Publications by authors named "Clara Natoli"

94 Publications

Long-term outcome of pemetrexed maintenance for advanced nonsquamous non-small-cell lung cancer: a real-world observational cohort study.

Recenti Prog Med 2020 12;111(12):761-768

Department of Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy.

Introduction: Pemetrexed maintenance significantly improved progression-free survival (PFS) and overall survival (OS) in advanced nonsquamous non-small-cell lung cancer (NSCLC) patients not progressing after induction chemotherapy.

Objectives: This study is aimed at examine the association of various clinical factor and survival in a real-world cohort analysis.

Materials And Methods: One hundred ninety-four patients were included and classified as "PM" cohort ("Pemetrexed Maintenance", including patients given with pemetrexed maintenance after induction chemotherapy, n=112), and "noPM" cohort ("no Pemetrexed Maintenance" including those discontinuing pemetrexed, n=82).

Results: The median PFS was 8.8 and 5.4 months in the PM and noPM cohorts, respectively (p=0.001). The median OS was 19.6 months in the "PM" cohort and 13.2 months in the "noPM" cohort (p<0.02). In the multivariate analysis, ECOG Performance Status (PS) 0 and maintenance therapy were independently associated with improved PFS and OS. A longer median PFS was reported in patients given ≥5 cycles of pemetrexed maintenance (p<0.01).

Discussion: These results further confirm the survival benefit of pemetrexed maintenance in a real-word population. All eligible advanced NSCLC patients should be strongly considered for at least 5 of pemetrexed maintenance.
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http://dx.doi.org/10.1701/3509.34967DOI Listing
December 2020

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

J Exp Clin Cancer Res 2020 Dec 10;39(1):279. Epub 2020 Dec 10.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.

Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.

Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).

Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
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http://dx.doi.org/10.1186/s13046-020-01797-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731769PMC
December 2020

Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

Chemotherapy based on the sequential use of anthracyclines and taxanes has long represented the most efficacious approach in the management of early-stage, triple-negative breast cancer, whose aggressive behavior is widely renowned. This standard chemotherapy backbone was subsequently enriched by the use of carboplatin, based on its association with increased pathologic complete response and efficacy in the metastatic setting. Following the results from the IMpassion130 trial, the recent approval of the immunotherapic agent atezolizumab in combination with chemotherapy as first-line treatment for programmed-death ligand 1-positive, unresectable locally advanced, or metastatic triple-negative breast cancer increasingly fueled the flourishing of trials of immune-checkpoint inhibitors in the early setting. In this work, we review the most recent inherent literature in light of key methodological issues and provide a quantitative summary of the results from phase II-III randomized trials of immunotherapic agents combined with chemotherapy in the setting of interest. Hints regarding future directions are also discussed.
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http://dx.doi.org/10.3390/cancers12092497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565914PMC
September 2020

Analysis of systemic inflammatory biomarkers in neuroendocrine carcinomas of the lung: prognostic and predictive significance of NLR, LDH, ALI, and LIPI score.

Ther Adv Med Oncol 2020 11;12:1758835920942378. Epub 2020 Aug 11.

Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, Palermo, Italy.

Background: Lung neuroendocrine carcinoma (NEC) is characterized by aggressive clinical behavior and lack of treatment advances. We evaluate the prognostic and the predictive roles of systemic inflammatory biomarkers in patient circulating blood: neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), advanced lung cancer inflammation index (ALI), and the Lung Immune Prognostic Index (LIPI) score.

Methods: A total of 120 patients with small-cell lung cancer (SCLC) ( = 110) and large cell neuroendocrine carcinoma (LCNEC) ( = 10) were enrolled. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS while χ test was used for categorical data.

Results: NLR cutoff value was 1.93. NLR was measured before and after first-line chemotherapy; 25 (21%) patients had higher NLR (delta NLR >1), whereas NLR was lower in 37 (31%). At the univariate analysis, median OS was 12 months: OS for SCLC and LCNEC were 11 months and 14 months, respectively. OS had a prognostic positive value in patients with pre-treatment NLR <1.93 ( = 0.0002), LDH <600 U/L ( = 0,03) and ALI ⩾34 ( = 0,0065). At the multivariate analysis, Eastern Cooperative Oncology Group performance status, LDH levels and response after first-line chemotherapy were independently associated with OS. Median OS for good, intermediate, and poor LIPI was 15 months, 11 months, and 9 months, respectively( = 0.091). Patients with higher NLR (>1.93) had an increased probability of tumor progression ( = 0.045, χ test).

