Targeting HER2 in Gastroesophageal Adenocarcinoma: Molecular Features and Updates in Clinical Practice.

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

Circulating Tumor DNA in Gastric Adenocarcinoma: Future Clinical Applications and Perspectives.

Gastric cancer (GC) is still one of the most aggressive cancers with a few targetable alterations and a dismal prognosis. A liquid biopsy allows for identifying and analyzing the DNA released from tumor cells into the bloodstream. Compared to tissue-based biopsy, liquid biopsy is less invasive, requires fewer samples, and can be repeated over time in order to longitudinally monitor tumor burden and molecular changes. Circulating tumor DNA (ctDNA) has been recognized to have a prognostic role in all the disease stages of GC. The aim of this article is to review the current and future applications of ctDNA in gastric adenocarcinoma, in particular, with respect to early diagnosis, the detection of minimal residual disease (MRD) following curative surgery, and in the advanced disease setting for treatment decision choice and therapeutic monitoring. Although liquid biopsies have shown potentiality, pre-analytical and analytical steps must be standardized and validated to ensure the reproducibility and standardization of the procedures and data analysis methods. Further research is needed to allow the use of liquid biopsy in everyday clinical practice.

Krukenberg Tumor Related to Gallbladder Cancer in a Young Woman: A Case Report and Review of the Literature.

A gallbladder tumor is a rare condition, which usually spreads to the liver, lymph nodes, and other organs. A Krukenberg tumor, derived from the biliary tract and gallbladder cancers (GBCs), is an uncommon finding in routine clinical practice. Here, a case of a young woman with a Krukenberg tumor related to a previous diagnosis of GBC is reported. Differential diagnosis of an ovarian malignant lesion is challenging for both clinicians and pathologists. In order to provide a proper diagnosis, integrated multidisciplinary management is essential. The occurrence of Krukenberg tumors should be evaluated in the management of GBC, even if this is rare in clinical practice.

Anti-Claudin Treatments in Gastroesophageal Adenocarcinoma: Mainstream and Upcoming Strategies.

Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells.

Quantification of 3/4D ultrasound pelvic floor changes induced by postpartum muscle training in patients with levator ani muscle avulsion: a parallel randomized controlled trial.

Background: We believe that physiotherapy with muscle training (MT) of the postpartum pelvic floor may lead to a change in the clinical management of patients with avulsion of the puborectal portion of the levator ani muscle (LAM). Our objective is to assess whether physiotherapy with MT of the postpartum pelvic floor in patients with LAM avulsion produces changes in pelvic floor morphology evaluated by 3/4D transperineal ultrasound. Methods: This parallel randomized controlled trial (RCT) included 97 primiparous patients. A study was conducted in three parts. In the first part (3 months postpartum), primiparous patients with LAM avulsion were recruited, and the levator hiatus and the LAM areas were measured using 3/4D transperineal ultrasound. In the second part (3 to 6 months postpartum), patients were randomized into two groups, with one undergoing rehabilitation (experimental group) and another without rehabilitation (control group). At the end of 6 months, a new transperineal ultrasound was performed. In the third part (9 months postpartum), the levator hiatus and LAM dimensions were analyzed again. The RCT was registered at ClinicalTrials.gov (NCT03686956). Project PI16/01387 funded by Instituto de Salud Carlos III (Spain) integrated in the national I+D+i 2013-2016 and cofounded by the European Union (ERDF/ESF, "Investing in your future"). Results: A total of 92 completed the study, including 46 patients in the experimental group and 46 in the control group. The experimental group had a greater LAM area at 6 months (9.2±1.9 vs. 7.6±2.1 cm2, P=0.008; 95% CI: 0.6-3.0) and 9 months after labor (9.4±2.7 vs. 7.6±2.0 cm2, P=0.012; 95% CI: 0.4-3.2), which was not observed at 3 months postpartum (8.3±1.6 vs. 7.5±2.3 cm2; P=0.183; 95% CI: 0.39-1.99). The levator hiatus area decreased more in the experimental group in almost all comparisons. The most significant change occurred from 3 to 6 months during the Valsalva maneuver (-3.92±5.12 vs. 0.45±3.06 cm2; P<0.005; 95% CI: 2.64-5.00). Conclusions: Women with a rehabilitated LAM through physiotherapy showed a significant reduction in the levator hiatus area during Valsalva while receiving in-person physical therapy (3 to 6 months after delivery). These differences did not persist once physical therapy was completed (6 to 9 months after delivery). Trial Registration: ClinicalTrials.gov identifier NCT03686956.

Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma. METHODS: RAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36. FINDINGS: Between Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths. INTERPRETATION: Ramucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting. FUNDING: Eli Lilly Italy. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.

Early fetal morphological evaluation (11-13 + 6 weeks) accomplished exclusively by transabdominal imaging and following routine midtrimester fetal ultrasound scan recommendations. Since when can it be performed?

Objectives: To establish the best timing for the realization of first-trimester-morphologic-evaluation, following routine midtrimester fetal-ultrasound-scan-recommendations (RFUSR), by performing exclusive transabdominal exploration, and to determine the sensitivity of the mentioned scan for diagnosis of major structural abnormalities.Method: Prospective observational study with 512 pregnant women with singleton gestations (438 low-risk, 74 high-risk) was conducted. Early fetal morphological evaluation (EFME) is performed in line with RFUSR (18-22 weeks) (ISUOG 2010) and a check-list structured evaluation was followed, between 11-13 + 6 weeks. Its performance is assessed in the correct identification of normal fetal anatomy, and its effectiveness in the detection of structural defectsResults: Five hundred and four pregnant women were evaluated, of which, 58.3% EFME are considered complete fetal anatomical surveys. Complete fetal anatomical surveys scans rise from 23.1% at 11-11 + 6 weeks to 63.8% at 13 + 3-13 weeks, with a clear turning point at 12 + 6-13 + 3 weeks (63.8%) (p < .05). From 12 + 6-13 + 3 weeks only renal (26.3%) and cardiac assessments (31.6%) present an inconclusive evaluation greater than 20%. Body mass index (23.9 versus 29.8) and estimated fetal weight (63 versus 86.7 g) influence EMFE's ability of identifying fetal structures (p < .05). EMFE presents sensitivity for the identification of structural malformations of 83.3% (20/24).Conclusions: From 12 + 6 weeks of gestation onwards, a complete fetal morphological evaluation can be performed in 63.8% of cases following the routine midtrimester fetal ultrasound scan recommendations (ISUOG's 20 weeks scan).

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p < 0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p = 0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

Impact of Exon 19 Deletion Subtypes in EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer Treated With First-Line Tyrosine Kinase Inhibitors.

BACKGROUND: Common epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. PATIENTS AND METHODS: In this retrospective analysis, 106 patients with metastatic NSCLC harboring EGFR exon 19 deletions and treated with first-line TKIs were included. The primary end point was overall survival (OS), the secondary end point progression-free survival (PFS). Analyses were performed by grouping exon 19 deletions according to 2 models: we compared different type of deletion (delE746_A750 vs. deletions other than delE746-A750, defined as "uncommon") or different starting codon of deletion (E746 vs. L747). RESULTS: The frequency of uncommon deletions of exon 19 was 36%. When delE746_A750 (n = 68) was compared to the other deletions in exon 19 (n = 38), no differences were found, either in terms of OS (P = .65) or PFS (P = .65). Similarly, no difference in OS (P = .74) or PFS (P = .99) emerged when comparing the E746 group (n = 81) to the L747 group (n = 25). On multivariate analysis including clinical characteristics and type of deletions (delE746_A750 vs. uncommon deletions or E746 vs. L747), only the presence of brain metastases at diagnosis or during TKI treatment was associated with shorter PFS but not with worse OS. CONCLUSION: Different exon 19 deletions are equally sensitive to first-line EGFR-TKIs in EGFR-mutant NSCLC.

A simple model to predict the complicated operative vaginal deliveries using vacuum or forceps.

