The Role of T2 Mapping in Cardiac Amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy divided into two types: light-chain (LA) and transthyretin (ATTR) CA. Cardiac magnetic resonance (CMR) has emerged as an important diagnostic tool in CA. While late gadolinium enhancement (LGE), T1 mapping and extracellular volume (ECV) have a consolidate role in the assessment of CA, T2 mapping has been less often evaluated. We aimed to test the value of T2 mapping in the evaluation of CA. This study recruited 70 patients with CA (51 ATTR, 19 AL). All the subjects underwent 1.5 T CMR with T1 and T2 mapping and cine and LGE imaging. Their QALE scores were evaluated. The myocardial T2 values were significantly (p < 0.001) increased in both types of CA compared to the controls. In the AL-CA group, increased T2 values were associated with a higher QALE score. The myocardial native T1 values and ECV were significantly (p < 0.001) higher in the CA patients than in the healthy subjects. Left ventricular (LV) mass, QALE score and ECV were higher in ATTR amyloidosis compared with AL amyloidosis, while the LV ejection fraction was lower (p < 0.001). These results support the concept of the presence of myocardial edema in CA. Therefore, a CMR evaluation including not only myocardial T1 imaging but also myocardial T2 imaging allows for more comprehensive tissue characterization in CA.

A pharmacogenetic interaction analysis of bevacizumab with paclitaxel in advanced breast cancer patients.

To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1, and TSP-1 SNPs and their role on progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with bevacizumab plus first-line paclitaxel or with paclitaxel alone. Analyses were performed on germline DNA, and SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction (MDR) methodology was applied to investigate the interaction between SNPs. The present study was an explorative, ambidirectional cohort study: 307 patients from 11 Oncology Units were evaluated retrospectively from 2009 to 2016, then followed prospectively (NCT01935102). Two hundred and fifteen patients were treated with paclitaxel and bevacizumab, whereas 92 patients with paclitaxel alone. In the bevacizumab plus paclitaxel group, the MDR software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes. Median PFS for favorable genetic profile was 16.8 vs. the 10.6 months of unfavorable genetic profile (p = 0.0011). Cox proportional hazards model showed an adjusted hazard ratio of 0.64 (95% CI, 0.5-0.9; p = 0.004). Median OS for the favorable genetic profile was 39.6 vs. 28 months of unfavorable genetic profile (p = 0.0103). Cox proportional hazards model revealed an adjusted hazard ratio of 0.71 (95% CI, 0.5-1.01; p = 0.058). In the 92 patients treated with paclitaxel alone, the results showed no effect of the favorable genetic profile, as compared to the unfavorable genetic profile, either on the PFS (p = 0.509) and on the OS (p = 0.732). The pharmacogenetic statistical interaction between VEGF-A rs833061 and VEGFR-2 rs1870377 genotypes may identify a population of bevacizumab-treated patients with a better PFS.

Predictive and prognostic role of p53 according to tumor phenotype in breast cancer patients treated with preoperative chemotherapy: a single-institution analysis.

INTRODUCTION AND AIMS: The p53 protein is a mediator of the cellular response to DNA damage. The aim of this study was to evaluate the predictive and/or prognostic value of p53 expression in relation to the molecular subtypes of breast cancer in patients treated with preoperative chemotherapy. PATIENTS AND METHODS: Patients with stage II-III breast cancer were included in the study. The expression of p53 was evaluated by immunohistochemistry on the diagnostic core biopsy specimen. Patients received 4-6 courses of preoperative chemotherapy. Pathological complete response (pCR) was defined as complete disappearance of invasive tumor in the breast and axillary lymph nodes. RESULTS: 154 patients were included in the study and the molecular subtypes of their tumors were classified as follows: triple negative 18.2%, hormone receptor positive 60.4%, and HER2 positive 21.4%. p53 was expressed in 43.5% of the patients. A significant association between p53 expression and breast cancer molecular subtypes, tumor differentiation, and proliferation was observed. pCR was achieved in 8 patients (5.2%). p53 expression, molecular subtype, and nuclear grading were significant predictors of pCR (odds ratio for pCR in patients with p53-expressing tumors 10.03, p=0.0077). In univariate analysis, the expression of p53 as well as high proliferation and lymph node involvement after preoperative chemotherapy were predictors of a worse disease-free survival. Patients with p53 positivity also had a worse overall survival. In multivariate analysis, both p53 expression and nodal status after preoperative chemotherapy were significantly associated with disease-free and overall survival: the hazard ratios for relapse and death in patients with p53-expressing versus non-p53-expressing tumors were 2.29 (p=0.015) and 7.74 (p=0.002), respectively. The hazard ratios for relapse and death in node-positive versus node-negative patients were 3.63 (p=0.003) and 3.64 (p=0.041), respectively. CONCLUSIONS: In this series of patients, p53 expression was significantly associated with markers of aggressive tumor biology, and with a higher likelihood of attaining pCR. p53 expression was a negative prognostic parameter for disease free and overall survival in univariate and multivariate analysis.

Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management.

INTRODUCTION: The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patients.

Letrozole versus letrozole plus Lapatinib (GW572016) in hormone-sensitive, HER2-negative operable breast cancer: a double-blind, randomized, phase II study with biomarker evaluation (EGF109077-LAP107692/LETLOB).

