Neoadjuvant Combination Chemotherapy Research Articles

A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced gastric cancer.

4057 Background: We have previously reported that phase II studies of combination chemotherapy with docetaxel, cisplatin and S-1 (DCS) demonstrated a very high response rate (87.1%) and a promising survival time (MST 687 days) in patients with unresectable advanced gastric cancer (BJC 2008, CCP 2009). This regimen showed no case of PD and an appreciable rate of downstaging, suggesting the applicability of DCS to neoadjuvant chemotherapy (NAC). We therefore conducted a multicenter phase II trial to evaluate the efficacy and safety of neoadjuvant DCS for locally advanced gastric cancer. Methods: The study included patients (pts) with histologic confirmation of gastric cancer, no prior chemotherapy, adequate organ function, PS 0-1, age 20-80, and clinical stages of cT3-4, cN0-3, and cM0 (Japanese staging system). S-1 80 mg/m2 was administered orally on days 1-14, followed by intravenous administration of cisplatin 60 mg/m2on day 8, and docetaxel 60 mg/m2on day 8. All pts received 2 courses of treatment every 3 weeks and responders received a maximum of 4 courses, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability and the secondary endpoints included response rate, histological response, survival time, and safety. Results: From July 2006 to November 2010, 40 pts (median age 66, male/female 28/12, PS0/1 29/11) were enrolled. The median number of courses received was 2 (1-4). Response rate was 71.8% with 29 PR and 11 SD cases. Grade 3/4 adverse events were leukopenia (55.0%), neutropenia (55.0%), febrile neutropenia (17.5%), diarrhea (22.5%), anorexia (25.0%), and nausea (17.5%), but they were generally transient and manageable. Curative surgery was performed in 39 pts; 36 pts (92.3%) underwent R0 resection. Downstaging was achieved in 26 pts and pathological response was found in 24 pts. There were no treatment-related deaths and no major surgical complications. Conclusions: Neoadjuvant DCS chemotherapy demonstrated a high response rate and a sufficient R0 resection rate for locally advanced gastric cancer with manageable toxicities. The results suggested the efficacy of DCS regimen in the neoadjuvant setting.

Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study

The admitted benefits of intraperitoneal chemotherapy during postoperative administration for the treatment of peritoneal carcinomatosis from ovarian origin are limited by their associated morbidity and restricted diffusion by the presence of multiple intra-abdominal adherences. The purpose of the study was to evaluate the security, effectiveness, and cytoreduction optimization of intraperitoneal paclitaxel administration previously to radical surgery/peritonectomy/HIPEC (hyperthermic intraoperative intraperitoneal chemotherapy) either in monotherapy or combined with intravenous carboplatin. Prospective pilot study of 10 patients with ovarian peritoneal carcinomatosis in stage IIIc-FIGO without previous treatment. After staging of the diseases by laparoscopy, five patients received paclitaxel by weekly intraperitoneal administration (60mg/m(2), 10 cycles), and other five patients additionally received intravenous carboplatin every 21days (AUC 6, 4 cycles). Subsequently radical surgery/peritonectomy with HIPEC was performed. The presence of moderate abdominal pain was the most common (70%) side effect associated with neoadjuvant paclitaxel intraperitoneal administration. The intravenous carboplatin administration was not associated with significant increase in adverse effects. It boosted intraperitoneal paclitaxel-associated antitumoral activity with a high average decrease in Index Cancer Peritoneal (21.2 vs. 14.4, P=0.066) and CA 125(1,053 vs. 346, P=0.043). All the patients who received combined neoadjuvant chemotherapy obtained R0 cytoreduction. Five-year overall survival was 62%. The intraperitoneal paclitaxel weekly administration combined with intravenous carboplatin administration prior to radical surgery/peritonectomy with HIPEC is a safe and effective option in the treatment of ovarian peritoneal carcinomatosis. This study shows the possibility to investigate other forms of intraperitoneal chemotherapy and their combinations thoroughly.

