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Background: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. Methods: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31). Findings: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). Interpretation: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

10.3389/fonc.2022.1088962 Abstract: Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

PURPOSE Despite extensive research on cancer and work-related outcomes, evidence from longitudinal cohort studies is limited, especially in young women with breast cancer (BC). We aimed to investigate employment trajectories in young BC survivors and to identify potential factors associated with changes in work activity. METHODS The HOHO European prospective multicenter cohort study enrolled 300 young women (≤ 40 years) with newly diagnosed BC. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years to assess, among other variables, employment status, sociodemographic, medical, and treatment data. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Univariable and multivariable multinomial logistic regression analyses identified factors associated with changes in employment status. RESULTS Among the 245 women included in this analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). At 5 years, women had a 29.4% probability (95% CI: 23.6-35.5) of experiencing any reduction and a 14.9% probability (95% CI: 10.6-19.9) of experiencing any increase in work activities. Being enrolled in Switzerland (vs. Italy) and reporting more trouble in performing daily activities were significantly associated with work reduction. CONCLUSION Our results suggest that most young BC survivors remain employed in the long-term. IMPLICATIONS FOR CANCER SURVIVORS Regular evaluation of symptoms which may interfere with daily life and identification of financial discomfort is critical in providing timely and individually tailored interventions and in limiting unwanted reductions in work activities.

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

Introduction: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC). Areas covered: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients. Expert opinion: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. Abbreviations: ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.

223 Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.

Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38–5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60–4.53, p = 0.002; HR = 2.11, 95% CI 1.29–3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.

Currently, renal cell carcinoma is characterized by encouraging benefits from immunotherapy that have led to significant results in treatment outcome. The approval of nivolumab primarily as second-line monotherapy and, more recently, the approval of new combination therapies as first-line treatment have confirmed the importance of immunotherapy in this type of tumor. In this context, the chimeric antigen receptor (CAR)-T represents a further step forward in the field of immunotherapy. Initially tested on hematological malignancies, this new therapeutic approach is also becoming a topic of great interest for solid tumors. Although the treatment has several advantages over previous T-cell receptor-dependent immunotherapy, it is facing some obstacles in solid tumors such as a hostile tumor microenvironment and on-tumor/off-tumor toxicities. Several strategies are under investigation to overcome these problems, but the approval of CAR-T cell therapy is still some way off. In renal cancer, the significant advantages obtained from immune checkpoint inhibitors represent a good starting point, but the potential nephrological toxicity of CAR-T cell therapy represents an important risk. In this review, we provide the rationale and preliminary results of CAR-T cell therapy in renal cell malignancies.

152 Background: Accurate monitoring response of bone mets to treatment is an active need for mCRPC patients (pts). Recently, ctDNA has been showed as an early biomarker efficacy of androgen receptor signaling inhibitor (ARSI) therapy for mCRPC ( Conteduca, Br J Cancer 2020). In this study, we aimed to reveal if ctDNA analysis can permit more reliable prediction of bone mets burden and radiographic progression disease (PD). Methods: In a biomarker study (REC 2192/2013), targeted next generation sequencing was performed to assess ctDNA fraction. Radiographic evidence of bone disease was documented by conventional imaging according to PCWG3 criteria ( Scher, J Clin Oncol 2018), and was classified on the basis of mets number (≤5, 6 -19, ≥20) in oligometastatic (O), diffuse (D), and widespread (W), respectively. Associations were explored both through uni/multivariate logistic regressions. Results: Serial plasma samples and radiographic scans on ARSI treatment were prospectively collected from 73 CRPC with bone mets. Median age was 74 years [interquartile range (IQR) 69-79]. Bone mets patterns were significantly associated with median baseline ctDNA level (O = 0.16, D = 0.33, and W = 0.46, p 0.0003). Similar results were reported on treatment and at PD (p 0.0003 and p 0.0007, respectively). In 24 pts with a progressive worsening of bone mets pattern (O→D→W) compared to pts with no change in bone mets pattern on ARSI, we observed an early meaningful ctDNA rise with a % ctDNA variation from baseline to 3 month therapy of 150.6% (IQR 104.9-210.7) vs 11.1% (IQR 0-36.6), p < 0.0001. Univariate analysis showed that early ctDNA rise was significantly associated with radiographic progression free/overall survival (rPFS/OS): hazard ratio (HR) 2.06, 95% confidence interval (CI) 1.30-3.27, p 0.002, and HR 1.82, 95% CI 1.15-2.88, p 0.01, respectively]. In multivariable analyses including ctDNA variation, changing bone mets pattern, age, performance status, and presence of concomitant visceral mets, ctDNA change at 3 month ARSI resulted the only independent predictor of both rPFS/OS (HR 2.27, 95% CI 1.04-4.94, p 0.027 and HR 2.98, 95% CI 1.31-6.81, p 0.033, respectively). Visceral mets were associated with only OS (HR 3.87, 95% CI 1.76-8.51, p 0.0008). Conclusions: Early ctDNA variation may reflect changes in bone mets pattern on ARSI allowing to track pattern of bone progression and predict outcome. Further studies to validate these findings are warranted.

