Effect of metformin and lifestyle intervention on adipokines and hormones in breast cancer survivors: a pooled analysis from two randomized controlled trials.

PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p < 0.01) and HOMA-IR (- 0.48 vs - 0.25; p = 0.03), and an increase in SHBG (2.80 vs 1.45 nmol/L; p < 0.01). Excluding women taking aromatase inhibitors, metformin (n = 84) compared to placebo (n = 99) decreased estradiol (- 4 vs 0 pmol/L; p < 0.01), estrone (- 8 vs 2 pmol/L; p < 0.01) and testosterone (- 0.1 vs 0 nmol/L-; p = 0.02). LSI favorably affected adiponectin (0.45 vs - 0.06 ug/mL; p < 0.01), leptin (- 10.5 vs - 4.4 ng/mL; p < 0.01), HOMA-IR (- 0.6 vs 0.2; p = 0.03), and SHBG (2.7 vs 1.1 nMol/L; p = 0.04) compared to controls. The strongest impact was observed combining metformin with LSI on adipokines, CRP, SHBG, and estrogens. CONCLUSIONS: Supportive healthy lifestyle programs combined with metformin to achieve maximal risk reduction among BC cancer survivors are recommended, especially for those with obesity in menopause.

Diagnostic effectiveness of [18F]Fluoroestradiol PET/CT in oestrogen receptor-positive breast cancer: the key role of histopathology. Evidence from an international multicentre prospective study.

INTRODUCTION: [18F]Fluoroestradiol ([18F]FES) PET/CT has been proposed as a tool for detecting the oestrogen receptor density in patients with metastatic breast cancer (BC) non-invasively across all disease localizations. However, its diagnostic potential in terms of the detection rate (DR) of metastases is unclear. In this study, we pitted this method against [18F]FDG PET/CT and tried to identify predictors of the diagnostic superiority of the [18F] FES-based method. MATERIALS AND METHODS: From a multicentre database, we enrolled all patients with metastatic BC who had undergone both [18F]FES PET/CT and [18F]FDG PET/CT. Two readers assessed both images independently and used a patient-based (PBA) and lesion-based analysis (LBA) to calculate the DR. Pathology-related and clinical factors were tested as predictors of [18F]FES PET/CT superiority using a multivariate model. RESULTS: 92 patients, bearing a total of 2678 metastases, were enrolled. On PBA, the DR of [18F]FDG and [18F]FES PET/CT was 97% and 86%, respectively (p = 0.018). On LBA, the [18F]FES method proved more sensitive than [18F]FDG PET/CT in lymph nodes, bone, lung and soft tissue (p < 0.01). This greater sensitivity was associated with lobular histology, both on PBA (Odds Ratio (OR) 3.4, 95%CI 1.0-12.3) and on LBA (OR 4.4, 95%CI 1.2-16.1 for lymph node metastases and OR 3.29, 95%CI 1.1-10.2 for bone localizations). CONCLUSIONS: The overall DR of [18F]FES PET/CT appears to be lower than that of [18F]FDG PET/CT on PBA. However, the [18F]FES method, if positive, can identify more lesions than [18F]FDG at most sites. The higher sensitivity of [18F]FES PET/CT was associated with lobular histology.

Taste and Smell Disorders in Cancer Treatment: Results from an Integrative Rapid Systematic Review.

Taste and smell disorders (TSDs) are common side effects in patients undergoing cancer treatments. Knowing which treatments specifically cause them is crucial to improve patients' quality of life. This review looked at the oncological treatments that cause taste and smell alterations and their time of onset. We performed an integrative rapid review. The PubMed, PROSPERO, and Web of Science databases were searched in November 2022. The article screening and study selection were conducted independently by two reviewers. Data were analyzed narratively. Fourteen studies met the inclusion criteria and were included. A high heterogeneity was detected. Taste disorders ranged between 17 and 86%, while dysosmia ranged between 8 and 45%. Docetaxel, paclitaxel, nab-paclitaxel, capecitabine, cyclophosphamide, epirubicin, anthracyclines, and oral 5-FU analogues were found to be the drugs most frequently associated with TSDs. This review identifies the cancer treatments that mainly lead to taste and smell changes and provides evidence for wider studies, including those focusing on prevention. Further studies are warranted to make conclusive indication possible.

Randomized phase II trial of weekly paclitaxel vs. cediranib-olaparib (continuous or intermittent schedule) in platinum-resistant high-grade epithelial ovarian cancer.

