5564 Background: Irinotecan and bevacizumab have single agent activity in both platinum sensitive and resistant recurrent ovarian cancer. We sought to evaluate the efficacy and safety of the combination in this setting. The primary endpoint is to estimate the progression free survival (PFS) at 6 months. Secondary objectives include overall survival (OS), observed response rate (ORR), duration of response, and toxicity. Methods: Ovarian cancer patients with recurrence after any number of prior regimens were eligible. Irinotecan 250 mg/m2 (amended to 175 mg/m2 after treatment-related toxicities in the first 6 patients) and bevacizumab 15 mg/kg were administered every 3 weeks until disease progression or toxicity. Response was assessed by RECIST every 2 cycles and by CA-125 criteria for those without measurable disease. Results: Of the 29 patients enrolled, 10 were platinum-sensitive and 19 were platinum-resistant. The median number of prior regimens was 5 (range 1-12): 13 patients had prior bevacizumab and 11 patients prior topotecan. The median number of study cycles given was 7 (range 1-34); 5 patients withdrew after 1 cycle (3 due to toxicity). Of the 24 patients assessable for response, 8 patients experienced partial response (PR), 13 maintained stable disease (SD), and 3 had progressive disease; 12 patients with PR/SD were platinum resistant. The ORR was 27.6% (95% CI: 0.127-0.472) and the clinical benefit rate was 72.4% (95% CI: 0.565-0.873) for the intention-to-treat population (n=29). Twelve patients had longer than 6 months of sustained response. Median PFS was 8.1 months (95% CI: 5.1-12.3 months); median OS was 15.9 months (95% CI: 13.4 months- upper bound not reached). The PFS rate at 6 months was 55.2% (95% CI: 0.397-0.766). The most common grade 3/4 toxicities included diarrhea (5 pts), neutropenia (3), hypertension (3), proteinuria (2), fatigue (2), nausea (2), abdominal pain (2), and GI perforation (1). No treatment-related deaths were observed. Conclusions: The combination of irinotecan and bevacizumab showed encouraging activity in heavily-pretreated patients with recurrent ovarian cancer. The median PFS of 8.1 months is comparable to other bevacizumab-containing doublets reported in the AURELIA trial. Clinical trial information: NCT01091259.

541 Background: Most of BC express the AR, and this is considered to be a good prognostic factor. However, AR signalling has also been implicated as a possible mechanism to aromatase inhibitors (AIs) resistance. Cell line models suggest a switch from estrogen to androgen-dependent growth as they become resistant to estrogen deprivation therapies. The goal of this study is to examine, in vivo, changes in AR and its phosphorylated sepecies during AI therapy, and to assess its potential role in outcome. Methods: Eighty four, consecutive, postmenopausal women, stage II-III primary estrogen receptor positive BC, were treated, in the same institution, with preoperatory letrozole between 2005 and 2012. Pre- and post-treatment BC tissues were examined by inmunohistochemestry for total AR and the phosphorylation of AR at serine 213 (pAR-S213) and serine 650 (pAR-S650). Results: Letrozole decreased the expression of pAR-S213, that was positive (H-score≥10) in 65% of pre-treatment samples vs 30% of post-treatment samples (p=0.001). No changes were observed for total AR (90% pre- vs 88% post-) and pAR-S650 (39% pre- vs 41% post-). Only pAR-S213 positivity after treatment was associated with a decreased rate of relapse free survival at 55 months (post-pAR-S213 negative: 90% vs post-pAR-S213 positive: 60%, p=0.0004), and remained significantly associated in a multivariate analysis including classic prognostic factors (PEPI score, Ki-67, ypTNM, ER). Conclusions: High expression of pAR-S213 after treatment with letrozole is associated with poor outcome, which suggest the possibility of therapeutic intervention with antagonist of AR activation.

While a prominent role for HE4 in these areas remains to be determined, this thorough review of HE4 demonstrates that the biomarker is complementary to, and occasionally more useful than, the widely used CA 125 in the management of gynecologic malignancies.

