Faculty Bibliography

Nuclear expression of the cell cycle inhibitor p27(KIP1) is reduced in a variety of human malignancies, including breast cancer. Loss of nuclear p27(KIP1) during tumor progression, documented by immunohistochemistry (IHC), has been studied for its potential prognostic implication. We examined by IHC the association between nuclear p27(KIP1) expression and hormone receptor status in T1N0M0 breast cancer. PATIENTS AND METHODS: The correlation between nuclear p27(KIP1) expression and estrogen (ER) and progesterone (PR) hormone receptor status was analyzed in 122 human T1N0M0 (68 T1a/b, 54 T1c) breast cancer specimens. All patients were staged as N0 by axillary node dissection. RESULTS: A statistically significant reduction in p27(KIP1) expression was observed as tumor size increased from T1a/b (7%) to T1c (22%). The proportion of tumors with low nuclear p27(KIP1) expression was higher in the ER-negative/PR-negative group compared to the ER-positive/PR-positive group, but this difference was only statistically significant in the T1a/b subgroup (p=0.0007). CONCLUSION: Further investigations into causes of p27(KIP1) deregulation and their relationship to hormone receptor expression in T1N0M0 breast ductal carcinomas are warranted. Such studies may help identify prognostic, as well as predictive, markers of therapy resistance

Details on the 28-year treatment history of a patient with an endocrine-responsive breast cancer are provided. She was originally diagnosed as having a T1N0M0 cancer after a modified radical mastectomy at age 41. Fifteen years later, in 1998, she presented with hemoptysis and pleuritic chest pain: a 10 cm right atrial tumor and estrogen receptor (ER) positive endobronchial and adjacent lung parenchyma adenocarcinoma were documented. Epithelial markers normalized as she manifested a partial response (PR) lasting 3 years with tamoxifen treatment. From 2001 to 2007 she benefitted from exemestane treatment. Upon progression in the previous lung area and left adrenal, exemestane withdrawal led to transient decrease in markers. Six months later (in July 2008), with growth in her adrenal tumor, laparoscopic adrenalectomy was performed: in addition to ER positivity, the tumor showed Her2 overexpression and amplification. She has subsequently had some control of disease with fulvestrant, letrozole + trastuzumab, and subsequently letrozole + lapatinib. In addition to the chronicity of disease, this history illustrates the expanding range of treatments available for endocrine-responsive breast cancer commensurate to our greater understanding of tumor biology

This clinical vignette illustrates how our therapeutic approaches to early stages of multiple myeloma have changed over the past decade with novel therapies reducing disease and preventing disease progression. Recent paradigms of multiple myeloma describe the disease as a spectrum of clinical stages, including asymptomatic 'smoldering' states that progress to symptomatic states. The average 5-year survival rate of patients with multiple myeloma diagnosed between 1996 and 2004 according to surveillance epidemiology and end results (SEER) data is 35.9%. Here, we describe the use of novel therapeutic agents including bortezomib, lenalidomide, bisphosphonates, Doxil/Caelyx, and dexamethasone, and their success in affecting the course of disease. Multiple trials have shown an increased benefit of these newer agents over prior multiple myeloma treatment regimens. At 13 years and 8 months from diagnosis, our patient is doing well, and thus is a model of how long-term control of multiple myeloma prolongs survival.

PURPOSE: The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment. RESULTS: Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone. CONCLUSION: When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

Objective: OVA-301 was an open-label, multicenter, randomized Phase III study comparing Tr+ PLD to PLD alone in 672 pts with ROC. The combination significantly improved PFS and RR, with a trend toward longer OS and manageable noncumulative toxicity (Monk, Ann Oncol 2008, Abs. N8LBA4). Protracted tolerability of trabectedin 1.1 mg/m² and PLD 30 mg/m², 3 h-q3 weeks vs. PLD 50 mg/m2 q4 weeks in pts receiving over 6 cycles was analyzed. Materials and methods: Safety evaluated in 320 (of 663 treated) pts receiving >6 cycles by adverse events (AEs), laboratory data and physical findings (NCI CTC Version 3.0). Results: Balanced baseline characteristics: median age 56 years; ECOG 0: 68%; median platinum-free interval: 9.2 months; prior taxanes: 78%; papillary/serous histology: 72%. (See Table 1) Conclusions: This novel non-platinum, non-taxane combination is an efficacious regimen in pts with ROC with reasonable long-term tolerability in pts that received C6 cycles. Hematological toxicity and transaminase elevations were more common in the combination arm, yet transient, and not cumulative; and less frequent than at <6 cycles. HFS, mucosal inflammation and stomatitis were more common with PLD. Discontinuation rates due to AEs were low. Updated data will be presented

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response