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking. The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab. Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms. In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p

To date, results of combination therapy studies have shown no meaningful clinical benefit over monotherapy and an unacceptably high degree of toxicity in the treatment of metastatic renal cell carcinoma (RCC), with the exception of a combination of immune-checkpoint inhibitors and the association of lenvatinib with everolimus. Lenvatinib is a potent multi-targeted tyrosine kinase inhibitor that targets VEGFR pathways. Everolimus inhibits primarily mTORC1 complex, a downstream effecter of the intracellular PI3K/AKT/mTOR pathway. The association of these two drugs was demonstrated to enhance the inhibitory activity against VEGF and FGF-induced angiogenesis by a vertical inhibition of angiogenic signaling pathways, suggesting a synergistic activity. Areas covered: In this review we summarize the lenvatinib pharmacokinetics, pharmacodynamics, characteristics and the main clinical trial that showed lenvatinib activity in advanced RCC. Expert opinion: Lenvatinib plus everolimus showed promising results in a phase II trial, leading to FDA approval of this combination. Their synergic action on inhibiting the VEGF/VEGFR, FGF (a compensatory mechanism to VEGFR inhibition) and mTOR pathway could be a potential mechanism to overcome treatment resistance. Given that the activity of lenvatinib as an immune-regulator in tumor microenvironment has been demonstrated in cell lines, novel combinations, in particular with immune-checkpoint inhibitors, are under development.

Contrast-enhanced computed tomography (CECT) is an indispensable tool in the management of cancer patients. However, this procedure can be complicated by the development of acute adverse reactions (ARs) to iodinated contrast media (ICM). On the basis of the hypothesis that cancer immunotherapy, in particular with immune checkpoint inhibitors, increases the incidence of allergic-like immediate ARs to ICM with respect to “standard” cancer chemotherapy/targeted therapy (CHT) we retrospectively evaluated the incidence of CECT-related immediate ARs in cancer patients undergoing cancer treatments. All patients who underwent at least one CECT scan after starting any cancer treatment between 2006 and 2014 were included in a mono-institutional radiological database. The staff of the Radiology Unit recorded any ARs that occurred within 30 min of the ICM injection and classified them as “allergic-like” or “physiologic” and graded as mild, moderate, or severe according to the American College of Radiology (ACR) Manual on Contrast Media, version 10.1. Fifty-nine of the 3,521 patients included in the database received ipilimumab (Ipi), 75 received cytokines (Cys), and the remaining 3,387 received non-immunologic agents (CHT). Overall, 71 (2%) patients suffered ICM-related ARs. The incidence of ICM-related ARs was higher in Ipi- and Cy-treated patients than in those who received CHT (12%, 5%, and 2%, respectively). Our data show that immunological cancer treatments, particularly Ipi, considerably increase the proportion of patients suffering CECT-related immediate ARs with respect to non-immunologic agents. Although these findings need to be validated in larger prospective studies, they serve as a “wake-up call” for radiologists to closely monitor patients who have previously received cancer immunotherapy with anti-cytotoxic T-lymphocyte antigen-4 antibodies when using ICM in order to reduce the risk of potentially severe immediate ARs.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Purpose Our study aims to investigate the association between copy number of the androgen receptor (AR) and testosterone levels in metastatic castration-resistant prostate cancer (mCRPC) treated with second-generation antiandrogen therapies. Materials and methods We retrospectively collected data from mCRPC treated with abiraterone acetate and enzalutamide. Serum testosterone levels were collected at baseline, at 3 months since the start of therapy and at disease progression. A cohort of cases treated with docetaxel was also used to evaluate the impact of testosterone levels. Results Patients treated with abiraterone with AR copy number aberrations and basal testosterone levels below 0.09 nmol/L had worse progression-free survival (PFS) compared to patients with no AR copy number abnormalities (8.5 vs 2.9 months, P = 0.005). No relevant differences were observed in the enzalutamide group with a PFS of 3.9 months (no AR gain) vs 2.7 months ( AR gain, P = 0.004) for patients with below 0.09 nmol/L testosterone levels. Similar results are obtained for univariate analysis for overall survival (OS). The negative prognostic role of AR copy number gain in OS for both treatment groups (25.5 vs 10.6 months, P = 0.0002 for abiraterone and 14.1 vs 8.3 months, P = 0.031 for enzalutamide) was confirmed, and it was recognized the negative prognostic impact of testosteronemia below 0.09 only for patients treated with enzalutamide (8.8 vs 42.8 months, P = 0.016). On multivariate analysis for patients treated with abiraterone, low testosterone levels below 0.09 and plasma AR gain were significantly associated with worse PFS and OS. These data are confirmed in the enzalutamide group for PFS. Conclusions Testosterone levels and the AR copy number alterations were considered as independent prognostic factors. The results of this study show that serum testosteronemia associated with changes in copy number of AR gene could represent a noninvasive biomarker useful to identify a subgroup of patients with worse prognosis that can benefit less from second-generation antiandrogen therapies in the mCRPC setting.

Background The purpose of this study was to evaluate the clinical impact of oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-4) chemotherapy in terms of the response rate, progression-free/overall survival (PFS/OS) and safety profile in patients with heavily pretreated recurrent epithelial ovarian cancer. Methods Clinical data were reviewed in 29 patients who received FOLFOX-4 as more than third-line chemotherapy, consisting of 85 mg/m2 of oxaliplatin, 200 mg/m2 of leucovorin, and bolus 400 mg/m2 on day 1 of 5-fluorouracil, followed by a 22-h infusion of 600 mg/m2 of 5-fluorouracil for 2 consecutive days every 3 weeks. We also compared the efficacy and toxicity of FOLFOX-4 with that of topotecan, a standard treatment, given at a dosage of 1.5 mg/m2 every three weeks in 26 patients. Results The median age of enrolled patients was 60 years (range 33 to 85). A median of 4 cycles (range 1–17) of FOLFOX-4 were administered. Complete response and partial response were observed in one (3.5%) and 5 (17.2.2%) patients, respectively, while stable disease was reported in 8 (27.6%) patients. Among all patients, grade 3–4 anemia, neutropenia, and thrombocytopenia were observed in 0 (0%), 5 (17.2%), and 3 (10.3%) cases, respectively. Grade 3–4 fatigue was recorded in one (3.4%) patient and diarrhea in 2 (6.9%). Median PFS and OS were 2.8 months [95% confidence interval (CI) 1.7–4.9] and 6.2 months (95% CI 2.4–14.6), respectively. No significant differences in terms of efficacy and toxicity were observed between patients receiving FOLFOX-4 and those treated with topotecan. Conclusions The FOLFOX-4 regimen would seem to obtain similar survival rates to those of standard therapy with topotecan in platinum-resistant ovarian cancer. Further randomized trials are warranted to confirm our findings.

