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Introduction: To determine whether the levels of expression of 17 candidate genes were associated with locoregional control after breast conserving treatments of early-stage breast cancers in young, premenopausal women.Methods: Gene expression was measured using RT-PCR in the breast tumors of a series of 53 young (≤40 years), premenopausal patients. All treatments consisted in primary breast conserving surgery followed by whole-breast radiotherapy (+/- regional lymph nodes) with or without systemic treatments (chemotherapy +/- hormone-therapy). The median follow-up was 10 years.Results: The 10-year locoregional recurrence rate was 70% (95% CI 57%-87%). In univariate analysis, no clinical/pathological prognostic factors were found to be significantly associated with a decreased loco-regional control. Expression of three genes was found to be significantly associated with an increased loco-regional recurrence rate: low estrogen receptor beta, low aromatase, high GATA3. Two others were associated with only a trend (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6035.

BackgroundWe have recently shown that pT1ab HER2 positive tumors carry a poor prognosis, which may be alleviated by trastuzumab (T) based therapy (Rodrigues et al, ASCO 2009). We had also reported that heterogeneous expression of HER2 (hetHER2) may be associated with a poor outcome depending on the HER2 overexpressing subclone (Cottu et al, Ann Oncol 2007). Meanwhile, ASCO/CAP guidelines have questioned the minimum valid score for HER2 expression (Moeder et al, J Clin Oncol 2007; Wolff et al, J Clin Oncol 2007). We describe here the characteristics and outcome of a series of patients with hetHER2 disease.Patients and methodsHER2 status is routinely assessed in our institution in advanced breast cancer patients since 1999, and in early patients since 2002. Out of 1300 HER2 positive cases, we have been able to identify 12 pts with heterogeneous expression of HER2 in the primary tumor ( Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6034.

e22150 Background: Distinction of primary ovarian tumors from metastatic tumors involving the ovary is in some cases challenging for final pathologic diagnosis and for treatment with efficient chemotherapy Methods: We gathered from our biobank 16 pairs of breast/ovarian tumors for some of which the diagnosis was uncertain. We investigated the possibility to improve diagnosis using genomic and transcriptomic tools. The pangenomic profiles of 16 pairs of primary breast carcinoma and ovary tumors (primary tumors or metastases from breast carcinoma) from the same patients were analyzed using the Affymetrix GeneChip Mapping 50K (XbaI) SNP arrays. The data were normalized with ITALICS algorithm. We analyzed the transcriptome of the paired samples using Affymetrix U133plus2 arrays. The data were normalized with GCRMA algorithm and a hierarchical clustering of these samples was performed, together with a dataset of primary and secondary ovary tumors. Results: Primary infiltrating lobular carcinoma (ILC) was observed in 6 patients, infiltrating ductal carcinoma (IDC) in 7 patients, 1 patient had one ILC and one IDC, 1 patient had a mixed IDC+ILC and 1 patient an undifferentiated cancer. All patients received adequate loco-regional and systemic therapies. Median time to diagnosis of ovarian tumor was 54 months. Ovarian tumors were considered as primary in 7 patients, and metastatic in 9 patients, and diagnosis was ambiguous in 4 of them. Four patients developed extra-abdominal metastases. Median survival from breast cancer diagnosis was 78 months, and from ovarian tumor diagnosis was 29 months. CGH array: In 12 pairs, the comparison of genomic profiles one with each other, confirmed the pathological characteristics of the tumors. In 4 cases, the genomic profiles established clearly the status of the ovary tumor whereas the pathological analysis did not. Transcriptome: The status established by the transcriptomic analysis was for each sample in total agreement with the status established by the genomic analysis. Conclusions: We clearly established in this training series that CGH array analysis could help to discriminate between primary and secondary ovarian tumors from breast cancer. Transcriptomic data confirmed these results. Further validation data are warranted. No significant financial relationships to disclose.

5572 Background: M-AEOC have been consistently associated with worse prognosis than the most common serous (S) histologic subtype; however it is unclear if this observation is related to more aggressive clinical presentation and/or chemoresistance behaviour. Methods: Data from four randomized phase III and one phase II AEOC first-line clinical trials were collected and retrospectively analyzed. Study selection criteria included: completed study, platinum-based chemotherapy and stage IIB to IV AEOC patients (pts). Results: Data on 1118 pts with advanced AEOC were analysed, of whom 94% were treated with paclitaxel-carboplatin-based CT. 786 pts had S-AEOC and 54 pts M-AEOC (5%). Peritoneal metastasis (mets) appeared more limited in M- than in S-AEOC pts since stages IIB-IIIB were more frequent (31% versus 19%, p = 0.001) and complete resection more frequently obtained (45% of stage II-III pts versus 29%, p = 0.06) in M-AEOC. Extra-peritoneal mets (stage IV) were more frequent in M- than in S-AEOC pts (30% versus 15%, p = 0.004), specially liver mets (44% of stage IV pts versus 23%, p = 0.06). Progressive disease during CT was observed in 40% of pts with stage IV M-AEOC. Progression free survival (PFS) was worse in M- than in S-AEOC pts both in stage IV (1y PFS: 15% versus 51%, p = 0.02) and in stage III with optimal resection (2y PFS: 42% versus 66%, p = 0.05). Conclusions: Compared to S-AEOC, M-AEOC is characterized by more limited peritoneal carcinomatosis but more frequent liver mets. M-AEOC appears to be a highly chemoresistant disease and complete resection of peritoneal mets is unable to reverse its adverse prognosis. New therapeutics options are needed. No significant financial relationships to disclose.