Conclusion: This study demonstrated that systemic inflammatory biomarkers could facilitate the understanding of survival differences in the clinical management of lung NEC patients, underlying the need for prospective biomarker-driven studies in the immune checkpoint inhibitors setting.
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http://dx.doi.org/10.1177/1758835920942378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425322PMC
August 2020

Predictive Ability for Disease-Free Survival of the GRade, Age, Nodes, and Tumor (GRANT) Score in Patients with Resected Renal Cell Carcinoma.

Curr Urol 2020 Jun 23;14(2):98-104. Epub 2020 Jun 23.

Medical Oncology Unit, St. Salvatore Hospital, L'Aquila.

Background: Recently, the GRANT (GRade, Age, Nodes, and Tumor) score was validated through an adjuvant trial population.

Methods: This retrospective study evaluated the performance of the GRANT score as a prognostic model for disease-free survival (DFS), compared to the University of California Los Angeles Integrated Staging System (UISS) score, in a "real-life" population of early renal cell carcinoma patients. A uni-/multivariate analysis of DFS was also performed, to weigh the roles of baseline clinical factors.

Results: From February 1998 to January 2018, 134 consecutive patients were enrolled, of which 85 patients (63.4%) had a favorable GRANT score, 49 (36.6%) an unfavorable GRANT score, and 21 (15.7%), 84 (62.6%), and 29 (21.6%) patients had a low, intermediate, or high risk of recurrence according to the UISS score, respectively. The median follow-up was 96 months. The median DFS of the overall study population was 53.7 months (95% CI: 38.4-87.8). Only bilateral renal cell carcinoma (p = 0.0041), Fuhrman grade 3/4 (p = 0.0008), pT3b- 4 (p = 0.0324), and pN1-2 (p = 0.0303) pathological status were confirmed as independent predictors of a shorter DFS by the multivariate analysis. The median DFS of patients with favorable and unfavorable GRANT scores were 84.9 (95% CI: 49.8-129) and 38.4 months (95% CI: 24.4-87.8), respectively, with a statistically significant difference (p = 0.0147). The median DFS of patients with low, intermediate, and high risk of recurrence according to the UISS score were 92.3 (95% CI: 18.1-153.9), 51.7 (95% CI: 36.2-87.8), and 49.8 months (95% CI: 31.3-129), respectively, without statistically significant differences (p = 0.4728). DFS c-statistic values were 0.59 (95% CI: 0.51-0.67) and 0.51 (95% CI: 0.42-0.60) for the GRANT and the UISS scores, respectively.

Conclusion: The GRANT score might be a useful tool that is user-friendly and easy to perform in clinical practice.
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http://dx.doi.org/10.1159/000499252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390980PMC
June 2020

Enzalutamide in patients with castration-resistant prostate cancer: retrospective, multicenter, real life study.

Minerva Urol Nefrol 2020 Aug 4. Epub 2020 Aug 4.

Department of Urology, ASL Abruzzo2, Chieti, Italy -

Background: Metastatic castration-resistant prostate cancer (mCRPC) is the final stage of pCa history and represents a clinically relevant phenotype with an elevated burden of mortality. The aim of the present study is to evaluate the efficacy and safety of enzalutamide in a "real-life" setting in mCRPC patients.

Methods: Data about all mCRPC patients treated with enzalutamide from September 2017 to September 2018 were collected. Demographics, comorbidities, clinical parameters, outcomes, toxicity, overall survival and progression free survival were analyzed.

Results: Overall 158 patients were enrolled. Mean age was 75.8 (±8.7) years with a baseline median PSA of 16.5 (IQR 7.4-47.8) ng/mL. The median follow-up lasted 7.7 (IQR 4-14.1) months. Of all the 10.1% of patients reported grade 3-4 adverse events. 43.7% of patients experienced a progression. Overall the 6 and 12 months PFS rates were 69.5% (95% CI: 61.7-78.3%) and the 45.6% (95% CI: 36.5-57.1%); a median baseline PSA >16 ng/mL (HR:2.0, 95% CI: 1.2-3.3, p=0.005), the use of opioid (HR:3.1, 95% CI 1.9-5.0, p<0.001), a previous treatment (abiraterone, docetaxel or abiraterone + docetaxel) were significantly associated with higher rates of cancer progression. Conversely, a brief pain questionnaire of 0-1 (HR: 0.4, 95% CI: 0.2-0.7, p<0.001), a 12 weeks 50% PSA reduction (HR: 0.4, 95% CI: 0.2-0.8, p=0.006) and a longer time to mCRPC (HR: 0.4, 95% CI: 0.3-0.7, p=0.002) were related to lower cancer progression rates.

Conclusions: Our data shows an effective and safe profile of enzalutamide in a "realworld" perspective in patients with mcRPC.
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http://dx.doi.org/10.23736/S0393-2249.20.03723-6DOI Listing
August 2020

Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives.

Int J Mol Sci 2020 May 16;21(10). Epub 2020 May 16.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.

In locally advanced (LA) breast cancer (BC), neoadjuvant treatments have led to major achievements, which hold particular relevance in HER2-positive and triple-negative BC. Conversely, their role in hormone receptor positive (HR+), hormone epidermal growth factor 2 negative (HER2-) BC is still under debate, mainly due to the generally low rates of pathological complete response (pCR) and lower accuracy of pCR as predictors of long-term outcomes in this patient subset. While administration of neoadjuvant chemotherapy (NCT) in LA, HR+, HER2- BC patients is widely used in clinical practice, neoadjuvant endocrine therapy (NET) still retains an unfulfilled potential in the management of these subgroups, particularly in elderly and unfit patients. In addition, NET has gained a central role as a platform to test new drugs and predictive biomarkers in previously untreated patients. We herein present historical data regarding Tamoxifen and/or Aromatase Inhibitors and a debate on recent evidence regarding agents such as CDK4/6 and PI3K/mTOR inhibitors in the neoadjuvant setting. We also discuss key issues concerning the optimal treatment length, appropriate comparisons with NCT efficacy and use of NET in premenopausal patients.
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http://dx.doi.org/10.3390/ijms21103528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278946PMC
May 2020

Is There Still a Role for Endocrine Therapy Alone in HR+/HER2- Advanced Breast Cancer Patients? Results from the Analysis of Two Data Sets of Patients Treated with High-Dose Fulvestrant as First-Line Therapy in the Real-World Setting: The EVA and GIM-13 AMBRA Studies.

Breast Care (Basel) 2020 Feb 17;15(1):30-37. Epub 2019 Apr 17.

Oncology Unit, ARNAS Civico Palermo, Palermo, Italy.

Background: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting.

Methods: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies).

Results: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35-82) for the EVA and 57.8 years (range 35.0-82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1-48) and 12.4 months (range 2.9-70.0) in the two data sets, respectively.

Conclusion: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.
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http://dx.doi.org/10.1159/000495469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098305PMC
February 2020

Alectinib Induced Regression of Renal and Hepatic Cysts Caused by Crizotinib.

Int Med Case Rep J 2020 16;13:89-93. Epub 2020 Mar 16.

Department of Medical, Oral and Biotechnological Sciences University "G. D'Annunzio", Chieti-Pescara, Italy.

Background: Crizotinib is the first tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase () rearranged non-small cell lung cancer (NSCLC). An increased incidence of renal cysts has been described during the crizotinib treatment.

Case Presentation: We herein report the case of a 74-year-old woman who received crizotinib for metastatic -positive NSCLC. During the crizotinib treatment, complex renal cystic lesions with invasion of perirenal spaces and iliopsoas muscle appeared; two complex hepatic cysts were also observed. Almost all lesions disappeared after switching to alectinib, a second-generation inhibitor.

Conclusion: It would seem that alectinib is able to reduce in size and number hepatic and renal cysts caused by the crizotinib treatment. Nevertheless, further studies are needed to clarify the role of both crizotinib in the onset of renal and hepatic cysts and alectinib in their disappearance.
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http://dx.doi.org/10.2147/IMCRJ.S229080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083626PMC
March 2020

Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events.

Eur J Cancer 2020 03 5;128:17-26. Epub 2020 Mar 5.

Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy.

Background: Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.

Patients And Methods: We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.

Results: One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p < 0.0001), G3/G4 irAEs (p < 0.0001) and irAEs leading to discontinuation (LTD) (p < 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p < 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p < 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.

Conclusions: Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.
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http://dx.doi.org/10.1016/j.ejca.2019.12.031DOI Listing
March 2020

Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

J Cell Physiol 2020 11 15;235(11):7900-7910. Epub 2020 Jan 15.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.
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http://dx.doi.org/10.1002/jcp.29445DOI Listing
November 2020

Palliative radiotherapy in advanced cancer patients treated with immune-checkpoint inhibitors: The PRACTICE study.

Biomed Rep 2020 Feb 13;12(2):59-67. Epub 2019 Dec 13.

Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, I-67100 L'Aquila, Italy.

In the present study, the influence of purely palliative radiotherapy (pRT) on the outcomes of patients with advanced cancer undergoing immune checkpoint blockade was evaluated. Patients were stratified into three groups: Patients who had received pRT within 6 months prior to the initiation of immunotherapy (previous pRT); patients who received pRT during immunotherapy (concurrent pRT); and patients who did not receive RT prior to or during immunotherapy (no RT group), and these groups were compared. The median overall survival (mOS), median progression free survival (mPFS) and median time-to-treatment failure (mTTF) for the previous pRT group were significantly shorter compared with the no RT group (mOS, 3.6 vs. 12.1 months, respectively, P=0.0095; mPFS 1.8 vs. 5.4 months, respectively, P=0.0016; mTTF 1.8 vs. 5.7 months, respectively, P=0.0035). The concurrent pRT group had a longer mTTF compared with the previous pRT group and similar outcomes to the no RT group. In the previous pRT group, 26.9% of the patients experienced immune-related adverse events compared with 40.1% of patients in the no RT group. Despite the use of pRT during immunotherapy being considered safe, the results of the present study suggest that pRT has a negative effect on immune balance.
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http://dx.doi.org/10.3892/br.2019.1265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951237PMC
February 2020

Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study.

J Cancer 2019 15;10(24):5926-5934. Epub 2019 Oct 15.

Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy.

Emerging evidence supports a prognostic role of primary tumor location in metastatic colon cancer (mCC). We conducted a retrospective analysis to evaluate the effect of tumor location on prognosis and efficacy of biological agents (anti-EGFR, Cetuximab and Panitumumab, or anti-VEGF, Bevacizumab) added to first-line chemotherapy in patients with RAS wild-type (wt) mCC. Patients with newly diagnosed RAS wt mCC candidates to first-line chemotherapy with anti-EGFRs or Bevacizumab were selected. Clinical outcomes were assessed and stratified by tumor location and type of treatment. Overall, 351 patients met the inclusion criteria. Primary colon cancer was right-sided (RCC) in 105 (29.9%) patients and left-sided (LCC) in 246 (70.1%). Patients with LCC had a better OS compared to those with RCC (33.6 vs 23.5 months, HR 0.74; 95% CI, 0.55 to 0.99; p=0.049). In the overall study population, OS was not significantly different for patients treated with Cetuximab or Panitumumab as compared to those receiving Bevacizumab. However, when comparing treatment outcome according to tumor sidedness, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer PFS (12.4 vs 10.7 months; HR: 0.69; 95% CI, 0.51 to 0.93; p= 0.015) and OS (40.7 vs 28.6 months; HR: 0.67; 95% CI 0.47 to 0.95; p= 0.026). No relevant differences were observed in patients with RCC. We found evidence in support of the impact of tumor location in RAS wt mCC treated with first-line chemotherapy in association with targeted therapy. More favorable outcomes were observed in LCC patients, but not in RCC patients, treated with anti-EGFR agents compared with those who received Bevacizumab. Further, prospective and adequately sized studies are warranted to confirm our findings.
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http://dx.doi.org/10.7150/jca.34550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856567PMC
October 2019

Eribulin in Triple Negative Metastatic Breast Cancer: Critic Interpretation of Current Evidence and Projection for Future Scenarios.

J Cancer 2019 12;10(24):5903-5914. Epub 2019 Oct 12.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy.

Triple negative breast cancer (TNBC) is characterized by distinctive biological features that confer an aggressive clinical behavior. In TNBC patients, the absence of well-defined driver pathways such as hormonal receptor expression or hyperactivation of the human epidermal growth factor receptor 2 (HER2) significantly reduce the spectrum of therapeutic options, which are currently mainly confined to chemotherapy. Thus far, median overall survival for patients with metastatic TNBC is about 9-12 months with conventional cytotoxic agents. However, the heterogeneity recently revealed at a gene expression level inside the TNBC family may help inform therapeutic decisions concerning the use of chemotherapy and hopefully lead the way to novel targeted options that include immunotherapy. Eribulin, a halichondrin class antineoplastic drug, is currently recommended for treatment of HER2 negative metastatic or recurrent breast cancer (BC) previously exposed to anthracyclines and taxanes, also for patients with a TNBC. It is currently indicated from the second line of treatment. In this review, we aim to analyze a wide range of cumulated evidence on eribulin use in TNBC including preclinical studies, intervention and observational clinical trials. Data from the real-world setting and the emerging evidence increasingly substantiating the rationale for combinations with new generation treatment strategies, e.g., PARP-inhibitors, immune checkpoint inhibitors, will be also discussed.
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http://dx.doi.org/10.7150/jca.35109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856581PMC
October 2019

Prognostic relevance of DNA damage and repair biomarkers in elderly patients with hormone-receptor-positive breast cancer treated with neoadjuvant hormone therapy: evidence from the real-world setting.

