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Supplementary Table S4 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

Purpose: To gain insight into genomic and trancriptomic subtypes of ductal carcinomas in situ of the breast (DCIS).Experimental Design: We did a combined phenotypic and genomic analysis of a series of 57 DCIS integrated with gene expression profile analysis for 26 of the 57 cases.Results: Thirty-two DCIS exhibited a luminal phenotype; 21 were ERBB2 positive, and 4 were ERBB2/estrogen receptor (ER) negative with 1 harboring a bona fide basal-like phenotype. Based on a CGH analysis, genomic types were identified in this series of DCIS with the 1q gain/16q loss combination observed in 3 luminal DCIS, the mixed amplifier pattern including all ERBB2, 12 luminal and 2 ERBB2-/ER- DCIS, and the complex copy number alteration profile encompassing 14 luminal and 1 ERBB2-/ER- DCIS. Eight cases (8 of 57; 14%) presented a TP53 mutation, all being amplifiers. Unsupervised analysis of gene expression profiles of 26 of the 57 DCIS showed that luminal and ERBB2-amplified, ER-negative cases clustered separately. We further investigated the effect of high and low copy number changes on gene expression. Strikingly, amplicons but also low copy number changes especially on 1q, 8q, and 16q in DCIS regulated the expression of a subset of genes in a very similar way to that recently described in invasive ductal carcinomas.Conclusions: These combined approaches show that the molecular heterogeneity of breast ductal carcinomas exists already in in situ lesions and further indicate that DCIS and invasive ductal carcinomas share genomic alterations with a similar effect on gene expression profile.

Supplementary Data from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

Background: All methods available for SNB identification suffer from many flaws including cost of the probes, allergies or management of radioactive material. Breast cancer is a challenging issue in LMIC [1]. Fluorescein has been described first in this meeting [2-3] as an alternative cheap and safe tracer in SNB mapping [4]. Our aim was to reproduce the feasibility and the safety of fluorescein SNB mapping compared with Isosulfan blue dye as a reference. Methods: Ten patients, with biopsy proven BC, were operated on for SNB biopsy and prospectively included over a period of one year (April 2018 - April 2019). Patients had 2 cc Isosulfan blue dye and 2 cc 10% fluorescein mixed with 4 cc of 9% saline solution injected subcutaneously in the peri-areolar area prior to lymph node biopsy. Fluorescent lymph nodes were detected by 5 nm ultra-violet light-emitting diode flashlight. They were removed and then remaining blue and/or suspicious nodes were removed. The detection rate and the complications were the primary objectives in this study. Results: Mean age was 40 years old (range 27 - 72). Mean size of the tumor was 20 mm (5 - 70mm). All patients but one had invasive breast carcinoma and one had ductal carcinoma in situ. All patients had no clinical or radiological suspicious nodal involvement before surgery. Six patients had a breast conserving surgery and four had a mastectomy. After a mean delay of 15,5 minutes after injection, SLN sampling was performed. All patients had fluorescent and blue nodes. A total of 27 fluorescent nodes and 25 blue nodes were harvested during these procedures. All blue nodes were fluorescent. Two nodes had micro-metastasis on final pathology. One of them was only detected by fluorescein. Adverse effects were represented by 2 seromas. No patient experienced an allergic reaction. Conclusion: In this pilot study, we were able to reproduce the published data where fluorescein based SNB detection was feasible, efficient in the detection rate and safe. We emphasize the need for a larger multicenter study to confirm the clinical utility of this tracer. The low cost of this technique will greatly help the development of SNB in LMIC Refernces: 1. Bellanger M, Zeinomar N, Tehranifar P, Terry MB. Are Global Breast Cancer Incidence and Mortality Patterns Related to Country-Specific Economic Development and Prevention Strategies? JGO. 8 juin 2018;(4):1-16. 2. Srivastava A, Suresh J, Ranjan P, et al: Fluorescent fluorescein with methylene blue compared to radioactive sulphur colloid with methylene blue: a randomised comparison. Proc SABCS 2017; abstr PD2-03. 3. Srivastava A, Kumar C,Kataria K fluorescence guided breast conserving surgery Proc SABCS 2018 PD 08 06 4. Chang YW, Lee HY, Lee CM, Jung SP, Kim WY, Woo SU, et al. Sentinel lymph node detection using fluorescein and blue light-emitting diodes in patients with breast carcinoma: A single-center prospective study. Asian Journal of Surgery [Internet]. 20 mars 2019. Citation Format: Remy Jacques Salmon, Mehdi Benna. Sentinel node biopsy mapping using fluoresceine in breast cancer. An alternative for low and middle income countries [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-18.