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

The association between obesity and prognosis in early breast cancer (EBC) is unclear, especially when aggressive phenotypes are considered. We evaluated the influence of BMI on the prognosis of women with high-risk EBC enrolled in a phase III trial of adjuvant chemotherapy (CT). The association was assessed in 1066 patients with rapidly proliferating tumors, randomized to receive adjuvant CT with or without anthracyclines. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier; multivariate analysis was performed according to age, tumor size, nodal, estrogen receptor (ER), and HER2 status and type of CT. Information on BMI was available for 959 women. Of these, 529 (55.2 %) were overweight or obese. Median age was 52 years. A total of 457 (47.7 %) patients had nodal involvement. Centralized pathology was performed in 850 cases: 522 (61.4 %) were ER positive, and 194 (22.8 %) were HER-2 positive. At a median follow-up of 103 months (range 1-188), 5-year DFS was 81 % (95 % CI 77-85), 82 % (95 % CI 77-86), and 76 % (95 % CI 70-83), in normal, overweight, and obese women, respectively (p = 0.44). Five-year OS was 92 % (95 % CI 89-95), 94 % (95 % CI 91-96), and 89 % (95 % CI 84-93), respectively (p = 0.60). BMI was not associated by multivariate analysis with differences in DFS or OS. Higher BMI had no influence on prognosis in high-risk EBC patients treated with CT. These data are consistent with prior observations and suggest that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor.

Background Immune checkpoint inhibitors (ICIs) have been revolutionizing the treatment landscape of metastatic renal cell carcinoma (mRCC). The use of ICIs in elderly RCC patients has become a daily practice, although their real impact in elderly patients is nowadays not completely clarified. It has been hypothesized that ICIs might not perform as effectively in the elderly as in younger patients, likely because of the gradual deterioration of the immune system brought on by natural age advancement, namely immunosenescence. Methods We reviewed all clinical trials with ICIs in mRCC focusing on efficacy and toxicity of elderly patients. Results Among the 21 trials reviewed, only 5 of them provided data on elderly patients. With the limits of low accrual and events for elderly patients, the efficacy of ICIs in patients ≥ 65 years seems as relevant as for younger patients, but not reliable for patients ≥ 75 years, group with overall low number of events, both in pre- or previously untreated mRCC patients. These currently available data seem not to support the hypothesis of a lower efficacy of ICIs in elderly patients, at least for mRCC. These trials reported very few data about toxicities in the specific population of elderly patients. Conclusions Although available data from clinical trials are poor, currently, they do not support the efficacy of ICIs is less in elderly mRCC patients.

6053 Background: Hypersensitivity reactions (HSRs) to platinum salts are an important issue in the treatment of ovarian cancer (OC) patients (pts). Few data suggest that, along with number of previous cycles, germline BRCA mutations could be a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum salts in a large group of OC pts with known BRCA status and correlated them with drug exposure time. Methods: Between March 2003 and September 2019, 432 pts with a diagnosis of OC and a known BRCA status, were recorded in our 5 Institutions and retrospectively analyzed. The following data were collected: histology, BRCA status, type of surgery and first line therapy, number of total lines and cycles received, line and cycle of HSR onset, symptoms, history of other allergies and if desensitization was attempted. We graded the severity of HSRs according to CTCAE v5.0. We calculated the total duration of exposure to platinum salts, summing up the duration of all platinum lines received by the pts. Results: Four hundred nine of 432 (94.7%) pts were treated with at least one platinum-based line of therapy and were eligible for the analysis. Among them, 314 pts were BRCA wild type (BRCAwt) (76.8%) and 95 were BRCA mutated (BRCAmut) (23.2%). There was no statistical difference in number of prior lines of therapy [median 1 (2-6) for BRCA wt and 2 (1-6) for BRCAmut pts (p = 0.194)] and duration of exposure to platinum [median 126 (42 – 893) and 197 (42 – 896) days for BRCAwt and BRCAmut pts, respectively (p = 0.145)]. Incidence of any grade HSRs was 29 / 314 (9.2%) among BRCAwt pts vs. 17/ 95 (17.9%) among BRCAmut pts (Odds ratio [OR] 0.47, 95% CI 0.24 – 0.89, p= 0.019). All recorded HSRs to platinum salts were related to carboplatin. We observed a numerically higher incidence of Grade 3-4 HSRs in BRCAmut pts (5.1% in BRCAwt vs. 10.5% in BRCAmut cohort, OR 0.46, 95% CI 0.20 – 1.04, p = 0.057). The risk to develop HSRs increases with duration of exposure to platinum, particularly in BRCAmut pts. The cumulative incidence of any grade HSRs was 20.6% vs. 23.3% after 12 months and 38.4% vs. 59.7% after 18 months in BRCAwt and BRCAmut pts, respectively (Hazard Ratio [HR] 1.72, 95% CI 0.94 – 3.12, p = 0.073). The cumulative incidence of severe HSRs was 10.9% vs. 15.7% after 12 months and 26.5% vs. 41.0% after 18 months in BRCAwt and BRCAmut pts, respectively (HR 1.88, 95% CI 0.85 – 4.16, p = 0.11). Conclusions: In BRCAmut OC pts, there is a significantly higher incidence of HSRs to carboplatin, that seems not justified by longer drug exposure only.

