).MethodsExpression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs.ResultsAll tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC.ConclusionOur study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.

Breast-Conserving Treatment in the Elderly: Long-Term Results of Adjuvant Hypofractionated and Normofractionated Radiotherapy

PURPOSE To evaluate the long-term cause-specific survival (CSS), locoregional recurrence-free survival (LRFS), and metastases-free survival (MFS) in elderly breast cancer patients receiving adjuvant normofractionated (NF) or hypofractionated (HF) radiotherapy (RT). METHODS AND MATERIALS Between 1995 and 1999, 367 women aged >or=70 years with nonmetastatic Stage T1 or T2 tumors were treated by breast-conserving surgery and adjuvant RT at the Institut Curie. They underwent wide tumor excision with or without lymph node dissection followed by RT. They received either a NF-RT schedule, which delivered a total dose of 50 Gy (25 fractions, 5 fractions weekly) to the whole breast, followed by a boost to the tumor bed when indicated, or a HF-RT schedule, which delivered a total dose of 32.5 Gy (five fractions of 6.5 Gy, once weekly) with no subsequent boost. The HF-RT schedule was indicated for the more elderly patients. RESULTS A total of 317 patients were in the NF-RT group, with 50 in the HF-RT group. The median follow-up was 93 months (range, 9-140). The 5- and 7-year CSS, LRFS, and MFS rates were similar in both groups. The 5-year NF-RT and HF-RT rate was 96% and 95% for CSS, 95% and 94% for LRFS, and 94% and 95% for MFS, respectively. The 7-year NF-RT and HF-RT rate was 93% and 87% for CSS, 93% and 91% for LRFS, and 92% and 93% for MFS, respectively. CONCLUSION According to the findings from this retrospective study, the HF-RT schedule is an acceptable alternative to NF-RT for elderly patients. However, large-scale prospective randomized trials are needed to confirm these results.

How to Boost the Breast Tumor Bed? A Multidisciplinary Approach in Eight Steps

PURPOSE To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. PATIENTS AND METHODS This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. RESULTS Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5-10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. CONCLUSIONS We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

Conservative Treatments of Intraocular Retinoblastoma

OBJECTIVE To describe the efficacy of conservative management of retinoblastoma by an association of conservative ocular therapies and chemothermotherapy. DESIGN Phase II prospective nonrandomized trial. PARTICIPANTS Eighty-three children were included (115 eyes). METHODS Conservative ocular therapies and chemothermotherapy (intravenous carboplatin followed by transpupillary thermotherapy to the tumor) after chemoreduction by 2 cycles of carboplatin and etoposide. MAIN OUTCOME MEASURES Use of external beam therapy and ocular tumor control. RESULTS One hundred fifteen of the 147 affected eyes were eligible for conservative management. Nineteen children had unilateral lesions (22.8%), and 64 (77.1%) had bilateral lesions. Sixty-six children received neoadjuvant chemotherapy before ocular therapy, which consisted of one or a combination of several techniques: chemothermotherapy (65 children [86 eyes]) with a mean of 3 cycles per child, thermotherapy alone (22 children [24 eyes]), cryoapplication (49 children [58 eyes]), and iodine 125 brachytherapy (26 children [29 eyes]). Tumor control was achieved for 97 eyes (84%). At the end of the study, external beam radiotherapy (EBR) was necessary for a total of 9 children (11%) and 13 eyes (12%). Enucleation was necessary for a total of 23 eyes (20%), because of complications in 5 cases. CONCLUSIONS Neoadjuvant chemotherapy with 2 cycles of carboplatin and etoposide followed by ocular therapy and chemothermotherapy achieves satisfactory tumor control and permits a low need for EBR.

Simultaneous integrated boost in breast conserving treatment of breast cancer: A dosimetric comparison of helical tomotherapy and three-dimensional conformal radiotherapy

BACKGROUND AND PURPOSE To evaluate the dosimetry of helical tomotherapy (HT) and three-dimensional conformal radiotherapy (3D-CRT) in breast cancer patients undergoing whole breast radiation with simultaneous integrated boost (SIB) of the tumor bed. MATERIAL AND METHODS Thirteen patients with breast cancer treated by lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned using both HT and 3D-CRT using the field-in-field technique. The whole breast and tumor bed were prescribed 50.68 Gy and 64.4 Gy, respectively, in 28 fractions. Dosimetries for both techniques were compared. RESULTS Coverage of the whole breast was adequate with both techniques (V(95%)=96.22% vs. 96.25%, with HT and 3D-CRT, respectively; p=0.64). Adequate tumor bed coverage was also achieved, although it was significantly lower with HT (V(95%)=97.18% vs. 99.72%; p<0.001). Overdose of the breast volume outside the tumor bed was significantly lower with HT (V(54.23 Gy)=12.47% vs. 30.83%; p<0.001). Ipsilateral lung V(20 Gy) (6.34% vs. 10.17%; p<0.001), V(5 Gy) (16.54% vs. 18.53%; p<0.05) and mean dose (4.05 Gy vs. 6.36 Gy; p<0.001) were significantly lower with HT. In patients with left-sided tumors, heart V(30 Gy) (0.03% vs. 1.14%; p<0.05) and mean dose (1.35 Gy vs. 2.22 Gy; p<0.01) were significantly lower with HT, but not V(5 Gy). Contralateral breast V(5 Gy) (0.27% vs. 0.00%; p<0.01) and maximum dose were significantly increased with HT. CONCLUSIONS In breast cancer treated with SIB, both HT and 3D-CRT provided adequate target volume coverage and low heart doses. Tumor bed coverage was slightly lower with HT, but HT avoided unnecessary breast overdosage while improving ipsilateral lung dosimetry.

