18F-fluorodeoxyglucose positron emission tomography in the management of patients with thymic epithelial tumors.

PURPOSE: There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography ([(18)F]-FDG PET) imaging in management of patients with thymic epithelial tumors (TET). The primary objective of this study was to assess the usefulness of early [(18)F]-FDG PET to monitor treatment efficacy and its correlation with Response Evaluation Criteria in Solid Tumors (RECIST) in patients with TETs. EXPERIMENTAL DESIGN: [(18)F]-FDG PET/computed tomographic (CT) scans were conducted at baseline and after 6 weeks of treatment in patients enrolled in two phase II and one phase I/II clinical trials. On the basis of data from other solid tumors, metabolic response was defined as a reduction of [(18)F]-FDG uptake by more than 30% as assessed by average standardized uptake values (SUV) of up to five most metabolically active lesions. RESULTS: Fifty-six patients with unresectable Masaoka stage III or IV TETs were included. There was a close correlation between early metabolic response and subsequent best response using RECIST (P < 0.0001-0.0003): sensitivity and specificity for prediction of best response were 95% and 100%, respectively. Metabolic responders had significantly longer progression-free survival (median, 11.5 vs. 4.6 months; P = 0.044) and a trend toward longer overall survival (median, 31.8 vs. 18.4 months; P = 0.14) than nonresponders. [(18)F]-FDG uptake was significantly higher in thymic carcinoma than in thymoma (P = 0.0004-0.0010). CONCLUSION: In patients with advanced TETs, early metabolic response closely correlates with outcome of therapy. [(18)F]-FDG PET may be used to monitor treatment efficacy and assess histologic differences in patients with advanced TETs.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. EXPERIMENTAL DESIGN: Patients with measurable HER2(+) metastatic breast cancer, < or = 3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) > or = 55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. RESULTS: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). CONCLUSION: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Circulating biomarkers of bevacizumab activity in patients with breast cancer.

PURPOSE: Noninvasive markers of anti-vascular endothelial growth factor (VEGF) therapy are needed. Soluble vascular cell adhesion molecule (sVCAM-1), soluble VEGF receptor-2 (sVEGFR-2), and plasma VEGF levels were assessed as potential biomarkers of therapy with bevacizumab. Tumor samples were evaluated for VEGFR-2 mutations before and after bevacizumab. EXPERIMENTAL DESIGN: Twenty-one patients with breast cancer underwent neoadjuvant treatment with bevacizumab for 1 cycle followed by 6 cycles of bevacizumab, chemotherapy, and filgrastim. Peripheral blood samples were collected at baseline, post cycles 1, 4 and 7. sVCAM-1, VEGF and sVEGFR-2 levels were measured by enzyme-linked immunosorbent assay (ELISA). Exons 17-26 of VEGFR-2 were sequenced on tissue samples from 20 patients at baseline and post cycle 1 to evaluate for tumor mutations. RESULTS: From baseline to post cycle 1, sVCAM-1 and sVEGFR-2 values increased by a median of 180.5 ng/ml (p < 0.0001) and 1927 ng/ml respectively (p = 0.0003). Baseline VEGF, sVEGFR-2, and sVCAM-1 levels nor changes in sVEGFR-2 and sVCAM-1 levels were associated with clinical response. Median baseline sVEGFR-2 levels were 11322 ng/ml and 7524 ng/ml in patients with (n = 5) and without (n = 6) wound healing problems respectively, (p = 0.052). In 40 samples where tumor VEGFR-2 sequencing was obtained, no mutations were seen compared to the reference sequence. CONCLUSIONS: sVCAM-1 and sVEGFR-2 values increased significantly after treatment with bevacizumab, possibly due to compensatory mechanisms secondary to VEGF inhibition. sVEGFR-2 levels were somewhat higher in patients with wound healing problems and may potentially predict patients at higher risk of this complication. There were no tumor VEGFR-2 mutations.

Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes.

PURPOSE: Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer. PATIENTS AND METHODS: Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m(2)/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated alpha-tubulin, tau-1, and p53 expression when possible. RESULTS: Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor alpha-tubulin acetylation after treatment. Baseline or cycle 2 acetylated alpha-tubulin, tau-1, or p53 expression did not correlate with clinical response. CONCLUSION: Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer.

Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m(2)/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m(2)/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m(2), 8 mg/m(2) and 10 mg/m(2) dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes.

A prospective study of adjuvant CMF in males with node positive breast cancer: 20-year follow-up.

