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546 Purpose: To evaluate whether estrogen receptor (ER) and HER-2 receptor status in breast cancer is accurately determined using gene expression profiles. Patients and Methods: Gene expression pro...

3117 Background: The anti-apoptotic Bcl-2 protein has been associated with drug resistance in BC cells. Oblimersen sodium (Genasense; G3139; GNS) downregulates bcl-2 expression in target tissues at 2–7 mg/kg/d. Preclinical synergy was reported between GNS and DOX, and between GNS and DOC. This phase I trial was conducted to evaluate the PK and safety of GNS in combination with DOX and DOC in patients (pts) with advanced BC. Methods: GNS was administered as a 5-day continuous infusion. DOX (50 mg/m2) and DOC (75 mg/m2) were given i.v. on day 3. Three dose levels (DL) of GNS were evaluated: DL-I (3mg/kg/d), DL-II (5 mg/kg/d), and DL-III (7 mg/kg/d). Three pts were treated at each DL. During cycle 1 of therapy, serial plasma samples were obtained before and for up to 72 h after the start of each infusion. Plasma doxorubicin and docetaxel concentrations were measured using separate validated HPLC assays (DOX LLQ 1 ng/ml, DOC LLQ 10 ng/ml). Individual PK parameters were calculated using compartmental modeling....

3102 Background: The ubiquitin proteasome pathway plays an important role in cell cycle regulation, cancer growth and metastases representing a novel target for therapy. PS-341 (Bortezomib -Velcade) is a depeptidyl boronic acid inhibitor with high specificity for the proteasome and represents the first agent of this class approved for treatment of hematologic neoplasms. We initiated a Phase 2 single Institution trial testing PS-341 in minimally pretreated metastatic breast cancer (MBC). Methods: Twelve patients (pts) with minimally treated (1 previous regimen) measurable disease were enrolled and treated with PS-341 at 1.5mg/m2 intravenously bi-weekly for 2 consecutive weeks in a 21-day cycle. Pts. were evaluated clinically every 3 weeks to assess toxicity. Correlative studies include: level of 20-S proteasome activity in whole blood lysate before and after 1 hour of administration of the first dose (expressed as specific chymotryptic activity, SpA). Additionally we plan for evaluation of angiogenic and i...

585 Background: Recent publications suggested that extended adjuvant systemic therapy (AST) started 5 years after diagnosis following standard adjuvant therapy further reduced risk of recurrence. Residual risk of recurrence 5 years after state-of-the-art adjuvant therapy is not well defined. Methods: We identified all patients (pts) treated on prospective clinical trials of AST at our institution between 4/74 and 7/98 and who remained without recurrence 5 years after diagnosis. All received postoperative anthracycline-based AST and endocrine therapy when indicated. 5 and 10-year relapse-free survival (RFS) rates were calculated. Results: 2246 pts were registered on 6 AST trials. 839 pts were excluded because of relapse during first 5 years, follow-up < 5years or death without recurrence. The 1407 patients relapse-free at 5 years had a median follow-up of 74 months from the 5th anniversary of diagnosis. 101 had stage I BC, 1104 stage II and 202 stage III; 823 were younger than age 50. 407 had ER/PR-negativ...

520 Background: In patients (pts) with metastatic BC, trastuzumab [Herceptin (H)] in combination with CT results in higher response rates, longer control of disease, and superior survival. The objective of this study was to determine whether the addition of H to CT in the neoadjuvant setting could increase PCR rate in pts with HER/2 positive disease. Methods: 42 pts with HER/2-positive disease (IHC 3+ or FISH +) with operable BC were randomized to 4 cycles of P followed by 4 cycles of FEC, or the same CT with simultaneous weekly H at 2 mg/kg for 24 weeks.The primary objective was to demonstrate a 20% improvement in PCR (assumed 21% to 41%) with addition of H to CT. At the end of CT±H, pts had definitive surgery. The planned sample size was 164 pts. Results: Prognostic factors were similar in the two groups. After 34 pts had completed therapy, the trial's Data Monitoring Committee stopped the trial for superiority of CT + H. PCR rates were 25% and 67%, respectively, for CT alone (n=16) and CT + H (n=18) (P...