BACKGROUND: Complicated operative vaginal deliveries are associated with high neonatal morbidity and maternal trauma, especially if the procedure is unsuccessful and a cesarean delivery is needed. The decision to perform an operative vaginal delivery has traditionally been based on a subjective assessment by digital vaginal examination combined with the clinical expertise of the obstetrician. Currently there is no method for objectively quantifying the likelihood of successful delivery. Intrapartum ultrasound has been introduced in clinical practice to help predict the progression and final method of delivery. OBJECTIVE: The aim of this study was to compare predictive models for identifying complicated operative vaginal deliveries (vacuum or forceps) based on intrapartum transperineal ultrasound in nulliparous women. STUDY DESIGN: We performed a prospective cohort study in nulliparous women at term with singleton pregnancies and full dilatation who underwent intrapartum transperineal ultrasound evaluation prior to operative vaginal delivery. Managing obstetricians were blinded to the ultrasound data. Intrapartum transperineal ultrasound (angle of progression, progression distance, and midline angle) was performed immediately before instrument application, both at rest and concurrently with pushing. Intrapartum evaluation of fetal biometric parameters (estimated fetal weight, head circumference, and biparietal diameter) was also carried out. An operative vaginal delivery was classified as complicated when 1 or more of the following complications occurred: ≥3 tractions needed; third- to fourth-degree perineal tear; severe bleeding during episiotomy repair (decrease of ≥2.5 g/dL in the hemoglobin level); or significant traumatic neonatal lesion (subdural-intracerebral hemorrhage, epicranial subaponeurotic hemorrhage, skeletal injuries, injuries to spine and spinal cord, or peripheral and cranial nerve injuries). Six predictive models were evaluated (information available in Table 2). RESULTS: We recruited 84 nulliparous patients, of whom 5 were excluded because of the difficulty of adequately evaluating the biparietal diameter and head circumference. A total of 79 nulliparous patients were studied (47 vacuum deliveries, 32 forceps deliveries) with 13 cases in the occiput-posterior position. We identified 31 cases of complicated operative vaginal deliveries (19 vacuum deliveries and 12 forceps deliveries). No differences were identified in obstetric, neonatal, or intrapartum characteristics between the 2 study groups (operative uncomplicated vaginal delivery vs operative complicated vaginal delivery), with the following exceptions: estimated fetal weight (3243 ± 425 g vs 3565 ± 330 g; P = .001), biparietal diameter (93.2 ± 2.1 vs 95.2 ± 2.3 mm; P = .001), head circumference (336 ± 12 vs 348 ± 6.4 mm; P = .001), sex (female 62.5% vs 29.0%; P = .010), newborn weight (3258 ± 472 g vs 3499 ± 383 g; P = .027), and number of tractions (median, interquartile range) (1 [1-2] vs 4 [3-5]; P < .0005). To predict complicated operative deliveries, all 6 of the studied models presented an area under the receiver-operating characteristics curve between 0.863 and 0.876 (95% confidence intervals, 0.775-0.950 and 0.790-0.963; P < .0005). The results of the study met the criteria of interpretability and parsimony (simplicity), allowing us to identify a binary logistic regression model based on the angle of progression and head circumference; this model has an area under the receiver-operating characteristics curve of 0.876 (95% confidence interval, 0.790-0.963; P < .0005) and a calibration slope B of 0.984 (95% confidence interval, 0.0.726-1.243; P < .0005). CONCLUSION: The combination of the angle of progression and the head circumference can predict 87% of complicated operative vaginal deliveries and can be performed in the delivery room.

Prognostic and predictive role of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy.

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG-PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed-based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first-line pemetrexed-based chemotherapy, and evaluated by FDG-PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were correlated with FDG-PET parameters, such as maximum standardized uptake value (SUVmax ), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG-PET in a large series of MPM patients treated with first-line pemetrexed-based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut-off values to define early metabolic response supported the role of FDG-PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.

Clinical staging of malignant pleural mesothelioma: current perspectives.