Clinical rationale: A significant proportion of post-menopausal, patients treated with AI reports side-effects, especially bone pain. In such patients, the difficulties to treat pain and to clearly identify its causes may lead to treatment discontinuation. Individual cases reported an improvement in AI tolerance when dosage is reduced. The aim of this work was thus to analyse pharmacological data in order to validate this concept ie. ensuring that intermittent dosing would not result in a possibly deleterious under-dosing of AI. Pharmacological rationale: Ageing is associated with physiological modifications that may impair drug pharmacokinetics (PKs). The elimination can be altered, with decreased drug clearance (CL), resulting in an increased exposure to the drug, reflected by increased AUCs. Drugs benefit-risk balance can thus be modified. The major sources of PKs alterations in the elderly are hepatic and/or renal impairments (HI/RI). It has been shown that AI PKs are altered in the elderly and/or in case of HI or RI. Exemestane AUC is increased 3-fold in the elderly and in case of RI [1,2]. Letrozole AUC can double in case of HI [3] and a 42%-increase has been reported in the elderly [4]. The renal CL of anastrozole is reduced by 50% in RI, resulting in a 10% decrease in total body CL. In HI, total body CL is 30% lower as compared to normal [5]. These data demonstrate that elderly patients may be overexposed to AI when treated with the usual dosage, resulting in safety issues occurring in some patients. As a result, a dosage adjustment approach could help prevent over-exposure and reduce side-effects incidence/severity. Proof-of-Concept studies: The reported increases in AI exposure being around 50%, an intermittent dosing schedule of 1 administration every other day could result in a similar drug exposure as compared to the usual daily schedule. AI elimination half-lives in the absence of any alteration also are consistent with this dosing schedule (24, 48, and 50 hours for exemestane, letrozole, and anastrozole, respectively). In order not to impair plasma concentrations, such a schedule is preferably suggested as compared to a half-dose daily schedule. Prospective studies are needed, in which the PKs, efficacy, and safety of this intermittent dosing schedule should be conducted. References: [1] Aromasin® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020753s014lbl.pdf; accessed 04/29/2014 [2] Jannuzzo MG, et al. Cancer Chemother Pharmacol. 2004; 53(6): 475-81. [3] Femara® FDA Labeling Information; 2014 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf; accessed 04/29/2014 [4] Pfister CU, et al. Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos. 2001; 22(5): 191-7. [5] Arimidex® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020541s027lbl.pdf; accessed 04/29/2014. Citation Format: Vincent Launay-Vacher, Rémy Salmon, Jean-Baptiste Rey. Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in post-menopausal women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-15.

Purpose The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna’s assay information on physicians’ adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results. Methods Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians’ opinion on the test results and the patients’ degree of anxiety, difficulties with therapy and quality of life. Results Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p

International audience; BACKGROUND:Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)-positive, postmenopausal patients not eligible for primary breast-conserving surgery (BCS).METHODS:This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse-free survival (RFS), and predictive markers of responses and outcomes.RESULTS:From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2-T4, N0-N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%-64%) in arm A and 36.8% (95% CI, 25%-49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated.CONCLUSIONS:Both drugs are effective and well tolerated as NET in postmenopausal women with HR-positive/HER2-negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032-3040. © 2016 American Cancer Society.

The aim of this study was to determine, in a population with metastatic breast cancer treated with bevacizumab therapy, the incidence of wound dehiscence after placement of an implantable venous access device (VAD) and to study the risk of catheter thrombosis. This study enrolled all VADs placed by 14 anesthetists between 1 January 2007 and 31 December 2009: 273 VADs in patients treated with bevacizumab therapy and 4196 VADs in patients not treated with bevacizumab therapy. In the bevacizumab therapy group, 13 cases of wound dehiscence occurred in 12 patients requiring removal of the VAD (4.76%). All cases of dehiscence occurred when bevacizumab therapy was initiated less than 7 days after VAD placement. Bevacizumab therapy was initiated less than 7 days after VAD placement in 150 cases (13 of 150: 8.6%). The risk of dehiscence was the same from 0 to 7 days. In parallel, the VAD wound dehiscence rate in patients not receiving bevacizumab therapy was eight of 4197 cases (0.19%) (Fisher's test significant, P

Background Digestive metastasis of breast cancer are rare but when they do occur the stomach is one of the commoner sites. Aim To describe the clinical, endoscopic, pathological features and treatment. Methods 35 cases of gastric metastasis were identified retrospectively between 1980 and 2008. Results The location of the gastric metastasis was fundus (n = 15, 43%), antrum (n = 15, 43%) or both (n = 5, 14%). The histological subtype of primary breast cancer was invasive lobular carcinoma in 34 patients (97%). Hormonal receptors were positive in 19 out of 24 cases (79%), two out of 22 analysed were HER2 positive (9%). There were 16 (46%) patients with peritoneal carcinosis. The treatment was chemotherapy (n = 13, 37%), hormonotherapy (n = 2, 6%) or both (n = 13, 37%). The 2-year survival rate after gastric metastasis diagnosis was 53% with a median follow up of 31 months [7–84 months]. Conclusion Ninety-seven percent of gastric metastasis from breast cancers are derived from invasive lobular carcinoma. Seventy-nine percent of these are HER+ and comparison with the original histopathological slides of primary breast carcinoma should be performed to differentiate gastric metastasis from primary gastric carcinoma. Peritoneal carcinomatosis accompanied gastric metastasis in almost half the cases in this series and treatment was generally chemotherapy.