Ten patients (pts) with MBC who had primary/secondary resistance to Taxol (135−250 mg/m 2 over 3−24 hours) were treated with Taxotere 100 mg/m 2 every 21 days. Pts characteristics (10) Med age, 47 yrs (37–61); med Zubrod PS, 1 (0−2); med # sites 3 (2−5); disease sites: liver 9/10, bone 4/10, soft tissue/LN 7/10; med # of prior CT was 2 (1−3); 9/10 had prior anthracycline therapy. Results 10 pts were evaluable for response. Responses: 1 MR, 4 NC and 4 PD. Toxicity To date, 10 pts received 30 cycles. Hematological Med nadir granulocytes (×10 3 )/dl: 0.3, med nadir platelet count (× 10 3 )/dl: 236,000. 4 pts had 8 cycles complicated with neutropenic fever. Other toxicity (grade 2 or greater) by # pts f# cycles) stomatitis 3 (5), diarrhea 4 (5), fatigue 8 (14), myalgias 7 (12), skin 5 (9), paresthesias 7 (13). Conclusion The preliminary data of this ongoing trial showed that Taxotere has activity in TRMBC.

We have studied the clinical impact of elective brain irradiation (EBI) in patients with locally advanced, non-small cell lung cancer (LA-NSC). All patients received combination chemotherapy (cyclophosphamide + doxorubicin (Adriamycin) + cisplatin = CAP) or CAP plus radiotherapy as the initial treatment for their active tumor or as an adjuvant therapy. Of 97 evaluable patients, 46 were randomized to receive EBI (3 000 rad in 10 fractions given over two weeks). The characteristics of both groups were comparable by sex, age, performance status, pretherapy weight loss, histologic cell type, clinical staging, and type of prior therapy. EBI significantly decreased the incidence of central nervous system (CNS) metastasis in the treated group compared to the control group (4% vs 27%, p = .002). CNS involvement occurred in the treated group after failure at other sites whereas 12 of 14 control patients had CNS metastases as the first site of relapse. EBI decreased the incidence of CNS metastasis in all prognostic categories. Using multivariate analysis, the beneficial effect was shown to be significant in females, patients with good performance status, weight loss less than 6%, squamous cell histology, state III disease or no prior therapy. EBI significantly increased CNS metastasis-free interval with a beneficial effect that was significant in males, patients with weight loss less than 6%, squamous cell histology or responders. Although no survival benefit was observed for the treated group because of the adverse effect from other relapses, EBI will become more important as better treatment programs are developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Esophageal complications from combined chemoradiotherapy (CCRT) were analyzed in 55 patients with limited non-small cell lung cancer. CCRT consisted of chemotherapy (cyclophosphamide, doxorubicin (Adriamycin), and cisplatin: CAP) and chest irradiation (5000 rad in 25 fractions/5 weeks). Forty-five patients received two courses of CAP, followed by five weekly courses of low dose CAP and irradiation followed by maintenance courses of CAP (Group 1). Ten patients received concomitant CCRT from the onset of treatment (Group 2). Esophagitis occurred in 80% of all patients. Severe esophagitis occurred in 27% of patients of Group 1 and 40% of patients of Group 2. Esophageal stricture or fistula developed in 1 of 45 (2%) patients in Group 1, and 3 of 10 (30%) patients in Group 2 (p less than 0.025). Weekly low-dose chemotherapy administered concomitantly with chest irradiation (R) at the onset of treatment significantly increases esophageal complications. A review of the literature suggests that CCRT may be used safely with split courses of R. The duration between onset of chemotherapy either before or after R should be greater than one week.

A phase II clinical study of dihydroxyanthracenedione ( DHAD ) was conducted in 50 patients with advanced lung cancers. DHAD was administered intravenously on a 5-day schedule repeated every 4 weeks. Most patients had adenocarcinoma (46%), and had received previous chemotherapy (66%) and radiation therapy (50%). Among 41 evaluable patients, there were four partial remissions, eight disease stabilizations and 29 disease progressions. Remissions were more common among previously untreated patients (20% vs. 4%), particularly in patients with adenocarcinoma and large cell carcinomas of whom 3/10 (30%) responded. Responses lasted 9+, 9, 7, and 3 months, respectively. Cardiac toxicity was not observed. Other toxicities were tolerable. DHAD is a potentially useful agent for the therapy of adenocarcinoma and large cell lung cancers.