1411 ONCOLOGIC OUTCOMES AND EVOLUTION IN PATIENTS WITH PT0 DISEASE FOLLOWING RADICAL CYSTECTOMY FOR BLADDER CANCER. A MULTICENTRIC STUDY

1411 ONCOLOGIC OUTCOMES AND EVOLUTION IN PATIENTS WITH PT0 DISEASE FOLLOWING RADICAL CYSTECTOMY FOR BLADDER CANCER. A MULTICENTRIC STUDY

The role of neoadjuvant and adjuvant treatment for adenocarcinoma of the upper gastrointestinal tract

Both locally advanced adenocarcinoma of the stomach and gastro-esophageal junction are associated with poor prognosis due to the lack of effective treatment. Recently multimodal treatment consisting of neoadjuvant chemotherapy in combination with radiotherapy is reported to improve survival when compared to surgery alone. Neoadjuvant therapy in these locally advanced tumors allows for early tumor responses and the extent of tumor regression that can be achieved is considered a significant prognostic factor. This, in turn, increases the resectability of these tumors. Also due to the high frequency of lymph node metastasis, patients with locally advanced adenocarcinoma should undergo a D2 lymphadenectomy. Postoperative chemoradiation and perioperative chemotherapy have been studied in gastric adenocarcinomas and showed a survival benefit. However, the surgical techniques used in these trials are no longer considered to be standard by today's surgical practice. In addition, there are no standard recommendations for adjuvant chemotherapy or chemoradiation after R0 resection and adequate lymph node dissection.

Locally advanced nasopharyngeal carcinoma: Current and emerging treatment strategies

Although nasopharyngeal carcinoma (NPC) is a widespread malignant tumor, it is particularly frequent in Southeast Asia. Although T1 tumors can be effectively controlled with exclusive radiotherapy, this treatment modality is insufficient for most NPC patients, who present with locally advanced disease at diagnosis. In fact, for stages ranging from T2b N0 to T4 N3, definitive scientific evidence supports the use of concurrent platinum-based chemotherapy with standard external beam radiotherapy. This treatment approach has shown a statistically significant advantage in terms of overall survival, with respect to radiotherapy alone. Several trials have also investigated the use of neoadjuvant and adjuvant chemotherapy in combination with radiotherapy or chemo-radiotherapy. Platinum compounds, anthracyclines and taxanes are among the chemotherapy agents employed. This review focuses on the clinical results obtained in the field of adjuvant/concurrent/neoadjuvant chemotherapy for locally advanced NPC, for which exclusive concurrent chemo-radiotherapy currently represents the standard treatment approach.

CK5/6, EGFR, Ki-67, cyclin D1, and nm23-H1 protein expressions as predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer patients

The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in patients with locally advanced triple-negative breast cancers (TNBCs). Forty-one patients (18.6%) among 220 breast cancer patients were identified as TNBCs from March 2006 to 2009 were included in this prospective study. The pre-NCT treatment expression levels of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), CK5/6, epidermal growth factor receptor (EGFR), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). A total of 180 cycles were administered with the median number of four cycles per patient (range, 4-6). The pCR rate was 34.1% (95% CI, 19.6-48.6%). In univariate analysis, early T stage, clinical response after 2 cycles, negative basal-like, negative EGFR, high Ki-67 proliferation index, and positive nm23-H1 were found to be significantly predictive of a pCR (P = 0.010, 0.040, 0.007, 0.001, 0.019, and 0.010, respectively). Basal-like status and nm23-H1 status were significant for pCR on multivariate analysis (P = 0.004 and 0.031, respectively). Basal-like status and nm23-H1 are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with TNBCs.

Topo2α protein expression predicts response to anthracycline combination neo-adjuvant chemotherapy in locally advanced primary breast cancer

Background:This study aimed to identify predictors of response to anthracycline-based chemotherapy (5-fluoro-uracil, epirubicin, cyclophosphamide (FEC)) in locally advanced primary breast cancer (LAPC).Methods:A total of 91 LAPC patients were treated with six cycles of FEC before surgery. Protein expression of nine biomarkers (topoisomerase2α (Topo2α), ER, PR, HER2, Ki67, p53, EGFR, CK5/6 and CK14) was assessed in pre-chemotherapy core biopsies using immunohistochemistry (IHC) and results correlated with clinical and pathological response.Results:Clinical (cCR) and pathological (pCR) complete response were seen in 34.1% (n=31) and 20% (n=18), respectively. Pathological complete response was concordant with cCR in 14/31 cases; in four cases of cPR with palpable residual breast tumours, histology showed fibrous tissue only (pCR). On univariate analysis, pre-chemotherapy high expression of Topo2α protein (P=0.031), and negativity for ER and EGFR (P=0.001 and P=0.005, respectively) correlated with pCR. Positivity for p53 also showed significance (P=0.015), whereas basal phenotype, HER2, and all the clinicopathological variables of LAPC included in this study did not show significant correlation with response. On multivariate analysis, Topo2α expression had the strongest correlation with pCR (P=0.021) followed by EGFR (P=0.044).Conclusion:The study suggests that pre-chemotherapy Topo2α protein expression measured by IHC strongly correlates with pathological CR to neo-adjuvant anthracyclines in this group of LAPC studied.