Harnessing the immune system to battle cancer, long a medical utopia, is becoming a reality. With the advent of immunotherapy, substantial progresses have been made in improving patients outcome, but only for a minority of them.

We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response.

Prostate cancer is one of the most common malignant neoplasms in men worldwide, and is the fifth cause of cancer-related death. In recent years, a new generation of therapies have been approved for the management of metastatic disease. Moreover, the development of new immunotherapeutic drugs has become a novel frontier for the treatment of several tumor types; to date, numerous studies have investigated their potential activity, including in prostate cancer. In this article, we discuss the role of emerging immunotherapeutic drugs in prostate cancer patients.

Breast cancer treatment includes many options depending on the tumor clinicopathological profile, which groups breast cancer into various subtypes. Bevacizumab is currently the only drug capable of targeting angiogenesis in breast cancer. Sorafenib has also been studied in combination with other agents. Areas covered: Pharmacological aspects of sorafenib, including results from preclinical studies on breast cancer cells; findings about clinical efficacy and safety in both single-arm and randomized clinical trials; ongoing trials. Expert opinion: Since sorafenib as a single agent has shown limited efficacy in breast cancer, its combination with other drugs is under investigation. Dose reduction is the main challenge when sorafenib is combined with chemotherapy or endocrine therapy. Although randomized phase-II trials on sorafenib plus chemotherapy versus chemotherapy alone have shown potential benefits in progression-free survival, preliminary results from a phase-III study in combination with capecitabine are negative. The definitive results of this trial and results from other ongoing phase-II trials will determine further developments of sorafenib in breast cancer. Although these additional data could help determine the most appropriate dose, drug combination and patient settings, a confirmation of the preliminary negative results reported in the phase-III trial are likely to discourage further use of sorafenib in breast cancer, given its non-negligible toxicity, lack of predicting markers, and the number of more promising drugs for breast cancer.

// Alberto Farolfi 1 , Paolo Silimbani 2 , Davide Gallegati 3 , Elisabetta Petracci 4 , Alessio Schirone 1 , Mattia Altini 5 and Carla Masini 2 1 Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 2 Oncology Pharmacy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 3 Financial and Management Control, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 4 Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy 5 Healthcare Administration, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Correspondence to: Alberto Farolfi, email: alberto.farolfi@irst.emr.it Keywords: breast cancer, economic evaluation, oncology, subcutaneous trastuzumab Received: February 07, 2017 Accepted: June 02, 2017 Published: June 16, 2017 ABSTRACT We conducted an economic evaluation of intravenous (IV) vs subcutaneous (SC) trastuzumab for the treatment of patients with early breast cancer (EBC). Data of patients receiving adjuvant IV trastuzumab at our institute in 2014 were used to study three different treatment scenarios: 1) IV trastuzumab, 2) SC trastuzumab, and 3) IV trastuzumab during chemotherapy followed by SC trastuzumab. Our cohort included 114 patients with a median weight of 63.75 kg. Scenario 2 was the most time-saving treatment, with 71.7% reduction in preparation time and 89.3% reduction in chair time compared to scenario 1. Considering full costs, the mean costs per patient/year were € 14,233 ± 8,698 for scenario 1, € 14,272 ± 8,312 for scenario 2, and € 14,535 ± 8,646 for scenario 3 ( p = 0.959). When mean body weight was > 65.2 kg, the mean cost was lower in scenario 2 than in scenario 1. Scenario 2 proved a valuable time-saving and cost-saving option. A shift from IV to SC trastuzumab should be considered, especially in capacity-constrained oncology departments.

The publisher regrets that the collaborators for this paper were not listed as such within the author details of the published paper. The collaborators were published in the Acknowledgements and are as follows: Alberto Farolfi, Silvia Ruscelli, Martina Valgiusti, Sara Pini, Marina Faedi, Department of Medical Oncology, IRST IRCCS, Meldola; Angela Ragazzini, Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola; Cristina Pittureri and Elena Amaducci, Palliative Care and Hospice Unit, AUSL Romagna, Cesena; Irene Guglieri, Psychooncology Service, Veneto Institute of Oncology IOV – IRCCS, Padua; Francesca Bergamo, Sara Lonardi, Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology IOV – IRCCS, Padua; Camilla Di Nunzio, Medical Oncology Unit, Oncology–Hematology Department, Guglielmo da Saliceto Hospital, Piacenza; Monica Bosco, Palliative Care Unit, Oncology–Hematology Department, Guglielmo da Saliceto Hospital, Piacenza; Barbara Bocci, Medical Oncology Unit, San Paolo Hospital, Milan; Alfina Bramanti and Chiara Gandini, Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia; Angela Buonadonna, Medical Oncology Unit, Aviano National Cancer Institute, Aviano; Alessandro Comandone, Medical Oncology Unit, Presidio Humanitas Gradenigo, Turin; Sonia Zoccali, Coordinamento Cure Palliative (supported by F.I.L.E., Leniterapia Italian Foundatio), Florence; Maria Simona Pino, Medical Oncology Unit, Oncology Department, S. Maria Annunziata Hospital, Florence; Davide Dalu, Palliative Care Unit, Oncology Department, L. Sacco Hospital, Milan; Pietro Sozzi, Oncology Unit, Ospedale degli Infermi, Ponderano; Alberto Gozza, Medical Oncology, Department of Medicine, E.O. Galliera Hospitals, Genoa; Monica Giordano and Carla Longhi, Oncology Unit, Sant'Anna Hospital, Como; Cristina Autelitano, Palliative Care Unit, Arcispedale S. Maria Nuova – IRCCS, Reggio Emilia; Teresa Gamucci, Oncology Unit, SS Trinità Hospital Sora, ASL Frosinone, Frosinone; Cataldo Mastromauro, Oncology Unit, ULSS 12 Veneziana, Venice; Rodolfo Scognamiglio, Hospice Nazareth, Mestre; Daniela Degiovanni, Palliative Care Unit, Casale Monferrato, ASL Alessandria; Federica Negri, Medical Oncology Unit, Istituti Ospitalieri, Cremona; Augusto Caraceni, Palliative Care, Pain Therapy and Rehabilitation Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; and Luigi Montanari, Palliative Care Unit Ravenna, AUSL Romagna, Italy. The publisher would like to apologise for any inconvenience caused.

