Longitudinal liquid biopsy anticipates hyperprogression and early death in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised treatment of advanced non-small cell lung cancer (aNSCLC), but a proportion of patients had no clinical benefit and even experienced detrimental effects. This study aims to characterise patients experiencing hyperprogression (HPD) and early death (ED) by longitudinal liquid biopsy. METHODS: aNSCLC receiving ICIs were prospectively enrolled. Plasma was collected at baseline (T1) and after 3/4 weeks of treatment, according to the treatment schedule (T2). Cell-free DNA (cfDNA) was quantified and analysed by NGS. cfDNA quantification and variant allele fraction (VAF) of tumour-associated genetic alterations were evaluated for their potential impact on outcome. The genetic alteration with the highest VAF (maxVAF) at baseline was considered as a reference. RESULTS: From March 2017 to August 2019, 171 patients were enrolled. Five cases matched criteria for HPD and 31 ED were recorded; one overlapped. Quantification of cfDNA at T2 and its absolute and relative variation (T2-T1) were significantly associated with the risk of ED (P = 0.012, P = 0.005, P = 0.009). MaxVAF relative change (T2-T1/T1) was significantly associated with the risk of HPD (P = 0.02). After identifying optimal cut-off values, a two-step risk assessment model was proposed. DISCUSSION: Liquid biopsy performed early during treatment has the potential to identify patients at high risk of ED and HPD.

First-Line Osimertinib in Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Outcome and Safety in the Real World: FLOWER Study.

BACKGROUND: Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. METHODS: We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. RESULTS: At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3-4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). CONCLUSION: Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported.

Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial.

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Correction to: Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

Following publication of the original article [1], the authors reported the following errors in the article.

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).

Complete response to weekly carboplatin-docetaxel chemotherapy in a 91-year-old woman with anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is an unusual tumor with the worst prognosis among thyroid malignancies. Treatment of the patients diagnosed with ATC is not standardized and the feasible options include surgery, radiotherapy and chemotherapy. ATC cannot be regarded as a very chemo-sensitive tumor. Herein, we reported a case of a 91-year-old woman with complete response after induction chemotherapy (weekly carboplatin and docetaxel) that underwent subsequent radiotherapy.

Tumor size, node status, grading, HER2 and estrogen receptor status still retain a strong value in patients with operable breast cancer diagnosed in recent years.

Breast cancer prognosis has improved greatly in recent years. Consequently, a thorough search for sensitive prognostic factors, able to help clinicians offer appropriate therapy, has become a priority in this area. In this study, we considered all new cases of invasive breast cancer diagnosed in the Province of Modena, Italy, between 1997 and 2007, registered by the Modena Cancer Registry. The principal endpoint of this study was relapse-free survival (RFS). A set of 11 clinic and pathological parameters was investigated. After a median follow-up of 73 months, 494 relapses were recorded. Tumor size, node status, grading, HER2 and estrogen receptor status were retained as independent factors in a multivariate analysis. Using these variables, a prognostic model was devised to identify three groups at different risk. In the training sample, the 5-year RFS rates resulted 96.0%, 82.9% and 63.7% in patients at low, intermediate and high risk, respectively (p < 0.0001). In the validation sample, the 5-year RFS was 96.2%, 85.4% and 66.9%, respectively. To conclude our study demonstrates that a very simple prognostic index based on easily available clinical data may represent a useful tool for the identification of patients at different risk of relapse and may be a notable device to predict who truly benefits from medical treatment.

Breakthroughs in research and treatment of early breast cancer: an overview of the last three decades.

Breast cancer has become curable for the majority of women in Western Europe and North America. Advances have been made in imaging diagnostics as well as the implementation of nationwide screening programmes. Nowadays, we talk about prevention as well as treatment. Pathology has moved from pure morphology (tumour type, grade and stage) to biological characterisation of the tumour. Treatment has changed considerably through a better understanding of the disease; from a local disease predominated by extensive and mutilating surgical techniques to a point where breast cancer has come into its own as a systemic disease with equal "rights" to local as well as systemic treatment. This paradigm shift has led to a multidisciplinary approach of the understanding and treatment of breast cancer. Molecular classification has changed the understanding of breast cancer and will be the basis for an even more individualised treatment. New (biological) agents will help to further tailor treatment to response or resistance. While systemic treatment has been increased in number and duration surgical/local strategies have been reduced to minimum. Evidence-based medicine has helped to improve and standardise treatment of breast cancer. This review summarises the 10th Biedenkopf meeting that was held to review the advances in breast cancer understanding and treatment.

