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1.
Genes (Basel) ; 12(12)2021 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-34946865

RESUMO

High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of all ovarian carcinomas. HGSOC harboring BRCA1/2 germline or somatic mutations are sensitive to the poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi). Therefore, detecting these mutations is crucial to identifying patients for PARPi-targeted treatment. In the clinical setting, next generation sequencing (NGS) has proven to be a reliable diagnostic approach BRCA1/2 molecular evaluation. Here, we review the results of our BRCA1/2 NGS analysis obtained in a year and a half of diagnostic routine practice. BRCA1/2 molecular NGS records of HGSOC patients were retrieved from our institutional archive covering the period from January 2020 to September 2021. NGS analysis was performed on the Ion S5™ System (Thermo Fisher Scientific, Waltham, MA, USA) with the Oncomine™ BRCA Research Assay panel (Thermo Fisher Scientific). Variants were classified as pathogenic or likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics by using the inspection of Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) and ClinVar (NCBI) databases. Sixty-five HGSOC patient samples were successfully analyzed. Overall, 11 (16.9%) out of 65 cases harbored a pathogenic alteration in BRCA1/2, in particular, six BRCA1 and five BRCA2 pathogenic variations. This study confirms the efficiency and high sensitivity of NGS analysis in detecting BRCA1/2 germline or somatic variations in patients with HGSOC.

2.
Cancers (Basel) ; 13(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638422

RESUMO

Patients with locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) do not present distant metastases but are not eligible for surgery upfront. Chemotherapy regimens, such as FOLFIRINOX (FFN) or nab-paclitaxel plus gemcitabine (GemNab) in combination with loco-regional treatments are generally used in this setting. However, the best treatment choice is unknown. We retrospectively analyzed the information of 225 patients with stage II-III PDAC treated at our institution between October 2011 and December 2020. A total of 94 patients with LA PDAC who are non-eligible for surgery upfront received neoadjuvant FFN or GemNab. Of the 67 patients receiving FFN, 28 (41.8%) underwent surgery after neoadjuvant therapy. Of the 27 patients treated with GemNab, 6 (22.2%) became eligible for resection. The median overall survival (OS) was 85.1 weeks and 54.3 weeks in the FFN and GemNab groups, respectively (HR = 0.54, p = 0.0109). The median OS was 189.7 weeks and 76.4 weeks in the resected and unresected cohorts, respectively (HR = 0.25, p < 0.0001). Neutropenia (37.3%), anemia (6.0%), and diarrhea (6.0%) in the FFN group and neutropenia (22.2%) and thrombocytopenia (18.5%) in the GemNab groups were the most frequent grade 3-4 side effects. Higher rates of thrombocytosis (p < 0.0001) and peripheral edema (p < 0.0001) were observed in the GemNab group. Our results suggest that the use of FFN is associated with more favorable clinical outcomes than GemNab for patients with LA PDAC. Future randomized and controlled clinical trials are needed to further elucidate the role of these regimens and loco-regional treatments in this setting.

3.
Cancers (Basel) ; 13(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34503231

RESUMO

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450-480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.

4.
Lancet Oncol ; 22(10): 1458-1467, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34543613

RESUMO

BACKGROUND: The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2-3 years of letrozole in postmenopausal patients with breast cancer who have already received 2-3 years of tamoxifen. METHODS: This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I-III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2-3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. FINDINGS: Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2-3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5-13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57-66) in the control group and 67% (62-71) in the extended group (hazard ratio 0·78, 95% CI 0·65-0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. INTERPRETATION: In postmenopausal patients with breast cancer who received 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2-3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2-3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. FUNDING: Novartis and the Italian Ministry of Health. TRANSLATION: For the Italian translation of the abstract see Supplementary Materials section.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Letrozol/administração & dosagem , Mastectomia , Pós-Menopausa , Idoso , Antineoplásicos/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Itália , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Fatores de Tempo
6.
NPJ Breast Cancer ; 7(1): 82, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183674

RESUMO

The GIM2 phase III trial demonstrated the benefit of dose-dense chemotherapy in node-positive early breast cancer (eBC). To better define the dose-dense effect in the hormone receptor-positive subgroup, we evaluated its benefit through a composite measure of recurrence risk. We conducted an ancillary analysis of the GIM2 trial evaluating the absolute treatment effect through a composite measure of recurrence risk (CPRS) in patients with hormone receptor-positive HER2-negative eBC. CPRS was estimated through Cox proportional hazards models applied to the different clinicopathological features. The treatment effect was compared to the values of CPRS by using the Sub-population Treatment Effect Pattern Plot (STEPP) process. The Disease-Free Survival (DFS)-oriented STEPP analysis showed distinct patterns of relative treatment effect with respect to CPRS. Overall, 5-year DFS differed across CPRS quartiles ranging from 95.2 to 66.4%. Each CPRS quartile was characterized by a different patients' composition, especially for age, lymph node involvement, tumor size, estrogen and progesterone receptor expression, and Ki-67. A number needed to treat of 154 and 6 was associated with the lowest and the highest CPRS quartile, respectively. Dose-dense adjuvant chemotherapy showed a consistent benefit in node-positive eBC patients with hormone receptor-positive HER2-negative disease, but its effect varied according to CPRS.

7.
World J Clin Oncol ; 12(5): 355-366, 2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34131567

RESUMO

BACKGROUND: Sarcopenia is a condition characterized by decreased skeletal muscle mass due to physiological ageing or to a concomitant disease such as neoplasia. In cancer patients, a low lean body mass is suggested to be a negative prognostic factor for survival and for the development of dose-limiting chemotherapy toxicities irrespective of disease stage. AIM: To evaluate the prognostic role of sarcopenia in patients with metastatic colorectal cancer (mCRC) undergoing first-line chemotherapy. METHODS: Our retrospective analysis included 56 mCRC patients who received first-line chemotherapy from 2014 to 2017 at the Medical Oncology Unit of our hospital. Computerized scans were performed before starting chemotherapy and at the first disease reassessment. Sarcopenia was assessed using the skeletal mass index = muscle area in cm2/(height in m2) calculated at the L3 vertebra. Overall survival and objective response rate were evaluated. Toxicities were analyzed during the first four cycles of therapy and graded according to Common Terminology Criteria for Adverse Events version 4.0. A loss of skeletal muscle mass ≥ 5% was considered indicative of deterioration in muscle condition. RESULTS: Median age was 67 years and 35.7% of patients were ≥ 70 years old. Fourteen patients (25%) were sarcopenic at baseline computed tomography (CT) scan (7/33 men; 7/23 women); 5/14 sarcopenic patients were ≥ 70 years old. Median follow-up was 26.8 mo (3.8-66.8 mo) and median overall survival was 27.2 mo (95%CI: 23.3-37.3). Sarcopenia was not correlated to overall survival (P = 0.362), to higher toxicities reported during the first 4 cycles of chemotherapy (P = 1.0) or to response to treatment (P = 0.221). At the first disease reassessment, a skeletal muscle loss (SML) ≥ 5% was found in 17 patients (30.3%) 3 of whom were already sarcopenic at baseline CT scan, while 7 patients became sarcopenic. SML was not correlated to overall survival (P = 0.961). No statistically significant correlation was found between baseline sarcopenia and age (P = 1.0), body mass index (P = 0.728), stage at diagnosis (P = 0.355) or neutrophil/lymphocyte ratio (P = 0.751). CONCLUSION: Neither baseline sarcopenia nor SML affected survival. In addition, baseline sarcopenia was not related to worse treatment toxicity. However, these results must be interpreted with caution due to the limited sample size.

8.
Oncologist ; 26(10): e1854-e1861, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34101934

RESUMO

BACKGROUND: To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin-based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low-dose DEX on days 2 and 3, combined with an oral fixed-dose combination of netupitant and palonosetron (NEPA), compared with the guideline-consistent use of 4-day DEX. PATIENTS AND METHODS: In this open-label, multicenter study, chemotherapy-naïve patients undergoing high-dose cisplatin (≥70 mg/m2 ), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2-3 (DEX3), or (c) DEX (4 mg twice daily) on days 2-4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5-day overall phase. The noninferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea). RESULTS: Two-hundred twenty-eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX-sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, -12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups. CONCLUSION: A simplified regimen of NEPA plus single-dose DEX offers comparable chemotherapy-induced nausea and vomiting prevention throughout 5 days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting of cisplatin-based chemotherapy. IMPLICATIONS FOR PRACTICE: Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy-induced emesis. Although generally considered safe, even short-term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post-chemotherapy with a simplified regimen of netupitant/palonosetron plus single-dose DEX versus the standard 4-day DEX reference treatment in high-dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised.


