Management of advanced pancreatic cancer with gemcitabine plus erlotinib: efficacy and safety results in clinical practice.

CONTEXT: The combination of gemcitabine and erlotinib is a standard first-line treatment for unresectable, locally advanced or metastatic pancreatic cancer. We reviewed our single centre experience to assess its efficacy and toxicity in clinical practice. METHODS: Clinical records of patients with unresectable, locally advanced or metastatic pancreatic cancer who were treated with the combination of gemcitabine and erlotinib were reviewed. MAIN OUTCOME MEASURES: Univariate survival analysis and multivariate analysis were carried out to indentify independent predictors factors of overall survival. RESULTS: Our series included 55 patients. Overall disease control rate was 47%: 5% of patients presented complete response, 20% partial response and 22% stable disease. Median overall survival was 8.3 months). Cox regression analysis indicated that performance status and locally advanced versus metastatic disease were independent factors of overall survival. Patients who developed acne-like rash toxicity, related to erlotinib administration, presented a higher survival than those patients who did not develop this toxicity. CONCLUSIONS: Gemcitabine plus erlotinib doublet is active in our series of patients with advanced pancreatic cancer. This study provides efficacy and safety results similar to those of the pivotal phase III clinical trial that tested the same combination.

Trastuzumab for the treatment of salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy with high mortality and poor response to treatment. A significant fraction of SDCs are HER2 positive. This retrospective review examines HER2 testing in SDC and the outcome of trastuzumab-based therapy in adjuvant and palliative settings. METHODS: A total of 13 patients with SDC and HER2/neu expression by immunohistochemistry of 1-3+ were treated with trastuzumab in adjuvant (n = 8) or palliative (n = 5) setting. Adjuvant therapy consisted of concurrent radiation and chemotherapy with weekly paclitaxel, carboplatin, and trastuzumab (TCH) for 6 weeks followed by TCH for 12 weeks and trastuzumab alone for 1 year. Palliative treatment for metastatic disease consisted of TCH every 3 weeks for 6 cycles followed by trastuzumab for variable time periods with or without second-line chemotherapy for progression. All patients had fluorescence in situ hybridization testing for HER2/neu gene amplification. RESULTS: The median duration of follow-up was 27 months (range: 8-48 months). In all, 62% of adjuvant patients (5/8) had no evidence of disease more than 2 years from completion of therapy. All patients with metastatic disease (5/5 patients) responded to treatment with TCH. One patient achieved a complete response and remains with no evidence of disease 52 months after initiation of TCH. The median duration of response was 18 months (range: 8-52 months). CONCLUSION: HER2/neu positivity and treatment with trastuzumab correlated well with long-term survival and response in our patients. Based on this data, we propose that HER2/neu status be examined routinely in all patients with SDCs and the treatment be directed accordingly.

Machine Learning Models and Multiparametric Magnetic Resonance Imaging for the Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Most breast cancer (BC) patients fail to achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). The aim of this study was to evaluate whether imaging features (perfusion/diffusion imaging biomarkers + radiomic features) extracted from pre-treatment multiparametric (mp)MRIs were able to predict, alone or in combination with clinical data, pCR to NAC. METHODS: Patients with stage II-III BC receiving NAC and undergoing breast mpMRI were retrospectively evaluated. Imaging features were extracted from mpMRIs performed before NAC. Three different machine learning models based on imaging features, clinical data or imaging features + clinical data were trained to predict pCR. Confusion matrices and performance metrics were obtained to assess model performance. Statistical analyses were conducted to evaluate differences between responders and non-responders. RESULTS: Fifty-eight patients (median [range] age, 52 [45-58] years) were included, of whom 12 showed pCR. The combined model improved pCR prediction compared to clinical and imaging models, yielding 91.5% of accuracy with no false positive cases and only 17% false negative results. Changes in different parameters between responders and non-responders suggested a possible increase in vascularity and reduced tumour heterogeneity in patients with pCR, with the percentile 25th of time-to-peak (TTP), a classical perfusion parameter, being able to discriminate both groups in a 75% of the cases. CONCLUSIONS: A combination of mpMRI-derived imaging features and clinical variables was able to successfully predict pCR to NAC. Specific patient profiles according to tumour vascularity and heterogeneity might explain pCR differences, where TTP could emerge as a putative surrogate marker for pCR.

Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Successful Second-Line Metronomic Temozolomide in Metastatic Paraganglioma: Case Reports and Review of the Literature.

Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B (SDHB) mutations. Cyclophosphamide-dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB-related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses.