Generation of HER2-specific antibody immunity during trastuzumab adjuvant therapy associates with reduced relapse in resected HER2 breast cancer.

BACKGROUND: Resected HER2 breast cancer patients treated with adjuvant trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induce HER2-specific antibodies which correlate with improved survival in HER2 metastatic breast cancer patients. It remains unclear whether the generation of immunity required trastuzumab and whether endogenous antibody immunity is associated with improved disease-free survival in the adjuvant setting. In this study, we addressed this question by analyzing serum anti-HER2 antibodies from a subset of patients enrolled in the NCCTG trial N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. METHODS: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831. Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and compared between arms and with disease-free survival. RESULTS: Prior to therapy, across all three arms, N9831 patients had similar mean anti-HER2 IgG levels. Following treatment, the mean levels of antibodies increased in the trastuzumab arms but not the chemotherapy-only arm. The proportion of patients who demonstrated antibodies increased by 4% in Arm A and by 43% in the Arms B and C combined (p = 0.003). Cox modeling demonstrated that larger increases in antibodies were associated with improved disease-free survival in all patients (HR = 0.23; p = 0.04). CONCLUSIONS: These results show that the increased endogenous antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant, in view of its correlation with improved disease-free survival. The findings may have important implications for predicting treatment outcomes in patients treated with trastuzumab in the adjuvant setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00005970 . Registered on July 5, 2000.

A pilot investigation of a multidisciplinary quality of life intervention for men with biochemical recurrence of prostate cancer.

OBJECTIVE: This pilot project evaluated the acceptability and estimated the effect size of a tailored multidisciplinary quality of life (MQOL) intervention for men who have biochemical recurrence of prostate cancer. METHODS: Participants included 57 men with localized prostate cancer with biochemical recurrence (Median=76 years; 89% White). Participants were randomized to wait list control which offered the intervention upon conclusion of the study (n=27) or to an eight-session group-based, MQOL (n=30) intervention. Assessments were completed at baseline, end of treatment, and 6 months post-treatment. RESULTS: MQOL was acceptable as indicated by favorable participant retention (100% retained), treatment compliance (97% attended > 6 treatment sessions), and high ratings of helpfulness (80% rated helpfulness > 4 on 5-point scale). MQOL had a favorable impact on the mental health composite score of the Short Form-36 at the end of treatment but not at 6 months (effect size=0.52 and -0.04); health-related QOL as measured by the Functional Assessment of Cancer Therapy-Prostate at the end of treatment and 6 months (effect size=0.14 and 0.10); and prostate cancer specific anxiety as measured by the Memorial Anxiety Scale for Prostate Cancer at the end of treatment and 6 months (effect size=0.45 and 0.23). CONCLUSIONS: This pilot project provides preliminary data supporting the premise that a tailored behaviorally based MQOL intervention for men with biochemical recurrence of prostate cancer is acceptable to men and might reduce prostate cancer specific anxiety and enhance QOL. Further research examining the efficacy of this intervention in a larger randomized trial is warranted.

Quality of life of patients undergoing surgical treatment for newly-diagnosed, clinically localized renal cell carcinoma.

This investigation sought to evaluate the psychological needs of individuals (N = 28) undergoing nephrectomy for newly diagnosed, localized renal cell carcinoma (RCC) using a mixed qualitative-quantitative approach. The qualitative component consisted of individual semi-structured interviews ≥4 weeks postnephrectomy. The quantitative component involved standardized measures assessing anxiety, depressive symptoms, psychological distress, and general and disease specific quality of life (QOL) prior to nephrectomy and at 4, 12, and 24 weeks postnephrectomy. This investigation provides a unique view of the experiences and needs of persons undergoing surgery for newly diagnosed, localized RCC and reveals that these individuals experience fatigue, anxiety, and depressive symptoms.

Phase II Trial of Eribulin in Patients With Metastatic Hormone Refractory Prostate Cancer: A Trial of the ECOG-ACRIN Cancer Research Group (E5805).

BACKGROUND: Eribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels. METHODS: In a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata. RESULTS: In total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia. CONCLUSIONS: In summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.

Cushing's syndrome due to ectopic adrenocorticotropic hormone production secondary to hepatic carcinoid: diagnosis, treatment, and improved quality of life.