Assuntos
Antieméticos , Cisplatino , Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Dexametasona , Humanos , Palonossetrom/uso terapêutico , Piridinas , Quinuclidinas , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/prevenção & controle
9.
Oncotarget ; 12(9): 936-947, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33953847

RESUMO

Breast cancer is the most common tumour in women and the first cause of death for cancer in the female population. Preserving the quality of life has therefore become an important objective in the management of the disease. The benefits of adjuvant chemotherapy in patients with HR+ HER2- early breast cancer should always be balanced against its potential short and long-term adverse effects, and identifying the appropriate patients for whom chemotherapy can offer the highest clinical benefit is critical. Besides clinical and pathological factors, today four multigene tests able to guide the choice of the adjuvant therapy early breast cancer are available in Italy: Oncotype DX®, EndoPredict®, MammaPrint® e Prosigna®. This review evaluates the main characteristics of these diagnostic tests, the studies on clinical utility, their economic impact and their inclusion in international and national guidelines. The Oncotype DX Breast Recurrence Score® test is the only multigene test validated, with level IA evidence, to guide the adjuvant therapy decisions: hormone therapy alone for most patients with RS results 0-25, and chemotherapy for patients with RS results 26-100. Clinical data demonstrate that the Oncotype DX test is able to significantly impact therapeutic decisions, reducing chemotherapy use up to 49% and supporting the use of chemotherapy (up to 12%) in potentially under-treated patients. Based on the level of clinical evidence and established clinical utility, several multigene tests have been included in the main international guidelines, with recommendations ranging from "strong" to "moderate".

10.
Clin Genitourin Cancer ; 19(5): e286-e298, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33958297

RESUMO

INTRODUCTION: Metastatic castration-resistant prostate cancer (mCRPC) is a deadly disease. Enzalutamide is an oral second-generation anti-androgen that is active in mCRPC. Circulating tumor cells (CTC) count correlates with overall survival (OS) in mCRPC, whereas detection of the androgen-receptor splice variant 7 (AR-V7) in CTC predicts poor response to oral second-generation anti-androgens. Also, loss of PTEN (phosphatase and tensin homolog) in CTC is a biomarker of poor prognosis in mCRPC. PATIENTS AND METHODS: In this translational study, we employed flow cytometry to assess total, PTEN-, and AR-V7+ CTC count per 7.5 mL of whole blood in a prospective cohort of patients with mCRPC receiving enzalutamide. RESULTS: CTCs were assessed in a total of 45 men with mCRPC at baseline and at 12 weeks. Overall, CTC, PTEN- CTC, and AR-V7+ CTC detection rate was high, at baseline, with 84.4%, 71.1%, and 51.1% of samples showing at least 1 cell/7.5-mL blood, respectively, and after 3 months, with 93.3%, 64.4%, and 77.7% of samples showing at least 1 cell/7.5-mL blood, respectively. Median radiographic progression-free survival (rPFS) and OS were 6 (95% confidence interval [CI], 5.6-9) and 14.3 (95% CI, 12.8-20.3) months, respectively. Median (interquartile range) total CTC count at baseline was 5 (3; 8), whereas median (interquartile range) PTEN- CTC count was 2 (0; 4) and median (interquartile range) AR-V7+ CTC count was 1 (0; 3). At baseline, ≥ 5 versus < 5 total CTC count was associated with worse rPFS (hazard ratio [HR], 2.35; 95% CI, 1.14-4.84; P= .021) and OS (HR, 3.08; 95% CI, 1.45-6.54; P = .003), whereas ≥ 2 versus < 2 PTEN- CTC count was associated with worse rPFS (HR, 3.96; 95% CI, 1.8-8.72; P= .001) and OS (HR, 2.36; 95% CI, 1.12-5; P= .025). Finally, ≥ 1 versus < 1 AR-V7+ CTC count was also associated with worse rPFS (HR, 5.05; 95% CI, 2.4-10.64; P< .001) and OS (HR, 2.25; 95% CI, 1.1-4.58; P= .026). CONCLUSIONS: Despite multiple limitations, including the small sample size, our preliminary study suggests that assessment of CTC via flow cytometry may provide potentially useful prognostic and predictive information in advanced prostate cancer. Further studies are warranted. Micro-Abstract: In this study, men with metastatic castration-resistant prostate cancer, scheduled to start enzalutamide, were assessed for circulating tumor cell count and molecular characterization (total, PTEN-, and AR-V7+ circulating tumor cell count) by the use of flow cytometry. We found that flow cytometry could be used to enumerate circulating tumor cells, but also to assess molecular biomarkers on their surface.