Many hormone receptor-positive tumors show primary or acquired resistance, possibly because of a crosstalk with other growth factor-related transduction pathways (mainly epidermal growth factor receptor family related). The LETLOB study is a European multicenter, placebo-controlled, randomized phase II trial in postmenopausal patients with hormone-sensitive, HER2-negative, stage II-IIIA (T > 2 cm, N0-1, M0) breast cancer, in which letrozole or the combination of letrozole plus lapatinib will be administered for 6 months before surgery. Clinical endpoints (primary [ultrasonographic objective response], secondary [rate of pathologic complete response and of conservative surgery, safety, and time to treatment failure], and biologic [inhibition of intermediate and final biomarkers of the proliferative and apoptosis pathways and gene profile correlation with response]) will be evaluated.

Primary systemic therapy for operable breast cancer: a review of clinical trials and perspectives.

Primary systemic therapy represents the standard of care for locally advanced breast cancer and has becoming an attractive alternative in earlier stages. A part from the proven advantage of increasing the rate of breast conservative surgery, the up front use of systemic therapy can allow for an in vivo test of treatment sensitivity, and response to primary treatment discriminates patients at different prognosis. This review will summarize the more relevant data on the preoperative treatment with chemotherapy, hormonal therapy and targeted agents.

EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition.

BACKGROUND: We aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status. METHODS: One hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine-kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test. RESULTS: EGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p = 0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p = 0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p = 0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p = 0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p = 0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI. CONCLUSIONS: In our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation.

Phase II, randomized trial of preoperative epirubicin-paclitaxel +/- gefitinib with biomarker evaluation in operable breast cancer.

PURPOSE: To evaluate the in vivo effect of adding gefitinib to preoperative chemotherapy on the EGFR-dependent p42/44 MAPK in operable breast cancer (BC) patients. Secondary aims: to evaluate EGFR, (p)-EGFR, Ki67, apoptotic index (TUNEL test) and VEGFR2 expression from baseline to surgery, percentage of pathologic complete response (pCR), and toxicity. PATIENTS AND METHODS: 90 patients with stage II-IIIA BC have been randomized to receive epirubicin 90 mg/sqm and paclitaxel 175 mg/sqm on day 1 plus: gefitinib 250 mg daily from day 5 to 16 (Arm A, intermittent), gefitinib 250 mg daily from day 1 to 21 (Arm B, continuous), or placebo (Arm C). Treatment plan: 4 courses every 3 weeks, followed by surgery. RESULTS: After preoperative therapy, 86/90 patients underwent surgery; 46 patients (51%) received breast conservative surgery. A pCR was observed in 4 patients. No significant differences in the expression of p42/44 MAPK, EGFR, (p)-EGFR, VEGFR2, proliferation index and apoptosis were observed comparing the combined Arms A + B vs C, and comparing Arm A vs B. Hematologic toxicities were not significantly different comparing Arms A + B vs Arm C, and comparing Arm A vs B. Significantly higher skin and mucosal toxicities were observed when comparing the two gefitinib Arms (A + B) vs Arm C (32% vs 9.6%, P = 0.018; 57% vs 29%, P = 0.009 respectively), while no significant differences were observed comparing Arm A vs B. CONCLUSION: Adding gefitinib to chemotherapy did not result in different effects on the EGFR-dependent pathway, proliferation, apoptosis and VEGFR2 expression as compared to placebo, while enhancing skin and mucosal toxicity. The two schedules of gefitinib (intermittent vs continuous) did not result in different biologic effects.

Renal safety and efficacy of i.v. bisphosphonates in patients with skeletal metastases treated for up to 10 Years.

INTRODUCTION: Bisphosphonates (BPs) delay the onset or reduce the incidence of skeletal complications in patients with bone metastases. However, there are few data on the renal safety and activity of i.v. BPs beyond 2 years of administration. MATERIALS AND METHODS: We retrospectively analyzed serum creatinine (SCr) levels and skeletal-related events (SREs) in cancer patients receiving i.v. BPs for >or= 24 months. All patients received 90 mg pamidronate every 3-4 weeks. Pre- and post-treatment SCr levels and the peak levels attained were recorded. A notable SCr increase was defined as: an increase >0.5 mg/dl for patients with baseline SCr <1.4 mg/dl; an increase >1 mg/dl for patients with baseline SCr >1.4 mg/dl; or doubling over baseline. The following parameters were also analyzed: the proportion of patients with at least one SRE, the distribution of each type of SRE, the time to first SRE, and the skeletal morbidity rate (SMR). RESULTS: Fifty-seven patients with bone metastases resulting from breast cancer (BC) (n = 48), multiple myeloma (n = 7), renal cell carcinoma (n = 1), and prostate cancer (n = 1) were evaluated. The median age at the start of treatment was 57 years (range, 27-81); 25% of the patients were >70 years old. Forty-three patients received pamidronate then switched to zoledronic acid. The median overall duration of BP administration was 34 months (range, 24+ to 131+), with a median duration of zoledronic acid therapy of 25 months (range, 2-40). Twenty-seven of 48 BC patients received different chemotherapy regimens (median number of lines, 2; range, 1-6). The median SCr levels were: baseline, 0.82 mg/dl (range, 0.4-1.4); time of analysis, 0.89 mg/dl (0.4-2); highest level, 1.0 mg/dl (0.5-2). A notable SCr increase was observed in seven patients (12.2%; all grade 1). Twenty-six patients (45.6%) experienced SREs after starting BP treatment. The median time to first SRE was 911 days (95% confidence interval, 731; 1,023). The SMR was 0.20 events per year. Ten patients ceased treatment because of: an SCr level of 2 mg/dl (n = 1) physician decision (n = 6) and jaw osteonecrosis (n = 3). Ten patients died of progressive disease. CONCLUSION: i.v. BPs are safe and active during prolonged treatment administration, and renal function is maintained in patients receiving multiple cytotoxic therapies. Jaw osteonecrosis occurred in 5% of the study population, and its causal relationship with BP treatment requires further observation and study.