Background: Unresectable breast cancer chest wall recurrence (CWR) following radiation is very difficult to treat and often responds poorly to standard chemotherapy. Symptoms include pain, reduced range of motion, disfigurement, and skin erosions with bleeding and infection. We hypothesized that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD, ThermoDox®), given with mild local hyperthermia (MLHT) would be a safe and effective targeted therapy. LTLD is given by iv infusion; it then localizes in CWR tumors due to their leaky vasculature. When heated to ≥ 39.5°C, LTLD releases a high concentration of the heat-enhanced cytotoxic doxorubicin. Methods: The results of 2 similarly-designed independent phase I trials were combined for analysis. Eligible patients had CWR progressing after radiation, hormone therapy, and chemotherapy. Subjects were to get up to 6 cycles of LTLD every 21-35 days, followed immediately by chest wall MLHT for 1 hour at 40°- 42°C. In Trial A, 18 subjects received LTLD at 20, 30, or 40 mg/m 2 ; in Trial B, 11 subjects received LTLD at 40 or 50 mg/m 2 . The primary endpoint of each trial was to determine the maximum tolerated dose (MTD); secondary endpoints were local objective response and the pharmacokinetic (PK) and safety profiles of LTLD. Local response was assessed by serial photography and measurements of CWR. PK samples for total plasma doxorubicin and doxorubicinol were collected at Cycle 1 and Cycle 2 for both trials. Results: Twenty-nine subjects were enrolled and received ≥ 1 cycle (median 4, range 1-6). Median age was 57; 16 (55%) had triple negative disease and 13 (45%) had distant metastases. The median prior exposure to anthracylines was 256 mg/m 2 and the median prior dose of radiation was 6,100 cGy. Thirteen subjects were evaluable for MTD in Trial A and 9 in Trial B. Trial B established a phase II dose of 50 mg/m 2 recommended by a Data Safety Monitor Board, based on 1 of 6 subjects at the 50 mg/m 2 dose level having a DLT (grade 3 hypokalaemia unrelated to study treatment). In Trial A, 2 of 7 subjects at 40 mg/m 2 had a DLT (grade 4 neutropenia lasting > 5 days; grade 3 dehydration lasting 27 days). The C max concentrations between 18,400 to 20,700 ng/mL were consistent at an equal dose level (40 mg/m 2 ) between trials. Altogether, 7 (24%) subjects developed reversible grade 3-4 neutropenia and 4 (14%) reversible grade 3-4 leukopenia. No cardiac toxicity or hand-foot syndrome was seen. One case of CW thermal burn (grade 3) and one case of radiation recall (grade 2) were reported. Five (17%) complete local responses and 9 (31%) partial local responses were seen. The rate of local response was 48% (14/29; 95% CI: 30%-66%). Seven of 29 subjects (24%) progressed outside the study treatment field. Conclusion: LTLD plus MLHT is a novel therapy that is safe and produces objective responses in heavily pretreated CWR patients with limited therapeutic options. The primary toxicity is reversible bone marrow suppression. A phase II trial is ongoing at the MTD (50 mg/m 2 ). Future work should test thermally enhanced LTLD delivery in a less advanced, less heavily pretreated patient population. *Author note-M.W.D. and K.L.B. equally contributed. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-05.

Abstract Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. Clin Cancer Res; 19(17); 4570–7. ©2013 AACR.

Objective: To evaluate molecular and clinical markers previously linked to overall survival for their ability to predict residual disease status following primary surgical cytoreduction in advanced-stage epithelial ovarian cancer (EOC) patients enrolled in GOG trials.

Treatment options for hormone-dependent advanced breast cancer (BC) have evolved from surgical oophorectomy, first proposed over a century ago. The discovery of steroid hormones, steroid hormone receptors and the concept that inhibition of steroid biosynthesis or hormone receptor blockade prevents tumor growth, have been introduced and tested clinically. Today, the aromatase inhibitors are the current standard of care for metastatic hormone-sensitive BC in postmenopausal women. To get to this point, many others drugs have been investigated in the continuing search for improved treatment of advanced BC. Agents as high dose estrogens, progestins, antiprogestins, androgens and somatostatin analogues were tested time ago and novel and promising agents, as fulvestrant or sulfatase inhibitors are currently going through a comprehensive clinical trial program. By reviewing the clinical data on the endocrine therapy of advanced BC, we project those areas of future clinical research, beyond the well-known and established tamoxifen and aromatase inhibitors.

