Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all ...subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers.
We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50–69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis.
Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor–negative or HER2-positive status (odds ratio=1.7; 95% confidence interval CI: 1.1–2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%–94.5%) versus 93.8% (95% CI: 86.5%–100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6–16.7).
IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.
•pT1a N0M0 human epidermal growth factor receptor 2 (HER2)-positive interval cancers have a poorer outcome than HER2-positive screen-detected (SD) cancers.•Consider aggressive adjuvant treatments only in patients with interval-detected tumours.•Avoid overtreatment strategies in small, HER2-positive SD cancers.
The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) ...characterized by high cell proliferation, aggressive behavior, and chemo-resistance.
This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen.
From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.
The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity.
2012-003505-10.
•Eribulin plus gemcitabine showed a remarkable best ORR of 37.3% and a clinical benefit rate of 48.8%.•The most common grade 3/4 toxicities were liver toxicity and neutropenia without febrile neutropenia.•The study regimen partially lost its efficacy in patients harboring BRCA1/2 pathogenic variants.•SNPs in CYP3A4 and FGD4 genes were associated with increased risk of liver toxicity.•Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.
The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + ...taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting.
We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian ‘real-world’ setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant.
Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095).
Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.
•This is the first study comparing pertuzumab + trastuzumab + taxane (P + T + taxane) with T-DM1 in early-relapsing HER2+ MBC.•The majority of early-relapsing HER2+ MBC have high-grade, node-positive, large primary tumors.•First-line T-DM1 compared with P + T + taxane is associated with worse progression-free survival.•First-line T-DM1 compared with P + T + taxane is associated with worse overall survival.•Post-progression survival does not differ between the two treatments cohorts.
Turbulent diffusion flames are inherently complex due to the coupling of highly non-linear chemical kinetics and turbulence. It is necessary to understand this interdependency of transport and ...kinetic mechanisms in order to accurately predict non-equilibrium effects such as pollutant formation. Acoustically forced flames are useful because they exhibit a larger range of combustion conditions than those observed in steady flames. Thus, these flames give insights into a variety of chemistry-flow field interactions important in turbulent combustion. In this article, spatially and temporally resolved concentrations of PAH concentrations are presented for 1-500 Hz acoustically forced methane/air counter flow flames. Numerical results are compared with experimental measurements obtained in similar conditions. Both experimental and numerical results reveal a relevant net increase in aromatic concentrations accompanying flame forcing and PAHs appear to be a function of both flame strain rate and forcing frequency. Different size PAHs exhibit specific behaviour according to their characteristic chemical time scales that are longer than the one of the whole combustion process.
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