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e12582 Background: It has been demonstrated an increased risk of breast cancer (BC) incidence in patients with previous cervical dysplasia, suggesting a role of human papillomavirus (HPV) of cervical lesions in the development of BC. Although, the origin of HPV spreading to the mammary gland and its mechanism of dissemination is not clear. Methods: Seven serum samples from healthy donors and 58 from early BC patients collected pre-surgery were analyzed for the presence of HPV DNA. For 49/58 patients HPV DNA was analyzed also on the primary tumor tissue. 17 patients had luminal A BC (4 relapsed, 13 non relapsed), 16 had luminal B BC (5 relapsed, 11 non relapsed), 13 had triple-negative BC (6 relapsed, 7 non relapsed), 12 had HER2-positive BC (4 relapsed, 8 non relapsed). Circulating DNA was extracted from 500 μl of serum by Qiamp DNA Mini kit (Qiagen, Milan, Italy) and tumor DNA was extracted from at least four 10-micron sections by QIAamp DNA FFPE Tissue Kit (Qiagen, Milan, Italy). Circulating HPV DNA was amplified by a multiplex PCR with HPV E6 or E7 gene-specific primers and the sequence was assessed by a high-throughput MALDI-TOF mass spectrometry-based method. Results: HPV DNA was detected in only 5 serum of BC patients and in none of the healthy controls. 4/5 BC cases had high-risk HPV DNA (type 39,45,52,59) and 1 had type 73 low-risk HPV DNA. 4/5 HPV DNA-positive patients had previously low-grade cervical intraepithelial neoplasia (CIN I) detected by Pap smear. These 5 patients with circulating HPV DNA did not show HPV positivity in the BC tissue. 2 out of 49 cases were positive for universal HPV DNA sequence in tissue and only 1 case showed HPV type 51. No relation was found between HPV infection and tumor subtype or prognosis, neither for HPV DNA positivity between serum and tissue. Conclusions: Our data support the feasibility of HPV DNA detection by liquid biopsy in BC. The presence of circulating HPV could be due to a viral spread from other organs. More data are needed to establish the role of circulating HPV DNA and its potential association with HPV infection of the breast and/or of the cervix. [Table: see text]

545 Background: The prognostic role of progesterone receptor (PgR) in highly proliferating early breast cancer (BC) is not well established. We retrospectively explored this biomarker in a cohort of patients with highly proliferating tumors enrolled in a phase III trial of adjuvant therapy. Methods: 1066 patients with N- or 1-3 N+ BC were randomized to receive: epirubicin followed by CMF, CMF followed by epirubicin, or CMF alone. Rapidly proliferating tumors were defined by thymidine labeling index (TLI) > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%. We analyze the subgroup of 466 patients with hormone receptor (HR)-positive tumors treated with sequential epirubicin/CMF regimens followed by tamoxifen and for whom immunohistochemical assessments of estrogen receptor (ER), PgR, HER2 and Ki67 were available. Disease-free (DFS) and overall survival (OS) curves were built with the Kaplan–Meier estimator and compared by logrank test and Cox regression models. Results: PgR expression was significantly associated with ER expression, HER2 status, age and menopausal status, but not with Ki67, tumor size and nodal status. PgR cutoff values of 10% and 20% were chosen based on a Receiver Operating Characteristics analysis and the literature data. DFS and OS figures at 5 and 10 years, as well as the relative hazard ratios, according to the different PgR cutoff values, are reported in the table. Conclusions: Our results confirm the prognostic relevance of PgR expression in a cohort of patients with highly proliferating, HR-positive early BC treated with adjuvant chemotherapy and endocrine therapy. [Table: see text]