Phyllodes tumors are a rare distinctive fibroepithelial tumors of the breast and their management continues to be questioned. The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumors and to review the options for surgical management. This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumors. The median follow-up was 12.65 months [range 0-149.8]. The median age at diagnosis was 44 years [range 17-79]. One hundred and sixty patients (97%) had breast-conserving treatment, of whom 3 patients (1.8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumor of small size (p < 0.0001). Histologic examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumors (9%). The median tumor size was 30 mm [range 5-150]. The tumor margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumor grade was a significant risk factor for incomplete tumor margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histologic grade (p = 0.008), and tumor size (p = 0.02) were significative risk factors for local recurrence with an accentuated risk for "borderline" tumors and tumors of large size.).Similar results were obtained using multivariate analysis (p = 0.07). The mainstay of treatment for phyllodes tumors remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumors or in cases of local tumor recurrence, mastectomy, and immediate breast reconstruction may become the preferred option. Genetic analysis will potentially supplement classical histologic examination in order to improve our management of these tumors. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis.

Background: Synchronous plastic and oncological surgery is undertaken to improve the security of excision margins and yield high-quality aesthetic out-comes when conventional breast-conserving therapy either anticipates poor results or is not possible. Methods: A total of 540 consecutive patients underwent primary oncoplastic breast surgery for cancer with high tumor-to-breast volume ratios and locations precluding a good aesthetic result with simple tumor excision. A variety of techniques were employed at the Institut Curie between 1986 and 2007, and aesthetic outcomes were assessed on a five-point scale from 1 (excellent) to 5 (poor). Results: The median age was 52 years (range, 28 to 90 years), and median follow-up was 49 months (6 to 262 months). Median tumor size was 29.1 mm (range, 4 to 100 mm), with most patients (72.3 percent) having a brassiere cup size of B or C. Close or involved margins occurred in 18.9 percent, with mastectomy being necessary in 9.4 percent. A satisfactory aesthetic outcome (ratings of 1 to 3) at 5 years was obtained in 90.3 percent. Five-year overall and distant disease-free survival rates were 92.9 and 87.9 percent, respectively, with local recurrence in 6.8 percent. Conclusions: With local recurrence and survival rates similar to those for breast-conserving therapy, this series confirms the safety of oncoplastic breast surgery for tumors both high in volume and difficult in location. Highly satisfactory cosmetic outcomes extend the indications for conservative surgery, further reduce the mastectomy rate, and limit adverse aesthetic sequelae.

Objectives. The purpose of this retrospective evaluation of advanced-stage ovarian cancer patients was to compare outcome with published findings from other centers and to discuss future options for the management of advanced ovarian carcinoma patients.Methods. A retrospective series of 340 patients with a mean age of 58 years (range: 17–88) treated for FIGO stage III and IV ovarian cancer between January 1985 and January 2005 was reviewed. All patients had primary cytoreductive surgery, without extensive bowel, peritoneal, or systematic lymph node resection, thereby allowing initiation of chemotherapy without delay. Chemotherapy consisted of cisplatin-based chemotherapy in combination with alkylating agents before 2000, whereas carboplatin and paclitaxel regimes were generally used after 1999-2000. Overall survival and disease-free survival were analyzed by the Kaplan-Meier method and the log-rank test.Results. With a mean followup of 101 months (range: 5 to 203), 280 events (recurrence or death) were observed and 245 patients (72%) had died. The mortality and morbidity related to surgery were low. The main prognostic factor for overall survival was postoperative residual disease (P<.0002), while the main prognostic factor for disease-free survival was histological tumor type (P<.0007). Multivariate analysis identified three significant risk factors: optimal surgery (RR=2.2for suboptimal surgery), menopausal status (RR=1.47for postmenopausal women), and presence of a taxane in the chemotherapy combination (RR=0.72).Conclusion. These results confirm that optimal surgery defined by an appropriate and comprehensive effort at upfront cytoreduction limits morbidity related to the surgical procedure and allows initiation of chemotherapy without any negative impact on survival. The impact of neoadjuvant chemotherapy to improve resectability while lowering the morbidity of the surgical procedure is discussed.

Le statut ganglionnaire axillaire est le facteur pronostique le plus important dans les cancers du sein. L’atteinte du ganglion sentinelle (GS) comprend deux entites: les atteintes metastatiques pN1 et les atteintes lymphatiques minimes: pN1mi et pN0i+. La prise en charge therapeutique postoperatoire des patientes pN1 ayant eu la technique du GS est identique a la population des patientes pN1 ayant eu un curage axillaire (CA). Par contre, la prise en charge des patientes pN1mi ou pN0i+ fait l’objet de discussion avec une tendance a les reoperer (CA complementaire), car le risque d’atteinte metastatique est de l’ordre de 10 a 15% (les reclassant pN1), cela permet ainsi de decider des champs d’irradiation et des traitements systemiques adjuvants. Les etudes concernant le pronostic des patientes avec atteinte lymphatique minime font l’objet de publications tres recentes depuis 2008. Ainsi, la taille metastatique semble etre correlee au pronostic de ces patientes tant en survie sans metastase a cinq ans qu’en survie globale a dix ans et pourrait etre un facteur decisionnel de traitement systemique adjuvant. L’etude de l’atteinte ganglionnaire axillaire reste donc une necessite absolue dans la prise en charge des cancers du sein. L’etude des atteintes lymphatiques minimes ouvre ainsi un nouveau champ d’exploration ou les chirurgiens jouent leur role comme les autres acteurs de la cancerologie.