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

Pertuzumab is a recombinant, humanized monoclonal antibody that binds to the dimerization domain of human epidermal growth factor receptor 2 (HER2), inhibiting the heterodimerization of HER2 with other HER receptors. It has shown synergy with trastuzumab in preclinical studies, and has led to a significant prolongation of progression-free and overall survival compared with placebo when added to trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer (BC).The HER family of receptors and their pathways, pertuzumab pharmacodynamics and preclinical activity, results from the main clinical trials, new drug combinations being developed, and predictors of response are discussed.Pertuzumab represents an important anti-HER2 agent that differs from, but is synergistic with, trastuzumab. It is already a standard of care in the first-line treatment of HER2-positive metastatic BC, and studies are ongoing to define its role in the adjuvant setting. It is now imperative to identify which tumors need dual HER2 targeting and to study the activity of pertuzumab in combination with other HER-targeted agents, including anti-HER1, -HER3 or -HER4, which could also prove useful in HER2-normal cancers. Potential competitors are anti-HER3 antibodies and bi- or tri-specific antibodies. Development in combination with phosphoinositide 3-kinase inhibitors or with anti PD-L1 is warranted.

The analysis of the global thiol-disulfide redox status in tissues and cells is a challenging task since thiols and disulfides can undergo artificial oxido-reductions during sample manipulation. Because of this, the measured values, in particular for disulfides, can have a significant bias. Whereas this methodological problem has already been addressed in samples of red blood cells and solid tissues, a reliable method to measure thiols and disulfides in cell cultures has not been previously reported. Here, we demonstrate that the major artifact occurring during thiol and disulfide analysis in cultured cells is represented by glutathione disulfide (GSSG) and S-glutathionylated proteins (PSSG) overestimation, due to artificial oxidation of glutathione (GSH) during sample manipulation, and that this methodological problem can be solved by the addition of N-ethylmaleimide (NEM) immediately after culture medium removal. Basal levels of GSSG and PSSG in different lines of cultured cells were 3-5 and 10-20 folds higher, respectively, when the cells were processed without NEM. NEM pre-treatment also prevented the artificial reduction of disulfides that occurs during the pre-analytical phase when cells are exposed to an oxidant stimulus. In fact, in the absence of NEM, after medium removal, GSH, GSSG and PSSG levels restored their initial values within 15-30 min, due to the activity of reductases and the lack of the oxidant. The newly developed protocol was used to measure the thiol-disulfide redox status in 16 different line cells routinely used for biomedical research both under basal conditions and after treatment with disulfiram, a thiol-specific oxidant (0-200 μM concentration range). Our data indicate that, in most cell lines, treatment with disulfiram affected the levels of GSH and GSSG only at the highest concentration. On the other hand, PSSG levels increased significantly also at the lower concentrations of the drug, and the rise was remarkable (from 100 to 1000 folds at 200 μM concentration) and dose-dependent for almost all the cell lines. These data support the suitability of the analysis of PSSG in cultured cells as a biomarker of oxidative stress.

Hypocalcemia is an uncommon clinical symptom of patients with malignant tumors, and a number of factors may be involved in its development. The present study describes the case of a 67-year-old Caucasian female, presenting with severe refractory hypocalcemia and heart failure. The patient was subsequently diagnosed with breast cancer and bone metastases. The paraneoplastic origin of the syndrome was confirmed by its complete resolution once the tumor responded to specific antineoplastic treatments, comprising weekly paclitaxel and aromatase inhibitor administration. The present case report suggested the need for greater awareness of the possibility of paraneoplastic hypocalcemia in breast cancer patients, and suggested that this condition may also contribute to the occurrence of heart failure. The mechanisms potentially responsible for this event were discussed and a brief review of the literature presented.

Information on hormone receptor and human epidermal growth factor receptor-2 (HER2) expression in breast cancer is acknowledged as mandatory for prognostic stratification and treatment planning. Data on the biological features of African breast cancers are poor. We decided to compare histopathological and biomolecular characteristics (estrogen and progesterone receptor—ER, PgR, and HER2) of Tanzanian and Italian breast cancers. Differences in proliferating index and androgen receptor (AR) expression in triple-negative patients from the two case series were also assessed. Of the 103 consecutive patients seen at the Bugando Medical Center (Mwanza, Tanzania) from 2003 to 2010, who underwent biopsy or surgical resection of primary breast cancer, 69 patients had tissue samples that were evaluable for estrogen receptor (ER), progesterone receptor (PgR), and HER2. Histopathological assessment and biomolecular determinations were performed at the Cancer Institute of Romagna (IRST IRCCS, Meldola, Italy). Caucasian breast cancers were randomly extracted from an electronic database and matched (1:2 ratio) for year of diagnosis and age at diagnosis. Median age of both populations was 51 years (range 27–84). With respect to Caucasian tumors, Tanzanian breast cancers at diagnosis more frequently showed high histological grade (mainly grade 3) (P = 0.03), advanced clinical stage (III or IV) (P\0.001), ER negativity (52.2 %, P\0.001) and high proliferation (P = 0.0002). Triple-negative tumors were over-represented in Tanzanian women. AR was positive in 38.5 and 38 %of triple-negative Tanzanian and Italian breast cancers, respectively. Our results show that histopathological and biomolecular characteristics in Tanzanian and Italian breast cancers differ substantially. The high frequency of poorly differentiated, ER-negative, highly proliferating tumors, together with advanced stage at presentation, could be considered as the main prognostic factors linked to the high mortality rates for breast cancer in the African population.