517 Background: Trials have shown benefit of adjuvant trastuzumab (TZM) for node-positive (N+) or supra-centrimetric HER-2+ breast carcinomas. There are limited data concerning infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). These tumors are being recognized as a high-risk group among all T1a/b tumors. Methods: Retrospective multicenter series from 2000 to 2008 of infra-centimetric HER-2+ invasive breast carcinomas (InfraHER-2). Tumors with ≥80% of ductal carcinoma in situ, multifocal and metastatic tumors were excluded. Results: 96 cases have been evaluated, 75 were node negative (N- InfraHER-2). All patients had surgery. 57% (n = 43) had a sentinel lymph node procedure. 73% (n = 55) had a local irradiation and 36 a tumor bed boost. Nodal irradiation of internal mammar and infra/supraclavicular regions was done in 20% and 17% respectively. 44% (n = 33) had chemotherapy (CT), almost all (31) were associated to TZM. Anthracycline-based (A), taxane-based (T) and A/T combinations were chosen for 54%, 4% and 42% respectively. One patient developed myocardial infarction after A resulting in heart failure; 2 had a transient left ventricular ejection fraction decrease below 50% after TZM. Decision of adjuvant CT was associated (all p < 0.05) with hormonal receptors (HR) negative status, Elston-Ellis grade (EE) 2/3 and high mitotic index (MI) while patients with HR+/low MI tumors were rarely treated (p < 0.001). 32/39 HR+ patients received hormonotherapy (80%); 21 received aromatase inhibitors, 6 tamoxifen and 5 LHRH agonists. With a 25 months median follow-up, there was no invasive recurrence in TZM treated patients. 3 of the 44 patients treated without TZM nor CT (7%) had local or metastatic recurrence including one fatal; they had initially HR- EE 2/3 T1b tumors. Conclusions: In our practice, decision of TZM-based therapy for InfraHER-2 N- tumors is associated with high-risk profile. Indeed, N- InfraHER-2 tumors may have a significant risk of recurrence which could be avoided by adjuvant TZM. Patients with N- InfraHER-2 tumors should be included in HER-2-targeted adjuvant trials. [Table: see text]

Abstract #2039 Background: Invasive lobular carcinomas (ILCs) of the breast are characterized by morphological and phenotypical features such as small, non cohesive, estrogens receptors positive cells, low proliferation rates with a metastatic spreading in numerous and different unusual metastatic sites as compared to invasive ductal carcinomas (IDCs) (Ferlicot et al, 2004). We have previously shown that ILCs presented the same outcome than IDCs (Sastre-Garau et al, 1996). Beyond E-cadherin genomic inactivation, little is known about the underlying genomic and transcriptomic alterations that may discriminate both subtypes. Aims of the study: To get an insight into ILC biological specificities, we performed a combined genomic (aCGH), transcriptomic (Affymetrix U133A+B) and phenotypic analysis of a series of 24 lobular carcinomas and compared it to a series of 41 ER-positive IDCs. Results: Analysis of genomic copy number showed that ILCs and IDCs shared gains of the 1q11-q43 region and losses of 16q12.1-q24.2 and 17pter-p13.1 regions. ILCs presented the 22q12-q13 loss but not the 16pter-p11.2 gain and 11q23-q24 loss as observed in IDCs. Eight different regions of high level amplifications were found in 29% of ILC cases (7/24 cases). Only one region of amplification was recurrent and observed in 5 out of 24 tumors (21% of the cases). This recurrent region of amplification was localized on the 11q13.2 region and encompassed the Cyclin D1 (CCND1) and Cortactin (CTTN) genes. ILCs and IDCs had comparable overall survival rates, however, unsupervised hierarchical clustering of transcriptomic data showed that ILCs and IDCs clustered apart. Genes involved in cell adhesion and motility, lipid/fatty transport and metabolism and electron transport were differentially expressed between the two groups. Conclusions: This integrated analysis emphasized the biological differences between ILC and IDC and highlighted genes of interest that could be useful for diagnosis, and could be new putative therapeutical targets. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2039.