TPS117 Background: Breast cancer recurrence at the chest wall (RCW) typically causes pain, lymphedema, and/or loss of freedom of movement. Lyso-thermosensitive liposomal doxorubicin (LTLD) is a temperature-sensitive liposome that selectively accumulates in tumors due to their leaky vasculature. Doxorubicin is active against breast cancer. Local hyperthermia is lethal to cancer cells; in addition, it selectively increases liposomal permeability in tumor microvasculature, stimulates LTLD to release doxorubicin at the tumor site, and upregulates influx of doxorubicin into tumor cells. LTLD is not associated with congestive heart failure or palmar-plantar erythrodysesthesia. An earlier physician-sponsored phase I trial of LTLD and hyperthermia found that, for subjects treated at ≥ 30 mg/m2, 2 of 10 (20%) had a complete local response. (Jones E. An update of thermally sensitive liposomes for patients with breast cancer chestwall recurrence. Society for Thermal Medicine Annual Meeting, Tucson, AZ, 3-7 April 2009.). Methods: A phase I/II study is now enrolling RCW patients to assess dosing, safety, pharmacokinetics, and efficacy of LTLD/hyperthermia therapy. Eligible patients have RCW tumors < 3 cm deep and have failed standard therapy including surgery, radiation, hormones, and chemotherapy. Subjects are to receive 6 LTLD/hyperthermia treatments at 21-day intervals unless unacceptable toxicity or progressive disease is seen. Hyperthermia may be supplied from either microwave or ultrasound devices. Up to 9 subjects will be enrolled in phase I. LTLD dosing will start at 40 mg/m2 and escalate to 50 mg/m2. LTLD is infused intravenously over 30 minutes; then, within 60 minutes, hyperthermia is administered to the target field. This schedule is designed to optimize the accumulation of LTLD into tumors. The thermal dose goal is 40°C-42°C in > 90% of measured points for 60 minutes duration. In phase II, 100 evaluable patients will be enrolled; with the primary endpoint being the durable (lasting ≥ 3 month) complete local response rate. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celsion Corporation Celsion Corporation Celsion Corporation

© 2009 S. Karger GmbH, Freiburg Accessible online at: www.karger.com/brc Fax +49 761 4 52 07 14 Information@Karger.de www.karger.com … 292 Adjuvant Therapy of Breast Cancer: Can We Do better? Thomssen, C. (Halle/Saale); Janni, JW (Düsseldorf) … 294 Documentation and Communication of Psychooncological Findings in an Interdisciplinary Breast Cancer Center Grimm, A.; Voigt, B.; Georgiewa, P.; Fydrich, T.; Kleiber, D.; Klapp, BF; Rauchfuß, M. (Berlin) … 301 An Analysis of the Use of Complementary and Alternative Therapies in Patients with Breast Cancer Tarhan, MO; Muslu, U.; Somali, I.; Erten, C.; Alacacioglu, A.; Varol, S.; Aslan, SL (Izmir) … 308 A Clinicopathological Evaluation of Male Patients with Breast Cancer Ilhan, E.; Bati, B.; Alemdar, A.; Coskun, A.; Sezgin, A.; Yildirim, M.; Engin, O.; Purten, M. (Izmir) … 315 Reproductive Factors, Steroid Receptor Status, and Tumour Markers of HER2-Positive …

624 Background: P27kip1 is a nuclear protein that controls the cell cycle by inhibiting cyclin dependent kinases. In breast cancer cell lines, both estrogen and her-2/neu degrade p27 through the ubiquitin-proteasome pathway. T1N0M0 breast cancers with high p27 expression have excellent long-term survival (Loda et al, Cancer Research 1998), now we examine the association of low p27 and other prognostic factors in these patients. Methods: 122 T1N0M0 infiltrating ductal carcinoma were examined using immunohistochemistry. Specific monoclonal antibodies were used against estrogen receptor (ER), progesterone receptor (PR), Her-2/neu, p53 and p27. Percentage of cells stained were considered negative (or low for p27) if: ER <10%, PR <10%, p53<40%, her-2/neu DAKO score ≤ 1+, p27 (nuclear stain) <50%. Results: In T1a/bN0M0 tumors, 4/5 (80%) of low p27 tumors were also hormone receptor negative, while only 5/63 (8%) of the high p27 tumors were hormone receptor negative (P< 0.001, Fisher’s exact test). Although T1cN0M0 tumors showed a similar trend [4/12 (33%) of low p27 vs. 7/42 (17%) of high p27 tumors were hormone receptor negative], the difference was not statistically significant. No correlation was seen between low p27, her-2/neu, or p53 mutation. Conclusion: There is an association of low p27 and loss of hormone receptors in T1a/bN0M0 breast cancers, which may identify a subset of patients with a worse prognosis. Exploring the causes of p27 dysregulation (e.g., ubiquitin ligase overexpression) may shed further light on the significance of these associations. [Table: see text] No significant financial relationships to disclose.