Malignant pleural mesothelioma (MPM) is a disease with limited therapeutic options, the management of which is still controversial. Diagnosis is usually made by thoracoscopy, which allows multiple biopsies with histological subtyping and is indicated for staging purposes in surgical candidates. The recommended and recently updated classification for clinical use is the TNM staging system established by the International Mesothelioma Interest Group and the International Association for the Study of Lung Cancer, which is based mainly on surgical and pathological variables, as well as on cross-sectional imaging. Contrast-enhanced computed tomography is the primary imaging procedure. Currently, the most used measurement system for MPM is the modified Response Evaluation Criteria in Solid Tumors (RECIST) method, which is based on unidimensional measurements of tumor thickness perpendicular to the chest wall or mediastinum. Magnetic resonance imaging and functional imaging with 18F-fluoro-2-deoxy-D-glucose positron-emission tomography can provide additional staging information in selected cases, although the usefulness of this method is limited in patients undergoing pleurodesis. Molecular reclassification of MPM and gene expression or miRNA prognostic models have the potential to improve prognostication and patient selection for a proper treatment algorithm; however, they await prospective validation to be introduced in clinical practice.

Intrapartum transperineal ultrasound used to predict cases of complicated operative (vacuum and forceps) deliveries in nulliparous women.

INTRODUCTION: The objective of this study was to investigate the predictive value of intrapartum transperineal ultrasound in the identification of complicated operative (vacuum or forceps) deliveries in nulliparous women. MATERIAL AND METHODS: Prospective observational study of nulliparous women with an indication for operative delivery who underwent intrapartum transperineal ultrasound before fetal extraction. Managing obstetricians were blinded to the ultrasound data. Intrapartum transperineal ultrasound was performed immediately before blade application, both at rest and concurrently with contractions and active pushing. Operative delivery was classified as complicated when one or more of the following situations occurred: three or more tractions; a third-/fourth-degree perineal tear; significant bleeding during the episiotomy repair; major tear or significant traumatic neonatal lesion. RESULTS: A total of 143 nulliparous women were included in the study (82 vacuum-assisted deliveries and 61 forceps-assisted deliveries), with 20 fetuses in occiput posterior position. Forty-seven operative deliveries were classified as complicated deliveries (28 vacuum-assisted deliveries, 19 forceps-assisted deliveries). No differences in obstetric, intrapartum or neonatal characteristics were observed between the study groups, with the following exceptions: birthweight (3229 ± 482 uncomplicated deliveries vs. 3623 ± 406 complicated deliveries; p < 0.003) and number of vacuum tractions (1.4 uncomplicated deliveries, 4.5 complicated deliveries; p < 0.0005). The strongest predictors of a complicated delivery, using the area under the receiver-operating characteristics curve (AUC), were the angle of progression with active pushing (AoP2) (AUC 86.9%) and the progression distance with active pushing (PD2) (AUC 74.5%). The optimal cut-off value for predicting a difficult operative delivery was an AoP2 of 153.5° (sensitivity 95.2%; false-positive rate 5.9%) or PD2 of 58.5 mm (sensitivity 95.2%; false-positive rate 7.1%). CONCLUSIONS: The sonographic parameters AoP2 and PD2 can be used to predict cases of complicated operative deliveries in nulliparous women.

A Phase II Study of PF-03446962 in Patients with Advanced Malignant Pleural Mesothelioma. CCTG Trial IND.207.

There is no approved second-line systemic therapy option for malignant pleural mesothelioma (MPM), but targeting angiogenesis is an area of investigation. PF-03446962 is a fully human antibody against activin receptor-like kinase 1, which is commonly expressed in tumor vasculature. We performed a multicenter, open label, single-arm, two-stage phase II study of PF-03446962 in patients with MPM and progressive disease after platinum-based chemotherapy. In total, 17 patients were enrolled, but no partial or complete responses were observed. The trial did not meet the prespecified response criterion for moving to the second stage. There were only three grade 3 (G3) or higher nonhematological toxicities observed (G3 hypertension [n=2] and G3 fatigue [n=1]) and just one episode of G3 lymphopenia. In conclusion, PF-03446962, despite being generally well tolerated, failed to demonstrate efficacy in the treatment of advanced MPM as a single agent. There are no plans for further investigation of this agent in MPM.

Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer.

In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enumeration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7-5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3-9.7 m). The most common toxicities (all grades/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to foretinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484).