Ther Adv Med Oncol 2019 18;11:1758835919853192. Epub 2019 Aug 18.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: The logic behind the outcome of endocrine therapy in breast cancer has long remained poorly understood. The prognostic role of DNA damage and repair biomarkers (DDR) was explored in postmenopausal, hormone-receptor-positive breast cancer patients treated with neoadjuvant hormone therapy (NAHT).

Methods: Data on 55 patients were included. The phosphorylated ataxia-teleangectasia and Rad3-related protein (pATR), phosphorylated ataxia-telangiectasia mutated (ATM) kinase, and phosphorylated H2A Histone Family Member X (γ-H2AX) were evaluated by immunohistochemistry in paired tissues collected at baseline and following NAHT. Biomarkers were considered both singularly and within signatures. Ki-67 percentage change was the primary biomarker endpoint. Classical endpoints were also considered.

Results: The most favorable Ki-67 outcome was associated with the γ-H2AX/pATM signature ( = 0.011). In models of Ki-67 reduction, 'luminal B' subtype, higher grade of anaplasia, and the γ-H2AX/pATM signature tested as significant ( < 0.05 for all). Results were confirmed in multivariate analysis. No association was observed with pathologic response. An increase of ∆γ-H2AX in paired breast tissues was associated with longer event-free survival ( = 0.027) and overall survival ( = 0.042). In Cox models, both survival outcomes were solely affected by grade of anaplasia, with less favorable prognosis in the highest grades ( < 0.05 for both).

Conclusions: We report novel evidence of the prognostic role of DDR biomarkers on important patient outcomes in postmenopausal hormone-receptor-positive breast cancer patients treated with NAHT. If confirmed in future and adequately sized trials, our results may help inform therapeutic decisions and clarify underlying biological mechanisms.
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http://dx.doi.org/10.1177/1758835919853192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700857PMC
August 2019

A Case of Stage I Vulvar Squamous Cell Carcinoma with Early Relapse and Rapid Disease Progression.

Case Rep Oncol Med 2019 3;2019:1018492. Epub 2019 Jul 3.

Medical Oncology Unit, SS Annunziata Hospital, Chieti, Italy.

Squamous cell carcinoma (SCC) is the most common subtype of vulvar cancer. Locoregional surgery is often curative when the tumor is diagnosed at an early stage. However, the disease can unexpectedly evolve with a dismal prognosis even after an early diagnosis. We report a case of a woman who experienced a rapid, chemorefractory tumor progression after surgery for stage IB vulvar SCC.
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http://dx.doi.org/10.1155/2019/1018492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636578PMC
July 2019

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting.

Int J Cancer 2020 04 7;146(7):1917-1929. Epub 2019 Aug 7.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.
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http://dx.doi.org/10.1002/ijc.32583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027476PMC
April 2020

Weight loss and body mass index in advanced gastric cancer patients treated with second-line ramucirumab: a real-life multicentre study.

J Cancer Res Clin Oncol 2019 Sep 6;145(9):2365-2373. Epub 2019 Jul 6.

Medical Oncology, St. Salvatore Hospital, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy.

Aims And Methods: This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a "real-life" setting.

Results: From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02-5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2-40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6-6.8) and mOS was 8.7 months (95% CI 7.3-11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01-2.82), p = 0.04] [HR = 1.97 (95% CI 1.12-3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01-2.83), p = 0.04] [HR = 2.08 (95% CI 1.17-3.70), p = 0.01].

Conclusion: Efficacy of ramucirumab is confirmed in this "real-life" analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).
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http://dx.doi.org/10.1007/s00432-019-02971-7DOI Listing
September 2019

Long-term performance of risk scores for venous thromboembolism in ambulatory cancer patients.

J Thromb Thrombolysis 2019 Jul;48(1):125-133

Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio University, Chieti, Italy.