Mondor’s disease is an uncommon complication of breast and axillary surgery. Although self-limiting, the subcutaneous cords may be both painful and functionally limiting for the patient. Numerous pharmacologic approaches have been tried, but without widespread success, and we wished to evaluate the non-invasive technique of manual axial distraction in such patients. Thirty consecutive patients with axillary Mondor’s disease following surgery were treated solely with this technique by the senior author (RJS) over a 24-month period. Mean age was 45 years (range 32–72) with 27 having undergone formal axillary dissection and three sentinel node biopsy. 25 (83.3%) were successfully treated with a single procedure, three (10%) with two and two (6.7%) with three procedures. we present the initial results of the novel technique of manual axial distraction that has been found to be efficacious and without adverse effect. It provides a rapid and definitive cure in postoperative Mondor’s disease.

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.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a complex vascular lesion recently described. We present a case of SANT occurring in a 49-year-old woman who was treated for choroid melanoma. The computed tomography abdominal scan revealed an asymptomatic mass in the spleen. Splenectomy was performed due to the risk of metastasis from the melanoma. The histopathologic examination revealed an angiomatoid lesion composed of three types of vessels recapitulating the normal composition of the red pulp of the spleen. In this report, we discuss the pathology of this lesion and the differential diagnosis of SANT with other lesions such as hemangiomas, hamartomas and inflammatory pseudotumors.

Resume La reconstruction de la plaque areolo-mammelonnaire est un element essentiel pour apprecier la qualite d’une reconstruction mammaire. Elle peut etre realisee dans le meme temps operatoire que celle-ci (reconstruction immediate ou differee) ou dans un deuxieme temps. Nous exposons les techniques de reconstruction de plaque areolo-mamelonnaire faites en routine depuis 1992. Sous anesthesie locale au cours d’un deuxieme temps ou sous anesthesie generale pendant une reconstruction mammaire, le prelevement d’un lambeau cutaneo-graisseux (lambeaux « F »et « Z ») associe a un tatouage assure un resultat esthetique de grande qualite tant par la cicatrisation aisee que par la projection a long terme. Ces techniques sont reproductibles aisement, de realisation rapide et l’absence de prelevement a distance ainsi que des incisions rigoureusement choisies permettent une tres bonne tolerance. Les complications sont exceptionnelles et il est toujours possible d’associer d’autres techniques de reconstruction areolo-mamelonnaire en cas de resultat defavorable. Nous presentons egalement les principales techniques de reconstruction de la plaque areolo-mammelonnaire existantes avec leurs avantages et leurs limites.

Breast cancer surgery has long consisted in the sole use of mastectomy. Then, it was proved that, in terms of global survival, conservative treatments associated with radiotherapies could give the same results. But breast deformations due to classic conservative treatments led some authors to use plastic surgery procedures: breast plastic surgery. Some breast plastic surgery procedures are well-known, others have been adapted to breast cancer treatment and more particularly in case of tumor of superior and internal quadrants. After the retrospective analysis of a series of 298 cases from the Institute Curie, the aim of this survey is to find whether there is a difference between: breast plastic surgery and usual treatments like mastectomy and classic conservative treatments. For most cases, the tumors were invasive ductal carcinoma and T2N0M0 carcinoma. This survey showed, among these cases, 94.56% of global survival, 86.81% of survival without metastasis and a five-year 93.47% without local recurrence, which is comparable to the results for mastectomies and classic conservative treatments. In selected cases, the use of mammaplasty could be interesting for breast cancer surgery treatment.

Introduction This study aimed to evaluate responses and outcome of hormone-therapy (HT) and radiotherapy (RT) given concurrently for large breast cancers in post-menopausal women. Material and methods Forty-two breast carcinomas in 41 women were treated with HT and concurrent RT to the breast ± lymph node bearing areas. For 30 tumours this was followed by breast surgery (with axillary lymph node dissection when the axilla had not been irradiated). RT delivered a median dose to the tumour of 50 Gy (48–66) and 75 Gy (65–84) for, respectively, preoperative and exclusive RT–HT. Median follow-up was 64 months. Results Out of 42 clinically assessable tumours (after a mean dose of 50 Gy), 9 tumours (21%) had complete clinical responses, 24 (57%) partial responses, 9 (21%) stable disease. Breast-conserving surgery or exclusive RT–HT was possible in 74% of tumours. For 29 patients who underwent breast surgery, the rate of pathological complete responses was 17%. At 50 Gy no skin toxicity higher than grade 2 occurred. Five year OS, RFS and local control were, respectively, 85%, 84% and 97%. Lymphoedema occurred in one patient. Conclusion Concurrent association of RT–HT demonstrated good efficacy, both in terms of clinical and pathological complete responses. It allowed breast conservation with acceptable tolerance and good 5-year local control.