IMPROVING THE DEFINITION OF TUMOR BED BOOST WITH THE USE OF SURGICAL CLIPS AND IMAGE REGISTRATION IN BREAST CANCER PATIENTS

PURPOSE To evaluate the accuracy of a boost technique. METHODS AND MATERIALS Twenty-two patients underwent tumorectomy with placement of two or more clips in the surgical cavity before breast remodeling. Preoperative and postoperative computed tomography scans, with match-point registration, were performed on all patients. The relationship between the location of the gross tumor volume (GTV), defined on the preoperative scan, and clip clinical target volume (CTV) (clips with a 5-mm margin on the postoperative scan) was then studied, by use of commercial volume analysis software. RESULTS Of the patients, 4 had two clips, 2 had three clips, 8 had four clips, and 8 had five clips. The median GTV was 1.06 mL (range, 0.2-5.3 mL); clip CTV ranged from 2.4 to 21.5 mL. Volumetric analysis showed that in 7 cases (32%), there was no intersection between the GTV and the clip CTV, with the following distribution: 4 patients with two clips, 1 patient with three clips, 1 patient with four clips, and 1 patient with five clips. The common contoured volume was defined as the percent ratio between the intersection of the GTV and clip CTV and the GTV. It was found to be significantly increased if three or more clips were used vs. only two clips (common contoured volume, 35.45% vs. 0.73%; p = 0.028). Finally, the GTV and clip CTV volume relationship can be presented as follows: 12.5% to 33% overlap in 8 patients (36.4%), 50% to 75% in 5 patients (22.7%), and greater than 90% in 2 patients (9%). CONCLUSIONS The use of three or more clips during tumorectomy increases the accuracy of tumor bed delineation.

Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma

Objective This study investigated the capacity of genetic analysis of uveal melanoma samples to identify high-risk patients and discusses its clinical implications. Methods Patients with posterior uveal melanoma were prospectively enrolled. Tumour samples were derived from enucleated globe, fine-needle aspirates or endoresection. Chromosome 3 and 8 status was determined by array comparative genomic hybridisation (array-CGH). Patients were followed after treatment to detect metastasis. Results Four groups were classified by array-CGH. Patients were divided into disomy 3 and normal chromosome 8 (D3/8nl), disomy 3 and 8q gain (D3/8g), monosomy 3 and normal chromosome 8 (M3/8nl) and monosomy 3 and 8 or 8q gain (M3/8g). Median follow-up was 28 months (range: 1–147 months). At the end of the study, 128 patients (33.7%) had developed metastasis and 96 patients had died. Univariate Cox proportional hazard analysis showed that factors associated with metastasis included basal tumour diameter p=0.0007, tumour thickness p=0.01, mixed/epithelioid cell type p=0.0009 and genomic data p<0.0001. High-risk profile was more strongly associated with metastasis than the other prognostic factors p<0.001. Multivariate Cox modelling analysis showed that the status of chromosomes 3 and 8 were the only two variables that independently contributed to prognosis: monosomy 3 alone p=0.001 and monosomy 3 and 8q gain p<0.0001. Conclusions Array-CGH allowed identification of three prognostic groups with low, intermediate and high risk of developing metastasis. Array-CGH is a reliable and inexpensive method for uveal melanoma prognosis. This method is now currently used in France.

Treatment of Uveal Melanoma by Accelerated Proton Beam

Proton beam irradiation of uveal melanoma has great advantages compared to brachytherapy because of the homogenous dose delivered to the tumor and the possibility of sparing normal tissue close to the tumor. We describe the technique of proton beam therapy including the surgical technique of clip positioning, the radiotherapy delivery technique and the dose administered (60 Gy cobalt relative biological effectiveness in 4 fractions). Indications of proton beam are given and the follow-up procedure is described. An inactive residual tumor scar is observed after 2-3 years. Results are given comparing the most recent series of patients treated at the Institut Curie-Orsay proton therapy center with the data published in the literature. The metastasis rate at 10 years varies between 25 and 30%. Local control is excellent. The local recurrence rate at 10 years is usually around 5%. Secondary enucleation is performed in 10-15% of patients either due to complications or local recurrence. Complications such as retinal detachment, maculopathy, papillopathy, cataract, glaucoma, vitreous hemorrhage and dryness are described. The severest complication that usually leads to secondary enucleation is neovascular glaucoma and it is encountered after irradiation of large to extra-large tumors. The toxic tumor syndrome has recently been described. It is hypothesized that the residual tumor scar may produce proinflammatory cytokines and VEGF leading to intraocular inflammation and neovascular glaucoma. Additional treatments after proton beam such as transpupillary thermotherapy, endoresection of the tumor scar or intravitreal injections of anti-VEGF may reduce the rate of these complications.

