Breast cancer is comprised of a number of complex and heterogeneous subtypes with differing clinical behavior and outcomes. In recent years, significant advances have been made in discerning the ...molecular drivers of this disease, and characterizing distinct subtypes of breast cancer based on gene expression profiles. These advances have begun to translate into greater individualization of treatment for patients. Although these advances have shaped our understanding of the underlying biology of breast cancer, most clinical decisions are currently based on tumor expression of the estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). These biomarkers have prognostic and predictive significance in breast cancer and have important implications for tumor growth and metastatic patterns. In this review, we focus on the three broad phenotypes of breast cancer used in clinical practice; ER/PR positive, HER2 positive and triple negative breast cancer (TNBC), which is characterized by lack of expression of ER, PR and HER2. We discuss the influence of these tumor-related factors as well as histological subtype, on the potential for breast cancer recurrence and patterns of disease spread.
Purpose: We explored the relationship between circulating HER2 extracellular domain (ECD) and tissue HER2 status as determined by immunohistochemistry (IHC) and fluorescence in situ hybridization ...(FISH). We also examined its predictive value in a cohort of metastatic breast cancer patients treated with weekly trastuzumab and paclitaxel. Methods: Eligible patients had pre- and post-treatment stored serum specimens and were treated on a previously reported phase II trial. Retrospective analysis evaluated: the association between pretreatment serum HER2 ECD and tissue HER2 status by IHC and FISH; and the association between change in serum HER2 ECD after 12 weeks of therapy and response proportion. Results: Stored serum samples were available for 55/95 (58%) patients. Statistically significant associations were found between HER2 status as assessed by IHC and FISH, and baseline serum HER2 ECD level. Patients whose ECD normalized after 12 weeks of therapy had a higher response proportion compared with patients with persistently high ECD levels (68% versus 15%, P=0.005). A relative decline of over 55% from baseline HER2 ECD predicted response to therapy. Conclusion: A statistically significant association was observed between pretreatment serum HER2 ECD and tissue HER2 status as assessed by IHC and FISH. A decrease in serum HER2 ECD level was a significant predictor of response to trastuzumab-based therapy.
SRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either ...agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study.
Patients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m2 was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3+3 dose-escalation scheme.
Fifteen patients enrolled (median age 54 years, range 35–74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70–120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease.
In combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.
As a comment on the ESMO 2014 bone and cancer guidelines, this letter highlights atypical femur fracture as a rare but serious adverse effect of bisphosphonates and denosumab.
Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner.
In vivo , docetaxel must precede flavopiridol by at least 4 h to ...induce this effect. We conducted a phase I trial of weekly, sequential
docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors.
Experimental Design: Docetaxel at a fixed dose of 35 mg/m 2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m 2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle.
Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring
at flavopiridol 70 mg/m 2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m 2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in
pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies
showed C max ranging from 1.49 ± 0.69 μmol/L (flavopiridol 20 mg/m 2 ) to 4.54 ± 0.08 μmol/L (flavopiridol 60 mg/m 2 ) in cycle 1.
Conclusions: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol
dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both
in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with
gemcitabine-refractory metastatic pancreatic cancer.
Oral Diseases (2012) 18, 602–612
Objective: Infection has been hypothesized as a contributing factor to bisphosphonate (BP)‐related osteonecrosis of the jaw (BRONJ). The objective of this study was ...to determine the bacterial colonization of jawbone and identify the bacterial phylotypes associated with BRONJ.
Materials and methods: Culture‐independent 16S rRNA gene‐based molecular techniques were used to determine and compare the total bacterial diversity in bone samples collected from 12 patients with cancer (six, BRONJ with history of BP; six, controls without BRONJ, no history of BP but have infection).