Surgical margins in head and neck squamous cell carcinoma: what is 'close'?

The aim of this systematic review is to evaluate the definition of close margin in head and neck squamous cell carcinoma (HNSCC), and its possible prognostic significance. An appropriate string was run on PubMed to retrieve articles discussing the 'close' surgical margin issue in HNSCC. A double cross-check was performed on citations and full-text articles retrieved. In total, 348 articles were identified. Further references were included by using the option "Titles in your search terms" option in PubMed. 15 papers were finally included for qualitative synthesis. In vocal cord surgery of HNSCC, a close margin could be considered to be ≤1 mm, in the larynx ≤5 mm, in the oral cavity ≤4 mm, and in the oropharynx ≤5 mm. In each patient, the choice of extent of close margin should be balanced against general condition, tumor stage, and functional issues to indicate appropriate adjuvant therapy.

Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey.

UNLABELLED: What's known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not significantly alter plasma concentrations. In this retrospective study we define the safety and efficacy of tyrosine kinase inhibitors in patients with metastatic RCC (mRCC) and end-stage renal disease requiring haemodialysis. Even though the retrospective nature of this survey and the relatively small sample size represent major limitations, these data indicate that treatment with sunitinib and sorafenib in this cohort of patients is feasible with no unexpected toxicity and good efficacy, results similar to those in the general population of patients with mRCC. OBJECTIVE: To investigate the safety and efficacy of tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring haemodialysis (HD). PATIENTS AND METHODS: Between July 2006 and December 2010, 24 patients undergoing HD were treated with sunitinib and/or sorafenib for mRCC in 14 Italian institutions. We retrospectively reviewed the medical records of these patients to evaluate the administered doses of TKIs, treatment-related toxicities and the clinical response to therapy. RESULTS: Sunitinib was administered at 50 mg daily for 4-6 weeks in six patients, 37.5 mg daily for 4-6 weeks in seven patients (one patient subsequently increased the dose to 50 mg daily), 25 mg daily for 4-6 weeks in two patients and 12.5 mg daily for 4-6 weeks in one patient. Among the eight patients treated with sorafenib, four patients received 800 mg daily (400 mg every 12 h), three patients 400 mg daily and one patient 200 mg daily with a continuous schedule. The estimated median progression-free and overall survival periods of this cohort of patients were 10.3 months and 22.6 months, respectively. With regard to tolerability and safety, no unexpected adverse events were registered and no grade 4 haematological or non-haematological toxicities were reported. CONCLUSIONS: Sunitinib and sorafenib treatment is not contraindicated in patients with mRCC undergoing HD. The outcome of this patient population is similar to that observed in patients with normal renal function treated with TKIs. These results merit further confirmation by a larger prospective trial.

Achievements and unmet needs in the management of advanced ovarian cancer.

Ovarian cancer is the second most common gynaecological malignancy, and represents the leading cause of gynecologic cancer-related death in Europe and United States. The majority of the cases are in fact diagnosed in advanced stage, with limited chance to be cured. Optimal management of advanced ovarian cancer includes histopathological diagnosis, accurate surgical staging, debulking surgery and platinum-based chemotherapy. The combination of carboplatin and paclitaxel is commonly recognised as the standard regimen because of tolerability and activity. Intraperitoneal chemotherapy provides superior efficacy results, but its use is still controversial because of poor tolerability and compliance. Unfortunately, despite its chemosensitivity, the majority of ovarian cancer patients, including those who achieve a complete response to first-line chemotherapy, will relapse and eventually die. Among the strategies to improve patient outcome, maintenance therapy has failed to show a consistent benefit across clinical trials. Salvage second-line therapy is generally based on rechallenge with platinum in patients with platinum sensitive disease. Patients with platinum resistant/refractory might benefit from liposomal doxorubicin or topotecan. Other active cytotoxics include docetaxel, gemcitabine, etoposide and vinorelbine as well as epothilone derivatives such as patupilone which is still in development. Among targeted agents, the antiangiogenic agent bevacizumab seems extremely promising and is actively investigated in combination with first-line chemotherapy. More recently, interesting results have been obtained with the inhibitors of poly-ADP-ribose polymerase (PARP) in patients with BRCA-mutated tumors.

A computational workflow for the design of irreversible inhibitors of protein kinases.