The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, governing the cell cycle restriction point, is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy. Palbociclib (PD 0332991) , a potent and selective inhibitor of CDK4 and CDK6, inhibits proliferation of several Rb-positive cancer cell lines and xenograft models.The basic features and abnormalities of the cell cycle in breast cancer are described, along with their involvement in estrogen signaling and endocrine resistance. The pharmacological features of palbociclib, its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated, and its clinical development in breast cancer described. A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years.The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy. Further, potentially useful combinations are those with drugs targeting mitogenic signaling pathways, such as HER2- and PI3K-inhibitors. Combination with chemotherapy seems more problematic, as antagonism has been reported in preclinical models. The identification of predictive factors, already explored in preclinical studies, must be further refined and validated in clinical trials.

The interesting paper by Dieci et al. highlights once again that the estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor type 2 (HER-2) status between primary breast cancer and paired metastases may change. In Dieci’s study, discordance rates in the receptor status were 13.4%, 39% and 11.8% for ER, PgR and HER-2, respectively [1], comparable with those of the prospective study conducted by Amir et al. [2]. The exact reason for such discordance has yet to be determined. Possible biological explanations include limited accuracy and reproducibility of receptor assays, intratumor heterogeneity, clonal selection in tumor biology determined by therapy and variable ER-lineage differentiation of putative disseminated breast cancer stem cells during the course of the disease [3]. Whatever the reason, Dieci’s single-institution retrospective study also addressed the clinical significance of single-receptor discordance in terms of prognosis, observing that a loss of ER or HER-2 expression resulted in poorer post-recurrence survival (PRS) [1]. We identified a similar discordance rate in our recently published paper: 16.4%, 41.7%, 17.5% for ER, PgR and HER-2, respectively, as well as a trend toward poorer PRS in patients whose tumors showed a loss of ER expression [4] Similarly, other authors reported that patients with ER-positive

Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors.Retrospective study.Institute for Cancer Research and Treatment, Medical Oncology Department.Consecutive patients who started adjuvant trastuzumab between 2007 and 2010.Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥ 15 points from baseline or a LVEF50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers).Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose240 mg/m(2) of doxorubicin or500 mg/m(2) of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011).TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.

Introduction: After an enthusiastic and promising start to the large scale use of screening programs for the detection of small in situ breast cancers, an analysis of results from different screening studies has led to disappointing and somewhat alarming conclusions. A problem of over diagnosis has emerged, involving, in many cases, unnecessary treatments, and causing a negative psychological and social impact on patients and a considerable economic burden on Health Services. Ductal carcinoma in situ (DCIS) is a heterogeneous disease that has not been investigated as widely as invasive breast cancer. Today women with in situ breast cancer are mainly treated with conservative surgery and often with radiotherapy, even though the real impact of this treatment is still not known. New diagnostic and therapeutic information is thus needed. Although conventional steroid hormone receptors, cell proliferation and other important tumor markers have been extensively studied in invasive tumors, little is known about the role played by androgen receptors (ARs), widely expressed in DCIS. We previously demonstrated in a series of DCIS patients treated with surgery alone that the AR/estrogen receptor (ER) ratio is an important prognostic marker. In the present study, we analyzed these markers in a series of DCIS patients treated with surgery and radiotherapy. Methods: We performed a retrospective study on a series of 42 DCIS patients treated with quadrantectomy and radiotherapy and followed up for a period ranging from 5 to 13 years to evaluate the prognostic relevance of ER and ARs determined by immunohistochemistry. Results: Our findings showed that AR expression was significantly higher in relapsed patients than in non relapsed patients, and that ER levels were higher in patients who did not relapse with respect to those who did. The AR/ER ratio was significantly different in the two subgroups. Moreover, when the variables were considered singly, area under the curve (AUC) values were 0.85 for ARs, 0.62 for ER and 0.79 for the AR/ER ratio. Conclusions: In agreement with our previous work on a series of DCIS patients treated with surgery alone, the preliminary results from the present study highlight the important role of AR and of the AR/ER ratio as prognostic indicators of relapse in patients treated with surgery and radiotherapy. Our findings also suggest that the treatment used was not capable of controlling disease or of eliminating the risk of recurrence. New avenues for tailored therapy must be sought. Citation Format: Sara Bravaccini, Sara Ravaioli, Maria Maddalena Tumedei, Rosella Silvestrini, Flavia Foca, Ilaria Massa, Roberta Maltoni, Andrea Rocca, Secondo Folli, Federico Buggi, Annalisa Curcio, Maurizio Puccetti, Luigi Serra, Elisabetta Pietri, Daniele Andreis, Alberto Farolfi, Dino Amadori. Clinical relevance of androgen and estrogen receptors in patients with ductal carcinoma in situ of the breast treated with surgery and radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B44.