The long-term performance of prediction scores for venous thromboembolism (VTE) in cancer patients has been poorly investigated. We evaluated the discriminatory performance of the Khorana, PROTECHT, CONKO, and ONKOTEV scores for the first 3-6 months and for 12 months, and re-assessed scores after 3-6 months to determine the influence of variations in patients' risk classification on performance. Retrospective cohort of ambulatory patients with active cancer who were scheduled to receive first or new line of chemotherapy. The primary outcome was symptomatic or incidental VTE. A total of 776 patients were included of whom 540 (70%) had distant metastases. The time-dependent c-statistics of Khorana, PROTECHT, CONKO, and ONKOTEV scores at 6 months were 0.61 (95% CI 0.56 to 0.66), 0.61 (95% CI 0.55 to 0.66), 0.60 (95% CI 0.54 to 0.66), and 0.59 (0.52 to 0.66), respectively, with a tendency to decrease during follow-up. None of the scores discriminated between high and low risk patients at the conventional 3-point positivity threshold. The use of a 2-point positivity threshold improved performance of all scores and captured a higher proportion of VTE. The accuracy of risk scores re-assessed at 3-6 months was modest. The Khorana, PROTECHT, CONKO, and ONKOTEV scores are not sufficiently accurate when used at a conventional threshold of 3 points. Performance improves at positivity threshold of 2 points, as evaluated in recent randomized studies on VTE prophylaxis. Score accuracy tends to decrease over time suggesting the need of periodic re-evaluation to estimate possible variation of risk.
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http://dx.doi.org/10.1007/s11239-019-01845-6DOI Listing
July 2019

A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable.

J Immunother Cancer 2019 02 27;7(1):57. Epub 2019 Feb 27.

Department of Medical, Oral & Biotechnological Sciences University G. D'Annunzio, Chieti-Pescara, Italy.

Background: Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients.

Patients And Methods: We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (< 25). A gender analysis was also performed, using the same binomial cut-off. Further subgroup analyses were performed categorizing patients into underweight, normal weight, overweight and obese.

Results: Between September 2013 and May 2018, 976 patients were evaluated. The median age was 68 years, male/female ratio was 663/313. Primary tumors were: NSCLC (65.1%), melanoma (18.7%), renal cell carcinoma (13.8%) and others (2.4%). ECOG-PS was ≥2 in 145 patients (14.9%). PD-1/PD-L1 inhibitors were administered as first-line treatment in 26.6% of cases. Median BMI was 24.9: 492 patients (50.6%) were non-overweight, 480 patients (50.4%) were overweight/obese. 25.2% of non-overweight patients experienced irAEs of any grade, while 55.6% of overweight/obese patients (p < 0.0001). ORR was significantly higher in overweight/obese patients compared to non-overweight (p < 0.0001). Median follow-up was 17.2 months. Median TTF, PFS and OS were significantly longer for overweight/obese patients in univariate (p < 0.0001, for all the survival intervals) and multivariate models (p = 0.0009, p < 0.0001 and p < 0.0001 respectively). The significance was confirmed in both sex, except for PFS in male patients (p = 0.0668).

Conclusions: Overweight could be considered a tumorigenic immune-dysfunction that could be effectively reversed by ICIs. BMI could be a useful predictive tool in clinical practice and a stratification factor in prospective clinical trials with ICIs.
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http://dx.doi.org/10.1186/s40425-019-0527-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391761PMC
February 2019

Combination of peripheral neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is predictive of pathological complete response after neoadjuvant chemotherapy in breast cancer patients.

Breast 2019 Apr 2;44:33-38. Epub 2019 Jan 2.

Department of Medical, Oral and Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti, Italy.

The immune system seems to play a fundamental role in breast cancer responsiveness to chemotherapy. We investigated two peripheral indicators of immunity/inflammation, i.e. neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in order to reveal a possible relationship with pathological complete response (pCR) in patients with early or locally advanced breast cancer treated with neoadjuvant chemotherapy (NACT). We retrospectively analyzed 373 consecutive patients affected by breast cancer and candidates to NACT. The complete blood cell count before starting NACT was evaluated to calculate NLR and PLR. ROC curve analysis determined threshold values of 2.42 and 104.47 as best cut-off values for NLR and PLR, respectively. The relationships between NLR/PLR and pCR, along with other clinical-pathological characteristics, were evaluated by Pearson's χ 2 or Fisher's exact test as appropriate. Univariate and multivariate analyses were performed using a logistic regression model. NLR and PLR were not significantly associated with pCR if analyzed separately. However, when combining NLR and PLR, patients with a NLR/PLR profile achieved a significantly higher rate of pCR compared to those with NLR and/or PLR (OR 2.29, 95% CI 1.22-4.27, p 0.009). Importantly, the predictive value of NLR/PLR was independent from common prognostic factors such as grading, Ki67, and molecular subtypes. The combination of NLR and PLR may reflect patients' immunogenic phenotype. Low levels of both NLR and PLR may thus indicate a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.
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http://dx.doi.org/10.1016/j.breast.2018.12.014DOI Listing
April 2019

Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials.