Neoadjuvant systemic therapy for urological malignancies

Neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes.

Loss of Tumor-Initiating Cell Activity in Cyclophosphamide-Treated Breast Xenografts

Cancer stem cells (CSCs) are a subpopulation of tumor cells with preferential tumor-initiating capacity and have been purported to be resistant to chemotherapy. It has been shown that breast CSC are, on average, enriched in patient tumors after combination neoadjuvant chemotherapy including docetaxel, doxorubicin, and cyclophosphamide (CPA). Here, we investigate the resistance of breast CSC to CPA alone in a xenograft model. CPA treatment led to a 48% reduction in tumor volume during a 2-week period. Cells bearing the CD44+ CD24− phenotype were reduced by 90% (2.5% to 0.24%) in CPA-treated tumors, whereas cells with aldehyde dehydrogenase activity were reduced by 64% (4.7% to 1.7%). A subsequent functional analysis showed that CPA-treated tumors were impaired in their ability to form tumors, indicating loss of functional tumor-initiating activity. These results are consistent with a CSC phenotype that is sensitive to CPA and indicate that some patient CSC may not display the expected resistance to therapy. Deciphering the mechanism for this difference may lead to therapies to counteract resistance.

Phase II study of tri-weekly cisplatin and irinotecan as neoadjuvant chemotherapy for locally advanced cervical cancer

The present study aimed to assess the antitumor response and safety of a tri-weekly neoadjuvant chemotherapy regimen consisting of cisplatin and irinotecan for the treatment of locally advanced cervical cancer with a bulky mass. Between June 2002 and March 2008, 20 patients with locally advanced squamous cell carcinoma of the uterine cervix at clinical stage Ib2-IIIb were studied. Two 21-day cycles consisting of intravenous administration of cisplatin at 70 mg/m(2) (Day 1) and irinotecan at 70 mg/m(2) (Days 1 and 8) were performed. Antitumor responses, adverse events and the surgery completion rate were investigated. The response rate of the 15 stage I-II patients was 86.7%, while that of the 5 stage III patients was 20%. Grade 3 or 4 neutropenia was noted in 12 patients, and 4 patients had grade 3 or 4 anemia. Queasiness and vomiting, as grade 3 or 4 non-hematotoxic events, occurred in 1 patient, but none of the patients had diarrhea. The surgery completion rate was 75%. The present data indicate that the tri-weekly cisplatin and irinotecan combination neoadjuvant chemotherapy involves only controllable toxicity and yields a high response rate, suggesting that this combination is a useful therapy regimen.

Chirurgische Therapie von Lebermetastasen

The treatment of liver metastases has become more and more complex in recent years. More individualized therapeutic concepts have become feasible by the increase in different treatment options (surgical, interventional and oncological). In the field of surgery the definition of resectability could be broadened. More extensive liver resections are being performed, which are partly carried out as staged resections after neoadjuvant chemotherapy in combination with portal vein embolization (PVE), radio frequency ablation (RFA) or other procedures in order to increase complete resection rates and patient survival. Consequently the overall 5 year survival rate of patients with resected colorectal liver metastases has doubled from 30% to nearly 60% in the past decade. Due to the complexity of the different treatment approaches an interdisciplinary assessment of the individual patient in experienced centers is necessary.