Purpose: To evaluate the accuracy of clinical examination and of three imaging modalities (ultrasound [US] scan, mammography, and magnetic resonance imaging [MRI]) to assess the tumor response of breast cancer to a preoperative regimen of concurrent radiochemotherapy for large breast cancers, using pathologic data as the reference. Methods and Materials: Sixty women were accrued. Treatment consisted of 4 cycles of (5-fluorouracil-vinorelbine) chemotherapy with, starting with the second cycle of chemotherapy, locoregional radiotherapy to the breast and the internal mammary and supraclavicular and infraclavicular lymph nodes. Breast surgery and axillary lymph node dissection were subsequently performed. Breast imaging assessments were performed both before chemotherapy and preoperatively. Results: The correlation coefficients between tumor dimension at imaging and pathology were statistically significant for US scan ( r = 0.4; p = 0.006) and MRI ( r = 0.4; p = 0.004) but not for clinical examination ( r = 0.2; p = 0.16) or mammography ( r = −0.15; p = 0.31). Furthermore, the area under the receiver operating characteristic curve for MRI was 0.81, compared with 0.67 for US scan. At the optimal threshold score, MRI performed with 81% sensitivity and 75% specificity. Conclusion: Compared with clinical examination, US scan, or mammography, MRI substantially improved the prediction of pathologic tumor response to preoperative concurrent radiochemotherapy for large breast cancers.

Breast cancer is one of the most frequently diagnosed cancers in women in France, but its aetiology remains unknown. Viruses including Epstein-Barr virus (EBV), a human equivalent of murine mammary tumour virus (MMTV) and human papillomavirus (HPV) have been detected in benign breast tissues and breast tumours and are considered to be involved in the aetiology of breast cancer. The aim of this study was to determine the prevalence of high-risk oncogenic HPVs in breast carcinoma from French patients. Fifty unselected DNA samples extracted from invasive breast carcinoma tissues were analysed. Polymerase chain reaction (PCR) was performed to amplify both consensus GP5 + /GP6 + HPV sequences and specific sequences for HPV types 16, 18, 33, 45 and 6-11. No HPV-DNA sequences were detected in our series of 50 samples. These data argue against the role of oncogenic HPV in the pathogenesis of breast cancer.

Axillary lymph node dissection (ALND) for patients with positive sentinel lymph nodes (SLNs) is currently under discussion in the literature. The breast cancer nomogram (BCN), an online tool developed by the Memorial Sloan-Kettering Cancer Center (MSKCC), aims to predict the risk of positive non-SLN in SLN-positive patients. The purpose of this study was to test the accuracy of the nomogram on patients with macrometastatic and micrometastatic SLN-positive biopsy findings.Patient characteristics, tumor pathology, and positive SLN characteristics were collected on 588 consecutive patients who underwent completion ALND. The MSKCC BCN tool was used to calculate risk of metastases for all 588 cases that included a subgroup of the 213 patients with SLN micrometastases. The BCN was performed for positive SLN biopsy findings regardless of the method of metastasis detection. Evaluation of the BCN was performed by the area under the curve method.The BCN applied to all 588 patients achieved an area under the receiver operating characteristic curve (ROC) of .724 (range, .677-.771) compared with .76 in the MSKCC study. When the tool was applied solely to micrometastases found by hematoxylin and eosin staining and metastases found by immunohistochemistry, the area under the ROC was .538 (range, .423-.653).The MSKCC nomogram has been validated for all the patients having a metastatic SLN at the Institut Curie. However, this model was not reliably predictive for positive non-SLN in cases with micrometastic positive SLN.

Recent biological studies have classified breast carcinomas into HER2-overexpressing, estrogen receptor-positive/luminal, basal- and normal-like groups. According to this new biological classification, the objectives of our study were to assess the clinical, morphologic and immunophenotypic characteristics of adenoid cystic carcinoma of the breast in order to classify this subtype of breast carcinoma. A total of 18 cases of adenoid cystic carcinoma were identified from the Institut Curie files. Clinical information was available for 16 patients with a median follow-up of 6.5 years. Morphologically, all tumors were graded according to the system defined by Kleer and Oberman (histologic and nuclear grade). Immunophenotype was assessed with anti-ER, PR, HER-2, KIT, basal (CK5/6) and luminal cytokeratins (CK8/18) and p63 antibodies. One out of 18 tumors was nuclear grade 1 (16%), nine were nuclear grade 2 (50%) and eight were nuclear grade 3 (44%). All cases were estrogen receptor, progesterone receptor and HER-2 negative. Epithelial cells were strongly positive around glandular lumina with one or both cytokeratins, identifying the coexistence of CK5/6+ cells, CK5/6 and CK8/18+ cells, CK8/18+ cells and p63+ cells. All cases (100%) were also KIT positive. In all, 15 patients were treated by surgery. Nine of them received adjuvant radiotherapy. Follow-up was available for 16 patients. In all, 14 patients were alive. Two of them, initially treated by surgery only, presented a local recurrence. Two patients died (one of them treated by radiation therapy only died from her disease). Our study shows that adenoid cystic carcinoma of the breast is a special, estrogen receptor, progesterone receptor, HER-2 negative and highly KIT-positive, basal-like breast carcinoma, associated with an excellent prognosis. This highly specific immunophenotype could be useful to differentiate adenoid cystic carcinoma of the breast from other subtypes of breast carcinoma such as cribriform carcinoma.