INTRODUCTION: We describe a previously healthy 40-year-old woman with Cushing's syndrome caused by adrenocorticotropic hormone (ACTH) secretion from metastatic carcinoid. CASE REPORT: Over a 2-year period, the patient had multiple hospitalizations for uncontrolled hypertension, hyperglycemia, and hypokalemia. She had transient flushing, rashes, and a rapid weight gain. In addition, she developed anasarca and had a nontraumatic hip fracture 1 month before presentation. Subsequently, a hypertensive crisis resulted in admission to the intensive care unit and fine-needle aspiration of a liver lesion. DISCUSSION: A diagnosis of metastatic carcinoid was established. She was transferred to our hospital for further evaluation and management. On arrival, she had the signs of Cushing's syndrome. Despite extensive evaluation, her primary carcinoid tumor was not localized. She was treated successfully with bilateral adrenalectomy and octreotide. CONCLUSION: This case illustrates how early recognition of the signs and symptoms of excess ACTH is important for prompt and appropriate treatment.

Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy.

BACKGROUND: Data exist that demonstrate isoflavones' potent antiproliferative effects on prostate cancer cells. We evaluated the efficacy of isoflavone in patients with PSA recurrent prostate cancer after prior therapy. We postulated that isoflavone therapy would slow the rate of rise of serum PSA. METHODS: Twenty patients with rising PSA after prior local therapy were enrolled in this open-labeled, Phase II, nonrandomized trial (Trial registration # NCT00596895). Patients were treated with soy milk containing 47 mg of isoflavonoid per 8 oz serving three times per day for 12 months. Serum PSA, testosterone, lipids, isoflavone levels (genistein, daidzein, and equol), and quality of life (QOL) were measured at various time points from 0 to 12 months. PSA outcome was evaluated. RESULTS: Within the mixed regression model, it was estimated that PSA had increased 56% per year before study entry and only increased 20% per year for the 12-month study period (p = 0.05). Specifically, the slope of PSA after study entry was significantly lower than that before study entry in 6 patients and the slope of PSA after study entry was significantly higher than before study entry in 2 patients. For the remaining 12 patients, the change in slope was statistically insignificant. Nearly two thirds of the patients were noted to have significant levels of free equol in their serum while on therapy. CONCLUSION: Dietary intervention with isoflavone supplementation may have biologic activity in men with biochemical recurrent prostate cancer as shown by a decline in the slope of PSA. This study may lend support to the literature that nutritional supplements have biologic activity in prostate cancer and therefore, further studies with these agents in randomized clinical trials should be encouraged.

The role of mammography in male patients with breast symptoms.

OBJECTIVE: To determine the contribution of mammography to the comprehensive clinical evaluation of men with breast symptoms. PATIENTS AND METHODS: We retrospectively reviewed the records of all men who underwent mammography between January 1, 2001, and December 31, 2004, at the Mayo Clinic In Jacksonville, Fla. Medical history, mammographic findings, and breast cancer diagnoses were assessed. RESULTS: A total of 198 men had 212 mammograms. Nine mammograms (from 9 different men) (4%) showed suspicious findings. Eight men underwent biopsy, which yielded a breast cancer diagnosis in 2 (1%). Of the 212 mammograms, 203 (96%) showed benign findings, including gynecomastia on 132 (62%). One patient with a benign-appearing mammogram later underwent breast biopsy, and malignant disease was diagnosed. All the men with breast cancer had a dominant mass on clinical examination and other findings suggestive of breast cancer. Of the 132 mammograms showing gynecomastia, 110 (83%) were from men who had taken predisposing medications or who had predisposing medical conditions. CONCLUSIONS: Mammography added little information to the initial patient evaluation. Breast cancer may be suspected by the presence of a dominant mass. Gynecomastia can be predicted on the basis of the patient's symptoms or preexisting condition. Patients with suspicious findings on examination warrant appropriate clinical management regardless of mammographic findings. Mammography in men may be of benefit only for image guidance of percutaneous biopsy of a suspicious mass.

Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients.