BACKGROUND: Previous findings showed that cediranib-olaparib increased PFS in women with recurrent platinum-sensitive ovarian cancer compared to olaparib alone. METHODS: BAROCCO trial randomized 123 patients: 80mg/m2 paclitaxel weekly up to 24 weeks (control), olaparib 300mg tablets twice daily together with 20mg cediranib daily (continuous schedule) or with 20mg cediranib 5 days/week (intermittent schedule) until progression. The primary objective was the PFS comparison between each experimental arm and the control (alpha one-sided 5%; power 80%; HR 0.5). RESULTS: The median platinum-free interval was 1.9 months, 60% of patients had been pretreated with 3 or more chemotherapy lines. Median PFS for paclitaxel, the continuous, and the intermittent schedules were 3.1, 5.6, and 3.8 months. The HR for PFS in the continuous arm vs control was 0.76 (90% CI: 0.50-1.14, p = 0.265). The HR for PFS in the intermittent arm vs control was 1.03 (90% CI: 0.68-1.55, p = 0.904). Treatment was discontinued due to adverse events in 15%, 20%, and 5% of patients in the control, continuous and intermittent arms. Grade ≥ 3 anemia and diarrhea and hypertension of any grade occurred only in the experimental arms, and peripheral neuropathies and alopecia only in the control arm. Five serious adverse drug reactions occurred and two were fatal: one in the control and one in the continuous arm. CONCLUSIONS: The combination of cediranib-olaparib was not superior to chemotherapy in terms of PFS in heavily pretreated platinum-resistant ovarian cancer patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population. CLINICAL TRIAL IDENTIFICATION: IRFMN-OVA-7289, EudraCT: 2016-003964-38, NCT03314740.

Patient- versus physician-reported outcomes in a low-dose tamoxifen trial in noninvasive breast cancer.

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.

A Presurgical Study of Curcumin Combined with Anthocyanin Supplements in Patients with Colorectal Adenomatous Polyps.

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 ß-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.

To Enhance or Not to Enhance? The Role of Contrast Medium 18F-FDG PET/CT in Recurrent Ovarian Carcinomas.

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.

Predictors of poor seroconversion and adverse events to SARS-CoV-2 mRNA BNT162b2 vaccine in cancer patients on active treatment. Role of the Research Nurse.

BACKGROUND: Vaccines have shown 95% protection from COVID-19 disease in healthy populations. Initial findings in cancer patients suggest a lower seroconversion and greater toxicity possibly related to myelo-immunosuppressive therapies. AIM: 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. METHODS: Blood samples were collected by the research nurse at first dose (visit 1), second dose (visit 2), after 42 days (visit 3) and after 6 months (visit 4). At visit 1, 3 and 4 participants received: Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer. Patients who ended treatment >6 months on active surveillance served as controls. RESULTS: Between March and July 2021, 320 subjects were recruited and 291 were assessable. The lack of seroconversion at 21 days from the second dose 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 targeted therapy and 4.8% (0.12-23.8) on immunotherapy. Compared to controls, the risk of no IgG response was greater for chemotherapy (P=0.033), targeted therapy (0.005) and hormonotherapy (P=0.051). Lymphocyte count less than 1x109/L, older age and advanced stage also significantly 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). CONCLUSIONS: A third booster dose and long-term serological testing is required in subjects who have not responded to the vaccine. NURSING IMPLICATIONS: nurses must take responsibility for promoting and protecting the health of cancer patients.

Pharmacokinetics, safety, and activity of trabectedin as first-line treatment in elderly patients who are affected by advanced sarcoma and are unfit to receive standard chemotherapy: A phase 2 study (TR1US study) from the Italian Sarcoma Group.

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.

Prognostic and predictive value of cell cycle progression (CCP) score in ductal carcinoma in situ of the breast.

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.

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

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 < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.

Aromatase Inhibitors as Adjuvant Treatment for ER/PgR Positive Stage I Endometrial Carcinoma: A Retrospective Cohort Study.

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; 0.04-1.27) for PFS and HR= 0.11 (95% CI; 0.01-1.36) 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.

Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer.

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.

Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma.

Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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. TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.

Endocrine therapy in ovarian cancer: where do we stand?

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Repurposing metformin for the prevention of cancer and cancer recurrence.

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.

Clinical benefit and risk of death with endocrine therapy in ovarian cancer: A comprehensive review and meta-analysis.

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.

Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer: ROSiA Single-Arm Phase 3B Study.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer. PATIENTS AND METHODS: In this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m q3w or 80 mg/m weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety. RESULTS: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months). CONCLUSION: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.