Patients with metastatic melanoma have a poor prognosis; the results of chemotherapy remain unsatisfactory. Ipilimumab, an anticytotoxic T lymphocyte-associated antigen-4 antibody, has shown promising results in several clinical trials. In this report, advanced melanoma patients receiving ipilimumab were scored according to novel immune-related response criteria (irRC) in an attempt to capture additional response patterns and to avoid premature treatment cessation. Thirty-six heavily pretreated metastatic melanoma patients recieved ipilimumab within five international clinical trials at our Institution from May 2006 to August 2008. Disease progression was defined as an increase in tumor burden by at least 25% compared with the nadir, irrespective of any initial increase in baseline lesions or the appearance of new lesions. We report unusually long-lasting responses in patients treated with ipilimumab 10 mg/kg. An overall response was observed in six out of 30 patients (20%), a complete response in three (10%), and disease control in 11 (37%), which seemed to be of a long duration (median of 16 months; complete response 36+, 34+, and 41+ months). All irRC patterns seemed to be strongly associated with an improvement in overall survival. Interestingly, we found a correlation between the presence of a grade 3/4 immune-related adverse event and responses, time to progression, and overall survival. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, supporting the need for further irRC validation.

Introduction: The optimal time from surgery to commencing chemotherapy in early breast cancer (EBC) remains unclear. We assessed the influence of time to initiation of adjuvant chemotherapy (TTC) on the outcome of EBC patients enrolled onto a phase III clinical trial (NCT01031030). Methods: The relationship between TTC, calculated as the time (in weeks) from definitive surgery to initiation of adjuvant chemotherapy, and disease-free (DFS) or overall survival (OS) was assessed in 1066 EBC patients with rapidly proliferating tumors (thymidine labeling index > 3% or G3 or Ki67 > 20%), randomized to receive adjuvant chemotherapy with or without anthracyclines (epirubicin → CMF vs CMF → epirubicin vs CMF). DFS, OS and their 95% confidence intervals (95% CI) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation to nodal involvement, estrogen receptor and HER2 status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumor size. Results: Information on TTC was available for 713 women. At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase of 16% in the risk of relapse (95% CI 1.03–1.30, p = 0.016) in a multivariable Cox regression model (Table 1). The impact on OS was not significant. Using a backward elimination procedure, TTC, tumor size and nodal involvement remained significantly associated with DFS (Hazard ratio [HR] = 1.15, 95% CI 1.02-1.29, p = 0.018; HR = 1.44, 95% CI 1.08-1.92, p = 0.012; HR = 1.44, 95% CI 1.08-1.92, p = 0.012, respectively). Again, nodal involvement and Ki67 were associated with OS (HR = 1.66, 95% CI 1.11-2.49, p = 0.014; HR = 1.63, 95% CI 1.03-2.59, p = 0.039, respectively). DFS OS HR (95% CI) p HR (95% CI) p TTC 1.16 (1.03–1.30) 0.016 1.14 (0.97–1.35) 0.121 Age 0.99 (0.97–1.02) 0.829 0.99 (0.96–1.03) 0.615 ER Positive 1.00 1.00 Negative 1.20 (0.89–1.61) 0.242 1.20 (0.78–1.84) 0.397 HER2 Positive 1.00 1.00 Negative 0.99 (0.73–1.33) 0.929 0.92 (0.60–1.42) 0.713 Lymph node status Negative 1.00 1.00 Positive 1.53 (1.14–2.04) 0.004 1.71 (1.13–2.59) 0.011 Menopausal status Premenopausal 1.00 1.00 Postmenopausal 1.32 (0.85–2.04) 0.219 1.56 (0.82–2.97) 0.177 Tumor size 1.00 1.00 ≥2 cm 1.41 (1.05–1.88) 0.020 1.44 (0.95–2.18) 0.085 Ki67 ≤20% 1.00 1.00 >20% 1.06 (0.77–1.44) 0.724 1.54 (0.96–2.48) 0.073 Treatment arm E»CMF 0.72 (0.49–1.04) 0.079 0.69 (0.41–1.16) 0.161 CMF»E 0.79 (0.55–1.14) 0.202 0.75 (0.45–1.25) 0.273 CMF 1.00 1.00 Conclusions: Our results suggest that patients with rapidly proliferating EBC should be treated as soon as possible once their recovery from surgery is complete. Disclosure: All authors have declared no conflicts of interest.

Aim: Although high body mass index (BMI) has been associated with advanced colorectal cancer (ACC) prognosis, this effect is not consistent across different studies. As bevacizumab is the backbone therapy of ACC and obesity is associated with increased serum levels of vascular endothelial growth factor (VEGF), the aim of this study was to evaluate the impact of BMI on prognosis in ACC patients enrolled onto a phase III randomized clinical (NCT01878422). Methods: The relationship between baseline BMI and progression-free (PFS) and overall survival (OS) was assessed in 376 patients randomized to receive FOLFOX4 or FOLFIRI with or without bevacizumab. BMI was defined as follows: normal Results: Information on BMI at baseline was available in 368 ACC patients. Of these, 198 (53.8%) showed normal weight, 133 (36.1%) were overweight and 37 (10.1%) were obese. At a median follow up of 36 months (range 1-65), median PFS was 8.9 months (95% CI 8.0-9.6), 8.9 months (95% CI 7.4-9.9) and 7.8 months (95% CI 4.7-9.7) in normal, overweight and obese patients, respectively (p 0.251). Median OS was 21.3 months (95% CI 18.4-23.6), 21.0 months (95% CI 17.5-25.4) and 21.7 months (95% CI 14.0-28.8), respectively (p 0.461). Of the 368 patients, 175 received first-line chemotherapy with bevacizumab and 193 underwent chemotherapy alone. No statistically significant differences in terms of mPFS or mOS were observed in the two arms with regard of BMI (see table). Conclusions: Chemotherapy + bevacizumab Chemotherapy BMI Category No. of patients No. of events Median PFS (95% CI) No. of patients No. of events Median PFS (95% CI) p 87 83 9.7 (8.1-11.3) 111 106 8.3 (7.0-9.0) 0.409 25-29.9 66 58 9.8 (7.4-13.1) 67 59 8.6 (6.3-9.5) 0.436 ≥30 22 21 7.8 (4.6-11.3) 15 14 6.5 (2.3-9.7) 0.843 p 0.261 0.681 BMI Category No. of patients No. of Events Median OS (95% CI) No. of patients No. of Events Median OS (95% CI) p 87 62 21.8 (16.3-27.4) 111 86 20.8 (18.4-23.5) 0.844 25-29.9 66 49 19.3 (12.7-24.8) 67 46 24.3 (18.2-29.1) 0.287 ≥30 22 20 20.5 (10.4-25.2) 15 11 24.9 (11.5-29.6) 0.265 p 0.230 0.612 BMI at baseline was not associated with the prognosis of ACC patients. Although adipose tissue may release angiogenic factors, obesity does not seem to be a predictive factor for response to a first-line bevacizumab- based therapy in ACC patients. Disclosure: All authors have declared no conflicts of interest.