Abstract #3152 Background: According to the adjuvant trastuzumab (T) trials, node-positive infracentimetric tumors stand for around 7% of all HER2+ breast carcinomas. The benefit of adjuvant T for women with node positive or supracentrimetric HER2+ breast tumors is established. There are no firm data establishing efficacy of T for infracentrimetric node-negative HER2+ tumors. We report our experience on infracentimetric tumors describing the received treatment, its efficacy and tolerance and the criteria that lead to therapeutic decision. Methods: We retrospectively reviewed electronic records of patients (pts) with invasive infra-centimetric HER2+ breast tumors treated in our institution from 2000 to 2008. Clinical, pathological, biological and therapeutic data were assessed. Tumors with a majority (≥80%) of ductal carcinoma in situ (DCIS) were excluded from this analysis. Results: 43 case records have been evaluated. Median age at diagnosis was 56 years (31-84). All tumors were treated by local surgery. 11 pts (26%) had node-positive tumors when including pN0i+ and pNmi+ tumors. 9 pts (82%) had local irradiation. A majority (n=8, 73%) were treated by chemotherapy and T except 1 with a pN0i+ tumor and 2 pts treated before T approval (2000-2001).32 pts (74%) had pN0 tumors. Ductal carcinomas accounted for 91% of tumors (n=29), and 14 (44%) were hormonal receptors-negative. Radiotherapy was given in 28 (88%) of them. 8 (29%) had nodal irradiation covering internal mammar chains, infra and supraclavicular regions. 21 of these pts (75%), had a 16 Gy breast tumor bed boost. Half the pts had chemotherapy (n=16). A sequential anthracycline/taxan (ATx)regimen was chosen for 10 pts (63%). Other regimen were A-based for 5 pts (31%) and Tx-based for 1 pt (6%). 1 pt developped myocardial infarction after her third anthracycline cycle. 22 pts (69%) have been treated with T. 13 of them have been treated by a chemotherapy/T (59%) combination. No significant correlation was found between decision of systemic treatment and age, hormone receptor status, grade, mitotic index or lymphovascu lar emboles. T treatment was complicated for 2 pts (13%) by left ventricular ejection fraction diminution under 50% after 5 and 6 months.With a median follow-up of 18 months, none of the 43 pts have developed recurrent invasive disease. In one pure micropapillary case, in situ local recurrence with micro-infiltration was seen at 5 years.Conclusion: In our experience, almost all pts were treated by local surgery and radiotherapy and around half pts received T since its approval with no significative clinical nor pathological factor leading to this decision. Usefulness of adjuvant chemotherapy and T for this tumors should be analyzed with data from prospective ongoing or closed trials. Systemic adjuvant treatment should be proposed for stage II tumors and discussed for smaller tumors taking into account age, grade, mitotic index, hormonal receptors status and presence of vascular invasion. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3152.

16599 Background: Breast cancer often metastasizes to the ovary. Pathological differential diagnosis between primary ovarian carcinoma and breast cancer metastases may be difficult. We developed a ...

839 Background: We have previously reported the results of 2 gemcitabine-oxaliplatine (gem-ox) combinations in advanced breast cancer (Proc ASCO 2003 #310; Caruba et al). We present here updated Results: Methods: Patients with previously treated metastatic breast cancer (MBC) were eligible. Prior utilisation of anthracyclins and taxanes was mandatory. Two schedules were tested. Schedule A: gem D1 and ox D2 on a q2w schedule. Schedule B: gem D1–8 and ox D1, on a q3w schedule. In each schedule, administered doses were 1000 mg/m2 for gem, and 100 mg/m2 for ox. Results: 43 patients were included, respectively 21 and 22 for schedules A and B. 31/43 pts (72%) had multisite MBC, and all pts but 1 had received at least 2 lines of chemotherapy for metastatic disease. Pts characteristics were very close for both schedules. Objective Response Rate (WHO criteria) was 7.5% in 40 pts who were evaluable for response, Stable Disease was observed in 27.5% of those pts. Median TTP was 12 weeks for all patients, and was 42 ...

5023 Background: OXA is active in mismatch repair (MMR) deficient cells, a condition prevalent in pretreated AOC. OXA/P shows high activity in investigator initiated studies (Faivre et al, Ann Oncol 10:1125, 1999). We evaluated efficacy and safety of OXA/P in AOC pts with clinically evaluable disease pretreated with 1 platinum based regimen ± taxanes and a progression-platinum-free interval (PPFI) ≥6 months (mo). Methods: From Dec 99 to Apr 02, 105 pts, 14 centres received P 175 mg/m2, 3h iv followed by OXA 130 mg/m2, 2h iv, every 3 weeks, for up to 9 cycles (cy) without G-CSF. Median (m) age: 58 years (range 37–83), 96% PS 0/1. PPFI: 69 pts >12 mo, 34 pts 6–12 mo; 80 pts (76%) taxane-pretreated. Results: 708 cy administered; m 7 cy/pt (1–9). Relative dose intensity: OXA 0.95, P 0.97. Efficacy: 98 pts eligible, 7 non-eligible (3 bowel occlusion, 3 >1 prior platinum-based chemotherapy, 2 PPFI not determinable). 98 pts evaluable for response (see table) ORR: 81% (95%CI 71–88), all but 3 responses third part...