A prospective randomized study was done to determine the effect of different doxorubicin (Adriamycin [ADR], Adria Laboratories, Columbus, OH) administration (schedules every week versus every 3 weeks) on the productivity of a cyclophosphamide, ADR, cisplatin (CAP) chemotherapy regimen for patients with non-small cell lung cancer (NSCLC). Electrocardiograms, multigated cardiac scans, echocardiograms, and endomyocardial biopsies were done serially for cardiac monitoring. Of 102 patients, 47 ahd inoperable limited disease (LD), 47 had extensive disease (ED), and eight had no evidence of disease. In the last group chemotherapy was given adjuvantly. Fifty-one patients were entered into each treatment arm. The groups were formed according to extent of disease and were comparable in terms of patient characteristics. In these groups, the overall response rates using both schedules in LD patients were similar: in patients without chest irradiation previously, there was a response of 35% with ADR weekly, and 31% with ADR triweekly; in LD patients with chest irradiation previously, the response was 20% with ADR weekly, and 25% with ADR triweekly; and in ED patients, 16% with ADR weekly, and 11% with ADR triweekly. There was no significant difference in survival between the two treatment groups. However, results for all responders suggested a longer duration of response with weekly than with triweekly ADR (complete plus partial response: 35.8 versus 11.4 weeks, P = 0.06; minor response: 34 versus 11.5 weeks, P = 0.003, respectively). Results also suggested that weekly ADR was less cardiotoxic than triweekly ADR: 29% of patients in the former group had no changes or only minor changes in endomyocardial biopsy results, whereas all patients in the latter group had at least grade 0.5 changes at a similar dosage. The median doses of weekly ADR were higher at the same endomyocardial biopsy-defined toxicity levels. No correlation was found between toxic effects defined by endomyocardial biopsy results and those defined by noninvasive monitoring techniques, although the number of patients assessed was small. Weekly ADR produced less granulocytopenia and a lower incidence of fever (6% versus 16%, P less than 0.001) than did triweekly ADR. Alopecia, nausea, vomiting, and diarrhea were significantly less for weekly ADR than triweekly Adr (P less than 0.0005, less than 0.0005, and less than 0.005, respectively). These data suggest that weekly ADR can achieve the same therapeutic results as the standard triweekly regimen with less cardiotoxicity, myelotoxicity, alopecia, diarrhea, nausea, and vomiting in patients with NSCLC.

Forty-three patients with limited-disease, inoperable non-small cell lung cancer received two intravenous courses of cyclophosphamide, Adriamycin, and cisplatin (CAP) chemotherapy over a 6-week period. This was followed by 5 weeks of combined chemoradiotherapy (CCRT) consisting of low weekly doses of CAP for 5 weeks plus 50 Gy continuous X ray therapy (XRT) to the primary tumor site. Chemotherapy was continued until disease progression occurred or until the total dose of Adriamycin reached 450 mg/m2, whichever came first. CCRT improved the response rate [complete response (CR) plus partial responses (PR)] from 25% after two courses of CAP alone to 65% after CCRT. Previous response to two courses of CAP influences response subsequent to CAP plus XRT. A pretherapy weight loss of 6% or greater had a significant adverse effect on both response and survival time. The median survival time for all patients was 50 weeks; patients whose disease responded to treatment survived significantly longer than patients with nonresponding disease. The median time until disease progression was 37 weeks. Twenty-seven patients relapsed. The first sites of relapse were local in 30% of the patients, distant in 56% of them, and both local and distant in 15%. Severe esophagitis occurred in 30% of the patients and was dose-limiting. The administration of CCRT resulted in an improved response rate compared with the rates reported in previous studies of chemotherapy or radiotherapy alone. Further improvement of the CCRT program is needed to increase long-term survival time and to decrease esophageal toxicity.

1087Background: EGFR overexpression is an independent poor prognostic factor in patients with inflammatory breast cancer (IBC). Our IBC animal model indicated that EGFR-targeted therapy inhibited IBC tumor progression via reversing EMT and suppression of CSC phenotype. We hypothesized that the combination of an anti-EGFR monoclonal antibody to neoadjuvant chemotherapy for IBC produce higher pathological complete response (pCR; including breast and axilla) rates compared with our historic rates (triple-negative [TN], 12%; HR+/HER2-, 7%) of 527 patients. Methods: In this single-arm, phase II study (47 patients enrolled, closed in June 2015), patients received 1 dose of panitumumab in a window period followed by 4 cycles of the combination of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin (AUC 2) on a weekly (PNC) followed by 4 cycles of FEC (5-fluorouracil, 500 mg/m2; epirubicin, 100 mg/m2; cyclophosphamide, 500 mg/m2) was administered, followed by surgical resection, radiation, and ho...