Assuntos
Células Neoplásicas Circulantes , Neoplasias de Próstata Resistentes à Castração , Benzamidas , Biomarcadores Tumorais , Citometria de Fluxo , Humanos , Masculino , Nitrilas , PTEN Fosfo-Hidrolase/genética , Feniltioidantoína , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Isoformas de Proteínas , Receptores Androgênicos
11.
Cancers (Basel) ; 13(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810205

RESUMO

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26-41% and 12-27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60-0.65 vs. HR range for single agent ET: 0.59-1.37; OS HR range for combinations: 0.74-0.87 vs. HR range for single agent ET: 0.68-0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.

12.
Eur J Cancer ; 149: 134-152, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33862496

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt). METHODS: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied. RESULTS: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51-0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16-1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80-0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43-0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours. CONCLUSION: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Humanos , Mutação , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Reparo de DNA por Recombinação , Fatores de Risco , Fatores de Tempo
13.
Front Oncol ; 11: 602523, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33718150

RESUMO

The partner and localizer of BRCA2 (PALB2) is a major BRCA2 binding partner that participates in homologous recombination repair in response to DNA double-strand breaks. Germline alterations of the PALB2 gene have recently been associated with a high risk of developing breast cancer. We investigated a 37-year-old Caucasian woman with breast cancer and family history of breast cancer using targeted next generation sequencing. A novel heterozygous deletion involving exons 5 and 6 was found in the PALB2 gene, and resulted in the production of a truncated PALB2 protein. These findings expand the mutational spectra of PALB2-associated breast cancer, and may improve the mutation-based screening and genetic diagnosis of breast cancer.

14.
NPJ Breast Cancer ; 7(1): 1, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397968

RESUMO

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

15.
Crit Rev Oncol Hematol ; 157: 103198, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33316417

RESUMO

Although both docetaxel and androgen-receptor-axis-targeted (ARAT) agents have yielded survival improvements in combination with androgen deprivation therapy (ADT) compared to ADT alone in metastatic castration-sensitive prostate cancer (mCSPC) patients, the optimal therapeutic choice remains to be established. We analyzed estimates of the hazard ratios for death (OS-HRs) in patients treated in the first-line setting enrolled in the GETUG-AFU15, CHAARTED, STAMPEDE, LATITUDE, ENZAMET, and TITAN trials. Overall, men with mCSPC receiving ADT with vs. without either an ARAT agent or docetaxel as first-line systemic therapy showed a pooled OS-HR of 0.69 (95 % CI: 0.61-0.78), with significant heterogeneity (p = 0.045, I2 = 52.5 %). Network meta-analysis showed an OS-HR in patients receiving an ARAT agent vs. docetaxel of 0.78 (95 %CI: 0.67-0.91). In conclusion, the evidence analysed indicates that an ARAT agent may provide improved OS outcomes compared to docetaxel. Prospective randomized trials are warranted.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Antagonistas de Androgênios , Castração , Docetaxel/uso terapêutico , Humanos , Masculino , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
16.
Crit Rev Oncol Hematol ; 157: 103191, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33309572

RESUMO

The development of cyclin-dependent kinases (CDK) 4 and 6 inhibitors represented a substantial breakthrough in the treatment of estrogen receptor positive (ER+), human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. These drugs showed a significant clinical benefit in pivotal clinical trials. However, resistance eventually occurs, leading to disease progression. Next Generation Sequencing methodologies have been employed to investigate predictive biomarkers of response or resistance to CDK4/6 inhibitors. Whole exome and targeted sequencing of solid and liquid biopsies have revealed several possible genomic alterations associated with resistance. Notably, genomic alterations identified by DNA-sequencing did not fully recapitulate the entire landscape of resistance to CDK4/6 inhibitors. Gene expression analysis, such as RNA-Seq methodologies, have provided insights into transcriptional profiles and may need further application. Herein, we report the main findings derived from the use of NGS analysis in the context of resistance to CDK4/6 inhibitors in ER + breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
17.
Front Oncol ; 11: 754108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35047387

