Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

Approaching Neoadjuvant Therapy in the Management of Early-Stage Breast Cancer.

Neoadjuvant therapy is integral to the treatment of early-stage breast cancer. Goals of treatment include surgical downstaging of the tumor, rendering inoperable tumors resectable, and de-escalating axillary surgery in those with clinically positive nodes. Additionally, response to treatment provides important prognostic information regarding risk of recurrence and guides future adjuvant treatment. Although chemotherapy serves as the backbone of neoadjuvant treatment, an increased understanding of the tumor's clinical course as well as its molecular and genetic make-up aids in individualizing treatment and developing novel agents. This review summarizes current clinical approaches and the future direction to the management of breast cancer patients in the neoadjuvant setting.

Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.

PURPOSE: Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2-/cHER2+ can benefit from anti-HER2 targeted therapies. METHODS: cHER2 status was determined in 105 advanced-stage patients with tHER2- breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan-Meier method. RESULTS: Compared to the patients with low-risk cHER2 (cHER2+ < 2), those with high-risk cHER2 (cHER2+ ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20-3.88, P = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10-0.92, P = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36-1.38, P = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7 weeks vs. 2.0 weeks, log-rank P = 0.001). CONCLUSION: In advanced-stage breast cancer patients with tHER2- tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.

Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.

BACKGROUND: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients. METHODS: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models. RESULTS: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level. CONCLUSIONS: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.

Fibromyalgia with Gabapentin and Osteopathic Manipulative Medicine: A Pilot Study.

OBJECTIVES: This pilot study compares the safety and efficacy of three treatments in reducing pain and improving fibromyalgia symptoms. DESIGN: This study was an 8-week prospective, single center feasibility study. SETTING AND SUBJECTS: Forty subjects were recruited from Solano, Sonoma, and Contra Costa counties of California in 2006-2009. Subjects were aged 18-65 and met the American College of Rheumatology (ACR) 1990 criteria for fibromyalgia. INTERVENTIONS: This study had three treatment arms: gabapentin only (900 mg/day), osteopathic manipulative medicine (OMM) only, and combined treatment of gabapentin plus OMM. OMM treatment was administered by advanced medical students for 30 min, once a week. The trial lasted for 8 weeks, which included 6 weeks of treatment plus initial and final visits. OUTCOME MEASURES: Key outcome measures included Wong-Baker FACES Pain Rating Scale (WBF), Clinical Global Impression of Health (CGI), Fibromyalgia Impact Questionnaire (FIQ), and number of tender points. RESULTS: Twenty-nine subjects completed the trial; 8 subjects received gabapentin only, 11 patients received OMM only, and 10 patients received gabapentin plus OMM. Subjects receiving OMM alone and subjects receiving the combined treatment of OMM and gabapentin displayed clinical improvements based on WBF (p < 0.01 and p = 0.03, respectively), while the change among the gabapentin-only group was nonsignificant. The OMM only group was the only group to experience a significant decline in CGI scale (p < 0.01). No statistically significant changes were observed with the FIQ or number of tender points. No differences across groups were statistically significant. This is to be expected in a feasibility study with a small sample size. CONCLUSIONS: This pilot study suggests that OMM treatment and gabapentin are safe and clinically efficacious treatment of pain and other constitutional and somatic symptoms associated with fibromyalgia. A larger trial using the new ACR 2010 Fibromyalgia criteria is needed to confirm these findings.

HSP90 inhibitors in lung cancer: promise still unfulfilled.

Despite recent advances in the treatment of lung cancer, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the United States and worldwide, with a 5-year survival rate of less than 17%. Analysis of the molecular drivers of NSCLC led to the recognition that NSCLC is a collection of distinct, molecularly driven neoplasms. Several subsets of NSCLC with clinical relevance to targeted therapies are defined based on alterations in EGFR, ALK, and other key oncogenic drivers. However, for many oncogenic drivers-such as mutant KRAS-targeted therapies are lacking. Heat shock protein 90 (HSP90) is an adenosine triphosphate (ATP)-dependent molecular chaperone that is critically required for the stability of its clientele, many of which are driver oncoproteins. Therefore, HSP90 inhibitors could prove to be an effective and alternate approach to treat patients with NSCLC that has a specific molecular background or that has acquired resistance to other drugs. Over the last 2 decades, several HSP90 inhibitors have been developed that produced promising preclinical and clinical results. The quest is far from over, however. In this review, we discuss the development and the preclinical and clinical profiles of some of the HSP90 inhibitors that may help to improve the targeted treatment of NSCLC.

KRAS mutant lung cancer: progress thus far on an elusive therapeutic target.

The KRAS mutation remains the most common driver mutation in patients with non-small cell lung cancer (NSCLC) and confers a poor prognosis. Thus far, efforts to target this mutation over the last two decades have been unsuccessful. Over the past 5 years, many efforts to develop drugs that target the RAS-RAF-MEK-ERK (MAPK) pathway have resulted in enhanced understanding of the KRAS mutant NSCLC and have provided optimism that this disease can be targeted.

Hematopoietic growth factors: personalization of risks and benefits.

A common side effect of cancer treatment is bone marrow suppression. The resulting myelosuppression and anemia can cause significant morbidity and mortality for patients. Agents such as granulocyte colony stimulating factors (GCSF) and erythropoietin stimulating agents (ESAs) may be helpful to ameliorate this depression of blood counts; however these agents have risks which also need to be carefully weighed.

Hormonal therapy in breast cancer: a model disease for the personalization of cancer care.

The treatment of breast cancer is driven by subtype classification, of which the assessment of hormone receptor status is one of the important determinants of therapy. The use of hormonal therapy to treat estrogen-receptor positive breast cancer has been studied for over a century and is one of the well-described uses of personalized medicine. In this review, we will describe the classification of hormone receptor status and the various endocrine treatment strategies. Opportunities for personalization of care are illustrated.