e11521 Background: Commonly used biomarkers (ER, PR, HER2, Ki67) are thought to identify BC subtypes with different sensitivity to ET, but data on this are scarce for the metastatic setting, where changes in receptor status between primary tumor (T) and matched metastases (M) are reported. We investigate PR and Ki67 on T and M as predictors of clinical benefit from 1st line ET in mBC. Methods: We identified mBC patients (pts) treated in our Center with 1st line ET (2002-11), excluding those receiving concomitant chemotherapy (CT) or trastuzumab or pretreated with >2 lines of CT. PR and Ki67 were scored as IHC percentage of positive cells, with a cut-off of 20% for high vs low. Clinical benefit was evaluated by time-to-progression (TTP). Results: We identified 137 pts, median age 58 (29-85), only 28% with visceral metastases. ER was >50% in 94%, HER2+ in 17.5%. With 93% receiving an aromatase inhibitor, median TTP was 14 months (median follow-up 43 months). In 34 pts with Ki67 available from T and M a strong correlation between the 2 was shown (Spearman: 0.69, p20% on T (with a similar trend on M, n=58; p=0.06). In 48 pts with PR scored on T and M only a weak trend for correlation was found, with a discordant classification (≤ or >20%) in 44%. More than the score on T (n=118), PR on M (n=64) was a strong predictor of median TTP: 12 months for PR ≤20% vs 22 months for PR >20% (p=0.02). Pts with PR≤20% + Ki67>20% on M had a median TTP of only 4 months, vs 21 months for PR>20% + Ki67≤20%, vs 14 months for either PR>20% or Ki67≤20% (p=0.006). In a multivariate Cox analysis with clinical data and biomarkers from T, visceral disease and HER2 positivity were significantly associated with the risk of progression (HR 2.22 and 2.07, respectively). With biomarkers from M, the risk of progression correlated with relapse ≤5 vs >5 years from surgery (HR 3.48) and PR ≤20% (HR 2.47, p=0.01). Conclusions: In an ER-high population, PR >20% on M identifies pts with a long TTP on ET. Ki67 on T or M can also contribute in estimating the expected benefit, but an independent prognostic role could not be fully confirmed in this small cohort.

e11054 Background: Adjuvant trastuzumab improves survival in early breast cancer (EBC) patients (pts). However, trastuzumab-induced cardiotoxicity (TIC) renders it necessary to identify possible risk and protective factors. Methods: A retrospective study was conducted in which medical charts of pts treated with adjuvant trastuzumab were reviewed. Hypertension, smoking history, dysthyroidism, obesity, hypercholesterolemia, diabetes mellitus and anthracycline cumulative dose were considered as potential risk factors. The relationship between the use of beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) (either started before or during adjuvant therapy) and TIC development was also evaluated. TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥15 points from baseline or an absolute LVEF 240 mg/m2 conferred an odds ratio of 3.07 compared with treatmemt with lower doses (95% CI 1.29-7.27, p=0.0011). BB, ACEI and/or ARB neither reduced nor increased the risk of TIC. Conclusions: TIC is a frequent, albeit generally mild, adverse event in clinical practice. Closer collaboration between cardiologists and oncologists is needed to better define risk and protective factors of cardiotoxicity in order to avoid trastuzumab-therapy discontinuation.

e16539 Background: Cancer outcome is an emergency in low-income areas (LIAs) such as Tanzania, where incidence is 84 and 91 per 100,000 males and females, respectively. Prior to 2008, an Oncology D...

The therapeutic landscape of prostate cancer has expanded rapidly over the past 10 years, and there is now an even greater need to understand the biological mechanisms of resistance and to develop noninvasive biomarkers to guide treatment. The androgen receptor (AR) is known to be involved in the pathogenesis and progression of prostate cancer. Recently, highly sensitive next-generation sequencing and PCR-based methods for analyzing androgen receptor gene (AR) copy numbers (CN) and mutations in plasma were established in cell-free DNA (cfDNA) of patients with castration-resistant prostate cancer (CRPC) treated with different drugs. The study of cfDNA holds great promise for improving treatment in CRPC, especially in the advanced stage of the disease. Recent findings showed the significant association of plasma AR aberrations with clinical outcome in CRPC patients treated with AR-directed therapies, whereas no association was observed in patients treated with taxanes. This suggests the potential for using plasma AR as a biomarker for selecting treatment, i.e., hormone therapy or chemotherapy, and the possibility of modulating taxane dose. In recent years, plasma AR status has also been investigated in association with novel agents, such as 177Lu-PSMA radioligand therapy and PARP inhibitors. This review will focus on AR testing in plasma that may have clinical utility for treatment selection in advanced prostate cancer.