1042 Background: The androgen receptor (AR) is widely expressed in breast cancers but its role in estrogen receptor (ER)-positive tumors is still controversial. However, the AR/ER ratio may impact prognosis and the response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced breast cancer (ABC). We evaluated patients treated with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy. ER, progesterone receptor (PgR), Her2, Ki67 and AR expression was determined by immunohistochemistry. A cut-off of < 1% immunostained cells was used to categorize AR expression. AR expression was analyzed in relation to the other conventional biomarkers (ER, PgR, Her2 and Ki67), best response (CR, PR, SD, PD), and time to progression (TTP) (months). TTP was estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios and their 95% confidence intervals (95% CI) were estimated using the Cox regression model. The Chi-square test was used to evaluate correlations between categorical variables and best response. p values < 0.05 were considered statistically significant. Results: Of the 102 evaluable patients (93% were treated with an aromatase inhibitor), biomarkers were assessed in primary tumors in 70 cases, in metastases in 49 and in 17 in both). Median TTP was 17 months (95% CI 14-21.5, median follow-up 75 months). The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR expression. Differences in TTP according to AR status were not statistically significant. AR/PgR ≥ 0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.030). AR status in primary tumors or metastases was not associated with PD as best response. In contrast, Ki67 > 20% and PgR < 10% showed a significant association with PD as best response. Using a cut off of ≤10% for AR expression, results did not change. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in ABC. Ki67 and PgR exert a greater impact on the efficacy of hormone therapy than AR.

e23081Background: Conventional biomarkers used to define breast cancer (BC) subtypes are not always capable of predicting prognosis. Thus, the search for new biomarkers that can be easily detected ...

600Background: Conventional anthracyclines are particularly active in HER2-positive breast cancer (BC), but their use concomitantly with anti-HER2 agents is limited by cardiotoxicity. Pegylated lip...

e22227 Background: Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Thus, the search for biomarkers capable of identify...

2017 Background: Adult glioblastoma (GBM) is the most common type of malignant primary brain tumor. Despite advances in treatment, median survival is between 12 and 15 months. Standard care is conc...

e22028 Background: To date, studies conducted on circulating tumor cells (CTCs) and early breast cancer (EBC) have shown a CTC-positivity rate ranging from 9.4% to 48.6%. Although correlated with w...

e11521 Background: Commonly used biomarkers (ER, PR, HER2, Ki67) are thought to identify BC subtypes with different sensitivity to ET, but data on this are scarce for the metastatic setting, where changes in receptor status between primary tumor (T) and matched metastases (M) are reported. We investigate PR and Ki67 on T and M as predictors of clinical benefit from 1st line ET in mBC. Methods: We identified mBC patients (pts) treated in our Center with 1st line ET (2002-11), excluding those receiving concomitant chemotherapy (CT) or trastuzumab or pretreated with >2 lines of CT. PR and Ki67 were scored as IHC percentage of positive cells, with a cut-off of 20% for high vs low. Clinical benefit was evaluated by time-to-progression (TTP). Results: We identified 137 pts, median age 58 (29-85), only 28% with visceral metastases. ER was >50% in 94%, HER2+ in 17.5%. With 93% receiving an aromatase inhibitor, median TTP was 14 months (median follow-up 43 months). In 34 pts with Ki67 available from T and M a strong correlation between the 2 was shown (Spearman: 0.69, p20% on T (with a similar trend on M, n=58; p=0.06). In 48 pts with PR scored on T and M only a weak trend for correlation was found, with a discordant classification (≤ or >20%) in 44%. More than the score on T (n=118), PR on M (n=64) was a strong predictor of median TTP: 12 months for PR ≤20% vs 22 months for PR >20% (p=0.02). Pts with PR≤20% + Ki67>20% on M had a median TTP of only 4 months, vs 21 months for PR>20% + Ki67≤20%, vs 14 months for either PR>20% or Ki67≤20% (p=0.006). In a multivariate Cox analysis with clinical data and biomarkers from T, visceral disease and HER2 positivity were significantly associated with the risk of progression (HR 2.22 and 2.07, respectively). With biomarkers from M, the risk of progression correlated with relapse ≤5 vs >5 years from surgery (HR 3.48) and PR ≤20% (HR 2.47, p=0.01). Conclusions: In an ER-high population, PR >20% on M identifies pts with a long TTP on ET. Ki67 on T or M can also contribute in estimating the expected benefit, but an independent prognostic role could not be fully confirmed in this small cohort.