J Clin Med 2018 Dec 12;7(12). Epub 2018 Dec 12.

Department of Medical, Oral and Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, 66100 Chieti, Italy.

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, < 0.001 and HR 0.77, < 0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, < 0.012), with the exception of melanoma (in women, HR 0.80, = 0.006). PFS was longer in men than in women (HR 0.67, < 0.001 and HR 0.77, = 0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.
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http://dx.doi.org/10.3390/jcm7120542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306894PMC
December 2018

Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor-positive, advanced breast cancer: A real-world experience.

J Cell Physiol 2019 06 10;234(6):7708-7717. Epub 2018 Dec 10.

Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Data from 423 human epidermal growth factor receptor 2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6-35.4) and clinical benefit was 52.7% (95% CI, 48-57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line-treatment ( p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8-16) and median overall survival was 24 months (95% CI, 17-30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2-, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.
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http://dx.doi.org/10.1002/jcp.27832DOI Listing
June 2019

A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study.

Cancer Biol Ther 2019 7;20(2):192-200. Epub 2018 Nov 7.

c Division of Medical Oncology 2 , IRCCS Regina Elena National Cancer Institute , Rome , Italy.

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.
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http://dx.doi.org/10.1080/15384047.2018.1523095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343690PMC
April 2020

Efficacy of nivolumab in pre-treated non-small-cell lung cancer patients harbouring KRAS mutations.

Br J Cancer 2019 01 31;120(1):57-62. Epub 2018 Oct 31.

Istituto Tumouri "Giovanni Paolo II", Bari, Italy.

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.

Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.

Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.

Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
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http://dx.doi.org/10.1038/s41416-018-0234-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325128PMC
January 2019

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study.

Immunotherapy 2018 10;10(14):1229-1239

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

Aim: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population.

Methods: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017.

Results: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001.

Conclusion: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.
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http://dx.doi.org/10.2217/imt-2018-0080DOI Listing
October 2018

Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells.

J Exp Clin Cancer Res 2018 Sep 21;37(1):236. Epub 2018 Sep 21.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini, 66100, Chieti, Italy.

Background: Pancreatic cancer (PC) is the fourth most common cause of cancer death. Combination therapies with classical chemotherapeutic agents improved treatment of advanced PC at the cost of a relevant toxicity, but the 5-year survival rate remains below 5%. Consequently, new therapeutic options for this disease are urgently needed. In this study, we explored the effect of two repurposed drug candidates nelfinavir and nitroxoline, approved for non-anticancer human use, in PC cell lines. Nelfinavir and nitroxoline were tested as single agents, or in combinations with or without erlotinib, a targeted drug approved for PC treatment.

Methods: The effects of the drugs on the viability of AsPC-1, Capan-2 and BxPC-3 PC cell lines were assessed by MTT. The impact of the treatments on cell cycle distribution and apoptosis was analyzed by flow cytometry. The effects of treatments on proteins relevant in cell cycle regulation and apoptosis were evaluated by western blot. Self-renewal capacity of PC cell lines after drug treatments was assessed using a clonogenic assay.

Results: When used as single agents, nelfinavir and nitroxoline decreased viability, affected cell cycle and reduced the expression of relevant cell cycle proteins. The effects on apoptosis were variable among PC cell lines. Moreover, these agents drastically impaired clonogenic activity of the three PC cell lines. Combinations of nelfinavir and nitroxoline, with or without erlotinib, resulted in dose- and cell-dependent synergistic effects on cell viability. These effects were paralleled by cell cycle alterations and more consistent apoptosis induction as compared to single agents. Treatments with drug combinations induced drastic impairment of clonogenic activity in the three cell lines.

Conclusions: This study shows that two non-antitumor drugs, nelfinavir and nitroxoline, as single agents or in combination have antitumor effects that appear comparable, or in some case more pronounced than those of erlotinib in three PC cell lines. Our results support repurposing of these approved drugs as single agents or in combination for PC treatment.
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http://dx.doi.org/10.1186/s13046-018-0904-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151049PMC
September 2018

Adherence to hormonal deprivation therapy in prostate cancer in clinical practice: a retrospective, single-center study.

Minerva Urol Nefrol 2019 Apr 19;71(2):181-184. Epub 2018 Sep 19.