Since more than twenty years, methods of breast reconstruction using implants have continued to evolve in order to improve their aesthetic results. Shapes and materials of these implants have also evolved to obtain contours similar to that of the natural opposite breast. Therefore it can be considered that the use of asymmetric implants is the last step in implant technology before using made to measure implants. Asymmetric implants allow obtaining different contours in harmony to the different breast shapes according to the side, left or right, of the reconstructed breast which maximise the naturalness of the result. Such implants have an axis directed towards the exterior and lower part of the chest wall, are wider than high with a thinner part on their inner edge and a concave rear side moulding the curves of the chest wall. In our own experience, we placed more than 500 asymmetric implants. When analysing retrospectively the medical records of 156 patients, no distinctive features were observed when compared to symmetric classic implants in easiness in the surgical procedure or in complications except a slightly higher rate of seroma formation. When compared to usual implants the main benefits of asymmetric implants are: to offer a wider breadth, to slope down gently on their upper and inner sides according to their concave rear side, and therefore to better match subtle curves of a normal breast. Moreover such contours allow a distribution of the volume which fit better to the usual natural breast configuration of patients who underwent surgery for breast carcinoma. At last, such implants are easy to place and a very low rate of secondary rotation has been observed. In summary, for all these reasons, asymmetric implants, can be considered to be the class one in the choice of implants for breast reconstruction after breast surgery.

Specific HPV DNA sequences are associated with more than 90% of invasive carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators in cell transformation by disrupting TP53 and RB pathways. To investigate molecular mechanisms involved in the progression of invasive cervical carcinoma, we performed a gene expression study on cases selected according to viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting Points Into Neighbourhoods methods, we identified a 'cervical cancer proliferation cluster' composed of 163 highly correlated transcripts. Most of these transcripts corresponded to E2F pathway genes controlling cell division or proliferation, whereas none was known as TP53 primary target. The average expression level of the genes of this cluster was higher in tumours with an early relapse than in tumours with a favourable course (P = 0.026). Moreover, we found that E6/E7 mRNA expression level was positively correlated with the expression level of the cluster genes and with viral DNA load. These findings suggest that HPV E6/E7 expression level plays a key role in the progression of invasive carcinoma of the uterine cervix via the deregulation of cellular genes controlling tumour cell proliferation. HPV expression level may thus provide a biological marker useful for prognosis assessment and specific therapy of the disease.

La maladie de Mondor a ete decrite en 1939. Elle se voit apres traumatisme thoracique et notamment apres traitement de cancer du sein. Elle a ete rapportee a une «tronculite sub-aigue de la paroi thoracique antero-laterale» et habituellement liee a une phlebite. Nous lions la maladie de Mondor aux brides aponevrotiques retractiles cicatricielles observees apres curage axillaire pour cancer du sein et/ou a la section des lymphatiques au niveau du creux axillaire. La rupture manuelle de brides au prix d’une douleur breve permet une recuperation fonctionnelle immediate et la disparition tout aussi immediate des douleurs.

Purpose Axillary dissection is the standard management of the axilla in invasive breast carcinoma. This surgery is responsible for functional sequelae and some options are considered, including axillary radiotherapy. In 1992, we published the initial results of a prospective randomized trial comparing lumpectomy plus axillary radiotherapy versus lumpectomy plus axillary dissection. We present an update of this study with a median follow-up of 180 months (range, 12 to 221 months). Patients and Methods Between 1982 and 1987, 658 patients with a breast carcinoma less than 3 cm in diameter and clinically uninvolved lymph nodes were randomly assigned to axillary dissection or axillary radiotherapy. All patients underwent wide excision of the tumor and breast irradiation. Results The two groups were similar for age, tumor-node-metastasis system stage, and presence of hormonal receptors; 21% of the patients in the axillary dissection group were node-positive. Our initial results showed an increased survival rate in the axillary dissection group at 5 years (P = .009). At 10 and 15 years, however, survival rates were identical in both groups (73.8% v 75.5% at 15 years). Recurrences in the axillary node were less frequent in the axillary dissection group at 15 years (1% v 3%; P = .04). There was no difference in recurrence rates in the breast or supraclavicular and distant metastases between the two groups. Conclusion In early breast cancers with clinically uninvolved lymph nodes, our findings show that long-term survival does not differ after axillary radiotherapy and axillary dissection. The only difference is a better axillary control in the group with axillary dissection.