INTRODUCTION: Histone deacetylase inhibitors have been found to restore sensitivity to the estrogen receptor in endocrine-resistant and triple-negative breast cancer cell lines. We decided to test panobinostat, a pan-histone deacetylase inhibitor, because of preclinical data, combined with letrozole in a phase I study. PATIENTS AND METHODS: We enrolled patients with metastatic breast cancer to determine the safety and tumor response using Response Evaluation Criteria In Solid Tumors. Dose level 1 was panobinostat 20 mg orally 3 times weekly with oral letrozole 2.5 mg daily. Dose level 2 was panobinostat 30 mg orally 3 times weekly, with the same dose of letrozole. RESULTS: A total of 12 patients (6 at each dose level) were enrolled, and 43 cycles of treatment were given. Of the 6 patients at dose level 1, 1 experienced dose-limiting toxicity (20-mg dose level; an increase in creatinine). At the 30-mg dose level, 3 of 6 patients experienced dose-limiting toxicity, 1 each of grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, and grade 3 diarrhea. The maximum tolerated dose was 20 mg. Of the 12 patients, 2 experienced a partial response, and 5 had stable disease. The most common severe adverse event was thrombocytopenia, occurring in 4 of 12 patients. CONCLUSION: The recommended phase II starting dose is panobinostat 20 mg orally 3 times weekly (eg, Monday, Wednesday, Friday) and oral letrozole 2.5 mg daily. This dose should be escalated to 30 mg orally 3 times weekly if no grade 3 toxicity has developed, because the partial responses occurred in patients receiving the 30-mg dose.

Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for clear cell renal cell carcinoma.

PURPOSE: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. EXPERIMENTAL DESIGN: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. RESULTS: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. CONCLUSIONS: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease.

Effect of leuprolide on serum amyloid-ß peptide levels and memory in patients with prostate cancer with biochemical recurrence.

OBJECTIVE: To investigate whether prostate cancer patients receiving leuprolide demonstrated objective cognitive decline accompanied by a change in plasma levels of amyloid-ß. METHODS: Between November 19, 2003, and July 21, 2008, we prospectively enrolled 50 patients with biochemical recurrence of prostate cancer and measured plasma amyloid-ß peptide 40 and amyloid-ß peptide 42 levels with sandwich enzyme-linked immunosorbent assay at baseline before the first leuprolide injection and at 2, 4, and 12 months. The Mini-Mental State Examination was used to assess 49 patients at baseline and at subsequent visits, and 24 were also assessed by the California Verbal Learning Test-Short Form. RESULTS: Patients were a median age of 71 years (range, 59-89 years). Compared with baseline levels, plasma amyloid-ß peptide 40 levels were increased at 2 months (P=.04) and 4 months (P=.02). Age was correlated with plasma amyloid-ß peptide 40 levels (P=.003) and likely accounted for this relationship. Plasma amyloid-ß peptide 42 and performance on cognitive tasks did not differ from baseline, but memory measures improved slightly after baseline, most likely due to a practice effect. CONCLUSION: Leuprolide therapy was not associated with a decline in cognition or memory function or with elevated plasma amyloid short-term. Larger studies are needed to confirm these findings.

Phase II interventional study (N0337) of capecitabine in combination with vinorelbine and trastuzumab for first- or second-line treatment of HER2-positive metastatic breast cancer: a north central cancer treatment group trial.

BACKGROUND: We conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2(+)) metastatic breast cancer (MBC). PATIENTS AND METHODS: The study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m² orally on days 1 to 14, vinorelbine 25 mg/m² intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR. RESULTS: Of 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months). CONCLUSIONS: This triplet combination demonstrated promising activity in patients with HER2(+) MBC.

Current therapeutic strategies for invasive and metastatic bladder cancer.

BACKGROUND: Bladder cancer is one of the most common cancers in Europe, the United States, and Northern African countries. Muscle-invasive bladder cancer is an aggressive epithelial tumor, with a high rate of early systemic dissemination. Superficial, noninvasive bladder cancer can most often be cured; a good proportion of invasive cases can also be cured by a combined modality approach of surgery, chemotherapy, and radiation. Recurrences are common and mostly manifest as metastatic disease. Those with distant metastatic disease can sometime achieve partial or complete remission with combination chemotherapy. RECENT DEVELOPMENTS: Better understanding of the biology of the disease has led to the incorporation of molecular and genetic features along with factors such as tumor grade, lympho-vascular invasion, and aberrant histology, thereby allowing identification of 'favorable' and 'unfavorable' cancers which helps a more accurate informed and objective selection of patients who would benefit from neoadjuvant and adjuvant chemotherapy. Gene expression profiling has been used to find molecular signature patterns that can potentially be predictive of drug sensitivity and metastasis. Understanding the molecular pathways of invasive bladder cancer has led to clinical investigation of several targeted therapeutics such as anti-angiogenics, mTOR inhibitors, and anti-EGFR agents. CONCLUSION: With improvements in the understanding of the biology of bladder cancer, clinical trials studying novel and targeted agents alone or in combination with chemotherapy have increased the armamentarium for the treatment of bladder cancer. Although the novel biomarkers and gene expression profiles have been shown to provide important predictive and prognostic information and are anticipated to be incorporated in clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

Treatment of men with rising prostate-specific antigen levels following radical prostatectomy.