RESUMO

Uveal melanoma is the most common primary intraocular malignancy. The aim of this retrospective study was to report the results after ruthenium-106 (Ru-106) plaque brachytherapy for uveal melanoma in terms of tumor control, visual acuity, radiation-related complications, tumor recurrence, metastases, and patients' survival rate during 4 years' follow-up. A total of 355 eyes from 355 patients have been treated with Ru-106 plaque brachytherapy for uveal melanoma between February 2011 and March 2020. Five patients were lost to follow-up, and then 350 eyes of 350 patients (mean age 58 ± 11 years) were enrolled in this retrospective study. All patients underwent a complete ophthalmic examination including echography and spectral domain-optical coherence tomography. The mean follow-up was 4 years (3 months to 9 years). After treatment, the mean tumor thickness was reduced to 1.75 ± 0.21 mm. Radiation complications were found in 63% of patients: 38% showed radiation maculopathy, 11% had optic neuropathy, and 14% developed cataracts. Cancer-free survival was 99%, 97%, and 85%, respectively, at 5, 7, and 9 years. Ru-106 plaque brachytherapy represents a reliable treatment of uveal melanoma. This technique is valid and safe with a low rate of ocular complications during a long-term follow-up.

18.
Ther Adv Med Oncol ; 12: 1758835920968725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193831

RESUMO

Background: Real-world data on chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone plus prednisone are limited, largely deriving from small retrospective studies. Methods: ABitude is an Italian, observational, prospective, multicenter study of mCRPC patients receiving abiraterone plus prednisone in clinical practice. Chemotherapy-naïve mCRPC patients were consecutively enrolled at abiraterone start (February 2016 to June 2017) and are being followed for 3 years, with evaluation approximately every 6 months. Several clinical and patients reported outcomes were examined. Results: In this second interim analysis, among 481 enrolled patients, 453 were evaluable for analyses. At baseline, the median age was 77 years and ~69% of patients had comorbidities (mainly cardiovascular diseases). Metastases were located mainly at bones and lymph nodes; 8.4% of patients had visceral metastases. During a median follow-up of 18 months, 1- and 2-year probability of radiographic progression-free survival were 73.9% and 56.2%, respectively; the corresponding rates for overall survival were 87.3% and 70.4%. In multivariable analyses, the number of bone metastases significantly affected radiographic progression-free survival and overall survival. During abiraterone plus prednisone treatment, 65% of patients had a ⩾50% prostate-specific antigen decline, and quality of life remained appreciably high. Among symptomatic patients according to the Brief Pain Inventory) (32%), scores significantly declined after 6 months of treatment. Overall, eight patients (1.7%) had serious adverse reactions to abiraterone. Conclusions: Abiraterone plus prednisone is effective and safe for chemotherapy-naïve mCRPC patients in clinical practice.

19.
Ther Adv Med Oncol ; 12: 1758835920947970, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062062

RESUMO

Background: Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. In cases with metastasis, the combination of 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine-based chemotherapy regimens are considered the standard of care. However, the optimal sequence of these regimens is unclear. Methods: This retrospective study initially evaluated 186 patients with locally advanced/metastatic pancreatic cancer at three Italian institutions between February 2013 and October 2019. All patients had progressed after receiving gemcitabine-based first-line chemotherapy and were subsequently offered second-line FOLFIRINOX, FOLFOX-6, or FOLFIRI treatment. This study evaluated progression-free survival (PFS), overall survival from the start of second-line treatment (OS2), overall survival from the start of first-line treatment (OS1), and safety outcomes. Results: A total of 77 patients received ⩾4 cycles of second-line chemotherapy and were considered eligible: 15 patients received FOLFIRINOX, 32 patients received FOLFOX-6, and 30 patients received FOLFIRI. The FOLFIRINOX group had median PFS of 26.29 weeks and median OS2 of 47.86 weeks, while the FOLFIRI group had median PFS of 10.57 weeks and median OS2 of 25.00 weeks (p = 0.038). No significant differences were observed between the FOLFIRINOX and FOLFOX-6 groups in terms of PFS (26.29 weeks versus 23.07 weeks) or OS2 (47.86 weeks versus 42.00 weeks). The most common grade 3-4 toxicities were anemia, neutropenia, and thrombocytopenia, which occurred more frequently in the FOLFIRINOX and FOLFOX-6 groups. Conclusion: Relative to the FOLFIRI regimen, the FOLFIRINOX regimen had a favorable toxicity profile and better survival outcomes. No significant differences were observed relative to the FOLFOX-6 regimen.

20.
J Immunother Cancer ; 8(2)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33060148

RESUMO

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Oncologia/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Geografia , Humanos , Controle de Infecções/normas , Itália/epidemiologia , Masculino , Oncologia/normas , Neoplasias/imunologia , Oncologistas/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Prevalência , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , SARS-CoV-2 , Inquéritos e Questionários/estatística & dados numéricos , Tempo para o Tratamento
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