e16530 Background: In Tanzania, cervical cancer is the leading cause of death after breast cancer, with the majority of tumors diagnosed at a very advanced stage. Little information is available on the characteristics of cervical cancer in Sub-Saharan African women. We aimed to evaluate histopathological features of cervical cancers and relative margins in a group of African women and to characterize HPV infection. Methods: Tissue samples from32 Tanzanian women with invasive cervical cancer were evaluated in the Biosciences Laboratory of our Institute (IRCCS IRST, Meldola, Italy) as part of a global cancer control project currently ongoing in close cooperation with the Bugando Medical Center of Mwanza, Tanzania. Results: 24/32 (75%) women had squamous carcinoma and 4/32 (12.5%) had adenocarcinoma of the cervix. The HPV test was performed in the entire series but DNA amplification by pyrosequencing was only possible in 27/32 (84.4%). The presence of HPV infection was confirmed in 26/27 (96.3%) cases in both tumor and relative margins. Typization of the virus revealed that a high percentage of the women had HPV 16 virus of whom 12 (46.2 %) had African type 1 and 4 (15.4%) African type 2. Conclusions: A major problem in the cancer tissue samples from the Tanzanian patients was the poor evaluability of DNA amplification due to suboptimal fixation which compromised tissue morphology. Our preliminary study shows that cervical cancer in Tanzanian women is characterized by a very high frequency of HPV-positive tumors, with a high prevalence of HPV 16 African type 1 and 2 infections. The substantial number of HPV infections could explain the high rate of cervical cancer and subsequent mortality in this African population. [Table: see text]

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF 240 mg/m2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.

1031 Background: Anthracycline-containing regimens are considered superior to cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant therapy for early breast cancer, but predictors of a...

e11566 Background: Patients who experience at least some degree of neutropenia whilst receiving adjuvant chemotherapy for breast cancer show improved survival. Tumor proliferation is a prognostic m...

673 Background: Amplification of c-myc is found in about 15% of breast cancers, half of which show HER2 coamplification. c-myc protein regulates cell proliferation, differentiation and apoptosis, but its prognostic impact remains controversial and varies on the basis of levels of cyclins and growth factors. Methods: c-myc amplification was retrospectively assessed in 67 consecutive HER2-amplified primary breast cancers (PBCs) and in 70 HER2-negative PBC controls using fluorescence in situ hybridization. We evaluated the correlation between c-myc and HER2 amplification, the association between c-myc amplification and pathological features such as estrogen receptors (ER), progesterone receptors (PgR), grade, tumor size, and lymph node metastasis, and the impact of c-myc and HER2 amplification on disease-free survival (DFS) and overall survival (OS). Correlations among qualitative variables were assessed using the chi-square test, while DFS and OS were estimated by the product-limit method and compared using...

560 Background: Antimetabolites are active in proliferating cells, and the adjuvant schedule CMF is highly effective in RPBC, whereas the sequential administration of doxorubicin (D) and CMF is superior to CMF–>D, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant E followed by CMF is superior to the inverse sequence in RPBC. Methods: Patients with N-, T > 1 cm or ≤ 3 N+ and any T RPBC (defined by thymidine labeling index or grade or S-phase or Ki67/MIB1) were randomized to receive E (100 mg/m2 i.v. d 1, q 21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 4 cycles) (arm A) or CMF followed by E (arm B) or CMF (600, 40, 600 mg/m2 i.v. d 1 and 8, q 28 days for 6 cycles) (arm C). Arm C was closed after the EBCTCG 2000 meta-analysis (data not shown). The main endpoint was overall survival (OS), and the study had 80% power to detect a 7% absolute increase in 5-year OS with 400 patients per arm. Results: From November 1997 to December 2004, 1066 patients were enrolled (arms A/B/C: 440/438/188): N- 53%, estrogen receptor positive 63%, grade 3, 77%. At a median follow up of 69 months, 5-year disease-free survival was 80% in both arms (A and B) (p = 0.93, logrank test), with adjusted hazard ratio (AHR) 0.99 (95% CI 0.73–1.33, Cox model), and OS was 91% in arm A and 93% in arm B (p = 0.66, logrank), with AHR 0.88 (95% CI 0.58–1.35, Cox model). Adverse events were similar, apart from a small increase in grade 4 neutropenia in arm B. Conclusions: No relevant differences in clinical outcome were observed with the 2 different sequences. Further subgroup analyses are ongoing to verify the efficacy of each sequence as a function of biomolecular and hormonal profiles. No significant financial relationships to disclose.