Department of Urology, ASL Abruzzo 2, Chieti, Italy.

Background: Androgen-deprivation therapy is one of the options available for treating both advanced and metastatic prostate cancer (PCa). It is used as an adjuvant or neoadjuvant therapy, either alone or in combination with radiotherapy (RT) or surgery. The aim of this study was to appraise adherence to androgen-deprivation therapy (ADT).

Methods: A total of 136 PCa patients on ADT (leuprorelin, triptorelin, and degarelix) were monitored between January 2008 and December 2015. Demographic, histopathological, and clinical data were collected.

Results: Mean age was 76 years and PSA was 91.9 ng/mL. Forty-six patients (34%) had a Gleason Score >7. One hundred and eight patients were treated exclusively with ADT (53 [49%] leuprorelin, 45 [42%] triptorelin, and 10 [9%] degarelix). Mean follow-up was 3.5 years, with a mean overall prescription time of 3.4 years. Adherence to ADT was 95%. Sixty-three patients are currently on therapy, while 45 have discontinued treatment. Reasons for discontinuation were death (56%), physician's choice (33%), and patient's preferences (11%).

Conclusions: Adherence to ADT was optimal, probably owing to its balanced side effect and benefit profile. Patient's death was the most frequent reason for discontinuation.
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http://dx.doi.org/10.23736/S0393-2249.18.03109-0DOI Listing
April 2019

Risk factors for locoregional disease recurrence after breast-conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis.

Cancer 2018 07 3;124(14):2923-2930. Epub 2018 May 3.

Centre for Clinical Research, Vastmanlands County Hospital, Vasteras, Sweden.

Background: Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast-conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT.

Methods: Individual patient data sets from 9 studies were pooled. The outcomes of interest were the occurrence of LR and/or LRR. A 1-stage meta-analytic approach was used. Cox proportional hazards regression models were applied to identify factors that were predictive of LR and LRR, respectively.

Results: A total of 9 studies (4125 patients) provided their data sets. The 10-year LR rate was 6.5%, whereas the 10-year LRR rate was 10.3%. Four factors were found to be associated with a higher risk of LR: 1) estrogen receptor-negative disease; 2) cN + disease; 3) a lack of pathologic complete response in axilla (pN0); and 4) pN2 to pN3 disease. The predictive score for LR determined 3 risk groups: a low-risk, intermediate-risk, and high-risk group with 10-year LR rates of 4.0%, 7.9%, and 20.4%, respectively. Two additional factors were found to be associated with an increased risk of LRR: cT3 to cT4 disease and a lack of pathologic complete response in the breast. The predictive score for LRR determined 3 risk groups; a low-risk, intermediate-risk, and high-risk group with 10-year LRR rates of 3.2%, 10.1%, and 24.1%, respectively.

Conclusions: BCT after NCT appears to be an oncologically safe procedure for a large percentage of patients with breast cancer. Two easy-to-use clinical scores were developed that can help clinicians to identify patients at higher risk of LR and LRR after NCT and BCT and individualize the postoperative treatment plan and follow-up. Cancer 2018;124:2923-30. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31518DOI Listing
July 2018

Relationship and Predictive Role of the Dual Expression of FGFR and IL-8 in Metastatic Renal Cell Carcinoma Treated with Targeted Agents.

Anticancer Res 2018 05;38(5):3105-3110

Department of Radiology, Oncology and Human Pathology, Oncology Unit, Sapienza University of Rome, Rome, Italy.

Background/aim: The expression of IL-8 and FGFR has been related to prognosis and pathological features in renal cell carcinoma. We investigated the relationship between IL-8 and FGFR and the outcome in metastatic renal cell carcinoma (mRCC) patients.

Materials And Methods: Clinical data and histological samples of patients affected by mRCC and treated with targeted agents were reviewed. The expression of proteins was assessed using immunohistochemistry.

Results: FGFR1, FGFR2, and IL-8 were found to be expressed in 16%, 30%, and 50% of cases, respectively. Significant correlations were found between selected proteins. A lack of expression of FGFR2 and IL8 was found to be correlated with increased progression-free survival (PFS). The survival rate at 24 months was 44%, 38%, and 79% of those expressing both, one, or none of the evaluated proteins, respectively (p=0.047).

Conclusion: This analysis found a relationship between the expression of IL-8 and FGFR2 in mRCC patients treated with targeted agents.
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http://dx.doi.org/10.21873/anticanres.12569DOI Listing
May 2018