The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study.

BACKGROUND To evaluate the skin and heart toxicity of a concurrent adjuvant trastuzumab-radiotherapy for breast cancer (BC), especially in the case of internal mammary chain (IMC) irradiation. MATERIAL AND METHODS Prospective study of 106 patients treated between 06/2003 and 03/2007 by concurrent trastuzumab-radiotherapy for non-metastatic BC. Left ventricular ejection fractions (LVEF) was assessed at baseline, before and after radiotherapy and then every 4-6 months. All toxicities were evaluated using CTCAEV3. RESULTS Median age was 52 years (25-76). Chemotherapy with anthracycline was administered in 92% of patients. All patients received trastuzumab every three weeks (8 mg/kg followed by 6 mg/kg) for a median duration of 12 months (3-40). The IMC was irradiated in 83% of patients. There were: 87 grade 1, 14 grade 2 and 2 grade 3 skin reactions. There were 13 oesophagitis: 9 grade 1; 3 grade 2, and 1 grade 3. Out of 101 patients with assessments after 6 months, late telangiectasia grade 1 occurred in 5 patients, local pain grade 1 in 19 patients and grade 2 in 3 patients, fibrosis grade 1 in 16 patients. A reversible grade ≥2 left ventricular systolic dysfunction occurred in 6 patients. CONCLUSION In this prospective study of breast cancer patients treated with trastuzumab-radiotherapy with, in most cases, anthracycline-based chemotherapy and IMC irradiation, both the rate of abnormal LVEF after concurrent trastuzumab-radiotherapy and the skin toxicity were deemed acceptable. Further follow-up is needed.

Facteurs pronostiques du mélanome malin de l’uvée: Étude rétrospective sur 2 241 patients et apport recent de la recherche de la monosomie 3

Introduction Nous avons realise une etude retrospective des facteurs cliniques influencant le pronostic local et general chez des patients atteints de melanome choroidien. Nous avons effectue une analyse preliminaire de la valeur pronostique de la monosomie 3. Patients et methode Les patients adresses a l’Institut Curie pour un melanome de l’uvee ont un bilan initial complet, un traitement conservateur radiotherapique ou une enucleation et un suivi a long terme local et general. Depuis 5 ans, les tumeurs traitees par enucleation ont une etude du statut du chromosome 3 par FISH. Les donnees concernant le bilan initial, le traitement et le suivi sont enregistrees systematiquement de maniere prospective. Nous avons realise une etude retrospective avec analyse multivariee des facteurs cliniques influencant la recidive locale, la conservation oculaire, les metastases et la survie, et en particulier des effets de la monosomie 3. Resultats Deux mille deux cent quarante et un patients ont ete traites avec un recul median de 72 mois. 92,8 % des patients ont eu un traitement conservateur par curietherapie a l’iode 125 ou par protontherapie, et 7,2 % des patients ont eu une enucleation (n = 160). Parmi les patients enuclees, 120 ont eu une etude genetique de leur tumeur par FISH. La survie globale a ete de 76,3 %, et le taux de metastases, de 19,5 %. Les facteurs cliniques influencant la survie en analyse multivariee sont la taille et la localisation de la tumeur, l’âge, le sexe et le traitement initial. Les facteurs influencant le risque metastatique sont identiques, avec en plus, l’existence d’un decollement de retine initial et la recidive locale. La monosomie 3 influence de facon significative le risque metastatique. Discussion Cette etude retrouve les facteurs de risque habituels, mais differe legerement des precedentes series car la localisation a cheval sur l’equateur apparait plus pejorative que la localisation au niveau du corps ciliaire pour les metastases et la survie. Par ailleurs, le decollement de retine initial apparait comme un facteur de risque significatif pour la recidive locale et les metastases. Actuellement, la recherche de la monosomie 3 n’est possible que sur des pieces d’enucleation ; mais, il est probable qu’elle puisse etre applicable aux biopsies a l’aiguille. Cette recherche pourrait etre proposee en meme temps que le traitement conservateur. Conclusion Cette etude confirme les resultats precedents sur les facteurs pronostiques du melanome uveal et la valeur pronostique de la monosomie 3. L’identification de plus en plus precise d’un groupe de patients a haut risque devrait permettre prochainement de proposer des therapeutiques adjuvantes a ces patients et d’adapter le suivi a long terme.INTRODUCTION We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3. PATIENTS and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3. RESULTS A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease. DISCUSSION This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well. CONCLUSION This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.