Abstract 3732: Drug signaling network-based prediction of therapeutic response to anti-cancer agents

Abstract Background: A large number of biomarkers that are potentially predictive of a patient's clinical response to various anti-cancer agents have been reported in recent cancer therapeutics. These biomarker models, however, have not been able to provide a comprehensive understanding on why a specific drug works or does not work for different patients even with the same type of tumor. In our current study, we demonstrated that drug signaling network-based biomarker models could not only predict such therapeutic responses but also provide more direct insight on drug signaling gene networks of individual patients. Methods: In vitro drug activity and gene expression data of 60 NCI and 106 GSK cancer cell lines were first used to identify candidate drug sensitivity biomarkers for Paclitaxol, a standard chemotherapeutic agent, and erlotinib, a targeted therapeutic EGFR inhibitor. Next, known functional biomarkers related to each drug's molecular mechanisms of action were obtained from literature and then examined and filtered for their expression correlations with each drug activity using the above cell line data. Two biomarker sets of each drug were combined to discover gene-network modules by a hierarchical clustering analysis. We then developed candidate multivariate gene-network models and identified the final models that were highly predictive of drug activities on the cell lines. The final signaling network signature models were independently applied to three human patient sets treated with relevant anti-cancer agent therapies. Results: For the application of Paclitaxol in breast cancer, we derived a highly predictive gene-network signature model of 8 taxane signaling pathways including ATP-binding cassette transporters and tumor progression mechanisms. Its prospective applications to two independent human datasets of 133 and 100 breast cancer patients treated with a neoadjuvant combination chemotherapy with Paclitaxol were highly significant in stratifying patients with a complete response against the ones with poor or no clinical response (two-sample t-test p-value=0.048, 5.3E-06, respectively). Our gene network model of erlotinib signaling pathways was also made with 16 sub-networks including drug metabolism and tumor proliferation mechanisms for predicting this drug's sensitivity in metastatic colorectal cancer patients. Predictive scores of this model for 43 colon cancer patients with K-RAS wild type treated with cetuximab, another EGFR inhibitor, were again highly associated with heterogeneous clinical responses of patients (Jonckheere-Terpstra ordered difference test p-value=0.03). Conclusions: Drug signaling network-based biomarker models were highly predictive of taxane and cetruximab therapeutic responses of patients with breast and colorectal cancer providing a better understating on individual patients’ molecular mechanisms of drug response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3732.

460 Gemcitabine, carboplatin and paclitaxel as neoadjuvant combination chemotherapy in patients with locally advanced (stage III) or inflammatory breast cancer – a non-anthracycline alternative

460 Gemcitabine, carboplatin and paclitaxel as neoadjuvant combination chemotherapy in patients with locally advanced (stage III) or inflammatory breast cancer – a non-anthracycline alternative

Phase 1/2 study of preoperative docetaxel and mitoxantrone for high‐risk prostate cancer

: A study was conducted to determine the 5-year recurrence-free survival in patients with high-risk prostate cancer after neoadjuvant combination chemotherapy followed by surgery. Secondary endpoints included safety, pathologic effects of chemotherapy, and predictors of disease recurrence. : Fifty-seven patients were enrolled in a phase 1/2 study of weekly docetaxel 35 mg/m(2) and escalating mitoxantrone to 4 mg/m(2) before prostatectomy. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. A tissue microarray, constructed from the prostatectomy specimens, served to facilitate the exploratory evaluation of biomarkers. The primary endpoint was recurrence-free survival. Disease recurrence was defined as a confirmed serum prostate-specific antigen (PSA) >0.4 ng/mL. : Of the 57 patients, 54 received 4 cycles of docetaxel and mitoxantrone before radical prostatectomy. Grade 4 toxicities were limited to leukopenia, neutropenia, and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months, 27 of 57 (47.4%) patients recurred. The Kaplan-Meier recurrence-free survival at 2 years was 65.5% (95% confidence interval [CI], 53.0%-78.0%) and was 49.8% at 5 years (95% CI, 35.5%-64.1%). Pretreatment serum PSA, lymph node involvement, and postchemotherapy tissue vascular endothelial growth factor expression were independent predictors of early recurrence. : Preoperative chemotherapy with docetaxel and mitoxantrone is feasible. Approximately half of the high-risk patients remain free of disease recurrence at 5 years, and clinical and molecular predictors of early recurrence were identified. Cancer 2010. (c) 2010 American Cancer Society.