PURPOSE: To determine the long-term overall survival of male patients with stage II node positive breast cancer treated with adjuvant chemotherapy. PATIENTS AND METHODS: Between 1974 and 1988, 31 male breast cancer patients were prospectively enrolled on study MB-82 in the National Cancer Institute. Following mastectomy, patients were treated with 12 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. RESULTS: Median patient age was 61 years (38-74 years). Twenty-one patients (68%) had 1-3 positive axillary lymph nodes while ten patients (32%) had four or more positive nodes. Estrogen receptor status was positive in 22 (71%), negative in 1 (3%), and unknown in 8 (26%) tumors. Progesterone receptor status was positive in 18 (58%), negative in 3 (10%), and unknown in 10 (32%) tumors. Median potential follow-up for all patients is 22.5 years with a median survival of 16.3 years. Twenty-one of 31 patients have died; one from a treatment-related complication, nine patients from recurrent breast cancer, five from other cancers, one from non-cancer related causes, and five from unknown causes. Ten patients remain alive at a median of 19.2 years. The overall survival probability at 10 years is 64.5% (95% CI: 46.9-78.9%), at 15 years is 51.6% (95% CI: 34.8-68%), and at 20 years is 42.4% (95% CI: 25.8-60.8%). CONCLUSION: To our knowledge, 20-year prospective data with adjuvant chemotherapy in male breast cancer has never been reported. Adjuvant chemotherapy may benefit male breast cancer patients with positive nodes.

Changes in neurologic function tests may predict neurotoxicity caused by ixabepilone.

PURPOSE: To investigate baseline factors and neurologic function tests (NFTs) that may predict the development of grade 2 or higher peripheral neuropathy (PN) after treatment with ixabepilone, an epothilone microtubule-stabilizing agent with antitumor activity. PATIENTS AND METHODS: Advanced breast cancer patients were treated with ixabepilone (6 mg/m2) for 5 consecutive days every 3 weeks in a phase II clinical trial. Physical examinations, questionnaires, nerve conduction studies, and NFTs, including the Jebsen Test of Hand Function (JTH) and the Grooved Pegboard Test (GPT), were performed at baseline and during subsequent cycles. RESULTS: Forty-seven patients assessable for PN received a median of five cycles of therapy (range, one to 22 cycles). Nine of these patients developed grade 2 PN, and two developed grade 3 PN, with a median time to onset of 144 days (range, 6 to 189 days). Among these 11 patients, PN resolved in eight patients, with a median of 15 days (range, 6 to 346 days) after onset, but PN did not resolve in three patients during follow-ups at 76, 361, and 746 days after onset. GPT and changes of JTH scores at onset of PN were significantly different between patients with and without PN at comparable follow-up times (P = .006 and P = .002, respectively). Changes in GPT and JTH scores over the first two cycles were often associated with the development of PN by exploratory actuarial analysis. CONCLUSION: Serious ixabepilone-induced neuropathy was relatively rare on the treatment schedule used. NFTs, such as JTH and GPT, may have utility for predicting PN, but further testing is needed.

A novel case of bisphosphonate-related osteonecrosis of the torus palatinus in a patient with metastatic breast cancer.

Bisphosphonates administered orally and intravenously are used for a variety of endocrine and oncologic indications. Long-term intravenous use of bisphosphonates has been shown to cause osteonecrosis of the jaw. We report a case in which a 58-year-old woman with metastatic breast cancer received 18 doses of 4 mg intravenous zoledronic acid over a period of 16 months and developed a region of osteonecrosis on the posterior edge of a large, lobular torus palatinus. Torus palatinus, a type of maxillary exostosis, is common among postmenopausal women, and is vulnerable to blunt trauma that could predispose to osteonecrosis. Sequestrum of dead bone was removed and the site healed within 4 weeks. This case demonstrates that patients with a torus palatinus may be at high risk for osteonecrosis, and reinforces the need for good oral hygiene and frequent dental examination while receiving bisphosphonate therapy.

Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer.

PURPOSE: Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. PATIENTS AND METHODS: Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated alpha-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. RESULTS: Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy. CONCLUSION: An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.

Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy.

PURPOSE: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. RESULTS: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.

CA 125 elevation in breast cancer: a case report and review of the literature.

A 69-year-old postmenopausal woman with newly diagnosed inflammatory breast cancer was evaluated for a pelvic mass found incidentally during staging computed tomography (CT) scans. Her serum cancer antigen (CA) 125 was greater than 900 U/ml, but laparoscopic examination of the ovaries was normal. Her breast cancer was deemed metastatic by virtue of a supraclavicular lymph node, but she had no visceral or bone metastasis. She was begun on primary chemotherapy and her CA 125 normalized. CA 125 is a tumor-associated antigen that is most commonly seen in advanced ovarian cancer. It is predominantly derived from coelomic epithelium, which explains elevations in benign conditions or other malignancies. The significance of CA 125 elevations in breast cancer is uncertain. Although CA 125 production has been demonstrated in the normal breast, it has been reported most often as a marker of pleural involvement with metastatic breast cancer. Further information on CA 125 in breast cancer is required to delineate its role in the management of this disease.