Design of irreversible inhibitors is an emerging and relatively less explored strategy for the design of protein kinase inhibitors. In this paper, we present a computational workflow that was specifically conceived to assist such design. The workflow takes the form of a multi-step procedure that includes: the creation of a database of already known reversible inhibitors of protein kinases, the selection of the most promising scaffolds that bind one or more desired kinase templates, the modification of the scaffolds by introduction of chemically reactive groups (suitable cysteine traps) and the final evaluation of the reversible and irreversible protein-ligand complexes with molecular dynamics simulations and binding free energy predictions. Most of these steps were automated. In order to prove that this is viable, the workflow was tested on a database of known inhibitors of ERK2, a protein kinase possessing a cysteine in the ATP site. The modeled ERK2-ligand complexes and the values of the estimated binding free energies of the putative ligands provide useful indicators of their aptitude to bind reversibly and irreversibly to the protein kinase. Moreover, the computational data are used to rank the ligands according to their computed binding free energies and their ability to bind specific protein residues in the reversible and irreversible complexes, thereby providing a useful decision-making tool for each step of the design. In this work we present the overall procedure and the first proof of concept results.

Use of Electronic Administrative Databases to Measure Quality Indicators of Breast Cancer Care: Experience of Five Regional Oncology Networks in Italy.

PURPOSE: Assuring quality of care, while maintaining sustainability, in complex conditions such as breast cancer (BC) is an important challenge for health systems. Here, we describe a methodology to define a set of quality indicators, assess their computability from administrative data, and apply them to a large cohort of BC cases. MATERIALS AND METHODS: Clinical professionals from the Italian Regional Oncology Networks identified 46 clinically relevant indicators of BC care; 22 were potentially computable using administrative data. Incident cases of BC diagnosed in 2016 in five Italian regions were identified using administrative databases from regional repositories. Each indicator was calculated through record linkage of anonymized individual data. RESULTS: A total of 15,342 incident BC cases were identified. Nine indicators were actually computable from administrative data (two structure and seven process indicators). Although most indicators were consistent with guidelines, for one indicator (blood tumor markers in the year after surgery, 44.2% to 64.5%; benchmark ≤ 20%), deviation was evident throughout the five regions, highlighting systematic overlooking of clinical recommendations. Two indicators (radiotherapy within 4 months after surgery if no adjuvant chemotherapy; 42% to 83.8%; benchmark ≥ 90%; and mammography 6 to 18 months after surgery, 55.1% to 72.6%; benchmark ≥ 90%) showed great regional variability and were lower than expected, possibly as result of an underestimation in indicator calculation by administrative data. CONCLUSION: Despite highlighting some limitations in the use of administrative data to measure health care performance, this study shows that evaluating the quality of BC care at a population level is possible and potentially useful for guiding quality improvement interventions.

SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer.

BACKGROUND: The role of MET alterations in non-small cell lung cancer (NSCLC) is increasing and several targeted agents are under evaluation. MET exon 14 skipping mutations and MET amplifications are associated with potential sensitivity to MET inhibition, though resistance mechanisms are emerging. In MET addicted cells, MET inhibition leads to activation of proviral integration site for Moloney murine leukemia virus-1 (PIM1). PIM1 and proto-oncogene tyrosine-protein kinase Src (SRC) can regulate the expression of receptor tyrosine kinases (RTKs), potentially inducing resistance to MET inhibition through cross-activation. METHODS: We evaluated the activity of class I-II MET inhibitors, the SRC inhibitor dasatinib, and pan-PIM inhibitors in four MET addicted cell lines. We assessed the effect of the dual MET/PIM and MET/SRC inhibition on cell viability and at the protein level. We evaluated RNA expression profiles of the cell lines. Advanced NSCLCs were also screened for MET alterations. RESULTS: All cell lines were sensitive to class I-II MET inhibitors. All cell lines were resistant to single PIM and SRC inhibition. Dual MET/PIM inhibition was synergistic or additive in MET amplified cell lines and dual MET/SRC inhibition was highly synergistic in all MET addicted cell lines. The addition of an SRC inhibitor partially prevents the RTKs cross-activation. MET alterations were found in 9 out of 97 evaluable samples (9.3%); median overall survival in MET altered patients was 5 months (95% CI, 3 m-NA). CONCLUSIONS: We identified a potential role of PIM inhibition in MET amplified tumors and of SRC inhibition in MET addicted tumors. Potential applications of this new treatment strategy warrant further evaluation.

HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis.

BACKGROUND: HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT). METHODS: A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins' I2 was used to quantify heterogeneity. RESULTS: Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001, I2 = 33%), in HR+ (OR = 3.61, p < 0.001, I2 = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I2 = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR = 5.52, p < 0.001, I2 = 0%) and in HR + disease (OR = 4.08, p = 0.001, I2 = 0%). HR-negative status was significantly associated with pCR compared to HR + status in all patients (OR = 2.41, p < 0.001, I2 = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I2 = 0%). CONCLUSIONS: The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.

Weekly low-dose paclitaxel as maintenance treatment in patients with advanced ovarian cancer who had microscopic residual disease at second-look surgery after 6 cycles of paclitaxel/platinum-based chemotherapy: results of an open noncomparative phase 2 multicenter Italian study (After-6 Protocol 2).

The aim of this paper was to assess whether weekly intravenous 60-mg/m2 paclitaxel for 21 weeks is feasible and effective as maintenance treatment in 64 patients with advanced ovarian cancer who had microscopic residual disease after 6 cycles of paclitaxel/platinum-based chemotherapy. Forty-eight patients completed the planned cycles of weekly paclitaxel. The worst toxicities were grade 2 leukopenia in 22.4% of the patients, grade 2 neutropenia in 25.9%, grade 2 sensorial neurotoxicity in 20.7%, and grade 2 motor neurotoxicity in 6.9%. Seventeen patients underwent a third-look surgery that showed a pathological complete response in 6 (35.3%, 95% confidence interval [CI], 17.3%-59.0%) cases. The 3-year progression-free survival rate was 18% (95% CI, 9.6%-33.8%), and the 3-year overall survival rate was 64% (95% CI, 52.0%-78.0%). Weekly low-dose paclitaxel is a feasible and well-tolerated maintenance treatment.

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.

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients.

BACKGROUND: HER2+ metastatic breast cancer (MBC) is a poor prognosis disease, unusually curable. To date, no predictive factors have been clearly correlated with long-term response to anti-HER2 agents. METHODS: 54 HER2+ MBC patients treated with HER2 targeted therapy as first line treatment were analysed: 40 with a time to progression longer than 3 years in Long Responders (LR) group and 14 with a progression disease within one year of anti-HER2 therapy in a control group named Early Progressors (EP). The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on FFPE BC tissues. RESULTS: Considering baseline patients and tumor characteristics, EP women had more CNS spread and more metastatic burden of disease compared to LR (p > 0.05). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down regulated, all in EP group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways. MAPK pathway was differently expressed between LR and EP (p = 0.05). PI3K was the only pathway overexpressed in EP patients. CONCLUSIONS: Whole genome expression analysis comparing LR vs. EP identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathway could be a positive predictive factors. Further clinical implications are warranted. ABBREVIATIONS: BC: breast cancer; MBC: metastatic breast cancer; LR: long responder; EP: early progressor; FFPE: formalin-fixed paraffin-embedded; CNS: central nervous system; PFS: progression free survival; OS: overall survival.

Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus.

BACKGROUND: Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. PATIENTS AND METHODS: Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. RESULTS: The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. AKT1E17K was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (AKT1E17K, PI3KCAE545K, and KITG565R,S709F). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. CONCLUSIONS: The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.

Prognostic and predictive value of baseline and posttreatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

PURPOSE: To evaluate expression of a panel of molecular markers, including p53, p21, MLH1, MSH2, MIB-1, thymidylate synthase, epidermal growth factor receptor (EGFR), and tissue vascular endothelial growth factor (VEGF), before and after treatment in patients treated with neoadjuvant chemoradiotherapy for locally advanced rectal cancer, to correlate the constitutive profile and dynamics of expression with pathologic response and outcome. METHODS AND MATERIALS: Expression of biomarkers was evaluated by immunohistochemistry in tumor samples from 91 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy (50 Gy) plus concurrent 5-fluorouracil by continuous intravenous infusion. RESULTS: A pathologic complete remission was observed in 14 patients (15.4%). Patients with MLH1-positive tumors had a higher pathologic complete response rate (24.3% vs. 9.4%; p = 0.055). Low expression of constitutive p21, absence of EGFR expression after chemoradiotherapy, and high Dworak's tumor regression grade (TRG) were significantly associated with improved disease-free survival and overall survival. A high MIB-1 value after chemoradiotherapy was significantly associated with worse overall survival. Multivariate analysis confirmed the prognostic value of constitutive p21 expression as well as EGFR expression and MIB-1 value after chemoradiotherapy among patients not achieving TRG 3-4. CONCLUSIONS: In our study, we observed the independent prognostic value of EGFR expression after chemoradiotherapy on disease-free survival. Moreover, our study suggests that a constitutive high p21 expression and a high MIB-1 value after neoadjuvant chemoradiotherapy treatment could predict worse outcome in locally advanced rectal cancer.