Neoadjuvant combination chemotherapy with pegylated liposomal doxorubicin and vinorelbine for locally advanced breast cancer

OBJECTIVE In China, vinorelbine plus an anthracycline is a common neoadjuvant regimen for locally-advanced breast cancer (LABC). Pegylated liposomal doxorubicin (PLD) is an alternate anthracycline formulation with a more favorable safety profi le compared with conventional anthracyclines. METHODS In this open-label trial, 61 women with LABC received up to 6 cycles of PLD 30 mg/m2 on Day 1 and vinorelbine 25 mg/m2 on Days 1 and 8 every 21 days. Hormone receptor and/or HER2 status was not routinely available. RESULTS The overall clinical response rate (primary efficacy endpoint) was 80% (95% CI: 68%-89%). Two patients achieved a pathological complete response (3%), with 75% having their tumor down-staged, and 89% proceeding to tumor resection. The most frequent nonhematologic adverse events were stomatitis, fever, rash, and palmar-plantar erythrodysesthesia, with none considered serious. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 10% and 2% of patients, respectively. CONCLUSION PLD plus vinorelbine demonstrated comparable efficacy to conventional anthracyclines plus vinorelbine in the neoadjuvant treatment of LABC, but may offer safety advantages.

Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 trial

Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population. Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051. 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism). Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted. UK National Health Service, Sanofi-Aventis.

Patient Characteristics and Patterns of Therapy Use among Patients Newly Diagnosed with Early Breast Cancer: Results from a US Claims Data Analysis.

Abstract Background: Following a diagnosis of early breast cancer (BC), there are a variety of treatment options open to physicians. However, with the development of alternative therapies and rapidly changing clinical guidelines, there are limited data available evaluating current patterns of care. This study investigated current treatment patterns following an initial diagnosis of early BC and examined demographic and clinical differences among patients receiving tamoxifen versus aromatase inhibitors (AI) as a preliminary analysis to inform a more in-depth study assessing early BC recurrence rates between therapy groups.Methods: In a retrospective cohort analysis among enrollees in managed care health plans, we identified female patients aged 55 years or older from 2004 to 2008 who were newly diagnosed with BC and had no evidence of prior BC surgery, chemotherapy, radiotherapy, or hormone therapy. Patients were followed from the date of first BC diagnosis until evidence of first (“index”) treatment with tamoxifen or an AI (anastrozole or letrozole). Outcomes of interest included differences between hormone therapy cohorts in patient characteristics (age, payer type) and clinical characteristics (risk group, Charlson comorbidity index [CCI]). Risk group was defined by treatments identified between the time of first BC diagnosis and index hormone therapy and included low (surgery only), medium (surgery and radiotherapy), higher (surgery then chemotherapy), and highest (neoadjuvant chemotherapy or combination surgery, radiotherapy, and chemotherapy). Unadjusted comparisons between cohorts were performed, with a p-value <0.05 considered statistically significant.Results: Of 4,191 newly diagnosed early BC patients identified, 950 (22.7%) received tamoxifen as first hormone therapy while 3,241 (77.3%) had evidence of AI therapy. There were no significant differences between therapy cohorts for geographic region or payer type, while differences in health plan type were marginally significant (p=0.05). Mean (median) age was 60.7 (59) years for tamoxifen patients and 61.4 (60) years for AI patients (p<0.001). Almost 60% of patients on AI therapy had 3 or more comorbidities as defined by the CCI compared to 45% of tamoxifen patients (p<0.001). Differences in the proportion of hormone therapy patients by risk group are provided in Table 1; compared to tamoxifen patients, a larger proportion of patients receiving AI therapy were found to be in the higher or highest risk groups (34.9% vs. 17.1%, p<0.001).Conclusion: According to real-world data, it appears that upfront AI therapy is the most widely used treatment option for early BC patients, regardless of risk group. The results indicate a tendency to use AI therapy significantly more often in patients defined as higher or highest risk. These baseline data are crucial in informing the design and statistical analyses of the next phase of this study to evaluate rates of early BC recurrence between therapy cohorts.Table 1. Hormone Therapy Patients by Risk Group.Risk GroupTamoxifen (N=950)AI Therapy (N=3,241)P-valueLow339 (35.7%)920 (28.4%)p=0.001Medium449 (47.3%)1,190 (36.7%) Higher57 (6.0%)416 (12.8%) Highest105 (11.0%)715 (22.1%) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2060.

Significance of Viral Reactivation in Hepatitis B Virus Carriers with Early Breast Cancer Receiving Anthracycline- or Taxane-Containing Chemotherapy.