Approximately one-third of patients who undergo radical prostatectomy for prostate cancer will develop a detectable prostate-specific antigen (PSA) level within 10 years. Biochemical recurrence of disease is defined as a rising PSA level in the absence of clinical or radiographic evidence of disease. Management of PSA recurrence is controversial, as prostate cancer may take an indolent course, or it may aggressively develop into metastatic disease. The only potentially curative treatment for biochemical failure after prostatectomy is salvage radiotherapy. Noncurative treatment options include hormone therapy or clinical trials of a novel systemic agent. This article will address management options for a rising PSA level after prostatectomy, as well as ongoing studies exploring molecular biomarkers as prognostic tumor markers and potential targets for prostate cancer therapy.

Update on options for treatment of metastatic castration-resistant prostate cancer.

BACKGROUND: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA) testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC), the median survival is about 1-2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC. RECENT FINDINGS: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99-16) in CRPC, several newer cytotoxic drugs (epothilones, satraplatin), targeted agents (abiraterone, MDV3100) and vaccines have been tested in phase II and III setting with promising results. CONCLUSIONS: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, 'circulating tumor cells', have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.

Quality of life of men with biochemical recurrence of prostate cancer.

This investigation evaluated the psychological needs of men (n = 28) with biochemical recurrence of prostate cancer. A mixed qualitative-quantitative approach was employed. The qualitative component consisted of focus groups and the quantitative component included administration of standardized measures assessing quality of life (QOL), anxiety, and mood. Participants reported substantial anxiety and other negative moods secondary to prostate cancer. Responses form the quantitative instruments suggest participants experience significant health problems specific to prostate cancer, while their general QOL is superior to other chronically ill medical populations. In contrast to the qualitative data, participants rated their mood as favorable on the quantitative measures. Data were used to guide development of a novel QOL intervention.

Novel agents and targets in managing patients with metastatic prostate cancer.

BACKGROUND: Docetaxel has recently been found to improve survival in patients with metastatic androgen-independent prostate cancer (AIPC). Chemotherapy as a first-line option leaves room for improvement, while second-line options are multiple and somewhat controversial. METHODS: Clinically relevant articles focusing on chemotherapy drugs for metastatic prostate cancer and their mechanism of action and efficacy were reviewed from January 2004 through April 2006. RESULTS: Docetaxel is the standard of care for AIPC. However, for doublets with docetaxel or second-line chemotherapy, multiple studies have shown interesting and promising results with calcitriol, thalidomide, bevacizumab, satraplatin, vaccines, ixabepilone, and atrasentan. CONCLUSIONS: Docetaxel should be considered for first-line treatment of metastatic AIPC. Due to its progression-free survival of only 6 months, more effective drugs and drug combinations need to be developed to treat patients with AIPC. Combination treatments with docetaxel and other new agents are promising, but adequately powered phase III trials need to be conducted with survival as the principal endpoint for these promising drug combinations.

Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor.

The identification of novel biomarkers for early prostate cancer diagnosis is highly important because early detection and treatment are critical for the medical management of patients. Disruption in the continuity of both the basal cell layer and basement membrane is essential for the progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive adenocarcinoma in human prostate. The molecules involved in the conversion to an invasive phenotype are the subject of intense scrutiny. We have previously reported that matrix metalloproteinase-26 (MMP-26) promotes the invasion of human prostate cancer cells via the cleavage of basement membrane proteins and by activating the zymogen form of MMP-9. Furthermore, we have found that tissue inhibitor of metalloproteinases-4 (TIMP-4) is the most potent endogenous inhibitor of MMP-26. Here we demonstrate higher (p<0.0001) MMP-26 and TIMP-4 expression in HGPIN and cancer, compared to non-neoplastic acini. Their expression levels are highest in HGPIN, but decline in invasive cancer (p<0.001 for each) in the same tissues. Immunohistochemical staining of serial prostate cancer tissue sections suggests colocalization of MMP-26 and TIMP-4. The present study indicates that MMP-26 and TIMP-4 may play an integral role during the conversion of HGPIN to invasive cancer and may also serve as markers for early prostate cancer diagnosis.