Faculty Bibliography

Genes implicated in the devastating occurrences of cancers mostly arising in the breast and ovaries within certain 'high-risk' families were mapped and then cloned not even two decades ago. Some clairvoyant students of the subject anticipated that this 'assignation of risk' would herald a new era in the prevention, treatment and insights into pathogenesis of neoplasia. However, few would have predicted the accelerated pace of knowledge that ensued. The successive symposia that we held on this subject have given us a unique perspective on the extent of this progress. This supplement and the selected papers that have been assembled document accomplishments in genetics, epidemiology, early detection, treatment, preventive measures, as well as in the ethical and psychosocial consequences enveloping families at risk. It also reveals how the convergence of the laboratory, the clinic and the public across two continents is able to ignite discovery and its applications.

Advances in the study of BRCA1 and BRCA2 gene functions have relied on the development of animal models for seeking to explore further what we have learned from the human disease. Specifically, mouse models of a 'triple-negative' breast cancer (utilizing conditional knockout of BRCA1 and p53 in the breast), of an endometrioid ovarian cancer (based on oncogenic kras and loss of function of pten), and of anatomic and functional consequences of BRCA1 mutations in granulosa cells, have led to further inquiry into the pathogenesis and therapeutic consequences of genetic alterations. A striking susceptibility of these murine malignancies to platinum drugs has emerged, providing further confidence in their relevance to the human disease. In addition to these models, the pathogenesis of high-grade serous disease derived from risk-reducing surgeries in mutation carriers has pointed to a role of mutations in p53 commonly encountered in tubal intraepithelial carcinomas.

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

BACKGROUND: The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). METHODS: Patients with stage III-IV OFPC initiated treatment within 12weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175mg/m(2)) and carboplatin (AUC 6) every 3weeks for up to 6 cycles, plus oral erlotinib 150mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10). RESULTS: The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC

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

BACKGROUND: Darinaparsin is a novel organic arsenic that reaches higher intracellular concentration with decreased toxicity compared to inorganic arsenic. We conducted a multi-center phase II study with darinaparsin in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, up to two prior systemic treatments, ECOG performance status < or = 2, Child Pugh Class A or B and adequate organ functions. Darinaparsin was administered at 420 mg/m(2) intravenously, twice weekly at least 72 h apart for 3 weeks in a 4-week cycle. The primary end point was response rate. A Simon two-stage design was used. RESULTS: Among 15 patients in the first stage, no objective responses were observed. Two patients had stable disease. The median number of cycles on study per patient was 2 (1-6). The median progression free survival and overall survival were 55 days (95% confidence interval: 50-59) and 190 days (95% confidence interval: 93-227), respectively. No treatment related hospitalizations or deaths occurred. Treatment related grade 1-2 toxicities included nausea, vomiting (26.7% each), fatigue (20%), anorexia and diarrhea (13.3% each). Grade 3 anorexia, wheezing, agitation, abdominal pain and SGPT were observed in 1 patient each (6.7%). One patient experienced grade 4 hypoglycemia (6.7%). CONCLUSIONS: Darinaparsin could be safely administered with tolerable toxicity profiles, and no QTc prolongation in patients with advanced HCC. However, at this dose and schedule, it has shown no objective responses in HCC and this trial was terminated as planned after the first stage of efficacy analysis

PURPOSE: Dose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen. PATIENTS AND METHODS: Women with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m(2) day one, and pegfilgrastim 6 mg day two every 2 weeks for six cycles. RESULTS: Between 9/06 and 9/08, 43 patients enrolled. Thirty-one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had >or=grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19). CONCLUSION: Dose-dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification

OBJECTIVE: Imatinib mesylate (IM, Gleevec), a potent PDGF/PDGFR tyrosine kinase inhibitor, affects stroma and vascular endothelial cells. Our study sought to determine the safety and activity of paclitaxel with an intermittent schedule of IM. MATERIALS AND METHODS: rEOC patients previously treated with platinum/paclitaxel and </=2 regimens for recurrence were enrolled. Paclitaxel 80 mg/m(2) was given on days 3, 10, 17 every 28 days and oral IM 300 mg bid on days 1-4, 8-11, and 13-18. RESULTS: Between 2007-2009, 14 patients enrolled, 12 were evaluable. Nine patients were on study at 12 weeks. Objective responses (by RECIST and/or CA125) occurred in 4 patients. There were no grade 4, and only four grade 3 toxic events: diarrhea, edema and 2 cases of neutropenia. Early study closure was due to sufficient safety information with preliminary encouraging efficacy results. CONCLUSION: This weekly paclitaxel regimen with intermittent IM is tolerable with anti-tumor activity, making it suitable as part of future studies