Results: Denaturing gradient gel electrophoresis profile and Dice coefficient displayed a statistically significant clustering of profiles, indicating different bacterial population in BRONJ subjects and control. The top three genera ranked among the BRONJ group were Streptococcus (29%), Eubacterium (9%), and Pseudoramibacter (8%), while in the control group were Parvimonas (17%), Streptococcus (15%), and Fusobacterium (15%). H&E sections of BRONJ bone revealed layers of bacteria along the surfaces and often are packed into the scalloped edges of the bone.
Conclusion: This study using limited sample size indicated that the jawbone associated with BRONJ was heavily colonized by specific oral bacteria and there were apparent differences between the microbiota of BRONJ and controls.
Prognostic tools in early breast cancer are inadequate. The evolving field of metabolomics may allow more accurate identification of patients with residual micrometastases.
Forty-four early breast ...cancer patients with pre- and postoperative serum samples had metabolomic assessment by nuclear magnetic resonance. Fifty-one metastatic patients served as control. Differential clustering was identified and used to calculate individual early patient ‘metabolomic risk’, calculated as inverse distance of each early patient from the metastatic cluster barycenter. Metabolomic risk was compared with Adjuvantionline 10-year mortality assessment.
Innate serum metabolomic differences exist between early and metastatic patients. Preoperative patients were identified with 75% sensitivity, 69% specificity and 72% predictive accuracy. Comparison with Adjuvantionline revealed discordance. Of 21 patients assessed as high risk by Adjuvantionline, 10 (48%) and 6 (29%) were at high risk by metabolomics in pre- and postoperative settings, respectively. Of 23 low-risk patients by Adjuvantionline, 11 (48%) preoperative and 20 (87%) postoperative patients were at low risk by metabolomics.
This study identifies metabolomic discrimination between early and metastatic breast cancer. Micrometastatic disease may account for metabolomic misclassification of some early patients as metastatic. Metabolomics identifies more patients as low relapse risk compared with Adjuvantionline. Further exploration of this metabolomic fingerprint is warranted.
Background: Drugs that target microtubules, including paclitaxel (Taxol) and docetaxel (Taxotere), are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based ...therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones are a novel class of antimicrotubule agents that have demonstrated antitumor activity in the setting of resistance. Design: This review summarizes clinical studies of epothilones in patients with metastatic breast cancer. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006. Results: The epothilones have demonstrated promising antitumor activity and manageable toxicity in phase II studies of heavily pretreated patients with metastatic breast cancer, including patients with resistance to taxanes and other cytotoxic agents. Neuropathy associated with ixabepilone appears to be schedule dependent and comparable to that observed with paclitaxel. Ixabepilone appears to be active in combination with capecitabine. Conclusions: Ongoing and planned trials promise to elucidate the benefits of ixabepilone in combination with other agents including capecitabine, bevacizumab, and trastuzumab in patients with metastatic breast cancer as well as those receiving neo-adjuvant therapy.
This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical ...and fluorescent in situ hybridization (FISH) assay results.
Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH.
Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications.
Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.
Deposition is one of the key terms of the mineral dust cycle. However, dust deposition remains poorly constrained in transport models simulating the atmospheric dust cycle. This is mainly due to the ...limited number of relevant deposition measurements. This paper aims to present an automatic collector (CARAGA), specially developed to sample the total (dry and wet) atmospheric deposition of insoluble dust in remote areas. The autonomy of the CARAGA can range from 25 days to almost 1 year depending on the programmed sampling frequency (from 1 day to 2 weeks respectively). This collector is used to sample atmospheric deposition of Saharan dust on the Frioul islands in the Gulf of Lions in the Western Mediterranean. To quantify the mineral dust mass in deposition samples, a weighing and ignition protocol is applied. Almost 2 years of continuous deposition measurements performed on a weekly sampling basis on Frioul Island are presented and discussed with air mass trajectories and satellite observations of dust. Insoluble mineral deposition measured on Frioul Island was 2.45 g m−2 for February to December 2011 and 3.16 g m−2 for January to October 2012. Nine major mineral deposition events, measured during periods with significant MODIS aerosol optical depths, were associated with air masses coming from the southern Mediterranean Basin and North Africa.
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