Resumen La cirugia es un aspecto esencial del tratamiento del cancer de mama. Permite el control local de la enfermedad y establecer su pronostico. Requiere un conocimiento anatomico preciso de la vascularizacion y del drenaje linfatico de la mama. Gracias al tratamiento multidisciplinario del cancer de mama, a su deteccion precoz y al desarrollo de nuevas tecnicas quirurgicas, el tratamiento conservador es cada vez mas frecuente, con un doble objetivo permanente: mejorar las tasas de curacion y dejar una mama sin deformidades ni secuelas. La cirugia ganglionar sigue basandose en la linfadenectomia axilar, pero la busqueda del ganglio centinela con metodos colorimetricos o isotopicos es cada vez mas popular, especialmente en los tumores pequenos, en los que las metastasis axilares son cada vez mas raras. En este articulo se tratan las tecnicas de referencia, tales como la tumorrectomia, la mastectomia y la limpieza axilar, y se comentan los fundamentos basicos de la cirugia oncoplastica y de la tecnica del ganglio centinela.

Aims To investigate sporadic results demonstrating prolonged survival after surgical resection and/or intraarterial chemotherapy (IACH) for liver metastases from uveal melanoma. Methods From December 1992 to March 1997 every patient with liver metastases from uveal melanoma was enrolled in a prospective study including: (1) aggressive surgical approach removing as much liver disease as possible; (2) implantation of an intraarterial catheter; (3) intraarterial chemotherapy for 6 months. 75 patients were enrolled: 38 men, 37 women, mean age 51 years (range: 18–72), mean time from initial diagnosis of uveal melanoma to liver metastases 37 months (ranged: 1–168). Results Disseminated disease in both lobes was present in all but one patient. Macroscopically curative surgery was possible in 27.5%. Significant tumour reduction was performed in 49.3% and a simple biopsy was possible in 23.2%. Eight patients did not receive chemotherapy and died soon after. IACH included Fotemustine and/or DTIC-Platinum for 4–9 cycles. Overall median survival was 9 months; very similar to non-operated historical controls. In the 61 patients receiving complete treatment surgery plus chemotherapy, median survival improved to 10 months. When curative resection was possible, survival increased to 22 months ( P Conclusions Aggressive surgical resection, when possible, appears to be the best method of improving survival of liver metastases from uveal melanoma. New drug combinations are also required to improve survival.

We report the cytogenetic study of 9 colorectal tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC). According to the cytogenetic classification of colorectal tumors previously proposed by us, 2 cases were of the trisomic type, 2 were of the monosomic type, and 5 had a normal karyotype. This represents a significant excess of tumors with normal karyotype in HNPCC tumors (56%) compared to sporadic cases (10/184 = 5%).

The DNA-repeat [(CA)n] instability of colorectal cancer cells was studied relative to our previously defined classification based on chromosome alterations. Of the 23 tumors analyzed, 13 belonged to the "monosomic" type (MT) characterized by simultaneous loss of chromosome 18 and chromosome arm 17p, and many structural rearrangements, 7 to the "trisomic" type (TT) with many chromosome gains but few rearrangements, and 3 had a normal karyotype (NT). (CA)n repeat sequences were examined on chromosomes 2, 5, 11, 13, 18, and 20. We found sequence alterations in 12 tumors at 1 or several loci, 9 of which (1/13 MT, 5/7 TT, and 3/3 NT) exhibited a typical shift in allele size defined as microsatellite instability. Furthermore, a single alteration was observed for the MT tumor, whereas one NT tumor displayed instability on two and all the other tumors on three or more loci. These results suggest an inverse relationship between the occurrence of chromosome structural rearrangements and microsatellite instability, providing another argument for the subdivision of colorectal cancers into groups of distinct oncogenic pathways.

543Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue using nCounter Technology (...

Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women.

Essai randomise comparant deux doses de fulvestrant IM, 500 mg contre 250 mg tous les 28 jours apres une dose de charge J1, J14, J28 (tableau I).

Ce rapport dresse un etat des connaissances relatives aux biomarqueurs tissulaires uPA/PAI-1, Oncotype DX™ et MammaPrint® dans la prise en charge du cancer du sein.

Introduction:Exclusive chemoradiotherapy (including brachytherapy) is the current standard of care for locoregionally advanced cervical cancer. The aim of the present study was to evaluate the responsiveness and to identify factors predicting the response to concomitant chemoradiotherapy before surgery in cervical adenocarcinoma.Methods:A multicentric retrospective study was done in 9 French centers. A total of 54women with cervical adenocarcinoma stage IB2 to IIIB who had undergone concurrent chemoradiation therapy followed by surgical treatment were included. The patients were stratified by histopathologic response after concomitant chemoradiotherapy (lesions smaller than 1 cm or larger).Results:The median (SD) age at diagnosis was 44.2 (12.4) years (range, 19.3-77 years). The median (SD) follow-up duration was 30.9 (36.5) months (range, 4.1-17 years). After clinical evaluation, the mean (SD) tumor size was 5 (1.2) cm (range, 2-7 cm).The patients achieved a clinical complete response after concurrent chemoradiation in 18 cases (33.5%). Pathologic residual tumor was noted in 36 cases (67%); tumors smaller than 1 cm were found in 18 cases (33.5%), and lesions greater than 1 cm were observed in 18 cases (33.5%). Factors being associated with a significant decreased sensitivity to neoadjuvant chemoradiotherapy were the following: menopause (P = 0.012), parametrial invasion (P < 0.001), lymphvascular space invasion (P = 0.003), and mucinous subtype (P = 0.001).Conclusions:Identification of predictive markers associated with incomplete response to neoadjuvant chemoradiotherapy in cervical adenocarcinoma may prove clinically useful and implement an individualized treatment plan.