Abstract Background :It is known that cancer patients in healthy hepatitis B viral (HBV) carrier status are prone to develop hepatic dysfunction during cytotoxic chemotherapy. The objectives of this study were to determine the frequency of healthy HBV carrier status and subsequent viral reactivation resulting in hepatic dysfunction during cytotoxic chemotherapy, and its significance in early breast cancer patients.Methods :Among 3,433 patients with operable breast cancer diagnosed at the National Cancer Center, Korea between January 2001 and March 2009, 3,337 patients were tested for HBsAg. Retrospectively, medical records were reviewed for 139 (4.2%) patients who were positive for HBs Ag.Results :Of 139 patients, 112 patients received anthracycline or taxane based neoadjuvant (n=25) or adjuvant (n=87) combination chemotherapy. Prophylactic lamivudine therapy was administered in 33 patients (29.5%).Thirty of 112 (26.8%) patients developed reactivation of HBV with deterioration of hepatic function during chemotherapy. The rate of reactivaton was not different with or without further taxane therapy (43% vs. 44%, p=0.408).Although there was no significant difference in the rate of chemotherapy delay between two groups, the incidence of early termination of planned chemotherapy was higher in B viral reactivation group (23.3% vs. 4.9%, p=0.008). Within a median follow-up duration of 39 mo (range 1 mo to 95 mo), the rate of disease recurrence was comparable between two groups (10% vs. 18.3%, p=0.390).Lamivudine prophylaxis decreased the rate of HBV reactivation without statistical significance (15.1% vs. 35.4%, p=0.101). Despite more patients without prophylaxis developed G 3/4 AST/ALT elevation (40% vs. 84%, p=0.068), the majority of patients recovered to G 1/2 AST/ALT level within 12 months with anti-viral or supportive treatment (0% vs. 14.3%, p=1.00). One patient without lamivudine prophylaxis developed fulminant hepatic failure after 3rd cycles of neo-adjuvant chemotherapy and received living donor liver transplantation. After that, she received radical mastectomy and maintained adjuvant anti-hormonal therapy.Conclusions :Although lamivudine prophylaxis in HBV healthy carrier decreased the rate of viral reactivation during neo- or adjuvant chemotherapy, the majority of patients irrespective of prophylaxis recovered hepatic function in a year with conservative treatment. Early detection and intensive supportive care are as important as anti-viral prophylaxis in HBV healthy carrier when treated with cytotoxic chemotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1113.

Reactive antibodies against bacillus Calmette‐Guerin heat‐shock protein‐65 potentially predict the outcome of immunotherapy for high‐grade transitional cell carcinoma of the bladder

Intravesical immunotherapy with Mycobacterium bovis (M. bovis) bacillus Calmette-Guerin (BCG) is the current standard of care against superficial, high-grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle-invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG-induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy. Because host immunoresponse mediates BCG activity, the authors screened a combinatorial random peptide library on the circulating pool of immunoglobulins (Igs) purified from an index patient after successful BCG immunotherapy to identify the corresponding target antigen(s). An immunogenic peptide motif was selected, isolated, and validated from M. bovis BCG heat-shock protein 65 (HSP-65) as a dominant epitope of the humoral response to treatment. Increasing IgA and IgG anti-HSP-65 titers specifically predicted a positive patient outcome in a cohort of patients with bladder cancer relative to several cohorts of control patients. The current results indicated that antibody production against M. bovis BCG HSP-65 can serve as a serologic marker for the predictive outcome of BCG immunotherapy. Subsequent studies will determine the value of this candidate marker to modify BCG-based treatment for individual patients with bladder cancer.

Functional genome screen for therapeutic targets of osteosarcoma

Osteosarcoma (OS) is the most frequent primary malignant bone tumor of children and young adults. Although the introduction of combined neoadjuvant chemotherapy has markedly improved survival, the outcome of OS patients with distant metastasis and/or poor response to chemotherapy is still unsatisfactory. Therefore there is a need to develop new therapeutic agents that suppress OS cell proliferation with higher efficacy. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for OS, we screened a panel of small interfering RNAs (siRNAs) that target 691 genes encoding human protein kinases and related proteins. We found that different constructs of siRNA specifically targeting polo-like 1 kinase (PLK1) significantly caused mitotic cell cycle arrest and subsequent apoptotic cell death in a variety of OS cell lines. siRNA targeting PLK1 also suppressed the growth of OS xenografts established in immunodeficient mice. Recently, phase I clinical trials of PLK1 chemical inhibitors have been reported. Our results indicate that PLK1 is a promising molecular target for pharmacologic intervention in OS.