5052 Objectives: The aims were to determine whether erlotinib (erl; OSI774, Tarceva), an orally-active selective inhibitor of the EGFR tyrosine kinase, given with paclitaxel (T) and carboplatin (CBDCA) to patients (pts) with ovarian (OC), fallopian tube (FT) or primary peritoneal (PPC) cancers is tolerable, to evaluate response rates and to correlate molecular markers of response. This report addresses the degree and type of toxicity associated with this combined regimen. Methods: Since June 2003, pts with histologically-confirmed Stage III or IV OvC, FTC or PPC received T (175 mg/m2) and CBDCA (AUC 6) every 21 days, along with erl (150 mg) by mouth daily, continuously. Pts had adequate bone marrow, renal and liver function. Informed consent and IRB approval were obtained. Results: We report on 28 pts so far enrolled in this trial. Of these, 24 have completed or withdrawn from study, and four continue treatment. A total of 123 cycles with erl have been analyzed. 16 pts completed the full six cycles of chemotherapy with erl, and 13 have undergone reassessment surgery. Four did not continue on erl following 1, 3, 6 and 1 cycles due to dissatisfaction with the skin changes associated with treatment in three, and allergy in one; these pts did complete the total planned six cycles of chemotherapy. One pt showed disease progression after cycle three and expired. One pt came off study after two cycles due to underlying cardiac issues, and one was lost to follow up after three cycles. Another pt did not receive erl on cycle 1 by error, and was not continued on trial. Among the pts completing therapy, all experienced at least a g1 rash, and three experienced g2 or 3 rash. Severity of rash did not correlate with withdrawal from study, and did not increase with repeated cycles. Three pts had wound-related complications after their initial surgeries. Other side effects noted were not different from those experienced with standard T/CBDCA treatment, and dose modifications or dose delays have been infrequent. Conclusions: The addition of erl to T/CBDCA as a front line regimen for OC and related epithelial cancers is feasible and well-tolerated similar to standard chemotherapy, with the exception of skin rash. No significant financial relationships to disclose.

5114 Background & Objectives: We sought to develop a less toxic combination regimen for use in cervical cancer than cisplatin with paclitaxel. Carboplatin AUC 5 and VNR D1 (IV, 25 mg/m2) & D8 (PO, 60 mg/m2) have been previously studied in chemonaive non-small cell lung cancer (O’Brien et al, Ann Oncol 2004; 15: 921). Methods: Metastatic solid tumor cohort, 3+3 dose escalation design, with standard entry/evaluation criteria and separate escalation based on extent of prior treatment. Common Toxicity Criteria V.3 were applied. Results: L1 accrued 3 extensively pre-treated patients (= or > 3 myelosuppressive regimens and/or radiation): all progressed after 2 cycles with no Grade 3 or 4 toxicities, one Grade 2 neutropenia. At L2, 6 extensively pretreated were evaluable, 1 minimally pre-treated was inevaluable due to withdrawal of consent after C1,d1. Myelosuppression was the prominent toxicity after 2, 2+, 2+, 2+, 3, 8 + cycles. Table 1 shows all hematologic toxicities at L2 dosing level of the 6 evaluable patients. The patient with dose-limiting thrombocytopenia had similar episodes on prior chemotherapy. Responses: 3 patients had stable disease with subjective or marker improvement: breast cancer (1), endometrial cancer (1), and granulosa cell tumor (1). One prostate cancer patient received 8+ cycles, with slowly rising PSA. Conclusions: L2 is the recommended phase II dose and may be suitable for Phase II study in cervical cancer, with potential advantages over IV vinorelbine (absence of phlebitis, decreased tumor pain). No significant financial relationships to disclose.

The Oncologist 2004;9:228-231 www.TheOncologist.com Correspondence: Franco M. Muggia, M.D., Director of Medical Oncology, Kaplan Comprehensive Cancer Center, 550 First Avenue, New York, New York 10014, USA. Telephone: 212-263-6485; Fax: 212-263-8210; e-mail: muggif01@gcrc.med.nyu.edu Received June 9, 2003; accepted for publication October 13, 2003. ©AlphaMed Press 10837159/2004/$12.00/0 INTRODUCTION The emerging roles of screening and prevention in women’s cancer were presented during a symposium hosted by The Lynne Cohen Foundation for Ovarian Cancer Research. The April 26, 2003 meeting, held at the University of Southern California Health Sciences Campus in Los Angeles, was divided into three sessions: Research on High Risk Identification and Preventive Measures; Intervention Outcomes and Psycho/Social Repercussions of Preventive Measures; and Research on Screening and Early Detection: New Methods. This report summarizes the salient presentations and ensuing discussions during these sessions.