Objective Lobular intra-epithelial neoplasia (LIN) is a rare breast disease that has been regarded alternately as a risk factor for invasive breast cancer in both breasts or a true breast cancer precursor. The controversy is largely dependent on the estimation of the IBC (Invasive Breast Cancer) risk after LIN; however a systematic review of the published data has not been previously performed. We aimed to review the IBC after LIN and the characteristics of those cancers. Methods A PubMed search was performed to identify the published articles in English addressing the breast cancer risk after LIN. Results There was a wide range in the figures estimating the risk of the breast cancer among the 22 studies that form the basis of this review. The cumulative average risk of invasive breast cancer (IBC) was 8.7% (range 0–33). It was 4.7% (range 0–25) for the ipsilateral and 4.2% (range 0–16) for the contralateral breast. 52% of the breast cancers occurred more than 10 years after the initial LIN. A lobular histotype was present in 30% (range 0–67%) of all IBC. Conclusions LIN should be considered both as a risk factor (low and similar level of IBC risk for both breasts, long delay between LIN and IBC) and a precursor for IBC (over-representation of lobular histotype).

Background Suboptimal aesthetic outcomes after conservative therapy for breast cancer are not uncommon, with reported rates up to 30 percent, of which 5 percent may be considered severe. With radiotherapy being an essential component of breast-conserving therapy, surgical correction of deformities is challenging, and guidance as to reparative technique selection is currently limited. Methods One hundred forty-one patients have undergone surgical correction of breast-conserving therapy-induced deformity since its inception at our institution in 1991. This consecutive series has been analyzed with respect to surgical procedure, complications, revisional surgery, and aesthetic outcome (with a five-point scale) to July of 2008. Results The overall aesthetic result was considered to be at least satisfactory in 94.5 percent at 1 year and in 88.8 percent at 5 years. Secondary surgery was required in 19.1 percent and a third procedure was required in 6.4 percent. Complications were encountered in 14.2 percent. A classification into five grades of deformity was found to be practical and effective for surgical planning. Conclusions Reparative surgery for aesthetic deformity in scarred and irradiated breasts is able to produce satisfactory aesthetic results; however, revisional surgery and complications are not inconsiderable, and the authors hope the new classification based on their long-term experience will provide practical guidance for surgical planning to other surgeons encountering such patients.

To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations: histological staging (P less than 0.00001), preoperative serum carcinoembryonic antigen concentration (P less than 0.002), DNA content (P less than 0.009), and allelic loss on the short arm of chromosome 17 (P less than 0.002) and 1 (P less than 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P less than 0.0001 and P less than 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered. (Gastroenterology 1992 Apr;102(4 Pt 1):1136-41)

BACKGROUND Potentiation of the antitumor activity of fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase, fluorodeoxyuridine monophosphate, and methylene tetrahydrofolate, which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C-6 carbon of the pteridine ring. Only the levorotatory (6S)-stereoisomer of folinic acid is transformed into active folate cofactors. However, the (6R)-stereoisomer of folinic acid is not inert; it was shown to interfere with the (6S) form at the cellular level. PURPOSE The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out a phase I-II study of 5-FU combined with the (6S)-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. We also determined the plasma pharmacokinetics of folates after intravenous (IV) injection of (6S)-folinic acid at the dose used in this study. METHODS Treatment consisted of 5-FU (350-550 mg/m2 per day by IV infusion for 2 hours) and (6S)-folinic acid (100 mg/m2 per day by IV bolus injection) given for 5 consecutive days; the treatment was repeated every 21 days. Twenty-five patients with advanced colorectal carcinoma, who had had no prior chemotherapy, were evaluated for antitumor activity. The quantity of folates in plasma was measured using a microbiological assay. RESULTS The median follow-up time was 9 months (range, 3.5-15.2 months). The response rate was 52% (complete response, 12%; partial response, 40%). The median time to disease progression for responding patients was 9.2 months (range, 5.9-15+ months). The estimated probability of survival at 12 months was 73%. Palliative improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects were grade 3 diarrhea, dermatitis, and oral mucositis. Grade 4 toxicity did not occur. Myeloid toxicity was minor. After IV injection, (6S)-folinic acid was rapidly cleared from plasma (mean half-lives: alpha = 7.2 minutes and beta = 126 minutes). The mean concentration of the unchanged compound 2 hours after injection was 5.8 mumol/L. CONCLUSION The (6S)-form of folinic acid potentiates the antitumor effect of 5-FU given concomitantly. IMPLICATION Our results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines.