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Background Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. Methods The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m2 ) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. Results Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin Cmax , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m2 (SD, 14.08 L/h/m2 ), and 1460 L/m2 (SD, 561 L/m2 ), respectively. Conclusion Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Objective: Although endometrial cancer (EC) is a hormone dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. The purpose of this study was to explore the effect of adjuvant aromatase inhibitors (AIs) on progression-free survival (PFS) and overall survival (OS) in patients with early stage and steroid receptors-positive EC. Methods: We retrospectively analyzed clinical and pathological factors in 73 patients with high-risk (49.3%) or low-risk (50.7%) stage I (n = 71) or II (n = 2) endometrial cancer who received by their preference after counseling either no treatment (reference group) or AI. Prognostic factors were well balanced between groups. Expression of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 index was correlated with clinical outcomes. Results: Univariate and multivariate Cox proportional regression analyses, adjusted for age, grade, stage, depth of myometrial invasion, lymphovascular space invasion, BMI, ER, PgR and Ki-67 labeling index levels, showed that PFS and OS had a trend to be longer in patients receiving AI than in the reference group HR= 0.23 (95% CI, 0.04&ndash, 1.27) for PFS and HR= 0.11 (95% CI, 0.01&ndash, 1.36) for OS. Conclusion: Compared with no treatment, AI exhibited a trend toward a benefit on PFS and OS in patients with early stage hormone receptor-positive EC. Given the exploratory nature of our study, randomized clinical trials for ER/PgR positive EC patients are warranted to assess the clinical benefit of AI and the potential predictive role of steroid receptors and Ki-67.

Background We recently conducted a de-escalation trial of low-dose tamoxifen 5 mg/day ("babytam", BT) or placebo given for 3 years in 500 women with noninvasive breast cancer. Women on babytam had a 52% reduction of recurrence (invasive breast cancer or DCIS) after 5 years. Since menopausal symptoms are major reasons for treatment withdrawal during tamoxifen preventive therapy, we compared and analyzed the patient-reported outcomes (PROs) with the physician-reported adverse events and studied their association with recurrence. Methods Menopausal symptoms recorded by physicians using the Common Terminology Criteria (CTCAEs) were compared with a patient self-reported validated questionnaire reviewed by a research nurse at baseline and every 6 months up to 36 months. Hot flashes (HF), the main outcome measure, were detected through a self-report 7-day diary for frequency and intensity. Treatment adherence and efficacy were assessed by the Kaplan-Meier curves and the Cox model. Results The number of HF events at 12, 24, and 36 months for PROs versus CTCAEs was 246 versus 12, 238 versus 8, and 210 versus 4, respectively. The majority of events were grade 1. There was no difference in PROs between babytam and placebo except for HF daily frequency, which increased by 1.5 events (95% CI, 1.1-1.8) on placebo to 2.1 on babytam (95% CI, 1.7-2.5, p = 0.05). The presence of HF at baseline was a favorable prognostic factor for recurrence and a predictive factor for response to babytam. Adherence was similar between babytam and placebo. Conclusions The use of PROs is effective for identifying frequent mild grade menopausal symptoms which are underestimated by physicians but important prognostic and predictive factors. Research nurse can use these results as a tool to reassure patients about symptoms, improve adherence to treatment, and limit dropouts.

Background: We recently showed that low dose (5mg/d) tamoxifen (babytam) for 3 years can halve the incidence of new breast neoplastic events in hormone sensitive or unknown breast pre-invasive neoplasia after surgery with limited toxicity (DeCensi et al JCO 2019; 37:1629-37). Here we report the results of circulating surrogate endpoint biomarkers of breast cancer risk with special attention to the risk of ovarian stimulation observed with the full dose in premenopausal women. Methods: Five hundred women 75 years old or younger were randomized to babytam or placebo (PLA). A subgroup of 406 women consented for collection of morning fasting serum at baseline (0), 1 (1Y) and 3 years (3Y) of treatment. There was a loss of about 25% of blood sampling at 3Y. Serum IGF-I, IGFBP-3, SHBG and C-reactive Protein (CRP) were performed on all available samples. Estradiol and testosterone were determined in a subsample (n=285) to determine the extent of ovarian stimulation by babytam in premenopausal women. We used Mann-Whitney test for univariate comparisons and linear regression modeling for multivariate analyses setting changes from baseline (1Y or 3Y minus baseline values) as dependent variable and treatment arm, age, BMI and baseline biomarkers values as explanatory factors. We tested treatment*menopausal status as interaction term. COX P-H model was used to calculate hazard ratio for CRP increase. Results: At baseline, all biomarkers were evenly balanced between arms (data not shown). IGF-I decreased significantly on babytam as compared to PLA. The difference of the changes between arms was -20 ng/mL after 1Y (p Citation Format: Harriet Johansson, Matteo Puntoni, Debora Macis, Valentina Aristarco, Aliana Guerrieri-Gonzaga, Davide Serrano, Silvia Caviglia, Laura Cortesi, Cristiana Taverniti, Antonio Ponti, Maria Grazia Pacquola, Marcella Gulisano, Fabio Falcini, Maria Digennaro, Anna Carriello, Katia Cagossi, Graziella Pinotti, Tania Buttiron Webber, Matteo Lazzeroni, Bernardo Bonanni, Luca Boni, Andrea DeCensi. Effects of low dose tamoxifen on circulating risk biomarkers in a phase III trial in breast pre-invasive disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-08.

Background: The aromatase inhibitor exemestane (EXE) has shown to lower cancer incidence in high-risk postmenopausal women. However, undesirable symptoms and side effects (i.e., bone density loss, musculoskeletal ache, climacteric syndrome) may compromise patient motivation and adherence to a long-term preventive treatment. A less frequent drug schedule, compared to the standard regimen, may be more acceptable to healthy at-risk women. We hypothesized that comparison of two alternative less frequent dose regimens with the standard daily dose regimen will show that it is possible to decrease undesirable symptoms of EXE while still effectively reducing serum estradiol. Trial Design: We are conducting a multi-center, pre-surgical, double-blind, non-inferiority phase IIb study in which 180 postmenopausal women will be randomized to receive either EXE 25 mg/day or 25 mg/three times a week or 25 mg/week for 4 to 6 weeks prior to surgery. Surgery will occur on day 29, 36 or 43 after treatment initiation. Eligible subjects are postmenopausal women with histologically-confirmed ER-positive (ER >10%) primary breast cancer candidates for surgery. Participants with T0-2, N0-1, Mx or with larger tumors who refuse neo-adjuvant therapy before surgery are eligible. Subjects are stratified according to participating site and body mass index (25 kg/m2). The primary objective is to assess if the reduction in estradiol with EXE 25 mg/three times a week and EXE 25 mg/week is comparable with the standard dose of 25 mg/day of EXE. Methods: Blood will be collected at baseline and at the end of treatment. Tissue samples will be collected from the diagnostic biopsy and at the time of surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery in the three arms in a CLIA certified laboratory. Given the expected reduction of at least 80% change with EXE at 25 mg daily considered as reference group (control arm) against 25 mg/three times a week or 25 mg weekly, for the power calculation we assume a non-inferiority difference of 6% in percentage changes of circulating estradiol after treatment from baseline, using a one-sided, two-sample t-test. Secondary outcome measures are the incidence of toxicity and menopausal symptoms according to the CTCAE (v4) and by the self-administered MENQoL; the effect of the three regimens on sex hormones (estrone, estrone sulphate, SHBG, testosterone, DHEAS and FSH) and the effect on circulating estradiol levels using an ultrasensitive method given that the serum levels in postmenopausal women under EXE may be very low. Drug and metabolites levels will be measured in blood, cancer tissue and non-cancer tissue. Evaluation of serum insulin, glucose (homeostatic model assessment index), and lipid profile (total cholesterol, high-density lipoprotein cholesterol and triglycerides), leptin and adiponectin will be performed before and after treatment. Additionally, we will measure breast estradiol concentration in cancer and non-cancer tissue and compare changes in ER, PgR, and proliferation in cancer and non-cancer tissue samples obtained at time of biopsy and definitive surgery. Finally, we will also analyze the role of the polymorphic UGT2B17 gene (involved in EXE and 17-dihydroexemestane metabolism) as well as tissue proteomics. Preliminary results: Enrollment started in February 2017 and as of July 3, 2019, a total of 170/180 participants have been randomized (94% of the expected sample size). Preliminary data will be presented at the conference. IND Sponsor: NCI/DCP NCI contract: HHSN26120120034I Citation Format: Aliana Guerrieri-Gonzaga, Parjhitham Thomas, Andrea DeCensi, Katherine D Crew, Nagi Kumar, Sara Gandini, Lana Vornik, Brandy Heckman-Stoddard, Eva Szabo, Eileen Dimond, Jack Lee, Diane Liu, Matteo Lazzeroni, Sara Cagnacci, Davide Serrano, Mauro D'Amico, Flavio Guasone, Tania Buttiron Webber, Powel Brown, Bernardo Bonanni. Alternative dosing of exemestane before surgery in postmenopausal patients with stage 0-II estrogen receptor positive breast cancer: Design and methodology [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-03.

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20–1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P

Purpose Initial findings in patients with cancer suggest a lower seroconversion to SARS-COV-2 vaccination possibly related to myelo-immunosuppressive therapies. We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in patients on active treatment. Patients and methods Cancer patients candidate to two doses of BNT162b2 SARS-COV-2 vaccination were enrolled. Patients on active surveillance served as controls. The primary endpoint was poor seroconversion (anti S1/S2 IgG

Cancer patients are exposed to a greater risk of COVID-19 infection, resulting in treatment delays and unnecessary hospitalizations. International authorities have suggested reducing visits to hospitals and guarantee continuity of care. We developed a home care project called Home Se-Cure (HSC) to guarantee the continuity of oral, intramuscular, and subcutaneous cancer therapy during COVID-19. The Home Se-Cure project included cancer patients living near Galliera Hospital. Patients received home visits by registered nurses (RNs), whoperformed blood tests and delivered cancer therapies. Patients were instructed to take drugs after blood test results and therapy confirmation by oncologists. Sixty-six patients decided to participate and 38 declined the service. A customer satisfaction questionnaire was administered to a subgroup of patients participating in the project. The most prevalent disease in the HSC group was prostate cancer. The mean age of the patients in HSC was 78.4 years and 68.9 in the decliner group. The majority of the HSC participants appreciated the project because they could stay at home (71%) and reduce the risk of COVID-19 contagion (67.7%). Compared to decliners, the time the study group saved was 2033 hours. HSC guaranteed the continuity of care during the COVID-19 pandemic by reducing the number of patients in the hospital and avoiding crowds in the waiting room.

Background and Objectives: 18F-fluorodeoxyglucose (FDG) positron emission tomography/X-ray computed tomography (PET/CT) represents the mainstay diagnostic procedure for suspected ovarian cancer (OC) recurrence. PET/CT can be integrated with contrast medium and in various diagnostic settings, however, the effective benefit of this procedure is still debated. We aimed to compare the diagnostic capabilities of low-dose and contrast-enhanced PET/CT (PET/ldCT and PET/ceCT) in patients with suspected ovarian cancer relapse. Materials and Methods: 122 OC patients underwent both PET/ldCT and PET/ceCT. Two groups of nuclear medicine physicians and radiologists scored the findings as positive or negative. Clinical/radiological follow-up was used as ground truth. Sensitivity, specificity, negative/positive predictive value, and accuracy were calculated at the patient and the lesion level. Results: A total of 455 and 474 lesions were identified at PET/ldCT and PET/ceCT, respectively. At the lesion level, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were not significantly different between PET/ldCT and PET/ceCT (98%, 93.3%, 97.4%, 94.9%, and 96.9% for PET/ldCT, 99%, 95.5%, 98.3%, 97%, and 98% for PET/ceCT, p = ns). At the patient level, no significant differences in these parameters were identified (e.g., p = 0.22 and p = 0.35 for accuracy, in the peritoneum and lymph nodes, respectively). Smaller peritoneal/lymph node lesions close to physiological FDG uptake sources were found in the cases of misidentification by PET/ldCT. PET/ceCT prompted a change in clinical management in four cases (3.2%) compared to PET/ldCT. Conclusions: PET/ceCT does not perform better than PET/ldCT but can occasionally clarify doubtful peritoneal findings on PET/ldCT. To avoid unnecessary dose to the patient, PET/ceCT should be excluded in selected cases.

Low-dose tamoxifen halves recurrence in non-invasive breast cancer without significant adverse events. Some adjuvant trials with tamoxifen 20 mg/day had shown an association between low endoxifen levels (9–16 nM) and recurrence, but no association with CYP2D6 was shown in the NSABP P1 and P2 prevention trials. We studied the association of CYP2D6 genotype and tamoxifen metabolites with tumor biomarkers and recurrence in a randomized phase III trial of low-dose tamoxifen. Median (IQR) endoxifen levels at year 1 were 8.4 (5.3–11.4) in patients who recurred vs 7.5 (5.1–10.2) in those who did not recur (p = 0.60). Tamoxifen and metabolites significantly decreased C-reactive protein (CRP, p P = 0.03). In conclusion, endoxifen is below 9 nM in most subjects treated with 5 mg/day despite strong efficacy and there is no association with recurrence, suggesting that the reason for tamoxifen failure is not poor drug metabolism. Trial registration: ClinicalTrials.gov, Identifier: NCT01357772.

The natural history of ductal carcinoma in situ (DCIS) is highly variable and difficult to predict. Biomarkers are needed to stratify patients with DCIS for adjuvant therapy. We investigated the prognostic and predictive relevance of cell cycle progression (CCP) score in women with DCIS. We measured the expression of 23 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumor samples, and assessed the correlation of a predefined score with histopathologic features and recurrence. The signature was analyzed in a cohort of 909 consecutive DCIS with full histopathological features treated in a single institution. The main outcome measure was ipsilateral breast event (IBE) as first event observed, be it in situ or invasive. Median follow-up time was 8.7 years (IQR 6.5-10.5 years). There were 150 ipsilateral IBEs, 84 (56%) of which were invasive. In the first 5 years of follow-up, the score provided statistically different findings (p = 0.009), with IBE rates of 14.7% (95% CI, 10.4-19.7) for the highest quartile of CCP score (Q4) and 8.7% (95% CI, 6.7-11.0) for the lowest quartiles (Q1-3). The prognostic value for IBEs approached significance also in women treated with mastectomy (adjusted hazard ratio [HR] Q4 vs. Q1-3 = 2.60; 95% CI: 0.96-7.08; P = 0.06). Radiotherapy provided a greater benefit in women with higher CCP score. In addition, Q4 predicted a different risk after tamoxifen depending on menopausal status, with a beneficial trend on IBEs in postmenopausal women (HR 0.30; 95% CI, 0.07-1.39), and an opposite trend in premenopausal women (HR 1.68; 95% CI, 0.38-7.44) (P-interaction = 0.03). The results of this study provide for the first time the evidence that CCP score is a prognostic marker, which, after additional validation, could have an important role in personalizing the management of DCIS.

IntroductionThe PENELOPE trial evaluated pertuzumab added to chemotherapy for biomarker-selected platinum-resistant ovarian cancer. As previously reported, pertuzumab did not statistically significantly improve progression-free survival (primary end point: HR 0.74, 95% CI 0.50 to 1.11), although results in the paclitaxel and gemcitabine cohorts suggested activity. Here, we report final overall survival and patient-reported outcomes.Patients and methodsEligible patients had ovarian carcinoma that progressed during/within 6 months of completing ≥4 platinum cycles, low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression, and ≤2 prior chemotherapy lines. Investigators selected single-agent topotecan, gemcitabine or weekly paclitaxel before patients were randomized to either placebo or pertuzumab (840→420 mg every 3 weeks), stratified by selected chemotherapy, prior anti-angiogenic therapy, and platinum-free interval. Final overall survival analysis (key secondary end point) was pre-specified after 129 deaths. Patient-reported outcomes (secondary end point) were assessed at baseline and every 9 weeks until disease progression.ResultsAt database lock (June 9, 2016), 130 (83%) of 156 randomized patients had died. Median follow-up was 27 months in the pertuzumab arm versus 26 months in the control arm. In the intent-to-treat population there was no overall survival difference between treatment arms (stratified HR 0.90, 95% CI 0.61 to 1.32; p=0.60). Results in subgroups defined by stratification factors indicated heterogeneity similar to previous progression-free survival results. Updated safety was similar to previously published results. Compliance with patient-reported outcomes questionnaire completion was >75% for all validated patient-reported outcomes measures. Pertuzumab demonstrated neither beneficial nor detrimental effects on patient-reported outcomes compared with placebo, except for increased diarrhea symptoms.DiscussionConsistent with the primary results, adding pertuzumab to chemotherapy for low tumor HER3 mRNA-expressing platinum-resistant ovarian cancer did not improve overall survival, but showed trends in some cohorts. Except for increased diarrhea symptoms, pertuzumab had no impact on patient-reported outcomes.ClinicalTrials.gov:ClinicalTrials.gov:NCT01684878.

Background: mRNA-based vaccines have shown 95% protection from SARS-COV-2 disease in healthy populations. Initial findings in cancer patients suggest a lower seroconversion and greater toxicity possibly related to myelo-immunosuppressive therapies. Methods: We conducted a prospective study to assess factors predicting poor seroconversion and adverse events following immunization (AEFI) to the BNT162b2 vaccine in cancer patients on active treatment. The primary endpoint was poor seroconversion (IgG 6 months on active surveillance served as controls. Multivariable logistic model and mixed effect models for repeated measures investigated independent factors associated with poor seroconversion and AEFI, adjusting for confounders. Findings: Between March 15 and July 21, 2021, 320 subjects were recruited and 291 were assessable for IgG response. The lack of seroconversion at 42 days was 1.6% (95% CI, 0.4-8.7) on active surveillance, 13.9% (8.2-21.6) on chemotherapy, 11.4% (5.1-21.3) on hormone therapy, 21.7% (7.5-43.7) on biological therapy and 4.8% (0.12-23.8) on immunotherapy. Compared to controls, risk of no IgG response was greater for chemotherapy (P=0.023), biological therapy (0.009) and hormonotherapy (P=0.052). Older age and advanced stage also predicted poor seroconversion. Overall, 43 patients (14.8%) complained of AEFI, mostly of mild grade. Risk of AEFI was greater in females (P=0.001) and younger patients (P=0.009). There was a trend to a D-dimer increase in IgG responders (p=0.01). Interpretation: Except for immunotherapy, chemotherapy, biological therapy and hormone therapy as well as increasing age and advanced stage predict poor seroconversion after two doses of BNT162b2 in up to 20% of patients, indicating the need for a booster dose and long-term serological testing in vaccine non-responders. AEFI occur much more frequently in women and younger subjects who may benefit from preventive medications. Trial Registration: ClinicalTrials.gov Identifier: NCT04932863 Funding: Ospedali Galliera, Associazione WeCare, Lions-Club Genova Sant’Agata. Italian Health Ministry, Ricerca Corrente and 5×1,000 (IEO). Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy, and the local Ethical Committee.

Ovarian hemangiomas are very rare benign tumors of the female genital tract. Most cases are small lesions that are discovered by chance. Although they are often an incidental finding at surgery, these lesions may sporadically be associated with systemic manifestations. Here, we describe a 63 year-old woman with a right ovary benign hemangioma who presented with a clinically suspicious left ovarian torsion.

Purpose: Low-dose tamoxifen halved recurrence after surgery in a phase III trial in breast noninvasive disease without increasing adverse events. We explored the effect of low-dose tamoxifen in clinically relevant subgroups, including menopausal status, estradiol levels, smoking, body mass index, and proliferation of baseline lesion. Patients and Methods: Incidence of invasive breast cancer or ductal carcinoma in situ was the primary endpoint. HRs and interaction terms were estimated using Cox models. Results: A favorable HR and 95% confidence interval (CI) could be demonstrated for postmenopausal status (HR = 0.30; 95% CI, 0.11–0.82 vs. HR = 0.73; 95% CI, 0.30–1.76 in premenopausal women; Pinteraction = 0.13), women with estradiol less than 15.8 pg/mL, presence of menopausal symptoms at baseline, and never smoking (Pinteraction = 0.07), although the interaction P value was >0.05 for all characteristics. Efficacy was similar in all body mass index categories. Tumors with Ki-67 above the median level of 10% had a greater benefit (HR = 0.27; 95% CI, 0.09–0.81) than those with Ki-67 ≤10% (HR = 1.58; 95% CI, 0.45–5.60; Pinteraction = 0.04). Conclusions: The efficacy of low-dose tamoxifen seems to be greater in postmenopausal women and in women with lower estradiol levels. Benefits appear to be larger also in women with menopausal symptoms, never smokers, and tumors with Ki-67 >10%. Our results by menopausal status provide important insight into low-dose tamoxifen personalized treatment, although caution is necessary given their exploratory nature. Observation of an improved response in tumors with Ki-67 >10% is consistent but the use of the marker in this setting is investigational. See related commentary by Fabian, p. 3510

Although screening has reduced mortality rates for colorectal cancer (CRC), about 20% of patients still carry metastases at diagnosis. Postsurgery chemotherapy is toxic and induces drug resistance. Promising alternative strategies rely on repurposing drugs such as aspirin (ASA) and metformin (MET). Here, tumor spheroids were generated in suspension by primary CRCs and metastatic lymph nodes from 11 patients. These spheroids presented a heterogeneous cell population including a small core of CD133+/ESA+ cancer stem cells surrounded by a thick corona of CDX2+/CK20+ CRC cells, thus maintaining the molecular hallmarks of the tumor source. Spheroids were exposed to ASA and/or MET at different doses for up to 7 days to assess cell growth, migration, and adhesion in three-dimensional assays. While ASA at 5 mM was always sufficient to mitigate cell migration, the response to MET was patient specific. Only in MET-sensitive spheroids, the 5 mM ASA/MET combination showed an effect. Interestingly, CRCs from diabetic patients daily pretreated with MET gave a very low spheroid yield due to reduced cancer cell survival. This study highlights the potential of ASA/MET treatments to modulate CRC spreading.

Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. EudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.

Aims Regular aspirin use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer. Preclinical data show that aspirin down-regulates PI3 kinase (PI3K) signalling activity through cyclo-oxygenase-2 (COX-2) inhibition, leading to the hypothesis that the effect of aspirin might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. The aim of this study was to assess the relationship between PIK3CA status and the efficacy of regular use of aspirin after diagnosis on overall survival in colorectal cancer patients. Materials and methods We identified studies that compared post-diagnosis aspirin efficacy in colorectal cancer patients identified by PIK3CA status. Hazard ratios for overall survival were meta-analysed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was carried out by weighted linear meta-regression. All statistical tests were two-sided. Results The overall effect of aspirin was not significant (summary risk estimate = 0.82; 95% confidence interval 0.63–1.08, P = 0.16; I 2 = 57%). In PIK3CA mutant disease ( n = 588), aspirin use reduced total mortality by 29% (summary risk estimate = 0.71; 95% confidence interval 0.51–0.99, P = 0.04; I 2 = 0%), whereas in PIK3CA wild-type disease ( n = 4001), aspirin use did not reduce overall mortality (summary risk estimate = 0.93; 95% confidence interval 0.61–1.40; P = 0.7; I 2 = 80%) ( P interaction = 0.39). There was a beneficial trend for aspirin on cancer-specific survival in PI3KCA mutated subjects (summary risk estimate = 0.37, 95% confidence interval 0.11–1.32, P = 0.1), albeit with high heterogeneity (Q chi-squared = 3.41, P = 0.07, I 2 = 70.7%). Conclusion These findings suggest that the benefit of post-diagnosis aspirin treatment on overall mortality in colorectal cancer may be more marked in PIK3CA mutated tumours, although the low number of studies prevents definitive conclusions. Trials addressing this issue are warranted to assess the efficacy of aspirin in the adjuvant setting.

Background Polymorphisms of genes involved in estrogen production have been linked to breast cancer risk, prognosis and treatment response. Polymorphisms of the aromatase gene CYP19A1 influence its activity. The UGT2B17 catalyzes glucuronic acid transfer to a variety of substrates, including steroids and drugs like the aromatase inhibitor exemestane. We investigated the impact of two variants of CYP19A1 (rs10046, rs4646) and the UGT2B17 gene deletion on disease outcome in 125 postmenopausal women operated for ER-positive primary breast cancer enrolled in a randomized pre-surgical trial. Patients Briefly, upon informed consent, postmenopausal patients with ER-positive breast cancer (stage T1–2, N0–1, M0) eligible for surgery were randomized to receive either exemestane (25 mg/day), or celecoxib (800 mg/day), or placebo for 6 weeks prior to surgery at the European Institute of Oncology (2004-2008). Exemestane showed a significant 10% absolute reduction in Ki67 labeling index compared to the other two arms. Serum and whole blood was taken at baseline and the day before surgery and stored at -80°C until assayed. Methods DNA was extracted from blood by QIAamp DNA Blood Kits. The CYP19A1 rs1004/rs46466 were analyzed by Taqman genotyping assays in real-time PCR. The UGT2B17 deletion was estimated by copy number assay (Lifetechnologies). Serum estradiol (E2) and estrone (E1) levels were measured by gas chromatography tandem mass spectrometry detection (GS-MS/MS) after liquid-liquid extraction. The lower limit of quantitation were 0.625 pg/mL for estradiol and 1.56 pg/mL for estrone. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders. Results The genetic polymorphisms did not deviate from Hardy-Weinberg equilibrium (P-value >0.41) and minor allele frequency of rs10046 (A/G), rs4646 (C/A), and UGT2B17Del were 0.45, 0.22, and 0.31, respectively. The rs10046 A and rs4646 C alleles were associated with higher estrogen levels. Carriers of rs10046 AA had median levels of 7.57 pg/ml E2 and 35.9 pg/mL E1 versus 3,9 pg/mL E2 and 27.4 E1 pg/mL in CA/AA genotypes (P Conclusions Our analysis confirms previous findings of an association of CYP19A1 rs10046/rs4646 with estrogen levels in postmenopausal women. Interestingly, the carriers of the variants associated with lower estrogen levels at diagnosis had better prognosis. Further genomic profiling in larger trials aimed to enhance tailored treatment efficacy in endocrine-responsive postmenopausal breast cancer are warranted. Citation Format: Johansson H, Gandini S, Aristarco V, Macis D, Guerrieri-Gonzaga A, Serrano D, Pruneri G, Lazzeroni M, Viale G, Toesca A, Rajasekaran A, Bonanni B, DeCensi A. Impact of common polymorphisms of CYP19A1 and UGT2B17 gene deletion on early endocrine-responsive postmenopausal breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-05.

Adenomatous polyps are precancerous lesions associated with a higher risk of colorectal cancer (CRC). Curcumin and anthocyanins have shown promising CRC-preventive activity in preclinical and epidemiological studies. The objective of this window-of-opportunity, proof-of principle trial was to evaluate the effect of curcumin combined with anthocyanin supplements on tissue biomarkers of colorectal adenomatous polyps. Eligible patients received either anthocyanin and curcumin supplementation or related matching placebo for 4–6 weeks before polyp removal. Adenomatous polyps and adjacent tissue biopsies were collected at baseline and after supplementation for immunohistochemical assessment of β-catenin, NF-kappa B (NF-κB), Ki-67, P53, and dysplasia. No differences were observed in baseline biomarker expression between normal and dysplastic tissues. The combination of anthocyanins and curcumin resulted in a significant borderline reduction of NF-κB immunohistochemistry (IHC) expression in adenoma tissue (geometric mean ratio (GMR): 0.72, 95% confidence interval (CI): 0.51–1.00, p-value: 0.05) and a trend to a reduction of Ki-67 (GMR: 0.73, 95% CI: 0.50–1.08, p-value: 0.11). No significant modulation of biomarkers in normal adjacent mucosa was observed. We concluded that the combined supplementation of anthocyanins and curcumin seems to lead to a potentially favorable modulation of tissue biomarkers of inflammation and proliferation in colon adenomas.

Our objective was to evaluate the biodistribution, kinetics, and radiation dosimetry of 64CuCl2 in humans and to assess the ability of 64CuCl2 PET/CT to detect prostate cancer (PCa) recurrence in patients with biochemical relapse. Methods: We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external-beam radiation therapy. All patients underwent 64CuCl2 PET/CT, 18F-choline PET/CT, and multiparametric MRI within 15 d of each other. Experienced readers interpreted the images, and the detection rate (DR) of each imaging modality was calculated. Histopathology, when available; clinical or laboratory response; and multidisciplinary follow-up were used to confirm the site of disease. In parallel, biodistribution, kinetics of the lesions, and radiation dosimetry of 64CuCl2 were evaluated. Results: From a dosimetric point of view, an administered dose of 200 MBq for 64CuCl2 translated into a 5.7-mSv effective dose. Unlike 18F-choline, 64CuCl2 was not excreted or accumulated in the urinary tract, thus allowing thorough pelvic exploration. The maximum 64CuCl2 uptake at the sites of PCa relapse was observed 1 h after tracer injection. In our cohort, 64CuCl2 PET/CT proved positive in 41 of 50 patients, with an overall DR of 82%. The DRs of 18F-choline PET/CT and multiparametric MRI were 56% and 74%, respectively. The difference between the DRs of 64CuCl2 PET/CT and 18F-choline PET/CT was statistically significant (P < 0.001). Interestingly, on considering prostate-specific antigen (PSA) value, 64CuCl2 PET/CT had a higher DR than 18F-choline PET/CT in patients with a PSA of less than 1 ng/mL. Conclusion: The biodistribution of 64CuCl2 is more suitable than that of 18F-choline for exploring the pelvis and prostatic bed. The 64CuCl2 effective dose is like those of other established PET tracers. In patients with biochemical relapse and a low PSA level, 64CuCl2 PET/CT shows a significantly higher DR than 18F-choline PET/CT.

There is increasing interest in combining postmenopausal hormone therapy (HT) and SERMs in midlife women. We previously showed that refusal to participate in a prevention trial of low dose tamoxifen in HT users was associated with higher worry about breast cancer. Given this counterintuitive finding, we studied which factors influenced worry and risk perception of breast cancer.We assessed the relationships of breast cancer worry and risk perception with age, age at menopause, Gail risk, education, adherence to mammographic screening, BMI, smoking, physical activity, alcohol use, anxiety and depression in 457 midlife HT users who were eligible to participate in the trial.Women with menopause48 years were more worried about breast cancer than women with menopause52 years (OR = 5.0, 95% CI, 1.2-21.1). Worry was also associated with high absolute risk perception and former smoking. Factors associated with higher risk perception were age60 years, at-risk life style, worry about breast cancer and depression.The inverse association between early menopause and worry about breast cancer is in contrast with the known protective effect of early menopause on breast cancer risk and seems to reflect a feeling of aging and disease vulnerability. Our findings indicate that worry about cancer has an affective construct which is independent of breast cancer biology but is engaged in health decision making. Increasing breast cancer risk awareness in subjects high in worry without a plan of emotional coping may therefore be counterproductive because of avoidant attitudes.

Introduction: Attempts to quit smoking have increased in recent years, but the patterns of variations over time are unknown. We aimed at describing time- and sex-related changes in a population of 2,231 subjects who adhered to a smoking-cessation programme lasting 13 years in Italy.Methods: We measured baseline expired carbon monoxide (expired-CO), Fagerstrom nicotine dependence, Q-MAT test, Zung depression and anxiety scale, Hospital anxiety and depression scale (HADS).Results: Study population included 1,278 men and 953 women who smoked a median of 25 (interquartile range, IQR: 20–32) and 20 (IQR: 20–30) cigarettes/day, respectively (p < 0.001). The proportion of female smokers increased from 37.5% in 2001–2003 to 46.9% in 2010–2013 (p = 0.003). There was a significant time-related reduction of median daily cigarette consumption, with a more noticeable decrease in men. Median expired-CO (parts per million (ppm)) increased only in women, from 18 (IQR: 14–23) in 2001–03 to 20 (IQR: 14–28) in 2010–13 (p = 0.001), whereas Fagerstrom test for nicotine dependence did not vary. Differences in psychological characteristics in the last 3 years showed that women were more clinically depressed than men (16.6% versus 7.6%, p < 0.001).Conclusions: Despite a decrease in the number of daily cigarettes with time, expired-CO tends to increase in women, who are also more clinically depressed and anxious than men. A personalised approach to specific subgroups of smokers, with special emphasis on a psychological support for women, seems appropriate.

Most patients with ductal carcinoma in situ of the breast (DCIS) are eligible for breast conservation treatment. The key management decision is whether to add radiotherapy and/or endocrine therapy to minimize the risk of a subsequent recurrence. Recent analyses indicating a lack of benefit in terms of breast cancer-associated mortality have suggested that more conservative approaches, omitting adjuvant therapy or even surgery, may be advisable in selected patients. These mortality observations are directly influenced by widespread use of mammographic screening which has opened a Pandora's box of subclinical DCIS and early invasive lesions. Confusion as to how aggressively such possibly indolent lesions should be treated has led to misunderstandings among patients and medical professionals. While awaiting further prospective evidence from clinical trials, we endorse an active treatment of DCIS as the standard of care. Our rationale is twofold: invasive recurrences are associated with an increase in breast cancer mortality, which is not the only relevant endpoint for DCIS. The benefit of complete surgical excision, adjuvant radiotherapy and endocrine treatment in preventing recurrence and invasive progression has been demonstrated in DCIS. The challenge now is how to identify DCIS patients who will not progress to invasive carcinoma even without complete excision and, at the other extreme, those patients at the highest risk who require mastectomy for local control. The current controversies over whether and which adjuvant therapy should be implemented can at least in part be addressed by developing effective doctor-patient communications that enable mutual understanding about the management of this biologically heterogeneous disease.

The challenge of effective management of ductal carcinoma in situ (DCIS) and other pre-malignant disorders of the breast is to select patients who will not progress to invasive carcinoma from those at the highest risk who require radiotherapy and/or endocrine therapy to minimize the risk of a subsequent invasive recurrence. Although IBIS-II and NSABP-B35 DCIS phase III trials proved that tamoxifen 20 mg/day and anastrozole reduce the risk of ipsilateral and contralateral events, the toxicities of both drugs have hampered the drug uptake by high-risk women. We recently reported results of a 3-year placebo-controlled trial of low-dose (5 mg/d) tamoxifen in 500 women with intraepithelial neoplasia (70% DCIS). At a median follow-up of 5 years, women randomly assigned to low-dose tamoxifen had half the number of subsequent diagnoses of DCIS or invasive cancer compared with those randomly assigned to placebo but no increase in thromboembolic events or endometrial cancers. The 5-year number needed to treat was 22 (95% CI, 20-27). Our attention is now focused on prognostic and predictive markers to identify patients who can derive the greatest benefits from low dose tamoxifen, such as for instance the expression of 23 genes involved in cell cycle progression (CCP). In conclusion, we endorse an active treatment of DCIS as the standard of care.

PURPOSE To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor–positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. UPDATED RECOMMENDATIONS In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines .

PURPOSE Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose. PATIENTS AND METHODS We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. RESULTS Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 v 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; P = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three v 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; P = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen ( P = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo. CONCLUSION Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders.

Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.

Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings.

Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2) = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC.

Background: Lynch syndrome (LS) is the most frequent form of hereditary colorectal cancer (CRC; up to 3–5% of the total CRC burden) and predisposes to the development of other cancers. Multidisciplinary diagnostic strategies are relevant both to the index cases and to their at-risk relatives, but their implementation is still limited. Our study aimed to explore LS testing practices in Italy. Methods: In order to ascertain the current practice of LS diagnosis and management, we conducted a qualitative assessment by sending a questionnaire to health care professionals at 4 Italian hospitals selected as “models” representing different hospital settings. Based on the surveys, we reconstructed the management pathways for CRC patients in terms of diagnostic strategies and health professionals involved. Results: Seven of the 8 invited professionals filled in the questionnaire. Noncompliance with the latest guidelines was reported, as no tumor “screening” was performed on CRC cases. The lack of a structured multidisciplinary team who manages CRC patients from risk assessment to diagnosis and follow-up was reported. The availability of professionals and laboratory technologies differ widely between hospitals. As for cascade testing of at-risk relatives, a systematic and active approach was absent in all the considered hospitals. Conclusions: Our study shows that no structured and standardized pathways for the diagnosis and management of LS patients are currently in place in Italy. We envisage that by extending our research to further experiences and countries, an increasing awareness of the topic can be translated into a health gain for hereditary CRC patients and their at-risk relatives.

Menopausal symptoms are the main reason for withdrawal in tamoxifen prevention trials. Here, we present Menopause Quality of Life (MenQoL) assessment within a randomized 2 × 2 phase II clinical trial of low-dose tamoxifen and the synthetic retinoid fenretinide. A total of 235 premenopausal women at higher risk for breast cancer were randomized to either tamoxifen 5 mg daily, fenretinide 200 mg daily, their combination, or placebo. Climacteric symptoms were investigated using the MenQoL questionnaire which was self-administered at each visit for 2 years of treatment and for 1 year of follow-up. CYP2D6 was genotyped in subjects taking tamoxifen to study the association with menopausal symptoms. The MenQoL effect size analysis showed no statistically significant difference among the four treatment arms for all four domains (vasomotor, physical, psychosocial, and sexual). Vasomotor symptoms only slightly increased under tamoxifen, with a score at year two of 1.45, 1.21, 0.58, and 1.17 in the combined, tamoxifen, fenretinide, and placebo arms, respectively. Compared with the slow metabolizers, a higher percentage of subjects with CYP2D6 extensive metabolizer genotype complained of a ≥3 score in the vasomotor, psychosocial, and sexual domain in the tamoxifen arms (P value = 0.01, 0.007, and 0.007, respectively). QoL in premenopausal or perimenopausal women was not significantly worsened by low-dose tamoxifen or fenretinide. Our findings suggest that a low dose of tamoxifen may increase its acceptability for breast cancer prevention.

A recent article published in The Lancet reports on the seAFOod trial, in which patients with colorectal adenomas received aspirin and/or eicosapentaenoic acid (EPA, an omega-3 polyunsaturated fatty acid) post-resection. The article's abstract indicates that the primary trial endpoint, adenoma detection rate, is negative, but it does not give any indication of the remarkable secondary endpoint (adenoma number) results, which strongly suggest chemopreventive efficacy of both agents. Given the difficulty researchers and physician-scientists experience in staying abreast of the latest literature in the field, inclusion of secondary findings in abstracts should be strongly considered.

Pharmacologic interventions for cancer risk reduction involve the chronic administration of synthetic or natural agents to reduce or delay the occurrence of malignancy. Despite the strong evidence for a favorable risk-benefit ratio for a number of agents in several common malignancies such as breast and prostate cancer, the public's attitude toward cancer chemoprevention remains ambivalent, with the issue of toxicity associated with drugs being perceived as the main barrier to widespread use of preventive therapy by high-risk subjects. Among the strategies to overcome such obstacles to preventive therapies, two novel and potentially safer modes of administering agents are discussed in this paper. The first strategy is to lower the dose of drugs that are in common use in the adjuvant setting based on the notion that prevention of cancer cells from developing should require a lower dose than eradicating established tumor cells. A second approach is to adopt an intermittent administration similar to what is used in the chemotherapy setting in an attempt to minimize risks while retaining benefits. This article provides a detailed discussion of the principles and future development of these two approaches in the direction of a precision preventive medicine.

Metformin is associated with lower breast cancer risk in epidemiologic studies and showed decreased proliferation in HER2-positive breast cancer in a presurgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 nondiabetic patients diagnosed with invasive breast cancer in core biopsies to metformin, 1,700 mg or placebo once daily for 28 days before surgery. Upon surgery, five to seven specimens of cancer adjacent (≤1 cm) and distant (>1 cm) tissue were screened for LCIS, ductal carcinoma in situ (DCIS), and ductal hyperplasia (DH). The prevalence of LCIS, DCIS, and DH was 4.5% (9/200), 67% (133/200), and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in premalignant disorders. The median posttreatment Ki-67 LI (IQR) in the metformin and placebo arm was, respectively, 15% (5–15) versus 5% (4–6) in LCIS (P = 0.1), 12% (8–20) versus 10% (7–24) in DCIS (P = 0.9), and 3% (1–4) versus 3% (1–4) in DH (P = 0.5). However, posttreatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was coexpressed: 22% (11–32) versus 35% (30–40) in HER2-positive DCIS (n = 22, P = .06); 12% (7–18) versus 32% (27–42) in ER-positive/HER2-positive DCIS (n = 15, P = .004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive breast cancer. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin versus placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted. Cancer Prev Res; 8(10); 888–94. ©2015 AACR.

Background Exemestane (EXE) is an aromatase inactivator used in the prevention and treatment of breast cancer (BC). The majority of EXE and its active metabolite 17-dihydroEXE are excreted as glucuronide conjugates by uridine diphosphate glucuronosyltransferase (UGT). The UGT2B17 enzyme is the most expressed in human liver. A deletion spanning the entire UGT2B17 gene (*2) decreased the EXE glucuronidation process by 14-fold in human liver microsomes (HLM) from UGT2B17(*2/*2) genotype subjects compared to wild-type UGT2B17(*1/*1) HLMs. Aim The aim of this study was to investigate whether the UGT2B17 deletion is associated with increased serum levels of EXE and 17-dihydroEXE and to assess if this deletion predicts the anti-proliferative effect of EXE in BC tissue as measured by Ki67 changes 6 weeks apart. Methods In a phase II pre-surgical trial, 50 postmenopausal women with histologically-confirmed ER positive BC; stage T1-2, N0-1, M0 were assigned to EXE 25 mg/d for 6 weeks before surgery. Morning fasting blood was collected at baseline (B) and after 6 weeks and stored at -80° C until assayed. Time of last drug intake was collected at blood draw. DNA was extracted from whole blood (Qiagen, Italy). We used Taqman copy number variation assay (Life Technologies, Monza, Italy) for the UGT2B17 genotyping. EXE and 17-dihydroEXE concentrations were determined by mass spectrometry (MS) using Waters® Xevo™ TQ MS in electrospray positive ionization mode (Waters, Manchester, UK), optimized by multiple reaction monitoring mode. We used Zorbax Eclipse Plus C18 columns and mobile phase MeOH/H2O with 0.1% formic acid. EXE pure substance was provided by Pfizer Inc.,17β-hydroxy EXE and EXE-19-d3 purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). Wilcoxon Signed Rank Test was used to assess differences in serum concentrations of EXE, its metabolites, and post-pretreatment tissue Ki67 changes according to UGT2B17 genotypes. Results Median age and BMI were 62 years and 26 kg/m2, respectively. The UGT2B17 genotype (n=50) was 24 homozygote wt (*1/*1), 20 heterozygote (*1/*2) and 6 homozygote variant (*2/*2). Minor allele frequency = 0.32. Hardy-Weinberg Equilibrium (P=0.57) was respected. Median and interquartile ranges (IQRs) of EXE and 17-dihydroEXE at 6 weeks, by time elapsed since last drug intakeTime since last drugEXE (nM)17-dihydroEXE (nM)≤24 hours (n=32)10.25 (5.55, 17.25)2.75 (1.85, 3.6)>24 hours (n=15)2.10 (1.20, 2.20)*1.50 (1.20, 2.00)*** P=.0001 vs ≤24h; **P=.0003 vs ≤24h ; Median and IQRs of EXE, 17-dihydroEXE and Ki67 change from B by UGT2B17 genotypesGenotypeEXE (nM)17-dihydroEXE (nM)Ki67 changeBMIUGT2B17 *1/*1 (n=22)5.3 (2.2, 11.4)1.85 (1.4, 3.06)-9 (-16, -5)28 (24, 32)UGT2B17 *1/*2, *2/*2 (n=25)9.3 (2.6, 17.6)*2.5 (2.0, 3.6)**-11 (-19, -3)♦26 (23, 30)♦♦P-values between genotype groups:*P=.28; **P=.04; ♦P=.82; ♦♦P=.41 Conclusions Our study demonstrates a significant association of the UGT2B17 deletion with increased serum concentrations of 17-dihydroEXE, irrespective of time since last drug intake. Neither 17-dihydroEXE, nor genotype explained the significant anti-proliferative effect of EXE on BC tissue. Larger studies should determine the clinical implications of this gene on EXE efficacy. Citation Format: Harriet Johansson, Valentina Aristarco, Jennifer Gjerde, Sara Gandini, Aliana Guerrieri-Gonzaga, Matteo Lazzeroni, Serena Mora, Debora Macis, Davide Serrano, Antonio Toesca, Luca Bottiglieri, Gunnar Mellgren, Giuseppe Viale, Andrea DeCensi, Bernardo Bonanni. A genetic deletion in the uridine diphosphate glucuronosyltransferase 2B17 affects the pharmacokinetics of exemestane [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-43.

Background: Epidemiological studies indicated that the presence of insulin resistance is an adverse prognostic factor in MBC. Recently increasing interest has focused on metformin, an oral insulin- sensitizing drug widely prescribed for type 2 diabetes; unexpensive and well tolerated, metformin has also been shown to have direct antiproliferative properties in breast cancer. We present here the final analysis of a phase II comparative multicentric study on the addition of metformin to first line chemotherapy in MBC non diabetic patients. Methods: This is a Phase II randomized study of HER-2 negative MBC patients with measurable or non-measurable disease; no prior chemotherapy for MBC was allowed. Patients were allowed to have had prior endocrine therapy for MBC and prior adjuvant chemotherapy if completed at least 1 year prior to study entry. Patients were stratified by HOMA Index (>2,5 vs Results: As of June 8th, 2014, 108 patients had been randomised. Median age was 60 yrs (range 36-77); 87% of patients were ER+, 60% had received prior adjuvant CT, with antracyclines in 51% of patients. Prior endocrine therapy for MBC was used in 39% of the patients. Measurable disease was present in 74% of the patients. 48% of the patients were insulin resistant by HOMA Index >2.5 and 60% were overweight (BMI > 25: 16% were obese, BMI >30). At a median follow up of 16 months (range 1 – 48), median PFS (ITT) was 9 months (95% CI 8-14) with AC + M and 11 months (95% CI 7-16) with AC alone, p=.84. No significant interaction was detected between HOMA Index and treatment arm (p = 0.15). Median OS was 30 months (95% CI 14-NE) in Arm A versus 27 (95% CI 17-33) in Arm B, p = .58. The most common toxicities observed were G3/4 neutropenia in 51.5% of patients in arm A vs 69.6% in arm B, with Febrile Neutropenia observed in 2,2% and 5.4% of patients, respectively. As expected G2 diarrhea was reported by 11.1% of patients in Arm A. Conclusions: The addition of M to AC in MBC patients receiving first line chemotherapy did not improve PFS compared with AC alone. M seems to have a protective effect on hematological toxicity. Final results including translational data will be available at SABCS 2014. Citation Format: Alessandra Gennari, Oriana Nanni, Andrea DeCensi, Samanta Sarti, Andrea Freschi, Alessandra Bologna, Lorenzo Gianni, Laura Amaducci, Francesco Rosetti, Filippo Giovanardi, Anna Fedeli, Massimo Ambroggi, Paolo Bruzzi, Dino Amadori. Phase II randomised clinical study of first line chemotherapy plus metformin versus first line chemotherapy alone in HER2 negative, non diabetic, metastatic breast cancer patients: Final results of the MYME study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-02.

Background: In a presurgical trial in 200 non-diabetic women with breast cancer, we previously showed a heterogeneous effect of metformin on the Ki67, with a decreased proliferation in women with insulin resistance (HOMA>2.8) and an opposite effect in women with HOMA≤ 2.8 (Bonanni et al. JCO 30:2593, 2012). Here we determined the effect of metformin on noninvasive proliferative disorders. Methods: Patients with operable breast cancer were randomly assigned to metformin, 850 mg or placebo once daily on days 1-3 followed by two 850 mg tablets after dinner on days 4 to 28. A total of 3-5 specimens of adjacent (≤1 cm from tumor) and distant (>1 cm from tumor) tissue were obtained from the surgical specimens to assess systematically the prevalence of LCIS and DCIS adjacent to invasive cancer and of distant ductal hyperplasia (DH) in normal tissue. We also determined the effect of metformin on Ki67 in these lesions overall and by molecular subtype. All HER2 2+ DCIS by IHC were assessed by FISH. Results: Overall, the prevalence of LCIS, DCIS and DH was 4.5% (9/200), 66% (132/200) and 35% (69/200), respectively. The Ki67 was positively associated with DCIS grade (p-trend Median (IQR) Ki67 level (%) in premalignant disorders by treatment armPremalignant groupPremalignant subgroupMetformin armPlacebo armp-value*p-interaction‡LCIS (n=9) 15 (5-15)5 (4-6)0.1 DH (n=69) 3 (1-4)3 (1-4)0.5 All DCIS (n=132) 12 (8-20)10 (7-24)0.9 DCIS grade 1/2 (n=108)10 (7-16)10 (6-17)0.90.2 DCIS grade 3 (n=24)33 (25-55)40 (32-40)0.2 HER2+ve (n=22)22 (11-32)35 (30-40)0.060.04 HER2-ve (n=58)16 (10-20)17 (8-26)0.7 ER+ve/HER2+ve (n=15)12 (7-18)32 (27-42)0.0040.001 ER+ve/HER2-ve (n=53)16 (10-20)15 (8-22)0.8 PR+ve/HER2+ve (n=12)18 (12-18)32 (24-44)0.020.05 PR+ve/HER2-ve (n=48)16 (10-20)12 (8-20)0.6 *Wilcoxon rank-sum test; ‡ p-interaction between treatment and DCIS grade or HER2 status from a linear regression model, adjusted for age and BMI. The effect of metformin on DCIS was different by HER2 status (p-interaction=.04) and, among this molecular subtype, by ER and PR status (p-interaction=.001 and .02, respectively). In HER2+ve DCIS, metformin decreased Ki67 by 40% overall (p=.06), by over 60% in ER+ve/HER2+ve DCIS (p=.004). and by 45% in PR+ve/HER2+ve DCIS (p=.02) There was no effect of metformin in HER2-ve DCIS, regardless of ER or PR status. Metformin did not affect Ki67 in DH overall, but showed a trend towards a decrease in women with abdominal adiposity (p-interaction=.05). Conclusions: Window of opportunity pre-surgical models provide insight into a drug’s preventive potential by targeting intraepithelial proliferations adjacent to invasive cancer. The model shows a high prevalence of preinvasive lesions (field cancerization) in apparently normal breast tissue adjacent to breast cancer. Metformin selectively decreased Ki67 in HER2+ve DCIS, particularly in the ER+ve subgroup, in line with a selective inhibitory effect on the HER2 pathway observed both in in vitro and in vivo preclinical models. Our results provide the background for a phase III trial of metformin in HER2+ve DCIS (ISRCTN16493703, Supported by AIRC, LILT and Health Ministry 2009-RF-153222). Citation Format: Bernardo Bonanni, Andrea DeCensi, Aliana Guerrieri-Gonzaga, Giancarlo Pruneri, Matteo Puntoni, Massimiliano Cazzaniga, Andrea Vingiani, Davide Serrano, Oreste Gentilini, Harriet Johansson, Valentina Aristarco, Matteo Lazzeroni, Clara Varicchio, Marilena Petrera, Giuseppe Viale. Metformin decreases Ki67 in HER2+ve ductal carcinoma in situ in a window of opportunity trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-02.

Background Steroid hormones promote epithelial ovarian cancer (EOC) growth and their receptor expression is associated with disease outcome. Hormone therapy is frequently used in pretreated EOC, but the magnitude of activity overall and by specific agents or tumor characteristics is unknown. Methods Clinical Benefit Rates (CBR) and deaths from clinical trials of endocrine agents were meta-analyzed. Summary estimates of CBR (SCBR) and Odd Ratio for death (SOR) were calculated according with type of drug, ER and PgR status, platinum resistance, line of therapy, tumor grade and tamoxifen dose. Results Fifty-three trials in 2490 patients were analyzed. Overall, SCBR was 41% (95%CI, 0.34–0.48) for any endocrine treatment, 43% (95%CI, 0.30–0.56) for tamoxifen, 39% (95%CI, 0.29–0.50) for aromatase inhibitors and 37% (95%CI, 0.26–0.48) for progestins. The SCBR for ER+ and/or PgR+ tumors was 46% (95%CI, 0.34–0.57) versus 37% (95%CI, 0.27–0.48) in tumors with unknown receptors and 55% in platinum sensitive (95%CI, 0.28–0.80) versus 40% (95%CI, 0.29–0.51) in platinum resistant tumors The SOR for death calculated from 6 out of 9 randomized clinical trials (RCTs) showed a reduced mortality with endocrine therapy (SOR=0.69, 95%CI, 0.50–0.97), with a possible tendency for a greater effect in first line and low grade tumors. The overall quality of the RCTs was low. Conclusions The activity of endocrine therapy in advanced EOC is worth considering and seems to support large properly designed randomized trials in the first treatment of hormone sensitive EOC.

Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained. Patients and methods: We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2 years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive. Results: Of the 1488 patients with DCIS under study, 35.1% had < 1%, 58.3% 1-49% and 6.5% ≥ 50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≥ 0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥ 50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (

SummaryAim: To compare 18F-FDG PET/CT and 18F-NaF PET/CT with respect to disease prognostication and outcome in patients affected by bone metastases from breast cancer (BC). Patients, methods: We retrospectively investigated 32 women with BC and documented bone metastases. Semi-quantitative parameters were applied to 18F-FDG PET/CT and 18F-Na PET/CT in order to evaluate disease extent and tumour metabolism. We used time-to-event analyses (Kaplan Meier and COX proportional hazard methods) to estimate progression-free (PFS) and overall survival (OS) in order to assess the independent prognostic value of 18F-FDG PET/CT and 18F-Na PET/CT. Results: The sensitivity of 18F-NaF PET/CT (100%) was higher (p < 0.05) than that of 18F-FDG PET/CT (72% and 72%). None of the 18F-FDG PET/CT-negative patients showed disease progression at the end of follow-up. After adjustment for age, Ki-67 levels, presence of visceral metastases, hormone therapy, duration of bone disease and response to first-line therapy, only 18F-FDG SUV mean [HR 15.7, 95% confidence interval (CI) 1.15-214.5] and 18F-FDG whole-body bone metabolic burden (WB-B-MB) (HR 16.9; 95%CI 1.87-152.2) were independently and significantly associated with OS. None of the 18F-NaF PET/CT parameters were associated with OS. None of the conventional clinical prognostic parameters remained significantly associated with OS after the inclusion of PET/ CT parameters in the model. Conclusion: 18F-FDG PET/CT is independently associated with OS in BC patients with bone metastases and its prognostic impact seems to be higher than conventional clinical and biological prognostic factors. Although 18F-NaF PET/CT has a higher diagnostic sensitivity than 18F-FDG PET/ CT, it is not independently associated with OS.

Hormonal factors play a pivotal role in epithelial ovarian tumorigenesis and steroid receptor expression has been associated with epithelial ovarian cancer (EOC) response and survival in recent studies. However, the degree of activity of endocrine therapy overall and by specific agents remains unclear. The purpose of this work is to summarize the evidence provided by the recent literature on the effectiveness of endocrine treatment for advanced EOC.The results of 53 trials of different endocrine therapies in EOC indicate a clinical benefit of 41% [95% confidence interval (CI), 0.34-0.48], with a trend for a higher benefit in those with estrogen receptor (ER) + and/or progesteron receptor (PgR) + tumors. Moreover, the odd ratio for death showed a reduced mortality with endocrine regimens (0.69, 95% CI, 0.50-0.97), with a propensity for a better outcome in first-line and low-grade tumors.We suggest that ER and PgR have a predictive role and their inhibition by endocrine therapy may be a treatment option for EOC. Randomized clinical trials in the first-line treatment of advanced hormone receptor positive EOC are warranted given the potential cost effectiveness of this approach.

Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials. Although repurposing drugs with excellent safety profiles is an appealing strategy for cancer prevention and treatment in the adjuvant setting, there is no substitute for well-executed, large randomised clinical trials to define efficacy and determine the populations that are most likely to benefit from an intervention. Thus, enthusiasm remains for understanding the role of metformin in cancer through ongoing clinical research.

The nurse-physician relationship is undergoing profound changes after the introduction of the degree in nursing sciences. We conducted a survey among 18 Internal Medicine Units in Liguria region to investigate the real picture of this collaboration, using the Jefferson collaboration scale (JCS) and the nurse-physician collaboration scale (NPCS). We sent anonymous questionnaires to 580 nurses and 180 physicians of whom over 50% responded. Of 15 items of JCS and 27 of NPCS, 9 (60%) and 13 (48.1%) did not show different opinions between nurses and physicians, respectively. However, significant differences were observed on several items, including the caring process, the nurse autonomy, the physician authority and the human relationship. On the question: The primary function of the nurse is to carry out the physician�s orders, 23% of the nurses and 33% of physicians agreed, whereas only 46% of the nurses and 22% of the physicians strongly disagreed (P