Progression-free survival as primary endpoint in randomized clinical trials of targeted agents for advanced renal cell carcinoma. Correlation with overall survival, benchmarking and power analysis.

PURPOSE: A correlation, power and benchmarking analysis between progression-free and overall survival (PFS, OS) of randomized trials with targeted agents or immunotherapy for advanced renal cell carcinoma (RCC) was performed to provide a practical tool for clinical trial design. RESULTS: For 1st-line of treatment, a significant correlation was observed between 6-month PFS and 12-month OS, between 3-month PFS and 9-month OS and between the distributions of the cumulative PFS and OS estimates. According to the regression equation derived for 1st-line targeted agents, 7859, 2873, 712, and 190 patients would be required to determine a 3%, 5%, 10% and 20% PFS advantage at 6 months, corresponding to an absolute increase in 12-month OS rates of 2%, 3%, 6% and 11%, respectively. CONCLUSIONS: These data support PFS as a reliable endpoint for advanced RCC receiving up-front therapies. Benchmarking and power analyses, on the basis of the updated survival expectations, may represent practical tools for future trial' design.

Impact of neoadjuvant single or dual HER2 inhibition and chemotherapy backbone upon pathological complete response in operable and locally advanced breast cancer: Sensitivity analysis of randomized trials.

The role of the dual HER2 inhibition, and the best chemotherapy backbone for neoadjuvant chemotherapy still represent an issue for clinical practice. A literature-based meta-analysis exploring single versus dual HER2 inhibition in terms of pathological complete response (pCR, breast plus axilla) rate and testing the interaction according to the chemotherapy (anthracyclines-taxanes or taxanes) was conducted. In addition, an event-based pooled analysis by extracting activity and safety events and deriving 95% confidence intervals (CI) was accomplished. Fourteen trials (4149 patients) were identified, with 6 trials (1820 patients) included in the meta-analysis and 31 arms (14 trials, 3580 patients) in the event-based pooled analysis. The dual HER2 inhibition significantly improves pCR rate, in the range of 16-19%, regardless of the chemotherapy backbone (relative risk 1.37, 95% CI 1.23-1.53, p<0.0001); pCR was significantly higher in the hormonal receptor negative population, regardless of the HER2 inhibition and type of chemotherapy. pCR and the rate of breast conserving surgery was higher when anthracyclines were added to taxanes, regardless of the HER2 inhibition. Severe neutropenia was higher with the addition of anthracyclines to taxanes, with an absolute difference of 19.7%, despite no differences in febrile neutropenia. While no significant differences according to the HER2 inhibition were found in terms of cardiotoxicity, a slightly difference for grade 3-4 (1.2%) against the addition of anthracyclines was calculated. The dual HER2 inhibition for the neoadjuvant treatment of HER2-positive breast cancer significantly increases pCR; the combination of anthracyclines, taxanes and anti-Her2 agents should be currently considered the standard of care.

Anti-angiogenic drugs and biomarkers in non-small-cell lung cancer: a 'hard days night'.

The discovery of specific molecular alterations (i.e. EGFR activating mutations, EML4/ALK translocation, ROS1 rearrangements) in a selected population of patients affected by non small cell lung cancer (NSCLC) translated into effective treatments for this small but well defined fraction of patients, driven by the use of predictive biomarkers of efficacy for targeted agents. Unfortunately, the same reliable predictive biomarkers are lacking for anti-angiogenic drugs. Angiogenesis plays a major role in the progression of NSCLC, however, anti-angiogenic agents provided a minimal, although significant, clinical benefit in unselected populations, burdened by a not negligible toxicities. In this context, no validated angiogenic factor or other molecular biomarker of angiogenesis can reliably predict clinical outcome, sensitivity, early response or resistance to any of the investigated anti-angiogenic therapies currently used. Moreover, the available clinical data are prevalently retrospective, underpowered, and, in many cases, contradictory, thus underscoring that the understanding of the complex architecture of angiogenic signaling is still incomplete. We here review the currently available studies on the effect of anti-angiogenic drugs in NSCLC, with a particular focus on bio-molecular factors that are regarded as potential predictors of treatment efficacy.